Preparation method of palmitic acid paliperidone intermediate

A technology for palmitic acid and intermediates, applied in the field of preparation of paliperidone palmitic acid intermediates, can solve the problems of low total yield and high cost of raw materials, and achieve the advantages of reducing impurity content, reducing purification operations and saving production costs. Effect

Pending Publication Date: 2020-08-11
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Documents US8481729B2, US7629469B2, US8940749B2, CN101014601B provide several synthetic methods of paliperidone palmitate, but the total yield of these methods is less than 9%, and the cost of raw materials is very high

Method used

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  • Preparation method of palmitic acid paliperidone intermediate
  • Preparation method of palmitic acid paliperidone intermediate
  • Preparation method of palmitic acid paliperidone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Under the protection of argon, 14.4 g of m-difluorobenzene was added to 20 ml of dichloromethane, and the temperature dropped to 10±5°C, and 14.17 g of trimethylsilyl trifluoromethanesulfonate was added dropwise in batches to control The temperature in the system is 8±3°C, add 6.5g of N-acetylpiperidine-4-formyl chloride into the system, raise the temperature of the system to 35±5°C and keep it for 11 hours, add 30ml of 6mol / L hydrochloric acid solution for washing, and add bicarbonate Wash with 30 ml of sodium solution, add 30 ml of purified water for washing, and concentrate under reduced pressure to obtain 7.1 g of product with a purity of 98.95%.

Embodiment 2

[0026] Example 2: Under the protection of argon, 14.4g of m-difluorobenzene was added to 20ml of dichloromethane, the temperature dropped to 10±5°C, 9.05g of boron trifluoride ether was added dropwise, and the internal temperature of the system was controlled at 8±5°C Add 6.5g of N-acetylpiperidine-4-formyl chloride to the system at 3°C, raise the temperature of the system to 35±5°C and keep it warm for 11 hours, add 30ml of 6mol / L hydrochloric acid solution to wash, add 30ml of sodium bicarbonate solution to wash, Add 30ml of purified water for washing, and concentrate under reduced pressure to obtain 6.7g of product with a purity of 98.42%.

Embodiment 3

[0027] Example 3: Under the protection of argon, 14.4g of m-difluorobenzene was added to 20ml of dichloromethane, the temperature dropped to 10±5°C, 8.5g of aluminum trichloride was added in batches, and the internal temperature of the system was controlled at 8±3°C , add 6.5g of N-acetylpiperidine-4-formyl chloride to the system, increase the temperature of the system to 35±5°C and keep it warm for 11 hours, add 30ml of 6mol / L hydrochloric acid solution for washing, add 30ml of sodium bicarbonate solution for washing, add purification Washed with 30ml of water and concentrated under reduced pressure to obtain 4.7g of product with a purity of 94.95%.

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PUM

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Abstract

The invention relates to a preparation method of a palmitic acid paliperidone intermediate, and relates to a synthesis method of a palmitic acid paliperidone intermediate with a structure shown as a formula II. According to the method, the purity and the yield of the intermediate can be greatly improved so that the purification operation of the paliperidone palmitate is reduced, in the synthesis process of the paliperidone palmitate, organic Lewis acid is used as a catalyst for the first time to complete the Friedel-Crafts reaction, and the yield of the prepared paliperidone palmitate intermediate is improved by more than 2.5 times.

Description

technical field [0001] The invention relates to a preparation method of a paliperidone palmitate intermediate. Background technique [0002] Paliperidone palmitate is developed and marketed by Johnson & Johnson, and its injection is a long-acting new anti-schizophrenia drug. Paliperidone is the major metabolite of risperidone. Its mechanism of action is not clear, but it is currently considered to be mediated through the combined action of central dopamine 2 (D2) receptor and 5-hydroxytryptamine 2 (5HT2A) receptor antagonism. Paliperidone is also an antagonist of alpha1 and alpha2 adrenergic receptors and H1 histamine receptors, which may account for some of the drug's other effects. Paliperidone has no affinity for cholinergic muscarinic receptors or β1- and β2-adrenergic receptors. In vitro, the pharmacology of the (+)- and (-)-paliperidone enantiomers is similar. [0003] Paliperidone palmitate has a structure as shown in Formula 1: [0004] [0005] Formula 1: Pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32
CPCC07D211/32
Inventor 闫雪峰张海明张小兵
Owner JIANGSU HANSOH PHARMA CO LTD
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