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New technology for synthesizing rivaroxaban intermediate

A technology of compound and action, applied in the fields of heterocyclic chemistry and nitrogen-oxygen heterocyclic chemistry, can solve the problems of high price, difficult separation and purification, and high toxicity of reagents, achieve high industrial application and economic value, increase reaction yield, and reduce price cheap effect

Active Publication Date: 2015-04-29
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The purpose of the present invention is to overcome the disadvantages of the above-mentioned prior art, such as expensive starting raw materials, high reagent toxicity, serious equipment corrosion, difficult separation and purification, and difficult industrialization, and to provide a new synthetic method for rivaroxaban intermediates

Method used

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  • New technology for synthesizing rivaroxaban intermediate
  • New technology for synthesizing rivaroxaban intermediate
  • New technology for synthesizing rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: the preparation of formula b-1 compound

[0063]

[0064] Add 4-(4-aminophenyl)morpholin-3-one (20.0g, 104mmol) into a 1000mL three-neck flask, then add 350mL of acetone, stir to dissolve, then add an aqueous solution of sodium bicarbonate (19.5g, 195mmol) 170mL; under the condition of 0~5℃, benzyl chloroformate (15.6mL, 109mmol) was added dropwise over 30 minutes, after the drop was completed, the reaction was continued for 20 hours under the condition of 20~45℃, and the reaction was completed. Filtration to obtain a light gray solid; recrystallization from acetone-water mixed solution to obtain 27.10 g of benzyl 4-(3-oxomorpholinyl))carbamate in the form of white powder, with a yield of 79.8%.

[0065] 1 H NMR (CDCl 3 , Me 4 Si, 400Mz): δ3.70(t, J=5.2Hz, 2H), 4.00(t, J=5.2Hz, 2H), 4.31(s, 2H), 5.20(s, 2H), 6.99(bs, 1H ), 7.20(d, J=8.8Hz, 2H), 7.34-7.42(m, 7H);

[0066] 13 C NMR (CDCl 3 , Me 4 Si, 100Mz): δ49.95, 64.15, 67.00, 68.55, 199.57, 12...

Embodiment 2

[0068] Embodiment 2: the preparation of formula b-2 compound

[0069]

[0070] Get 4-(4-aminophenyl)morpholin-3-ketone (20g, 104mmol) and chloroformic acid-(4-chloro)benzyl ester (22g, 107mmol) in the same way as in Example 1, to obtain formula b -2 compound 26.7g, yield 71.2%.

[0071] MS(EI+): 360[M+].

Embodiment 3

[0072] Embodiment 3: the preparation of formula b-3 compound

[0073]

[0074] Get 4-(4-aminophenyl)morpholin-3-ketone (20g, 104mmol) and chloroformic acid-(2-nitro)benzyl ester (23g, 107mmol) in the same way according to the method of Example 1, to obtain the formula Compound b-3 was 33.0 g, and the yield was 85.6%.

[0075] MS(EI+): 371[M+].

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Abstract

Disclosed in the present invention are a synthetic Rivaroxaban intermediate and a preparation method thereof. The method comprises: morpholine-3-one and 4-fluoro nitrobenzene are used as the raw materials to obtain a compound of formula b, then the compound of formula b is reacted with the compound of formula c or c' in the presence of a base to obtain the compound of formula d, wherein the compound of formula d is an intermediate commonly used for preparing Rivaroxaban. Also disclosed in the present invention is that the compound of formula b is directly reacted with the compound of formula f or f' in the presence of a base to obtain Rivaroxaban. In these formulae, R is an aryl radical, and X is a halogen.

Description

technical field [0001] The invention relates to the technical field of heterocycle chemistry, in particular to the technical field of nitrogen-oxygen heterocycle chemistry. Background technique [0002] Rivaroxaban, chemical name: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- 1,3-Oxazolidin-5-yl}-methyl)-2-thiophene carboxamide is the world's first direct oral factor Xa inhibitor, used to prevent and treat venous thrombosis, especially for the treatment of myocardial Infarction, angina, etc. [0003] [0004] A lot of research work has been carried out on the preparation of rivaroxaban. Among the existing synthetic routes, each route has its own uniqueness and also has some shortcomings. At present, the common synthetic routes at home and abroad mainly include the following types. [0005] Route 1: The route announced in the patent document CN1262551 authorized by Bayer in China is as follows: [0006] [0007] Wherein NMP is N-methylpyrrolidone, EDCI ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/32C07D413/14
CPCC07D265/32C07D413/14
Inventor 李贵杰郑建兵高红军车大庆
Owner ZHEJIANG JIUZHOU PHARM CO LTD