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Chemical synthesis method of paliperidone intermediate

A technology for chemical synthesis and catalyst, applied in the environment-friendly field, can solve the problems of phosphorus pollution, lack of atom economy, lower yield, etc., and achieve the effects of improving yield, environment-friendly production process and convenient operation.

Inactive Publication Date: 2010-05-26
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Whether it is one-step process step simplification or step-by-step process in order to increase the yield, a large amount of phosphorus oxychloride is required, which causes a large amount of phosphorus pollution in the production process.
At the same time, a large amount of alkali needs to be used for neutralization in the post-treatment, which not only lacks atom economy, but also produces a large amount of viscous phosphate solids, which reduces the yield

Method used

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  • Chemical synthesis method of paliperidone intermediate
  • Chemical synthesis method of paliperidone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The amount ratio of the feed material is 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one:bis(trichloromethyl ) carbonate: catalyst=1: 0.34: 0.05; the organic solvent used is 1,2-ethylene dichloride, dissolves 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyridine The quality of the organic solvent of [1,2-a]pyrimidin-4-one is 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a ] 1 time of the quality of pyrimidin-4-one, the quality of the organic solvent used to dissolve bis(trichloromethyl) carbonate is 3 times of the quality of bis(trichloromethyl) carbonate; Catalyst is N,N-two Methylformamide.

[0021]In a 500ml four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a ]pyrimidin-4-one (100.0g, 0.32mol), N,N-dimethylformamide (1.17g, 0.016mol), 1,2-dichloroethane (100.0g), controlled at 50-55°C Add dropwise the 1,2-dichloroethane (96.9g) solution that...

Embodiment 2

[0023] The organic solvent is changed to chloroform, the organic solvent of dissolving 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one The mass is 1 times that of 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, used to dissolve bis(tri The quality of the organic solvent of chloromethyl) carbonate is 3 times of two (trichloromethyl) carbonate quality; Other proportioning and operation are with embodiment one, obtain 9-benzyloxy-3-(2-chloroethyl Base)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one product 65.7g, yield 62.6%, content 92.8% (HPLC), other spectrogram data are the same as in Example 1.

Embodiment 3

[0025] Change the organic solvent to 1,1,2,2-tetrachloroethane to dissolve 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a] The quality of the organic solvent of pyrimidin-4-one is the quality of 9-benzyloxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 1 time, the quality of the organic solvent used to dissolve bis(trichloromethyl)carbonate is 3 times of the quality of bis(trichloromethyl)carbonate; the temperature change of dropping bis(trichloromethyl)carbonate solution 65~70°C, other proportions and operations are the same as in Example 1 to obtain 9-benzyloxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine -4-ketone product 62.0g, yield 59.0%, content 91.6% (HPLC), other spectrogram data are the same as Example 1.

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Abstract

The invention discloses a chemical synthesis method of a paliperidone intermediate-3-(2- chloroethyl)-2-methyl-9-benzyloxy group-4H-pyridino[1,2-a]pyridine-4-ketone. The method comprises the following steps of: reacting 9-benzyloxy group-3-(2-ethoxy)-2-methyl-4H-pyridino [1,2-a]pyridine-4-ketone with bis(trichloromethyl) carbonate in an organic solvent serving as a reaction solvent in the presence of a catalyst at the temperature of between 50 and 90 DEG C for 2 to 4 hours; and after the reaction, separating and purifying reaction solution to obtain the paliperidone intermediate. Molar ratio of the charged 9-benzyloxy group-3-(2-ethoxy)-2-methyl-4H-pyridino [1,2-a]pyridine-4-ketone to the charged bis(trichloromethyl) carbonate and the charged catalyst is 1:0.34 to 2: 0.05 to 1.0. The method has the advantages that: the operation is simple and safe operation; environment-unfriendly reagent such as phosphorus oxychloride, thionyl chloride and the like are not used; fewer three wastes in are produced in the reaction process; the target product yield and purity are high, and the industrial application prospect is promising.

Description

(1) Technical field [0001] The present invention relates to a kind of paliperidone intermediate——9-hydroxyl-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one chemistry Synthetic methods, especially environmentally friendly, high-yield synthetic methods. (2) Background technology [0002] 9-Hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is an important intermediate for the synthesis of the new antipsychotic drug paliperidone, Existing synthetic method mainly contains: (1) synthetic route one is reported in the patent US5158952 by 3-benzyloxy-2-aminopyridine, α-acetyl-γ-butyrolactone as raw material in phosphorus oxychloride Under the action, using toluene as a solvent, one-step synthesis of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[1,2-a]pyrimidin-4-one, which The total yield of the two steps is 62.3%; (2) The second synthetic route is reported in the patent WO2008024415. First, 3-benzyl-2-aminopyridine and α-acetyl-γ-butyrolactone are cy...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 李振华苏为科施湘君冯雯蔡继平杨顶孝
Owner ZHEJIANG UNIV OF TECH