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Crystal forms of {[(2r)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride

A technology of dichlorophenyl and benzofuran, applied in {[(2R)-7-(2, can solve the problem of not lowering the level of dopamine

Inactive Publication Date: 2008-04-16
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 5-HT 2C Agonists do not reduce dopamine levels in the striatum and brain regions most associated with extrapyramidal side effects

Method used

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  • Crystal forms of {[(2r)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride
  • Crystal forms of {[(2r)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride
  • Crystal forms of {[(2r)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Preparation of Form I (without seed crystals)

[0074] Add 10g {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol to 100ml tert-butyl methyl ether amine (free base) and the resulting mixture was heated to 52°C. Then 2.7 ml HCl solution (36% wt / wt) was added and the temperature was lowered to room temperature over 2 hours. A crystalline solid precipitated, corresponding to Form I according to XRPD. The yield is about 90%.

Embodiment 2

[0076] Conversion of Form I to Form II

[0077] Form I was slurried in water for 1 day and stirred at 25°C for 5 days. After 1 day, XRPD showed that the solid had substantially converted from Form I to Form II. After 5 days, no detectable amount of Form I was observed.

Embodiment 3

[0079] Preparation of Form II with seed crystals

[0080] Method A

[0081]Add 3.1g {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol to 15ml isopropanol Base}amine (free base). The mixture was heated to 75°C and the resulting suspension was stirred (RPM = 200) until all solids were dissolved. Then 1 g of HCl solution (36% wt / wt) was added to the base solution over a period of 1 minute. No nucleation was observed. Seed crystals of Form II were added and the suspension was stirred for 30 minutes. After 4.5 hours the temperature was lowered to 0°C and a crystalline solid with Form II was recovered (ca. 80% yield).

[0082] Method B

[0083] To 642 g of isopropanol (IPA) was added 260 g of free base at room temperature. To this solution was added a solution of 218 g of HCl:IPA (16.7% HCl by weight; about 1.2 equivalents of HCl relative to free base) at 15-25°C. To the resulting white suspension was added 196 g of IPA. The total amount of IPA a...

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PUM

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Abstract

The present invention is directed to crystalline forms of the 5-HT2C agonist {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride, as well as compositions, processes of preparation, and uses thereof.

Description

[0001] This application claims the benefit of US Provisional Patent Application Serial No. 60 / 674,318, filed April 22, 2005, which is incorporated herein by reference in its entirety. field of invention [0002] The present invention relates to 5-HT 2c Agonist {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride Crystal form, and its composition, preparation method and use. Background of the invention [0003] Schizophrenia affects about 5 million people. The most common current treatments for schizophrenia are "atypical" antipsychotics, which combine dopamine (D 2 ) and 5-hydroxytryptamine (5-HT 2A ) receptor antagonism. Despite reports of improved efficacy and a tendency towards side effects of atypical antipsychotics relative to typical antipsychotics, these compounds clearly do not adequately treat all symptoms of schizophrenia and are associated with problematic side effects such as weight gain (Allison, D.B., et al., Am. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/81A61K31/34A61P25/00
CPCC07D307/81A61P1/04A61P3/04A61P13/02A61P15/10A61P25/00A61P25/06A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/32A61P25/36A61P43/00
Inventor A·塔戴安于庆M·贝尔纳切斯
Owner WYETH LLC
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