AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Jan 212017
 

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03123D, Paper
Maurice A. Marsini, Frederic G. Buono, Jon C. Lorenz, Bing-Shiou Yang, Jonathan T. Reeves, Kanwar Sidhu, Max Sarvestani, Zhulin Tan, Yongda Zhang, Ning Li, Heewon Lee, Jason Brazzillo, Laurence J. Nummy, J. C. Chung, Irungu K. Luvaga, Bikshandarkoil A. Narayanan, Xudong Wei, Jinhua J. Song, Frank Roschangar, Nathan K. Yee, Chris H. Senanayake
A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03123D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

*Corresponding authors
aDepartment of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, USA
E-mail: maurice.marsini@boehringer-ingelheim.com
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03123D

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1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

m.p. = 140-144 °C;

1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.93 (s, J1 = 8.8 Hz, J2 = 4.7 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J = 4.1 Hz, 1H), 7.49 (t, J = 8.7 Hz, 1H), 3.29 (s, 3H), 1.61 (bs, 4H);

13C NMR (100 MHz, CDCl3) δ 166.1, 162.7, 160.3, 158.4, 156.9, 150.6, 139.2, 138.2, 135.8, 135.6, 125.4 (d, JC-F = 8.8 Hz), 123.3, 121.9, 117.2 (d, JC-F = 23.1 Hz), 116.4, 40.2, 34.9, 20.9;

HRMS: calcd for C22H19FN5O3S [M + H+ ]: 452.1187. Found: 452.1189.

 

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Jan 192017
 

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http://www.fda.moph.go.th/eng/index.stm

 

[PDF]Regulatory Requirement for the Approval of generic Drug in Thailand …

www.jpsbr.org/index_htm_files/JPSBR14RV4029.pdf

Apr 13, 2014 – Thailand has its own drug registration format and also follows. ASEAN CTD. … Transparency in the regulatory authorities of member countries.

THAILAND PHARMACEUTICAL REGISTRATION AND APPROVAL

The Thai FDA (TFDA), one of several agencies under the Ministry of Public Health (MPH), is the regulatory body administering drugs in Thailand. The Drug Control Division of the TFDA is responsible for registration, licensing, surveillance, inspection and adverse event monitoring for all pharmaceuticals and pharmaceutical companies in Thailand. Foreign pharma companies dominate the Thai drug market. Due in part to trade negotiations, regional harmonization and positive economic trends, the pharmaceutical market in Thailand is predicted to double by 2022.There are several versions of the Drug Act currently in effect, and the Thai government is working on a revised version with updated regulations. Under the current laws, pharmaceuticals are categorized as either traditional or modern medicines, with different applications and oversight. Modern medicines are subdivided into three categories, each of which has separate registration requirements. Licenses currently do not require renewal.

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link……….http://drug.fda.moph.go.th/eng/

FIRST ASEAN COUNTRY WITH A NATIONAL eCTD PROGRAM

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Thai FDA intends to accept dossier in eCTD format: The Drug Regulatory Authority of Thailand (Thai FDA) has initiated the acceptance of Pilot eCTD from October 2014.Read More

eCTD requirements

http://drug.fda.moph.go.th/eng/files/2_eSubmission%20FAQ1_0921.pdf

http://drug.fda.moph.go.th/eng/files/1_TH%20Module%201%20and%20Regional%20Specification_0921_Tch.pdf

http://drug.fda.moph.go.th/eng/files/TH%20Regional%20Specification%20and%20Validation%20Criteria.pdf

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Step to be followed to submit eCTD application

Taken from

https://www.linkedin.com/pulse/deep-dive-thai-ectd-overview-requirement-amar-tandon?trk=hp-feed-article-title-like

Regulatory Scientist at Kinapse

A) Prepare Application to get a eSubmission Identifier for every application issued. A request to the THAI FDA online service should be submitted to obtain an eSubmission identifier which will require following details.

  • Licensee Number
  • Description of Application
  • Dosage Form
  • INN or Generic Name
  • Strength
  • WHO ATC Code
  • Sequence Type
  • Application form
  • CPP (In case of Importer)

The eSubmission Identifier will be issued within 10 days of application. The Applicant must then make an appointment for submission within 30 days.

B) Prepare valid application along with validation reports as per country (Thailand) specific requirement with regional eSubmission Identifier provided.

The M1 requirements to be kept in consideration while compiling the Submission.

  • Enhanced granularity for each sections
  • Country code is not required in filenames
  • Information relating to orphan market is not mandatory
  • For LCM (Life cycle management) submissions the Operation attribute should be “Replace” in Tracking Table
  • Validation report should be submitted along with the sequence
  • 1.3.1 Product Information has been broken down into three specific sections for Labelling, SPC and the Package leaflet. No other product types are expected. If one file is submitted for this section, it should be submitted under 1.3.1.1 Labelling.
  • 1.3.1.3 Package Leaflet has been broken down into language sections for English, Thai and Other languages.
  • It is recommended that separate files should be submitted for each language.
  • Applicants can re-use the content submitted in other regions (including STF).
  • The identifier is a combination of a letter and seven digits.
  • Working documents are not needed and do not need to be provided within the eCTD framework for Thailand
  • Section 1.5.2 “Information for Generic, ‘Hybrid’ or Bio-similar Applications” has been broken down into three sections and given a section number to make expectations and cross referencing clearer.
  • Only one file should be provided for 1.6 Environmental Risk Assessment. It is not allowed to provide content in both 1.6.1 and 1.6.2.
  • During lifecycle, 1.8.2 Risk management plan should always use the lifecycle operator replace.

C) Dispatch Activity Delivery of the application at Thai FDA in CD/DVD (make an prior appointment with HA at drug_esubmissions@fda.moph.go.th

Thai FDA has proposed a set of media formats to be used while submission of eCTD

  • (CD-R) i.e. Compact Disc-Recordable
  • Digital Versatile Disc-Random Access Memory (DVD-RAM)
  • Digital Versatile Disc-Recordable (DVD+R/-R) recorded

Future Aspect-Import: The eCTD will be validated and imported into the THAI FDA Review System

Feedback: Application feedback (if there are problems experienced during the upload) and review of application by Thai FDA

Ensure that you do not use. 1. Double-sided discs 2. Re-writable disc (protection, authenticity and Stability of information cannot

Ensure that you do not use:

  • Double-sided discs,
  • Re-writable discs (protection, authenticity, and stability of information cannot be guaranteed)
  • Compressed or zipped files (except for validation reports)
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Jan 172017
 

 

 

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In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.

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http://www.gmp-compliance.org/enews_05736_EMA-publishes-Q-A-on-Health-Based-Exposure-Limits—Does-the-1-1000-dose-criterion-come-again-into-play-in-Cleaning-Validation_15560,15661,15963,Z-VM_n.html

In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.

The document altogether comprises five pages with 14 questions and answers.

The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.

Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.

There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.

The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.

Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.

At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.

 

some pics

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///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion,  Cleaning Validation,

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Jan 132017
 

 

Image result for CGMP for Combination Products.

 

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version of the FDA Guideline for Combination Products?

http://www.gmp-compliance.org/enews_05738_FDA-publishes-Final-Guideline-on-GMP-for-Combination-Products_15649,16021,15963,Z-VM_n.html

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version? In the following you will find an overview:

The final guideline has expanded to now 59 pages (draft: 46 pages). And also the number of footnotes increased from 85 (draft) to 147 (final).

In the table of content there are one new subchapter (II B  Quality and Current Good Manufacturing Practice) and one new chapter (VII Glossary). Subchapter III C was expanded to definitions and terminology. In the following the table of content is listed:

I. Introduction

II. Background
A. Definition of a combination product
B. Quality and Current Good Manufacturing Practices
C. Overview of the final rule
D. The role of the lead center and other agency components

III. General Considerations for CGMP Compliance
A. Demonstrating compliance
B. Investigational products
C. Definitions and terminology
D. What CGMP requirements apply to a product or facility?
E. Control of changes to a combination product

IV. What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)?
A. Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1)
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)
C. Combination products that include biological products and HCT/Ps

V. Application of CGMP requirements to specific types of combination products
A. Prefilled syringe
B. Drug-coated mesh
C. Drug Eluting Stent (DES)

VI. Contact Us

VII. Glossary

VIII. References

In the introduction it is explicitly stated, that “The final rule did not establish any new requirements”. In a footnote the guideline gives an explanation why the term “legacy” combination product has not been used.

In the new subchapter II B  (Quality and Current Good Manufacturing Practice) the guideline mentions, that “the core requirements embedded in these regulations provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. This includes establishing a strong quality management system, using appropriate quality raw materials, establishing robust manufacturing and control procedures based on sound design principles, and detecting and investigating product quality deviations. In addition, these regulations call for ongoing assessment of systems and the implementation of corrective actions where appropriate”.

The final document introduces in Section C the new term “CGMP operating system”. This means the operating system within an establishment that is designed and implemented to address and meet the current good manufacturing practice requirements applicable to the manufacture of a combination product. A clarification about constituent parts of cross-labeled combination products is also implemented. Further, there is a new passage about the choice of the GMP-approach (QS regulation vs drug CGMPs) also regarding a streamlined approach and for companies manufacturing different products. Completely new is the passage with the title “Documentation of CGMP Approach”. Here you can also find hints that manufacturerers with products that have been on the market since before GMP for Combination Products (21 CFR 4) came into operation, have to be compliant too. The guideline requires that the information about the “CGMP operating system” should be shared with FDA investigators in the beginning of an inspection.

In the “Demonstrating compliance” subchapter (III A) there is additional information about crossreferenced approaches (21 CFR 820 vs 21 CFR 211 and vice versa). For investigational products (III B) you can find more detailed information about exemptions from part 820 regarding 21 CFR 820.30 (Design).

In the Definition and terminology section (III D) there are amendments regarding container closure aspects and kits. Section III D (What CGMP requirements apply to a product or facility?) details the responsibility of the owner of a combination product and CAPA procedures in shared facilities.

In section III E. (Control of changes to a combination product) information for single entity and co-packed combination product manufacturers has been amended. The passages in IV A (Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) with regard to 21 CFR 820 about Management Responsibility, Design Controls, Purchasing Controls and CAPA have been extended – including examples – and “modernised”. Terms like quality oversight and QTTP are now mentioned there. Vice versa the passages with regard to 21 CFR 211, 211.84. 211.103, 211.132, 211.137, 211.165, 211.166, 211.167, and 211.170,  (IV B  Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)) have also been extended – likewise with examples – and have been “modernised” as well (e.g. parametric release is mentioned).

In the example about prefilled syringes (V A) one can find an amended passsage about Design Controls and a new section about Design History File. In the example about drug-coated mesh (V B) there has also been included a new section about Design History File. In the drug eluting stent example (V. C) there are amendments in the section about 21 CFR 211.184, 21 CFR 211.103 and 21 CFR 211.170. Furthermore all examples comprise editorial changes.

