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Preparation method of 4-[(3-chlorine-4-methoxyl benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidyl]-pyrimidine-5-nonanoic acid-ethyl ester

A methoxybenzyl and methoxybenzylamine technology, applied in the field of medicine, can solve the problems of high price of oxidant peroxybenzoic acid, flammable and explosive peroxybenzoic acid, unsuitable for large-scale production, etc. Achieve the effect of continuity and automation, low cost, and fewer reaction steps

Active Publication Date: 2015-02-18
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has the problem that the price of oxidant peroxybenzoic acid is relatively expensive, while the yield is low, the production cost is high, and peroxybenzoic acid is flammable and explosive, has potential safety hazards, and is not suitable for large-scale production

Method used

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  • Preparation method of 4-[(3-chlorine-4-methoxyl benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidyl]-pyrimidine-5-nonanoic acid-ethyl ester
  • Preparation method of 4-[(3-chlorine-4-methoxyl benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidyl]-pyrimidine-5-nonanoic acid-ethyl ester
  • Preparation method of 4-[(3-chlorine-4-methoxyl benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidyl]-pyrimidine-5-nonanoic acid-ethyl ester

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Effect test

Embodiment 1

[0026] Such as figure 1 As shown, the microreactor of the present invention includes a preheating unit, a mixing unit, a reaction unit and a cooling unit connected in sequence. The solutions of compound 1 and L-prolinol first enter the preheating unit of the microreactor respectively, and are heated to 100-130°C, and then the two solutions are mixed in the mixing unit, and then enter the reaction unit at 100-130°C Insulate and react for 15-20 minutes (ie T1 = 15-20 minutes); after the reaction is completed, enter the cooling unit to drop below 30°C (T2 = 10-20 minutes), and then exit the microreactor for the next step.

Embodiment 2

[0028] Preparation of ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine-5-carboxylate (Compound 2)

[0029] Dissolve 100g of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-methylthiopyrimidine-5-carboxylate in 1000ml of DMSO, dissolve 55g of L-prolinol in 500ml of DMSO, Respectively control the flow rate of 5.0ml / min and 2.5ml / min into the microreactor, heat it to 100-130°C through the preheating unit, and mix it into the reaction unit through the mixing unit, control the temperature at 100°C-130°C to control the reaction The residence time is 18min, and then the temperature is lowered to below 30°C through the cooling unit of the microreactor. Slowly add 1000ml of water dropwise to the feed liquid received from the cooling unit, and white solids will slowly precipitate out. After the dropwise addition, heat and crystallize at 20-30°C for 2 hours, filter with suction, wash with 200ml of water, and air-dry to obtain white 106.5 g of solid, yie...

Embodiment 3

[0031] Preparation of ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine-5-carboxylate

[0032] Dissolve 100g of 4-(3-chloro-4-methoxybenzylamino)-2-methylthiopyrimidine-5-carboxylic acid ethyl ester in 1000mlDMF, dissolve 55gL-prolinol in 500mlDMF, control The flow rate is 5.0ml / min and 2.5ml / min into the microreactor, preheated to 100°C-130°C by the preheating unit respectively, mixed by the mixing unit and then enters the reaction unit of the microreactor, and the temperature is controlled at 100°C- 130°C, the reaction residence time is controlled to be 15min, and then the temperature is lowered to below 30°C through the cooling unit of the microreactor. Slowly add 1000ml of water dropwise to the feed liquid received from the cooling unit, and white solids will slowly precipitate out. After the dropwise addition, heat and crystallize at 20-30°C for 2 hours, filter with suction, wash with 200ml of water, and air-dry to obtain white The ...

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Abstract

The invention discloses a preparation method of 4-[(3-chlorine-4-methoxyl benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidyl]-pyrimidine-5-nonanoic acid-ethyl ester. The method comprises the following steps: dissolving 4-(3-chlorine-4-methoxyl benzyl amido)-2-methylmercapto pyrimidine-5-nonanoic acid-ethyl ester in an organic solvent; dissolving L-Prolinol in the same organic solvent; respectively controlling flow velocity to put a material liquid into a micro reactor; preheating, mixing, reacting and cooling in the micro reactor to obtain a reactant material liquid, and then discharging the reactant material liquid out of the micro reactor; dripping water into the reactant material liquid for crystallization and then performing suction filtration, washing and drying to obtain the 4-[(3-chlorine-4-methoxyl benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidyl]-pyrimidine-5-nonanoic acid-ethyl ester. By adopting the micro reactor for reaction, instant full mixing of reactant materials of each reaction unit and precise control on reaction temperature can be realized, so that higher reaction yield and selectivity can be obtained, continuity and automation of a reaction process are realized, and the product is high in yield and good in quality.

Description

technical field [0001] The present invention relates to avanafil intermediate 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine-5-carboxy The invention discloses a preparation method of ethyl acetate, which belongs to the technical field of medicine. Background technique [0002] Avanafil (Avanafil), chemical name: 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N -(2-pyrimidinylmethyl)-5-pyrimidinemethanesulfonamide, molecular formula: C 23 h 26 ClN 7 o 3 ; Molecular weight: 483.95, the structural formula is as follows: [0003] [0004] Avanafil (Avanafil) is authorized by Mitsubishi Tanabe Pharmaceutical Co., Ltd. of Japan and developed by Vivus Pharmaceutical Company of the United States for the treatment of male erectile dysfunction. Avanafil is an oral, fast-acting, highly selective phosphodiesterase-5 (PDE) inhibitor, which can inhibit the metabolism of cyclic guanosine monophosphate in the body, there...

Claims

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Application Information

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IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 高大龙杨庆坤李亚鹏李保勇吴柯张兆珍董廷华周先国张雷雷周学文
Owner QILU PHARMA HAINAN
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