Preparation methods of anticoagulant and key intermediate of anticoagulant

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] ...

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, The experimenters found that 3-morpholinone is very unstable in alkaline aqueous solution, and the method reported in the patent is to post-treat and add acid solution to adjust the pH value. Since the reaction is carried out under strong alkali conditions, during the acid adjustment process, start The stage system is under alkaline conditions, and the target product is decomposed in large quantities, which greatly affects the reaction yield

[0016] Other methods of morpholinone synthesis are shown in US5002937A1, WO2006 / 63293A2, and the disclosed route is obtained by reacting aminoethanol with ethyl chloroacetate or methyl in the presence of sodium or sodium hydride, but there are harsh reaction conditions (using metal Sodium or sodium hydrogen), the disadvantages of high risk of operation and low yield are not suitable for industrial production

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