Preparation methods of anticoagulant and key intermediate of anticoagulant

A technology of anticoagulant drugs and intermediates, which is applied in the field of preparation of anticoagulant drugs and their key intermediates, can solve the problems of complex components, many side reactions, and affecting the reaction yield, and achieve simple and easy process. The effect of the operation

Active Publication Date: 2012-10-24
CHANGZHOU PHARMA FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

We researched the experimental method reported in this patent and found two shortcomings. First, in the process of preparing N-chloroacetylaminoethanol from the reaction of aminoethanol and chloroacetyl chloride, since aminoethanol structure has amino and Hydroxyl active group, it is difficult to obtain the target product with high selectivity when reacting with chloroacetyl chloride, and the target product is obtained by washing and extraction in the post-treatment, but N-chloroacetylaminoethanol is very soluble in water, and the hydrophobic solvent is in It is difficult to extract it from water in the post-treatment process, try a variety of extraction solvents, the yield is extremely low, and the product is oily, with complex components, it is directly used in the next step without purification, and there are many side reactions; second,...

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  • Preparation methods of anticoagulant and key intermediate of anticoagulant
  • Preparation methods of anticoagulant and key intermediate of anticoagulant
  • Preparation methods of anticoagulant and key intermediate of anticoagulant

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Experimental program
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Embodiment 1

[0029] Embodiment 1: the preparation of 4-[(4-aminophenyl)-]3-morpholinone (II)

[0030] 1.1 Preparation of N-{2-(O-chloroacetyl)-hydroxyethyl}-chloroacetamide

[0031] Suspend 255g of potassium carbonate in 1400ml of dichloromethane, cool to 0°C, add 173.7g of chloroacetyl chloride dropwise for about 1 hour, after the addition is complete, add 100ml of ethanolamine in dichloromethane solution (containing 40g of ethanolamine), dropwise Adding time is about 3 hours. After the addition is complete, react at 0°C for 30 minutes, then raise the temperature to 20°C for 3 hours. After the reaction is completed, cool to 0°C, add 400ml of water, separate layers, wash the organic layer with 400ml×2 water, dry over anhydrous sodium sulfate, filter, concentrate to dryness, add 200ml of methyl tert-butyl ether, heat to dissolve, Crystallize at 0°C for 1 hour, filter, and dry to obtain 118 g of a white solid, with a yield of 83%. 1 H-NMR (CDCl 3 ): δ3.6-3.7 (m, 2H) δ4.09 (s, 2H) δ4.11 (s...

Embodiment 2

[0040] Embodiment 2: the preparation of rivaroxaban

[0041] 2.1 Preparation of (5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-5-yl]-phenyl}-morpholin-3-one hydrogensulfate

[0042] 26g 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholine)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-iso Indole-1,3(2H)-dione was suspended in 195ml of absolute ethanol, 31.2g of 25% methylamine aqueous solution was added to the reaction solution, the temperature was raised to 65°C, the temperature was kept for 2 hours, 5g of activated carbon was added, and filtered. Add 10 g of concentrated sulfuric acid dropwise, after the addition is complete, cool to 20° C. for crystallization for 1 hour, filter, beat with 50 ml of ethanol, and dry to obtain 20.9 g of white solid with a yield of 87%.

[0043] 2.2 The preparation method of rivaroxaban (1)

[0044] 167g 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-5-yl]-phenyl}-morpholin-3-one sulfhydryl Suspend in 500ml of dichloromethane at room temperature, add 135g of triethy...

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Abstract

The invention relates to a synthesis method of an anticoagulant and a key intermediate, namely 3-morpholinone and 4-[(4-nitrophenyl)]-3- morpholinone, of the anticoagulant. The synthesis of intermediate uses aminoethanol and chloroacetyl chloride as starting materials. And the intermediate is obtained through condensation, transesterification, cyclization, recondensation and reduction reaction. The operation is simple and suitable for industrial production. Dichloromethane or triethylamine is used as a solvent in the synthesis process of the product. The product is obtained after simple post-treatment. The purity of HPLC (high performance liquid chromatography) is more than or equal to 99.5%. The process is simple and easy to operate, and is suitable for industrial production.

Description

technical field [0001] The invention relates to an improved synthesis process of anticoagulant rivaroxaban and a synthesis method of key intermediates 3-morpholinone and 4-[(4-aminophenyl)]-3-morpholinone. Background technique [0002] Rivaroxaban is a new anticoagulant compound, the Chinese name is 5-chloro-nitrogen-((5S)-2-oxo-3-[-4-(3-oxo-4-morpholinyl)phenyl] -1,3-oxazolidin-5-yl-2-thiophene-carboxamide. This compound is first disclosed in patent WO01 / 47919A1, and rivaroxaban is a small molecule high-efficiency FXa inhibitor for hip or knee The prevention of venous thromboembolism after joint replacement has excellent in vivo activity and bioavailability. At the same time, rivaroxaban is undergoing clinical trials for other indications to determine its use in atrial fibrillation and acute coronary syndrome potential benefits. [0003] Patent WO01 / 47919A1 discloses the chemical synthesis of rivaroxaban and intermediates, the synthetic route is as follows: [0004] ...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D265/32
Inventor 孙海江孙光祥王敏峰付军
Owner CHANGZHOU PHARMA FACTORY
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