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One-pot method for preparing rivaroxaban

A technology of rivaroxaban and oxo-generation, which is applied in the fields of organic chemistry and bulk chemical production, and can solve the problems of inappropriate preparation of rivaroxaban and difficult removal

Active Publication Date: 2021-05-28
JIANGSU ZHONGBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Phthalimide is produced in the method for preparing rivaroxaban disclosed in Chinese patent CN1900074B, and it is difficult to remove
[0010] In summary, prior art methods are not suitable for the preparation of rivaroxaban in laboratory-scale and commercial-scale operations

Method used

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  • One-pot method for preparing rivaroxaban
  • One-pot method for preparing rivaroxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Add 42.2g 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]- 1H-isoindole-1,3(2H)-dione, 8.6g 40% methylamine aqueous solution and 200g absolute ethanol; start stirring and heat up to 60°C, keep the temperature for 3 hours, cool the system to 25°C, add 2.8gDMTMM As a condensing agent, dissolve 17.8g of 5-chlorothiophene-2-carboxylic acid in 35.6g of absolute ethanol and add it to the system, react at 25°C for 12 hours to detect the completion of the reaction, filter to obtain a white solid, and use 100g of absolute ethanol and water mass ratio Wash with a 1:1 mixed solution, filter to obtain a white solid, dry under reduced pressure at a temperature of 55°C and a pressure of ≤0.08MPa for 8 hours, and obtain rivaroxaban dry product 40.5g (yield: 92.8%; HPLC chiral Purity: 99.9%), melting point 233.1°C, 1 H-NMR (DMSO, 400MHz, δppm): 3.61(t, 2H, J=5.6Hz), 3.71(t, 2H, J=5.2Hz), 3.89(m, 1H), 3.97(t, 2H, J= 4.4Hz), 4.20(m, 3H), 4.85(m, 1H), 7.18(d, 1H,...

Embodiment 2

[0036] Add 42.2g 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]- 1H-isoindole-1,3(2H)-dione, 8.6g 40% methylamine aqueous solution and 200g methanol; start stirring, raise the temperature to 60°C, keep the temperature for 3 hours, cool the system to 25°C, add 2.8g DMTMM Mixture, 17.8g of 5-chlorothiophene-2-carboxylic acid was dissolved in 35.6g of methanol and added to the system, reacted for 12 hours at 25°C, a large amount of white solid was precipitated, filtered to obtain the white solid, and mixed with 100g of methanol and water with a mass ratio of 1:1 The mixed solution was washed, filtered to obtain a white solid, and dried under reduced pressure at a temperature of 55° C. and a pressure of ≤0.08 MPa for 8 hours to obtain 39.3 g of dry rivaroxaban (yield: 90.1%; HPLC chiral purity: 99.9%).

Embodiment 3

[0038] Add 42.2g 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl] in the reaction flask -1H-isoindole-1,3(2H)-dione, 9.3g 40% methylamine aqueous solution and 200g absolute ethanol; start stirring, heat up to 60°C, keep warm for 3 hours, cool the system to 10°C, add 2.8g of DMTMM condensing agent, dissolve 17.8g of 5-chlorothiophene-2-carboxylic acid in 35.6g of absolute ethanol and add to the system, react at 10°C for 16 hours to detect the completion of the reaction, filter to obtain a white solid, and use 100g of absolute ethanol and water quality Wash with a mixed solution with a ratio of 1:1, filter to obtain a white solid, and dry under reduced pressure at a temperature of 55 °C and a pressure of ≤0.08 MPa for 8 hours to obtain 40.0 g of dry product of rivaroxaban (yield: 91.7%; HPLC chiral purity: 99.9%).

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Abstract

The invention discloses a method for preparing rivaroxaban by a one-pot method, which uses 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl ]-5-oxazolidinyl]methyl]-1H-isoindole-1,3(2H)-diketone is used as raw material, and the intermediate 4-[4-[( 5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyl] morpholin-3-ketone, and then with 5-chlorothiophene under the effect of condensing agent ‑2‑Formic acid undergoes amidation to rivaroxaban. The present invention adopts a one-pot method, uses DMTMM as a condensation agent, undergoes a condensation reaction in an alcohol and / or water system to obtain rivaroxaban, simplifies the reaction, shortens the reaction time, and has high yield and high purity of rivaroxaban; at the same time Post-processing is simple, requires no additional purification, and reduces chemical waste.

Description

technical field [0001] The invention relates to a method for preparing rivaroxaban by a one-pot method, in particular to a method for preparing rivaroxaban by using a novel condensing agent. Background technique [0002] Rivaroxaban, chemical name: 5-Chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3 -Oxazolidin-5-yl]methyl]thiophene-2-carboxamide, the structure is shown in formula I: [0003] [0004] Rivaroxaban is a highly effective FXa inhibitor jointly developed by Bayer and Johnson & Johnson, and first launched in Canada in 2008. Rivaroxaban is sold as a tablet containing 10 mg rivaroxaban for the prevention of venous thromboembolism after hip or knee replacement, and has excellent in vivo activity and bioavailability. At the same time, clinical trials for other indications of rivaroxaban are being conducted to determine its potential benefits for atrial fibrillation and acute coronary syndrome. [0005] U.S. Patent No. 7,585,860B2 makes 4-[4-[(5S)-5-(am...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14
CPCC07D413/14Y02P20/55
Inventor 吴四清蒋海松王红喜许鹏飞黄双
Owner JIANGSU ZHONGBANG PHARMA
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