AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Drug Patent expiry in 2017

 PATENTS  Comments Off on Drug Patent expiry in 2017
Jan 102017
 

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“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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How to Extend the Life of a Patent

 PATENTS  Comments Off on How to Extend the Life of a Patent
Dec 182016
 

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ALL CREDIT TO WIKIHOW

How to Extend the Life of a Patent

Three Methods:

Determining Eligibility

Extending Your Patent

Contacting Congress

A patent ensures that an inventor is able to profit from his or her invention by preventing others from making, using, selling, or importing it without consent. Once the patent expires, the invention is free for the public to use without paying you. If you meet certain requirements, you may wish to extend your patent.Take advantage of this opportunity to have extra time added to your patent term and keep your invention out of the public domain longer.

1

Determining EligibilityImage titled Get a Patent Step 3

  1. Determine the status of your patent. The United States Patent and Trademark Office (USPTO) keeps a website database of patent information. Access the USPTO database to check on your patent status. If you can’t find all the information you are looking for in the text-based display, then look at the patent image in PDF format.

    • You can also look up European patents here.
    • Or check Google Patents.
    • Patents cannot be renewed and you can’t get the rights to an expired patent. [1]
  2. Image titled Patent an Idea Step 7
    Know what kind of patent you have. In the US, 2 main types of patents are given: utility patents or design patents. Utility patents cover the function of an invention and design patents protect the way an invention looks. Utility patents generally last 20 years, while design patents last 14 years or 15 years for those filed on or after May 13, 2015. There are also 20 year long plant patents for inventors who asexually reproduce a newly discovered or invented variety of plant.[2]
  3. Image titled Do Research Step 14
    Find out if you qualify. Patent extensions are sometimes granted if there are government regulatory delays or if newer laws extend the length of a patent. Sometimes, with very strong justification, you can try to get Congress to pass a bill to extend your patent. If you fall into one of these categories, then you may be able to get your patent extended.
  4. Image titled Interrogate Someone Step 16
    Be aware that extensions may not be an option. For most inventions, the given term for your patent will stand. Recognize that you may not be able to extend your patent for this particular invention. Focus, instead, on developing a new invention that you can then get a new patent for.
 2
Extending Your Patent
  1. Image titled Calculate Profit Step 12
    Get a term adjustment. If you filed your patent after May 29, 2000 and your patent was delayed because the USPTO was taking longer than normal to process the paperwork, you may be eligible to file for an extension. The extension will cover the time lost from your patent term for the delay. The length of the extension you are approved for will depend on the delay time frame, but will not be longer than 5 years.
  2. Image titled Buy a Stock Without a Stockbroker Step 5
    Increase your original patent term. If you were initially granted less time than later legislation allows, you may be eligible to request an extension on your patent for the newer patent term. Under the Uruguay Rounds Agreements Act, utility patents granted before June of 1995 may be given an extension to 20 years instead of the original 17 years. This does not apply to design patents.
  3. Image titled Be a Successful Entrepreneur Step 2
    Get an extension under the Hatch-Waxman Act. A patent term restoration under the Hatch-Waxman Act is sometimes given to those who qualify.This applies to those whose products or processes, such as medications, medical devices, food and color additives, require testing and approval by the Food and Drug Administration’s (FDA) before they can be marketed. The period of time that you were unable to sell your product because you were awaiting FDA approval may be restored as an extension to the original patent. [3]
  4. Image titled Patent an Idea Step 11

    File for an extension with the United States Patent and Trademark Office (USPTO). All application forms for patent extensions can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Know that there are filing fees associated with this application.The process for filing for the extension depends upon which reason for extension the patent falls under.

    • Generally, the application for extension must be in writing, include the identifying information for the patent, information about why the applicant is entitled to an extension, relevant dates to determine the length of the extension, copies of the patent documents, etc.
    • Be sure to check with the USPTO for the exact amount of the fee (around $1,000) and the proper procedure for requesting the extension for your case.
  5. Image titled Delegate Step 11
    Wait to hear back from the USPTO. It can take up to several months for the USPTO to process your request. As with any government process, patience is best. If you are eligible and have a good reason for an extension, then there’s a chance you could be approved so waiting is worth it.
  6. Image titled Get a Patent Step 9

    Request an administrative hearing. If your extension request is denied, you have the right to appeal your denied request. Appeal forms can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Reasons for denial include defects in the paperwork you submitted to the USPTO asking for the extension and your invention being ineligible for extension. File an appeal and address any of the issues that your extension was denied in your written appeal.

    • The appeals process begins with your Notice of Appeal and fee payment. It will continue through various steps until it reaches the Patent Trial and Appeal Board. The board will make a decision on your case and complete the appeals process.
  7. Image titled Announce Your Retirement Step 3
    Meet with an intellectual property lawyer. It could be very beneficial to consult with an attorney to review your options, especially if your request is denied. Your lawyer may be able to offer suggestions and ways to supplement your application. Filing for a patent extension can be complex and your lawyer can ensure that it is done correctly.
 3

Contacting Congress

  1. Image titled Develop Critical Thinking Skills Step 18

    Be realistic. This is the least common form of attempting to extend a patent. Congress may not grant your request unless you have very convincing evidence for doing so. You also may need strong support from the community or a special interest group with persuasive lobbyists on your side.

    • Congress extended the copyright of works to 95 years over the original 75 in 1998. This was due mainly to influential corporations like the Walt Disney Company lobbying for the modification.[4] Keep the kind of influence you may require in mind when you decide to send a bill requesting a patent extension through Congress on your behalf.
  2. Image titled Get a Job Fast Step 1
    Find a representative. Do some research on representatives in your area or someone you think would want to sponsor you in extending your patent. You will need to convince him or her that there is a very important reason you must extend your patent. It is best if they have a record of supporting the type of invention you have or are connected in some way to that field.
    • Only a member of Congress can propose private legislation to the legislative body.
  3. Image titled Do Research Step 10
    Draft a bill. It’s a good idea to do as much of the legwork as possible before approaching your representative. Your bill should be written in legal language and go over the reasons your patent should be granted an extension. You can check existing bills on the Congress website to get an idea what a bill looks like. It might be helpful to consult with a patent attorney when you’re writing this as legalese can be difficult to master.[5]
    • Create a preamble. This is an introduction and general overview about your patent, the date it will expire and an explanation of why you need an extension on your patent.
    • Write up a body clause. This is the meat of your biIl and contains clauses that show what action needs to be taken—in this case, you want your patent to be extended.
    • Finish with an enactment clause. This tells when you want the bill to take effect. This will be the day your patent is due to expire.
    • Know that bills which need to take effect in 90 days or less will need 2/3 majority vote, while those that take effect after that time period will only require a majority vote. Send your bill in as early as possible.[6]
  4. Image titled Write a Grant Proposal Step 22
    Submit your bill to your potential sponsor. Contact your representative by phone or email. Many have websites where you can fill out a form to submit your case. Be sure to ask what the process is like and when you can expect to hear back.
  5. Image titled Communicate Effectively Step 9
    Get a lobbyist to represent you. If your patent is important to certain groups or not extending it could cause harm, then look for someone with contacts to represent you. Lobbyist groups can put pressure on Congress to extend your patent. In order to do this, you need to have a good cause with far-reaching effects if your patent is not extended.
  6. Image titled Excel in a Retail Job Step 2
    Be patient. The legislative process can take time. It must go through multiple committees before the house will vote on it. After that, it must be signed in. The length of time this will take varies and is something you should discuss with your sponsor.
Tips
  • It is best to file for an extension as soon as possible, as the USPTO generally takes months to process most filings.
 Warnings
  • The request for patent extension should be made 3 months prior to the date on which the patent is set to expire.

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WO 2016181414, IVACAFTOR, NEW PATENT, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

 PATENTS  Comments Off on WO 2016181414, IVACAFTOR, NEW PATENT, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Nov 242016
 

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CSIR, Dr. D. Srinivasa Reddy

WO2016181414, PROCESS FOR THE SYNTHESIS OF IVACAFTOR AND RELATED COMPOUNDS

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016181414&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

REDDY, Dumbala Srinivasa; (IN).
NATARAJAN, Vasudevan; (IN).
JACHAK, Gorakhnath Rajaram; (IN)

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH [IN/IN]; Anusandhan Bhawan, Rafi Marg New Delhi 110001 (IN)

The present patent discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of [Formula (I)], wherein R1, R2, R3, R4, R5, R6, R7 and Ar1are as described above; its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides

See Eur J Org Chem, Nov 2015, for an article by the inventors, describing a process for preparing ivacaftor using 4-quinolone-3-carboxylic acid amides. The inventors appear to be based at National Chemical Laboratories of CSIR.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula (A):

Formula (A)

[003] Ivacaftor was approved by FDA and marketed by vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets. Kalydeco® is indicated for the treatment of cystic fibrosis in patients age 6 years and older who have a G55ID mutation in the CFTR (cystic fibrosis transmembrane conductance regulator)gene.

[004] U.S. 20100267768 discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-l,4-dihydro-3- quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T3P®) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. The publication also discloses the use of highly expensive coupling reagent, propyl phosphonic anhydride; which in turn results to an increase in the manufacturing cost. The process disclosed is schematically represented as follows:

[005] Article titled “Discovery of N-(2,4-Di-te -butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiator” byHadida,S et. al in . Med. Chem., 2014, 57 (23), pp 9776-9795 reportsN-(2,4-di-teri-butyl-5-hydroxyphenyl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.

[006] WO 2014125506 A2 discloses a process for the preparation of ivacaftor in high yield and purity by using novel protected quinolone carboxylic acid compounds as intermediates.

[007] Article titled “Expeditious synthesis of ivacaftor” by Jingshan Shen et. al in Heterocycles, 2014, 89 (4), pp 1035 – 1040 reports an expeditious synthesis for ivacaftor featuring modified Leimgruber-Batcho procedure. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.

[008] U.S.2011/064811 discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-l,4-dihydro-3- quinolone carboxylic acid with 5- amino-2,4-di-(tert-butyl)phenol in the presence of HBTU followed by the formation of ethanol crystalate, which is then treated with diethyl ether to yield ivacaftor as a solid.

[010] U.S. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and a process for the preparation of modulators of ATP-binding cassette transporters such as quinolone compounds. The process includes condensation of 4-oxo-l,4-dihydro-3 -quinolone carboxylic acid with aniline in presence of 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate methanaminium (HATU) as shown:

[011] U.S. 2011/230519 discloses a process for preparation of 4-oxo-l,4-dihydro-3-quinoline carboxylic acid by reaction of aniline with diethylethoxymethylenemalonate at 100-110°C followed by cyclization in phenyl ether at temperature 228-232°C and then hydrolysis, as shown below:

[012] US 7,402,674 B2 discloses 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments.

[013] US 4,981,854 discloses l-aryl-4-quinolone-3 carboxylic acids, processes for their preparation and anti-bacterial agents and feed additives containing these compounds.

Article titled “Ozonolysis Applications in Drug Synthesis” by Van Ornum,S.G. ; Champeau,R.M.; Pariza,R. in Chem. Rev., 2006, 106 (7), pp 2990-3001 reports that ozonolysis for the synthesis of numerous interesting bioactive natural products and pharmaceutical agents.

[014] Article titled “Safe Execution of a Large-Scale Ozonolysis: Preparation of the Bisulfite Adduct of 2-Hydroxyindan-2-carbox-aldehyde and Its Utility in a Reductive Animation” by RaganJ.A. et. al. in Org. Proc. Res. Dev., 2003, 7 (2), pp 155-160 reports various routes to bisulfite adduct, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHS03 to effect reduction and bisulfite formation in a single pot. The utility of bisulfite adduct is as an aldehyde surrogate in a reductive amination reaction.

[015] The reported methods for the synthesis of ivacaftor suffered from several drawbacks such as harsh conditions, high temperature reactions and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride etc. Furthermore, synthesis of ivacaftor requires use of high performance liquid chromatography (HPLC) techniques for the separation of ivacaftor and their analogues.

[016] Therefore, development of a simple and efficient synthetic route is in urgent need. Accordingly the present inventors developed environmentally benign, cost effective and short synthetic route for the synthesis of ivacaftor and their analogues.

Example 1:

Procedur A:

To a solution of indole acetic acid (500 mg, 2.85 mmol), aniline (2.85 mmol), HOBt (3.4 mmol) in acetonitrile (10 mL), EDC.HCl (3.4 mmol) followed by DIPEA (11.4 mmol) was added, and mixture was stirred for 16 h at ambient temperature. The

reaction mixture was evaporated to dryness, diluted with EtOAc (25 mL), washed with saturated aqueous NaHC03 solution (5 mL), H20 (5 mL), brine (5 mL), and dried over Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate – pet ether) to afford corresponding amide as a colorless solid.

[040] Example 2:

2-(lH-indol-3-yl)-N-phenylacetamide (1) :

Yield: 570 mg; 80%; 1H NMR (200MHz, DMSO-d6) δ = 10.95 (brs, 1 H), 10.14 (s, 1 H), 7.64 (d, J = 7.8 Hz, 3 H), 7.47 – 7.24 (m, 4 H), 7.21 – 6.92 (m, 3 H), 3.76 (s, 2H); MS: 273 (M+Na)+.

[041] Example 3:

5-(2-(lH-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2): Yield: 800 mg; 64%; 1H NMR (200 MHz, DMSO-d6) δ = 11.51 (brs, 1 H), 9.41 (s, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.96 – 7.78 (m, 3 H), 7.71 – 7.42 (m, 3 H), 4.34 (s, 3 H), 4.30 (s, 2 H), 1.79 (s, 9 H), 1.64 (s, 9 H); MS: 459 (M+Na)+.

[042] Example 4:

(S)-2-(lH-indol-3-yl)-N-(l-phenylethyl)acetamide (3):

Yield: 620 mg; 78%; 1H NMR (400MHz ,DMSO-d6)5 = 10.88 (brs, 1 H), 8.48 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.39 – 7.26 (m, 5 H), 7.25 – 7.16 (m, 2 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.02 – 6.95 (m, 1 H), 4.96 (t, J = 7.3 Hz, 1 H), 3.59 (s, 2H), 1.38 (d, J = 7.1 Hz, 3 H).

[043] Example 5:

N-(4-Fluorophenyl)-2-(lH-indol-3-yl)acetamide (4):

1H NMR (400 MHz, DMSO-d6) : δ 10.93 (brs, 1H), 10.17 (s, 1H), 7.68 – 7.61 (m, 3H), 7.36 (d, J= 8.1 Hz, 1H), 7.27 (d, J= 2.0 Hz, 1H), 7.15 – 7.13 (m, 3H), 7.11 – 6.99 (m, 1H), 3.73 (s, 2H); 13C NMR (100 MHz, DMSO-d6) : δ 170.1, 159.5, 157.1, 136.6, 136.3, 127.7, 124.4, 121.5, 121.3, 121.2, 119.1, 118.9, 115.8, 115.6, 111.8, 108.9, 34.2; MS: 269 (M+H)+

[044] Example 6:

N-(4-Chlorophenyl)-2-(lH-indol-3-yl)acetamide (5):

1H NMR (200 MHz, DMSO-d6): 510.93 (brs, 1H),10.24 (s, 1H), 7.67 – 7.59 (m, 3H), 7.36 – 7.27 (m, 4H), 7.12 – 6.98 (m, 2H), 3.74 (s, 2H); 13CNMR (100 MHz, DMSO-d6): 5170.4, 138.9, 136.7, 129.1, 127.8, 127.1, 124.5, 121.6, 121.2, 119.2, 119.0, 115.7, 111.9, 108.9, 34.3; MS: 285 (M+H)+.

[045] Example 7:

2-(lH-Indol-3-yl)-N-(p-tolyl)acetamide (6) :

1H NMR (400 MHz, DMSO-d6): 510.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.50 (d, J= 8.6 Hz, 2H), 7.37 (d, J= 8.1 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.10 – 7.07 (m, 3H), 7.01 – 6.99 (m, 1H), 3.71 (s, 2H), 2.23 (s, 3H); 13C NMR (100 MHz, DMSO-de): 5170.0, 137.4, 136.6, 132.4, 129.5, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 34.2, 20.9; MS: 265 (M+H)+.

[046] Example 8:

N-(4-Ethylphenyl)-2-(lH-indol-3-yl)acetamide (7):

XH NMR (400 MHz, DMSO-d6): 510.91 (brs, 1H), 10.01 (s, 1H), 7.61 (s, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.36 (d, J= 8.1 Hz, 1H), 7.26 (s, 1H), 7.15 – 7.04 (m, 3H), 6.99 (s, 1H), 2.55 (t, J= 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): 5169.9, 138.9, 137.6, 136.6, 128.3, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 34.2, 28.0, 16.2; MS: 279 (M+H)+.

[047] Example 9:

2-(lH-Indol-3-yl)-N-(4-propylphenyl)acetamide (8):

1H NMR (400 MHz, DMSO-d6): 58.48 (brs, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.33 – 7.15 (m, 6H), 7.07 (d, J= 8.3 Hz, 2H), 3.92 (s, 2H), 2.52 (t, J= 7.6 Hz, 2H), 1.65 – 1.53 (m, 2H), 0.91 (t, J= 7.3 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): 5169.7, 138.9, 136.5, 135.2, 128.8, 126.9, 124.0, 122.8, 120.4, 120.1, 118.7, 111.6, 108.7, 37.4, 34.5, 24.6, 13.7; MS: 315 (M+Na)+.

[048] Example 10:

2-(lH-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9) :

yield 79% ; 1H NMR (400 MHz, DMSO-d6): δ 10.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, = 7.8 Hz, 1H), 7.55 – 7.49 (m, = 8.6 Hz, 2H), 7.37 (d, = 8.1 Hz, 1H), 7.26 (d, = 2.0 Hz, 1H), 7.18 – 7.11 (m, = 8.6 Hz, 2H), 7.11 – 7.05 (m, 1H), 7.02 – 6.95 (m, 1H), 2.95 – 2.71 (m, 1H), 1.17 (d, = 6.8 Hz, 6H); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 143.5, 137.6, 136.6, 127.7, 126.8, 124.3, 121.4, 119.7, 119.2, 118.8, 111.8, 109.2, 24.4; MS: 315 (M+Na)+.

[049] Example 11:

2-(lH-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10):

Yield 85% ; 1H NMR (400 MHz, CDC13): δ 8.35 (brs., 1 H), 7.44 – 7.38 (m, 2 H), 7.27 – 7.21 (m, 3 H), 7.12 – 7.05 (m, 1H), 7.03 – 6.95 (m, 2H), 6.93 (d, = 8.6 Hz, 2H), 3.75 (s, 2H); 13C NMR (100 MHz, CDC13): δ 170.0, 145.3, 136.5, 136.2, 126.8, 124.1, 123.0, 121.6, 121.2, 120.5, 118.5, 111.7, 108.2, 34.4; MS: 335 (M+Na)+.

[050] Example 12:

N-(2-chloro-5-methoxyphenyl)-2-(lH-indol-3-yl)acetamide (11):

Yield 75% ; XH NMR (200 MHz, DMSO-d6): δ 10.98 (brs, 1H), 9.27 (s, 1H), 7.59 (d, = 7.8 Hz, 1H), 7.53 (d, = 2.9 Hz, 1H), 7.39 – 7.32 (m, 3H), 7.09 – 6.99 (m, 2H), 6.74 (dd, = 3.0, 8.8 Hz, 1H), 3.85 (s, 2H), 3.71 (s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 170.4, 160.1, 141.1, 136.7, 130.0, 127.8, 124.4, 121.6, 119.2, 119.0, 111.9, 109.1, 105.4, 55.4, 34.4; MS: 315 (M+Na)+.

[051]Example 13:

N-(2-ethylphenyl)-2-(lH-indol-3-yl)acetamide (12):

Yield 78% ; 1H NMR (400 MHz, CDC13): δ 8.68 (brs, 1H), 7.95 (d, = 8.1 Hz, 1H), 7.67 (d, = 7.8 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.29 – 7.23 (m, 1H), 7.22 – 7.20 (m, 3H), 7.05 (d, = 4.4 Hz, 2H), 2.00 (q, = 7.4 Hz, 2H), 0.67 (t, = 7.6 Hz, 3H); 13C NMR (100 MHz, CDC13): δ 169.9, 136.6, 135.0, 134.3, 128.7, 126.7, 125.1, 124.1, 123.0, 122.5, 120.4, 118.7, 111.6, 108.6, 34.4, 24.2, 13.6.

[052] Example 14:

N-(2-bromophenyl)-2-(lH-indol-3-yl)acetamide(13):

Yield 76%; 1H NMR (200 MHz, DMSO-d6): δ 11.00 (brs, 1H), 9.30 (s, 1H), 7.81 -7.77 (m, 1H), 7.63 – 7.56 (m, 2H), 7.41 – 7.35 (m, 3H), 7.11 – 7.05 (m, 3H), 3.85 (s, 2H);13C NMR (100 MHz, DMSO-d6): δ 169.9, 136.2, 132.5, 128.0, 127.2, 126.4, 125.5, 124.4, 121.2, 118.7, 118.5, 116.4, 111.4, 108.0, 33.2.

