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Preparation process for rivaroxaban

A technology for the preparation of rivaroxaban, which is applied in the field of medicinal chemistry, can solve the problems of expensive raw materials, low safety, and low material collection, and achieve the effects of cheap and easy-to-obtain reagents, simple operation, and rapid response

Inactive Publication Date: 2018-10-23
苏州盛达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve the problems of low safety, high price of raw materials and low yield in the existing rivaroxaban preparation process, the purpose of the present invention is to provide a preparation process of rivaroxaban, which is cheap, easy to obtain, and easy to operate. , the reaction conditions are mild, green and environmentally friendly, and the advantages of increasing the yield

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  • Preparation process for rivaroxaban

Examples

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Effect test

Embodiment 1

[0027] A preparation process for rivaroxaban, comprising the steps of:

[0028] S1. Add phthalimide potassium salt (73.4g, 0.39mol) to a solution of (S)-4-chloro-3-hydroxybutyronitrile (39.5g, 0.33mol) in DMF (330ml), heat After reacting at 70°C for 4h, pour the reaction solution into water (440ml), stir for 10min, a white solid precipitated out, filter with suction, and dry the filter cake under reduced pressure to obtain a white solid (73.6g, 97.0%); mp137~140°C , [α]D 25 -21.8°(c1, CHCl 3 ). ESI-MS(m / z):231[M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ: 7.88(d, J=8.9Hz, 2H), 7.85(d, J=8.9Hz, 2H), 4.23~4.26(m, 1H), 3.63(d, J=5.6Hz, 2H), 3.34( s,1H), 2.62~2.68(m,2H), compared with the literature, it can be known as (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyronitrile;

[0029] S2. Add (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyronitrile (63.4g, 0.28mol) obtained in step S1 to chloroform (330ml), Under the condition of ice-water bath, add 30% hydrogen peroxide (122ml, 3.95mo...

Embodiment 2

[0035] A preparation process for rivaroxaban, comprising the steps of:

[0036] S1. Add phthalimide potassium salt (60.0g, 0.32mol) to a solution of (S)-4-chloro-3-hydroxybutyronitrile (32.3g, 0.27mol) in DMF (270ml), heat React at 70°C for 4h, pour the reaction solution into water (360ml), stir for 10min, a white solid precipitates out, filter with suction, and dry the filter cake under reduced pressure to obtain a white solid (60.2g, 96.6%); mp137~140°C , [α]D 25 -21.8°(c1, CHCl 3 ). ESI-MS(m / z):231[M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ: 7.88(d, J=8.9Hz, 2H), 7.85(d, J=8.9Hz, 2H), 4.23~4.26(m, 1H), 3.63(d, J=5.6Hz, 2H), 3.34( s,1H), 2.62~2.68(m,2H), compared with the literature, it can be known as (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyronitrile;

[0037] S2. Add (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyronitrile (51.8g, 0.22mol) obtained in step S1 to chloroform (270ml), Under the condition of ice-water bath, add 30% hydrogen peroxide (100ml, 2.96mol), tetra...

Embodiment 3

[0043] A preparation process for rivaroxaban, comprising the steps of:

[0044] S1. Add phthalimide potassium salt (66.7g, 0.36mol) to (S)-4-chloro-3-hydroxybutyronitrile (35.9g, 0.3mol) in DMF (300ml) solution, heat After reacting at 70°C for 4h, pour the reaction solution into water (400ml), stir for 10min, a white solid precipitated out, filter with suction, and dry the filter cake under reduced pressure to obtain a white solid (66.9g, 96.8%); mp137~140°C , [α]D 25 -21.8°(c1, CHCl 3 ). ESI-MS(m / z):231[M+H] + ; 1 H NMR (300MHz, DMSO-d 6 )δ: 7.88(d, J=8.9Hz, 2H), 7.85(d, J=8.9Hz, 2H), 4.23~4.26(m, 1H), 3.63(d, J=5.6Hz, 2H), 3.34( s,1H), 2.62~2.68(m,2H), compared with the literature, it can be known as (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyronitrile;

[0045] S2. Add (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyronitrile (57.6g, 0.25mol) obtained in step S1 to chloroform (300ml), Under the condition of ice-water bath, add 30% hydrogen peroxide (110ml, 3.59mol), te...

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Abstract

The invention provides a preparation process for rivaroxaban, and particularly relates to the technical field of pharmaceutical chemistry. The preparation process comprises the following steps: (S)-4-chloro-3-hydroxylbutyronitrile reacts with phthalimide potassium salt, (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyramide is obtained by nitrile group hydrolysis, (S)-2-[[2-oxo-1,3-oxazolidine-5-yl]methyl]-1H-isoindol-1,3(2H)-diketone is obtained by rearrangement under the action of iodobenzene, and carries out Ullmann coupling with 4-(4-bromophenyl)morpholine-3-ketone, so that 2-[[(S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl]methyl]-1H-isoindol-1,3(2H)-diketone is obtained, and by hydrazinolysis and amidation, rivaroxaban is obtained. The preparation process has the advantages of easiness in operation, moderate reaction conditions and higher yield.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation process of rivaroxaban. Background technique [0002] Rivaroxaban is a new type of anticoagulant that can be directly taken orally. It directly inhibits the activated blood coagulation factor Xa. It has a definite anticoagulant effect and does not require continuous monitoring. In 2008, rivaroxaban was approved for marketing in Canada and the European Union respectively, under the product name Xarelto. On July 1, 2011, Bayer and Johnson & Johnson jointly announced that the anticoagulant drug rivaroxaban had been approved by the FDA for the prevention of deep vein thrombosis (DVT). On November 4, 2011, rivaroxaban was approved by the US FDA for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. The existing rivaroxaban preparation process has the problems of low safety, expensive raw materials an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07B2200/07C07D413/14
Inventor 周自金陈锋罗新祖黄军豪
Owner 苏州盛达药业有限公司
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