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Crystalline forms of linezolid intermediate

a linezolid intermediate and crystalline form technology, applied in the field of solid state chemistry of the linezolid intermediate, can solve the problem of producing an undesirable level of reaction by-products

Inactive Publication Date: 2006-11-16
TEVA PHARM USA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The novel crystalline forms of the intermediate amine exhibit improved purity and stability, reducing by-product formation and enhancing the production of linezolid, with each form having unique PXRD patterns for identification and quantification of impurities, thus addressing the issues of reaction by-products and storage stability.

Problems solved by technology

These reaction conditions lead to the production of an undesirable level of reaction by-products, and, following the acetylation of the intermediate amine (II) to linezolid (I), to undesirably high levels of bis-linezolid (IV).

Method used

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  • Crystalline forms of linezolid intermediate
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  • Crystalline forms of linezolid intermediate

Examples

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example 1

Preparation of Intermediate Amine (II) Crystalline Form B

[0034] In a 1L reactor, 6 g R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged with 150 ml ethyl acetate, followed by 0.6 g 10% Pd / C. The system was flushed 3 times with nitrogen and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT and the reaction followed by TLC or HPLC until completion. The reaction mixture was filtered through celite and the solution was evaporated to obtain 4.6 g S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) as a white solid. The crystals were analyzed by PXRD and showed a novel form of) the intermediate amine (II) (Form B, 91.7% total purity by HPLC).

example 2

Preparation of Intermediate Amine (II) Crystalline Form C

[0035] In a 10L reactor, 150 g R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged, followed by 15 g Pd / C in 5L toluene. Finally 500 ml ammonium hydroxide was added. The system was flushed 3 times with nitrogen and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT and the reaction followed by TLC or HPLC until completion. The reaction mixture was filtered through celite. S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) precipitated on standing and / or cooling as a white solid, was filtered, and dried at 50° C. overnight. The crystals obtained were analyzed by PXRD and showed a novel form of the intermediate amine (II) (Form C, 98.6% total purity by HPLC).

example 3

Preparation of Intermediate Amine (II) Crystalline Form A

[0036] In a three necked flask, 6.4 g R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged, followed by 2.5 g ammonium formate, 23 ml ethanol, and 2.6 g zinc powder. The reaction mixture was stirred at RT and the reaction followed by TLC or HPLC until completion. 60 ml acetone were then added. The reaction mixture was filtered and by evaporation S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) was obtained as a solid. The crystals obtained were analyzed by PXRD and showed a novel form of the intermediate amine (II) (Form A, 96.5% total purity by HPLC).

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Abstract

The present invention relates to novel crystalline forms of the linezolid intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine referred to herein as Form A, Form B, and Form C.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of provisional application Ser. Nos. 60 / 656,778, filed Feb. 24, 2005, 60 / 656,646, filed Feb. 24, 2005, and 60 / 690,822, filed Jun. 14, 2005, which are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to the solid state chemistry of the linezolid intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine. BACKGROUND OF THE INVENTION [0003] Linezolid [(S)—N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C16H20FN3O4 and the following structure (I): [0004] Linezolid is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5°. Linezolid, as well as a process for its preparation, is disclosed in U.S. Pat. No. 5,688,792 (Example ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377C07D413/02
CPCA61K31/5377C07D413/14C07D413/10C07D263/20A61P31/14
Inventor KOLTAI, TAMASNIDAM, TAMARBRAUDE, VIVIANAFINE, SERGUEI
Owner TEVA PHARM USA INC
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