Beta type efficient vortioxetine hydrobromide crystal transformation method

A technology of vortioxetine hydrobromide and hydrobromic acid, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of low total yield, cumbersome synthesis and subsequent refining, and achieve simplified refining operations and improved overall synthesis. Yield effect

Active Publication Date: 2017-01-11
BEIJING SHENLANHAI BIO PHARM TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But after above-mentioned improvement, synthesis and follow-up refining are more loaded down with trivial details, and overall yield is lower about 50-60% (with tert-butyl-4-(2-(2,4-dimethylthiophenol) phenyl)piperene Oxyzine-1-carbonate to calculate the overall yield)

Method used

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  • Beta type efficient vortioxetine hydrobromide crystal transformation method
  • Beta type efficient vortioxetine hydrobromide crystal transformation method
  • Beta type efficient vortioxetine hydrobromide crystal transformation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In 100g tert-butyl-4-(2-(2,4-dimethylthiophenol)phenyl)piperazine-1-carbonate, activated carbon (10g) was added 600mL mixed solvent IV 异丙醇∶40％氢溴酸 =10:1 (V:V), heated and reacted at 50 ° C for 1.5 hours, filtered while hot; filter cake was mixed with pre-cooled 50mL isopropanol, water mixed solvent (V 异丙醇∶水 =10:1) Rinse. Collect the filter cake, add 300 ml of water, and distill about 100 ml of solvent at atmospheric pressure, stop heating, naturally cool to room temperature 15-25 ° C, stir for crystallization, filter, rinse the filter cake with water (50 mL), collect the filter cake, Vacuum drying at 50-55°C for 12-13 hours to obtain 71.0 g of off-white crystalline solid powder, yield 75%, HPLC purity 99.96%, maximum single impurity less than 0.1%, total impurity less than 0.04%; residue on ignition < 0.01 % qualified; isopropanol was not detected by GC; XRD was consistent with the β-crystal data of vortioxetine hydrobromide reported by the original research CN102617513...

Embodiment 2

[0027] In 100g tert-butyl-4-(2-(2,4-dimethylthiophenol)phenyl)piperazine-1-carbonate, activated carbon (10g) was added 800mL mixed solvent IV 异丙醇∶40％氢溴酸 =10:1 (V:V), heated and reacted at 50 ° C for 1.5 hours, filtered while hot; filter cake was mixed with pre-cooled 50mL isopropanol, water mixed solvent (V 异丙醇∶水 =10:1) Rinse. Collect the filter cake, add 300 ml of water, and distill about 100 ml of solvent at atmospheric pressure, stop heating, naturally cool to room temperature 15-25 ° C, stir for crystallization, filter, rinse the filter cake with water (50 mL), collect the filter cake, Vacuum drying at 50-55°C for 12-13 hours to obtain 68.0 g of off-white crystalline solid powder, yield 72%, HPLC purity 99.98%, maximum single impurity 0.1%, total impurity 0.02%; residue on ignition <0.01% Qualified; Isopropanol was not detected by GC; XRD was consistent with the β-crystal data of vortioxetine hydrobromide reported by the original research CN102617513A.

Embodiment 3

[0029] In 100g of tert-butyl-4-(2-(2,4-dimethylthiophenol)phenyl)piperazine-1-carbonate, activated carbon (10g) was added 400mL of mixed solvent IV 异丙醇∶40％氢溴酸 =10:1 (V:V), heated and reacted at 50 ° C for 1.5 hours, filtered while hot; filter cake was mixed with pre-cooled 50mL isopropanol, water mixed solvent (V 异丙醇∶水 =10:1) Rinse. Collect the filter cake, add 300 ml of water, and distill about 100 ml of solvent at atmospheric pressure, stop heating, naturally cool to room temperature 15-25 ° C, stir for crystallization, filter, rinse the filter cake with water (50 mL), collect the filter cake, Vacuum drying at 50-55°C for 12-13 hours to obtain 75.0 g of off-white crystalline solid powder, yield 79%, HPLC purity 99.88%, maximum single impurity 0.07%, total impurity 0.12%; residue on ignition < 0.01% qualified ; Isopropanol was not detected by GC detection; XRD was consistent with the β-crystal data of vortioxetine hydrobromide reported by the original research CN102617513A. ...

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Abstract

The invention provides an efficient and concise method for refining and crystal transformation of vortioxetine hydrobromide, and belongs to the technical field of chemical drug synthesis. A vortioxetine synthesis precursor tert-butyl-4-(2-(2,4-dimethyl thiophenol)phenyl)piperazine-1-carbonate has an N-Boc protection group removed by adopting an isopropanol-hydrobromic acid mixed solution, a reaction system is cooled and crystallized, a vortioxetine hydrobromide isopropanol solvate is obtained and is subjected to water azeotropic distillation for one time, and the beta type vortioxetine hydrobromide can be safely and efficiently obtained. The method reduces multi-step tedious refining operation, and also can effectively solve the problems that toluene solvent residues, inorganic salt residues and metal palladium residues in the prior art; and the obtained beta type vortioxetine hydrobromide meets medical needed chemical purity and crystal form purity, and is suitable for industrial production.

Description

[0001] Field of Invention [0002] The invention relates to a preparation method of high-efficiency vortioxetine hydrobromide, and belongs to the technical field of chemical drug synthesis. [0003] Background of the Invention [0004] Vortioxetine, approved by the U.S. Food and Drug Administration (FDA) in September 2013, is a new antidepressant drug jointly developed by Denmark's Lundbeck Pharmaceuticals and Japan's Takeda Pharmaceuticals. Vortioxetine, a phenylpiperazine psychotropic drug with a new structure, can be described as a novel multi-action mechanism antidepressant. According to relevant research reports, the drug not only selectively inhibits the reuptake of serotonin (5-HT), but also has 5-HT 1A Receptor agonists, 5-HT 1B Receptor partial agonists and 5-HT 3 , 5-HT 1D and 5-HT 7 The role of receptor antagonists. The diversity makes it possible to modulate neurotransmission in several systems, primarily serotonin, and presumably also norepinephrine, dopamine...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07B2200/13C07D295/096
Inventor 甄志彬吕健张翔刘琨高世静陶新华
Owner BEIJING SHENLANHAI BIO PHARM TECH
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