Completely new is the chapter VII (Glossary). The number of references (Chapter VIII) increased to 31 (draft: 19).

Summary:
There are a lot of changes from the draft to the final document. One chapter (Glossary) and a subchapter ( Quality and Current Good Manufacturing Practices) are new, but there are also new passages and amendments in the final document. Helpful are the examples that have been integrated.

Please also see the Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products for more details.

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Jan 112017
 

Figure

Improved synthetic approach: route A (feasibility) and B (after optimization)

 

Rakeshwar Bandichhor Ph.D. FRSC, CChem, SSWB,BB,MB

Rakeshwar Bandichhor Ph.D. FRSC, CChem, SSWB,BB,MB

Director at Dr. Reddy’s Laboratories, Vice-Chair, ACS-India Chapter (South India)

Dr. Reddy&#39;s Laboratories Logo

They have developed an improved process for pioglitazone which appears to be more compatible with industrial scale and has some advantages over the existing synthesis.

Preparation of Pioglitazone Hydrochloride (1·HCl) salt

1H NMR (400 MHz, DMSO-d6) 12.08 (s, 1H), 8.73 (d, 1H, J = 1.6 Hz), 8.43 (dd, 1H, J = 2.0, 8.0 Hz), 8.01 (d, 1H, J = 8.0 Hz), 7.16 (d, 2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.8 Hz), 4.88 (dd, 1H, J = 4.4, 8.8 Hz), 4.34 (t, 2H, J = 6.2 Hz), 3.55 (t, 2H, J = 6.2 Hz), 3.30 (dd, 1H, J = 4.4, 14.0 Hz), 3.06 (dd, 1H, J = 8.8, 14.0 Hz), 2.80 (q, 2H, J = 7.6 Hz), 1.24 (t, 3H, J = 7.6 Hz); 13C NMR (400 MHz, DMSO-d6) 175.6, 171.5, 156.9, 151.0, 145.2, 141.3, 139.8, 130.3, 129.0, 127.1, 114.4, 65.4, 52.8, 40.1, 39.9, 39.7, 39.5, 39.2, 39.0, 38.8, 36.2, 32.1, 24.5, 14.5; IR (KBr) 2928, 2742, 1743, 1694, 1616, 1510, 1461, 1313, 1243, 1038, 850, 712 cm−1; HRMS (Cl) calcd For C19H20N3O3S (M+) 356.44; found (MH+) 357.5.

An Improved Process for Pioglitazone and Its Pharmaceutically Acceptable Salt

Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur, R.R. District – 500 073, Andhra Pradesh, India, and Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India
Org. Process Res. Dev., 2009, 13 (6), pp 1190–1194
DOI: 10.1021/op900131m
†DRL-IPD Communication number: IPDO-IPM-00169.
, * Corresponding author. E-mail: rakeshwarb@drreddys.com. Telephone: +91 4044346000. Fax: +91 4044346285.,
‡Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd.
, §Institute of Science and Technology, Center for Environmental Science, JNT University.

Abstract

Abstract Image

An improved process for pioglitazone (1) is described. The process features high-yielding transformations employing inexpensive reagents and recoverable solvents.

link is

http://pubs.acs.org/doi/full/10.1021/op900131m

The original paper in OPRD is interesting example of process improvement

References

http://shodhganga.inflibnet.ac.in/bitstream/10603/19311/9/09_chapter%201.pdf

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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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Jan 092017
 

Amtolmetin guacil.png

Amtolmetin guacil,

ST-679, MED-15, Eufans

CAS 87344-06-7
UNII: 323A00CRO9, 

Molecular Formula, C24-H24-N2-O5, Molecular Weight, 420.463,

2-Methoxyphenyl 1-methyl-5-p-methylbenzoylpyrrole-2-acetoamidoacetate

Glycine, N-((5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetyl)-, 2-methoxyphenyl ester

Trade names: Amtoril®, Artricol®, Artromed®

US 4578481, US 6288241,

MEDOSAN RICERCA S.R.L. [IT/IT]; Via Cancelliera, 12 I-00040 Cecchina RM (IT) (For All Designated States Except US).
SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A. [IT/IT]; Viale Shakespeare, 47 I-00144 Roma (IT)

Launched – 1993 ITALY, SIGMA TAU, Non-Opioid Analgesics FOR Treatment of Osteoarthritis, Treatment of Rheumatoid Arthritis,

  • Originator sigma-tau SpA
  • Class Amino acids; Antipyretics; Nonsteroidal anti-inflammatories; Pyrroles; Small molecules
  • Mechanism of Action Cyclooxygenase inhibitors
    • Marketed Inflammation

    Most Recent Events

    • 01 Jun 1999 A meta-analysis has been added to the adverse events section
    • 22 Jul 1995 Launched for Inflammation in Italy (PO)

Amtolmetin guacil is a NSAID which is a prodrug of tolmetin sodium.

Amtolmetin guacil  is a nonacidic prodrug of tolmetin that has similar nonsteroidal antiinflammatory drug (NSAID) properties to those of Tolmetin with additional gastroprotective advantages. The term “nonsteroidal” is used to distinguish these drugs from steroids that have similar eicosanoid-depressing and antiinflammatory actions. Moreover, it possesses a more potent and long-lasting antiinflammatory activity than tolmetin  and is marketed for the treatment of rheumatoid arthritis, osteoarthritis, and juvenile rheumatoid arthritis.

Background

Tolmetin sodium is an effective NSAID approved and marketed for the treatment of rheumatoid arthritis, osteoarthritis and juvenile rheumatoid arthritis. In humans, tolmetin sodium is absorbed rapidly with peak plasma levels observed 30 min after p.o. administration, but it is also eliminated rapidly with a mean plasma elimination t½ of approximately 1 hr. The preparation of slow release formulations or chemical modification of NSAIDs to form prodrugs has been suggested as a method to reduce the gastrotoxicity of these agents.

Amtolmetin guacil is a non-acidic prodrug of tolmetin, having similar NSAID properties like tolmetin with additional analgesic, antipyretic, and gastro protective properties. Amtolmetin is formed by amidation of tolmetin by glycine

Pharmacology

  • Almost is absorbed on oral administration. It is concentrated maximum in internal the gastric wall, and highest concentration reached in 2 hours after administration.
  • Amtolmetin guacil hydrolysed in to following metabolites Tolmetin, MED5 and Guiacol.
  • Elimination will complete in 24 hours. Happens mostly with urine in shape of gluconides products (77%), faecal (7.5%).
  • It is advised to take the drug on empty stomach.
  • Permanent anti-inflammatory action is continued up to 72 hours, with single administration.

Mechanism of action

Amtolmetin guacil stimulates capsaicin receptors present on gastro intestinal walls, because of presence of vanillic moiety and also releases NO which is gastro protective. It also inhibits prostaglandin synthesis and cyclooxygenase (COX).

Figure

 

Structure of amtolmetin 1 and tolmetin 2.

26171-23-3 TOLMETIN FREE FORM

http://shodhganga.inflibnet.ac.in/bitstream/10603/2173/11/11_chapter%204.pdf

Tolmetin sodium

64490-92-2
Thumb
  • Average Mass: 279.2663

 

Image result for tolmetin

26171-23-3 TOLMETIN FREE FORM

1-methyl-5-p-tolylpyrrole-2-acetic acid

Image result for tolmetin

Melting point 155-158 °C, IR (KBr, cm-1): 3205 (OH), 2958 (Aliphatic C-H), 1731 (Acid, C=O), 1700 (C=O), 1616 (C=C), 1267 (C-O); 1H NMR (CD3OD, 400 MHz): δ 7.63 ( d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 6.63 (d, J = 3.9 Hz, 1H), 6.11 (d, J = 4.3 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 2H), 2.40 (s, 3H); MS (ESI): m/z calcd for C15H15NO3 (M + H): 258.11; found: (M + H) 257.9. (Fig. 4.12 – 4.14)

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INNTERMEDIATE

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1-methyl-5-p-toluoyl-2-acetamidoacetic acid

Melting point: 200-202° C. IR (KBr, cm-1): 3282 (NH), 3060 (OH), 1741 (Acid, C=O), 1637 (Amide, C=O), 1608 (C=C), 1178 (C-N); 1H NMR (CD3OD, 400 MHz): δ 7.64 ( dd, J =6.3 Hz, 1.9 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.65 (d, J = 3.9 Hz, 1H), 6.17 (d, J = 3.9 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 3.30 (t, J =1.4 Hz, 2H), 2.41(s, 3H); MS (ESI): m/z calcd for C17H18N2O4 (M + H): 315.13; found: (M + H) 315. (Fig. 4.20 – 4.22)

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SYNTHESIS

 

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1H  and 13 C NMR PREDICT

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SYNTHESIS

Amtolmetin guacil (CAS NO.: 87344-06-7), with its systematic name of N-((1-Methyl-5-p-toluoylpyrrol-2-yl)acetyl)glycine o-methoxyphenyl ester, could be produced through many synthetic methods.

Following is one of the synthesis routes: 1-Methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid (I) is condensed with glycine ethyl ester (II) in the presence of carbonyldiimidazole (CDI) and triethylamine in THF to afford the corresponding acetamidoacetate (III), which is hydrolyzed with NaOH in THF-water yielding 2-[2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetamido]acetic acid (IV). Finally, this compound is esterified with 2-methoxyphenol (guayacol) (V) by means of CDI in hot THF.

Image result for Amtolmetin

PATENT

https://www.google.com/patents/WO1999033797A1?cl=tr

The present invention relates to a new crystalline form of 1- methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaiacyl ester, a process for its preparation and to pharmaceutical compositions endowed with antiinflammatory, analgesic and antipyretic activity containing same.

The ester of 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid (hereinafter referred to as MED 15, form 1) is a known compound.

In fact, US Patent 4,882,349 discloses a class of N-mono- substituted and N,N-disubstituted amides of l-methyl-5-p- toluoylpyrrole-2-acetic acid (known as Tolmetin) endowed of anti- inflammatory, analgesic, antipyretic, antisecretive and antitussive properties.

US Patent 4,578,481 claims a specific compound, endowed with valuable pharmacological activity, encompassed in the above- mentioned class, precisely 1-methyl-5-p-toluoylpyrrole-2-acetamido- acetic acid guaiacyl ester (which is MED 15, form 1), and a process for its preparation.

The process disclosed in US 4,578,481 presents some drawbacks, since it is not easily applicable on industrial scale and gives low yields.

According to the above-mentioned process, Tolmetin was reacted with N,N’-carbonyldiimidazole in tetrahydrofuran (THF), and aminoacetic acid ethyl ester hydrochloride was added to the reaction mixture.

Following a complex series of washings in order to remove the unreacted starting compounds, and crystallisation from benzene/ cyclohexane, 1-methyl-5-p-toluoylpyrrole-2-acetamidoace-tic acid ethyl ester was obtained. This compound was subsequently transformed into the corresponding acid.

