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Synthetic method of high-selectivity 4-(4-aminophenyl) morpholine-3-one

An aminophenyl, high-selectivity technology, applied in the synthesis of 4-morpholin-3-one and the synthesis of morpholin-3-one derivatives, can solve the problems of being unfavorable for the preparation of high purity and high activity, and achieve The effect of avoiding competing side reactions, high reaction selectivity, and few separation processes

Active Publication Date: 2019-04-19
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 the further condensation reaction of by-product p-nitrophenoxyethylamine and chloroacetyl chloride is non-selective, causes a series of by-products, as shown in following scheme 6, is unfavorable for preparing high-purity 4-(4-aminophenyl) Morpholin-3-one

Method used

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  • Synthetic method of high-selectivity 4-(4-aminophenyl) morpholine-3-one
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  • Synthetic method of high-selectivity 4-(4-aminophenyl) morpholine-3-one

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Experimental program
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Effect test

Embodiment 1

[0064] Embodiment 1: the preparation of 4-(4-aminophenyl) morpholin-3-ketone (II)

[0065] In a 500 ml four-necked flask connected with a stirrer, a thermometer, and a condenser tube, add 70.5 grams (0.5 moles) of p-nitrofluorobenzene, 266.5 grams (2.0 moles) of methyl 2-aminoethoxyacetate, and 75.0 grams of carbonic acid Potassium, heating, stirring at 100-105°C for 4 hours (condensation reaction), cooling to 20-25°C, filtering, and washing the filter cake twice with dichloromethane, 50 grams each time. Combine the filtrates, the filtrate is first atmospheric distillation to reclaim methylene chloride, then vacuum distillation to reclaim 2-aminoethoxyacetic acid methyl ester, and the residue is 128.2 grams of 2-(4-nitrophenyl) aminoethoxyacetic acid methyl ester (V1), the yield is 100%, and the GC purity is 99.8%, which is directly transferred to 500 milliliters of stainless steel autoclave, and the former flask is washed with 300 gram of methanol, and the washing liquid is t...

Embodiment 2

[0069] Embodiment 2: Preparation of 4-(4-aminophenyl) morpholin-3-ketone (II)

[0070] In a 250 ml four-necked flask connected with a stirrer, a thermometer, and a condenser tube, add 14.1 grams (0.1 moles) of p-nitrofluorobenzene, 73.5 grams (0.5 moles) of ethyl 2-aminoethoxyacetate, and 15.0 grams of carbonic acid Potassium, heating, stirring at 100-105°C for 3 hours, cooling to 20-25°C, filtering, and washing the filter cake twice with dichloromethane, 50 grams each time. Combine the filtrates, the filtrate is first atmospheric distillation to reclaim dichloromethane, then vacuum distillation to reclaim 2-aminoethoxy ethyl acetate, and the residue is 27.1 grams of 2-(4-nitrophenyl) aminoethoxy ethyl acetate (V2), the yield is 100%, and the GC purity is 99.7%, which is directly transferred to 500 milliliters of stainless steel autoclave, and the former flask is washed with 100 grams of ethanol, and the washing liquid is transferred to the autoclave together, and 5.0 grams of...

Embodiment 3

[0071] Embodiment 3: Preparation of 4-(4-aminophenyl) morpholin-3-ketone (II)

[0072] In the 250 milliliter four-necked flask that is connected with stirrer, thermometer, condenser tube, add 15.8 grams (0.1 moles) p-nitrochlorobenzene, 80.5 grams (0.5 moles) isopropyl 2-aminoethoxyacetate, 15.0 grams Potassium carbonate, heated, stirred at 100-105°C for 3 hours, cooled to 20-25°C, filtered, and the filter cake was washed twice with dichloromethane, 50 grams each time. Combine the filtrates, the filtrate is first normal pressure distillation to reclaim methylene chloride, and then vacuum distillation to reclaim 2-aminoethoxyacetic acid isopropyl ester, and the residue is 28.2 grams of 2-(4-nitrophenyl) aminoethoxyacetic acid isopropyl ester. Propyl ester (Ⅴ 3), yield is 100%, GC purity is 99.8%, is directly transferred to in the stainless steel autoclave of 500 milliliters, and washes former flask with 100 gram isopropanols, and washing liquid is transferred in the autoclave t...

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Abstract

The invention relates to a synthetic method of high-selectivity 4-(4-aminophenyl) morpholine-3-one; according to the method, by condensation of p-nitrohalobenzene and 2-aminoethoxy acetate in the presence of an alkali, 2-(4-nitrophenyl) aminoethoxy acetate is obtained, by hydrogenation reduction under the action of a solvent and a hydrogenation catalyst, 2-(4-aminophenyl) aminoethoxy acetate is obtained, and the 4-(4-aminophenyl) morpholine-3-one is obtained by intramolecular dealcoholization cyclization. The reaction route disclosed by the invention is high in reaction selectivity, the reaction selectivity of each step reaches more than 99.0%, and the total yield is up to 96.0%. The raw materials are cheap and easy to obtain, the separation process is few, the process route is concise, and the method is low in wastewater quantity, high in reaction atom economy, green and environment-friendly in process.

Description

technical field [0001] The invention relates to a method for synthesizing morpholin-3-one derivatives, in particular to a method for synthesizing highly selective 4-(4-aminophenyl)morpholin-3-one, which belongs to the technical field of pharmaceutical biochemistry . 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...

Claims

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Application Information

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IPC IPC(8): C07D265/32
CPCC07D265/32Y02P20/584
Inventor 戚聿新刘月盛鞠立柱钱余锋杨嘉民
Owner XINFA PHARMA
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