Processes for the preparation of linezolid intermediate

A technology of linezolid and pure linezolid, applied in the field of preparation of linezolid intermediates, capable of solving the problems of low yield of linezolid

Inactive Publication Date: 2008-02-20
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lower yield of linezolid due to necessary workup required for recovery

Method used

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  • Processes for the preparation of linezolid intermediate
  • Processes for the preparation of linezolid intermediate
  • Processes for the preparation of linezolid intermediate

Examples

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preparation example Construction

[0046] A process for the preparation of linezolid disclosed in Example 5 of the '792 patent, wherein the corresponding azide (III) is reduced to the corresponding amine (II) by hydrogenation using ethyl acetate as a solvent. In contrast, the hydrogenation in the reduction method disclosed in the present invention is carried out in the absence of ethyl acetate solvent, or in various solvents or solvent systems using ammonium formate as a reducing agent.

[0047] In one embodiment of the invention, the reduction process is carried out by catalytic hydrogenation, said method comprising:

[0048] (a) R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) is selected from the following except ethyl acetate Organic solvent mix: C 1 -C 8 Straight or branched fatty alcohols, C 6 -C 12 Aromatic hydrocarbons, and mono-, di-, tri-C 1 -C 4 Alkyl-substituted or unsubstituted benzenes, C other than ethyl acetate 1 -C 4 Alkyl esters and chlorinated aromatic hydroc...

Embodiment

[0088] Example 1 - Comparative Example, according to U.S. Patent No. 5,688,792

[0089] Preparation of linezolid from an azide (III) intermediate by catalytic hydrogenation

[0090] Add 6g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and 150ml ethyl acetate in 1L reactor, then Add 0.6g Pd / C. The system was flushed 3 times with nitrogen and 3 times with hydrogen. The pressure of the hydrogen gas was set to 1.5 atm. The reaction mixture was stirred at RT and monitored by periodic TLC or HPLC until complete. The reaction mixture was filtered through celite and the resulting solution was treated with acetic anhydride at RT in the presence of triethylamine. The precipitate was filtered off and dried to obtain crystalline form IV of linezolid (I) containing 3.2% of bis-linezolid (IV).

Embodiment 2

[0091] Example 2 - Preparation of Linezolid from an Azide (III) Intermediate by Catalytic Hydrogenation

[0092] Add 9g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and 150ml toluene in 1L reactor, then add 0.6 g Pd / C and 20ml ammonium hydroxide. The system was flushed 3 times with nitrogen and 3 times with hydrogen. The pressure of the hydrogen gas was set to 1.5 atm. The reaction mixture was stirred at RT and monitored by periodic TLC or HPLC until complete. The reaction mixture was filtered through celite and the resulting solution was treated with 1.5-5 equiv of acetic anhydride at RT. The formed precipitate was filtered off and dried to give Linezolid (I). No trace of bis-linezolid (4) was detected, indicating that no more than 0.01% (w / w) of bis-linezolid (4) was present.

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Abstract

The present invention provides improved methods of converting R-N-(4-morpholiyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) to the intermediate S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) that involve the production of fewer by-products than previous methods. The amine (II) may then be converted into linezolid (I) of high chemical purity with respect to the inactive R-enantiomer and bis-linezolid (IV), and is in high yield, without the need for tedious, complicated purification steps, such as chromatography.

Description

[0001] Cross References to Related Applications [0002] This application claims provisional serial numbers 60 / 656,778 filed February 24, 2005, serial numbers 60 / 656,646 filed February 24, 2005 and provisional serial numbers 60 / 690,822 filed June 14, 2005 application, which is incorporated herein by reference. field of invention [0003] The present invention relates to the conversion of the intermediate R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide into the intermediate S-N-(4-morpholine An improved process for the production of -3-fluorophenyl)-2-oxo-5-oxazolidinyl-methylamine, and the use of said process for the preparation of linezolid. Background of the invention [0004] Linezolid [(S)N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is an antimicrobial agent . Linezolid is an oxazolidinone with the empirical formula C 16 h 20 FN 3 o 4 , have the structure of following formula (I): [0005] [0006] Linezolid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20
Inventor S·法恩T·尼达姆V·布劳德
Owner TEVA PHARMA IND LTD
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