The acid was reacted with N,N’-carbonyldiimidazole obtaining the corresponding imidazolide, to which a solution of guaiacol in

THF was added.

From the reaction mixture, following several washings, neutralisation and crystallisation from benzene/ cyclohexane MED 15 form 1 was obtained.

The main physico-chemical characteristics of MED 15 form 1 are shown in table 1, left column.

The above mentioned process comprises the following steps:

(a) hydrolysing TOLMETIN 1 methyl ester with an alkaline hydroxide in a basic environment, obtaining TOLMETIN 2 alkaline salt;

(b) condensing 2 with isobutylchloroformate 3 obtaining the mixed anhydride 4;

(c) reacting 4 with glycine 5 obtaining 1-methyl-5-p-toluoylpyrrol-2- acetoamidacetic acid 6;

(d) condensing 6 with isobutylchloroformate 3 obtaining the mixed anhydride 7; and

(e) reacting the mixed anhydride 7 with guaiacol 8 obtaining 9 , MED 15, form 2.

The following non-limiting example illustrates the preparation of MED 15, form 2, according to the process of the present invention.

Preparation of 1-methyl-p-toluoylpirrol-2-acetoammidoacetic acid.

A mixture of 500 mL of toluene, 100 g of Tolmetin ethyl ester and 10 g of Terre deco in 1L flask, was heated to 70° C and maintained at this temperature for 20-30 min, under stirring. The mixture was then filtered on pre-heated buckner, and the solid phase washed with 50 mL of heated toluene. The discoloured toluene solution was transferred in a 2 L flask, 15 g of sodium hydroxide (97%) dissolved in 100 mL of water were added thereto.

The solution was heated at reflux temperature and refluxed for 1 hour. 22 mL of isobutyl alcohol were added to the solution which was heated at reflux temperature; water (about 120 mL) was removed completely with Marcusson’s apparatus arriving up to 104-105°C inner temperature.

To a suspension of Tolmetin sodium, cooled under nitrogen atmosphere to -5°C ± 2°C, 0.2 mL of N-methyl Morpholine were added. Maintaining the temperature at 0°C ± 3°C, 53 mL of isobutyl chloroformate were added dropwise in 5-10 min. After about 1 hour the suspension became fluid. Following 3 hours of reaction at 0°C + 3°C, over the glycine solution previously prepared, the mixed anhydride solution was added dropwise. The glycine solution was prepared in a flask containing 230 mL of demineralised water, 47 g of potassium hydrate (90%), cooling the solution to 20°C ± 2, adding 60 g of glycine, and again cooling to 10°C ± 2°C.

To the glycine solution, the mixed anhydride was added dropwise under stirring, in 5-10 min., maintaining the temperature at 20°C ± 2°C.

At the end of the addition, temperature was left to rise to room temperature, 1 hour later the reaction was complete. To the mixture 325 mL of demineralised water were added, the mixture was brought to pH 6.0 +2 using diluted (16%) hydrochloric acid (about 100 mL).

The temperature of the solution was brought to 73°C ±2°C and the pH adjusted to pH 5.0 ±0.2.

The separation of the two phases was made at hot temperature: the toluene phase was set aside for recovering acid-Tolmetin if any, the water phase was maintained at 73°C ±2°C and brought to pH 4.0 ±0.2 using diluted hydrochloric acid.

At the beginning of the precipitation the solution was slowly brought to pH 3.0 ±0.2 using diluted (16%) hydrochloric acid (100 mL).

The mixture was cooled to 15°C ±3°C and after 30 min. filtered. The solid cake was washed with 2×100 mL of demineralised water, the product was dried at 60°C under vacuum till constant weight. 100 g of 1-methyl-p-toluoylpirrol-2-acetoammidoacetic acid were obtained.

Preparation of MED 15, form 2

To a 2 L flask containing 730 mL of toluene, 100 g of dried compound of the above step were dissolved. To this solution 18.8 g of potassium hydrate (tit. 90%) in 65 mL of water were added.

The solution was dried maintaining the internal temperature at 95-100°C, and cooled to 55-60 °C. A solution of potassium hydrogen carbonate was then added and the resulting mixture was dried maintaining the internal temperature at 105°C ±2°C.

The mixture was cooled under nitrogen atmosphere to 5°C

±2°C, 24 mL of isobutyl alcohol and 0.3 mL of N-methyl morpholine were added thereto.

Maintaining the temperature at 10°C ±3°C, 47 mL of isobutyl-chloroformate were added dropwise in 5-10 minutes. The mixture was left to react for two hours at 10°C ±3°C obtaining an anhydride solution, which was added to a guaiacol solution previously prepared.

The guaiacol solution was prepared by loading in a 2L-flask 295 mL of water, 25 g of potassium hydrate (90%), and 0.3 g of sodium metabisulfite.

At the end of the loading the temperature was brought to 35-40°C.

The anhydride was added dropwise in 5- 10 min and the temperature was left to rise to room temperature.

The suspension was kept under stirring for 1 hour and brought to pH 6.0 ±0.5 with diluted hydrochloric acid. The suspension was heated to 70°C ± 5°C and maintained at pH 3-4 with diluted hydrochloric acid.

The phases were separated while hot. The aqueous phase was discharged, and to the organic phase, 250 mL of water were added.

Maintaining the temperature at 70 ±5°C the solution was brought to pH 8.0 ±0.5 with diluted sodium hydrate, the phases were separated while hot and the acqueous phase was discharged.

The organic phase was washed with 250 mL of water. At 70 ± 5°C the phases were separated. The toluene phase was then cleared with dicalite, filtered and left to crystallise.

The mixture was slowly cooled to 30°C – 35°C, the temperature was then brought to 10 ± 3°C and after 1 hour filtered, washed with toluene (2×100 mL).

The product was brought to dryness at 60°C under vacuum, thus giving 100 g of compound MED 15, form 2.

Theoretical yield: 133.7 g; Yield %: 74.8%.

PATENT

https://www.google.com/patents/WO2000032188A2?cl=un

PATENT

CN-100390144 

PATENT

CN 1827597

Example 1: Steps:

Equipped with a trap, 2000ml four-neck reaction flask with a mechanical stirrer and a thermometer, 加入托 US buna 100.0g (0.358mol) and 500ml of toluene, turned stirred and heated under reflux with toluene with water, drying the solution, when When the internal temperature reaches 95-100 ℃, the solution was cooled to 55-60 ℃, dissolved in 30ml of water was added portionwise 11.5g of potassium bicarbonate was added, and refluxed to remove water, until the internal temperature reaches 105 ± 2 ℃. The mixture was cooled to ice-water bath 5 ± 2 ℃, to which was added 24ml of isobutyl alcohol and 0.3ml N- methylmorpholine. The temperature was maintained at 10 ± 3 ℃, with a pressure-equalizing dropping funnel was added dropwise isobutylchloroformate 45.5ml (0.400mol), 10min addition was complete, so the mixture was 10 ± 3 ℃ 2hr reaction solution to obtain an acid anhydride, it has been prepared dropwise glycine guaiacol ester solution, 5-10min the addition was complete. Glycine guaiacol ester solution was prepared by adding 295ml of water in a 2000ml flask, 27g of potassium hydroxide (82%) and 0.3g of sodium metabisulfite, stirring to dissolve, the temperature was controlled at 10 ± 3 ℃, to which was added 82.7g (0.38mol) glycine guaiacol ester hydrochloride and prepared. Dropwise addition, the temperature was raised to room temperature, the reaction 2hr, diluted with 16% hydrochloric acid to adjust the mixture to pH 6.0 ± 0.5. The suspension was heated to 70 ± 5 ℃, and then 16% diluted hydrochloric acid to adjust the pH to 3.5 to 4.5, while hot liquid separation, discarding the aqueous phase, the organic phase was added to 250ml of water, maintaining the temperature at 70 ± 5 ℃ with dilute (2N) sodium hydroxide solution to adjust the solution to pH 8.0 ± 0.5, and then hot liquid separation, aqueous phase was discarded. With 2 × 250ml The organic phase was washed with water, the phases were separated at 70 ± 5 ℃, then clean the toluene organic phase through celite, cooled to room temperature, allowed to set freezer cooling crystallization, filtration, filter cake washed with 2 × 50ml of cold washed with toluene, and dried in vacuo at 60 ℃ to constant weight to give 1- methyl-5-p-toluoylpyrrole-2-acetamido acid guaiacol ester crude 135.5 g, yield 90%. The crude product was recrystallized from acetone to give 1-methyl-5-acyl-2-acetyl-p-toluene amino acid ester of guaiacol boutique 127.9 g, yield 94.4%, mp128.7 ~ 131.9 ℃. Elemental analysis: C, 68.53%; H, 5.76%; N, 6.65%. IR spectrum (KBr tablet method): 3318,3142,2963,1778,1652,1626,1605,1500,1480,1456,13731255 and 1153cm-1.

Example 2: Procedure: equipped with a water separator, 2000ml four-neck reaction flask with a mechanical stirrer and a thermometer, 加入托 US buna 100.0g (0.358mol) and 500ml of toluene, turned stirred and heated under reflux with toluene with water , drying the solution, when the internal temperature reaches 95-100 ℃, the solution was cooled to 55-60 ℃, dissolved in 30ml of water was added portionwise 11.5g of potassium bicarbonate was added, and refluxed to remove water, until the internal temperature reaches 105 ± 2 ℃. The mixture was cooled to ice-water bath 5 ± 2 ℃, to which was added 24ml of isobutyl alcohol and 0.3ml N- methylmorpholine. The temperature was maintained at 10 ± 3 ℃, with a pressure-equalizing dropping funnel dropwise isopropyl 46.5ml (0.41mol), 10-15min addition was complete, the mixture was allowed at 10 ± 3 ℃ reaction 2hr derived anhydride solution, it would have been prepared dropwise to glycine guaiacol ester solution, 5-10min the addition was complete. Glycine guaiacol ester solution was prepared by adding 295ml of water in a 2000ml flask, 27g of potassium hydroxide (82%) and 0.3g of sodium metabisulfite, stirring to dissolve, the temperature was controlled at 10 ± 3 ℃, to which was added 82.7g (0.38mol) glycine guaiacol ester hydrochloride and prepared. Dropwise addition, the temperature was raised to room temperature, the reaction 2hr, diluted with 16% hydrochloric acid to adjust the mixture to pH 6.0 ± 0.5. The suspension was heated to 70 ± 5 ℃, and then 16% diluted hydrochloric acid to adjust the pH to 3.5 to 4.5, while hot liquid separation, discarding the aqueous phase, the organic phase was added to 250ml of water, maintaining the temperature at 70 ± 5 ℃ with dilute (2N) sodium hydroxide solution to adjust the solution to pH 8.0 ± 0.5, and then hot liquid separation, aqueous phase was discarded. With 2 × 250ml The organic phase was washed with water, the phases were separated at 70 ± 5 ℃, then clean the toluene organic phase through celite, cooled to room temperature, allowed to set freezer cooling crystallization, filtration, filter cake washed with 2 × 50ml of cold washed with toluene, and dried in vacuo at 60 ℃ to constant weight to give 1- methyl-5-p-toluoylpyrrole-2-acetamido acid guaiacol ester crude 138.5 g, yield 92%. The crude product was recrystallized from acetone to give 1-methyl-2-acyl-5-toluene acetaminophen acid ester guaiacol boutique 128.8 grams.

