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Preparation method of high-purity paliperidone intermediate

A technology of paliperidone and intermediates, applied in the direction of organic chemistry, etc., can solve the problems of poor product properties, cumbersome recrystallization and purification operations, and low product purity, and achieve good properties, shortened hydrogenation reaction time, and high yield. Effect

Inactive Publication Date: 2017-11-03
JINAN KANGHE MEDICAL TECH
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Problems solved by technology

This patent uses a second-class solvent, dichloromethane, to prepare key intermediate I from intermediate IV through two steps of first removing the benzyl group and then further hydrogenation and reduction. The process is cumbersome and unfavorable for industrial production.
[0013] Analysis and replication of the prior art revealed that the preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2 -a] There are the following problems in the process of pyrimidin-4-one: ① During the preparation of intermediate IV, the recrystallization and purification operation after separation by column chromatography is cumbersome; Solvent dichloromethane, the process is not friendly to the environment, and the residual solvent also brings potential safety hazards to the finished product paliperidone; ③The hydrogenation reaction time is long, reaching 120 hours; ④The resulting product has poor properties, gray in color, and product purity Low, easy to produce chlorine by-product compound V; unfavorable for industrial scale-up production

Method used

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  • Preparation method of high-purity paliperidone intermediate
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  • Preparation method of high-purity paliperidone intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Example 1: Preparation of intermediate II: 2-amino-3-benzyloxypyridine

[0036]Control the temperature below 40°C, add 48L of purified water to a 300L stainless steel reaction kettle, slowly add 48kg of sodium hydroxide under stirring conditions, and stir until dissolved. Add 16kg of 2-amino-3-hydroxypyridine, 1.6kg of tetrabutylammonium bromide, and 17.92L of benzyl chloride to the sodium hydroxide solution in sequence, and after the addition, raise the temperature to 70-75°C for 6 hours, stop stirring, and let stand , liquid separation; the water phase was extracted with toluene (20Lx3); the purified water was washed (30Lx2), the organic phase was collected, concentrated until a large amount of solids were precipitated, the temperature was controlled at 0-5°C, stirred and crystallized for 2 hours, centrifuged, and the filter cake was washed with 3.2 Rinse with L pre-cooled toluene, and vacuum dry at 50-55°C for 3 hours to obtain Intermediate II, a bright yellow solid,...

Embodiment 2

[0037] Example 2: Preparation of intermediate III: 9-(benzyloxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0038] Under the condition of stirring, add 13.6L toluene, 8.5kg 2-amino-3-benzyloxypyridine, 8.4kgα-acetyl-γ-butyrolactone, 450g p-toluenesulfonic acid successively in the 50L glass reactor, after adding, Raise the temperature to reflux, and separate the water generated by the reaction in time. It is detected by HPLC that the remaining 2-amino-3-benzyloxypyridine is less than 2%. Stop heating, distill under reduced pressure until most of the solids are precipitated, stop the distillation under reduced pressure, and cool down to 0 ~5°C, stirred and crystallized for 2 hours, and filtered with suction to obtain 11.7kg of crude product. Blow dry to constant weight, put the crude product into a 50L reaction kettle filled with 7.7L methanol, heat and reflux for about 1 hour, then cool down to 0-5°C, keep stirring for 1 hour, filter with suction, and blow dr...

Embodiment 3

[0039] Example 3: Preparation of intermediate IV: 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0040] Under the condition of stirring at room temperature, 3600ml of ethylene glycol dimethyl ether and 1800g of 9-(benzyloxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1 ,2-a] pyrimidin-4-one, after uniform dispersion, slowly add 1620ml of phosphorus oxychloride dropwise. After the addition, the temperature was raised to reflux for 6h, the heating was stopped, and the temperature was lowered to room temperature. Slowly add the reaction solution into a 50L glass reaction kettle filled with 7.5L cold water at 0-5°C to quench it. After the addition, a yellow solution is obtained. Use 20% sodium hydroxide solution to adjust the pH to 7-8, and the solution turns brick red. A large amount of solids are produced, continue to stir for 1 hour, filter with suction, wash the filter cake three times (1800mlx3) with purified water at 40-50°C, put the filter cake in an...

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Abstract

The invention belongs to the technical field of medicine, and particularly discloses a preparation method of a high-purity paliperidone intermediate 3-(2-chloroethyl)-9-hydroxyl-2-methyl-6,7,8,9-tetrahydro-4H-pyridino[1,2-a] pyrimidine-4-ketone. The preparation method particularly comprises the following steps: preparing 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyridino[1,2-a] pyrimidine-4-ketone by taking 2-amino-3-hydroxypyridine as a starting raw material and through benzyl protection, ring closure of alpha-acetyl-gamma-butyrolactone and chloro-substitution; dissolving the 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyridino[1,2-a] pyrimidine-4-ketone into an alcohol solvent, adding acid and a palladium-charcoal catalyst, controlling hydrogen pressure, and after the reaction is completed, performing processes of filtering, concentrating, adjusting the pH value, extracting, concentrating and refining to obtain white-like powdered 3-(2-chloroethyl)-9-hydroxyl-2-methyl-6,7,8,9-tetrahydro-4H-pyridino[1,2-a] pyrimidine-4-ketone. The preparation method is short in cycle, the product is white-like, the yield reaches 70 percent or higher, the purity reaches 99 percent or higher, related impurities of chlorine-removed byproducts are avoided, and the preparation method is suitable for industrialized enlarged production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a paliperidone intermediate 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyridine And the preparation method of [1,2-a] pyrimidin-4-one. technical background [0002] Paliperidone Chinese name: (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6 ,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; English name: [0003] (±)-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; CAS Registry Number: 144598-75-4. [0004] The structural formula is as follows: [0005] [0006] Paliperidone (Paliperidone) is an atypical antipsychotic drug developed by Johnson & Johnson, and belongs to the 5-HT antagonist of benzisoxazole derivatives. A new type of antipsychotic drug approved by the FDA on December 19, 2006. Paliperidone developed as a sustained-release prepar...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 张冬梅张颖许嘉平艾雷锋郑良文孙丽梦
Owner JINAN KANGHE MEDICAL TECH
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