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Polymorphic Forms of Teriflunomide

IP.com Disclosure Number: IPCOM000237636D
Publication Date: 2014-Jun-28
Document File: 5 page(s) / 275K

Publishing Venue

The IP.com Prior Art Database

Related People

Dr. Dhananjay Sathe: AUTHOR [+4]

Abstract

The present publication describes polymorphic forms of Teriflunomide.

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 52% of the total text.

Page 01 of 5

Polymorphic Forms of Teriflunomide

Teriflunomide chemically identified as 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2- butenamide is used as Immunosuppressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide which is an active metabolite of Leflunomide was first disclosed and claimed in U.S. Pat. No. 5,679,709, but this application does not mention the process of preparation.

U.S. Pat. No. 5,494,911 discloses process for preparation of Teriflunomide in as shown in given below.

  O N

O CF3

NH2

Cl

O CF3

NH

+

ACN

 O N

O CF3

NH MeOH, NaOH conc. HCl OH

CN

O CF3

NH

 O N

The process involves reacting 5-methylisoxazole-4-carbonyl chloride with 4- trifluoromethylaniline in acetonitrile to give Leflunomide.

Leflunomide upon hydrolysis with aqueous sodium hydroxide solution in methanol, followed by acidification gives Teriflunomide.

Leflunomide chemically identified as 5-methylisooxazole-4-carboxylic acid-(4- trifluoromethyl)anilide is disclosed in European specification 13,376 and the process for the preparation of the same have also be disclosed in a number of publications and patent literatures. One such patent document (US 4,284,786) describes the process variants for the synthesis of Leflunomide.

1


Page 02 of 5

We herein wish to report the polymorphic patterns observed when attempting the preparation of Teriflunomide by the processes mentioned in the prior art.

Process followed using Example 4 (A) of US'911, gives the crude Lef...