Example 3: equipped trap, 2000ml four-neck reaction flask with a mechanical stirrer and a thermometer, 加入托 US buna 100.0g (0.358mol) and 500ml of toluene, turned stirred and heated under reflux with toluene with water, dried solution, when the internal temperature reaches 95-100 ℃, the solution was cooled to 55-60 ℃, dissolved in 30ml of water was added portionwise 10-12.5g potassium bicarbonate solution, refluxing was continued for removal of water, until the internal temperature reaches 105 ± 2 ℃. The mixture was cooled to ice-water bath 5 ± 2 ℃, added thereto 20-30ml of isobutyl alcohol 0.2-0.5mlN- methylmorpholine. The temperature was maintained at 10 ± 3 ℃, with a pressure-equalizing dropping funnel was added dropwise isobutylchloroformate 40.5-48.5ml, 10-15min addition was complete, so the mixture was 10 ± 3 ℃ 2hr reaction solution to obtain an acid anhydride, it has been prepared dropwise glycine guaiacol ester solution, 5-10min the addition was complete. Glycine guaiacol ester solution was prepared by adding 295ml of water in a 2000ml flask, 25-30g of potassium hydroxide (82%) or 15-17 grams of sodium hydroxide and sodium metabisulfite 0.2-0.5g or insurance powder, stirring to dissolve the temperature is controlled at 10 ± 3 ℃, to which is added 80-84g glycine guaiacol ester hydrochloride and prepared. Dropwise addition, the temperature was raised to room temperature, the reaction 2hr, the mixture was adjusted with dilute hydrochloric acid to pH 6.0 ± 0.5. The suspension was heated to 70 ± 5 ℃, with dilute hydrochloric acid to adjust the pH to 3.5 to 4.5, while hot liquid separation, discarding the aqueous phase, the organic phase was added to 250-280ml of water, maintaining the temperature at 70 ± 5 ℃ , adjusted with dilute sodium hydroxide solution and the solution to pH 8.0 ± 0.5, and then hot liquid separation, aqueous phase was discarded. With 2 × 250ml The organic phase was washed with water, the phases were separated at 70 ± 5 ℃, then clean the toluene organic phase through celite, cooled to room temperature, allowed to set freezer cooling crystallization, filtration, filter cake washed with 2 × 50ml of cold washed with toluene, and dried in vacuo at 60 ℃ to constant weight to give 1- methyl-5-p-toluoylpyrrole-2-acetamido acid guaiacol ester crude 130-139 grams. The crude product was recrystallized from acetone to give 1-methyl-5-acyl-2-acetyl-p-toluene amino acid ester boutique guaiacol 120-129 grams.

PATENT

Indian Pat. Appl. (2010), IN 2008MU01617

str1

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides safe, environment friendly, economically viable and commercially feasible processes for the production of Amtolmetin guacil. There are two methods for the preparation of Amtolmetin guacil. The processes for the production of Amtolmetin guacil (I) comprise:
Method-1:
Step-A:- Treating 2-methoxy phenol of Formula VI with 2-(benzyloxycarbonylamino) acetic acid of Formula VII in the presence of an organic base and a condensing agent in chlorinated solvent to yield 2-methoxyphenyl-2- (benzyloxycarbonylamino) acetate of Formula V.
Step-B:- Acid addition salt of 2-methoxyphenyl -2-aminoacetate of Formula II may be prepared by treating 2-methoxyphenyl-2- (benzyloxycarbonylamino) acetate of Formula V with an acid and followed by crystallization in aprotic solvent.
7

Step-C):- l-methyl-5-p-toluoylpyrrole-2-acetic acid of Formula III is reacted with a condensing agent to form-activated moiety, which is reacted with acid addition salt of 2-methoxyphenyl -2-aminoacetate of Formula II in chlorinated solvent to produce Arntolmetin guacil of formula (I).
In a preferred embodiment of present invention, condensing agent used in step-A is selected from group consisting of dicyclohexylcarbodiimide, N, N’-carbonyl diimidazole, hydroxy benzotriazole. The most preferred condensing agent is Dicyclohexyl carbodiimide for the reaction.
The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran, 1,4-dioxane, the most preferred solvent for the reaction methylene dichloride.
In another embodiment of the present invention, the reaction is performed in the presence of an organic base. The organic base is selected from the group consisting of trimethylamine, triethylamine, N-methyl morpholine, N-methylpyrrolidinone, 4-dimethyl Aminopyridine; the most preferred base is 4-dimethyl Aminopyridine.
In a preferred embodiment of present invention, the non-polar solvent used in step-B is selected from group consisting of ethers, hexanes, aromatic hydrocarbons and esters.
In another preferred embodiment of present invention, the most suitable solvents are esters.
In another preferred embodiment of present invention, condensing agent used in step-C is selected from group consisting of dicyclohexylcarbodiimide, N, N’-carbonyl diimidazole, hydroxy benzotriazole. The most preferred condensing agent is N, N’-carbonyl diimidazole for the conversion of the reaction.
8

The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran, 1,4-dioxane, the most preferred solvent for the reaction methylene dichloride.
In yet another embodiment of the present invention, the reaction is performed at a temperature in the range of -20°C to 50°C. Most preferred temperature range for the reaction is (-) 10°C to 0°C.
Method-2:
Treating 2-(2-(I-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid with 2-methoxy phenol in presence of condensing reagent and an organic base to obtain Amtolmetin guacil.
In a preferred embodiment of present invention, the condensing agent used is selected from group consisting of dicyclohexyicarbodiimide, hydroxy benzotriazole or a mixture thereof. The most preferred condensing agent is Dicvclohexyl carbodiimide for the aforementioned reaction.
The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran. 1,4-dioxane, the most preferred solvent for the reaction is methylene dichloride.
In another embodiment of the present invention, the reaction is performed in the presence of an organic base. The organic base is selected from the group consisting of triethylamine, triethylamine, N-methyl morpholine, N-methylpyrrolidinone, 4-dimethyl Aminopyridine; the most preferred base is 4-dimethyl Aminopyridine.
9

In yet another embodiment of the present invention, the reaction is performed at a temperature in the range of -20°C to 50°C. Most preferred temperature range for the reaction is (-) 10°C to 0°C.
In another embodiment of present invention, crude amtolmetin guacil is directly purified using polar and non-polar solvent or a mixture thereof. The most preferred solvents are Isopropanol and toluene.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in anyway.
Preparation of Amtolmetin guacil: Example-1;
Charged MDC (600 ml) and N-benzyloxycarbonyl glycine (100 gm) in a 2L-4NRBF under N2 atmosphere. Reaction mass was cooled down to -5°C. Added N, N’-dicyclohexylcarbodiimide solution (108.5 gm in 300 ml MDC) at-5°C to 0°C. Maintained temperature of reaction for 10 minutes at -5°C to 0°C. Added guaiacol solution (59.36 gm in 180 ml MDC) at -5°C to 0°C followed by addition of N, N-dimethyl aminopyridine (1 gm) at -5°C to 0°C. Monitored the reaction over TLC till the completion of reaction, while maintaining reaction at 0°C. Filtered the undissolved Dicyclohexyl urea and washed the solids with methylene dichloride (125 ml X 2). Collected filtrate and washing. Washed methylene dichloride with water (1000 ml X 2), lN-NaOH (500 ml X 2) and 1% HC1 solution (500 ml X 2), water (500 ml X 2) respectively. Organic methylene dichloride layer was dried over anhydrous sodium sulphate. Filtered sodium sulphate and collected methylene dichloride filtrate. Distilled out methylene dichloride under vacuum below 40°C to get oil. HPLC purity :> 90%
10

Added 33% HBr in acetic acid solution (262,5 gm) into reaction vessel at 25-30°C. Monitored the reaction over TLC till the completion of reaction, while maintaining the reaction at 25-30°C. Added ethyl acetate (1200 ml) slowly at 25-30°C after completion of reaction. Stirred the resultant slurry for 2.5 hours at 25-30°C for complete crystallization. Filtered the solids and washed it with ethyl acetate (200 ml). Dried solids at 50-55°C. Dry weight: 102 gm. HPLC Purity: >98%
Example-2:
Charged MDC (1400 ml) and N, N’-carbonyl di imidazole (69.34 gm) into a 3L-4NRBF under N2 atmosphere. Cooled it down to -15°C. Charged Tolmetin acid (100 gm) slowly into reaction vessel at -10° ± 5°C. Monitored the progress of reaction of over HPLC. After completion of reaction, charged slowly 2-methoxyphenyl-2- (benzyloxy carbonylamino) acetate hydrobromide salt (112.05 gm) at -10° ± 5°C.Monitored the reaction over HPLC. After completion of reaction, washed the organic layer with water (300 ml), 1% NaOH solution (100 ml) and water (300 ml X 2) respectively at 3-8°C. Treated organic layer with activated carbon (2.5 gm) and filtered over hyflow bed. Washed hyflow bed with methylene dichlonde (100 ml X 2). Distilled out methylene dichloride below 40°C under vacuum and stripped off traces with toluene (100 ml X 2) at 50-55°C. Charged toluene (600 ml) and Isopropanol (50ml). Heated the mass to 63-68°C. Stirred the clear solution at 63-68°C for 1 hour. Cooled it down slowly to 30°C followed by further cooling to 5°C. Stirred the resultant slurry for 3 hours at 0-5°C. Filtered solids and washed with toluene (100 ml X 2). Dried solids at 55-60°C under vacuum. Dry Weight: 130 gm. HPLC Purity: >99%
Example-3:
Charged MDC (333 liter) and 2-(2-(l-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid (55.5 Kg) in reactor under N2 atmosphere at 25-30°C. Cool down reaction mass to -15 to -12°C. Added a freshly prepared solution of N, N’-dicyclohexyl
11

carbodiimide (47.39 Kg in 166.5 liter) slowly at -10° ± 5°C within 1 hour. Rinsed the addition funnel with MDC (55.5 liter) and added it to the reaction at -10° ± 5°C. Added guaiacol solution (24.14 Kg in 99.9 liter MDC) to the reaction mass at -10° ± 5°C within 1 hour. Rinsed the addition funnel with MDC (11.1 liter) and added to the reaction -10° ± 5°C. Charged N, N’-dimethyl aminopyridine (0.555 Kg) at -15°C. Maintained temperature of reaction mass at -10° ± 5°C for 3 hours. Monitored the reaction over TLC, After the completion of reaction, filtered the dicyclohexyl urea and washed the solids with MDC (55.5L X 2). Collected MDC filtrate and wash it with water (166.5 L X 2). Collected MDC layer and treated it with activated carbon (2.77 Kg) and filtered through sparkler. Washed the sparkler with MDC (111 L). Distilled out MDC below 40°C under vacuum and stripped off traces with toluene (55.5 L X 2) at 50-55°C. Charge toluene (333L) and Isopropanol (27.75 L). Heated reaction mass to 63-68°C to get a clear solution. Stirred the clear solution at 63-68°C for 1 hour. Cooled it down slowly to 30°C followed by further cooling to 20oC. Stirred the resultant slurry for 2 hours at 17-20°C. Filtered the solids and washed with toluene (55.5 L X 3). Dried the solids at 55-60°C under vacuum. Dry Weight: 48 Kg. HPLC Purity:>99%

