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Novel asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid

A carbamoyl and methyl technology, applied in the field of -pregabalin and -pregabalin intermediates, synthesis of -3--5-methylhexanoic acid, can solve the problem of product loss

Inactive Publication Date: 2008-09-17
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Of course, this results in a 50% loss of product, a serious disadvantage

Method used

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  • Novel asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
  • Novel asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid
  • Novel asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] Example 1: (3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl)hexanoylation Preparation of compound (24)

[0268] Toluene (400ml), (S)-(-)-phenethylamine (142.35g, 1.1764mol) and 4-dimethyl Aminopyridine (0.7176 g, 0.0059 mol). The mixture was cooled to a temperature of -10°C to -15°C, followed by the addition of a solution of 3-isobutylglutaric anhydride (100 g, 0.59 mol) in toluene (100 ml) over a period of 45-60 minutes, and at -10°C Stir for an additional 1.5-2 hours to a temperature of -15°C. The mixture was then extracted with 10% aqueous NaOH (500ml) and the aqueous phase was washed with toluene (1 x 250ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding aqueous hydrochloric acid (1-12N). The aqueous phase was further extracted with toluene (1 x 800ml) at a temperature of 70-80°C. The toluene layer was washed with 10% sodium chloride solution (700ml) at 70-80°C, followed by crystallization to give 125g (73.0% yield) of (3S)-5-methyl-3-(...

Embodiment 2

[0269] Example 2: (3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl)hexanoylation Preparation of compound (24)

[0270] Toluene (400ml), (S)-(-)-phenylethylamine (38.59g, 0.0.319 moles) and 4-bis Methylaminopyridine (0.358 g, 0.0029 moles). The mixture was cooled to a temperature of -40°C to -50°C, then a solution of 3-isobutylglutaric anhydride (50 g, 0.294 mol) in toluene (100 ml) was added over a period of 45-60 minutes and heated at -40°C Stir for an additional 1.5-2 hours to a temperature of -50°C. The mixture was then extracted with 3.5-4.0% aqueous NaOH (1000ml), and the aqueous phase was washed with toluene (1 x 250ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding aqueous hydrochloric acid (1-12N). The aqueous phase was further extracted with ethyl acetate (1 x 300ml and 1 x 100ml), then the combined ethyl acetate extracts were dried over anhydrous sodium sulfate, and the solvent was removed to obtain a residue. The residue was crystallize...

Embodiment 3

[0271] Example 3: (3S)-5-methyl-3-(2-oxo-2{[(1S)-1-phenylethyl]amino}ethyl)hexanoylation Preparation of compound (24)

[0272] Toluene (1000ml), (S)-(-)-phenylethylamine (266.9g, 2.206mol) and 4-dimethyl Aminopyridine (1.79 g, 0.0147 mol). The mixture was cooled to a temperature of -40°C to -50°C, followed by the addition of a solution of 3-isobutylglutaric anhydride (250 g, 1.471 mol) in toluene (250 ml) over a period of 45-60 minutes, and at -40°C Stir for an additional 1.5-2 hours to a temperature of -50°C. The mixture was then extracted with 3.5-4.0% aqueous NaOH (2350ml), and the aqueous phase was washed with toluene (1 x 250ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding aqueous hydrochloric acid (1-12N). The aqueous phase was further extracted with ethyl acetate (1 x 1250ml and 1 x 500ml), then the combined ethyl acetate extracts were dried over anhydrous sodium sulfate, and the solvent was removed to obtain a residue. The residue was crystalliz...

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PUM

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Abstract

The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2{[(lR)- l-phenylethyl]amino} ethyl)hexanoic acid.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to the following U.S. Provisional Patent Applications: U.S. Provisional Patent Application Serial No. 60 / 718,689, filed September 19, 2005; 60 / 754,392, filed December 27, 2005; January 30, 2006 60 / 763,593 filed December 20, 2005; 60 / 753,220 filed December 21, 2005; 60 / 763,696 filed January 30, 2006; and August 23, 2006 60 / 839,947, these provisional applications are incorporated herein by reference. field of invention [0003] The present invention includes methods for the synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-pregabalin and (S)-pregabalin intermediates. Background of the invention [0004] (S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the following chemical structure, [0005] [0006] Also known as gamma-aminobutyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, trade name Has been found to activate GAD (L-glutamic ac...

Claims

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Application Information

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IPC IPC(8): C07C229/14C07C233/05C07C271/22C07C227/32
Inventor A・P・蒂瓦里V・K・坎萨尔B・P・乔拉西亚V・G・劳
Owner TEVA PHARMA IND LTD
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