Improved method for preparing penfuridol

A technology of pentafluridol and fluorophenyl, which is applied in the field of preparation of pentafluridol, can solve the problems of many impurities and low product purity, and achieve the effects of good purity, high yield and mild reaction

Pending Publication Date: 2020-05-26
湖南中南制药有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the total yield of the three-step reaction from 4,4-bis(4-fluorophenyl)butyric acid to pentafluridol is only 40%-50%, especially in the last step of the amide reduction reaction, which has more impurities , the product has low purity and needs to be refined and purified many times to meet the qualified requirements

Method used

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  • Improved method for preparing penfuridol
  • Improved method for preparing penfuridol
  • Improved method for preparing penfuridol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] (1) Synthesis of intermediate Ⅰ

[0050]Put 20 g (0.072 moles) of 4,4-bis(4-fluorophenyl) butanoic acid into a three-necked flask, stir and dissolve 172 g (2.00 moles) of methyl tetrahydrofuran, add 5.4 g (0.039 moles) of potassium carbonate, and control the temperature Below 10°C, slowly add 2.89g (0.076 mol) of lithium aluminum tetrahydrogen, and keep stirring at about 0-10°C for 1-2h. After the reaction, the temperature was controlled below 10°C, and 2.9g (0.161 mol) of water, 2.9g (0.011 mol) of 15% sodium hydroxide solution (mass fraction) and 8.7g (0.483 mol) of water were added dropwise in sequence. , naturally heated to 25°C-30°C for filtration, the filter cake was washed with methyl tetrahydrofuran, the combined filtrates were concentrated to dryness to obtain 17.5g of the product 4,4-bis(4-fluorophenyl)-1-butanol (yield 92.6%).

[0051] The general reaction formula is as follows:

[0052]

[0053] (2) Synthesis of Intermediate II

[0054] Under nitrogen...

Embodiment 2

[0062] (1) Synthesis of intermediate Ⅰ

[0063] Put 20 g (0.077 moles) of 4,4-bis(4-fluorophenyl) butanoic acid into a three-necked flask, stir and dissolve 172 g (2.38 moles) of tetrahydrofuran, add 5.4 g (0.052 moles) of neutral alumina, and control the temperature Below 10°C, slowly add 2.00g (0.072 mol) of diborane, keep warm at 0-20°C and stir for 2-3h. After the reaction was completed, the temperature was controlled below 10°C, and 2.9g (0.016 moles) of water, 2.9g (0.011 moles) of 15% sodium hydroxide solution, and 8.7g (0.483 moles) of water were added dropwise successively. After quenching, stir and naturally Raise the temperature to 25°C-30°C for filtration, wash the filter cake with tetrahydrofuran, combine the filtrates, and concentrate to dryness to obtain 17 g of 4,4-bis(4-fluorophenyl)-1-butanol (yield 84.1%).

[0064] (2) Synthesis of Intermediate II

[0065] Under nitrogen protection, get 9g (0.034 moles) of 4,4-bis(4-fluorophenyl)-1-butanol obtained in step...

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Abstract

The invention discloses an improved method for preparing penfuridol, comprising the following steps: using 4, 4-bis (4-fluorophenyl) butyric acid as a starting material, carrying out reduction synthesis to synthesize an intermediate I [4, 4-bis (4-fluorophenyl)-1-butanol]; carrying out esterification with a sulfonyl chloride compound to synthesize an intermediate II [4, 4-bis (4-fluorophenyl)-1 (4-methyl-phenyl)-butyl sulfonate] or [4, 4-bis (4-fluorophenyl)-1-methyl-butyl sulfonate]; and condensing with pipradrol to obtain penfuridol. According to the preparation method, 4, 4-bis (4-fluorophenyl) butyric acid is used as a raw material, penfuridol is obtained through a reduction reaction, an esterification reaction and a condensation reaction, the total yield is 81.3%, the whole process isconvenient to operate and mild in reaction, the obtained product is high in yield and purity, and the preparation method is more economical and more suitable for industrial application. The technicalproblems that an existing method is low in yield and poor in purity are solved. The reaction general formula is as shown in the specification.

Description

technical field [0001] The invention relates to a method for preparing penfluridol. Background technique [0002] Its chemical name is [1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidine Alcohol], the English name is Penfluridol, and its chemical structural formula is: [0003] [0004] Penfluridol is a diphenylbutazone compound. This product is white or off-white crystalline powder; odorless and tasteless; easily soluble in methanol, ethanol, acetone or trichloromethane; almost insoluble in water; melting point is 105°C-108°C. Penfluridol is a long-acting oral antipsychotic drug that was launched in the 1960s. It is suitable for acute and chronic schizophrenia, and is especially convenient for long-term maintenance treatment to prevent relapse. [0005] Chinese patent document CN106187863A discloses a method for preparing pentafluorolidol. The method uses fluorobenzene as a starting material, undergoes double reaction, reduction react...

Claims

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Application Information

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IPC IPC(8): C07D211/52
CPCC07D211/52Y02P20/55
Inventor 彭正中申玉良袁着耕曹春宇舒志坚刘红
Owner 湖南中南制药有限责任公司
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