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High-purity 4-(4-aminophenyl)morpholine-3-one preparation method

A technology of aminophenyl and morpholine, which is applied in the field of preparation of morpholin-3-one derivatives, can solve the problems that are not conducive to the preparation of high purity and high activity of nitrohalogenated benzene, and achieve high selectivity, simple process route, Simple effect of separation and purification

Active Publication Date: 2019-02-26
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the activity of p-nitrohalogenated benzene is higher, while p-nitrohalogenated benzene and ethanolamine react to generate product p-nitroanilinoethanol, generate a small amount of by-product p-nitrophenoxyethylamine, product p-nitroanilinoethanol And by-product p-nitrophenoxyethylamine continues to further condense with chloroacetyl chloride and causes a series of by-products, as shown in synthetic route 5, is unfavorable for preparing high-purity 4-(4-aminophenyl) morpholine-3 -ketone

Method used

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Experimental program
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Effect test

Embodiment 1

[0064] Embodiment 1: the preparation of chloroethyloxyacetonitrile (Ⅳ1)

[0065] In a 1-liter four-necked flask connected with a stirrer, a thermometer, and a condenser tube, add 142.5 grams (1.0 moles) of hydroxyacetonitrile with a mass concentration of 40%, 300 grams of methylene chloride, 120 grams of 1,2-dichloroethane and 145 grams of potassium carbonate was heated, refluxed at 38-40°C for 5 hours, filtered, and the filter cake was washed twice with dichloromethane, 50 grams each time. Layered, the aqueous layer was extracted 3 times with dichloromethane, each with 30 grams of dichloromethane, the organic phase was combined, the organic phase was washed once with 30 grams of water, the organic phase was distilled to recover the dichloromethane, and then distilled under reduced pressure to obtain 79.2 grams Chloroethyloxyacetonitrile (Ⅳ1), yield 66.3%, GC purity 99.8%.

[0066] GC-MS analysis result (EI+, m / z): 119:121=3:1.

Embodiment 2

[0067] Embodiment 2: the preparation of chloroethyloxyacetonitrile (Ⅳ1)

[0068] In a 1-liter four-neck flask connected with a stirrer, a thermometer, and a condenser tube, add 142.5 grams (1.0 moles) of mass concentration and be 40% hydroxyacetonitrile, 300 grams of 1,2-dichloroethane and 120 grams of sodium carbonate, and heat , reacted at 60-65°C for 5 hours, filtered, and the filter cake was washed twice with 1,2-dichloroethane, 50 grams each time. Layering, the aqueous layer was extracted 3 times with 1,2-dichloroethane, each with 30 grams, the organic phase was combined, the organic phase was washed once with 30 grams of water, the organic phase was distilled to recover 1,2-dichloroethane, and then Distilled under reduced pressure to obtain 92.5 g of chloroethyloxyacetonitrile (Ⅳ1), with a yield of 77.4% and a GC purity of 99.9%.

Embodiment 3

[0069] Embodiment 3: the preparation of chloroethyloxyacetonitrile (Ⅳ1)

[0070] In a 1-liter four-necked flask connected with a stirrer, a thermometer, and a condenser tube, add 142.5 grams (1.0 moles) of mass concentration and be 40% hydroxyacetonitrile, 400 grams of methylene chloride, and 150 grams of 1-chloro-2-bromoethane And 145 grams of potassium carbonate, heated, reflux reaction at 38-40 ℃ for 4 hours, filtered, and the filter cake was washed twice with dichloromethane, each 50 grams. Separate the layers, extract the aqueous layer 3 times with dichloromethane, each time with 30 grams of dichloromethane, combine the organic phase, wash the organic phase with 30 grams of water once, distill the organic phase to recover dichloromethane and excess 1-chloro-2-bromo Ethane was then distilled under reduced pressure to obtain 103.2 g of chloroethyloxyacetonitrile (Ⅳ1), with a yield of 86.4% and a GC purity of 99.8%.

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Abstract

The invention relates to a low-cost high-purity 4-(4-aminophenyl)morpholine-3-one (II) preparation method, which comprises: carrying out a substitution reaction on hydroxyacetonitrile and 1,2-dihaloethane to prepare haloethyloxyacetonitrile (IV), carrying out a substitution reaction on the haloethyloxyacetonitrile (IV) and p-nitroaniline (III), carrying out cyclization under an acid condition to form 4-(4-nitrophenyl)morpholine-3-one (V), and carrying out hydrogenation reduction on the 4-(4-nitrophenyl)morpholine-3-one (V) to obtain the 4-(4-aminophenyl)morpholine-3-one (II). According to thepresent invention, the preparation method has characteristics of inexpensive and easily-available raw materials, low cost, simple process route, safety, environmental protection, high selectivity of each designed step and high yield, ensures the preparation of the high-purity 4-(4-aminophenyl)morpholine-3-one, and easily performs the industrial preparation of high-purity rivaroxaban.

Description

technical field [0001] The invention relates to a preparation method of morpholin-3-one derivatives, belonging to the field of pharmaceutical biochemical industry. Background technique [0002] Rivaroxaban, known in English as Rivaroxaban, is a new oral anticoagulant drug that is absorbed orally and has a long-lasting effect. It is used to prevent and treat venous thrombosis. It has a wide therapeutic range and does not require routine coagulation function monitoring. The world's first direct factor Xa inhibitor developed for Bayer was approved by the US Food and Drug Administration (FDA) in 2011. Clinically, it is mainly used to prevent the formation of deep vein thrombosis and pulmonary thrombosis in patients after hip and knee replacement. It can also prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce the recurrence of coronary artery syndrome. risk. Its market sales from 2011 to 2016 have grown rapidly a...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32
Inventor 戚聿新刘月盛鞠立柱钱余锋杨嘉民
Owner XINFA PHARMA
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