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Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate

A technology of -AT-OL and phenylglycolic acid salt, applied in the field of preparing duloxetine intermediates, can solve problems such as shortage

Inactive Publication Date: 2009-03-18
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, prior art methods lack a continuous one-pot process that efficiently recycles (R)-AT-OL using the starting solvent system for chiral resolution

Method used

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  • Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate
  • Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate
  • Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: Repeat chiral resolution of Preparation 1 in US 5362886 (2x scale)

[0072] The chiral resolution of AT-OL with mandelic acid in MTBE / ethanol was repeated (Repeat 1 in US 5,362,886). The enantiomer R level was measured to be 7.01%.

[0073] A solution of 8.2 g of (S)-mandelic acid in 25 ml of ethanol (heated to dissolve at 50°C) was added to a solution of 20 g of (R,S)-AT-OL in 300 ml of MTBE at 50°C. The resulting mixture was heated to reflux for 45 minutes, then cooled to room temperature and stirred overnight (1 hour in this patent). The resulting solid was filtered and dried in a vacuum oven to give 16 g of (S)-AT-OL mandelic acid salt (enantiomer R: 7.01%).

Embodiment 2

[0074] Example 2: Chiral resolution of AT-OL in IPA

[0075] A solution of 2 g (S)-mandelic acid in 10 ml IPA (heated to dissolve at 50°C) was added to a solution of 5 g (R,S)-AT-OL in 40 ml IPA at 50°C. The resulting mixture was heated to reflux for 45 minutes and then cooled to room temperature. The resulting solid was filtered and dried in a vacuum oven to yield 3.5 g of (S)-AT-OL mandelic acid salt (enantiomer R: 15.03%).

Embodiment 3

[0076] Example 3: Chiral resolution of AT-OL in MIBK

[0077] A solution of 2 g (S)-mandelic acid in 10 ml MIBK (heated to dissolve at 50° C.) was added to a solution of 5 g (R,S)-AT-OL in 10 ml MIBK at 50° C. The resulting mixture was heated to reflux for 45 minutes and then cooled to room temperature. The resulting solid was filtered and dried in a vacuum oven to yield 3.8 g of (S)-AT-OL mandelic acid salt (enantiomer R: 3.87%).

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Abstract

A chiral resolution process for the preparation of (S)-AT-OL, and a process for the racemization of AT-OL are provided. A one pot continuous process for preparing (S)-AT-OL or (S)-AT-OL mandelate comprising: a) converting (R) -AT-OL to (R / S) -AT-OL in a mixture of a Cl-8 alcohols and a C2-8 ether in presence of an acid; b) reacting the (R / S) -AT-OL with (S) - ( + ) -mandelic acid in the mixture to obtain (S)-AT-OL mandelate; and c) optionally converting the (S)-AT-OL mandelate to (S)-AT-OL.

Description

[0001] Refer to related applications [0002] This application claims the benefit of the following US Provisional Patent Applications: 60 / 775593, filed February 21, 2006; 60 / 791103, filed April 10, 2006; and 60 / 792812, filed April 17, 2006. technical field [0003] The invention provides a method for preparing duloxetine intermediate. Background technique [0004] Duloxetine is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It has utility in the treatment of stress urinary, urinary incontinence (SUI), depression and pain. Duloxetine hydrochloride has the following chemical name: (+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride and structure: [0005] [0006] Duloxetine base and its preparation are disclosed in US Patent 5,023,269 (US '269). European Patent No. 457559 and U.S. Patent Nos. 5,491,243 (US '243) and 6,541,668 provide an improved synthetic route for the preparation of duloxetine base. [0007] Preparat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20
Inventor S·伊尼Y·什米利M·阿布拉莫夫
Owner TEVA PHARMA IND LTD
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