[053] Example 15:

N-benzyl-2-(lH-indol-3-yl)acetamide (14):

Yield 85%; 1H NMR (400 MHz, DMSO-d6): δ 10.89 (brs., 1H), 8.40 (t, = 5.7 Hz, 1H), 7.57 (d, = 7.8 Hz, 1H), 7.36 (d, = 8.1 Hz, 1H), 7.32 – 7.18 (m, 6H), 7.08 (t, = 7.5Hz, 1H), 7.03 – 6.90 (m, 1H), 4.28 (d, = 5.9Hz, 2H), 3.60 (s, 2H); 13C NMR (100 MHz, DMSO-de): δ 171.2, 140.1, 136.6, 128.7, 127.7, 127.2, 124.3, 121.4, 119.2, 118.7, 111.8, 109.3, 42.7, 33.2.

[054] Example 16:

2-(lH-indol-3-yl)-N-(4-methoxybenzyl)acetamide(15):

Yield 85% ; 1H NMR (400 MHz, DMSO-d6): δ 10.87 (brs, 1 H), 8.32 (t, = 5.6 Hz, 1 H), 7.55 (d, = 7.8 Hz, 1H), 7.35 (d, = 8.1 Hz, 1H), 7.22 – 7.13 (m, 3H), 7.11 – 7.05 (m, 1 H), 7.00 – 6.94 (m, 1H), 6.84 (d, = 8.6 Hz, 2H), 4.20 (d, = 6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 158.6, 136.6, 132.0, 129.0, 127.7, 124.2, 121.4, 119.2, 118.7, 114.1, 111.8, 109.4, 55.5, 42.1, 33.2.

[055] Example 17:

N,N-dibenzyl-2-(lH-indol-3-yl)acetamide (16):

Yield 70% ; 1H NMR (400 MHz, DMSO-d6): δ 10.91 (brs, 1H), 7.50 (d, = 7.8 Hz, 1H), 7.37 – 7.34 (m, 3H), 7.30 (d, = 6.6 Hz, 1H), 7.25 – 7.19 (m, 3H), 7.17 (t, = 6.6 Hz, 5H), 7.16 (d, = 7.8 Hz, 1H), 7.00 – 6.97 (m, 1H), 4.59 (s, 2H), 4.50 (s, 2H), 3.86 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 171.7, 138.2, 136.6, 129.2, 128.8, 128.1, 127.8, 127.7, 127.5, 127.1, 124.2, 121.5, 119.2, 118.8, 111.8, 108.5, 50.7, 48.4, 31.2.

[056] Example 18:

2-(lH-indol-3-yl)-N-propylacetamide (17):

Yield 75% ; XH NMR (200 MHz, DMSO-d6): δ 10.86 (brs, 1H), 7.88 – 7.80 (m, 1H), 7.56 (d, = 7.6 Hz, 1H), 7.31 (d, = 7.8 Hz, 1H), 7.17 (d, = 2.3 Hz, 1H), 7.06 – 6.92 (m, 2H), 3.48 (s, 2H), 3.00 (q, J = 6.8 Hz, 2H), 1.39 (sxt, / = 7.2 Hz, 2H), 0.88 – 0.75 (t, = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 136.6, 127.8, 124.2,

121.4, 119.2, 118.7, 111.8, 109.6, 39.4, 33.3, 22.9, 11.9.

[057] Example 19:

N-hexyl-2-(lH-indol-3-yl)acetamide (18) :

Yield 87% ; 1H NMR (400 MHz, DMSO-d6): δ 10.84 (brs, 1H), 7.83 (brs, 1H), 7.54 (d, = 7.8 Hz, 1H), 7.33 (d, = 8.1 Hz, 1H), 7.21 – 7.13 (m, 1H), 7.06 (t, = 7.6 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 3.47 (s, 2H), 3.03 (q, / = 6.8 Hz, 2H), 1.37 (t, = 6.5 Hz, 2H), 1.30 – 1.15 (m, 6H), 0.84 (t, = 6.7 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 136.6, 127.7, 124.2, 121.3, 119.1, 118.7, 111.7, 109.5, 39.06, 33.2, 31.5, 29.6, 26.5, 22.5, 14.4.

[058] Example 20:

Methyl (2-(lH-indol-3-yl)acetyl)-L-alaninate (19):

Yield 79% ; 1H NMR (400 MHz, CDC13): δ 8.53 (brs, 1H), 7.60 (d, = 7.8 Hz, 1H), 7.41 (d, = 8.1 Hz, 1H), 7.25 – 7.23 (m, 1H), 7.19 – 7.14 (m, 2H), 6.27 (d, = 7.3 Hz, 1H), 4.63 (t, = 7.3 Hz, 1H), 3.78 (s, 2H), 3.68 (s, 3H), 1.31 (d, = 7.3 Hz, 3H); 13C NMR (100 MHz, CDC13): δ 173.4, 171.2, 136.4, 127.0, 123.8, 122.5, 119.9, 118.7,

111.5, 108.5, 52.4, 48.0, 33.3, 18.2.

[059] Example 21:

-(6-chloro-lH-indol-3-yl)-N-phenylacetamide(20):

To a solution of 6-Chloro indole 20a (300 mg, 1.98 mmol )in anhydrous THF, Oxalyl chloride (186 μΤ, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-Diisopropylethylamine (758 μΤ, 562 mg, 4.35 mmol) was

introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The temperature was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (10 – 20% EtOAc : Petroleum ether) to afford 20b (295 mg, 51% yield) as a yellow coloured solid. IR Omax(film): 3346, 3307,2853, 1724, 1678 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.41 – 7.30 (m, 3H), 7.19 – 7.13 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 182.5, 162.5, 140.0, 138.4, 137.4, 129.2, 128.5, 125.4, 124.8, 123.4, 122.9, 120.8, 113.0, 112.3; HRMS (ESI) Calculated for Ci6HnN2OCl[M+H]+: 299.0582, found 299.0580;

A solution of 20b (300 mg, 0.99 mmol) dissolved in MeOH (40 mL) was added to NaBH4 (45 mg, 1.23 mmol). The reaction was stirred for 4h and then added to saturated solution of Na2S04. The reaction mixture was further stirred for lh and then filtered through Celite.The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was forwarded for next step without further purification.In an N2 atmosphere, TMSC1 (1.272 mL, 9.9 mmol) in CH3CN (40 mL) was added to sodium iodide (1.488 mg, 9.9 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol (0.99 mmol) in CH3CN (10 mL) was then added drop wise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (7g in 40 mL of water) and then extracted with ethyl acetate (15×2). The organic layer was washed with aq.Na2S203, dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 20 as a off white solid (two steps 38 % ); IR Umax(film): 3273, 3084,2953, 2857, 1629, 1562 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 11.06 (br. s., 1H), 10.13 (br. s., 1H), 7.62 – 7.57 (m, 3H), 7.40 (s, 1H), 7.30 – 7.25 (m, 3H), 7.04 – 6.99 (m, 2H), 3.71 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 170.1,

139.7, 136.9, 129.2, 126.5, 126.3, 125.5, 123.7, 120.6, 119.6, 119.3, 111.5, 109.4, 34.0; HRMS (ESI):Calculated for Ci6Hi4N2OCl[M+H]+: 285.0789, found 285.0786.

[060] Example 22:

2-(5-chloro-lH-indol-3-yl)-N-phenylacetamide(21):

21a 21b 21

To a solution of 5-Chloro indole 21a (300 mg, 1.98 mmol )in anhydrous THF(20 mL), Oxalyl chloride (186 ^L, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-diisopropylethylamine (758 μΕ, 562 mg, 4.35 mmol) was introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The tempera ture was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (10 – 20% EtOAc : Petroleum ether) to afford (21b) (305 mg, 53% yield) as a yellow coloured solid. IR rjmax(film): 3346, 3307,2853, 1724, 1678 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.42 – 7.30 (m, 3H), 7.20 – 7.14 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 182.4, 162.4, 140.3, 138.4, 135.4, 129.2, 127.9, 124.8, 124.1, 120.8, 114.8, 112.0; HRMS (ESI) Calculated for Ci6HnN2OCl[M+H]+: 299.0582, found 299.0580; A solution of 21b (200 mg, 0.66 mmol) dissolved in MeOH (30 mL) was added to NaBH4 (30 mg, 0.82 mmol). The reaction was stirred for 4h and then added to saturated solution of Na2S04. The reaction mixture was further stirred for lh and then filtered through Celite. The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was forwarded for next step without further purification. In an N2 atmosphere, TMSC1 (848 mL, 6.6 mmol) in CH3CN (25 mL) was added to sodium iodide (992 mg, 6.6 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol(0.66 mmol) in CH3CN (5 mL) was then added dropwise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (5g in 30 mL of water) and then extracted with ethyl acetate(15×2). The organic layer was washed with aq.Na2S203, dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 22 as a off white solid (two steps 42 % ); IR Umax(film): 3273, 3084,2955, 2857, 1629, 1562 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 11.13 (br. s., 1H), 10.11 (s, 1H), 7.67 (s, 1H), 7.60 (d, = 7.8 Hz, 2H), 7.39 – 7.27 (m, 4H), 7.13 – 7.02 (m, 2H), 3.16 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 139.8, 135.0, 129.2, 128.9, 126.2, 123.6, 121.4, 119.6, 118.6, 113.4, 109.0, 34.0; HRMS (ESI) Calculated for Ci6H14N2OCl[M+H]+: 285.0789, found 285.0786.

[061] Example 23:

2-(l-benzyl-lH-indol-3-yl)-N-phenylacetamide (22):

Yield 79% ; 1H NMR (400 MHz, DMSO-d6): δ 7.67 (d, = 7.8 Hz, 1H), 7.54 (brs, 1H), 7.43 – 7.31 (m, 6H), 7.31 – 7.25 (m, 3H), 7.23 – 7.15 (m, 4H), 7.12 – 7.06 (m, 1H), 5.36 (s, 2H), 3.91 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 169.7, 137.7, 137.2, 137.0, 128.9, 128.9, 127.9, 127.6, 126.9, 124.3, 122.7, 120.2, 119.9, 119.0, 110.2, 107.9, 77.4, 77.1, 76.8, 50.1, 34.5.

[062] Example 24:

Procedure B:

2-(lH-indol-3-yl)-N-phenylacetamidel(100 mg; 0.4 mmol) was dissolved in DCM:MeOH(50 mL; 5: 1), then a stream of 03 was passed through the solution until a blue color developed (10 min). The 03 stream was continued for 4 min. Then surplus O3 was removed by passing a stream of 02 through the solution for 10 min or until the blue colorcompletely vanished. Afterwards pyridine (0.1 mL;1.2mmol) was added to the cold (- 78 °C) mixture. The mixture was allowed to warm to room temperature (1 h) and then Et3N (0.35 mL; 2.4 mmol) were added. After stirring at room temperature overnight the reaction mass was concentrated under reduced pressure to dryness, diluted with EtOAc (30 mL), washed with H20 (5 mL), brine (5 mL), and dried over Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, MeOH – DCM) to give desired quinolone carboxamide as colorless solid.

[063] Example 25:

4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide (23):

Yield: 65 mg; 62%; XH NMR (200MHz ,DMSO-d6) δ = 12.97 (brs, 1 H), 12.49 (s, 1 H), 8.89 (s, 1 H), 8.33 (d, J = 8.2 Hz, 1 H), 7.91 – 7.69 (m, 4 H), 7.62 – 7.50 (m, 1 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.18 – 7.01 (m, 1 H); MS: 287 (M+Na)+.

[064] Example 26:

2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (24):

Yield: 35 mg; 34%; 1H NMR (400MHz ,DMSO-d6) δ = 12.96 (brs, 1 H), 12.08 (s, 1 H), 8.94 – 8.82 (m, 1 H), 8.44 – 8.28 (m, 1 H), 7.86 – 7.79 (m, 1 H), 7.78 – 7.73 (m, 1 H), 7.59 (s, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.39 (s, 1 H), 3.86 (s, 3 H), 1.46 (s, 9 H), 1.32 (s, 9 H).

[065] Example 27:

(S)-4-oxo-N-(l-phenylethyl)-l,4-dihydroquinoline-3-carboxamide (25):

Yield: 56 mg; 53%; 1H NMR (500MHz ,DMSO-d6) δ = 12.75 (brs, 1H), 10.54 (d, J = 7.6 Hz, 1H), 8.73 (brs, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.73 -7.68 (m, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.42 – 7.34 (m, 4 H), 7.29 – 7.23 (m, 1 H), 5.18 (t, J = 7.2 Hz, 1 H), 1.50 (d, J = 6.7 Hz, 3 H).

[066] Example 28:

Synthesis of ivacaftor (26):

To a solution of 2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 5 (30 mg, 0.06mmol) in MeOH (2 mL) was added NaOH (5.3 mg, 0.13mmol) dissolved in H20 (2 mL), and the reaction mixture was stirred at room temperature for 5h. Reaction mass was evaporated to one third of its volume (temperature not exceeding 40°C) and acidified with aq.2N HC1 to pH 2-3. The resulting precipitate was collected by suction filtration give desired compound 7 (19 mg, 76%) as off white solid H NMR (400MHz ,DMSO-d6) δ = 12.88 (d, J = 6.6 Hz, 1 H), 11.81 (s, 1 H), 9.20 (s, 1 H), 8.86 (d, J = 6.6 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 7.88 – 7.65 (m, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.16 (s, 1 H), 7.10 (s, 1 H), 1.38 (s,9H), 1.36 (s, 9H).

[067] Example 29:

N-(4-fluorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (27):

Yield 56% ; 1H NMR (400 MHz, DMSO-d6): δ 12.96 (br. s., 1H), 12.50 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.3 Hz, 1H), 7.86 – 7.72 (m, 4H), 7.54 (t, = 7.3 Hz, 1H), 7.20 (t, = 8.8 Hz, 2H); 13C NMR (400 MHz, DMSO-d6): δ 176.8, 163.2, 159.7, 157.3, 144.6, 139.6, 135.7, 133.5, 126.4, 125.9, 125.8, 121.8, 119.7, 116.1, 115.9, 110.9.

[068] Example 30:

N-(4-chlorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (28):

Yield 51% ; 1H NMR (400 MHz, DMSO-d6): δ 13.00 (brs., 1H), 12.59 (br. s., 1H), 8.89 (s, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.83 – 7.76 (m, 4H), 7.56 (s, 1H), 7.42 (d, = 7.9 Hz, 2H); 13C NMR (400 MHz, DMSO-d6): δ 176.8, 163.4, 144.7, 139.6, 138.2, 133.5, 129.4, 127.4, 126.4, 125.9, 125.8, 121.6, 119.7, 110.8.

[069] Example 31:

4-oxo-N-(p-tolyl)-l,4-dihydroquinoline-3-carboxamide (29):

Yield 57% ; 1H NMR (400 MHz, DMSO-d6): δ 12.94 (brs., 1H), 12.40 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8Hz, 1H), 7.82 – 7.80 (m, 1H), 7.76 – 7.7 (m, 1H), 7.63 (d, = 8.3 Hz, 2H), 7.53 (t, = 7.3 Hz, 1H), 7.17 (d, = 8.1 Hz, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO-de): δ 176.8, 163.1, 144.5, 139.6, 136.8, 133.4, 132.8, 129.9, 126.4, 125.9, 125.7, 120.0, 119.6, 111.1, 20.9; HRMS (ESI):Calculated for Ci7H1502N2[M+H]+: 279.1128, found 279.1127.

[070] Example 32:

N-(4-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (30):

Yield 51% ; 1H NMR (400 MHz, DMSO-d6): δ 12.95 (br. s., 1H), 12.40 (d, = 7.8 Hz, 1H), 8.87 (d, = 6.1 Hz, 1H), 8.33 (d, = 8.1 Hz, 1H), 7.81 – 7.76 (m, 2H), 7.66 – 7.62 (m, = 8.3 Hz, 2H), 7.53 (t, 7 = 7.5 Hz, 1H), 7.22 – 7.17 (m, = 8.3 Hz, 2H), 2.58 (q, = 7.6 Hz, 2H), 1.18 (t, = 7.6 Hz, 3H); 13C NMR (400 MHz, DMSO-d6): δ 181.5, 167.8, 149.3, 144.3, 144.0, 141.7, 138.2, 133.4, 131.1, 130.7, 130.5, 124.8, 124.4, 115.9, 32.8, 20.9.

[071] Example 33:

4-Oxo-N-(4-propylphenyl)-l,4-dihydroquinoline-3-carboxamide (31):

Yield 51%; 1H NMR (500 MHz, DMSO-d6): δ12.93 (brs, 1H), 12.40 (s, 1H), 8.87 (s, 1H), 8.36 – 8.29 (m, 1H), 7.86 – 7.78 (m, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.68 – 7.61 (m, J= 8.2 Hz, 2H), 7.54 (t, J= 7.6 Hz, 1H), 7.22 – 7.14 (m, J= 8.2 Hz, 2H), 2.55 – 2.51 (m, 2H), 1.64 – 1.53 (m, 2H), 0.90 (t, J= 7.3 Hz, 3H); 13C NMR (500 MHz, DMSO-d6): 176.8, 163.1, 144.5, 139.6, 137.6, 137.0, 133.5, 129.3, 126.4, 125.9, 125.7, 120.0, 119.7, 111.1, 37.2, 24.6, 14.1.

[072] Example 34:

N-(4-isopropylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (32):

Yield 46% ; 1H NMR (500 MHz, DMSO-d6): δ 12.93 (br. s., 1H), 12.40 (br. s., 1H), 8.89 – 8.86 (m, 1H), 8.33(d, = 7.6 Hz, 1H), 7.81 – 7.50 (m, 5H), 7.25 – 7.21 (m, 2H), 2.90-2.83 (m, 1H), 1.22-1. l l(m, 6H); 13C NMR (100 MHz, DMSO-d6): δ 176.8, 163.1, 144.5, 143.9, 139.6, 137.1, 133.4, 127.2, 126.4, 125.9, 125.7, 120.1, 119.6, 111.1, 33.4, 24.4.

[073] Example 35:

4-oxo-N-(4-(trifluoromethoxy)phenyl)-l,4-dihydroquinoline-3-carboxamide(33):

Yield 57% ; 1H NMR (400 MHz, DMSO-d6): δ 12.98 (br. s., 1H), 12.63 (s, 1H), 8.88 (d, = 4.9 Hz, 1H), 8.32 (d, = 7.8 Hz, 1H), 7.89 – 7.83 (m, = 8.8 Hz, 2H), 7.79 (d, = 7.6 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 – 7.34 (m, = 8.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 176.8, 163.5, 144.7, 144.0, 139.5, 138.5, 133.5, 126.3, 125.9, 125.8, 122.3, 121.4, 119.7, 110.7.

[074] Example 36:

N-(2-chloro-5-methoxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(34):

Yield 54% ; XH NMR (400 MHz, DMSO-d6): δ 12.98 (br. s., 1H), 12.49 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8 Hz, 1H), 7.83 – 7.75 (m, 1H), 7.56-7.48 (m, 3H), 7.27 – 7.21 (m, 1H), 6.67 (d, = 7.8 Hz, 1H), 3.77 (s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 176.8, 163.4, 160.2, 144.7, 140.4, 139.6, 133.5, 130.3, 126.4, 125.9, 125.8, 119.7, 112.3, 111.0, 109.5, 105.7, 55.5.

[075] Example 37:

N-(2-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(35):

Yield 58% ; 1H NMR (400 MHz, DMSO-d6): δ 12.94 (br. s., 1H), 12.37 (s, 1H), 8.90 (s, 1H), 8.36 (dd, = 8.1, 1.4 Hz, 2H), 8.32 (dd, = 8.1, 1.4 Hz, 2H), 7.82 – 7.74 (m, 1H), 7.53- 7.19 (m, 3H), 7.15 – 7.06(m, 1H), 2.79 (q, = 7.3 Hz, 2H), 1.26 (t, = 7.5 Hz, 3H); 293 (M+H)+.

[076] Example 38:

N-(2-bromophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(36):

Yield 47% ; 1H NMR (200 MHz, DMSO-d6): δ 12.98 (br. s., 1H), 12.69 (s, 1H), 8.90 (d, = 5.9 Hz, 1H), 8.54 (dd, 7 = 1.4, 8.3 Hz, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.86 – 7.67 (m, 3H), 7.57 – 7.49 (m, 1H), 7.40 (t, = 7.2 Hz, 1H), 7.10 – 7.05 (m, 1H); 13C NMR (100 MHz, DMSO-de): δ 176.7, 163.7, 145.0, 139.5, 137.7, 133.5, 133.1, 128.6, 126.4, 126.0, 125.8, 125.3, 122.9, 119.7, 113.4, 110.8.

[077] Example 39:

N-benzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(37):

Yield 58% ; 1H NMR (400 MHz, CD3OD-d6): δ 8.82 (s, 1 H), 8.35 (d, = 8.1 Hz, 1 H), 7.79 – 7.77 (m, 1 H), 7.65 (d, = 8.3 Hz, 1 H), 7.52 (t, = 7.6 Hz, 1 H), 7.42 – 7.34 (m, 4 H), 7.31 – 7.26 (m, 1 H), 4.67 (s, 2 H); 13C NMR (400 MHz, DMSO-d6): δ 176.6, 165.0, 144.2, 140.0, 139.5, 133.2, 128.9, 128.7, 127.8, 127.3, 126.6, 125.9, 125.4, 119.5, 111.2, 42.6.

