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Method for preparing 3-(2-chloroethyl)-2-methyl-4H- naphthyridine[1,2-a]pyrimidine-4-ketone

A technology of chloroethyl and aminopyridine, which is applied in the field of compound preparation, can solve the problems of long reaction time of materials, large amount of phosphorus oxychloride, low yield, etc., achieve simplified process, improve safety and operability , the effect of dosage reduction

Active Publication Date: 2008-12-24
CSPC OUYI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the method recorded in WO2004 / 035573, this method has a different order of adding materials, which reduces the amount of phosphorus oxychloride slightly, but for actual production, the amount of phosphorus oxychloride is still relatively large, so that there is a potential for actual production. The danger of the material, coupled with the long reaction time of the material, leads to the problem of high cost and low yield

Method used

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  • Method for preparing 3-(2-chloroethyl)-2-methyl-4H- naphthyridine[1,2-a]pyrimidine-4-ketone
  • Method for preparing 3-(2-chloroethyl)-2-methyl-4H- naphthyridine[1,2-a]pyrimidine-4-ketone
  • Method for preparing 3-(2-chloroethyl)-2-methyl-4H- naphthyridine[1,2-a]pyrimidine-4-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Under stirring at room temperature, add 37.64g (0.40mol) of 2-aminopyridine, 48ml (0.44mol) of 2-acetylbutyrolactone, and 100ml of toluene, heat up to 80-90°C, add and dilute with 3 times (v / v) toluene Phosphorus oxychloride 44ml (0.48mol). After dropping, the temperature was raised to 100-110° C., and the reaction was carried out under reflux for 4 hours. After the reaction, the temperature was lowered to 70° C., and 40 ml of water was added.

[0023] Add 20% sodium hydroxide aqueous solution dropwise to the feed liquid, adjust the pH=9-10, separate the phases, and extract the water phase with an appropriate amount of toluene. Combine the toluene phases, add 200ml of water, lower the temperature, add hydrochloric acid dropwise under stirring to adjust the pH of the water phase to 1-2, separate the phases, and extract the toluene phase with an appropriate amount of water. Combine the aqueous phases, add an appropriate amount of activated carbon, decolorize, and filter...

Embodiment 2

[0025] Under stirring at room temperature, add 37.64g (0.40mol) of 2-aminopyridine, 48ml (0.44mol) of 2-acetylbutyrolactone, and 370ml of toluene, and heat up to 80-90°C, add and dilute with 4 times (v / v) toluene Phosphorus oxychloride 40ml (0.44mol). After dropping, the temperature was raised to 100-110° C., and the reaction was carried out under reflux for 4 hours. After the reaction, the temperature was lowered to 70° C., and 40 ml of water was added.

[0026] Add 20% sodium hydroxide aqueous solution dropwise to the feed liquid, adjust the pH=9-10, separate the phases, and extract the water phase with an appropriate amount of toluene. Combine the toluene phases, add 200ml of water, lower the temperature, add hydrochloric acid dropwise under stirring to adjust the pH of the water phase to 1-2, separate the phases, and extract the toluene phase with an appropriate amount of water. Combine the aqueous phases, add an appropriate amount of activated carbon, decolorize, and fi...

Embodiment 3

[0028] Under stirring at room temperature, add 9.41g (0.10mol) of 2-aminopyridine, 11ml (0.10mol) of 2-acetylbutyrolactone, and 40ml of toluene. Phosphorus oxychloride 9ml (0.10mol). After dropping, the temperature was raised to 100-110° C., and the reaction was carried out under reflux for 4 hours. After the reaction, the temperature was lowered to 70° C., and 10 ml of water was added.

[0029] Add 20% sodium hydroxide aqueous solution dropwise to the feed liquid, adjust the pH=9-10, separate the phases, and extract the water phase with an appropriate amount of toluene. Combine the toluene phases, add 50ml of water, lower the temperature, add hydrochloric acid dropwise under stirring to adjust the pH of the water phase to 1-2, separate the phases, and extract the toluene phase with an appropriate amount of water. Combine the aqueous phases, add an appropriate amount of activated carbon, decolorize, and filter. Add 20% aqueous sodium hydroxide solution dropwise to the filtr...

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Abstract

The invention provides a method for preparing 3-(2-Chloroethyl)-2-methylpyrido[1,2-a]pyrimidin-4-one. The method uses 2-aminopyridine and 2-acetylbutyrolacton as raw materials and comprises steps of reactants preparation and separation and purification. The reactants are prepared by the following steps of: placing the 2-aminopyridine and the 2-acetylbutyrolacton into toluene, mixing and stirring the mixture to obtain a reactant liquid, heating the reactant liquid, diluting phosphorus oxychloride with the toluene in advance, dripping the diluted phosphorus oxychloride into the liquid, keeping the temperature at 110 DEG C, carrying out reflux, and obtaining the reactants. The invention can well control the dripping speed of the phosphorus oxychloride, thereby solving the problems of multiple solvents and complex operation caused by ammonia, methylene dichloride, isopropanol, etc. in the following operation, simplifying the process of separation and purification, improving the product yield, and achieving the pure product rate of more than 70 percent.

Description

technical field [0001] The present invention relates to a preparation method of a compound, in particular to a preparation method of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, which belongs to chemical synthesis technology field. Background technique [0002] Risperidone is the general name of the compound of structural formula (I), and its chemical name is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine Base]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, a potent A serotonin antagonist, especially for the treatment of schizophrenia. [0003] [0004] At present, a variety of methods for the synthesis of risperidone have been reported, and the intermediate 3-(2-chloroethyl)-2-methyl-6,7,8,9- Tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, the structure of which is shown in formula (II). [0005] [0006] The structural compound of formula (III) is 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, which is the precur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P25/18
Inventor 李瑞建房艳芬齐武肖王丽丽李国聪郑雪清郝小燕
Owner CSPC OUYI PHARM CO LTD
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