Preparation method and use of rivaroxaban intermediate

A technology of rivaroxaban and intermediates, applied in the preparation of rivaroxaban intermediate I, the field of preparing high-purity rivaroxaban, can solve the problems of long reaction time, large solvent amount, waste of energy and the like, and achieves The effect of easy industrial production, short reaction time and high conversion rate

Inactive Publication Date: 2019-04-02
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process has the following disadvantages: 1. the reaction process is cumbersome and needs to be reacted twice; 2. this process requires (S)-(+)-N-(2,3-ethoxypropyl) phthalimide in excess use, its consumption is 1.5 times of 4-(4-aminophenyl) morpholin-3-one, which causes waste of materials; 3. the reaction time is too long and wastes more energy; , producing more hazardous waste, which does not conform to the trend of green environmental protection
This process has the following disadvantages: 1. The process reaction time is longer and wastes more energy; 2. This process requires (S)-(+)-N-(2,3-ethoxypropyl) phthalimide Excessive use, its dosage is 1.5 times that of 4-(4-aminophenyl)morpholin-3-one, resulting in waste of materials; ③The mixed solvent is difficult to recycle, resulting in more hazardous waste, which does not meet the trend of green environmental protection
There are following deficiencies in this technique: 1. the reaction conversion rate of this technique is too low, TLC monitoring only reacts less than 1% after reacting 18h, is not suitable for industrialized large-scale production (see the comparative example 1 of specific embodiment for details); 2. the reaction time is longer, Excessive energy consumption; ③The use of organic solvents is not conducive to environmental protection

Method used

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  • Preparation method and use of rivaroxaban intermediate
  • Preparation method and use of rivaroxaban intermediate
  • Preparation method and use of rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of Rivaroxaban Intermediate I

[0021] 20kg 4-(4-aminophenyl) morpholin-3-one, 27.5kg (S)-(+)-N-(2,3-ethoxypropyl) phthalimide, 600kg Add purified water into a 1000L glass-lined reaction tank, stir and heat up to 75-85°C for 5 hours, cool down to room temperature, centrifuge, and dry the filter cake to obtain 39.1kg of rivaroxaban intermediate I with a yield of 95.0% and a purity of 96.90%.

[0022] MS (ESI, m / z): 396.17 (M+1)

[0023] 1 H NMR (300MHz, DMSO): δ=7.82~7.89(m,4H); 7.01~7.04(d,2H); 6.60~6.63(d,2H); 5.65~5.69(m,1H); 5.17~5.18( d,1H); 4.14(s,2H); 4.00~4.02(m,1H); 3.91~3.95(m,2H); 3.59~3.66(m,4H); 3.15~3.17(m,1H); 3.02~ 3.04(m,1H).

Embodiment 2

[0024] Example 2 Preparation of Rivaroxaban Intermediate I

[0025] 35.0g of 4-(4-aminophenyl)morpholin-3-one, 37.0g of (S)-(+)-N-(2,3-ethoxypropyl)phthalimide, Add 875mL of purified water into a 2000mL three-necked flask, stir and heat up to 80-90°C for 3 hours, cool down to room temperature, filter with suction, and dry the filter cake to obtain 68.1g of rivaroxaban intermediate I with a yield of 94.6% and a purity of 96.42%.

Embodiment 3

[0026] Example 3 Preparation of Rivaroxaban Intermediate I

[0027] 2.5kg of 4-(4-aminophenyl)morpholin-3-one, 3.42kg of (S)-(+)-N-(2,3-ethoxypropyl)phthalimide, Add 100L of purified water into a 200L glass-lined reaction tank, stir and heat up to 70-80°C for 4 hours, cool down to room temperature, centrifuge, and dry the filter cake to obtain rivaroxaban intermediate I 4.86kg, yield 94.5%, purity 96.59% .

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Abstract

The present invention relates to a preparation method of a rivaroxaban intermediate I. The method provided by the invention has the advantages of greatly shortening the reaction time, easy preparationby scale, simple operation, good stability, high purity, low environmental pollution and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a rivaroxaban intermediate I and the use of the intermediate for preparing high-purity rivaroxaban. Background technique [0002] Rivaroxaban (Rivaroxaban), the chemical name is 5-chloro-nitrogen-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1, 3-Oxazolidin-5-yl]methyl]-2-thiophenecarboxamide, which has a chemical structure shown in formula VII, is a new type of highly selective anticoagulant drug developed by Bayer AG of Germany. Rivaroxaban was approved for marketing by the European Commission in September 2008, and its trade name is Xarelto. [0003] [0004] Rivaroxaban intermediate I is a key intermediate for the synthesis of rivaroxaban, and its structure is as follows: [0005] [0006] The preparation of rivaroxaban intermediate I described in the compound patent WO0147919 and the document J.Med.Chem.2005,48,5900-5...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14
CPCC07D413/12C07D413/14C07B2200/07
Inventor 范传文冷传新王玉兵刘培元
Owner QILU PHARMA
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