Process for making linezolid

A technology of linezolid and oxazolidine, which is applied in the field of preparing compound linezolid, and can solve the problems of low yield, explosion hazard, harsh reaction conditions, etc.

Inactive Publication Date: 2013-06-05
SYNTHON BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the known methods have various disadvantages, such as severe toxicity and explosion hazard of azide salts, use of long reaction times and dangerous reagents (hydrazine, methylamine) in the phthalimide intermediate, in Low yields and many by-products in the ammonium hydroxide process, or harsh reaction conditions in the reaction with ammonia

Method used

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  • Process for making linezolid
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  • Process for making linezolid

Examples

Experimental program
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Effect test

preparation example Construction

[0041] The raw material in the method for preparing linezolid according to the present invention is a compound of general formula (VII)

[0042]

[0043] wherein L is a leaving group, typically a halo group or an alkylsulfonyloxy or arylsulfonyloxy group. A "halo" group includes a chloro or bromo group, preferably a chloro group. "Alkyl" includes C 1 -C 4 Alkyl, and preferably methyl. "Aryl" includes phenyl, which may optionally be replaced by at least one C 1 -C 4 Alkyl, nitro, hydroxyl, C 1 -C 4 Alkoxy substituted, and preferably p-tolyl or p-nitrophenyl.

[0044] Said compounds are known in the art or can be prepared according to methods known in the art, for example from the corresponding hydroxy-methyl compound of formula (X).

[0045]

[0046] The second reaction accompaniment is a metal salt of a diformylamide of formula (VIII).

[0047]

[0048] "Me + " is typically sodium or potassium, preferably sodium. Compound (VIII) is known in the art and can g...

Embodiment 1

[0063] Example 1 3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxo Oxazolidine-5(S)-ylmethyl)amine (II) hydrochloride

[0064] To a 5ml reaction flask equipped with a magnetic stirring bar was added 225mg (0.5mmol) of compound (VII) [L = p-toluenesulfonyloxy], followed by 96mg (1mmol) of sodium diformylamide and 2.5ml of dimethylformamide. The vessel was immersed in an oil bath preheated to 85°C and the mixture was stirred for 1 hour at an external temperature of 85°C. The volatiles were evaporated at reduced temperature (30 mbar, 60° C.), the residue was mixed with 10 ml of ethyl acetate and extracted with 10 ml of water. The organic layer was evaporated to dryness (45 °C, 25 mbar) to give a white solid.

[0065] The solid was mixed with 10 ml of methanol and 0.438 ml of concentrated hydrochloric acid (5.00 mmol) was added. The reaction mixture was warmed to 65°C in an oil bath and stirred at this temperature for 2 hours. The mixture was evaporated under reduced pressure and...

Embodiment 2

[0066] Example 2 3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxo Oxazolidine-5(S)-ylmethyl)amine (II)

[0067] A 250ml three-necked round-bottomed flask equipped with a paddle mechanical stirrer and an Ar inlet combined with a temperature sensor was placed under an argon atmosphere and added sodium diformylamide (5.6g) and compound (VII) [L = p-toluene Sulfonyloxy] (20.8 g). N,N-Dimethylformamide (52ml) was added and the reaction mixture was heated to 85°C for 2 hours. Hydrochloric acid (98ml) was carefully added to the reaction mixture so that the internal temperature did not exceed 96°C. The heterogeneous reaction mixture was heated to 85°C and the reaction was continued for 2.5 hours. The reaction mixture was transferred to a 500ml round bottom flask and cooled in an ice water bath. Dichloromethane (150ml) was added to the flask. The mixture was stirred vigorously and a solution of NaOH (54.0 g) in water (100 ml) was added such that the internal temperature did not exce...

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Abstract

The present invention relates to a process for making the compound 3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)amine of formula (II) and / or an acid addition salt thereof comprising: a) reacting the compound of formula (VII) wherein L is a leaving group, with a metal salt of diformylamide of formula (VIII) wherein Me+ is a sodium or potassium cation; and b) subjecting the reaction product of the step (a) comprising, alone or in admixture, compounds of formula (IXa) and / or (IXb), to a reaction with an acid. The invention further relates to a method for preparing linezolid by acetylation of the compound of formula (II).

Description

Background of the invention [0001] The present invention relates to an improved process for the preparation of the compound linezolid. [0002] Linezolid is a pharmaceutically active compound that can be used as an antibacterial agent, for example, in the treatment of diabetic food infections caused by Gram-positive bacteria. Linezolid is represented by the following formula (I). [0003] [0004] Commercially available pharmaceutical compositions are sterile isotonic solutions for intravenous infusion, tablets for oral administration and aqueous suspensions for oral administration. They are marketed under the trade name ZYVOX by the company Pfizer. [0005] The molecule of linezolid has an asymmetric carbon in the molecule, allowing the formation of two enantiomers; the commercially available compound is the (S)-enantiomer. In the above-mentioned commercially available compositions, linezolid exists in the form of free base. [0006] Hereinafter, the name Linezolid wil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor P·巴托斯
Owner SYNTHON BV
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