[078] ] Example 40:

N-(4-methoxybenzyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(38):

Yield 56% ; 1H NMR (400 MHz, DMSO-d6): δ 12.73 (br. s., 1H), 10.35 (t, = 5.3 Hz, 1H), 8.78 (d, = 6.1 Hz, 1H), 8.24 (d, = 8.1 Hz, 1H), 7.76 (d, = 7.1 Hz, 1H), 7.73 -7.68 (m, 1H), 7.48 (t, = 7.5 Hz, 1H), 7.28 (d, = 8.3 Hz, 2H), 6.91 (d, = 8.1 Hz, 2H), 4.49 (d, = 5.6 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 176.6, 164.8, 158.8, 144.1, 139.5, 133.1, 131.9, 129.2, 126.6, 125.8, 125.4, 119.5, 114.3, 111.3, 55.5, 42.0.

[079] Example 41:

N,N-dibenzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(39):

Yield 43% ; 1H NMR (400 MHz, DMSO-d6): δ 12.21 (br. s., 1H), 8.27 (d, = 4.9 Hz, 1H), 8.21 (d, = 7.6 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.41 – 7.35 (m, 3H), 7.33 – 7.20 (m, 5H), 7.20 – 7.11 (m, 7 = 7.1 Hz, 2H), 4.59 (br. s., 2H), 4.42 (s, 2H).

[080] Example 42:

4-oxo-N-propyl-l,4-dihydroquinoline-3-carboxamide(40):

Yield 47% ;1H NMR (400 MHz, DMSO-d6): δ 12.7 (br.s., 1H)10.05 (t, = 5.5 Hz, 1H), 8.74 (s, 1H), 8.26 (d, = 8.1 Hz, 1H), 7.83 – 7.66 (m, 2H), 7.52 – 7.44 (m, 1H), 3.33 – 3.22 (m, 2H), 1.61 – 1.49 (m, 2H), 0.93 (t, = 7.5 Hz, 3H); 13C NMR (100 MHz, DMSO-de): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 39.3, 23.1, 12.0

[081] Example 43:

N-hexyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(41):

Yield 51% ;1H NMR (400 MHz, DMSO-d6): δ 12.68 (m, 1H), 10.02 (t, = 5.5 Hz, 1H), 8.73 (d, = 6.1 Hz, 1H), 8.27 – 8.25 (m, 1H), 7.77 – 7.67 (m, 2H), 7.47 (t, = 7.5 Hz, 1H), 3.33 – 3.29 (m, 2H), 1.56 – 1.45 (m, 2H), 1.34 – 1.25 (m, 6H), 0.88 – 0.82 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 38.7, 31.5, 29.8, 26.7, 22.5, 14.4.

[082] Example 44:

Methyl (4-oxo-l,4-dihydroquinoline-3-carbonyl)-L-alaninate(42):

Yield 38% ; 1H NMR (400 MHz, CD3OD): δ 8.74 (s, 1H), 8.47 – 8.29 (m, 1H), 7.86 -7.76 (m, 1H), 7.64 (d, = 8.3 Hz, 1H), 7.58 – 7.44 (m, 1H), 4.69 (d, = 7.3 Hz, 1H), 3.79 (s, 3H), 1.55 (d, = 7.3 Hz, 3H); 13C NMR (100 MHz, CD3OD): δ 177.3, 173.3, 165.5, 143.6, 139.2, 132.9, 126.3, 125.4, 125.2, 118.5, 110.3, 51.5, 47.0, 17.0.

[083] Example 45:

7-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(43):

Yield 48% ; IR Omax(film): 2920, 2868, 1661, 1601 cm” 1; 1H NMR (400 MHz, DMSO-de): δ 12.91 (br. s., 1H), 12.30 (s, 1H), 8.90 (s, 1H), 8.29 (d, = 8.8 Hz, 1H), 7.80 -7.67 (m, 3H), 7.58 – 7.51 (m, 1H), 7.36 (t, = 7.7 Hz, 2H), 7.09 (t, = 7.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 176.3, 162.9, 145.4, 140.3, 139.2, 138.0, 129.5, 128.2, 126.1, 125.1, 123.9, 120.1, 118.8, 111.6.

[084] Example 46:

6-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(44):

Yield 52% ; 1H NMR (400 MHz, DMSO-d6): δ 13.05 (brs, 1H), 12.27 (s, 1H), 8.88 (s, 1H), 8.21 (d, = 2.2 Hz, 1H), 7.86 – 7.67 (m, 4H), 7.36 (t, = 7.8 Hz, 2H), 7.16 – 7.04 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 175.6, 162.9, 144.9, 139.1, 138.2, 133.5, 130.4, 129.5, 127.5, 124.9, 123.9, 122.0, 120.1, 111.4.

[085] Example 47:

l-benzyl-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(45)

Yield 55% ; 1H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 9.05 (s, 1H), 8.60 (dd, = 1.7, 8.1 Hz, 1H), 7.82 (d, = 7.8 Hz, 2H), 7.69 – 7.62 (m, 1H), 7.55 – 7.45 (m, 2H), 7.43 – 7.34 (m, 5H), 7.24 – 7.18 (m, 2H), 7.17 – 7.10 (m, 1H), 5.53 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 176.9, 162.9, 148.7, 139.3, 138.7, 134.1, 133.1, 129.4, 128.9, 128.7, 128.0, 127.4, 126.2, 125.5, 123.9, 120.5, 116.9, 112.3, 57.9; HRMS (ESI): Calculated for C23H1802N2Na [M+Na]+: 377.1260, found 377.1259; MS: 355 (M+H)+.

[086] Advantages of invention:

1. Cost-effective process for synthesis.

2. Carried out at environmentally benign conditions.

3. Short synthetic route.

4. Useful for making several related compounds of medicinal

 

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DR SRINIVASA REDDY recieving NASI – Reliance Industries Platinum Jubilee Award (2015) for Application Oriented Innovations in Physical Sciences.

 

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From left to right: Dr. D. Srinivasa Reddy, Shri Y. S. Chowdary, Dr. Harsh Vardhan, Dr. Girish Sahni

  • Dr D. Srinivasa Reddy receiving the prestigious “SHANTI SWARUP BHATNAGAR” award at the occasion of the 75th Foundation day of CSIR.

Shanti Swarup Bhatnagar awardees with the honorable Prime Minister of India

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//////////WO-2016181414, WO 2016181414,  IVACAFTOR, new patent, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH,  Anusandhan Bhawan, Rafi Marg New Delhi, INDIA, CSIR, Dr. D. Srinivasa Reddy

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Diacerein, US 8324411

 PATENTS  Comments Off on Diacerein, US 8324411
Sep 022016
 

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Patent US 8324,411

https://www.google.com/patents/US8324411

Inventors Annibale Salvi, Antonio Nardi, Stefano Maiorana, Mara Sada
Original Assignee Laboratorio Chimico Internazionale S.P.A.

Laboratorio Chimico Internazionale s.p.A., Milan, Italy
STR1
Diacerein, 20a, is used in the treatment of arthritis, and there are several methods available for its synthesis. The majority of these are said to involve an oxidation step that uses CrO3, and as a result, extensive purification is required to remove residues of Cr and reaction byproducts. The patent discloses an oxidation procedure in the preparation of 20a that avoids these problems and is claimed to be suitable for industrial production. Scheme 8 shows the route used to prepare 20athat starts with formation of the protected quinone, 19b. Despite the workup of the compound being quite lengthy, 19b is isolated in 74% yield with 98% purity. The next step is oxidation of the protected dihydroxy quinone 19b using TEMPO and an alkaline chlorite plus an alkaline hypochlorite. The chlorite is used in around 2 mol excess of the substrate and the hypochlorite at around 5 mol % of the substrate. After the oxidation the crude product is isolated in 98% yield and then purified by treatment with Et3N and DMF. The purified 20b is obtained in 76% yield, and then the protection is removed using FeCl3/Ac2O. The yield of crude 20a is 92%, and it is said to be purified by known techniques. The Cr content of the purified material is reported as <1 ppm, and genotoxic impurities such as 19a or acetyl derivatives are reported to be <2 ppm.

Figure

Scheme 8. a

aReagents and conditions: (a) (i) K2CO3, KI, Bu4NBr, DMF, 60 °C; (ii) 80 °C, 1 h; (iii) BnCl, 50 °C, 1 h; (iv) 80 °C, 1 h; (v) add MeOH at 50 °C; (vi) cool to <25 °C, filter; (vii) evaporate, add THF; (viii) wash at 60 °C with aq NaOH, H2O, brine; (ix) evaporate, add EtOAc, concentrate; (x) cool <4 °C, 1 h; (xi) filter, wash, dry. (b) (i) TEMPO, aq NaH2PO4, aq Na2HPO4, MeCN, 35 °C; (ii) add aq NaClO2, 35 °C, 50 min; (iii) add aq NaOCl, 65 °C, 3 h; (iv) cool rt, add H2O; (v) add H3PO4, pH 3; (vi) filter, H2O wash, dry; (vii) Et3N, DMF, EtOAc, 60 °C, 0.5 h; (viii) filter hot; (ix) add H2O, separate; (x) extract H2O phase at 60 °C with EtOAc (×6); (xi) cool organic phases to rt, add HCl to pH 2; (xii) cool <5 °C, 1 h; (xiii) filter, H2O wash, MeCN wash, dry. (c) (i) FeCl3, Ac2O, 65 °C, 1.5 h; (ii) cool <4 °C, 1 h; (iii) filter, wash in Ac2O, EtOAc wash, dry.

Advantages

The process produces the desired product without using heavy-metal oxidising agents; however, the workup procedures are quite lengthy.

Example 1 Preparation of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone (dibenzyl aloe-emodin)483 g (3.5 moles) of potassium carbonate, 16 g (0.1 moles) of potassium iodide and 16 g (0.05 moles) of tetrabutylammonium bromide are added to a solution of 270 g (1 mole) of 1,8-dihydroxy-3-(hydroxymethyl)anthraquinone (aloe-emodin) in 3500 ml of DMF at 60° C.; the reaction mixture is heated at 80° C. for 1 h. It is cooled to 50° C. and 443 g (3.5 moles) of benzyl chloride are added dropwise in approximately one hour. At the end of the dripping, the reaction mixture is brought back to 80° C. and left at that temperature under stirring for 45-60 minutes. It is then cooled to 50° C. and 200 ml of methyl alcohol are added. It is cooled to 20-25° C. and the inorganic salts are removed by filtering. The organic solvent is distilled at 60-70° C. at reduced pressure and the residue is dissolved in 3200 ml of tetrahydrofuran at 60° C. Maintaining the temperature at 50-60° C., the organic phase is washed twice with 1200 ml of 2.5 molar aqueous sodium hydroxide and once with 1000 ml of a saturated solution of sodium chloride in water. The organic phase is concentrated at reduced pressure at 60° C. and the residue is recovered with 2700 ml of ethyl acetate. The suspension thus obtained is concentrated to approximately ⅓ of the initial volume by distillation of the solvent at reduced pressure. It is gradually cooled to 0-4° C. and kept at that temperature for 1 hour. The solid is filtered and washed with ethyl acetate (100 ml×2). The damp product is dried at 45° C. at reduced pressure for 12-14 hours, providing 334 g (yield 74%) of dibenzyl aloe-emodin having a purity of 98% (HPLC).

melting point: 170-171° C.

IR cm−1: 1655, 1612, 1232

Example 2 Synthesis of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)10 g (0.06 moles) of radical 2,2,6,6-tetramethyl-1-piperidinyl-oxyl (TEMPO) and 1160 ml of an aqueous solution of 120 g (1 mole) of sodium dihydrogen phosphate and 180 g (1 mole) of disodium hydrogen phosphate are added in sequence to a suspension of 333 g (0.74 moles) of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone in 1660 ml of acetonitrile. The reaction mixture is heated to 35° C. and a solution of 167 g (1.5 moles) of sodium chlorite 80% in 513 ml of water is added dropwise in 40-50 minutes, maintaining the temperature around 35-40° C. 20 ml of aqueous sodium hypochlorite 10-12% are then dripped in and the reaction is heated to 60-65° C. for three hours. It is cooled to room temperature and 1400 ml of water are added. Phosphoric acid 85% is dripped in until reaching a pH of 2.8-3.2. The solid obtained is filtered and washed with water (350 ml×2). The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 337 g (yield 98%) of crude dibenzylrhein.

Example 3 Purification of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)337 g (0.72 moles) of crude 1,8-dibenzyloxyanthraquinone-3-carboxylic acid are dissolved in a solution of 134 ml of triethylamine in 900 ml of dimethylformamide DMF and 1800 ml of ethyl acetate, heating to 60° C. for 20-30 min. Any undissolved elements are removed by hot filtering and 2700 ml of water are added. The organic phase is separated and the aqueous phase is washed 6 times with 800 ml of ethyl acetate each time, maintaining the temperature at 60° C. The organic phase is cooled to room temperature and acidified with hydrochloric acid 33% until pH 2 is reached; the suspension thus obtained is cooled to 0-5° C. for approximately 1 hour. The product is filtered, washing it thoroughly with water (1200 ml) and then with 200 ml of acetonitrile. After drying at 50° C. at reduced pressure for 14-16 hours, 256 g of dibenzylrhein are obtained with a yield of 76%.

melting point: 250-251° C.

IR cm−1: 1666, 1621, 1587, 1524

Example 4 Synthesis of 1,8-diacetoxy-3-carboxyanthraquinone (diacerein)45 g (0.28 moles) of anhydrous iron trichloride are added in portions to a suspension of 255 g (0.55 moles) of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid in 1300 ml of acetic anhydride. The reaction mixture is heated to 65° C. for one hour and thirty minutes. It is gradually cooled to 2-4° C. and maintained at that temperature for 1 hour. The solid obtained is filtered and washed with 150 ml of acetic anhydride and then with 400 ml of ethyl acetate. The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 186 g of crude diacerein (yield 92%). The crude diacerein is purified according to the known techniques.

1H NMR (d6-DMSO) δ: 2.4 (6H, s); 7.6 (1H, dd); 7.9 (1H, t); 8.0 (1H, d); 8.1 (1H, dd); 8.5 (1H, d).

IR cm−1: 1763, 1729, 1655, 1619, 1591, 1183.

Chromium: not detectable (<1 ppm)

Genotoxic impurities (aloe emodin and acetyl derivatives)≦2 ppm.

/////////Diacerein, US 8324411, PATENT

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US 8362006, Intervet International B.V., Boxmeer, The Netherlands, Zilpaterol, PATENT

 PATENTS  Comments Off on US 8362006, Intervet International B.V., Boxmeer, The Netherlands, Zilpaterol, PATENT
Sep 022016
 

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US 8362006

http://www.google.co.in/patents/US8362006

Inventors Oliver Krebs, Stephane Dubuis
Original Assignee Intervet International B.V.

Intervet International B.V., Boxmeer, The Netherlands
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Process for Making Zilpaterol and Salts Thereof

Zilpaterol is a known adrenergic β-2 agonist having the following structure:

Figure US08362006-20130129-C00001

The IUPAC name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-(isopropylamino)imidazo[4,5,1-jk]-[1]benzazepin-2(1H)-one. The Chemical Abstracts name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-[(1-methyl-ethyl) amino]-imidazo [4,5,1-jk][1]benzazepin-2(1H)-one.It is well known that zilpaterol, various zilpaterol derivatives, and various pharmaceutically acceptable acid addition salts of zilpaterol and its derivatives may, for example, be used to increase the rate of weight gain, improve feed efficiency (i.e., decrease the amount of feed per amount of weight gain), and/or increase carcass leanness (i.e., increase protein content in carcass soft tissue) in livestock, poultry, and/or fish. In U.S. Pat. No. 4,900,735, for example, Grandadam describes zootechnical compositions of racemic trans zilpaterol and salts thereof that may be used to increase the weight and meat quality of warm-blooded animals, including cattle, pigs, and poultry. And U.S. Patent Appl. Publ. US2005/0284380 describes use of an ionophore/macrolide/zilpaterol dosing regimen to increase beef production, reduce feed intake while maintaining beef production, and reduce incidences of liver abscess in cattle.

Methods for making zilpaterol are known in the art. For example, in U.S. Pat. No. 4,585,770, Fréchet et al. describe compounds encompassed by a genus characterized as 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one derivatives and pharmaceutically acceptable acid addition salts thereof. The derivatives correspond in structure to the following formula:

Figure US08362006-20130129-C00002

Here, R can be various substituents, and the wavy lines indicate that the bonds to the 6-amino and 7-OH groups have the trans configuration. This genus encompasses racemic trans zilpaterol when R is isopropyl.The methods reported in U.S. Pat. No. 4,585,770 use 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime as an intermediate. This compound corresponds in structure to the following formula:

Figure US08362006-20130129-C00003

As indicated in U.S. Pat. No. 4,585,770, 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime may be formed from starting materials that have been long known in the art. U.S. Pat. No. 4,585,770 illustrates the use of two such starting materials. In both examples, the starting materials are used to form 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione, which, in turn, may be used to make 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime.In one of the examples in U.S. Pat. No. 4,585,770, the starting material is 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, which is described in J. Chem. Soc. Perkins, p. 261 (1982):

Figure US08362006-20130129-C00004

U.S. Pat. No. 4,585,770 indicates that 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one may be reacted with an alkyl 4-halobutyrate (i.e., RA—(CH2)3—COORB (wherein RA is Cl, Br, or I; and RB is C1-C4-alkyl), such as methyl or ethyl 4-bromobutyrate) and a base (e.g., an alkali metal) to form a butanoate, which, in turn may be hydrolyzed with an acid (e.g., H2SO4) in an alkanol (e.g., methanol or ethanol) to remove the methylethenyl substituent. The hydrolysis product then may be subjected to saponification by reacting it with a base (e.g., NaOH or KOH) in an alkanol to form a carboxylic acid. Subsequently, the carboxylic-acid-terminated side chain may be cyclized to form 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione by reacting the carboxylic acid with thionyl chloride to obtain a chloride, and then treating the chloride with a Lewis acid (e.g., aluminum chloride) in an organic solvent (e.g., methylene chloride or dichloroethane):

Figure US08362006-20130129-C00005

See U.S. Pat. No. 4,585,770, col. 4, line 3 to col. 5, line 14; and Example 14, col. 12, lines 1-68.In another example in U.S. Pat. No. 4,585,770, the starting material is 1,3-dihydro-1-benzyl-2H-benzimidazol-2-one, which is described in Helv., Vol 44, p. 1278 (1961):

Figure US08362006-20130129-C00006

U.S. Pat. No. 4,585,770 indicates that the 1,3-dihydro-1-benzyl-2H-benzimidazol-2-one may be reacted with ethyl 4-bromobutyrate and sodium hydride to form 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazol-1-butanoate, which, in turn may be subjected to saponification by reacting it with methanolic NaOH to form 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazol-1-butanoic acid. The butanoic acid side chain may then be cyclized by reacting the 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazol-1-butanoic acid with thionyl chloride to obtain a chloride, and then treating the chloride with aluminum chloride in dichloroethane. The cyclized product, in turn, may be hydrolyzed using o-phosphoric acid in phenol to form 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione. See U.S. Pat. No. 4,585,770, Example 1, Steps A-D, col. 6, line 10 to col. 7, line 35.Using the methods reported in U.S. Pat. No. 4,585,770, 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione may be reacted with an alkyl nitrite (e.g., tert-butyl nitrite or isoamyl nitrite), in the presence of a base or acid (e.g., HCl), to form 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime. The 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime, in turn, is reduced via catalytic hydrogenation (with, for example, hydrogen in the presence of palladium on carbon) or sodium borohydride to form racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one:

Figure US08362006-20130129-C00007

In the illustrative example in U.S. Pat. No. 4,585,770, the 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime is converted into racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one in two steps: the 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime is first reacted with H2 in the presence of Pd-on-carbon, and, then, after filtration, the hydrogenation product is reacted with sodium borohydride. See U.S. Pat. No. 4,585,770, col. 2, line 15 to col. 4, line 2; and Example 1, Steps E & F, col. 7, line 38 to col. 8, line 3.U.S. Pat. No. 4,585,770 reports that the trans stereoisomers of 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one may be alkylated with acetone in the presence of a reducing agent (e.g., an alkali metal borohydride or cyanoborohydride, such as sodium cyanoborohydride) to form racemic trans zilpaterol:

Figure US08362006-20130129-C00008

See U.S. Pat. No. 4,585,770, col. 2, line 46 to col. 4, line 2; and Example 13, col. 11, lines 41-68.In view of the importance of zilpaterol and its salts in animal production, there continues to be a need for cost-effective, high-yield processes for making zilpaterol and its salts. The following disclosure addresses this need.

