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Preparation method of rivaroxaban and intermediate thereof and intermediate compound

A technology for rivaroxaban and compounds, which is applied in the preparation of organic compounds, preparation of aminohydroxy compounds, chemical instruments and methods, etc., can solve the problems of unobtainable raw materials, low yield and high cost, and achieves easy availability of raw materials and high production efficiency. High rate and low cost effect

Inactive Publication Date: 2012-04-11
汕头经济特区鮀滨制药厂
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by the present invention is to overcome the defects of the existing rivaroxaban and its intermediates, such as difficult raw materials, long route, high cost and low yield, etc., and provide a Preparation method of rivaroxaban and its intermediate and intermediate compound

Method used

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  • Preparation method of rivaroxaban and intermediate thereof and intermediate compound
  • Preparation method of rivaroxaban and intermediate thereof and intermediate compound
  • Preparation method of rivaroxaban and intermediate thereof and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The synthesis of embodiment 1 compound 3

[0048]

[0049] Add 13.9g (0.15mol) (S)-epichlorohydrin and 20mL methanol to a 250mL eggplant-shaped bottle, then add 20g (0.1mol) dibenzylamine, and stir the mixture at room temperature for 24h. TLC shows that the raw material has disappeared, and remove it under reduced pressure. Methanol and excess epichlorohydrin, obtain dope (1), [M+H + ]: 290.1. It was directly used in the next reaction without purification.

[0050] Add the above-prepared product (1) into a 1L eggplant-shaped bottle, add 400mL 25-28% ammonia water and 200mL methanol, stir at room temperature for 2 days, remove methanol under reduced pressure, and extract the aqueous phase with dichloromethane 3 times (3*200mL) The combined organic layers were washed with saturated brine. Dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to 150 mL dichloromethane solution (2) for the next reaction.

[0051] 1 H-NMR (400MH, CDCl 3 )...

Embodiment 2

[0053] The synthesis of embodiment 2 compound 4

[0054]

[0055] In the nitrogen 500mL eggplant-shaped bottle, add p-bromoiodobenzene 58.6g (0.2mmol), 3-morpholinone 24.3g (0.24mmol), anhydrous potassium phosphate 106g (0.5mmol), cuprous iodide 3.81g ( 0.02mmol), and anhydrous dioxane 300mL, then add N,N'-dimethylethylamine 1.8g (0.02mmol, 2.16mL), heat to 110 degrees (internal temperature), react for 24h, TLC shows the reaction complete, cooled to room temperature, added ice water, extracted with ethyl acetate (3*200mL), combined the organic layers, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 35.8 g of off-white solid (4), the product The yield is 70%, and the purity is 96%.

[0056] 1 H-NMR (400MH, CDCl 3 )δ7.73(d, J=8.8Hz, 1H), 7.53(d, J=8.8Hz, 1H), 7.25(d, J=8.8Hz, 1H), 7.11(d, J=8.8HZ, 1H) , 4.33(s, 2H), 4.02(m, 2H), 3.75(m, 2H); MS: 256.1 / 258.1(1:1) (M+H + ).

Embodiment 3

[0057] The synthesis of embodiment 3 compound 5

[0058]

[0059] In a 500mL eggplant-shaped bottle replaced with nitrogen, add 13.7g (0.053mmol) of bromide (4), 19g (0.064mmol) of oxazolidinone derivative (3), 15g (0.107mmol) of anhydrous potassium carbonate, and Copper 1.03g (0.0053mmol), and anhydrous dioxane 150mL, then add N,N'-dimethylethylamine 0.5g (0.0053mmol, 0.61mL), heat to 110 degrees (internal temperature), react for 24h , TLC showed that the reaction was complete, cooled to room temperature, added ice water, extracted with ethyl acetate (3*150mL), combined organic layers, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column chromatography to obtain 21.5g of white solid, Yield 86%, purity 97%.

[0060] 1 H-NMR (400MH, CDCl 3 )δ7.44(m, 2H), 7.31(m, 10H), 7.25(m, 3H), 4.56(m, 1H), 4.34(s, 2H), 4.03(dd, J=4.2, 3.6Hz, 2H ), 3.75(m, 6H), 3.50(m, 2H), 3.48(q, J=6.4Hz, 1H), 2.84(m, 2H); MS: 472.2(M+H ...

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Abstract

The invention discloses a preparation method of intermediate of rivaroxaban of formula 6, which comprises the following steps of: carrying out reaction of removing benzyl protecting group of amino to the compound 5 in a solvent. The invention also discloses a preparation method of rivaroxaban and an intermediate compound thereof. The preparation method disclosed by the invention has the advantages of shorter process, lower cost, easily acquired material and high production rate, and the prepared product is suitable for industrial production.

Description

technical field [0001] The present invention specifically relates to a preparation method of rivaroxaban and its intermediates and intermediate compounds. Background technique [0002] The formation of thrombus is an important pathogenic factor of cardiovascular diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. Antithrombotic therapy has always been the core of rescue measures and prevention strategies for such diseases. Antithrombotic therapy mainly targets platelets and thrombin. Antithrombotic drugs are mainly divided into two categories: antiplatelet drugs and anticoagulant drugs. Antiplatelet drugs mainly include: cyclooxygenase inhibitors, adenosine diphosphate (ADP) receptor inhibitors and GP II b / IIIa receptor inhibitors; anticoagulant drugs mainly include classic heparin, low molecular weight heparin, Three types of dibeans anticoagulants and new anticoagulant drugs. In general surgical patients, if there is no prevent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D413/10C07C215/08C07C213/04
CPCY02P20/55
Inventor 不公告发明人
Owner 汕头经济特区鮀滨制药厂
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