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Preparation of beta-amino acids having affinity for the alpha-2-delta protein

A technology of alkyl and aryl groups, applied in the field of materials for preparing optically active β-amino acids, can solve problems such as preparation difficulties

Inactive Publication Date: 2007-08-29
WARNER-LAMBERT CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some of these compounds, like those represented by Formula 1 below, possess two or more stereogenic (chiral) centers, which makes their preparation somewhat difficult
Although a suitable method for preparing optically active β-amino acids on a laboratory scale has been described in the '251 application, most such methods are problematic for pilot-scale or full-scale production due to efficiency or cost considerations

Method used

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  • Preparation of beta-amino acids having affinity for the alpha-2-delta protein
  • Preparation of beta-amino acids having affinity for the alpha-2-delta protein
  • Preparation of beta-amino acids having affinity for the alpha-2-delta protein

Examples

Experimental program
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Effect test

Embodiment 1

[0305] Example 1. Preparation of (R)-3-methyl-hexanoic acid from (R)-2-methyl-pentan-1-ol via (R)-3-methyl-capronitrile

[0306] (R)-2-Methyl-pentan-1-ol, MeCl 2 The mixture with pyridine was cooled to 0°C to 10°C. To this mixture was added tosyl chloride and the resulting reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched by adding water and the mixture was separated into upper and lower layers. The lower layer was washed with dilute aqueous HCl. The organic layer was concentrated to an oil by vacuum distillation, which was then diluted with DMSO and allowed to react by adding sodium cyanide and heating to 50 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with hexane and water and the upper layer was washed with water. The hexane layer was concentrated by vacuum distillation to yield (R)-3-methyl-capronitrile as an oil. The oil was reacted by adding aqueous HCl and heating the mixture to 50-6...

Embodiment 2

[0307] Example 2. Preparation of (R)-5-methyl-3-oxo-octanoic acid ethyl ester from (R)-methyl-hexanoic acid and potassium ethylmalonate

[0308] To a stirred mixture of N,N carbonyldiimidazole (26.4 g) in THF (175 mL) was added (R)-3-methyl-hexanoic acid (20 g) at room temperature. The reaction mixture became clear after stirring at room temperature for 4 hours to give a solution of the active carboxylic acid. To a stirred mixture of potassium ethylmalonate (49.6 g) in acetonitrile (265 mL) was added Et 3 N (21.4 mL). To this mixture was added anhydrous magnesium chloride powder (35.1 g) in portions while maintaining the temperature at 15°C to 25°C. The resulting slurry was allowed to warm to room temperature and allowed to stir for 4 hours. The activated carboxylic acid solution was added to the slurry and the mixture was stirred at room temperature for 17 hours. The reaction was quenched with aqueous HCl and extracted with MTBE. With sodium bicarbonate and NaCl / H 2 The...

Embodiment 3

[0309] Example 3. Preparation of (R)-5-methyl-3-oxo-octanoic acid ethyl ester from (R)-methyl-hexanoic acid and potassium ethylmalonate

[0310] To a stirred mixture of N,N carbonyldiimidazole (33 kg) in EtOAc (217 L) was added (R)-3-methyl-hexanoic acid (25 kg) dissolved in EtOAc (30 L) at room temperature. The reaction mixture became clear after stirring at room temperature for 1 hour to give a solution of the active carboxylic acid. To a stirred mixture of potassium ethylmalonate (45.8 kg) and magnesium chloride (25.6 kg) in EtOAc (320 L) was added Et 3 N (31.1 kg). The activated carboxylic acid solution was added to this slurry and the resulting mixture was stirred at 40°C to 50°C for 11 hours. The mixture was cooled to 10°C to 15°C and quenched with aqueous HCl. The organic layer was washed sequentially with water and aqueous sodium bicarbonate and then concentrated by vacuum distillation to give the title compound as a yellow oil (38.2 kg, 92% pure product based on 10...

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Abstract

Disclosed are materials and methods for preparing optically active ss-amino acids of Formula (1), which bind to the alpha-2-delta (a2d) subunit of a calcium channel.

Description

technical field [0001] The present invention relates to materials and methods for preparing optically active beta-amino acids that bind to alpha-2-delta (alpha2delta) subunits of calcium ion channels. Such compounds, including their pharmaceutically acceptable complexes, salts, solvates and hydrates, are suitable for use in the treatment of pain, fibromyalgia and various psychiatric and sleep disorders. Background technique [0002] [beta]-amino acids that bind to the [alpha]2[delta] subunit of calcium ion channels are described in US Patent Application No. 2003 / 0195251 Al (the '251 application) to Barta et al. Such compounds, including their pharmaceutically acceptable complexes, salts, solvates and hydrates, are useful in the treatment of many conditions, conditions and diseases. These include (but are not limited to): sleep disorders such as insomnia, fibromyalgia, epilepsy, neuralgia including acute pain as well as chronic pain, migraine, hot flashes, pain associated wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/18C07C69/716C07C227/32C07C69/675C07C227/18C07C239/18C07C233/47C07D205/08C07C67/32C07C229/08C07C67/30
CPCY02P20/582
Inventor B·G·康韦T·N·纳宁加吴海峰G·霍格B·A·皮尔曼D·D·温克尔
Owner WARNER-LAMBERT CO
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