OVERVIEW
Zilpaterol 121 is used to increase the rate of weight gain in livestock, poultry, and fish. The drug is available as Zilmax and is marketed as beef improvement technology. There are a number of methods for preparing 121, and the patent specifically focuses on the method reported in a 1986 patent, U.S. 4,585,770, that is compared with the process described in the current patent.
The new process is outlined in Schemes 37 and 38, and the examples in the patent describe the manufacture of 121 on a commercial scale starting from 525 kg of 116a.
Unfortunately, the yield of the reaction products is not reported in any of the steps. The process starts with the chlorination of the acid 116a to give 116b that is carried out using (COCl)2, although COCl2 or triphosgene are also claimed to be suitable. The product is isolated as a solution in DCM after a workup involving transferring between three vessels, adding H2O, and distilling off the solvent.
In the next stage an intramolecular Friedel–Crafts alkylation of 116b in the presence of AlCl3 followed by acid hydrolysis forms 117. This is isolated as a wet solid and then is converted to the oxime 118a in DMF by treatment with NaNO2 followed by addition of HCl.

Figure

Scheme 37. a

aReagents and conditions: (a) (i) DMF, DCM, 10 °C; (ii) (COCl)2, 10 °C, 3 h; (iii) 20 °C, 3 h. (b) (i) AlCl3, DCM, 60 °C, 3 to 7 h; (ii) cool to <20 °C, add H2O/33% aq HCl; (iii) cool, evacuate, distill DCM; (iv) centrifuge, wash in PriOH. (c) (i) NaNO2, DMF, 45 °C; (ii) 33% HCl, 48 °C, 1 h; (iii) 60 °C, 0.5 h; (iv) cool to 45 °C, 2 h; (v) add DMF and H2O; (vi) cool, to 0 °C, 11 h; (vii) centrifuge at 0 °C; (viii) H2O wash, wash in Me2CO, dry.

Compound 118a is isolated as a dry solid that is converted to the potassium salt by treatment with 45% aq KOH as shown in Scheme 38. The salt is isolated as a solution that is treated with active C and then hydrogenated in the presence of Pd/C catalyst to form the amino alcohol salt 119.
This reaction appears to be stereoselective, although no reference to this is made in the patent. The salt, 119, is recovered as an aqueous solution that is used in the next step where it is reacted with Me2CO in the presence of HOAc at a pH of 7–8. This produces the isopropylidene amino compound, 120, that is not isolated but undergoes hydrogenation in the presence of Pt/C catalyst to give the HOAc salt, 121·HOAc.
The free base form, 121, is obtained by treating the salt with NaOH in EtOH, and from the free base, a HCl salt can be prepared.

Figure

Scheme 38. a

aReagents and conditions: (a) (i) H2O, 45 °C; (ii) 45% aq KOH, 40 °C; (iii) active C, 0.5 h; (iv) filter. (b) (i) Pd/C, H2O, 15 °C; (ii) H2, 10 bar, 40 °C, 6 h; (iii) filter, H2O wash. (c) HOAc to pH 8, 30 °C. (d) (i) cool 15 °C, Pt/C, H2O; (ii) H2 9 bar, 70 °C, 2 h; (iii) add HOAc, 30 °C, pH 6.8; (iv) filter at 30 °C; (v) wash in aq HOAc.

The patent discusses aspects of the process is some detail such as the quantities of washing solvents used.

Advantages

The process provides an effective route to the desired compound and is clearly suitable for large-scale manufacture.

The following Scheme I generically illustrates a scenario wherein all the above reactions are used:

Figure US08362006-20130129-C00017

The following Scheme II generically illustrates the above scenario wherein the chlorinating agent comprises oxalyl chloride; the Lewis acid comprises AlCl3; the hydrolysis acid following the Friedel-Crafts reaction comprises HCl; the inorganic nitrite comprises NaNO2; the acid used in the oximation comprises HCl; water is added to the oximation product mixture to foster isolation of the oxime product; the base used to form the oxime salt comprises KOH; the catalyst for the first hydrogenation comprises palladium on carbon; the acid used in the formation of the isopropylideneamino compound comprises acetic acid; the catalyst for the second hydrogenation comprises platinum on carbon; and the base and alcohol used to form the zilpaterol free base comprise NaOH and ethanol, respectively:

Figure US08362006-20130129-C00018

Example 1 Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione Part A. Preparation of chloro 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate

Figure US08362006-20130129-C00019

4-(2-Oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (50 g; 0.227 mol), N,N-dimethylformamide (1.84 g; 0.025 mol; 0.11 eq), and dichloromethane (480 g; 5,652 mol; 24.89 eq) were charged to a stirred-tank reactor. Oxalyl chloride (31.12 g; 0.245 mol; 1.08 eq) was then dosed at 10-20° C. over a 1-hour period while stirring. The resulting mixture was then stirred at 10-20° C. for an additional hour. All the above steps were conducted under a N2 atmosphere.Part B. Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione.

Figure US08362006-20130129-C00020

The reaction product mixture from Part A was added to a slurry of aluminum chloride (100 g; 0.75 mol, 3.3 eq) in dichloromethane (320 g; 3.768 mol; 16.59 eq) over 2-5 hours at 60° C. and a pressure of 2.7 bar (absolute) in a stirred-tank reactor that allowed HCl gas to escape through an overpressure vent. The resulting slurry was stirred for an additional hour at that temperature, and then cooled to 12° C. In a separate stirred-tank reactor, water (800 g; 44.407 mol; 195.59 eq.) and aqueous 32.5% HCl (118 g; 1.052 mol HCl; 4.63 eq. HCl) were mixed. This mixture was cooled to 0° C., and the gas in the headspace was evacuated to 300 mbar (absolute). The slurry from the first reactor was then added portion-wise to the second reactor, whereby the temperature increased to 10-15° C. under distillation of dichloromethane. The first reactor was rinsed with additional dichloromethane (25 g; 0.294 mol; 1.3 eq), which was then added to the second reactor. Distillation of the dichloromethane was then completed at 300 mbar to atmospheric pressure (absolute) and 12-40° C. The resulting suspension was cooled to 0° C. The solid was filtered off, and washed 4 times with water (291.25 g each time; 64.668 mol total; 284.83 eq. total) and once with isopropanol (80 g; 1.331 mol; 1.331 eq) at 0° C. All the above steps were conducted under a N2 atmosphere.Example 2 Preparation of 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime.

Figure US08362006-20130129-C00021

8,9-Dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione (50 g; 92.4% purity; 0.228 mol) prepared in accordance with the procedure in Example 1 was dried and mixed with isopropanol (7.23 g; 0.12 mol; 0.53 eq) and water (3.01 g; 0.167 mol; 0.73 eq) (in alternative experiments and in production, 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione prepared in accordance with the procedure in Example 1 was instead used as centrifuge-wet material without the addition of water and isopropanol). The resulting wet 8,9-dihydro-2H-7H-2,9a-diazabenzo[cd]azulene-1,6-dione was combined with sodium nitrite (19.05 g at 99.3% purity; 0.274 mol; 1.2 eq) and N,N-dimethylformamide (800 g; 10.945 mol; 47.9 eq) in a stirred-tank reactor. The mixture was heated to 50° C., and then 32% HCl (41.65 g; 0.366 mol HCl; 1.6 eq HCl) was added over a 30 minute period. Toward the end of the HCl addition (i.e., after greater than 1 eq HCl had been added), the temperature quickly increased to 60-70° C. After all the HCl was added, the mixture was stirred at 60° C. for an additional 30 minutes. The mixture then was cooled to 35° C. over a 2- hour period. Next, water (224.71 g; 12.473 mol; 54.6 eq) was added over a 2-hour period. The resulting mixture was then cooled to 0° C. over a 2-hour period, and maintained at that temperature for 2 hours. Afterward, the solid 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime product was removed by filtration and washed 4 times with water (70.1 ml each time; 15.566 mol total; 68.13 eq total) and once with acetone (115.9 g; 99.9% purity; 1.994 mol; 8.73 eq). All the above steps were conducted under a N2 atmosphere.Example 3 Scale-up Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione Part A. Preparation of chloro 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate

Figure US08362006-20130129-C00022

Dichloromethane (3772 L) and then 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (525 kg; 2.4 kmol) were charged to a stirred-tank reactor, followed by N,N-dimethylformamide (21 L). The resulting mixture was cooled to 10° C. Afterward, oxalyl chloride (326.8 kg)) was dosed at 10-15° C. over 2-3 hours while stirring. The resulting mixture was then stirred at 15-20° C. for an additional 1-3 hours. All the above steps were conducted under a N2 atmosphere. Conversion was checked by in-process control (“IPC”).Part B. Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione.

Figure US08362006-20130129-C00023

Aluminum chloride (1050 kg) and dichloromethane (2403 L) at 10-20° C. were charged to a stirred-tank reactor, followed by additional dichloromethane (112 L) at 10-20° C. to rinse the reactor. The reactor was then pressurized with N2 to 2.7 bar (absolute), and heated to 58-60° C. Next, the product mixture from Part A was added over 2−5 hours. The resulting slurry was stirred for an additional 1-2 hours, and then cooled to 10-20° C. Afterward, the pressure was released. In a second stirred-tank reactor at 5° C., water (3675 L) was charged, followed by aqueous 33% HCl (452 L). This mixture was cooled to 0° C., and the gas in the headspace was evacuated to 270-470 mbar (absolute). About half the content from the first reactor was added to the second reactor at from 5-20° C. The mixture was maintained at 10-30° C. for an additional 30-90 minutes. In parallel to and following the transfer, distillation of dichloromethane occurred. The line between the two reactors was rinsed with dichloromethane (150 ml). The resulting rinse and the contents in the second reactor were transferred to a thud stirred-tank reactor. The transfer line between the second and third reactors was rinsed with water (200 L). This rinse also was charged to the third reactor. Water (3675 L) at 5° C. and 33% HCl (452 L) were then added to the second reactor. The resulting mixture was cooled to 0° C., and the pressure in the headspace was set to between 270-470 mbar (absolute). The second half of the content from the first reactor was then added to the second reactor at 5-20° C. This mixture was maintained at 10-30° C. for an additional 30-90 minutes. In parallel to and following the transfer, distillation of dichloromethane occurred. The line between the first and second reactors was rinsed with dichloromethane (150 ml). The resulting rinse and the contents in the second reactor were transferred to the third reactor. The transfer line between the second and third reactors was then rinsed with water (200 L). This rinse was charged to the third reactor. In the third reactor, the dichloromethane was further distilled at 30-40° C. under atmospheric pressure. When the distillation was complete, the suspension was cooled to 0−5° C., and then centrifuged in two parts. Each of the resulting cakes was washed with four times water (390 L for each wash) and once with isopropanol (508 L) at 0−5° C. All the above steps were conducted under a N2 atmosphere.Example 4 Scale-up of Preparation of 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime.

Figure US08362006-20130129-C00024

At 20° C., N,N-dimethylformamide (7068 L) was charged to a stirred-tank reactor, followed by 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione (450 kg total wet material, approximately 405 kg pure) prepared in accordance with the procedure in Example 3. The addition funnel was rinsed with N,N-dimethylformamide (105 L), and the rinse was charged to the reactor. The resulting mixture was heated at 45° C. until all the 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione was in solution. IPC was used to check the amount of pure 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione in the mixture, and, from that measurement (together with the mass of wet 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione and N,N-dimethylformamide), the exact amount of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione was calculated, which, in turn, was used to calculate the amounts of N,N-dimethylformamide (17.3 kg/kg), sodium nitrite (0.412 kg/kg) and HCl 33% (0.873 kg/kg). For the duration of the IPC, the mixture was cooled to 20° C. Next, sodium nitrite (167 kg, based on 405 kg 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione) was added. The addition funnel was rinsed with N,N-dimethylformamide (105 L), and the rinse was charged to the reactor. The temperature was then increased to 45° C. Subsequently, additional N,N-dimethylformamide was charged in the amount calculated earlier (97 L, based on having a total of 7375 L DMF for 405 kg of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione). Next, the resulting mixture was warmed to 48° C., and then 33% HCl (353 kg, based on the batch size) was added over 1 hour, causing the temperature to increase to 60-65° C. by the end of the addition. The mixture was then stirred at 60° C. for another 30 minutes. Next, the mixture was cooled to 45° C. over 1-2 hours. The resulting mixture was transferred into a second reactor. The first reactor was subsequently rinsed with N,N-dimethylformamide (105 L), and the rinse was charged to the second reactor. Water (2000 L) was then added over a 2-hour period at 38° C. The resulting mixture was cooled to 0° C. over 2-3 hours, and then stirred at that temperature for another 2-8 hours. Afterward, the mixture was centrifuged at 0° C., and the resulting cake was washed with three times with water (810 L each time), washed with acetone (1010 L), and dried at 65° C. under vacuum. All the above steps, except for the IPC, were conducted under a N2 atmosphere.Example 5 Preparation of Zilpaterol Part A. Formation of Aminoalcohol Potassium Salt from Ketooxime

Figure US08362006-20130129-C00025

A stirred-tank reactor was purged 3 times with N2 between high pressure (3 bar, absolute) and low pressure (1 bar, absolute) for 10 minutes each. Then a pressure of 0.9 bar (absolute) was established. Water (790 kg) was then charged to the reactor, followed by 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime (255 kg) prepared in accordance with Example 4. The reactor contents were then heated to 40° C. Next, 45% KOH (214 kg) was continuously charged to the reactor, causing 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime to form the corresponding potassium salt, which, in turn, dissolved (this could be visually verified). The reactor was then charged with active charcoal (13 kg). The resulting mixture was then stirred for 30 minutes at 40° C. The resulting mixture was filtered through a filter loop for one hour to remove the active charcoal. The mixture was then cooled to 15° C. A 5% palladium-on-carbon catalyst (25.5 kg, Johnson-Matthey) was then charged to the reactor. The reactor was then rinsed with water (50 kg). The resulting mixture in the reactor was stirred for 2-6 hours at 40° C. and a H2 pressure of 5-10 bar (absolute). Afterward, the reactor was vented over 30 minutes, and the reaction was analyzed using HPLC. The contents were then filtered in a filter loop for 90 minutes. The filter cake was washed with water (50 L), and removed to recover palladium. The filtered solution was analyzed via HPLC to confirm complete conversion, and then used in the next step.Part B. Formation of zilpaterol-HOAc.

Figure US08362006-20130129-C00026

The solution from Part A was cooled to 30° C. Acetone (625 L) was then charged to the reactor. Acetic acid was added to adjust the pH to 7.5 (a pH of from about 7 to about 8 is preferred). The resulting mixture was then cooled to 15° C. Next, a 5% platinum-on-carbon catalyst (21.3 kg, Degussa) was charged to the reactor, followed by water (50 kg) to rinse the reactor. The head space was purged 3 times with H2 between a high pressure of 5 bar (absolute) and a low pressure of 1 bar (absolute) for 15 minutes each. Then a hydrogen pressure of 9.0 bar (absolute, for hydrogenation) was established. The mixture was heated to 70° C. over 1 hour while being stirred, and then maintained at that temperature for an additional hour while being stirred. The reactor was then vented, and the headspace was purged with N2. The reaction was analyzed using HPLC. Acetic acid (8 kg) was then charged to the reactor, and the resulting mixture was cooled to 30° C. More acetic acid was added to adjust the pH to 6.8. The mixture was then transferred through a filter loop for 1 hour while being maintained at 30° C. The resulting cake was washed with 7% aqueous acetic acid (75 L). The filtered solution was transferred to another stirred-tank reactor to be used in the next step.Part C. Formation of Zilpaterol Free Base

Figure US08362006-20130129-C00027

The stirred-tank reactor containing the product from Part B was purged 3 times with N2 between high pressure (2 bar, absolute) and low pressure (1 bar, absolute) for 10 minutes each. Then a pressure of 0.9 bar (absolute) was established. Next, the mixture was concentrated by distillation to 30-70%. The concentrated mixture was cooled to 65° C. Ethanol (331 L) was charged to the reactor, and the resulting mixture was cooled to 50° C. The pH was adjusted to 10 using 25% NaOH. This caused zilpaterol free base to precipitate. The temperature was decreased to 0° C. to facilitate the precipitation, and maintained at that temperature for an additional hour. The solids were filtered off, and washed with water (700 L).Example 6 Synthesis of an HCl Salt of the ZilpaterolThe free base of zilpaterol is dissolved in ethanol. Subsequently, ethyl acetate saturated with HCl is added. The resulting mixture is vacuum-filtered to obtain a crude product containing the HCl salt of the zilpaterol. The crude product is dissolved in hot methanol. Ethyl acetate is then added, and the mixture is filtered to obtain the final HCl salt product.

Example 7 First Illustration of a Contemplated Suitable Dosage FormA tablet is prepared containing 2.5 or 5 mg of the HCl salt of Example 6, and sufficient excipient of lactose, wheat starch, treated starch, rice starch, talc, and magnesium stearate for a final weight of 100 mg.

Example 8 Second Illustration of a Contemplated Suitable Dosage FormGranules are prepared containing 12.5 or 25 of the HCl salt of Example 6 in each daily dose of granules.

Example 9 Third Illustration of a Contemplated Suitable Dosage FormThe HCl salt of Example 6 is crystallized using the methodology discussed U.S. Pat. No. 5,731,028 for making crystalline racemic trans zilpaterol. Less than 5% of the crystals have a size of less than 15 μm, and at least 95% of the crystals have a size of less than 250 μm. A premix of the crystalline HCl salt secured to a 300-800 μm corn cob support is then obtained using the methodology discussed in European Patent 0197188 (incorporated by reference into this patent). The concentration of the HCl salt in the premix is 3% (by weight).

Cited Patent Filing date Publication date Applicant Title
US4585770 12 Oct 1983 29 Apr 1986 Roussel Uclaf Novel 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-j-k][1]-benzazepin-2-(1H)-one
US5731028 6 Jun 1996 24 Mar 1998 Roussel Uclaf Crystallized zilpaterol hydrochloride
US20060040950 17 Dec 2003 23 Feb 2006 Janssens Frans E Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
US20080267942 * 11 Apr 2008 30 Oct 2008 Pfizer Limited Benzazepin-2(1h)-one derivatives
US20100173892 * 31 Jan 2008 8 Jul 2010 Juan Jose Almena-Perea Enantioselective synthesis of 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-JK][1]-benzazepin-2[1H]-one and zilpaterol
WO2004056799A2 17 Dec 2003 8 Jul 2004 Janssen Pharmaceutica N.V. Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
WO2008119754A1 28 Mar 2008 9 Oct 2008 Intervet International B.V. Processes for making zilpaterol and salts thereof

////////US 8362006,  Intervet International B.V., Boxmeer, The Netherlands, Zilpaterol, PATENT

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Gefitinib, US 8350029, CIPLA

 PATENTS  Comments Off on Gefitinib, US 8350029, CIPLA
Sep 022016
 

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US 8350029

http://www.google.co.in/patents/US8350029

Inventors Dharmaraj Ramachandra Rao, Rajendra Narayanrao Kankan, Srinivas Laxminarayan Pathi,
Original Assignee Cipla Limited

CIPLA Limited, Mumbai, India
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Gefitinib is an anilinoquinazoline which is useful in the treatment of a certain type of lung cancer (non-small cell lung cancer or NSCLC) that has not responded to chemotherapy. The chemical name for gefitinib is 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline. Its structural formula is:

Figure US08350029-20130108-C00005

The earliest known synthesis of gefitinib was first disclosed in the patent application WO 96/33980. The synthetic method employed is depicted in the following reaction scheme 1.

Figure US08350029-20130108-C00006

The process involves selective demethylation of 6,7-dimethoxy quinazoline-4-one using methanesutfonic acid and L-methionine to get its 6-hydroxyl derivative, which is protected by acetylation. The acetoxy compound is chlorinated and condensed with chloro-fluoroaniline. Hydrolysis of the acetoxy compound followed by etherification with 3-morpholinopropyl chloride gives crude gefitinib which is purified by column chromatography. The process suffers from many disadvantages as it involves several protection and deprotection steps. The selective demethylation using methionine results in isomeric impurities and has to be purified or else the impurity carries over to subsequent steps in the preparation of gefitinib making it more difficult to isolate a pure product. The process also leads to formation of an N-alkylated impurity at the final stage which must be separated by column chromatography to obtain gefitinib.

Several other approaches are also described in the literature to make gefitinib.

WO 2004/024703 discloses a process for the preparation of gefitinib starting from 3-hydroxy-4-methoxy benzonitrile which involves condensation of 3-hydroxy-4-methoxy benzonitrile with morpholino propyl chloride, nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclisation in the presence of formamide to obtain quinazoline, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to obtain gefitinib. The process involves multiple steps and hence is time consuming.

WO 2005/023783 discloses a process for the manufacture of gefitinib starting from 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The process involves a rearrangement reaction of 3-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)3,4-dihydroqunazoline-4-imine. The process is not feasible industrially, as the basic raw material is not readily available on a commercial scale and involves the use of excess 3-chloro-4-fluoroaniline which is expensive. A further draw back of the process is in the isomerization of the 4-imine compound which requires anhydrous conditions at high temperature for a longer duration of 96 hours. All the problems associated with this prior art process are overcome by the novel process of the present invention.

