A kind of preparation method of rivaroxaban intermediate

A technology for rivaroxaban and intermediates, which is applied in the field of anticoagulant rivaroxaban intermediates and its preparation, can solve problems such as inability to industrialize, and achieve the effects of simple operation, less waste, and environmental friendliness

Inactive Publication Date: 2016-08-31
HANCHEM BIOPHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] The present invention overcomes the deficiencies of the prior art, and solves the...

Method used

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  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation of N-Hydroxyethylaniline (Ⅱ)

[0054] Add 21.2mL (0.20mol) of bromobenzene, 18.5mL (0.30mol) of ethanolamine, 4.0g (0.02mol) of cuprous iodide, and 55.2g of potassium carbonate into a 250mL four-necked flask equipped with mechanical stirring, a condenser, and a thermometer. (0.4mol), water 100mL, temperature controlled 80°C and stirred for 15h. After suction filtration, the filtrate was rectified to obtain 25.2 g of a colorless liquid (boiling point 165° C. at 10 mmHg), which was the target compound N-hydroxyethylaniline (II), with a yield of 91.1%.

Embodiment 2

[0056] Preparation of 4-nitroso-N-hydroxyethylaniline (Ⅲ)

[0057] Add 87.6g of 10% hydrochloric acid into a 500mL four-necked bottle equipped with a mechanical stirrer and a thermometer, cool to 5°C, add 29g (0.21mol) of N-hydroxyethylaniline (II), and add 58g of 30 % sodium nitrite aqueous solution (0.25mol), dropwise for about 3 hours, after dropping, keep warm for 2 hours, filter, wash the filter cake twice with an appropriate amount of water, and dry with hot air at 60°C to obtain 31.7g of yellow solid with a yield of 90.2%.

[0058] III: 1 H NMR (300MHz, DMSO-d 6 ):δ7.92(s,1H),6.67-6.74(br,3H),4.89(t,1H,J=4.2Hz),3.58(m,2H),3.30(m,2H); ESI-MS m / z=165(M-1), 201(M+Cl - ).

Embodiment 3

[0060] Preparation of 4-nitroso-N-hydroxyethylaniline (Ⅲ)

[0061] Add 87.6g of 10% hydrochloric acid into a 500mL four-necked bottle equipped with a mechanical stirrer and a thermometer, cool to 5°C, add 29g (0.21mol) N-hydroxyethylaniline (II), and add 58g dropwise at a temperature control of ≤ -10°C 30% aqueous solution of sodium nitrite (0.25mol), the time of dropping is about 2.5h, after dropping, keep warm for 6h, filter, wash the filter cake twice with an appropriate amount of water, and dry it with hot air at 60°C to obtain 30.2g of yellow solid, with a yield of 86.0% .

[0062] III: 1 H NMR (300MHz, DMSO-d 6 ):δ7.92(s,1H),6.67-6.74(br,3H),4.89(t,1H,J=4.2Hz),3.58(m,2H),3.30(m,2H); ESI-MS m / z=165(M-1), 201(M + Cl - ).

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Abstract

The invention discloses a synthetic method of rivaroxabanintermediate4-(4-nitrosobenzene)-3-morpholine. The method comprises steps as follows: (1), halogenated benzene (I) and ethanolamine react under the condition of a catalyst and alkali to generate N-ethoxylaniline (II), N-ethoxylaniline (II) and nitrous acid or nitrite react to generate 4-nitroso-N-ethoxylaniline (III), and 4-nitroso-N-ethoxylaniline (III) and chloroacetyl chloride react to generate 4-(4-nitrosobenzene)-3-morpholine (IV). According to the synthetic method of 4-(4-nitrosobenzene)-3-morpholine, required raw materials and reagents are cheap and are easy to obtain, the yield is high, and the cost is low; the reaction condition is mild; fewer three wastes are produced; and the product quality is reliable and stable, and the whole process is very suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to an anticoagulant rivaroxaban intermediate and a preparation process thereof. Background technique [0002] The chemical name of rivaroxaban is 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxa Azolin-5-yl)methyl)thiophene-2-carboxamide (VI), is a highly selective, oral drug that directly inhibits factor Xa. Inhibition of factor Xa can interrupt the intrinsic and extrinsic pathways of the blood coagulation cascade, inhibit the generation of thrombin and thrombus formation. [0003] [0004] According to the report of Wu Xiang's 2013 paper, compound (Ⅵ) is composed of 4-(4-aminophenyl)-3-morpholinone (Ⅴ), 5-chloro-N-(2-oxiranylmethyl )-2-thiophenecarboxamide (Ⅶ) etc. as raw materials for synthesis. [0005] [0006] WO-A 01 / 47919 describes the preparation of 4-(4-aminophenyl)-3-morpholinone (V) by first deprotonating the morpholin-3-one under st...

Claims

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Application Information

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IPC IPC(8): C07D265/32C07D413/14
CPCC07D265/32C07D413/14
Inventor 熊轶钟智奎林伟康伍立靖
Owner HANCHEM BIOPHARM TECH
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