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Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone

A technology of methyltetrahydro and chloroethyl, applied in the direction of organic chemistry, etc., can solve the problems such as dechlorination side reactions that cannot be solved, and achieve the effect of high selectivity

Inactive Publication Date: 2012-08-08
SHANGHAI TWISUN BIO PHARM
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  • Abstract
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Problems solved by technology

[0006] Another method is to protect the secondary hydroxyl group in the starting material with benzyl, then chlorinate, then hydrogenate pyrido[1,2-α]pyrimidin-4-one, and remove the protecting group benzyl ( The reaction formula is as follows), the advantage of this method is that the problem of polychlorination will not occur in the chlorination process, but it still cannot solve the catalytic hydrodechlorination side reaction in the hydrogenation process

Method used

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  • Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone
  • Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone
  • Preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone

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Experimental program
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Effect test

Embodiment 1

[0030] A preparation method of paliperidone intermediate, the method may further comprise the steps:

[0031] (1) Cyclization reaction

[0032]

[0033] The reaction flask was equipped with a water separator and a dropping funnel, and 1200 milliliters of toluene was added, and 110.12 grams of 2-amino-3-hydroxypyridine was added. Then, 134.53 g of 2-acetylbutyrolactone was added dropwise with stirring at room temperature. The dropping funnel was washed with 200 milliliters of toluene, dropped into the reaction flask, then 3 grams of dimethylaminopyridine was added as a catalyst, and the reaction system was heated to reflux for reaction (reflux started at 115 degrees). After reflux for 18 hours (divide water during this process), cool to 80 degrees, add 200 milliliters of isopropanol, 25 grams of gac, and then heat to reflux (100 degrees reflux) with 30 minutes. Then filter at 80 degrees to 85 degrees, the filter cake is washed with 100 milliliters of toluene (80 degrees te...

Embodiment 2

[0041]A kind of preparation method of paliperidone intermediate, this method is with nucleophilic organic small molecule catalyst dimethylaminopyridine (DMAP), 2-amino-3-hydroxypyridine and 2-acetylpyridine are stoichiometrically The cyclization reaction gives 3-(2-hydroxyethyl)-9-hydroxyl-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one, which is then catalyzed in the presence of palladium carbon catalyst Hydrogenation gives the diol intermediate 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro9-hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one , the reaction temperature is 40°C, the reaction pressure is 0.2 atmospheres of hydrogen overpressure, that is, the internal pressure of 1.2 atmospheres; then POCl 3 It is a chlorination reagent, at 50°C, the reaction time is 7h, and the primary hydroxyl group is selectively chlorinated to obtain the key intermediate of paliperidone: 3-(2-chloroethyl)-6,7,8,9-tetra Hydrogen 9-Hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one.

Embodiment 3

[0043] A kind of preparation method of paliperidone intermediate, this method is with nucleophilic organic small molecule catalyst dimethylaminopyridine (DMAP), 2-amino-3-hydroxypyridine and 2-acetylpyridine are stoichiometrically The cyclization reaction gives 3-(2-hydroxyethyl)-9-hydroxyl-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one, which is then catalyzed in the presence of palladium carbon catalyst Hydrogenation gives the diol intermediate 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro9-hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one , the reaction temperature is 60°C, the reaction pressure is 0.1 atmospheric pressure of hydrogen overpressure, that is, the internal pressure of 1.1 atmospheric pressure; then POCl 3 It is a chlorination reagent, at 70°C, the reaction time is 7h, selective chlorination of the primary hydroxyl group, that is, the key intermediate of paliperidone: 3-(2-chloroethyl)-6,7,8,9-tetra Hydrogen 9-Hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidi...

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Abstract

The invention relates to a preparation method of 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone, which adopts nucleophilicity organic small-molecular catalyst as a catalyst, 2 - amino -3-hydroxypyridine and 2 - acetyl pyridine have cyclization reaction according to a chemical measurement ratio to obtain 3 - (2 - hydroxyethyl) -9-- hydroxy -2-- Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4-ketone, then the 3 - (2 - hydroxyethyl) -9-- hydroxy -2-- Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4-ketone is catalyzed and hydrogenated to obtain diol intermediate 3 - (2 - hydroxyethyl) -6,7,8,9 - tetrahydro-9 - hydroxy -2-- Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4-ketone, and then primary hydroxyl group is selectively chloridized to obtain Paliperidone intermediate: 3-(2-chloroethyl)-6, 7, 8, 9 - tetrahydro-9 - hydroxy - 2 - Methylenetetrahydrofolate - pyrido [1,2-alpha] pyrimidine -4 - ketone. Compared with the prior art, the method has the advantages of low cost, small environmental pollution, high selectivity and the like.

Description

technical field [0001] The present invention relates to a pharmaceutical intermediate, in particular to a paliperidone intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro 9-hydroxyl-2-methyltetrahydro - Process for the preparation of pyridin[1,2-alpha]pyrimidin-4-ones. Background technique [0002] Compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro 9-hydroxyl-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one is a synthetic The intermediate A of the drug paliperidone mainly has two methods to be synthesized at present. 1) Starting from benzyl-protected 2-amino-3-hydroxypyridine, obtained through cyclization, chlorination and hydrogenation. 2) Starting from unprotected 2-amino-3-hydroxypyridine, it is obtained through cyclization, chlorination and hydrogenation. Both of these methods inevitably overhydrogenate the chlorinated product B to form C by-product. [0003] SiO 2 , activated carbon, Al 2 o 3 Metal palladium, etc. as the carrier, or Al(OH) 3 Metal nickel as the carrier...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
Inventor 李悌聪龚洪泉冯建青周凌云胡静波
Owner SHANGHAI TWISUN BIO PHARM
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