WO2005/070909 discloses a process for the preparation of gefitinib starting from isovanillin as depicted in scheme 2

Figure US08350029-20130108-C00007

The WO’ 909 process has disadvantages as it forms cis-trans geometrical isomers of the oxime, which have different reactivities. Furthermore, the process uses a large excess of acetic anhydride to convert the oxime to the nitrile at higher temperature.

The patent applications 901/CHE/2006 and 903/CHE/2006 disclose another route for preparing gefitinib starting from isovanillin. The process involves formation of a formamido compound [N′-[2-cyano-4-{3-(4-morpholinyl)propoxy}phenyl]-N,N-dimethyl formamide], which is unstable and may result in undesired impurities in the final condensation with 3-chloro-4-fluoro aniline, thereby making the process less feasible on an industrial scale.

The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making gefitinib which is suitable for industrial scale-up.

The process of the present invention avoids use of reagents such as sodium dithionite, acetic anhydride and allows substantial reduction in the number of problems associated with these reagents.

Process for Preparation of Gefitinib
Gefitinib, 66, is used in the treatment of certain types of lung cancer, and a number of methods are reported for its synthesis. These are described as cumbersome and can require excessive amounts of reagents or involve difficult purification methods. Some processes use reagents such as sodium dithionite or Ac2O, and these are said to create problems. This patent discloses two routes for the synthesis of 66 that are claimed to avoid such problems. The first route, shown in Scheme 22, is the subject of the claims of the patent and starts with the nitration of isovanillin 57ain HOAc to give 57b that is recovered in 65% yield. Treatment of 57b with 58 produces 59a that is isolated in 92% yield, and this is then oxidised with H2O2 to form the acid 59b that is isolated in 86% yield. Reduction of the nitro group is then carried out to give 60, and there are three methods described for this reaction. The first is catalytic hydrogenation with Pd/C that gives a 90% yield of60. The reaction pressure is reported as being 5–6 kg, a common term in India used as short-hand for the pressure unit of kg/m2. Reduction using H2NNH2 in the presence of FeCl3, Al2O3, and charcoal gives a 83.6% yield of 60. In a hydrogen-transfer reaction with HCO2NH4 and Pd/C compound, 60 is recovered in 84.5% yield. The cyclisation of 60 to form 61 is carried out in a Niementowski reaction using HCO2NH4 and HCO2NH2, and the product is recovered in 90% yield. Reaction of 61 with SOCl2 produces 62, and this is isolated in 95% yield. Only the main reagents are shown in the scheme, and workup details are omitted.

Figure

Scheme 22. a

aReagents and conditions: (a) (i) HNO3, HOAc, −5 °C; (ii) 30 °C, 12 h. (b) K2CO3, MeCN, reflux, 4 h. (c) (i) 30% NaOH/MeOH, 45 °C; (ii) add 35% H2O2 over 4 h, 45 °C, pH 11. (d) Pd/C, H2, EtOAc, 40 °C, 4 h. (e) HCO2NH4, HCO2NH2, 180 °C, 4 h. (f) SOCl2, DMF, reflux, 8 h.

In the next stage of the synthesis, shown in Scheme 23, compound 62 is reacted with morpholine63 to give 64 in 85% isolated yield. In the final step 64 is reacted with 65 to produce 66 that is recovered in 70% yield (purity not reported).

Figure

Scheme 23. a

aReagents and conditions: (a) (i) 75 °C, 8 h; (ii) cool to rt, add H2O; (iii) separate extract in DCM, H2O wash, dry, evaporate. (b) MeOH, 30 °C, 0.25 h; (ii) add 65, reflux 6 h; (iii) add HCl at 20 °C; (iii) <10 °C, 0.5 h; (iv) filter, MeOH wash; (v) dissolve in PhMe/MeOH, concentrate; (vi) cool <10 °C, filter, PhMe wash, dry.

The patent also describes an alternative route to 66 that is outlined in Schemes 24 and 25although it is not covered by the patent claims. The route starts with the oxidation of 57a using H2O2 to give the acid 67a that is esterified to form 67b that is isolated in 83% yield. Nitration of67b with HNO3 in HOAc produces 68a that is isolated in 74% yield and then reduced to 68b over Pd/C. The amine 68b is recovered in 93% yield and then reacted with 69 to give the quinazoline70a that is recovered in 92% yield and then acetylated to form 70b. There is no example describing this acetylation nor are there any for the remaining steps of this route shown in Scheme25, and the reactions are just generally referred to in the text.

Figure

Scheme 24. a

aReagents and conditions: (a) (i) 30% NaOH/MeOH, 45 °C; (ii) add 35% H2O2 over 3 h, 45 °C, pH 11. (b) 10% HCl/MeOH, reflux, 6 h. (c) 70% HNO3, HOAc, −5 °C, 18 h. (d) Pd/C, H2, EtOAc, 40 °C, 4 h. (e) MeOH, reflux, 10 h. (f) No details.

Figure

Scheme 25. a

aReactions: (a) Chlorination. (b) Condensation. (c) Hydrolysis. (d) Coupling.

The examples report experiments carried out on a reasonable scale with some producing up to 200 g of products. Unfortunately, there are no details of the purity of any of the intermediates, and although the patent states that the desired final product 66 is purified by acid/base treatment or crystallisation, there are no details provided.

Advantages

The process does avoid the use of some difficult reagents used elsewhere, but whether the process gives a higher-purity product than alternatives is not clear.

scheme 3.

Figure US08350029-20130108-C00025

scheme 4.

Figure US08350029-20130108-C00033

EXAMPLE 1 Preparation of 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline (gefitinib) (Formula I)Methanol (1200 ml) and 6-(3-morpholino propoxy)-7-methoxy-4-chloro quinazoline (200 gm) were stirred for 15 minutes at 25-30° C., then a solution of 4-fluoro-3-chloroaniline in methanol (213 gm in 400 ml) was charged and refluxed for 6 hours. The reaction mass was cooled to 15-20° C., hydrochloric acid (40 ml) was added drop wise, and stirred at 5-10° C. for 30 minutes. The solid obtained was filtered and washed with chilled methanol (150 ml). The solid was dissolved in a mixture of toluene (30 volume) and methanol (5 volume), the reaction mass was concentrated to half the volume and cooled to 5-10° C. The solid obtained was filtered, washed with toluene (200 ml) and dried at 45-50° C. to yield the title compound (183 gm, 70% yield).

EXAMPLE 2 Preparation of 6-(3-morpholino propoxy)-7-methoxy-4-chloroquinazoline (Formula VII)DMF (3 lt), 6-(3-chloropropoxy)-7-methoxy-4-chloro quinazoline (200 gm) and morpholine (210 gm), were heated to 70-75° C. for 6-8 hours. The reaction mass was cooled to room temperature, and methylene chloride (2.5 lt) and water (2.5 lt) were charged. The layers separated and the aqueous layer extracted with methylene chloride twice (500 ml). The combined methylene chloride layer was washed with water, dried over sodium sulphate (10 gm) and concentrated completely at 35-40° C. to yield the title compound (200 gm, 85% yield).

EXAMPLE 3 Preparation of 6-(3-chloropropoxy)-7-methoxy-4-chloroquinazoline (Formula VI)6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (400 gm), thionyl chloride (3.2 lt) and DMF (100 ml) were refluxed for 7-8 hours. Thionyl chloride was distilled off completely under reduced pressure below 45° C. Methylene chloride (2.5 lt) and water (1.5 lt) were charged, stirred for 30 minutes at room temperature and the layers separated. The aqueous layer was extracted twice with methylene chloride (500 ml), the combined methylene chloride layer was washed with 1% sodium bicarbonate solution (1 lt), dried over sodium sulphate (20 gm) and concentrated under reduced pressure at 35-40° C. The residue was stirred with isopropyl alcohol (400 ml) at 40-45° C. for 1 hour, cooled to 0-5° C., the solids filtered, washed with chilled isopropyl alcohol (200 ml) and dried under vacuum at 45° C. to yield the title compound (406 gm, 95% yield).

EXAMPLE 4 Preparation of 6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (Formula V)2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (450 gm), formamide (2250 ml) and ammonium formate (200 gm) were heated to 170-180° C. for 3-4 hours. The reaction mass was concentrated under reduced pressure at 140-150° C. The residue was stirred in methanol (1000 ml) at 45-50° C. and cooled to 5-10° C. The solid obtained was filtered to yield the title compound (420 gm, 90% yield).

EXAMPLE 5 Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (Formula IV) a) Preparation of 3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acidMethanol (4 lt), 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (560 gm) and 30% methanolic NaOH solution (5 ml) were heated to 45° C. To this reaction mass 35% of H2O2 solution (1200 ml) was added drop wise in 3-4 hours maintaining a pH of 10.5-11.5 with 30% methanolic NaOH solution. The reaction mass was quenched into ice water (10 kg) and the pH adjusted to 2.0-3.0 using hydrochloric acid. The solid obtained was filtered, washed with 50% aqueous methanol (500 ml) and dried at 45-50° C. to yield the title compound (510 gm, 86% yield).

bi) Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid—Using Hydrogen GasEthyl acetate (3 lt), Pd/C (50 gm) and 3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acid (500 gm) were hydrogenated under a hydrogen pressure of 5-6 kg at 35-40° C. for 3-4 hours. The reaction mass was filtered and the clear filtrate was distilled under reduced pressure at 45-50° C. To the residue, hexane (1 lt) was charged, stirred at room temperature, the solids filtered and dried at 45-50° C. to yield the title compound (403 gm, 90% yield).

(bii) Preparation of 2-amino-4methoxy-5-(3-chloropropoxy)benzoic acid—Using Hydrazine Hydrate3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acid (100 gm), hydrazine hydrate (50 gms), neutral alumina (20 gms), charcoal (10 gms), water (50 ml) and methanol (500 ml) were mixed together. The reaction mass was heated to 50° C. A solution of ferric chloride (2 gms, 0.012M) in 50 ml methanol was introduced slowly at 55-60° C. The reaction mass was filtered over hyflo and the clear filtrate evaporated. The residue obtained was dissolved in 1.0-lit ethyl acetate, washed organic extract with water, evaporated to obtain title compound. (75 gms, 83.6%)

(biii) Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid—Using Ammonium Formate3-(3-chloropropoxy)-4-methoxy-6-nitro benzoic acid (165 gms), 5% Paladium on carbon (16.5 gms) and DMF (0.66 lit) were mixed together. The reaction mass was heated to 40° C. Ammonium formate (82.5 gms) was charged in lots maintaining temperature below 50° C. The temperature of reaction mass slowly raised to 70° C. and maintained for 2 hours. The reaction mass was cooled to 30° C. and catalyst was removed by filtration and the clear filtrate evaporated. The residue was dissolved in ethyl acetate (0.825 lit), washed with water and evaporated to yield the title compound. (125 gms, 84.5%)

EXAMPLE 6 Preparation of 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (Formula III)5-nitro isovanillin (500 gm), acetonitrile (3.5 lts), K2CO3 (750 gm) and chlorobromopropane (780 gm) were refluxed for 4 hours. The reaction mass was filtered hot, washed with acetonitrile (1 lt) and the filtrate was distilled off to remove solvent. The residue was dissolved in methylene chloride (4 lt) and washed with water. Water (3 lt) was charged to the methylene chloride layer, the pH adjusted to 7.0 to 7.5 with acetic acid, the methylene chloride layer separated, dried over sodium sulphate (50 gm) and distilled out completely under reduced pressure below 40° C. The residue was stirred with 2 volumes of n-Hexane at 40-45° C., cooled slowly to 0-5° C., the solids filtered, washed with n-Hexane (250 ml) and dried at 40-45° C. to yield the title compound (638 gm, 92% yield).

EXAMPLE 7 Preparation of 5-nitro isovanillin (Formula II)Isovanillin (500 gm) and acetic acid (1750 ml) were cooled to −5 to 0° C. To this solution, nitric acid (750 ml) was charged slowly at −5 to 0° C. with stirring. The temperature of the reaction mass was slowly raised to 25-30° C. and maintained for 12 hours. The reaction mass was quenched into ice water (4 kg), the solids filtered and washed with water (2 lt). The solids were stirred with a 1% sodium bicarbonate solution (1 lt), filtered and dried at 45-50° C. The solid was dissolved in 6 volumes of ethyl acetate, ethyl acetate was distilled off up to half the volume and 3 volumes of n-Hexane were charged slowly at 45-50° C. The reaction mass was cooled slowly to 0-5° C., maintained for 1 hour, the solids filtered, washed with 0.5 volumes of 1:1 mixture of ethyl acetate:n-Hexane and dried at 45-50° C. to yield the title compound (423 gm, 65% yield).

EXAMPLE 8 Preparation of Methyl-2-hydroxy-3-methoxy benzoate (Formula VIII) a) Preparation of 3-hydroxy-4-methoxy benzoic acidMethanol (350 ml), isovanillin (50 gm) and 30% methanolic sodium hydroxide solution (1 ml), were heated to 45° C. To this solution, 35% hydrogen peroxide solution (107 ml) was charged slowly maintaining pH at 10.5 to 11.5 using methanolic sodium hydroxide solution over a period of 2-3 hours. The reaction mass was quenched into chilled water (1 lt) and the pH adjusted to 2-3 using hydrochloric acid. The solids were filtered, washed with 50% aqueous methanol (50 ml) and dried at 45-50° C. to yield 3-hydroxy-4-methoxy benzoic acid.

b) Preparation of Methyl-2-hydroxy-3-methoxy benzoateThe solid obtained in step a), was refluxed with 10% methanolic hydrochloric acid solution (250 ml) for 6 hours. The reaction mass was quenched into chilled water (1 lt) and repeatedly extracted with methylene chloride (250 ml). The combined methylene chloride layer was washed with water (100 ml×2) and methylene chloride distilled out completely at 35-40° C. The residue was stirred in hexane (1.50 ml), at 25-30° C. The solid obtained was filtered, washed with: hexane (25 ml) and dried at 40-45° C. to yield the title compound (50 gm, 83% yield).

EXAMPLE 9 Preparation of Methyl-5-hydroxy-4-methoxy-2-nitro benzoate (Formula IX)Methyl-2-hydroxy-3-methoxy benzoate (50 gm) and acetic acid (175 ml) were cooled to 0-5° C. To this solution, 70% nitric acid solution (75 ml) was charged slowly at 0-5° C. under stirring and the reaction mass was further stirred for 18 hours. The reaction mass was quenched into chilled water (800 ml) and extracted repeatedly with methylene chloride (400 ml). The combined methylene chloride layer was washed with water, followed by 1% potassium carbonate solution (100 ml), dried over sodium sulphate and methylene chloride distilled off completely at 35-40° C. The residue was dissolved in 10% aqueous methanol (250 ml). The filtrate was gradually cooled to 0-5° C. and maintained for 1 hour. The solid obtained was filtered, washed with 10% aqueous methanol (100 ml) and dried at 40-45° C. to yield the title compound (46 gm, 74% yield).

EXAMPLE 10 Preparation of Methyl-2-amino-5-hydroxy-4-methoxy benzoate (X)Ethyl acetate (300 ml), methyl-5-hydroxy-4-methoxy-2-nitro benzoate (50 gm) and 10% palladium/carbon (5 gm) were hydrogenated under a hydrogen gas pressure of 5-6 kg for 4 hours. The reaction mass was filtered to remove catalyst. The filtrate was distilled off to remove solvent. The residue obtained was stirred in n-hexane (100 ml) at 0-5° C. The solid obtained was filtered and washed with n-hexane (25 ml) to yield the title compound (40 gm, 93% yield).

EXAMPLE 11 Preparation of 6-hydroxy-7-methoxy-quinazoline-4-one (formula XI)Methyl-2-amino-5-hydroxy-4-methoxy benzoate (50 gm), methanol (400 ml) and formamidine acetate (30 gm) were refluxed for 10 hours. The reaction mass was gradually cooled to 5-10° C. and stirred for 1 hour. The solid obtained was filtered and washed with methanol (150 ml) and dried at 50-55° C. to yield the title compound (45 gm, 92% yield).

Cited Patent Filing date Publication date Applicant Title
US6297257 17 Dec 1998 2 Oct 2001 Zambon Group S.P.A. Benzazine derivatives phosphodiesterase 4 inhibitors
EP1477481A1 28 Jan 2003 17 Nov 2004 Ube Industries, Ltd. Process for producing quinazolin-4-one derivative
IN901CHE2006A Title not available
IN903CHE2006A Title not available
WO1996033980A1 23 Apr 1996 31 Oct 1996 Zeneca Limited Quinazoline derivatives
WO2004024703A1 9 Sep 2003 25 Mar 2004 Astrazeneca Ab Process for the preparation of 4- (3’-chloro-4’-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline
WO2005023783A1 1 Sep 2004 17 Mar 2005 Astrazeneca Ab Process for the manufacture of gefitinib
WO2005070909A1 27 Jul 2004 4 Aug 2005 Natco Pharma Limited An improved process for the preparation of gefitinib
WO2008125867A2 16 Apr 2008 23 Oct 2008 Cipla Limited Process for the preparation of gefitinib
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PATENT, US 8344136, PHF S.A., Brinzolamide

 PATENTS  Comments Off on PATENT, US 8344136, PHF S.A., Brinzolamide
Sep 022016
 

 

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US 8344136

http://www.google.co.in/patents/US8344136


PHF S.A., Lugano, Switzerland
Image result for PHF S.A.,
Process for the Preparation of Brinzolamide

Brinzolamide is a carbonic anhydrase II inhibitor, used to lower intraocular pressure and glaucoma. It is sold by Alcon under the name of Azopt, as 1% ophthalmic suspension.

EP 527801 claims Brinzolamide and describes a process to prepare it in 14 steps starting from 3-acetylthiophene (scheme 1). It is a synthesis typical of medicinal chemistry not applicable at industrial level, for which no specific preparations are described, because Brinzolamide is not among the preferred compounds of the invention.

Figure US08344136-20130101-C00001
Figure US08344136-20130101-C00002

This synthesis is not very efficient because requires the change of the oxidation status of the functional group in position 4 for three times; indeed this is first reduced with Sodium borohydride (step (5)) to α-bromoalcohol and then oxidized with Sodium dichromate (step (11)), a very toxic reagent. This sequence is necessary to obtain the cyclization (6), which brings only to degradation products on the ketone, and which requires a complex and not much efficient procedure as far as the quality and yield of the isolated product is concerned. The second reduction (12) occurs in the presence of (+)-β-chlorodiisopinocamphenylborane, an expensive enantioselective reducing agent, with a stoichiometric excess of 5:1, which requires reaction conditions not easily achievable at industrial scale (3 days of reaction at −22° C., difficult work up and chromatography) to isolate the product.

It can be inferred from the patent that there is the possibility to fix the stereogenic centre through selective crystallization of the salt of a chiral acid as di-p-toluoyl-D-tartaric acid, expensive resolution agent, with consequent loss of at least half of the substrate.

EP 617038 describes a process for the preparation of Brinzolamide and its analogues starting from 3-acetyl-2,5-dichlorothiophene (scheme 2).

Figure US08344136-20130101-C00003
Figure US08344136-20130101-C00004

The reduction (6) with (+)-β-chlorodiisopinocamphenylborane and the cyclization (7) bring to the optically active alcohol 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-, 1,1-dioxide, (4S)-. The formation of a product enriched with one of the enantiomer is too early in the synthesis, with a consequent risk of racemisation during the following steps, while the reduction would be more efficient if performed on a more advanced intermediate. The disadvantages of the use of the enantioselective reducing agent (6) and of the cyclization of the alcohol (7) are the same of the method described in Scheme 1. Another disadvantage is the alkylation (8) with 1-bromo-3-methoxypropane, that, in order to avoid the reaction of the oxydrilic group, is performed portionwise, with low temperatures and long reaction times.

The sulfonamide is introduced in position 6 through metallation with n-butyl lithium, an expensive raw material, and then with a reaction with sulphurous anhydride and hydroxylamino-O-sulphonic acid. The base should be used in substantial excess (2,3 eq.), because the oxydrilic group reacts with the first equivalent. In this case the protection of the oxydrilic group as described in Scheme 1 is not possible without running the risk of racemization of the substrate.

Lastly, the conversion of the secondary alcohol to the amine is difficult and requires the protection (10) of the primary sulfonamide with trimethyl orthoacetate, the activation (11) of the oxydrilic group with tosyl chloride and finally the substitution (12) of the tosyl group with ethylamine and at the same time the aminolysis of the protection of sulfonamide with the excess of ethylamine.

This synthesis is described in Org. Process Res. Dev. 3, 1999, 114, written by the R&D laboratories of Alcon. So it is reasonable to believe that this synthesis is used by Alcon at industrial level. Anyway, due to the low purity of the product obtained (97%), several crystallizations are needed to have a product of acceptable pharmaceutical grade.

U.S. Pat. No. 5,470,973 describes a variant of the synthesis in scheme 1, which involves an alternative preparation of the syntone 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (4S)- and the other analogues lacking chlorine in position 6 or the 3-methoxypropylic chain (scheme 3).