PAPER

Synthesis and Process Optimization of Amtolmetin: An Antiinflammatory Agent

Center of Excellence, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupalli, Qutubullapur, R. R. Dist. 500 072 Andhra Pradesh, India, and Center for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
Org. Process Res. Dev., 2010, 14 (2), pp 362–368
DOI: 10.1021/op900284w,

http://pubs.acs.org/doi/full/10.1021/op900284w

†DRL-IPD Communication number: IPDO IPM – 00202
, * Corresponding author. Telephone: +91 40 44346430. Fax: +91 40 44346164. E-mail:rakeshwarb@drreddys.com.,
‡Dr. Reddy’s Laboratories Ltd.
, §Jawaharlal Nehru Technological University.

Abstract

Abstract Image

Efforts toward the synthesis and process optimization of amtolmetin guacil 1 are described. High-yielding electrophilic substitution followed by Wolf−Kishner reduction are the key features in the novel synthesis of tolmetin 2 which is an advanced intermediate of 1.

Amtolmetin guacil
Amtolmetin guacil.png
Clinical data
ATC code none
Identifiers
Synonyms ST-679
CAS Number 87344-06-7 
PubChem (CID) 65655
ChemSpider 59091 Yes
UNII 323A00CRO9 
KEGG D07453 Yes
ChEMBL CHEMBL1766570 
ECHA InfoCard 100.207.038
Chemical and physical data
Formula C24H24N2O5
Molar mass 420.458 g/mol
3D model (Jmol) Interactive image

 

Amtolmetin Guacil
CAS Registry Number: 87344-06-7
CAS Name: N-[[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl]glycine 2-methoxyphenyl ester
Additional Names: N-[(1-methyl-5-p-toluoylpyrrol-2-yl)acetyl]glycine o-methoxyphenyl ester; 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaicil ester
Manufacturers’ Codes: ST-679; MED-15
Trademarks: Eufans (Sigma-Tau)
Molecular Formula: C24H24N2O5
Molecular Weight: 420.46
Percent Composition: C 68.56%, H 5.75%, N 6.66%, O 19.03%
Literature References: Ester prodrug of tolmetin, q.v. Prepn: A. Baglioni, BE 896018; idem, US 4578481 (1983, 1986 both to Sigma-Tau). Pharmacology: E. Arrigoni-Martelli, Drugs Exp. Clin. Res. 16, 63 (1990); A. Caruso et al., ibid. 18, 481 (1992). HPLC determn in plasma: A. Mancinelli et al., J. Chromatogr. 553, 81 (1991). Series of articles on pharmacokinetics and clinical trials:Clin. Ter. 142 (1 pt 2) 3-59 (1993).
Properties: Crystals from cyclohexane-benzene, mp 117-120°. Sol in common organic solvents. LD50 in male mice, rats (mg/kg): 1370, 1100 i.p.; >1500, 1450 orally (Baglioni).
Melting point: mp 117-120°
Toxicity data: LD50 in male mice, rats (mg/kg): 1370, 1100 i.p.; >1500, 1450 orally (Baglioni)
Therap-Cat: Analgesic; anti-inflammatory.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.

“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

/////////Amtolmetin guacil, ST-679, MED-15, Eufans,  87344-06-7, Amtoril®, Artricol®, Artromed®, амтолметин гуацил أمتولمتين غواسيل , 呱氨托美丁

n1(c(ccc1CC(NCC(=O)Oc1c(cccc1)OC)=O)C(=O)c1ccc(cc1)C)C

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FLOW CHEMISTRY ILLUSTRATION

Flow chemistry is also known as continuous flow or plug flow chemistry. It involves a chemical reaction run in a continuous flow stream.  The process offers potential for the efficient manufacture of chemical products. Recent breakthroughs using Vapourtec systems are in production of Tamoxifen (Breast Cancer) and Artemisinin (Malaria).

Reactants are first pumped into a mixing device. Flow continues through a temperature controlled reactor until the reaction is complete. The reactor can be a simple pipe, tube or complex micro-structured device. The mixing device and reactor are maintained at the temperature to promote the desired reaction. The reactants may also be exposed to an electrical flux or a photon flux to promote an electrochemical or photochemical reaction.

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[3 + 2] Dipolar Cycloadditions in Flow Reactors

 

The [3 + 2] dipolar cycloaddition of unstabilized azomethine ylides can be used to construct susbstituted pyrrolidines, which can be useful building blocks in pharmaceutical and natural product synthesis. A common experimental procedure involves in situ generation of the intermediate ylide in the presence of the dipolarophile; however, this technique can produce a significant exotherm when reactive dipolarophiles (e.g., acrylates, maleimides) are employed. Now Fray and co-workers at Pfizer describe efforts to conduct this chemistry using continuous flow technology, which is often beneficial when applied to systems involving highly energetic intermediates ( Tetrahedron Lett.2010, 51, 1026−1029).

The authors provide a description and schematic for the flow apparatus used and optimized the system for flow-rate/residence time, temperature, and pressure. It was found that the residence times could be reduced to 15 min if a higher operating temperature (100 °C) was used. The best conditions were then applied to a series of substrates, but it was determined that differences in reactivity required adjustment of parameters to achieve optimal results. For comparison, the authors also conducted the reaction in typical batch mode and found the yield to be higher. Nonetheless, the flow process was demonstrated to be capable of processing 30 g substrate within 1 h of operation (87% isolated yield after chromatography).

str1

To demonstrate the viability of performing the cycloaddition in flow on a reasonable scale, the Vapourtec™ R2+/R4 was equipped with four heated reaction loops (total volume 40 ml) so that we could react compound 1 with ethyl acrylate under the previously optimised conditions (0.5 M overall in MeCN, 70 C, 10 min). From a reaction on 30 g scale, we obtained compound 3a in 87% yield, after chromatography in only 1 h.

(e) Srihari, P.; Yaragorla, S. R.; Basu, D.; Chandrasekhar, S. Synthesis 2006, 2646. 12. An attractive alternative has been described for generating the azomethine ylide via decarboxylation, for example, N-benzylglycine, paraformaldehyde, toluene, reflux, see: Joucla, M.; Mortier, J. Bull. Soc. Chim. Fr 1988, 579; Rodriguez Sarmiento, R. M.; Wirz, B.; Iding, H. Tetrahedron: Asymmetry 2003, 14, 1547.

[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

  • Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom

Abstract

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20–100 °C, 10–60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77–83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59–63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.

Under continuous flow conditions an azomethine ylide precursor reacts with 12 electron-deficient alkenes to give the corresponding pyrrolidines. The most reactive and therefore hazardous dipolarophiles give the best yields.

image

MORE INSIGHT………..

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen.[1]Hence, the reaction is sometimes referred to as the Huisgen cycloaddition (this term is often used to specifically describe the 1,3-dipolar cycloaddition between an organic azide and an alkyne to generate 1,2,3-triazole). Currently, 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives.

Example of 1,3-dipolar cycloaddition.tif

Mechanistic overview

There were originally two proposals that describe the mechanism of the 1,3-dipolar cycloaddition: first, the concerted pericyclic cycloaddition mechanism, proposed by Rolf Huisgen;[2] and second, the stepwise mechanism involving a diradical intermediate, proposed by Firestone.[3] After much debate, the former proposal is now generally accepted[4]—the 1,3-dipole reacts with the dipolarophile in a concerted, often asynchronous, and symmetry-allowed π4s + π2s fashion through a thermal six-electron Huckel aromatic transition state. Although, there are few examples of stepwise mechanism of the catalyst free 1,3-dipolar cycloaddition reactions for thiocarbonyl ylides,[5] and nitrile oxides[6]

The generic mechanism of a 1,3-dipolar cycloaddition between a dipole and a dipolarophile to give a five-membered heterocycle, via a six-electron transition state. Note that the red curly arrows are conventionally used to denote the reaction process but do not necessarily represent the actual flow of electrons.

Pericyclic mechanism

Huisgen investigated a series of cycloadditions between the 1,3-dipolar diazo compounds and various dipolarophilic alkenes.[2] The following observations support the concerted pericyclic mechanism, and refute the stepwise diradical or the stepwise polar pathway.

  • Substituent effects: Different substituents on the dipole do not exhibit a large effect on the cycloaddition rate, suggesting that the reaction does not involve a charge-separated intermediate.
  • Solvent effects: Solvent polarity has little effect on the cycloaddition rate, in line with the pericyclic mechanism where polarity does not change much in going from the reactants to the transition state.
  • Stereochemistry: 1,3-dipolar cycloadditions are always stereospecific with respect to the dipolarophile (i.e., cis-alkenes giving syn-products), supporting the concerted pericyclic mechanism in which two sigma bonds are formed simultaneously.
  • Thermodynamic parameters: 1,3-dipolar cycloadditions have an unusually large negative entropy of activation similar to that of the Diels-Alder reaction, suggesting that the transition state is highly ordered, which is a signature of concerted pericyclic reactions.

1,3-Dipole

Structure and nomenclature of all second-row 1,3-dipoles consisting of carbon, nitrogen and oxygen centers. The dipoles are categorized as allyl-type or propargyl/allenyl-type based on the geometry of the central atom.

A 1,3-dipole is an organic molecule that can be represented as either an allyl-type or a propargyl/allenyl-type zwitterionic octet/sextet structures. Both types of 1,3-dipoles share four electrons in the π-system over three atoms. The allyl-type is bent whereas the propargyl/allenyl-type is linear in geometry. There are a total of 18 second-row 1,3-dipoles (see structures in the thumbnail on the right).[7]1,3-Dipoles containing higher-row elements such as sulfur or phosphorus are also known, but are utilized less routinely.

