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Refining and crystal transformation method for vortioxetine hydrobromide

A technology of vortioxetine hydrobromide and crystal transformation, applied in organic chemistry methods, organic chemistry, etc., can solve problems such as inorganic salt residues, toluene solvent residues, etc.

Inactive Publication Date: 2017-01-04
BEIJING SHENLANHAI BIO PHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method of the invention solves the problems of toluene solvent residues and inorganic salt residues, and the obtained vortioxetine hydrobromide meets the chemical purity and crystal form purity required by medicine, and is also suitable for industrial production

Method used

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  • Refining and crystal transformation method for vortioxetine hydrobromide
  • Refining and crystal transformation method for vortioxetine hydrobromide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: (repeat the embodiment of the original research CN102617513A)

[0024] 100g of crude tioxetine hydrobromide was dissolved in a mixed solvent (10:1, V / V) of toluene (800mL) and water (80mL) at 80°C, and then filtered hot; the filtrate was cooled to 9°C, crystallized, Filtration; the filter cake was washed with toluene (50mLx2), dried in vacuum at 50°C to constant weight, and 75g of white crystals were obtained, with a yield of 75%, an HPLC purity of 99.83%, a maximum single impurity of less than 0.1%, and a total impurity of less than 0.17%; the residue> 0.1% is unqualified; GC detection of toluene>0.15% is unqualified; XRD is consistent with the β crystal form data of vortioxetine hydrobromide reported by the original CN102617513A.

Embodiment 2

[0026] Use 200mL of methyl tert-butyl ether and ethanol mixed solvent (10:1, V / V) to beat 100g of tioxetine crude product at 50°C for 1 hour, filter; Slurry for 1 hour, filter; filter cake is heated to reflux with 400mL n-butanol and water mixed solvent (10:1, V / V) to dissolve, heat filter, cool to 9°C, crystallize, filter; filter cake is mixed with 300mL water After boiling, 150mL of water was distilled off, and the solution was slowly cooled to 9°C. After standing for 2 hours, crystallized and filtered, the filter cake was washed with water (50mLx2), and dried in vacuum at 50°C to constant weight to obtain 65g of white crystals. The yield 65%, HPLC purity 99.83%, maximum single impurity no more than 0.1%, total impurity no more than 0.17%; residue <0.01% qualified; GC detection of n-butanol not detected; XRD and original research CN102617513A reported vortioxetine hydrobromide The β crystal form data are consistent.

Embodiment 3

[0028] 100g of crude vortioxetine hydrobromide was beaten with 200mL of methyl tert-butyl ether and n-butanol mixed solvent (10:1, V / V) at 50°C for 1 hour, and filtered; Beat the slurry for 1 hour, filter; the filter cake is heated to reflux with 400mL n-butanol and water mixed solvent (10:1, V / V) to dissolve, heat filter, cool to 9 ° C, crystallize, filter; filter cake in 300mL water After azeotropy, 150mL of water was distilled off, and the solution was slowly cooled to 9°C. After standing for 2 hours, crystallized and filtered, the filter cake was washed with water (50mLx2), and dried in vacuum at 50°C to constant weight to obtain 74g of white crystals. The yield is 74%, the HPLC purity is 99.93%, the maximum single impurity is no more than 0.03%, the total impurity is no more than 0.07%; the residue <0.01% is qualified; GC detection of n-butanol is not detected; The data of Ting β crystal form are consistent.

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Abstract

The invention provides a refining and crystal transformation method for vortioxetine hydrobromide, belonging to the technical field of synthesis of chemical medicines. According to the invention, a novel recrystallization solvent system is used for safe and high-efficient preparation of beta-type vortioxetine hydrobromide. The method provided by the invention overcomes the problems of toluene solvent residues, inorganic salt residues and the like in the prior art; the obtained beta-type vortioxetine hydrobromide has chemical purity and crystal form purity meeting medicinal needs; and the method is suitable for industrial production.

Description

[0001] field of invention [0002] The invention relates to a method for refining and transforming vortioxetine hydrobromide, and belongs to the technical field of chemical drug synthesis. [0003] Background of the invention [0004] Vortioxetine is a new type of antidepressant drug jointly developed by Lundbeck Pharmaceuticals of Denmark and Takeda Pharmaceutical Company of Japan. In September 2013, it was approved for marketing by the US Food and Drug Administration (FDA), with the trade name Brintellix. The drug is a 5-HT3, 5-HT7, 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, and a 5-HT transporter inhibitor. It plays an antidepressant role by regulating 5-HT and is used for severe Treatment of adult patients with major depressive disorder (MDD). Its pharmaceutical form is the hydrobromide salt, in the beta crystal form. [0005] The chemical name of vortioxetine hydrobromide is: 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide, and its ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096C07B2200/13
Inventor 甄志彬吕健赵寅堡张翔
Owner BEIJING SHENLANHAI BIO PHARM TECH
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