Figure US08344136-20130101-C00005

To introduce the chiral centre, firstly the oxidation (8) with dichromate is performed, and then the stereoselective reduction (9) with (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrol[1,2-c][1,3,2]oxazaborole are performed. The need of oxidizing first and then reducing was already commented in the description of the first synthetic path; the low enantiomeric excess (92%) is another disadvantage.

So it is evident the need of an alternative process for the preparation of Brinzolamide which can resolve the above mentioned technical problems.

OVERVIEW
Brinzolamide, 56, is used to treat glaucoma and can be synthesised by a 14-step route from acetylthiophene. This route is described as inefficient because of several changes of the oxidation state of one of the functional groups. Other routes have fewer steps but are still not very efficient. This patent describes a method for making compounds that are intermediates in the synthesis of56. The route is outlined in Schemes 20 and 21 and starts from the thiophene 49a or its chloro-derivative 49b (X = Cl). The first step is protection of the carbonyl group in 49a by reaction with 50to form 51a that is isolated in 87% yield. In the next step 51a is treated with K2CO3 to effect intermolecular cyclisation and formation of 52a. This can be obtained in 90% yield, or the reaction mixture can be treated with 53 without isolation of 52a to form 54a that is isolated 90% yield.

Figure

Scheme 20. a

aReagents and conditions: (a) (i) TsOH, PhMe, reflux, 12 h; (ii) cool to rt, add Et3N, separate; (iii) H2O wash, evaporate. (b) (i) K2CO3, DMSO, 60 °C, 1 h; (ii) add H2O/EtOAc, acidify to pH 7; (iii) separate, H2O wash, evaporate. (c) (i) 60 °C, 8 h; (i) add H2O/PhMe, separate; (iii)H2O wash, evaporate.

The next stage is the introduction of the second sulphonamide group as shown in Scheme 21. This begins with treatment of 54a with BunLi followed by addition of liquid SO2. The intermediate reaction product is isolated as a solid and then treated with H2NOSO3H to form 54c that is recovered in 76% yield. The protective diol group is then removed by acid hydrolysis to give 55a in 97% yield. The conversion of 55a to 56 is not described in the patent, and reference to alternative syntheses of 56 indicate that this proceeds via asymmetric reduction of 56 to a hydroxy group that is then converted to the amine.

Figure

Scheme 21. a

aReagents and conditions: (a) BunLi, THF, −40 °C, 1 h; (ii) SO2, −40 °C; (iii) warm to rt, evaporate; (iv) add H2O, wash in DCM; (v) H2NOSO3H, NaOAc, H2O, rt, 8 h; (vi) extract in EtOAc, wash in aq NaHCO3, H2O wash; (vii) evaporate. (b) (i) Aq HCl, PhMe, 80 °C, 16 h; (ii) separate, evaporate. (c) No details.

Compound 55a can be prepared by the same sequence of reactions shown in Schemes 20 and21 when starting from 49b. The yields of the corresponding intermediates are similar to or better than those reported for the method starting from 49a. The patent does not indicate the scale of the reactions, and the examples merely state the amounts of reactants used in terms of equivalents. The purity of the intermediates is not given, although 1H NMR data are provided. The patent does not disclose how to obtain either of the starting materials, 49a or 49b, that are unlikely to be commercially available, and their synthesis will presumably add more steps to the synthesis of 56.

Advantages

The process provides an alternative route to the desired compound, but whether it is commercially viable and more efficient is not known.

Example 7 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide 9 (X=sulphonamide)

Figure US08344136-20130101-C00024

The desired compound is prepared according to general procedure 4 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 5 with a yield of 76%.

1H-NMR (300 MHz, DMSO-d6): 8.05 (s, 2H), 7.59 (s, 1H), 4.16 (m, 2H), 4.07 (m, 2H), 3.87 (s, 2H), 3.4-3.3 (m, 4H), 3.21 (s, 3H), 1.81 (m, 2H).

LC-MS: [M+H]+=399.

Example 8 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide 9 (X=sulphonamide)

Figure US08344136-20130101-C00025

The desired compound is prepared according to general procedure 4 starting from 6′-chloro-2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 6 with a yield of 89%.

General Procedure 5 Hydrolisis of the Protective GroupThe compound of formula 5 is dissolved in toluene (10-20 volumes) and an aqueous solution of hydrochloric acid 2-12 N is added. The mixture is stirred at a temperature which can vary between 20° C. and 80° C. for a time between 2 and 16 ore, until complete hydrolysis. The phases are separated and the product 1 is isolated through distillation of the organic solvent under vacuum, obtaining a solid with a HPLC assay of 85-95% and a yield of 65-99%.

Example 9 4H-thieno[3,2-e]-1,2-thiazin-4-one, 2,3-dihydro-, 1,1-dioxide 1 (X and R=hydrogen)

Figure US08344136-20130101-C00026

The desired compound is prepared according to the general procedure 5 starting from 2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 3 with a yield of 66%.

1H-NMR (300 MHz, DMSO-d6): 8.90 (bt, 1H), 7.98 (d, 1H), 7.46 (d, 1H), 4.23 (d, 2H).

LC-MS: [M+H]+=204.

Example 10 4H-thieno[3,2-e]-1,2-thiazin-4-one, 6-chloro 2,3-dihydro-, 1,1-dioxide 1 (X=chlorine and R=hydrogen)

Figure US08344136-20130101-C00027

The desired compound is prepared according to general procedure 5 starting from 6′-chloro-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 4 with a yield of 95%.

1H-NMR (300 MHz, DMSO-d6): 9.08 (bs, 1H), 7.56 (s, 1H), 4.26 (d, 2H).

GC-MS: [M]+•=237.

Example 11 4H-thieno[3,2-e]-1,2-thiazin-4-one, 2,3-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide 5 (X=hydrogen)

Figure US08344136-20130101-C00028

The desired compound is prepared according to the general procedure 5 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 5 with a yield of 97%.

1H-NMR (300 MHz, DMSO-d6): 8.05 (d, 1H), 7.49 (m, 1H), 4.58 (s, 2H), 3.3-3.1 (m, 7H), 1.73 (m, 2H).

LC-MS: [M+H]+=276.

Example 12 4H-thieno[3,2-e]-1,2-thiazin-4-one, 6-chloro 2,3-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide 5 (X=chlorine)

Figure US08344136-20130101-C00029

The desired compound is prepared according to the general procedure 5 starting from 6′-chloro-2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 6 with a yield of 99%.

1H-NMR (300 MHz, DMSO-d6): 7.59 (s, 1H), 4.50 (s, 2H), 3.3-3.2 (m, 4H), 3.18 (s, 3H), 1.74 (m, 2H).

LC-MS: [M+H]+=310.

Example 13 2H-thieno[3,2-e]-1,2-thiazin-6-sulphonamide, 3,4-dihydro-2-(3-methoxypropyl)-4-oxo-, 1,1-dioxide 5 (X=Sulphonamide)

Figure US08344136-20130101-C00030

The desired compound is prepared according to the general procedure 5 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide of examples 7 or 8 with a quantitative yield.

1H-NMR (300 MHz, DMSO-d6): 8.20 (s, 2H), 7.77 (s, 1H), 4.54 (s, 2H), 3.4-3.1 (m, 7H), 1.78 (m, 2H).

LC-MS: [M+H]+=355.

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Carbotegravir, Dolutegravir, New Patent, WO 2016113372, Lek Pharmaceutical and Chemical Co DD

 PATENTS  Comments Off on Carbotegravir, Dolutegravir, New Patent, WO 2016113372, Lek Pharmaceutical and Chemical Co DD
Jul 252016
 

 

WO 2016113372

Carbotegravir, New Patent, WO 2016113372, Lek Pharmaceutical and Chemical Co DD

LEK PHARMACEUTICALS D.D. [SI/SI]; Verovskova 57 1526 Ljubljana (SI)

MARAS, Nenad; (SI).
SELIC, Lovro; (SI).
CUSAK, Anja; (SI)

ViiV Healthcare is developing cabotegravir (first disclosed in WO2006088173), which in July 2016, was reported to be in phase 2 clinical development.

WO-2016113372

Process for preparing integrase inhibitors such as dolutegravir and cabotegravir and their analogs, useful for treating viral infections eg HIV infection. Also claims a process for preparing intermediates of dolutegravir and cabotegravir.

(4R, 12aS)-N-[(2,4-Difluorophenyl)methyl]-3 ,4,6,8, 12, 12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1-b][1 ,3]oxazine-9-carboxamide (Formula A):

Formula A

known by the INN name dolutegravir, is a new efficient antiviral agent from the group of HIV integrase inhibitors which is used in combination with some other antiviral agents for treatment of HIV infections, such as AIDS. The compound, which belongs to condensed polycyclic pyridines and was first disclosed in WO2006/1 16764, is marketed.

Another compound disclosed in WO2006/1 16764 is (3S, 1 1 aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 1 1 ,1 1 a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide (Formula

Formula C

known by the INN name cabotegravir.

The complex structures of dolutegravir and cabotegravir present a synthetic challenge. The first description of the synthesis in WO2006/1 16764 shows a 16-steps synthesis (see Scheme A), which is industrially impractical due to its length and low overall yield.

Scheme A

WO 2010/068253 and WO 2006/1 16764 describe an alternative synthesis. The 1 1 -step synthesis, shown in Scheme B1 and Scheme B2, is based on bromination of the 9-position for further introduction of the carboxylic group. The synthesis relies on the use of expensive palladium catalysts and toxic selenium compounds. Furthermore, some variations of these approaches involve pyrone intermediates in several steps. In some cases pyrones are liquids which can complicate purification, while further reactions form complex mixtures.

doiutegravir

Scheme B2

In further alternative syntheses, acetoacetates were used as starting materials. Such an approach is challenging in terms of introducing the hydroxy group in the 7-position. The variation in Scheme C1 , described in WO2012/018065, starts from 4-benzyloxyacetoacetate. The procedure requires 9 steps, but use expensive reagents like palladium catalysts. Moreover, there is described a possibility of formation a co-crystal between an intermediate and hydroquinone, wherein however the additional step may diminish yields and make the process longer and time consuming.

Scheme C1

The variation in Scheme C2, described in WO2012/018065, starts from 4-chloroacetoacetate. The process is not optimal because of problems in steps which include pyrones and because of problems with conversion of 7-chloro to 7-hydroxy group which includes a disadvantageous use of silanolates with low yield (25%).

Scheme C2

The variation in Scheme C3, described in WO201 1/1 19566, starts from unsubstituted acetoacetate. For the introduction of the 7-hydroxy group, bromination is used and substitution of bromo with hydroxy is performed by a use of silanolates. The substitution of the bromine is achieved in a 43% yield.

Scheme C3

The variation in Scheme C4, described in WO201 1/1 19566, starts from 4-methoxyacetoacetate aiming at preparing dolutegravir or cabotegravir. The process uses lithium bases to affect a difficult to control selective monohydrolysis of a diester.

The object of the present invention is to provide short, simple, cost-effective, environmentally friendly and industrially suitable processes for beneficially providing dolutegravir and analogues thereof and cabotegravir and analogues thereof, in particular dolutegravir.

 

Scheme 1

According to an embodiment of the process of the invention the building block 3-aminobutanol can suitably be substituted with other aminoalcohols to give dolutegravir analogues. For example, using (S)-alaninol gives cabotegravir as the final product. Similarly, using amines other than 2,4-difluorobenzylamine in the amidation step results in the synthesis of other dolutegravir analogues.

According to the another preferred embodiment cabotegravir or a pharmaceutically acceptable salt thereof is prepared by the analogue process, which comprises providing a compound of formula (5c)

5c

converting the compound of formula (5c) to a compound of formula (6c)

6c

by carrying out a chlorination reaction, and converting the compound of formula (6c) to cabotegravir and/or a pharmaceutically acceptable salt thereof.

The compound of formula (5c) can preferably be provided by converting a compound of formula (3) to a compound of formula (4c)

 

Scheme 2

1. ) EtOCOCI, Et3N / Me2CO

2. ) 2,4-difiuorobenzylamine

 

Scheme 3

Analogous compound of formula 7c is a useful intermediate in the synthesis of cabotegravir. Scheme 3a

 

Scheme 4

 

Examples

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way. The examples and modifications or other equivalents thereof will become apparent to those versed in the art in the light of the present entire disclosure. Particularly, all Examples related to the preparation of dolutegravir and intermediates thereof can be used by the analogy for the preparation of cabotegravir and intermediates thereof.

Example 1 :

Methyl acetoacetate (1 , 25.22 g) and dimethylformamide dimethyl acetal (DMFDMA, 35 mL) was heated at 50-55°C for 2 h, then methanol (60 mL), aminoacetaldehyde dimethyl acetal (24 mL) and acetic acid (4 mL) was added an the mixture was heated under reflux for one hour, then concentrated. MTBE (100 mL) was added and the mixture was kept at 5 °C overnight to crystallize. Upon filtration 46 g (92%) of product 2 was recovered.

1H NMR (DMSO-d6): δ 2.31 (s, 3H), 3.30 (s, 6H), 3.49 (m, 2H), 3.61 (s, 3H), 4.43 (m, 1 H), 8.02 (d, 1 H), 10.8 (bs, 1 H). 13C NMR (DMSO-d6): δ 30.52, 35.48, 50.53, 54.23, 98.99, 102.47, 160.70, 166.92, 197.21 .

Example 2:

Compound 2 (5.00 g) was dissolved in 2-propanol, dimethyl oxalate (7.02 g) was added and heated to 40 °C. Sodium methylate (25% in methanol; 20 mL) was slowly (10 min) added, the mixture was then heated to 50-55 °C and stirred at that temperature for 2-2.5 h. The mixture was cooled to ambient temperature, then sodium hydroxide solution (1 M, 65 mL) was added to the mixture and stirred for another 2 h, followed by addition of concentrated hydrochloric acid (1 1 mL) and stirred for another 2 h. The precipitate was filtered and dried to give 8.08 g (NMR assay 47%; 65% yield) of compound 3.

1H NMR (DMSO-d6): δ 2.50 (m, 2H), 3.30 (s. 6H), 4.49 (m, 1 H), 7.06 (s, 1 H); 8.70 (s, 1 H). 13C NMR (DMSO-d6): δ 55.23, 55.37, 102.34, 1 15.47, 120.24, 145.17, 162.71 , 165.22, 178.55.

Example 3:

Compound 2 (158.37 g) was dissolved in methanol (548 mL), followed by the addition of dimethyl oxalate (202.2 g). While keeping the temperature below 30°C, potassium ferf-butoxide (192.1 g) was added and reaction mixture was heated at 50 °C overnight. The suspension was then filtered and the filter cake washed with methanol. The filtrate was concentrated (approximately to 680 mL), then water (680 mL) was added, followed by addition of lithium hydroxide hydrate (143.7 g) while keeping the temperature below 40 °C. The suspension was then stirred at ambient temperature overnight and filtered. To the obtained filtrate, concentrated hydrochloric acid (339 mL) was added while keeping the temperature below 30 °C. The suspension was aged for 2 h and filtered to give 4 as a white powder (95.6 g, NMR assay 100%; 52% yield).

Example 4:

Compound 2 (5.00 g) was dissolved in 2-propanol, dimethyl oxalate (7.02 g) was added and heated to 40 °C. Sodium methylate (25% in methanol; 15 mL) was slowly (10 min) added then the mixture was heated to 50-55 °C and stirred at that temperature for 72 h. The mixture was concentrated and components were separated by flash column chromatography (ethyl acetate/methanol 9:1 to 6:4). Early fractions gave compound 22 upon concentration, late fractions gave compound 23.

Compound 22: 1H NMR (DMSO-d6): δ 2.49 (m, 2H), 3.28 (s, 6H), 3.73 (s, 3H), 3.85 (s, 3H), 4.41 (m, 1 H), 4.50 (m, 1 H), 6.65 (s, 1 H), 8.36 (s, 1 H). 13C NMR (DMSO-d6): δ 51.63, 53.36, 54.25, 55.47, 102.71 , 1 18.24, 123.60, 140.81 , 150.21 , 162.44, 164.49, 173.43.

Compound 23: 1H NMR (DMSO-d6): δ 2.49 (m, 2H), 3.26 (s, 6H); 3.70 (s, 3H); 4.33 (d, 1 H); 4.60 (m, 1 H), 6.19 (s, 1 H), 8.12 (s, 1 H). 13C NMR (DMSO-d6): δ 50.03, 51.34, 54.59, 54.85, 102.91 , 1 16.04, 1 18.19, 148.32, 152.12, 163.46, 165.24, 174.99

Example 5:

Compound 3 (5.5 g; assay 53%) was suspended in acetonitrile, acetic acid (6 mL) and methanesulfonic acid (2.5 mL) were added followed by the heating of mixture to 70 °C for 4 h. The suspension was filtered and filtrate cooled to ambient temperature. Triethylamine (6.6 mL) and (R)-3-amino-butan-1 -ol (1.24 mL) was added followed by heating the mixture at reflux temperature for 20-24 h. The mixture was filtered, filtrate concentrated and 1 M HCI (100 mL) was added, followed by extraction with dichloromethane (3 x 50 mL). Combined organic fractions were concentrated, 2-propanol was added (10 mL) and suspension was stirred at 70-80 °C for 10 min, left to cool to ambient temperature then filtered to give 2.19 g of compound 4 (73%).

1H NMR (DMSO-de): δ 1.31 (d, 3H), 1.52 (m, 1 H), 1 .97 (m, 1 H), 3.89 (m, 1 H), 4.01 (m, 1 H), 4.46 (m, 1 H), 4.64 (m, 1 H), 4.78 (m, 1 H), 5.50 (m, 1 H), 7.29 (s, 1 H), 8.88 (s, 1 H), 15.83 (s, 1 H). 13C NMR (DMSO-d6): δ 15.22, 29.14, 45.26, 51.13, 62.09, 76.03, 1 16.31 , 1 18.79, 140.53, 146.79, 155.36, 165.24, 178.75.

Example 6:

Compound 3 (14.55 g; assay 49%) was suspended in acetonitrile (125 mL), acetic acid (15 mL) and methanesulfonic acid (6.25 mL) were added followed by the heating of mixture to 70 °C for 4 h. The suspension was filtered and filtrate cooled to ambient temperature. Triethylamine (16.5 mL) and (S)-2-aminopropanol (2.45 mL) was added followed by heating the mixture at reflux temperature for 24 h. The insoluble product was filtered, washed with 2-propanol (20 mL) and dried to give (3S, 1 1 aR)-3-methyl-5,7-dioxo-2,3,5,7, 1 1 ,1 1 a-hexahydrooxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxylic acid (5.2 g, 75%).

1H NMR (DMSO-d6): δ 1.31 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.8 Hz, 1 H), 4.13 (dd, J = 1 1.7, 10.3 Hz, 1 H), 4.28 (m, 1 H), 4.39 (dd, J = 8.6, 6.8 Hz, 1 H), 4.92 (dd, J = 12.3, 4.2 Hz, 1 H), 5.45 (dd, J = 10.2, 4.1 Hz, 1 H), 7.16 (s, 1 H), 8.84 (s, 1 H), 15.74 (s, 1 H).

Example 7:

Compound 4 (0.63 g) was dissolved in dichloromethane (15 mL), cooled to 5°C, then triethylamine (0.31 mL) was added, followed by ethyl chloroformate (0.26 mL), followed by slow (30 min) addition of 2,4-difluorobenzylamine. The mixture was then stirred at ambient temperature for 24 h. Water (10 mL) was added, organic phase was separated and washed with 1 M HCI (15 mL) and water (15 mL), concentrated and treated with 2-propanol to give the product 5 in a quantitative yield.

1H NMR (CDCI3): δ 1.39 (d, 3H), 1.52 (s, 1 H), 2.19 (m, 1 H), 4.00 (m, 2H), 4.16 (m, 1 H), 4.31 (m, 1 H), 4.62 (d, 2H), 5.00 (m, 1 H), 5.27 (m, 1 H), 6.80 (m 2H), 7.33 (m, 2H), 8.49 (s, 1 H), 10.48 (s, 1 H). 13C NMR (CDCI3): 15.50, 29.22, 36.43, 45.19, 51.83, 62.79, 103.71 , 103.91 , 1 1 1 .0, 1 1 1 .18, 120.59, 123.04, 130.40, 137.41 , 144.58, 156.27, 163. 87, 177.83.

