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Preparation method of 5-aminomethyl oxazolidone compound

A technology for aminomethyl oxazolidinone and compound is applied in the field of preparation of 5-aminomethyl oxazolidinone compounds, and can solve the problems of low yield of aminolysis products, harsh reaction conditions, many reaction steps and the like, Achieve the effect of high optical purity of the product, mild reaction conditions and few reaction steps

Inactive Publication Date: 2014-05-21
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above method has many reaction steps and harsh reaction conditions. Explosive sodium azide and hydrazine hydrate need to be used. Hydrogen and noble metal palladium are needed for azide group reduction, and the overall yield is low, and the intermediate needs to be purified by column chromatography. And other issues
In order to overcome the above problems, we have studied the reaction conditions of the above-mentioned routes, and found through many tests that when 3-chloro-2-hydroxypropylaniline compounds (2) are reacted with a large excess of various ammonia, although Chlorine atoms can be converted into amino groups, but more secondary amines and tertiary amine by-products are generated at the same time, resulting in a lower than 30% yield of the desired ammonolysis product; and we also found that chloromethyl oxazolidinones ( 6) When reacting with a large excess of various ammonia, the reaction can hardly occur, and there is no expected amine formation
[0011] In summary, the synthesis techniques of linezolid and rivaroxaban disclosed in the current literature have harsh reaction conditions (low temperature and anhydrous operation), many reaction steps, The overall yield is low, the "three wastes" are seriously discharged during the preparation process, and the reaction operation and post-treatment process are cumbersome and other deficiencies, which make the preparation cost of linezolid and rivaroxaban relatively high, and the large-scale preparation is limited

Method used

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  • Preparation method of 5-aminomethyl oxazolidone compound
  • Preparation method of 5-aminomethyl oxazolidone compound
  • Preparation method of 5-aminomethyl oxazolidone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] ( R )- N -Methoxycarbonyl- N Preparation of -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline (3-1a)

[0025]

[0026] Add to the reaction bottle ( R )- N -(3-Chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline 0.05mol, calcium oxide 0.1mol and 2-methyltetrahydrofuran 100mL, stir well, put in ice bath and cool to 0- At 5°C, add 0.055 mol of methyl chloroformate dropwise, and stir at room temperature for 5 hours after the drop; after the reaction, filter and wash the filter cake with a small amount of 2-methyltetrahydrofuran. Washed with saturated NaCl aqueous solution, the organic layer was washed with anhydrous NaCl 2 SO 4 Dry, filter, and evaporate the solvent under reduced pressure to obtain a yellow oil ( R )- N -Methoxycarbonyl- N -(3-Chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline, yield 92.0%, was directly used in the next reaction. 1 HNMR (CDCl 3 )d:7.04-6.85(m,3H,Ar-H),4.06-4.01(m,1H,CHOH),3.85(t, J =4.8Hz, 4H, 2×OCH 2 ),3.74(s,3H,O...

Embodiment 2

[0028] ( S )- N -Methoxycarbonyl- N Preparation of -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline (3-1b)

[0029]

[0030] Operation process is the same as embodiment 1, just will ( R )- N -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline ( S )- N -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline was substituted, calcium oxide was substituted with triethylamine, 2-methyltetrahydrofuran was substituted with dichloromethane to obtain a yellow oil ( S )- N -Methoxycarbonyl- N -(3-Chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline, yield 90.0%, was directly used in the next reaction.

Embodiment 3

[0032] ( dl )- N -Methoxycarbonyl- N Preparation of -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline (3-1c)

[0033]

[0034] Operation process is the same as embodiment 1, just will ( R )- N -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline ( dl )- N -(3-chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline was substituted, calcium oxide was substituted by potassium carbonate, 2-methyltetrahydrofuran was substituted by acetone, and yellow oil ( dl )- N -Methoxycarbonyl- N -(3-Chloro-2-hydroxypropyl)-3-fluoro-4-morpholinoaniline, yield 96.0%, was directly used in the next reaction.

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Abstract

The invention discloses a preparation method of a 5-aminomethyl oxazolidone compound ((b)I( / b)), and the method comprises the steps of by taking a racemized or optically active 3-halogen-2-hydroxy propyl aniline compound as a starting raw material, carrying out reaction on the starting raw material and corresponding chloro-carbonic ester or Boc anhydride in proper solvent under alkaline condition to obtain a 3-halogen-2-hydroxy propyl-1-acyl aniline compound ((b)3( / b)), carrying out ammonolysis reaction on the compound (3) in the presence or absence of alkaline to obtain the racemized or optically active 5-aminomethyl oxazolidone compound (I). Formula, in the formula, R1 represents morpholinyl or 3-oxygen-4-morpholinyl, R2 represents H or F, and the compound is racemate, (i)(S)( / i)-optical isomer or (i)(R)( / i)-optical isomer.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a method for preparing a class of 5-aminomethyloxazolidinone compounds with chemical structures as shown in (I). [0002] [0003] Where: R 1 Represents morpholinyl or 3-oxo-4-morpholinyl; R 2 Represents H or F; the compound is a racemate, (S) - optical isomers, or (R) - optical isomers. Background technique [0004] Linezolid (linezolid), chemical name ( S )-5-(acetamidomethyl)-3-[(3-fluoro-4-morpholinyl)phenyl]-1,3-oxazolidin-2-one is a new type of oxazolidinone developed by Pharmacia & Upjohn Oxazolidinone antibacterial drugs, first launched in the United States in April 2000, with the trade name Zyvox, are clinically used to treat pneumonia and comprehensive skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA), as well as those caused by vancomycin-resistant Bacteremia caused by enterococci (VREF) or penicillin-resistant Streptococcus pneumonia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20C07D413/10
CPCC07D263/20C07D413/10
Inventor 邓勇李岩肖柑媛
Owner SICHUAN UNIV