Resonance structures can be drawn to delocalize both negative and positive charges onto any terminus of a 1,3-dipole (see the scheme below). A more accurate method to describe the electronic distribution on a 1,3-dipole is to assign the major resonance contributor based on experimental or theoretical data, such as dipole moment measurements[8] or computations.[9] For example, diazomethane bears the largest negative character at the terminal nitrogen atom, while hydrazoic acid bears the largest negative character at the internal nitrogen atom.

Calculated major resonance structures of diazomethane and hydrazoic acid (doi = 10.1021/ja00475a007)

Consequently, this ambivalence means that the termini of a 1,3-dipole can be treated as both nucleophilic and electrophilic at the same time. The extent of nucleophilicity and electrophilicity at each terminus can be evaluated using the frontier molecular orbitals, which can be obtained computationally. In general, the atom that carries the largest orbital coefficient in the HOMO acts as the nucleophile, whereas that in the LUMO acts as the electrophile. The most nucleophilic atom is usually, but not always, the most electron-rich atom.[10][11][12] In 1,3-dipolar cycloadditions, identity of the dipole-dipolarophile pair determines whether the HOMO or the LUMO character of the 1,3-dipole will dominate (see discussion on frontier molecular orbitals below).

Dipolarophile

The most commonly used dipolarophiles are alkenes and alkynes. Heteroatom-containing dipolarophiles such as carbonyls and imines can also undergo 1,3-dipolar cycloaddition. Other examples of dipolarophiles include fullerenes and nanotubes, which can undergo 1,3-dipolar cycloaddition with azomethine ylide in the Prato reaction.

Solvent effects

1,3-dipolar cycloadditions experience very little solvent effect because both the reactants and the transition states are generally non-polar. For example, the rate of reaction between phenyl diazomethane and ethyl acrylate or norbornene (see scheme below) changes only slightly upon varying solvents from cyclohexane to methanol.[13]

Effect of solvent polarity on 1,3-dipolar cycloaddition reactions(doi:10.3987/S(N)-1978-01-0109.)

Lack of solvent effects in 1,3-dipolar cycloaddition is clearly demonstrated in the reaction between enamines and dimethyl diazomalonate (see scheme below).[14] The polar reaction, N-cyclopentenyl pyrrolidine nucleophilic addition to the diazo compound, proceeds 1,500 times faster in polar DMSO than in non-polar decalin. On the other hand, a close analog of this reaction, N-cyclohexenyl pyrrolidine 1,3-dipolar cycloaddition to dimethyl diazomalonate, is sped up only 41-fold in DMSO relative to decalin.

Rate of polar nucleophilic addition reaction versus 1,3-dipolar cycloaddition in decalin and in DMSO (doi:10.1016/S0040-4039(00)70991-9)

Frontier molecular orbital theory

Orbital overlaps in types I, II and III 1,3-dipolar cycloaddition.

1,3-Dipolar cycloadditions are pericyclic reactions, which obey the Dewar-Zimmerman rules and the Woodward–Hoffmann rules. In the Dewar-Zimmerman treatment, the reaction proceeds through a 5-center, zero-node, 6-electron Huckel transition state for this particular molecular orbital diagram. However, each orbital can be randomly assigned a sign to arrive at the same result. In the Woodward–Hoffmann treatment, frontier molecular orbitals (FMO) of the 1,3-dipole and the dipolarophile overlap in the symmetry-allowed π4s + π2s manner. Such orbital overlap can be achieved in three ways: type I, II and III.[15] The dominant pathway is the one which possesses the smallest HOMO-LUMO energy gap.

Type I

The dipole has a high-lying HOMO which overlaps with LUMO of the dipolarophile. A dipole of this class is referred to as a HOMO-controlled dipole or a nucleophilic dipole, which includes azomethine ylide, carbonyl ylide, nitrile ylide, azomethine imine, carbonyl imine and diazoalkane. These dipoles add to electrophilic alkenes readily. Electron-withdrawing groups (EWG) on the dipolarophile would accelerate the reaction by lowering the LUMO, while electron-donating groups (EDG) would decelerate the reaction by raising the HOMO. For example, the reactivity scale of diazomethane against a series of dipolarophiles is shown in the scheme below. Diazomethane reacts with the electron-poor ethyl acrylate more than a million times faster than the electron rich butyl vinyl ether.[16]

This type resembles the normal-electron-demand Diels-Alder reaction, in which the diene HOMO combines with the dienophile LUMO.

doi:10.1016/S0040-4039(01)92781-9

Type II

HOMO of the dipole can pair with LUMO of the dipolarophile; alternatively, HOMO of the dipolarophile can pair with LUMO of the dipole. This two-way interaction arises because the energy gap in either direction is similar. A dipole of this class is referred to as a HOMO-LUMO-controlled dipole or an ambiphilic dipole, which includes nitrile imide, nitrone, carbonyl oxide, nitrile oxide, and azide. Any substituent on the dipolarophile would accelerate the reaction by lowering the energy gap between the two interacting orbitals; i.e., an EWG would lower the LUMO while an EDG would raise the HOMO. For example, azides react with various electron-rich and electron-poor dipolarophile with similar reactivities (see reactivity scale below).[17]

doi:10.1021/ja01016a011

Type III

The dipole has a low-lying LUMO which overlaps with HOMO of the dipolarophile (indicated by red dashed lines in the diagram). A dipole of this class is referred to as a LUMO-controlled dipole or an electrophilic dipole, which includes nitrous oxide and ozone. EWGs on the dipolarophile decelerate the reaction, while EDGs accelerate the reaction. For example, ozone reacts with the electron-rich 2-methylpropene about 100,000 times faster than the electron-poor tetrachloroethene (see reactivity scale below).[18]

This type resembles the inverse electron-demand Diels-Alder reaction, in which the diene LUMO combines with the dienophile HOMO.

doi:10.1021/ja01016a011

Reactivity

Concerted processes such as the 1,3-cycloaddition require a highly ordered transition state (high negative entropy of activation) and only moderate enthalpy requirements. Using competition reaction experiments, relative rates of addition for different cycloaddition reactions have been found to offer general findings on factors in reactivity.

  • Conjugation, especially with aromatic groups, increases the rate of reaction by stabilization of the transition state. During the transition, the two sigma bonds are being formed at different rates, which may generate partial charges in the transition state that can be stabilized by charge distribution into conjugated substituents.
  • More polarizable dipolarophiles are more reactive because diffuse electron clouds are better suited to initiate the flow of electrons.
  • Dipolarophiles with high angular strain are more reactive due to increased energy of the ground state.
  • Increased steric hindrance in the transition state as a result of unhindered reactants dramatically lowers the reaction rate.
  • Hetero-dipolarophiles add more slowly, if at all, compared to C,C-diapolarophiles due to a lower gain in sigma bond energy to offset the loss of a pi bond during the transition state.
  • Isomerism of the dipolarophile affects reaction rate due to sterics. trans-isomers are more reactive (trans-stilbene will add diphenyl(nitrile imide) 27 times faster than cis-stilbene) because during the reaction, the 120° bond angle shrinks to 109°, bringing eclipsing cis-substituents towards each other for increased steric clash.
See Huisgen reference doi:10.1002/anie.196306331.

Stereospecificity

1,3-dipolar cycloadditions usually result in retention of configuration with respect to both the 1,3-dipole and the dipolarophile. Such high degree of stereospecificity is a strong support for the concerted over the stepwise reaction mechanisms. As mentioned before, there are many examples that show that the reactions were stepwise, thus, presenting partial or no stereospecificity.

With respect to dipolarophile

cis-Substituents on the dipolarophilic alkene end up cis, and trans-substituents end up trans in the resulting five-membered cyclic compound (see scheme below).[19]

doi:10.3987/S-1978-01-0147

With respect to dipole

Generally, the stereochemistry of the dipole is not of major concern because only few dipoles could form stereogenic centers, and resonance structures allow bond rotation which scrambles the stereochemistry. However, the study of azomethine ylides has verified that cycloaddition is also stereospecific with respect to the dipole component. Diastereopure azomethine ylides are generated via electrocyclic ring opening of aziridines, and then rapidly trapped with strong dipolarophiles before bond rotation can take place (see scheme below).[20][21] If weaker dipolarophiles are used, bonds in the dipole have the chance to rotate, resulting in impaired cycloaddition stereospecificity.

These results altogether confirm that 1,3-dipolar cycloaddition is stereospecific, giving retention of both the 1,3-dipole and the dipolarophile.

doi:10.1021/ja00983a052

Diastereoselectivity

When two or more chiral centers are generated during the reaction, diastereomeric transition states and products can be obtained. In the Diels-Alder cycloaddition, the endodiastereoselectivity due to secondary orbital interactions is usually observed. In 1,3-dipolar cycloadditions, however, there are two forces that influence the diastereoselectivity: the attractive π-interaction (resembling secondary orbital interactions in the Diels-Alder cycloaddition) and the repulsive steric interaction. Unfortunately, these two forces often cancel each other, causing poor diastereoselection in 1,3-dipolar cycloaddition.

Examples of substrate-controlled diastereoselective 1,3-dipolar cycloadditions are shown below. First is the reaction between benzonitrile N-benzylide and methyl acrylate. In the transition state, the phenyl and the methyl ester groups stack to give the cis-substitution as the exclusive final pyrroline product. This favorable π-interaction offsets the steric repulsion between the phenyl and the methyl ester groups.[22] Second is the reaction between nitrone and dihydrofuran. The exo-selectivity is achieved to minimize steric repulsion.[23] Last is the intramolecular azomethine ylide reaction with alkene. The diastereoselectivity is controlled by the formation of a less strained cisfused ring system.[24]

doi:10.1021/ja00731a056

Directed 1,3-dipolar cycloaddition

Trajectory of the cycloaddition can be controlled to achieve a diastereoselective reaction. For example, metals can chelate to the dipolarophile and the incoming dipole and direct the cycloaddition selectively on one face. The example below shows addition of nitrile oxide to an enantiomerically pure allyl alcohol in the presence of a magnesium ion. The most stable conformation of the alkene places the hydroxyl group above the plane of the alkene. The magnesium then chelates to the hydroxyl group and the oxygen atom of nitrile oxide. The cycloaddition thus comes from the top face selectively.[25]

Directed dipolar cycloaddition.tif

Such diastereodirection has been applied in the synthesis of epothilones.[26]

Use of directed cycloaddition in Epothilones synthesis.tif

Regioselectivity

For asymmetric dipole-dipolarophile pairs, two regioisomeric products are possible. Both electronic/stereoelectronic and steric factors contribute to the regioselectivity of 1,3-dipolar cycloadditions.[27]

Electronic/Stereoelectronic effect

The dominant electronic interaction is the combination between the largest HOMO orbital and the largest LUMO orbital. Therefore, regioselectivity is governed by the atoms that bear the largest orbital HOMO and LUMO coefficients.[28][29]

