A kind of β-type efficient vortioxetine hydrobromide crystal conversion method

A technology of vortioxetine hydrobromide and hydrobromic acid, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of complex synthesis and subsequent refining, and low total yield

Active Publication Date: 2021-11-09
BEIJING SHENLANHAI BIO PHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But after above-mentioned improvement, synthesis and follow-up purification 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-carboxylate to calculate the overall yield)

Method used

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  • A kind of β-type efficient vortioxetine hydrobromide crystal conversion method
  • A kind of β-type efficient vortioxetine hydrobromide crystal conversion method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 600 mL of mixed solvent IV to 100 g of tert-butyl-4-(2-(2,4-dimethylthiophenol) phenyl) piperazine-1-carboxylate and activated carbon (10 g) 异丙醇：40％氢溴酸 =10:1 (V:V), heated to react at 50°C for 1.5 hours, filtered while hot; the filter cake was pre-cooled with 50mL isopropanol and water mixed solvent (V 异丙醇：水 =10:1) rinse. Collect the filter cake, add 300 ml of water, distill out about 100 ml of solvent under normal pressure, stop heating, naturally cool to room temperature 15-25 ° C, stir and crystallize, 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 grams of off-white crystalline solid powder, yield 75%, HPLC purity 99.96%, maximum single impurity no more than 0.1%, total impurity no more than 0.04%; residue on ignition <0.01 % qualified; GC detection of isopropanol was not detected; XRD was consistent with the vortioxetine hydrobromide β crystal form data reported by the original...

Embodiment 2

[0026] Add 800 mL of mixed solvent IV to 100 g of tert-butyl-4-(2-(2,4-dimethylthiophenol) phenyl) piperazine-1-carboxylate and activated carbon (10 g) 异丙醇：40％氢溴酸 =10:1 (V:V), heated to react at 50°C for 1.5 hours, filtered while hot; the filter cake was pre-cooled with 50mL isopropanol and water mixed solvent (V 异丙醇：水 =10:1) rinse. Collect the filter cake, add 300 ml of water, distill out about 100 ml of solvent under normal pressure, stop heating, naturally cool to room temperature 15-25 ° C, stir and crystallize, 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 grams of off-white crystalline solid powder, yield 72%, HPLC purity 99.98%, maximum single impurity no more than 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 CN102617513A.

Embodiment 3

[0028] Add 400 mL of mixed solvent IV to 100 g of tert-butyl-4-(2-(2,4-dimethylthiophenol) phenyl) piperazine-1-carboxylate and activated carbon (10 g) 异丙醇：40％氢溴酸 =10:1 (V:V), heated to react at 50°C for 1.5 hours, filtered while hot; the filter cake was pre-cooled with 50mL isopropanol and water mixed solvent (V 异丙醇：水 =10:1) rinse. Collect the filter cake, add 300 ml of water, distill out about 100 ml of solvent under normal pressure, stop heating, naturally cool to room temperature 15-25 ° C, stir and crystallize, 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 grams of off-white crystalline solid powder, yield 79%, HPLC purity 99.88%, maximum simple impurity 0.07%, total impurity 0.12%; residue on ignition <0.01% qualified ; Isopropanol was not detected by GC; XRD was consistent with the vortioxetine hydrobromide β crystal form data reported by the original CN102617513A.

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Abstract

The invention provides an efficient and simple method for refining and transforming vortioxetine hydrobromide, belonging to the technical field of chemical drug synthesis. In the present invention, the precursor tert-butyl-4-(2-(2,4-dimethylthiophenol) phenyl) piperazine-1-carbonate of synthetic vortioxetine adopts isopropanol-hydrogen bromide The acid mixed solution removes the N-Boc protecting group, the reaction system cools down and crystallizes to obtain the isopropanol solvate of vortioxetyl hydrobromide, and then undergoes a water azeotropic distillation to obtain β-type vortioxety hydrobromide safely and efficiently Sitin. The method of the present invention reduces multi-step tedious refining operations, and can effectively solve the problems of toluene solvent residues, inorganic salt residues, and metal palladium residues in the prior art, and the obtained β-type vortioxetine hydrobromide meets the requirements of the drug. With the required chemical purity and crystal form purity, it is suitable for industrial production.

Description

[0001] field of invention [0002] The invention relates to a preparation method of high-efficiency vortioxetine hydrobromide, which belongs to the technical field of chemical drug synthesis. [0003] Background of the invention [0004] Vortioxetine (Vortioxetine) was approved by the U.S. Food and Drug Administration (FDA) in September 2013. It is a new type of antidepressant drug jointly developed by Lundbeck Pharmaceuticals of Denmark and Takeda Pharmaceutical Company of Japan. 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 can not only selectively inhibit the reuptake of five serotonin (5-HT), but also has 5-HT 1A Agonists, 5-HT 1B Partial agonists and 5-HT 3 , 5-HT 1D and 5-HT 7 The effect of receptor antagonists. Diversity enables it to modulate neurotransmission in several systems, primarily serotonin, and presumably norepine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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