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

///////////Drug Patent,  expiry, 2017

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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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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
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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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PATENT, US 8344136, PHF S.A., Brinzolamide

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US 8344136

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PHF S.A., Lugano, Switzerland
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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.

///////////PATENT, US 8344136,   PHF S.A., Brinzolamide
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May 222014
 

09221-notw1-strucs

Misassigned (top) and corrected (bottom) structures of bioactive TIC10.

Tug Of War Over Promising Cancer Drug Candidate

Drug Discovery: Structure error threatens existing patent and clinical trials

A promising anticancer agent about to enter human clinical trials is on the hook because of a chemical structure error discovered by scientists at Scripps Research Institute California. The patented compound, known as TIC10 or ONC201, is owned by the biotech firm Oncoceutics. However, Scripps has applied for a patent on the corrected structure and has licensed it exclusively to another company, Sorrento Therapeutics.

The reanalysis and relicensing could lead to an unprecedented legal case—the first in which a structural reassignment puts in jeopardy a patent and clinical trials.

Lee Schalop, Oncoceutics’ chief business officer, tells C&EN that the chemical structure is not relevant to Oncoceutics’ underlying invention. Plans for the clinical trials of TIC10 are moving forward.

 

read at

http://cen.acs.org/articles/92/web/2014/05/Tug-War-Over-Promising-Cancer.html

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Glenmark conferred with Best Biotech New Molecular Entity Patent award

 companies, drugs  Comments Off on Glenmark conferred with Best Biotech New Molecular Entity Patent award
Jan 162014
 

GLENMARK PHARMA

IDMA best biotech NEW MOLECULAR ENTITY patent award to Glenmark

YEAR 2012-2013 YEAR in Mumbai India

PATENT  US 8236315

GLENMARK PHARMACEUTICALS, S.A., SWITZERLAND

INVENTORS

Elias LazaridesCatherine WoodsXiaomin FanSamuel HouHarald MottlStanislas BleinMartin BertschingerALSO PUBLISHED ASCA2712221A1CN101932606A,EP2245069A1US20090232804,WO2009093138A1

Publication number US8236315 B2
Publication type Grant
Application number US 12/358,682
Publication date 7 Aug 2012
Filing date 23 Jan 2009
Priority date 23 Jan 2008

USPTOUSPTO AssignmentEspacenetUS 8236315

The present disclosure relates generally to humanized antibodies or binding fragments thereof specific for human von Willebrand factor (vWF), methods for their preparation and use, including methods for treating vWF mediated diseases or disorders. The humanized antibodies or binding fragments thereof specific for human vWF may comprise complementarity determining regions (CDRs) from a non-human antibody (e.g., mouse CDRs) and human framework regions.

The present disclosure provides a humanized antibody or binding fragment thereof specific for vWF that comprises a heavy chain variable region sequence as set forth in SEQ ID NO: 19 and a light chain variable region sequence as set forth in SEQ ID NO: 28 ……….. CONT

MR GLEN SALDANHA

MD , CEO GLENMARK

INDIAN DRUG MANUFACTURERS’ ASSOCIATION   (IDMA)

102-B Poonam Chambers, Dr A B Road, Worli, Mumbai 400 018, INDIA
Tel : +91 – 22 – 24944625 / 24974308. Fax : ++91 – 22 – 24957023
email: ppr@idmaindia.com website : www.idma-assn.org

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