Example 8:

To a suspension of 4 (2.84 g, 10 mmol) in a mixture of triethylamine (2.24 mL, 16 mmol) and acetone (50 mL) stirring on an ice bath was added ethyl chloroformate (1 .20 mL, 12 mmol). After stirring for 10 min, 2,4-difluorobenzylamine (1.21 mL, 10 mmol) was added and the mixture left stirring at room temperature for 1 h. The product was isolated by slowly diluting the reaction mixture with water (50 mL), partial concentration, filtration, washing with water (2 50 mL) and drying. There was obtained 5 as a white powder (3.48 g, 86%): mp 181.0-184.7 °C. 1H NMR (DMSO-d6): δ 1.29 (d, J = 7.0 Hz, 3H), 1 .56 (dd, J = 13.9, 2.0 Hz, 1 H), 1 .93-2.06 (m, 1 H), 3.90 (ddd, J = 1 1.6, 5.0, 2.1 Hz, 1 H), 3.98 (td, J = 12.0, 2.2 Hz, 1 H), 4.45 (dd, J = 13.6, 6.6 Hz, 1 H), 4.72 (dd, J = 13.6, 3.8 Hz, 1 H), 4.74-4.81 (m, 1 H), 5.44 (dd, J = 6.6, 3.8 Hz, 1 H), 8.93 (s, 1 H), 15.14 (s, 1 H). 13C NMR (DMSO-d6): δ 15.78, 29.13, 44.89, 52.88, 61 .63, 75.61 , 1 13.54, 128.49, 136.42, 145.64, 154.62, 164.58, 174.58

Example 9:

To a suspension of 4 (1 1.36 g, 40 mmol) in acetonitrile (80 mL) stirring at room temperature was added TCCA (9.29 g, 38 mmol) and DABCO (0.23 g, 5 mol%). After stirring at room temperature for 1 h, the reaction was quenched with a mixture of DMSO (5.26 mL) and water (1.33 mL). The insoluble cyanuric acid was removed by filtration and the filtrate evaporated under reduced pressure to give viscous oil. This was triturated in methanol (20 mL) to induce crystallization. The product was filtered, washed with cold methanol (10 mL) and dried to give 7 as a yellowish powder (5.13 g, 41 %): mp 191 .3-198.7 °C.

Example 10:

Attempted chlorination of 23: Compound 23 (0.54g) was suspended in acetonitrile (10 mL) and trichlorocyanuric acid (0.44 g) was added and the solution was stirred at ambient temperature overnight. Precipitate was filtered. Only traces of a product corresponding to the compound 26 could be detected in the reaction mixture by LC-MS analysis. Conversion did not improve with time.

Example 11 :

Attempted chlorination of 3: Compound 3 (0.30 g) was suspended in acetonitrile (5 mL) and trichlorocyanuric acid (0.13 g) was added. The suspension was stirred at ambient temperature overnight. Only traces of a product corresponding to the compound 24 could be detected in the reaction mixture by LC-MS analysis.

Example 12:

9 10

Trichloroisocyanuric acid (0.23 g) was added in a single portion to a stirred solution of the diethyl 1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (9, 0.66 g) in dry acetonitrile (4 mL) at room temperature. The resulting suspension was stirred at room temperature for ca. 24 h. The reaction mixture was diluted with dichloromethane and filtrated. The filtrate was then concentrated in vacuo to afford crude oil (0.86 g). Purification by flash chromatography (eluting ethyl acetate/cyclohexane) furnished diethyl 3-chloro-1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate, 10 as a yellow semi-solid (0.38 g). 1H NMR (CDCI3): δ 1.28 (t, J=7A Hz, 3H), 1 .37 (t, J=7.2 Hz, 3H), 3.35 (s, 6H), 3.89 (d, J=5.0 Hz, 2H), 4.27 (q, J=l A Hz, 2H), 4.43 (q, J=l A Hz, 2H), 4.48 (t, J=4.9 Hz, 1 H), 8.15 (s, 1 H). 13C NMR (CDCI3): δ 13.83, 14.13, 55.82, 57.09, 61.41 , 63.72, 102.52, 1 17.35, 126.90, 140.22, 146.92, 160.67, 164.13, 168.95.

Example 13:

Diethyl 1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (9, 0.64 g) was dissolved in anhydrous acetonitrile (6 mL) and treated sequentially with acetic acid (560 μί) and methanesulfonic acid (40 μί). The resulting mixture was heated to 62 °C and stirred for 4 h and more methanesulfonic acid (40 μΙ_) was added. After additional 2 h, more methanesulfonic acid (80 μΙ_) was added. This was repeated after additional 2 h, when more methanesulfonic acid (80 μΙ_) was added. The reaction mixture was stirred additional 17 h at 62 °C then was treated with a mixture of (R)-3-aminobutanol (0.22 g), triethylamine (0.5 mL) and acetonitrile (0.7 mL). The reaction mixture was stirred additional 22 h at 62 °C and then concentrated in vacuo. The crude material was partitioned between dichloromethane and 1 M HCI solution (15 mL). The combined organic phases were dried (Na2S04), filtered and concentrated in vacuo to afford the crude (4R, 12aS)-ethyl 4-methyl-6,8-dioxo-3,4,6,8, 12,12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 -b][1 ,3]oxazine-9-carboxylate (11 ) as a brownish oil (0.61 g).

1H NMR (CD3OD): δ 8.44 (s, 1 H), 7.16 (m, 1 H), 5.48 (t, J=4.8 Hz, 1 H), 4.86 (m, 1 H), 4.49 (dd, J=13.6, 4.0 Hz, 1 H), 4.30-4.25 (m, 3H), 4.09 (dt, J=12.1 , 2.3 Hz, 1 H), 3.96 (ddd, J=1 1.7, 5.0, 2.1 Hz, 1 H), 2.18-2.10 (m, 1 H), 1.60-1 .56 (m, 1 H) 1 .39 (d, J=7A Hz, 3H), 1.33 (t, J=7A Hz, 3H). 13C NMR (CDCI3): δ 8.45, 14.08, 15.39, 29.17, 45.04, 45.72, 51 .56, 60.86, 62.61 , 76.33, 1 19.54, 123.72, 136.96, 145.67, 156.26, 163.68, 175.43

Example 14:

10

Diethyl 3-chloro-1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (10, 1.23 g) was dissolved in 85% formic acid (25 mL) at room temperature. The mixture was warmed to 40 °C and stirred for 23 h. The reaction mixture was concentrated in vacuo, and then partitioned between dichloromethane and aqueous NaHC03 solution. The combined organic phases were dried (Na2S04), filtered and concentrated in vacuo to afford brownish oil (0.49 g). The crude oil was dissolved in anhydrous toluene (5 mL) and treated sequentially with (R)-3-aminobutanol (0.19 g), methanol (0.2 mL) and acetic acid (96 μί). The resulting mixture was heated to 90 °C and stirred for 20 h. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and aqueous NaHC03 solution. The combined organic phases were dried (Na2S04), filtered and concentrated in vacuo to afford the crude (4R,12aS)-Ethyl 7-chloro-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5] pyrazino [2, 1-b][1 ,3]oxazine-9-carboxylate (12) as a brownish oil (0.24 g).

Example 15:

To a solution of 4 (5.68 g, 20 mmol) in dichloromethane (50 mL) stirring in an ice bath was added triethylamine (5.6 mL, 40 mmol), followed by ethyl chloroformate (2.61 mL, 26 mmol). After 20 min, ethanol (50 mL) was added. The mixture was then left stirring 24 h at room temperature and concentrated under reduced pressure. The residue was triturated in acetone (80 mL). The insoluble salt (triethylamine hydrochloride) was removed by filtration. The filtrate was evaporated under reduced pressure to give 11 as an amorphous solid in a quantitative yield (6.1 g).

Example 16:

To a stirring solution of 11 (0.94 g, 3.0 mmol) in acetonitrile (8 mL) heated at 40 °C was added TCCA in portions during 1 h (0.44 g, 1 .8 mmol). After an additional 1 h, the reaction mixture was diluted with a solution of NaHS03 (0.60 g) in water (60 mL), extracted with dichloromethane (50 mL) and the extract evaporated under reduced pressure to give a crude product which was purified by flash chromatography (CH2CI2 : MeOH, from 98 : 2 to 80 : 20) to give 12 (0.45 g, 44%).

1H NMR (CDCI3): δ 1.37 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1 .56 (dq, J = 13.9, 2.2 Hz, 1 H), 2.21 (m, 1 H), 3.99 (d, J = 2.3 Hz, 1 H), 4.00 (t, J = 1.8 Hz, 1 H), 4.10 (dd, J = 13.2, 6.6 Hz, 1 H), 4.37-4.27 (m, 3H), 4.98 (m, 1 H), 5.35 (dd, J = 6.6, 3.8 Hz, 1 H), 8.07 (s, 1 H).

13C NMR (CDCI3): δ 14.20, 16.09, 29.34, 44.87, 53.73, 61.49, 62.29, 76.01 , 1 16.22, 133.1 1 , 134.18, 144.52, 155.48, 163.88, 169.98.

Example 17:

To a mixture of 7 (3.89 g, 12.2 mmol) in methanol (12 mL) was added sodium methylate (22.3 mL, 97.6 mmol). The reaction mixture was stirred for 24 h at 30 °C and then quenched with a slow addition of 3M hydrochloric acid (35 mL) while stirring in an ice bath. The mixture was concentrated under reduced pressure to remove most of the methanol, then extracted with dichloromethane (2 30 mL), the combined extracts washed with water (30 mL) and evaporated under reduced pressure. Methanol (20 mL) was added to the obtained amorphous residue and removed under reduced pressure to yield the solid 8 (3.69 g, 98%).

1H NMR (CDCI3): δ 15.04 (s, 1 H), 8.42 (s, 1 H), 5.29 (dd, J=5.6, 3.9 Hz, 1 H), 5.01 -4.96 (m, 1 H), 4.42 (dd, J=13.6, 3.6 Hz, 1 H), 4.25 (dd, J=13.6, 6.0 Hz, 1 H), 4.05 (s, 3H), 4.00-3.97 (m, 2H), 2.21 -2-14 (m, 1 H), 1.53 (dd, J=14.1 , 1.9 Hz, 1 H), 1.36 (d, J=7 Hz, 3H). 13C NMR (CDCI3): δ 176.35, 165.94, 155.03, 153.70, 143.08, 130.90, 1 15.94, 76.05, 62.65, 61.45, 53.86, 44.96, 29.43, 16.06.

Example 18:

To a suspension of 7 (2.55 g, 8.0 mmol) in a mixture of triethylamine (1 .46 mL, 10.4 mmol) and acetone (32 mL) stirring on an ice bath was added ethyl chloroformate (0.88 mL, 8.8 mmol). After stirring for 10 min, 2,4-difluorobenzylamine (1.07 mL, 8.8 mmol) was added and the mixture left stirring at room temperature for 1 h. The product was isolated by slowly diluting the reaction mixture with water (40 mL), filtration, washing with water (2 30 mL) and drying. There was obtained 2.91 g of 6 as a white powder (83%).

1H NMR (CDCI3): δ 1.30 (d, J = 7.0 Hz, 3H), 1 .49 (dd, J = 14.0, 2.2 Hz, 1 H), 2.14 (ddd, J = 14.6, 1 1.1 , 6.4 Hz, 1 H), 3.89-3.95 (m, 2H), 4.09-4.15 (m, 1 H), 4.26 (dd, J = 13.4, 3.8 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 4.89-4.98 (m, 1 H), 5.18 (dd, J = 6.2, 3.8 Hz, 1 H), 6.68-6.79 (m, 2H), 7.23-7.31 (m, 1 H), 8.41 (s, 1 H), 10.24 (t, J = 5.8 Hz, 1 H). 13C NMR (CDCI3): δ 16.09, 26.95, 29.30, 36.79, 45.1 1 , 45.28, 53.86, 62.47, 75.93, 103.87 (t, J = 25.4 Hz), 1 1 1 .21 (dd, J = 21 .0, 3.4 Hz), 1 17.32, 130.58 (dd, J = 9.3, 5.8 Hz), 133.40, 143.54, 155.34, 163.16, 163.25, 163.35, 172.88.

Example 19:

To a suspension of 5 (1 .67 g, 4 mmol) in acetonitrile (20 mL) was added DABCO (23 mg, 5 mol%) and TCCA (0.62 g, 2.52 mmol). The mixture was stirred 18 h at 40 °C protected from light and then quenched with a mixture of DMSO (0.48 mL) and water (0.12 mL). The insoluble cyanuric acid was removed by filtration and washed with acetonitrile (5 mL). The filtrate was evaporated under reduced pressure to give viscous oil that was crystallized from a mixture of methanol (6 mL) and water (3 mL), by slowly cooling the solution from 60 °C to room

temperature. The product 6 was filtered, washed with cold methanol (5 mL) and dried to give an off-white powder (1.07 g, 61 %).

1H NMR (CDCI3): δ 1.30 (d, J = 7.0 Hz, 3H), 1 .49 (dd, J = 14.0, 2.2 Hz, 1 H), 2.14 (ddd, J = 14.6, 1 1.1 , 6.4 Hz, 1 H), 3.89-3.95 (m, 2H), 4.09-4.15 (m, 1 H), 4.26 (dd, J = 13.4, 3.8 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 4.89-4.98 (m, 1 H), 5.18 (dd, J = 6.2, 3.8 Hz, 1 H), 6.68-6.79 (m, 2H), 7.23-7.31 (m, 1 H), 8.41 (s, 1 H), 10.24 (t, J = 5.8 Hz, 1 H). 13C NMR (CDCI3): δ 16.09, 26.95, 29.30, 36.79, 45.1 1 , 45.28, 53.86, 62.47, 75.93, 103.87 (t, J = 25.4 Hz), 1 1 1 .21 (dd, J = 21.0, 3.4 Hz), 1 17.32, 130.58 (dd, J = 9.3, 5.8 Hz), 133.40, 143.54, 155.34, 163.16, 163.25, 163.35, 172.88.

Example 20:

To a suspension of 6 (0.44 g) in anhydrous methanol (1 mL) was added a 25% methanolic solution of sodium methylate (1 .14 mL) and the mixture stirred for 4 h at 40 °C. The reaction was quenched with acetic acid (0.4 mL), diluted with water (8 mL), extracted with 2-methyltetrahydrofuran (12 mL), the extract washed with 1 M NaOH(aq) (8 mL), water (8 mL) and evaporated under reduced pressure. To the oily residue was added methanol (8 mL) and evaporated under reduced pressure to give 27 as a white solid (0.38 g, 88%).

Example 21 :

The suspension of (4R, 12aS)-7-chloro-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 -b][1 ,3]oxazine-9-carboxamide (6, 0.44 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2 mL) was stirred at room temperature for 24 h. The reaction was quenched with 2M H2S04 (1 .18 mL) and left stirring for 2 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with water (2 x 2 mL). The obtained white precipitate (0.38 g) was suspended in THF-water (1 :1 , 4.5 mL) and stirred at room temperature for ca. 2 h. The reaction mixture was filtered through fitted funnel rinsing with water (2 χ 1 mL) and dried in vacuo at 40°C to afford pure dolutegravir as a white solid (0.33 g, HPLC purity: 99.38%).

1H NMR (DMSO-d6): δ 12.51 (s, 1 H), 10.36 (t, J=5.9 Hz, 1 H), 8.50 (s, 1 H), 7.41-7.36 (m, 1 H), 7.26-7.21 (m, 1 H), 7.07-7.03 (m, 1 H), 5.45 (dd, J=5.4, 4.3 Hz, 1 H), 4.81 -4.76 (m, 1 H), 4.59-4.53 (m, 3H), 4.36 (dd, J=13.8, 5.8 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.91-3.88 (m, 1 H), 2.05-1 .97 (m, 1 H), 1.55-1.52 (m, 1 H), 1 .33 (d, J=7.1 Hz, 3H). 13C NMR (DMSO-d6): δ 170.27, 163.68, 162.29, 161 .78 (dd), 159.82 (dd), 154.61 , 140.64, 130.74 (d), 130.67 (d), 122.37 (d), 1 16.73, 1 15.38, 1 1 1 .33 (d), 103.80 (t), 62.01 , 51 .16, 44.69, 35.74, 29.13, 15.21.

Example 22:

A suspension of dolutegravir (0.31 g) in methanol (4 mL) was cooled to 0 °C.25% Solution of sodium methoxide in methanol was added to the mixture and the resulting suspension was stirred at 0 °C for 2 h, then at room temperature for 23 h. The reaction mixture was then filtered through fitted funnel rinsing with methanol (3 x 10 mL). The white precipitate was dried overnight at room temperature to afford pure dolutegravir sodium as a white solid (0.26 g, HPLC purity: 99.84%).

1H NMR (DMSO-d6): δ 10.70 (t, J=5.8, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J=6.4Hz, 1H), 4.51 (d, J=5.5Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J=14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J=12.9 Hz, 1H), 1.24 (d, J=7.0Hz, 3H).13C NMR (DMSO-d6): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.

Example 23:

The suspension of 6 (0.44 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2 mL) was stirred at room temperature for 24 h. The reaction was diluted with absolute ethanol (10 mL) and left stirring for ca. 30 min at room temperature. The reaction mixture was filtered through fitted funnel rinsing with absolute ethanol (3 x 10 mL) and dried in vacuo at room temperature to afford dolutegravir sodium as a pale yellow solid (0.43 g, HPLC purity: 98.80%). 1H NMR (DMSO-d6): δ 10.70 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J= 14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J = 12.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H).13C NMR (DMSO-d6): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.

Example 24:

The suspension of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-6][1,3]oxazine-9-carboxamide (27, 0.43 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2.5 mL) was stirred at room temperature for ca.24 h. The reaction was diluted with mixture of water/ethanol (5 mL, 1:1) and left stirring for ca. 1.5 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with mixture of water/ethanol (3 x 5 mL, 1:1) and dried in vacuo at room temperature to afford 15 as a pale yellow solid (0.41 g, HPLC purity: 98.87%).

1H NMR (DMSO-de): δ 10.70 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J = 14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J = 12.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H).13C NMR (DMSO-d6): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.

Example 25:

The suspension of {4R, 12aS)-7-chloro-4-methyl-6,8-dioxo-3,4, 6,8, 12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-6][1,3]oxazine-9-carboxylic acid (7, 0.31 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2.5 mL) was stirred at 50 °C for 3 days. The reaction was quenched with 2M H2S04 (1.2 mL) and left stirring for 7 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with water (3×5 mL) and ethanol (5 mL) dried in vacuo at 40°C to afford 28 as a pale yellow solid (0.17 g).

1H NMR (DMSO-d6): δ 15.37 (s, 1H), 12.76 (s, 1H), 8.66 (s, 1H), 5.51-5.49 (m, 1H), 4.80-4.78 (m, 1H), 4.65 (dd, J=13.8, 3.7 Hz, 1H), 4.43 (dd, J=13.8, 5.9 Hz, 1H), 4.05 (t, J^^.b Hz, 1H), 3.91 (dd, J=11.4, 3.1 Hz, 1H), 2.07-2.00 (m, 1H), 1.56 (d, J=13.8 Hz, 1H), 1.34 (d, J=7.0 Hz, 3H).13C NMR (DMSO-de): δ 172.21, 165.39, 161.73, 153.61, 141.11, 118.66, 112.99, 75.95, 62.03, 51.50, 44.90, 29.08, 15.18.

Example 26:

The suspension of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 ,3]oxazine-9-carboxamide (27, 0.88 g) and solid sodium hydroxide (0.24 g) in absolute ethanol (20 mL) was stirred at 30 °C for 1.5 h. The reaction was quenched with 2M H2S04 (1 .5 mL) and left stirring for 3 hours at room temperature. The reaction mixture was filtered through fritted funnel and rinsed with water (3 x 2 mL) and ethanol (4 mL), and dried in vacuo at 40 °C to afford O-ethyl dolutegravir (29) as a pale yellow solid (0.25 g). The filtrate was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over MgS04, filtered and concentrated, then dried in vacuo at 40 °C to afford more 29 as a pale yellow solid (0.27 g).

1H NMR (CDCI3): δ 10.37 (t, J = 5.8 Hz, 1 H), 8.36 (s, 1 H), 7.37-7.32 (m, 1 H), 6.83-6.77 (m, 2H), 5.19 (dd, J = 5.9, 3.8 Hz, 1 H), 5.04-4.98 (m, 1 H), 4.61 (d, J = 6Hz, 2H), 4.26-4.22 (m, 3H), 4.1 1 (dd, J = 13.4, 5.9 Hz, 1 H), 3.97 (t, J = 2.4 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 1 H), 2.21-2.14 (m, 1 H), 1.51 (dq, J = 14.0, 2.3 Hz, 1 H), 1 .47 (t, J = 7.0 Hz, 3H), 1 .35 (d, J = 7.1 Hz, 3H).

13C NMR (CDCI3): δ 174.78, 164.17, 162.49 (dd), 160.51 (dd), 155.72, 154.08, 142.32, 130.60 (dd), 129.33, 121 .51 (dd), 1 18.67, 1 1 1 .23 (dd), 103.78 (t), 76.15, 69.74, 62.58, 53.42, 44.58, 36.50 (d), 29.44, 16.04, 15.64.

Example 27:

The suspension of (4R, 12aS)-7-(benzyloxy)-4-methyl-3,4, 12,12a-tetrahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1-b][1 ,3]oxazine-6,8-dione (30, 0.68 g, prepared according to prior art) and solid sodium hydroxide (0.40 g) in absolute ethanol (5 mL) was stirred at 50 °C for 14 h. The reaction was quenched with formic acid (0.35 mL), water (2 mL) was added and mixture was left stirring for additional 1 h at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 5 mL) and the combined organic layers concentrated to afford a crude oil. Purification by flash chromatography (eluting with CH2CI2/methanol) afforded 32 as an orange solid (0.26 g, 52 %).

The above procedure if done at room temperature in same time period, affords 31 as orange oil (0.24 g, 43 %).

