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Preparation method of high-purity Z-type flupentixol dihydrochloride

A technology of flupenthixol hydrochloride and flupenthixol, which is applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, and achieve the effects of low environmental protection pressure, low material cost, high yield and product purity

Active Publication Date: 2018-05-04
ZEIN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The E / Z configuration is separated by salting and crystallizing the mixed flupentixol free base in ether, but the Z-isomer separated by this method still contains part of the E-isomer, and ether is easily Toxic solvent, the use of ether as a solvent is not conducive to industrial production

Method used

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  • Preparation method of high-purity Z-type flupentixol dihydrochloride
  • Preparation method of high-purity Z-type flupentixol dihydrochloride
  • Preparation method of high-purity Z-type flupentixol dihydrochloride

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Embodiment 1

[0066] The preparation of embodiment 1 Z type flupentixol hydrochloride

[0067] Add 55g (0.1mol) of flupentixol hydrochloride type E into a three-necked flask, add 260-300g of ethanol, 50g (0.9mol) of potassium hydroxide, start stirring, raise the temperature to 60-65°C, react for 120-130 minutes, and cool down to 30~40℃, evaporate the solvent under reduced pressure, add 200~250g of dichloromethane, wash with (300~350g)*3 water, evaporate the solvent under reduced pressure, after evaporation, add 180~220g of acetone to dissolve, in 15~25 8.0-9.0g of hydrogen chloride gas is introduced at ℃, and after completion, the temperature is kept at 15-25℃ for 2-2.5 hours to crystallize, and suction filtration is added to the filter cake, and 100-150g of methanol is added, and the temperature is raised to dissolve, then cooled to 0-5℃, and suction-filtered , the filtrate was concentrated to dryness under reduced pressure, added 70-80g of isopropanol under reflux for beating for 1 hour, ...

Embodiment 2

[0068] The preparation of embodiment 2 Z type flupenthixol hydrochloride

[0069] Add 55g (0.1mol) flupentixol hydrochloride type E into the three-necked flask, add 260-300g methanol, 40g (1.0mol) sodium hydroxide, start stirring, raise the temperature to 60-65°C, react for 120-130 minutes, and cool down to 30~40℃, evaporate the solvent under reduced pressure, add 200~250g of dichloromethane, wash with (300~350g)*3 water, evaporate the solvent under reduced pressure, after evaporation, add 100~120g of ethyl acetate to dissolve, in 15 Add 70-80g of saturated hydrochloric acid ethyl acetate solution dropwise at ~25°C. After the addition is complete, keep warm at 15-25°C for crystallization for 2-2.5 hours, filter with suction, add 100-150g of methanol to the filter cake, heat up to dissolve, and then cool down to 0-2.5 hours. 5°C, filter with suction, concentrate the filtrate to dryness under reduced pressure, add 70-80g of isobutanol, beat under reflux for 1 hour, cool down to ...

Embodiment 3

[0070] Example 3 Preparation of Z-type flupenthixol hydrochloride

[0071] Add 50g of flupentixol hydrochloride raw material into a three-necked bottle, add 150-200g of methanol, heat up to dissolve, then cool down to 0-5°C, filter with suction, concentrate the filtrate to dryness under reduced pressure, add 70-80g of isopropanol, and reflux Beat for 1 hour, cool down to 0-5°C, crystallize for 2 hours, and filter with suction to obtain 43 g of Z-type flupenthixol hydrochloride with a yield of 90% and a purity of 98.8801%.

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Abstract

The invention discloses a preparation method of high-purity Z-type flupentixol dihydrochloride. The preparation method of the high-purity Z-type flupentixol dihydrochloride comprises the following steps: transforming E-type flupentixol dihydrochloride by using C1-C3 monohydric alcohol A and inorganic strong alkali to obtain a Z / E flupentixol mixture and performing separation to obtain the Z-type flupentixol dihydrochloride; or separating and purifying the raw material medicine of the flupentixol dihydrochloride to obtain the Z-type flupentixol dihydrochloride. The preparation method is low inmaterial cost, high in yield, high in product purity and low in environment-protecting pressure. (The formula is as shown in the description).

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of high-purity Z-type flupenthixol hydrochloride. Background technique [0002] Flupenthixol hydrochloride is an important component of the compound preparation Delixin, which has a strong antipsychotic effect, which is 4 to 8 times stronger than cloprothixol and has a weaker sedative effect. It also has anti-anxiety and anti-depressant effects. It is suitable for acute and chronic schizophrenia, depression and depressive neurosis. [0003] The raw material flupenthixol hydrochloride is composed of E-type flupenthixol hydrochloride and Z-type flupentixol hydrochloride, and the proportion of Z-type flupentixol hydrochloride in the raw drug is required to be between 42% and 52%. It is necessary to separate the E-type flupenthixol hydrochloride and the Z-type flupentixol hydrochloride with higher purity, and then mix them according to the above ratio ...

Claims

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Application Information

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IPC IPC(8): C07D335/12
CPCC07D335/12
Inventor 邓祥林代毅王飞谢侨黄超明谭瑶徐天帅
Owner ZEIN BIOTECHNOLOGY CO LTD