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Synthesis method of 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone

A 2-a, chloroethyl technology, applied in the field of risperidone, can solve problems such as unfavorable industrial production, high pressure on environmental protection, and cumbersome post-processing operations

Active Publication Date: 2021-05-14
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] This process uses a large amount of phosphorus oxychloride and toluene as the reaction solvent, which produces a large amount of waste gas and waste liquid, which has great pressure on environmental protection, and the post-processing operation is cumbersome, which is not conducive to industrial production.

Method used

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  • Synthesis method of 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone
  • Synthesis method of 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone
  • Synthesis method of 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone

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Experimental program
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Embodiment 1

[0038] Preparation of ethyl 2-acetyl-4-chlorobutyrate

[0039] 10ml of dried DMF was added in a 100ml three-neck flask under nitrogen protection conditions, after the reaction flask was cooled to -20°C, (0.92g, 23mmmol) sodium hydride (60%) was added in batches to the reaction flask, and then Add 2 times (v / v) DMF-diluted ethyl acetoacetate (3g, 23mmmol) solution dropwise, drop it off within 20min, control the temperature and continue stirring for 30min, then move the reaction bottle to room temperature and stir until the reaction solution recovers. To room temperature, add 1-bromo-2-chloro-ethane (3.1g, 27.7mmol) in one go, raise the temperature of the reaction solution to 100°C, the reaction is complete after 10-12h, quench the reaction with water, and use ethyl acetate / water The reaction solution was extracted, the ethyl acetate layers were combined, and concentrated to obtain 4.3 g of a colorless liquid with a yield of 97%.

[0040]2-Acetyl-4-chlorobutyric acid ethyl este...

Embodiment 2

[0042] Preparation of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0043] Add 2-acetyl-4-chlorobutyric acid ethyl ester (1.92g, 10mmmol), 2-aminopyridine (0.75g, 8mmol) and imidazole hydrochloride (0.52g, 5mmol) into a 10ml reaction flask, Stir the reaction under the condition of 100-110°C to control the temperature. After 6 hours, the reaction is complete. Cool to room temperature. After dissolving the reaction solution with methanol, decolorize it with activated carbon, filter, and remove the solvent from the filtrate under reduced pressure to obtain the crude product, which is obtained by recrystallization from ethyl acetate. The yield of white solid is 2.12g, and the yield is 95%.

[0044] 3-(2-Chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, white solid: 1H NMR (600MHz, DMSO) δ8.87 (d, J= 7.1Hz, 1H), 7.84(m, 1H), 7.56(d, J=8.9Hz, 1H), 7.26(t, J=6.9Hz, 1H), 3.56(t, J=7.0Hz, 2H), 2.80 (t,J=7.1Hz,2H),2.46(s,3H).13C NMR(151MHz,DMSO)δ161.16,156.58,147.4...

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Abstract

The invention provides a synthesis method of 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone. The method comprises the following steps: carrying out substitution reaction on ethyl acetoacetate and 1-bromo-2-chloroethane under an alkaline condition to obtain 2-acetyl-4-chlorobutyric acid ethyl ester, and reacting the 2-acetyl-4-chlorobutyric acid ethyl ester with 2-aminopyridine to obtain a risperidone intermediate 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone. The method is simple to operate and suitable for industrial production. The compound 2-acetyl-4-chlorobutyric acid ethyl ester provided by the invention can be used as a raw material or an intermediate for synthesizing 3-(2-chloroethyl)-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-ketone, and then risperidone is synthesized. The invention also provides an application of the compound 2-acetyl-4-chlorobutyric acid ethyl ester as an impurity reference substance of the 3-(2-chloroethyl)-2-methyl-4H-pyrido [1, 2-a] pyrimidine-4-ketone.

Description

technical field [0001] The present invention relates to risperidone, in particular to a method for synthesizing risperidone intermediate 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, belonging to Medicinal chemistry technology field. Background technique [0002] The chemical name of risperidone is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6, 7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is a new type of atypical antipsychotic drug developed by Janssen Pharmaceutical Company of Belgium in 1984. It is related to 5-HT 2 receptors and dopamine D 2 The receptor has a strong affinity and can also bind to the α 1 - Binds to adrenergic receptors and with lower affinity to H-receptors and alpha 2 - Binds to adrenoceptors, but not to cholinergic receptors. Risperidone has been widely used in the treatment of various types of schizophrenia, and its curative effect is better than that of traditional antipsychotic drugs. The patient'...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07C69/716C07C67/343
CPCC07D471/04C07C69/716C07C67/343Y02P20/584
Inventor 袁建勇李丹商素琴王印徐平
Owner CHONGQING MEDICAL UNIVERSITY
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