Preparation method of rivaroxaban

Abstract

The invention discloses a preparation method of rivaroxaban. With (S)-4-chloro-3-hydroxybutyronitrile (compound 1) as a raw material, the rivaroxaban is obtained through phthalimide potassium salt substitution, cyano hydrolysis, Hofmann rearranging cyclization, Ullmann coupling, hydrazinolysis and amidation. The rivaroxaban is introduced into a chiral center instead of (S)-epoxy chloropropane which is volatile, high in toxicity and unstable; the safety is relatively high; precious catalyst, raw materials and reagent with large environmental pollution are avoided in the total process in the total synthetic route; the overall synthesis process is small in pollution and easy to treat; the yield and the purity of various steps are high; the preparation method is environmentally friendly, low in production cost and suitable for industrial production.

Description

technical field

[0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of rivaroxaban. Background technique

[0002] Rivaroxaban (rivaroxaban), the chemical name is 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl]methyl]-2-thiophenecarboxamide is a highly selective blood coagulation factor Xa inhibitor jointly developed by Bayer and Johnson & Johnson. Launched in Canada, it is used to prevent and treat deep vein thrombosis in patients undergoing knee or hip replacement surgery. Compared with traditional anticoagulants, it has the characteristics of convenient administration, rapid onset of effect, and high safety. Its chemical structural formula is as follows:

[0003]

[0004] Several synthetic methods have been reported about the preparation of rivaroxaban at present, as follows:

[0005] Route 1: The patent document CN1262551C authorized by German Bayer Company in Ch...

Examples

Embodiment 1-1

[0059] Embodiment 1-1: Synthesis of Compound 2

[0060] Add phthalimide potassium salt (55.6g, 0.3mol), (S)-4-chloro-3-hydroxybutyronitrile (compound 1, 35.9g, 0.3mol) and 300mL DMF into the reaction flask, heat to 80 After reacting at ℃ for 3 h, the reaction solution was poured into 400 mL of water, stirred for 10 min, filtered with suction, and dried under reduced pressure to obtain 63.7 g of white solid (Compound 2), with a yield of 92.3%.

Embodiment 1-2

[0061] Embodiment 1-2: the synthesis of compound 2

[0062] Add phthalimide potassium salt (66.7g, 0.36mol), (S)-4-chloro-3-hydroxybutyronitrile (compound 1, 35.9g, 0.3mol) and 300mL DMF into the reaction flask, heat to 70 After reacting at ℃ for 4 h, the reaction solution was poured into 400 mL of water, stirred for 10 min, filtered with suction, and dried under reduced pressure to obtain 66.9 g of white solid (Compound 2), with a yield of 96.8%.

Embodiment 2-1

[0063] Embodiment 2-1: Synthesis of Compound 3

[0064] Under magnetic stirring, the compound 2 (57.6g, 0.25mol) prepared in Example 1-1 was added into dichloromethane (300mL) and cooled in an ice bath, 30% hydrogen peroxide (110mL) was added, tetrabutylsulfuric acid Ammonium hydrogen (17 g, 50 mmol), and 20% aqueous sodium hydroxide (100 mL). The reaction mixture was stirred and heated to room temperature. After 1.5 hours, dichloromethane was added, the organic layer was separated, washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain white solid compound 3 (60.7g) , the HPLC purity was 99.5%, and the yield was 97.3%.

technical field

[0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of rivaroxaban. Background technique

[0002] Rivaroxaban (rivaroxaban), the chemical name is 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl]methyl]-2-thiophenecarboxamide is a highly selective blood coagulation factor Xa inhibitor jointly developed by Bayer and Johnson & Johnson. Launched in Canada, it is used to prevent and treat deep vein thrombosis in patients undergoing knee or hip replacement surgery. Compared with traditional anticoagulants, it has the characteristics of convenient administration, rapid onset of effect, and high safety. Its chemical structural formula is as follows:

[0003]

[0004] Several synthetic methods have been reported about the preparation of rivaroxaban at present, as follows:

[0005] Route 1: The patent document CN1262551C authorized by German Bayer Company in Ch...

Examples

Embodiment 1-1

[0059] Embodiment 1-1: Synthesis of Compound 2

[0060] Add phthalimide potassium salt (55.6g, 0.3mol), (S)-4-chloro-3-hydroxybutyronitrile (compound 1, 35.9g, 0.3mol) and 300mL DMF into the reaction flask, heat to 80 After reacting at ℃ for 3 h, the reaction solution was poured into 400 mL of water, stirred for 10 min, filtered with suction, and dried under reduced pressure to obtain 63.7 g of white solid (Compound 2), with a yield of 92.3%.

Embodiment 1-2

[0061] Embodiment 1-2: the synthesis of compound 2

[0062] Add phthalimide potassium salt (66.7g, 0.36mol), (S)-4-chloro-3-hydroxybutyronitrile (compound 1, 35.9g, 0.3mol) and 300mL DMF into the reaction flask, heat to 70 After reacting at ℃ for 4 h, the reaction solution was poured into 400 mL of water, stirred for 10 min, filtered with suction, and dried under reduced pressure to obtain 66.9 g of white solid (Compound 2), with a yield of 96.8%.

Embodiment 2-1

[0063] Embodiment 2-1: Synthesis of Compound 3

[0064] Under magnetic stirring, the compound 2 (57.6g, 0.25mol) prepared in Example 1-1 was added into dichloromethane (300mL) and cooled in an ice bath, 30% hydrogen peroxide (110mL) was added, tetrabutylsulfuric acid Ammonium hydrogen (17 g, 50 mmol), and 20% aqueous sodium hydroxide (100 mL). The reaction mixture was stirred and heated to room temperature. After 1.5 hours, dichloromethane was added, the organic layer was separated, washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain white solid compound 3 (60.7g) , the HPLC purity was 99.5%, and the yield was 97.3%.

Images