Compound 32: 1H NMR (DMSO-d6): δ 7.64 (d, J = 7.4 Hz, 1 H), 6.20 (d, J = 7.3 Hz, 1 H), 5.40 (dd, J = 5.1 , 4.2 Hz, 1 H), 4.83-4.78 (m, 1 H), 4.35 (dd, J = 13.6, 3.9 Hz, 1 H), 4.13 (dd, J = 13.6, 5.4 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.90-3.85 (m, 1 H), 2.03-1.95 (m, 1 H), 1.52 (dd, J = 13.9, 1 .9 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 3H). 13C NMR (DMSO-d6): δ 170.96, 163.01 , 153.48, 137.96, 1 16.83, 1 13.52, 76.18, 62.05, 50.39, 44.53, 29.21 , 15.28.

Compound 31 : 1H NMR (DMSO-d6): δ 7.67 (d, J = 7.4 Hz, 1 H), 6.28 (d, J = 7.4 Hz, 1 H), 5.29 (dd, J = 5.4, 3.8 Hz, 1 H), 4.82-4.75 (m, 1 H), 4.32 (dd, J = 13.6, 3.6 Hz, 1 H), 4.10 (dd, J = 13.5, 5.6 Hz, 1 H), 4.03-3.93 (m, 3H), 3.85 (ddd, J = 1 1 .6, 5.0, 2.2 Hz, 1 H), 1.97-1 .89 (m, 1 H), 1 .48 (dd, J = 13.8, 2.1 Hz, 1 H), 1.27 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H). 13C NMR (DMSO-d6): δ 174.38, 156.1 1 , 150.82, 139.48, 1 16.39, 1 13.52, 75.92, 67.31 , 61 .80, 51 .36, 44.22, 29.29, 15.76, 15.36.

Exa

The transformation of 6 to dolutegravir with sodium hydroxide in ethanol was monitored for the interconversion of intermediates. The suspension of 6 (0.44 g) and solid sodium hydroxide (0.20 g) in ethanol (3.33 ml.) was stirred at 22 °C. Samples of the reaction mixture were taken after 3, 8 and 24 h for UPLC analysis. After 24 h, the reaction mixture was quenched with 2 M H2S04 (5 ml_), and left stirring at room temperature. The reaction mixture was filtered through fritted funnel, the product rinsed with water (30 ml.) and dried in vacuo at 50 °C overnight to afford dolutegravir as a white solid (0.27 g, 64 %).

The results of reaction monitoring:

Time UPLC analysis (area%)

Entry

(h) compound 6 compound 29 dolutegravir

1 3 h 37.50 20.63 39.99

2 8 h 0.78 15.46 80.32

3 24h 0.31 8.56 88.21

Example 29:

The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 27 (0.86 g) in MeOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2 ml.) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.

The results of reaction monitoring demethylation of 27 in MeOH:

Example 30:

The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 6 (0.88 g) in EtOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2 mL) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.

The results of reaction monitoring of the transformations of 6 in ethanol with NaOH:

dol. = dolutegravir

Exa

The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 27 (0.88 g) in EtOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2ml_) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.

The results of reaction monitoring of the transformations of 27 in ethanol with NaOH:

dol. = dolutegravir

Example 32:

Compound 3 (30 g, 1 10 mmol; assay 99%) was suspended in acetonitrile (450 mL), acetic acid (73 mL) and methanesulfonic acid (25 mL) were added. The reaction mixture was stirred 4 h at 70 °C. The clear red solution was cooled to 25 °C. Triethylamine (77 mL) and (S)-2-aminopropanol (17 mL) were added and the mixture was stirred at reflux temperature for 20 h. The reaction mixture was cooled to 25 °C and the insoluble product filtered, washed with 1 M HCI(aq) (60 mL), water (3 * 60 mL) and dried to give 4c (19.49 g, 67%): mp = 313-315 °C; 1H NMR (DMSO-d6): δ 1.31 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.8 Hz, 1 H), 4.13 (dd, J = 1 1.7, 10.3 Hz, 1 H), 4.28 (m, 1 H), 4.39 (dd, J = 8.6, 6.8 Hz, 1 H), 4.92 (dd, J = 12.3, 4.2 Hz, 1 H), 5.45 (dd, J = 10.2, 4.1 Hz, 1 H), 7.16 (s, 1 H), 8.84 (s, 1 H), 15.74 (s, 1 H); 13C NMR (DMSO-d6) 16.5, 51.6, 52.9, 72.4, 81.6, 1 15.8, 1 18.1 , 141.5, 147.6, 153.4, 165.3, 179.0.

Example 33

Compound 4c (2.78 g) was suspended in dimethylformamide (40 mL), cooled to 0 °C, then triethylamine (3.52 mL) was added, followed by ethyl chloroformate (1 .31 mL). After 10 min there was added 2,4-difluorobenzylamine (1 .57 mL). The mixture was then stirred at 25 °C for 1 h. Water (150 mL) was added and the mixture extracted with dichloromethane (50 mL). The organic phase was separated, washed with water (2 χ 50 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue (4.31 g) was treated with boiling 2-propanol (40 mL), the suspension cooled, the product filtered and dried to give the product 5c as a white powder (2.70 g, 69%): 99.80 area% by HPLC at 258 nm; mp = 222-223 °C; MS (ESI) m/z = 390 [MH]+; 1H NMR (DMSO-d6): δ 1 .30 (d, J = 6.3 Hz, 3H), 3.63 (dd, J = 8.6, 6.8 Hz, 1 H), 4.02 (m, 1 H), 4.26 (m, 1 H), 4.37 (dd, J = 8.6, 6.8 Hz, 1 H), 4.53 (d, J = 6.0 Hz, 2H), 4.84 (dd, J = 12.2, 4.2 Hz, 1 H), 5.40 (dd, J = 12.2, 4.2 Hz, 1 H), 6.91 (s, 1 H), 7.05 (m, 1 H), 7.24 (m, 1 H), 7.38 (m, 1 H), 8.62 (s, 1 H), 10.43 (t, J = 6.0 Hz, 1 H).

To a suspension of 5c (2.70 g, 6.9 mmol) in acetonitrile (32 mL) was added DABCO (39 mg, 5 mol%) and TCCA (1.01 g, 4.3 mmol). The mixture was stirred 20 h at 40 °C protected from light and then quenched with a mixture of DMSO (0.81 mL) and water (0.20 mL). The insoluble cyanuric acid was removed by filtration and washed with acetonitrile (10 mL). The filtrate was evaporated under reduced pressure to give viscous oil that was crystallized from a mixture of methanol (10 mL) and water (5 mL), by slowly cooling the solution from 60 °C to room temperature. The product 6c was filtered, washed with cold methanol (8 mL) and dried to give an off-white powder (1 .20 g, 41 %): mp = 225-227 °C; MS (ESI) m/z = 424 [MH]+; 1H NMR

(DMSO-d6): δ 1.28 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.9 Hz, 1 H), 4.09 (m, 1 H), 4.26 (m, 1 H), 4.35 (dd, J = 8.6, 6.6 Hz, 1 H), 4.54 (d, J = 5.9 Hz, 2H), 4.85 (dd, J = 12.3, 3.8 Hz, 1 H), 5.42 (dd, J = 10.1 , 3.8 Hz, 1 H), 7.06 (m, 1 H), 7.24 (m, 1 H), 7.40 (m, 1 H), 8.67 (s, 1 H), 10.24 (t, J = 6.0 Hz, 1 H).

Example 35

cabotegravir

The suspension of 6c (1.00 g, 2.4 mmol) and sodium hydroxide (0.57 g, 14.2 mmol) in absolute ethanol (7 mL) was stirred at 40 °C for 16 h. The reaction was quenched with 0.5M H2S04 (15 mL), extracted with dichloromethane (20 mL), the extract washed with water (20 mL) and evaporated under reduced pressure. The residue was triturated in MTBE (10 mL), the product filtered, washed with MTBE (10 mL) and dried to give cabotegravir as an off-white solid (0.74 g, 77%): MS (ESI) m/z = 405 [MH]+.

Lek, a Sandoz company, opens the first production facility in Slovenia for drug substances for innovative medicines at its Mengeš site

Vojmir Urlep, president of Lek Board of Management

 

Dr Miro Cerar, the Prime Minister of the Republic of SloveniaPhoto for print

Dr Miro Cerar, the Prime Minister of the Republic of Slovenia

Lek, a Sandoz company, awarded for cooperation in practical training of students of the Faculty of Chemistry and Chemical Technology

30. 1. 2015

At a ceremony held on 22 January 2015 at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, the Maks Samec awards and recognitions for 2014 were presented for the best doctoral thesis in the field of chemistry, the best doctoral thesis in the field of chemical engineering and chemical technology and for services and merits to the Faculty in the year 2014. On this occasion, the Faculty also wanted to thank all the companies and individuals who shared their knowledge and resources to help the Faculty on its education and research path.

Lek, a Sandoz company, received a plaque for taking part in the implementation of practical training, which was collected, on behalf of the company, by Samo Roš, Head of Human Resources and a Member of the Lek Board of Management. By doing so, the Faculty of Chemistry and Chemical Technology thanked all the mentors who directly transfer their expertise and valuable experience onto students, teaching them specific skills, encouraging their development, guiding them through the work process and ensuring that students become socialized in the workplace.

* * *

Lek, a Sandoz company, is one of key pillars of the second-largest generic pharmaceutical company globally. Its role within Sandoz is to act as: a leading global development center for technologically demanding products and technologies; a global manufacturing center for active pharmaceutical ingredients and medicines; a competence center for the development of vertically integrated products; a Sandoz competence center in the field of development and manufacturing of biosimilar products; and, a supply center for the markets of Central and Eastern Europe (CEE), South East Europe (SEE) and Commonwealth of Independent States (CIS), and it is responsible for sales on the Slovenian market. For further information please visit http://www.lek.si/en.

Sandoz, the generic pharmaceuticals division of Novartis, is a global leader in the generic pharmaceutical sector. Sandoz employs over 26,400 employees and its products are available in more than 160 countries, offering a broad range of high-quality, affordable products that are no longer protected by patents. With USD 9.6 billion in sales in 2014, Sandoz has a portfolio of approximately 1,100 molecules, and holds the #1 position globally in biosimilars as well as in generic injectables, ophthalmics, dermatology and antibiotics, complemented by leading positions in the cardiovascular, metabolism, central nervous system, pain, gastrointestinal, respiratory, and hormonal therapeutic areas. Sandoz develops, produces, and markets these medicines, as well as active pharmaceutical and biotechnological substances. Nearly half of Sandoz’s portfolio is in differentiated products, which are defined as products that are more difficult to scientifically develop and manufacture than standard generics. In addition to strong organic growth since consolidating its generics businesses under the Sandoz brand name in 2003, Sandoz has benefitted from strong growth of its acquisitions, which include Lek (Slovenia), Sabex (Canada), Hexal (Germany), Eon Labs (US), EBEWE Pharma (Austria), Oriel Therapeutics (US), and Fougera Pharmaceuticals (US).
Sandoz is on Twitter. Sign up to follow @Sandoz_global at http://twitter.com/Sandoz_Global.

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and over-the-counter products. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58.0 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 130,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit www.novartis.com

 

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WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone

 PATENTS  Comments Off on WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone
Jul 182016
 

Lurasidone.svgBall-and-stick model of the lurasidone molecule

Lurasidone – it having been developed and launched by Sumitomo Dainippon Pharma. Lurasidone was launched for schizophrenia in the US by Sumitomo’s US subsidiary Sunovion Pharmaceuticals.

WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone

An improved process for the preparation of lurasidone and its intermediate

PIRAMAL ENTERPRISES LIMITED [IN/IN]; Piramal Tower Ganpatrao Kadam Marg, Lower Parel Mumbai 400013 (IN)

GHARPURE, Milind; (IN).
TIWARI, Shashi Kant; (IN).
WAGH, Ganesh; (IN).
REVANAPPA, Galge; (IN).
WARPE, Manikrao; (IN).
ZALTE, Yogesh; (IN).

 

The Piramal family's purposeful philanthropy

From left: Anand Piramal, executive director, Piramal Group; Swati Piramal, vice-chairperson, Piramal Group; Ajay Piramal, chairman, Piramal Group; Nandini Piramal, executive director, Piramal Enterprises; and Peter DeYoung, president, Piramal Enterprises

 

 

Improved process for preparing pure (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium methanesulfonate, useful as a key intermediate in the synthesis of lurasidone. Also claims a process for purifying lurasidone hydrochloride, useful for treating schizophrenia and bipolar disorders. In July 2016, Newport Premium™ reported that Piramal Enterprises was capable of producing commercial quantities of lurasidone hydrochloride and holds an active US DMF for the drug since March 2015.

Lurasidone (the Compound-I), is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders.The drug is marketed as hydrochloride salt (the compound-I.HCl) by Sunovion Pharms Inc.under the tradename”LATUDA”, in the form of oral tablets. Latuda is indicated for the treatment of patients with schizophrenia. Lurasidone hydrochloride has the chemical name ((3aR,4S,7R,7aS)-2-[((lR,2R)-2-{ [4-(l,2-benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)-methyl]hexahydro-lH-4,7-methanisoindol-l,3-dione hydrochloride, and is structurally represented as follows;

Compound-I.HCl

Lurasidone being an important antipsychotic agent; a number of processes for its preparation as well as for its intermediates are known in the art.

US Patent No. 5,532,372 describe a process for the synthesis of Lurasidone, which is illustrated below in Scheme-I. In the process, the compound, cyclohexane- l,2-diylbis(methylene) dimethanesulfonate(referred to as the compound-Ill) is reacted with 3-(l-piperazinyl-l,2-benzisothiazole(referred to as the compound-IV) in acetonitrile, and in the presence of sodium carbonate to provide corresponding quaternary ammonium salt as 4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2, r-piperazin]-l’-ium methanesulfonate (the compound-II). The compound-II is further treated with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in xylene, in the presence of potassium carbonate and dibenzo-18-crown-6-ether to provide lurasidone.

Scheme-I

US Published Patent Application 2011/0263848 describes a process for the preparation of the quaternary ammonium salt (the compound-II) which comprises reacting 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)- cyclohexane in a solvent such as toluene in the presence of a phosphate salt.

Indian Published Patent Application 2306/MUM/2014 (” the IN’2306 Application”) describes a process for the synthesis of lurasidone and the intermediates thereof, comprising reacting (R,R) trans l,2-bis(methane sulphonyl methyl)cyclohexane with 3-(Piperazine-l-yl)benzo[d]isothiazole in presence of a mixture of two or more polar aprotic solvents selected from acetonitrile, N,N-dimethyl formamide (DMF) and/or Ν,Ν-dimethyl acetamide (DMAc), and a base at reflux temperature to obtain the quaternary ammonium salt (the compound II), which is then converted to lurasidone. The IN’2306 application demonstrated preparation of the compound II using the solvent combination such as acetonitrile-DMF and acetonitrile-DMAc.

US Published Patent Application 2011/0263847 describes a process for the preparation of the quaternary ammonium salt (the compound-II) comprising reacting 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent such as toluene, wherein the piperazine compound is used in an excess amount i.e. 1.8 to 15 moles with respect to ( 1R,2R)- 1 ,2-bis(methanesulfonyloxymethyl)cyclohexane.

Chinese Published Patent Application 102731512 describes a process for the preparation of the quaternary ammonium salt (the compound-II) comprises reaction of 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent such as toluene in the presence of a phase transfer catalyst.

In addition to the afore discussed patent documents, there are a number of patent documents that describe a process for the preparation of the quaternary ammonium salt (the compound-II), the key intermediate for the synthesis of lurasidone. For instance, Published PCT application WO2012/131606 A 1, Indian Published patent application 217/MUM/2013, Chinese published patent applications 102863437, 103864774 and 102827157 describe a process for the preparation of the quaternary ammonium salt (compound-II) comprises reaction of 4-(l,2-benzisothiazol-3-yl)piperazine with (lR,2R)-l,2-bis(methanesulfonyloxymethyl)cyclohexane in a solvent or a solvent mixture such as acetonitrile, acetonitrile : water solvent mixture, toluene or DMF, in the presence of a base.

It is evident from the discussion of the processes for the preparation of the quaternary ammonium salt (the compound-II), described in the afore cited patent documents that the reported processes primarily involve use of acetonitrile either as the single solvent or in a mixture of solvents. Acetonitrile is a relatively toxic, and not an environment friendly solvent. Due to its toxic nature, it can cause adverse health effects also. Acetonitrile is covered under Class 2 solvents i.e. solvents to be limited, and residual solvent limit of acetonitrile is 410 ppm in a drug substance as per the ICH (International Conference on Harmonisation) guidelines for residual solvents. Moreover, acetonitrile is a costlier solvent, which renders the process costlier and hence, is not an industrially feasible solvent.

It is also evident from the discussion of the processes described in afore cited patent documents that some of the reported processes involve use of high boiling solvents such as toluene and dimethylformamide as reaction solvent, which subsequently require high reaction temperatures, and this in turn leads to tedious workup procedures. In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of lurasidone and its intermediates; which is simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.

Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents. Moreover, the process does not require additional purification steps and critical workup procedure. Accordingly, the present invention provides a process for the preparation of lurasidone and its intermediates, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

Scheme-II

Scheme-Ill

EXAMPLES

Example-1: Preparation of (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,l’-piperazin]-l’-ium methanesulfonate(the compound II)

Charged 150.0 mL (3v) of isopropyl alcohol (IPA) in a flask followed by the addition of the compound-Ill (50.0 g) , 3-(l-Piperazinyl)-l, 2-Benzisothiazole (32.84 g), sodium carbonate granular (10.79 g) and water 50 mL (lv). The reaction mixture was heated at a temperature of 82-85 °C for 24 to 25 h. Cooled the reaction mixture to room temperature, filtered on Buchner funnel and the filtrate was collected.

The filtrate was evaporated under vacuum at 55-65°C till visible solid appears in the reaction mass. The solid was stirred in 75 mL of toluene at room temperature and the solid was filtered. The wet cake was transferred to a flask and added 125 mL of acetone to it; followed by stirring at room temperature. The resulting solid was filtered to yield the pure title compound (II).

Yield: 63.4 g (90 %)

Purity (by HPLC): 99.79 %

Unreacted compound-IV as impurity in 0.05 % .

Example-2: Preparation of Lurasidone free base.

Charged 150.0 mL of Ν,Ν-dimethylformamide (DMF) in a flask followed by the addition of 50.0 g of the compound-II (as obtained in the above example-1), 19.5 g (3aR,4S,7R,7aS)-4,7-methano-lH-isoindole-l,3(2H)-dione and 19.5 g of potassium carbonate. The reaction mixture was heated at a temperature of about 125 °C for 24 h. The reaction mixture was cooled to room temperature and 400 mL of water was added to it. The reaction mixture was stirred, and the precipitated product was filtered. The wet cake was washed with IPA and Lurasidone free base is obtained as the pure product. [Yield: 46.52 g (80 %)]

Example-3: Purification of Lurasidone hydrochloride.

Charged water (200 ml) and IPA (200 ml) in flask followed by the addition of Lurasidone hydrochloride (50 gm, residual acetone: 5769 ppm). The reaction mixture was heated at a temperature of 75-80 °C for about 30 min. The reaction mixture was cooled to 20-30 °C and stirred for about 2 hours. The precipitated solid was filtered and isolated as pure Lurasidone hydrochloride (residual acetone: 2 ppm)

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

///////////////WO 2016110798, Piramal Enterprises Ltd, New Patent, Lurasidone

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New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

 PATENTS, Uncategorized  Comments Off on New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd
Jul 182016
 

 

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection

WO-2016110874

KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)

 

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)

Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.

In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA’s website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.

The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application’s publication would suggest otherwise.

Writeup

Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant’s anti-malarial application was first described in a Chinese pharmacopeia, titled “Chinese Handbook of Prescriptions for Emergency Treatments,” written at around 340 A.D.

Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.

Artemisinin and its derivatives – dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

Dihydroartemisinin Artesunate

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.

Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.


acid

In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.

Amorpha -4, 11-diene

A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene – 11, 12 – epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.

Amorphadiene-11,12-epoxide

This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.

Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.

Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.

DHAA methyl ester

Scheme 2

 

Method 4 (From compound of formula IV (R = CI)):

In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30°C followed by heating and maintaining the temperature for 40 hours at 80°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50°C, and the crude mass degassed under vacuum at 50-55°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10°C. Ethyl acetate (60 ml) was added to the reaction mass at 10°C and stirred for 15 minutes at 15-20°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45°C and the obtained crude mass was degassed at 50-55°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85°C till reaction completion. The reaction mass was cooled up to 0-5°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (Purity: 90-95%).

b) Methyl ester of Dihydroartemisinic acid:

To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.

Weight: 41.88 gm

Yield = 98%

c) Artemisinin:

Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm

Yield= 70.7%

Purification of Artemisinin:

Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.

Weight: 4 gm

Yield: 40%

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer,  Parasitic infection,  Plasmodium falciparum infection,  Viral infection, artemether artemisinin,  artemotil,  artenimol,  artesunate,

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