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A kind of convenient preparation method of 2-aminopyrimidine-5-carboxylate

A technology of aminopyrimidine and formate, applied in the field of medicinal chemistry, can solve the problems of difficulty in obtaining, high price, no industrialization value, etc., and achieves the effects of simple operation, low cost and mild conditions

Active Publication Date: 2020-10-02
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the above synthetic route 2 can obtain the target product in one step, the raw material 3,3-dimethoxy-2-dimethoxymethylpropionate used is expensive, difficult to obtain, and has no industrial value

Method used

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  • A kind of convenient preparation method of 2-aminopyrimidine-5-carboxylate
  • A kind of convenient preparation method of 2-aminopyrimidine-5-carboxylate
  • A kind of convenient preparation method of 2-aminopyrimidine-5-carboxylate

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Experimental program
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Effect test

Embodiment 1

[0042] Embodiment 1: Preparation of ethyl 2-aminopyrimidine-5-carboxylate

[0043] In the 500 milliliters of four-neck flasks that are connected with stirring, thermometer, reflux condenser and 20wt% aqueous sodium hydroxide tail gas absorption device, add 200 grams of carbon tetrachloride, 22.8 grams (0.2 moles) of ethyl methacrylate, 0.5 g of benzoyl peroxide, under stirring, intermittently feed chlorine gas at 65-70°C, 29 g of chlorine gas in total for 2 hours, stir and react at 65-70°C for 3 hours, then nitrogen bubbles for 1 hour to replace residual chlorine and hydrogen chloride. Cool to room temperature, add 0.15 g of N,N-dimethylformamide to eliminate benzoyl peroxide; intermittently feed chlorine gas, control the temperature not to exceed 40°C, feed 15 g of chlorine gas for 2 hours, stir at 40-45°C React for 5 hours. Recover carbon tetrachloride by distillation, add 300 grams of 75wt% ethanol, 30 grams of guanidine nitrate, 80 grams of potassium carbonate, stir and r...

Embodiment 2

[0046] Embodiment 2: Preparation of 2-aminopyrimidine-5-methyl carboxylate

[0047]In the 500 milliliters of four-necked flasks that are connected with stirring, thermometer, reflux condenser and 20wt% aqueous sodium hydroxide tail gas absorption device, add 200 gram carbon tetrachlorides, 20.0 gram (0.2 moles) methyl methacrylate, 0.5 g of benzoyl peroxide, under stirring, intermittently feed chlorine gas at 65-70°C, 29 g of chlorine gas in total for 2 hours, stir and react at 65-70°C for 3 hours, then nitrogen bubbles for 1 hour to replace residual chlorine and hydrogen chloride. Cool to room temperature, add 0.15 g of N,N-dimethylformamide to eliminate benzoyl peroxide; intermittently feed chlorine gas, control the temperature not to exceed 40°C, feed 15 g of chlorine gas for 2 hours, stir at 40-45°C React for 5 hours. Recover carbon tetrachloride by distillation, add 300 grams of methanol, 45 grams of sodium hydroxide, 30 grams of guanidine nitrate, stir and react at 60-6...

Embodiment 3

[0048] Embodiment 3: Preparation of ethyl 2-aminopyrimidine-5-carboxylate

[0049] In the 500 milliliters of four-neck flasks that are connected with stirring, thermometer, reflux condenser and 20wt% aqueous sodium hydroxide tail gas absorption device, add 250 gram carbon tetrachlorides, 22.8 gram (0.2 mole) ethyl methacrylates, 0.5 grams of benzoyl peroxide, 36.0 grams of N-bromosuccinimide, stirred and reacted at 65-70 ° C for 5 hours, cooled to 10-15 ° C, filtered, and the filtrate was transferred to a device with stirring, thermometer, reflux condensation In a four-neck flask with a constant pressure low liquid funnel, add 0.15 g of N,N-dimethylformamide to eliminate benzoyl peroxide; add 32.0 g of bromine and 50 g of tetrachloromethane dropwise at 50-60°C Carbonization solution, after about 1 hour drop, stirred and reacted at 55-60°C for 3 hours. Recover carbon tetrachloride by distillation, add 300 grams of 75wt% ethanol, 30 grams of guanidine nitrate, 80 grams of potas...

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Abstract

The invention provides a simple preparation method of 2-aminopyrimidine-5-formate. The preparation method comprises: carrying out a substitution reaction on 2-methacrylate as a raw material and a halogenating reagent 1, carrying out an addition reaction with a halogenating reagent 2 to obtain 2,3,3-trihalogenated-2-halogenated methyl propionate, and condensing the obtained 2,3,3-trihalogenated-2-halogenated methyl propionate and a guanidine salt to prepare 2-aminopyrimidine-5-formate. According to the invention, the raw materials used in the method are cheap, easy to obtain and low in cost; and the preparation method has characteristics of simpleness, easily achieved conditions, good operation safety, little wastewater generation, environmental protection, high target product yield and high target product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a convenient preparation method of 2-aminopyrimidine-5-carboxylate, which belongs to the technical field of medicinal chemistry. Background technique [0002] 2-aminopyrimidine-5-carboxylate can be used to prepare Copanlisib, which is an important class of pyrimidine derivatives, and its structural formula is as follows: [0003] [0004] Currently reported 2-aminopyrimidine-5-formic acid esters mostly use methyl 3,3-dimethoxypropionate as a starting material, for example, Chinese patent document CN106103434A utilizes methyl 3,3-dimethoxypropionate Carry out nucleophilic addition elimination reaction with methyl formate to prepare (1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1 alkoxide sodium key intermediate, and then Guanidine hydrochloride was reacted to prepare 2-aminopyrimidine-5-carboxylate with a yield of 50%, which is described as the following synthetic scheme 1. [0005] [0006] Synthetic route 1 [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 崔庆荣王保林孙玉龙鞠立柱
Owner XINFA PHARMA
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