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Method for synthesizing rivaroxaban

A synthesis method and technology of rivaroxaban, applied in the direction of organic chemistry and the like, can solve the problems of many steps, low yield and high requirements for operating conditions, and achieve the effects of low cost, high yield and reduced dosage

Inactive Publication Date: 2012-11-21
HUNAN NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of intermediate synthesis, this scheme requires high operating conditions and many steps, resulting in low yield

Method used

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  • Method for synthesizing rivaroxaban
  • Method for synthesizing rivaroxaban
  • Method for synthesizing rivaroxaban

Examples

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Effect test

reference example 1

[0044] Preparation of compound Ⅰ (S)-1-chloro-3-[(4-chloro-E-benzylidene)-amino]-propan-2-ol

[0045]

[0046] Method A

[0047] Dissolve 20.0 g (142.9 mmol) of p-chlorobenzaldehyde in 80 ml of anhydrous methanol, add 13.7 ml (191.8 mmol of ammonia) of concentrated ammonia water, stir for 20 min, then add dropwise 13.3 g (143.8 mmol) of (S)-(+) -Epichlorohydrin, reacted at 20°C for 12 h; then raised the temperature to 40°C for 2 h; TLC monitored the complete reaction of p-chlorobenzaldehyde, concentrated under reduced pressure, recrystallized from toluene and n-heptane, and obtained 1.28 g of white snowflake-like crystals, obtained The rate is 85%.

[0048] Method B

[0049] Dissolve 1.12 g (7.80 mmol) of p-chlorobenzaldehyde in 5 ml of anhydrous methanol, add 1 ml (containing 20.00 mmol of ammonia) ammonia saturated methanol solution, stir for 20 min, then add dropwise 0.66 g (7.20 mmol) (S) -(+)-Epichlorohydrin, reacted at 20°C for 12 h; then raised the temperature to...

reference example 2

[0052] Preparation of compound Ⅰ (S)-1-chloro-3-[(4-methoxy-E-benzylidene)-amino]-propan-2-ol

[0053]

[0054] Dissolve 1.36 g (10.0 mmol) of 4-methoxybenzaldehyde in 5 ml of anhydrous methanol, add 1 ml (containing 20.00 mmol of NH 3 ) ammonia saturated methanol solution, stirred for 20 min, then added dropwise 0.92 g (10.0 mmol) (S)-(+)-epichlorohydrin, reacted at 20 °C for 12 h, then raised the temperature to 40 °C for 2 h; TLC monitored 4- Methoxybenzaldehyde was completely reacted, concentrated under reduced pressure, and recrystallized from toluene and n-heptane to obtain 2.08 g of white snowflake crystals with a yield of 92%.

[0055]1 H-NMR (CDCl 3 ) δ: 3.69 (2 H, bs), 3.80 (5 H, m), 4.15 (1 H, s), 7.41 (2 H, d, J =8.0 Hz), 7.69 (2 H, d, J =8.0 Hz), 8.33 (1 H, s)

Embodiment 1

[0057] Preparation of compound Ⅱ 4-(morpholin-3-onephenyl)-carbamate methyl ester

[0058]

[0059] Dissolve 0.3 g (1.56 mmol) 4-(4-aminophenyl)-3-morpholinone in 5 ml ethyl acetate, then add 0.36 g (4.29 mmol) NaHCO 3 and 2 ml of water, cooled to 0°C, added dropwise 0.15 ml (1.88 mmol) of methyl chloroformate and 0.8 ml of chloroform, gradually warmed to room temperature, and then continued to react for 1 h, TLC monitored the reaction was complete; then added 10 ml of acetic acid Extracted with ethyl ester, washed the organic layer with water, concentrated under reduced pressure, and dried in vacuo at 40°C to obtain 0.39 g of white solid with a yield of 100%.

[0060] 1 H-NMR (CDCl 3 ) δ: 3.73 (2 H, m), 3.78 (3 H, s), 4.03 (2 H, m), 4.33 (2 H, s), 6.69 (1 H, s), 7.27 (2 H, d, J =9.0 Hz), 7.42 (2 H, d, J =8.0Hz)

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Abstract

The invention relates to a method for synthesizing rivaroxaban, in particular to a method for preparing rivaroxaban from 4-(4-aminophenyl)-3-morpholinone. The method is easy to operate for synthesizing the rivaroxaban, does not adopt toxic substances, is high in yield of rivaroxaban and low in cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of rivaroxaban, in particular to a method for preparing rivaroxaban from 4-(4-aminophenyl)-3-morpholinone. Background technique [0002] The scientific name of rivaroxaban is 5-chloro-N-[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinone)phenyl]-1,3-oxazole Alkyl-5-base]-2-thiophenecarboxamide, its structural formula is as follows: [0003] [0004] Rivaroxaban is a novel inhibitor of blood coagulation factor Xa, which can be used for the prevention and treatment of thrombotic diseases. [0005] WO 01 / 47919 discloses a process for the preparation of rivaroxaban from 4-(4-aminophenyl)-3-morpholinone (1): [0006] [0007] However, the impurities are not easy to separate during the reaction of this scheme, and column chromatography is required for separation and purification. In addition, some raw materials are not easy to recycle and are not suitable for the preparation of rivaroxaban on an industrial scale. [...

Claims

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Application Information

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IPC IPC(8): C07D413/14
Inventor 唐博徐广宇张明忠
Owner HUNAN NORMAL UNIVERSITY
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