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Preparation method of Sendamaldine

A technology of azabicyclo and hexane hydrochloride, applied in organic chemical methods, medical preparations containing active ingredients, pharmaceutical formulations, etc., can solve problems such as difficult purification of crystalline polymorphs and difficulty in achieving repeatability

Pending Publication Date: 2022-05-27
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in order to utilize these purification methods on an industrial scale, there is a problem that it is difficult to achieve reproducibility, etc., because, for example, repeated complicated steps of heating, dissolving, and drying using several different types of organic solvents are required, and differences in solubility from each other Purification of mixtures of crystalline polymorphs with little difference is difficult

Method used

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  • Preparation method of Sendamaldine
  • Preparation method of Sendamaldine
  • Preparation method of Sendamaldine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Preparation of crystal form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (compound 1) (1)

[0099]

[0100] To a mixture of ethanol (178.2 mL) and water (1.8 mL) was added (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride under nitrogen atmosphere The crude product (20.0 g, 0.081 mol). The mixture was refluxed for more than 10 minutes to dissolve the crude product. The solution was left to cool until reflux ceased. To the solution was added activated carbon (2.0 g) and the mixture was refluxed for more than 30 minutes. The mixture was filtered while hot, and the activated carbon on the filter was washed with a mixture of ethanol (19.8 mL) and water (0.2 mL). The filtrate was refluxed again for more than 10 minutes (79°C) to completely dissolve the filtrate. The resulting solution was cooled to 60°C and then reheated to 70°C. The mixture was then stirred at 70°C for more than 60 minutes. The mixture was cooled to 10°...

Embodiment 2

[0105] Preparation of crystal form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (compound 1) (2)

[0106] To a mixture of ethanol (178.2 mL) and water (1.8 mL) was added (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride under nitrogen atmosphere The crude product (20.0 g, 0.081 mol). The mixture was refluxed for more than 10 minutes to dissolve the crude product. The solution was left to cool until reflux ceased. Activated carbon (2.0 g) was added to the solution and the mixture was refluxed for more than 30 minutes. The mixture was filtered while hot, and the activated carbon on the filter was washed with a mixture of ethanol (19.8 mL) and water (0.2 mL). The filtrate was refluxed again for more than 10 minutes (79°C) to completely dissolve the filtrate. The resulting solution was cooled to 51°C and then reheated to 70°C. The mixture was then stirred at 70°C for more than 60 minutes. The mixture was cooled to 10°C to precipi...

Embodiment 3

[0111] Preparation of crystal form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (compound 1) (3)

[0112] To a mixture of ethanol (178.2 mL) and water (1.8 mL) was added (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride under nitrogen atmosphere The crude product (20.0 g, 0.081 mol). The mixture was refluxed for more than 10 minutes to dissolve the crude product. The solution was left to cool until reflux ceased. Activated carbon (2.0 g) was added to the solution and the mixture was refluxed for more than 30 minutes. The mixture was filtered while hot, and the activated carbon on the filter was washed with a mixture of ethanol (19.8 mL) and water (0.2 mL). The filtrate was refluxed again for more than 10 minutes (79°C) to completely dissolve the filtrate. The resulting solution was cooled to 60°C and then reheated to 72°C. The mixture was then stirred at 72°C for over 60 minutes. The mixture was cooled to 10°C to precipitate ...

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Abstract

The present invention addresses the problem of finding a method for reliably preparing (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo [3.1. 0] hexane hydrochloride, in which the crystalline polymorph can be controlled using an industrially easy operation. The present invention provides a process for preparing a crystalline form of (1R, 5S)-1-(naphthalene-2-yl)-3-azabicyclo [3.1. 0] hexane hydrochloride, the process comprising: a step (a) of heating and dissolving (1R, 5S)-1-(naphthalene-2-yl)-3-azabicyclo [3.1. 0] hexane hydrochloride in a solvent comprising an alcohol-based solvent; a step (b) of cooling the dissolution product of step (a) to a temperature at which crystals of (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo [3.1. 0] hexane hydrochloride are precipitated to nucleate said crystals; a step (c) of heating the mixture containing the crystals obtained by nucleation to a temperature at which only a specific crystal form is selectively retained; and (d) cooling the mixture heated in step (c) to obtain the crystal form.

Description

technical field [0001] The present invention relates to a method for preparing a crystal form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. Background technique [0002] (1R,5S)- Also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (common name: centanafadine) - 1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is an inhibitor of norepinephrine reuptake, dopamine reuptake, and serotonin (5-HT) reuptake. Useful compounds (Patent Document 1, Patent Document 2). [0003] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (hereinafter also referred to as "compound 1") is known: [0004] [0005] Several crystalline forms are thermodynamically reversibly deformable polymorphs. Form A is higher than the phase transition temperature T t,B→A stable solid phase under ; Form B is in T t,C→B with T t,B→A stable solid phase between; Form C is lower than T t,C→B stable solid phase. T t,B→A Expected to be between 37 and 54°C, T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52C07B2200/13A61P43/00A61P25/00A61K31/403
Inventor 大塚怜安中正祥三谷光
Owner OTSUKA PHARM CO LTD
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