For example, consider the cycloaddition of diazomethane to three dipolarophiles: methyl acrylate, styrene or methyl cinnamate. The carbon of diazomethane bears the largest HOMO orbital, while the terminal olefinic carbons of methyl acrylate and styrene bear the largest LUMO orbital. Hence, cycloaddition gives the substitution at the C-3 position regioselectively. For methyl cinnamate, the two substituents (Ph v.s. COOMe) compete at withdrawing electrons from the alkene. The carboxyl is the better electron-withdrawing group, causing the β-carbon to be most electrophilic. Thus, cycloaddition yields the carboxyl group on C-3 and the phenyl group on C-4 regioselectively.

doi:10.1021/ja00444a013 and doi:10.1021/ja00436a062

Steric effect

Steric effects can either cooperate or compete with the aforementioned electronic effects. Sometimes steric effects completely outweighs the electronic preference, giving the opposite regioisomer exclusively.[30]

For example, diazomethane generally adds to methyl acrylate to give 3-carboxyl pyrazoline. However, by putting more steric demands into the system, we start to observe the isomeric 4-carboxyl pyrazolines. The ratio of these two regioisomers depends on the steric demands. At the extreme, increasing the size from hydrogen to t-butyl shifts the regioselectivity from 100% 3-carboxyl to 100% 4-carboxyl substitution.[31][32]

ISBN 0-471-08364-X. and Koszinowski, J. (1980) (Ph.D. Thesis)

Synthetic Applications

1,3-dipolar cycloadditions are important routes toward the synthesis of many important 5-membered heterocycles such as triazoles, furans, isoxazoles, pyrrolidines, and others. Additionally, some cycloadducts can be cleaved to reveal the linear skeleton, providing another route toward the synthesis of aliphatic compounds. These reactions are tremendously useful also because they are stereospecific, diastereoselective and regioselective. Several examples are provided below.

Nitrile oxides

1,3-dipolar cycloaddition with nitrile oxides is a widely used masked-aldol reaction. Cycloaddition between a nitrile oxide and an alkene yields the cyclic isoxazoline product, whereas the reaction with an alkyne yields the isoxazole. Both isoxazolines and isoxazoles can be cleaved by hydrogenation to reveal aldol-type β-hydroxycarbonyl or Claisen-type β-dicarbonyl products, respectively.

Nitrile oxide-alkyne cycloaddition followed by hydrogenation was utilized in the synthesis of Miyakolide as illustrated in the figure below.[33]

Application of nitrile oxide in the synthesis of miyakolide.tif

Carbonyl ylides

1,3-dipolar cycloaddition reactions have emerged as powerful tools in the synthesis of complex cyclic scaffolds and molecules for medicinal, biological, and mechanistic studies. Among them, [3+2] cycloaddition reactions involving carbonyl ylides have extensively been employed to generate oxygen-containing five-membered cyclic molecules.[34]

Preparation of Carbonyl Ylides for 1,3-Dipolar Cycloaddition Reactions

Ylides are regarded as positively charged heteroatoms connected to negatively charged carbon atoms, which include ylides of sulfonium, thiocarbonyl, oxonium, nitrogen, and carbonyl.[35] Several methods exist for generating carbonyl ylides, which are necessary intermediates for generating oxygen-containing five-membered ring structures, for [3+2] cycloaddition reactions.

Synthesis of Carbonyl Ylides from Diazomethane Derivatives by Photocatalysis

One of the earliest examples of carbonyl ylide synthesis involves photocatalysis.[36] Photolysis of diazotetrakis(trifluoromethyl)cyclopentadiene* (DTTC) in the presence of tetramethylurea can generate the carbonyl ylide by an intermolecular nucleophilic attack and subsequent aromatization of the DTTC moiety.[36] This was isolated and characterized by X-ray crystallography due to the stability imparted by aromaticity, electron withdrawing trifluoromethyl groups, and the electron donating dimethylamine groups. Stable carbonyl ylide dipoles can then be used in [3+2] cycloaddition reactions with dipolarophiles.

Scheme 1. Photolysis of DTTC in the presence of tetramethylurea. Modified from Janulis, E. P.; Arduengo, A. J. J. Am. Chem. Soc. 1983, 105, 5929.

Another early example of carbonyl ylide synthesis by photocatalysis was reported by Olah et al.[37] Dideuteriodiazomethane was photolysed in the presence of formaldehyde to generate the dideuterioformaldehyde carbonyl ylide.

Scheme 2. Photolysis of Dideuteriodiazomethane with formaldehyde. Modified from Prakash, G. K. S.; Ellis, R. W.; Felberg, J. D.; Olah, G. A. J Am Chem Soc 1986, 108, 1341.
Synthesis of Carbonyl Ylides from Hydroxypyrones via Proton Transfer

Carbonyl ylides can be synthesized by acid catalysis of hydroxy-3-pyrones in the absence of a metal catalyst.[38] An initial tautomerization occurs, followed by elimination of the leaving group to aromatize the pyrone ring and to generate the carbonyl ylide. A cycloaddition reaction with a dipolarophile lastly forms the oxacycle. This approach is less widely employed due to its limited utility and requirement for pyrone skeletons.

Scheme 3. Acid-Catalyzed Synthesis of Carbonyl Ylides from Hydroxy-3-Pyrones. Modified from Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982, 1056.

5-hydroxy-4-pyrones can also be used to synthesize carbonyl ylides via an intramolecular hydrogen transfer.[39] After hydrogen transfer, the carbonyl ylide can then react with dipolarophiles to form oxygen-containing rings.

Scheme 4. Intramolecular Hydrogen Transfer-Mediated Synthesis of Carbonyl Ylides from 5-Hydroxy-4-Pyrones. Modified from Garst, M. E.; McBride, B. J.; Douglass III, J. G. Tetrahedron Lett. 1983, 24, 1675.
Synthesis of α-Halocarbonyl Ylides from Dihalocarbenes

Dihalocarbenes have also been employed to generate carbonyl ylides. The electron withdrawing nature of dihalocarbenes has been exploited by Landgrebe and coworkers for this purpose.[40][41][42] Both phenyl(bromodichloromethyl)mercury and phenyl(tribromomethyl)mercury have been converted to dichlorocarbenes and dibromocarbenes, respectively. The carbonyl ylide can be generated upon reaction of the dihalocarbenes with ketones or aldehydes. However, the synthesis of α-halocarbonyl ylides can also undesirably lead to the loss of carbon monoxide and the generation of the deoxygenation product.

Scheme 5. α-Halocarbonyl Ylide Synthesis via Dihalocarbene Intermediates. Modified from Padwa, A.; Hornbuckle, S. F. Chem Rev 1991, 91, 263.
Synthesis of Carbonyl Ylides from Diazomethane Derivatives by Metal Catalysis

A universal approach for generating carbonyl ylides involves metal catalysis of α-diazocarbonyl compounds, generally in the presence of dicopper or dirhodium catalysts.[43] After release of nitrogen gas and conversion to the metallocarbene, an intermolecular reaction with a carbonyl group can generate the carbonyl ylide. Subsequent cycloaddition reaction with an alkene or alkyne dipolarophile can afford oxygen-containing five-membered rings. Popular catalysts that give modest yields towards synthesizing oxacycles include Rh2(OAc)4 and Cu(acac)2.[44][45]

Scheme 6. Metal-Catalyzed Synthesis of Carbonyl Ylides. Reproduced from Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter, A. G.; Redgrave, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5450.

Mechanism of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds

The universality and extensive use of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl molecules, for synthesizing oxygen-containing five-membered rings, has spurred significant interest into its mechanism. Several groups have investigated the mechanism to expand the scope of synthetic molecules with respect to regio- and stereo-selectivity. However, due to the high turn over frequencies of these reactions, the intermediates and mechanism remains elusive. The generally accepted mechanism, developed by characterization of stable ruthenium-carbenoid complexes[46] and rhodium metallocarbenes,[47] involves an initial formation of a metal-carbenoid complex from the diazo compound. Elimination of nitrogen gas then affords a metallocarbene. An intramolecular nucleophilic attack by the carbonyl oxygen regenerates the metal catalyst and forms the carbonyl ylide. The carbonyl ylide can then react with an alkene or alkyne, such as dimethyl acetylenedicarboxylate (DMAD) to generate the oxacycle.

Scheme 7. Accepted Mechanism of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis (Example Dirhodium Catalyst) of Diazocarbonyl Compounds. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.

However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles.[48] In these cases, the metallocarbene, such as the dirhodium(II)tetracarboxylate carbene, is stabilized through hyperconjugative metal enolate-type interactions.[49][50][51][52]Subsequent 1,3-dipolar cycloaddition reaction occurs through a transient metal-complexed carbonyl ylide. Therefore, a persistent metallocarbene can influence the stereoselectivity and regioselectivity of the 1,3-dipolar cycloaddition reaction based on the stereochemistry and size of the metal ligands.

The dirhodium(II)tetracarboxylate metallocarbene stabilized by πC-Rh→πC=O hyperconjugation. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.

The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole and alkynyl or alkenyl dipolarophiles has been extensively investigated with respect to regioselectivity and stereoselectivity. As symmetric dipolarophiles have one orientation for cycloaddition, only one regioisomer, but multiple stereoisomers can be obtained.[52] On the contrary, unsymmetric dipolarophiles can have multiple regioisomers and stereoisomers. These regioisomers and stereoisomers may be predicted based on frontier molecular orbital (FMO) theory, steric interactions, and stereoelectronic interactions.[53][54]

Scheme 9. Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.
Regioselectivity of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds

Regioselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkynyl or alkenyl dipolarophiles is essential for generating molecules with defined regiochemistry. FMO theory and analysis of the HOMO-LUMO energy gaps between the dipole and dipolarophile can rationalize and predict the regioselectivity of experimental outcomes.[55][56] The HOMOs and LUMOs can belong to either the dipole or dipolarophile, for which HOMOdipole-LUMOdipolarophile or HOMOdipolarophile-LUMOdipole interactions can exist. Overlap of the orbitals with the largest coefficients can ultimately rationalize and predict results.

Scheme 10. Diagram of the Molecular Orbital Interactions of HOMOdipole-LUMOdipolarophile or HOMOdipolarophile-LUMOdipole Between a Carbonyl Ylide Dipole and Alkenyl Dipolarophile.

The archetypal regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by carbonyl ylide dipoles has been examined by Padwa and coworkers.[54][57] Using a Rh2(OAc)4catalyst in benzene, diazodione underwent a 1,3-dipolar cycloaddition reaction with methyl propiolate and methyl propargyl ether. The reaction with methyl propiolate affords two regioisomers with the major resulting from the HOMOdipole-LUMOdipolarophile interaction, which has the largest coefficients on the carbon proximal to the carbonyl group of the carbonyl ylide and on the methyl propiolate terminal alkyne carbon. The reaction with methyl propargyl ether affords one regioisomer resulting from the HOMOdipolarophile-LUMOdipole interaction, which has largest coefficients on the carbon distal to the carbonyl group of the carbonyl ylide and on the methyl propargyl ether terminal alkyne carbon.

