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Method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one

An aminomethyl and aminophenyl technology, applied in the field of pharmaceutical synthesis, can solve the problems of expensive raw materials of epoxy compounds, unsuitable for industrial production, large energy consumption, etc., and achieve the effects of less pollution, easy operation and high yield

Active Publication Date: 2015-10-14
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The disadvantage of the above-mentioned route is that the epoxy compound raw material is expensive, the reaction time is long, the energy consumption is large, and it is not suitable for industrialized production

Method used

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  • Method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one
  • Method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one
  • Method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: Preparation of N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (formula III):

[0059]

[0060] In this embodiment, X=Cl in the above reaction formula.

[0061] Add 194.7g (1.8mol) of 1,4-diaminobenzene, 47.4g (0.6mol) of pyridine and 900ml of tetrahydrofuran into the reaction flask, stir evenly, cool down to 10°C to 20°C, and slowly add 2 -(2-Chloroethoxy)acetyl chloride 46.8g (0.3mol), the temperature of the dropping process was controlled at 10°C to 20°C, and the dropping time was controlled at 5 hours. Ethyl acetate:triethylamine=30:20:1, volume ratio) the raw materials basically disappear, stop the reaction, distill THF under reduced pressure (-0.1MPa~-0.09MPa) and recover excess 1,4-diaminobenzene, Add a mixed solvent of 600ml ethyl acetate and 300ml acetone, raise the temperature and reflux to dissolve the residual oil, drop to about 10°C for crystallization for 5 hours, filter, and dry under reduced pressure to obtain 61.8g of off-white intermedi...

Embodiment 2

[0063] Embodiment 2: Preparation of N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (formula III):

[0064] Add 129.8g (1.2mol) of 1,4-diaminobenzene, 31.6g (0.4mol) of pyridine and 600ml of tetrahydrofuran into the reaction flask, stir evenly, cool down to 10°C to 20°C, and slowly add 2 -(2-Chloroethoxy)acetyl chloride 31.2g (0.2mol), the temperature of the dropping process was controlled at 10°C to 20°C, and the dropping time was controlled at 3 hours. Ethyl acetate:triethylamine=30:20:1, volume ratio) the raw materials basically disappear, stop the reaction, distill THF under reduced pressure (-0.1MPa~-0.09MPa) and recover excess 1,4-diaminobenzene, Add a mixed solvent of 400ml ethyl acetate and 200ml acetone, raise the temperature and reflux to dissolve the residual oil, drop to about 10°C for crystallization for 5 hours, filter, and dry under reduced pressure to obtain 41.8g of off-white intermediate III, with a molar yield of 91.7 %, HPLC purity 97.8%.

[0065] The detec...

Embodiment 3

[0066] Embodiment 3: Preparation of 4-(4-aminophenyl)-3-morpholinone (formula IV):

[0067]

[0068] Add 45.6g (0.2mol) N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (formula III) prepared in Example 1, 250ml dichloromethane, 82.8g (0.6mol) potassium carbonate, 6.4g (0.02mol) tetrabutylammonium bromide, stir evenly, cool the reaction system to 0°C to 20°C, keep stirring for 5 hours, control in TLC (dichloromethane:methanol=20: 1, volume ratio), the raw materials basically disappeared. Remove insolubles by filtration, wash the organic layer with 80ml of purified water, separate the liquids, evaporate the organic layer to dryness under reduced pressure (-0.08MPa~-0.06MPa), add 150ml of acetone and stir for 3 hours, precipitate crystals, filter, and dry under reduced pressure to obtain 4-(4-aminophenyl)-3-morpholinone 35.2g, molar yield 91.6%, HPLC purity 98.5%.

[0069] The detection data of the title product obtained by mass spectrometry analysis are as follows: HR-MS (ESI...

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Abstract

The invention provides a method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one, wherein the method includes the steps of (1) performing a one-step cyclization reaction to an intermediate N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide to prepare 4-(4-aminophenyl)-3-morpholinone; and (2) carrying out a ring-opening reaction with an epoxy compound, a substitution reaction, a cyclization reaction and like to the 4-(4-aminophenyl)-3-morpholinone to obtain the key intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one, of rivaroxaban. The method is high in yield, is less in pollution, is free of an expensive metal palladium for performing nitro-reduction during the process and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} Process for the preparation of morpholin-3-ones. Background technique [0002] The chemical formula of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one is as follows: [0003] [0004] 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one is a new anticoagulant One of the important intermediates of Varoxaban. Rivaroxaban (Rivaroxaban), developed by Bayer AG, is the world's first direct oral factor Xa inhibitor for the prevention and treatment of blood clots. Rivaroxaban is a highly selective direct inhibitor of factor Xa, which prevents the intrinsic and extrinsic pathways of the coagulation cascade system by inhibiting coagulation factor Xa, thereby inhibiting the formation of thrombin thrombus. [0005] At present, the synthetic route of 4-{4-[(5...

Claims

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Application Information

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IPC IPC(8): C07D413/10C07D413/14
CPCY02P20/55C07D413/10C07D413/14
Inventor 王威徐虹窦麒麟
Owner NEW FOUNDER HLDG DEV LLC