Method for preparing linezolid

A technology of linezolid and a synthesis method, applied in the field of drug synthesis, can solve problems such as danger, and achieve the effects of stable yield, high yield and easy operation

Inactive Publication Date: 2013-01-30
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above route is slightly simpler than other synthetic routes, but because the side chain oxazolidinone is achiral, but linezolid itself is chiral, so the product has to be resolved, and theoretically only half of it can be obtained. product
At the same time, this route has to go through the conversion from hydroxyl to amino, and sodium azide is used, which has certain risks.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of (S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] from 3-fluoro-4-morpholinobromobenzene Methyl]acetamide

[0030]

[0031] Purified CuI (0.22mmol, 42mg), anhydrous K 2 CO 3 (7.35mmol, 1.02g), 3-fluoro-4-morpholino bromobenzene (4.41mmol, 1.15g) and acetyloxazolidinone (4.41mmol, 0.70g) were put into a 50mL two-port round bottom with a condenser in the flask. Evacuate and flush the bottle three times with nitrogen and blanket with nitrogen. A solution of (±)-1,2-cyclohexanediamine (0.22 mmol, 25 mg) in 1,4-dioxane (10 mL) was added via syringe, followed by stirring at 110° C. for 20 hours. The reaction was cooled to room temperature and filtered through celite, then washed with dichloromethane (2 x 50 mL). The organic layers were combined and concentrated, and the residue was separated and purified by silica gel column. The eluent is ethyl acetate:petroleum ether (60-90°C) (2:1) to obtain (S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-...

Embodiment 2

[0034] Preparation of (S)-N-[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]tert from 3-fluoro-4-morpholinobromobenzene butoxycarbamide methane

[0035]

[0036] Purified Cul (0.22mmol, 42mg), anhydrous K 2 CO 3 (7.35mmol, 1.02g), 3-fluoro-4-morpholinyl bromobenzene (4.41mmol, 1.15g) and Boc-oxazolidinone (4.41mmol, 0.95g) were dropped into a 50mL two-port circle with a condenser in the bottom flask. Evacuate and flush the bottle three times with nitrogen and blanket with nitrogen. A solution of (±)-1,2-cyclohexanediamine (0.22 mmol, 25 mg) in 1,4-dioxane (10 mL) was added via syringe, followed by stirring at 110° C. for 20 hours. The reaction was cooled to room temperature and filtered through celite, then washed with dichloromethane (2 x 50 mL). The organic layers were combined and concentrated, and the residue was separated and purified by silica gel column. The eluent is ethyl acetate:petroleum ether (60-90°C) (3:1) to obtain (S)-N-[3-(3-fluoro-4-morpholin...

Embodiment 3

[0039] Preparation of (S)-N-[3- (3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methylamine

[0040]

[0041](S)-N-[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]benzylaminomethane (1mmol, 385mg), formic acid in methanol Solution (10mL, 4.4%) and fresh palladium carbon (10%, 50mg) were added in the hydrogenation bottle, in 5atm of hydrogen, stirred at room temperature for 15 hours, filtered to remove the catalyst, concentrated and passed through silica gel (eluent was acetic acid Ethyl ester: Petroleum ether (60-90°C) (1:4)) to separate (S)-N-[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5- Oxazolidinyl]methylamine 271 mg (92% yield). 1 H NMR (CDCl 3 , 400MHz) δ1.47(s, 2H), 3.05(t, J=4.5Hz, 4H), 3.87(t, J=4.5Hz, 4H), 2.95-4.03(m, 4H), 4.64-4.70(m , 1H), 6.93(t, J=9.1Hz, 1H), 7.13-7.15(dd, J 1 =8.8Hz,J 2 = 1.4Hz, 1H), 7.45-7.49 (dd, J 1 =14.5Hz,J 2 =2.4Hz, 1H)

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Abstract

The invention relates to a method for preparing linezolid. The method comprises the following steps of: reacting 3-fluorine-4-morpholinyl bromobenzene used as a raw material, with a chiral oxazolidinone compound in the presence of a catalyst, so as to directly obtain the linezolid, or to obtain the linezolid after conversion. Compared with the existing method for synthesizing linezolid, the method disclosed by the invention is simple in route, convenient to operate, slight in pollution and stable in yield.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to linezolid ([(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl ] Methyl] acetamide] synthetic method. Background technique [0002] Linezolid is an antibacterial agent with the chemical name [(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl ]methyl]acetamide] is an antimicrobial agent with laboratory C 16 h 20 FN 3 o 4 , the CAS number is 165800-03-3, and the structure is as follows (I): [0003] [0004] US Patent No. 5688792, European Patent No. 717738, Israeli Patent No. 110802, Canadian Patent No. 2168560, International Patent Publication No. WO95 / 07271, No. WO200509353 and No. WO20066008754 disclose linezolid and its preparation method . [0005] Relatively speaking, the preparation method of the document ORGANIC LETTERS, Volume 5, Issue 7, 2003, 963-965 is relatively simple: [0006] [0007] The above route is slightly simpler than othe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20
Inventor 刘颜李雁武袁建勇贾云灿
Owner CHONGQING MEDICAL UNIVERSITY
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