Scheme 11. Regioselectivity and Molecular Orbital Interactions of the 1,3-Dipolar Cycloaddition Reaction Between a Diazodione and Methyl Propiolate or Methyl Propargyl Ether. Modified from Padwa, A.; Weingarten, M. D. Chem Rev 1996, 96, 223.

Regioselectivities of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl compounds may also be influenced by the metal through formation of stable metallocarbenes.[48][58] Stabilization of the metallocarbene, via metal enolate-type interactions, will prevent the formation of carbonyl ylides, resulting in a direct reaction between the metallocarbene dipole and an alkynyl or alkenyl dipolarophile (see image of The dirhodium(II)tetracarboxylate metallocarbene stabilized by πC-Rh→πC=O hyperconjugation.). In this situation, the metal ligands will influence the regioselectivity and stereoselectivity of the 1,3-dipolar cycloaddition reaction.

Stereoselectivity and Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds

The stereoselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles has also been closely examined. For alkynyl dipolarophiles, stereoselectivity is not an issue as relatively planar sp2 carbons are formed, while regioselectivity must be considered (see image of the Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles). However, for alkenyl dipolarophiles, both regioselectivity and stereoselectivity must be considered as sp3 carbons are generated in the product species.

1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles can generate diastereomeric products.[52] The exo product is characterized with dipolarophile substituents being cis to the ether bridge of the oxacycle. The endo product is characterized with the dipolarophile substituents being trans to the ether bridge of the oxacycle. Both products can be generated through pericyclic transitions states involving concerted synchronous or concerted asynchronous processes.

One early example conferred stereoselectivity in terms of endo and exo products with metal catalysts and Lewis acids.[59] Reactions with just the metal catalyst Rh2(OAc)4 prefer the exo product while reactions with the additional Lewis acid Yb(OTf)3 prefer the endo product. The endo selectivity observed for Lewis acid cycloaddition reactions is attributed to the optimized orbital overlap of the carbonyl π systems between the dipolarophile coordinated by Yb(Otf)3 (LUMO) and the dipole (HOMO). After many investigations, two primary approaches for influencing the stereoselectivity of carbonyl ylide cycloadditions have been developed that exploit the chirality of metal catalysts and Lewis acids.[52]

Facial Selectivity of the 1,3-Dipolar Cycloaddition Reaction using a Metal Catalyst and Lewis Acid
Rationale for the Endo Selectivity of the 1,3-Dipolar Cycloaddition Reaction with a Lewis Acid

The first approach employs chiral metal catalysts to modulate the endo and exo stereoselectivity. The chiral catalysts, in particular Rh2[(S)-DOSP]4 and Rh2[(S)-BPTV]4 can induce modest asymmetric induction and was used to synthesize the antifungal agent pseudolaric acid A.[60] This is a result of the chiral metal catalyst remaining associated with the carbonyl ylide during the cycloaddition, which confers facial selectivity. However, the exact mechanisms are not yet fully understood.

Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction with Chiral Metal Catalysts

The second approach employs a chiral Lewis acid catalyst to induce facial stereoselectivity after the generation of the carbonyl ylide using an achiral metal catalyst.[61] The chiral Lewis acid catalyst is believed to coordinate to the dipolarophile, which lowers the LUMO of the dipolarophile while also leading to enantioselectivity.

Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction with Chiral Lewis Acid Catalysts

Azomethine ylides

1,3-Dipolar cycloaddition between an azomethine ylide and an alkene furnishes an azacyclic structure, such as pyrrolidine. This strategy has been applied to the synthesis of spirotryprostatin A.[62]

Application of azomethine ylide in the synthesis of spirotryprostatin.tif

Ozone

Ozonolysis is a very important organic reaction. Alkenes and alkynes can be cleaved by ozonolysis to give aldehyde, ketone or carboxylic acid products.

Biological Applications

The 1,3-dipolar cycloaddition between organic azides and terminal alkynes (i.e., the Huisgen cycloaddition) has been widely utilized for bioconjugation.

Copper catalysis

The Huisgen reaction generally does not proceed readily under mild conditions. Meldal et al. and Sharpless et al. independently developed a copper(I)-catalyzed version of the Huisgen reaction, CuAAC (for Copper-catalyzed Azide-Alkyne Cycloaddition), which proceeds very readily in mild, including physiological, conditions (neutral pH, room temperature and aqueous solution).[63][64] This reaction is also bioorthogonal: azides and alkynes are both generally absent from biological systems and therefore these functionalities can be chemoselectively reacted even in the cellular context. They also do not react with other functional groups found in Nature, so they do not perturb biological systems. The reaction is so versatile that it is termed the “Click” chemistry. Although copper(I) is toxic, many protective ligands have been developed to both reduce cytotoxicity and improve rate of CuAAC, allowing it to be used in in vivo studies.[65]

Copper catalyzed AAC.tif

For example, Bertozzi et al. reported the metabolic incorporation of azide-functionalized sugars into the glycan of the cell membrane, and subsequent labeling with fluorophore-alkyne conjugate. The now fluorescently labeled cell membrane can be imaged under the microscope.[66]

Metabolic labeling with GlcNAz and click chemistry.tif

Strain-promoted cycloaddition

To avoid toxicity of copper(I), Bertozzi et al. developed the Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC) between organic azide and strained cyclooctyne. The angle distortion of the cyclooctyne helps to speed up the reaction, enabling it to be used in physiological conditions without the need for the catalyst.[67]

Strained promoted AAC.tif

For instance, Ting et al. introduced an azido functionality onto specific proteins on the cell surface using a ligase enzyme. The azide-tagged protein is then labeled with cyclooctyne-fluorophore conjugate to yield a fluorescently labeled protein.[68]

Enzyme-mediated labeling with azidooctanoic acid and SPAAC.tif
CLIP

Computational Studies of 1,3-Dipolar [3 + 2]-Cycloaddition Reactions of Fullerene-C60 with Nitrones

Richard Tia*, Jacob Amevor and Evans Adei

Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

*Corresponding Author:
Richard Tia
Department of Chemistry
Kwame Nkrumah University of Science and Technology
Kumasi, Ghana
Tel: 00233(0) 243574146
E-mail: richtiagh@yahoo.com

Received date: May 12, 2014; Accepted date: Septem

Image result for [3 + 2] Dipolar Cycloadditions

References

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///////////////[3 + 2] Dipolar Cycloadditions,  Flow Reactors

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Jan 082017
 

CrystEngComm, 2017, 19,335-345
DOI: 10.1039/C6CE01645F, Paper
Ruimiao Chang, Qiang Fu, Yong Li, Mingchan Wang, Wei Du, Chun Chang, Aiguo Zeng
In this paper, four amorphous samples of loratadine were prepared by quench-cooling the melted drug at different temperatures.
In this paper, four amorphous samples of loratadine were prepared by quench-cooling the melted drug at different temperatures. With these samples, the crystallization tendencies were tested by powder X-ray diffraction (PXRD), and non-isothermal cold crystallization kinetics was investigated by using differential scanning calorimetry (DSC) and the molecular dynamics both in super-cooled liquid and in glassy states was analyzed by using broadband dielectric spectroscopy (BDS) at a temperature range from 213 to 393 K. From the PXRD results, it was established that the four amorphous loratadine samples were apt to crystallize at a temperature below the glass transition temperature. From the DSC results, it was found that the non-isothermal crystallization mechanism of these four loratadine forms was similar. However, the fast crystallization tendency (low physical stability) was also observed for the amorphous loratadine which was obtained at a low quench-cooling temperature. The tendency was analyzed based on the BDS results which demonstrated that rapid molecular mobility could generate a low physical stability and was closely related to Johari–Goldstein relaxation. These results suggested that loratadine had a weak frustration against crystallization and its physical stability was affected by the quench-cooling temperature. This study laid a foundation for choosing the right technique to prepare the amorphous form of loratadine and improving its physical stability.

Crystallization and relaxation dynamics of amorphous loratadine under different quench-cooling temperatures

Ruimiao Chang,ab   Qiang Fu,a   Yong Li,c  Mingchan Wang,a   Wei Du,a   Chun Changa and  Aiguo Zeng*a  
*Corresponding authors
aSchool of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, PR China
E-mail: agzeng@mail.xjtu.edu.cn
Fax: +86 29 82655382
Tel: +86 29 82655136
bCollege of Pharmacy, Shanxi Medical University, Taiyuan, PR China
cDepartment of Pharmacy, Shanxi Dayi Hospital, Taiyuan 030032, PR China
CrystEngComm, 2017,19, 335-345

DOI: 10.1039/C6CE01645F

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Jan 062017
 

Figure imgf000014_0002

E/Z

WO2014147647

White solid; Ή NMR (200 MHz, CDC13 + CC14): δ 2.38-2.49 ( m,0.8H, E- Form), 2.63-2.73 ( m,1.2H, Z-Form), 3.53 (s, 2H), 3.68 (s, 3H), 3.75 (m, 0.8H, E-Form), 3.81 (t, J=6.3 Hz, 1.2H), 5.19 (brs, 2H), 5.73 (t, J=7.8 Hz, 0.6H, Z-Form), 6.06 (t, J=7.8 Hz, 0.4H, E-Form), 6.70 (d, J=8.2 Hz, 0.4 H, E-Form), 6.79 (d, J=8.2 Hz, 0.6 H, Z- Form), 7.00-7.34 (m, 6H), HRMS m/r. Calculated for C20H2,O4-325.1434, observed- 325.1437.

 

CLIP 2

SCHEMBL18101051.png

Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-dihydrobenz[b,e]oxepin-2-acetate 

916243-39-5  cas

mf C20 H20 O4
Dibenz[b,​e]​oxepin-​2-​acetic acid, 6,​11-​dihydro-​11-​(3-​hydroxypropylidene)​-​, methyl ester, (11Z)​-
Molecular Weight, 324.37
 white colorless crystal;
1H NMR (CDCl3, 300 MHz) δ 7.34–7.23 (m, 4H), 7.17 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.74 (t, J = 7.5 Hz, 1H), 5.18 (brs, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.69 (s, 3H), 3.53 (s, 2H), 2.68 (dt, J = 7.5, 6.1 Hz, 2H);
13C NMR (CDCl3, 75 MHz): δ 172.4, 154.6, 145.3, 141.4, 133.6, 132.1, 130.0, 129.1, 127.5, 126.2, 125.7, 124.0, 119.7, 70.5, 62.6, 52.1, 40.1, 33.3;
MS ESI (+) m/z 325 [M + H]+.
Org. Process Res. Dev., 2012, 16 (2), pp 225–231
DOI: 10.1021/op200312m
CLIP 3
Synthesis 2013; 45(24): 3399-3403
DOI: 10.1055/s-0033-1340008
str1
CLICK ON IMAGE
1H AND 13C NMR PREDICT

“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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