Method for preparing (3R)-(-)-3-(2- acetamino)-5-methylhexanol

A technology of acetylamino and methylhexanoic acid, which is applied in the field of medicine, can solve the problems of excessive waste water, waste of raw materials, and long reaction time, and achieve the effects of increased yield, reduced production cost, and shortened reaction cycle

Inactive Publication Date: 2013-01-30
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, this method uses a large amount of solvent during chiral resolution, is difficult to operate, and produces a large number of optical isomers
[0009] Re-racemization can be perfo

Method used

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  • Method for preparing (3R)-(-)-3-(2- acetamino)-5-methylhexanol
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  • Method for preparing (3R)-(-)-3-(2- acetamino)-5-methylhexanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Preparation of (3R)-(-)-3-(2-acetylamino)-5-methylhexanoic acid

[0030]

[0031] Put in 100g (±)-3-(2-acetylamino)-5-methylhexanoic acid racemate (prepared in Example 6), 2500g chloroform, 67.5g absolute ethanol, heat up to 55°C to dissolve, add 65g (S)-(-)-1-Phenylethylamine. Cool to 45°C, add 0.1g (3S)-(+)-3-(2-acetylamino)-5-methylhexanoic acid seed, cool to 25°C, filter with suction to get (3S)-(+)- 3-(2-Acetamido)-5-methylhexanoic acid phenethylamine salt 120g, set aside separately. The filtrate was concentrated to dryness under reduced pressure, 400 g of water and 2 g of activated carbon were added, stirred for decolorization, and suction filtered. The filtrate was adjusted to PH=1.5 with hydrochloric acid, cooled to 0~5°C, filtered with suction, and dried at 60°C to obtain 50 g of (3R)-(-)-3-(2-acetylamino)-5-methanol with an e.e. value of 90%. Hexanoic acid.

Embodiment 2

[0032] Example 2: Purification of (3R)-(-)-3-(2-acetylamino)-5-methylhexanoic acid

[0033]

[0034] 45g of (3R)-(-)-3-(2-acetylamino)-5-methylhexanoic acid (prepared in Example 1) with an e.e. value of 90% and 100g of absolute ethanol were dissolved at 60°C and cooled to Add 0.1g (3R)-(-)-3-(2-acetylamino)-5-methylhexanoic acid seed crystal at 45°C, cool at 5-10°C for 2 hours, filter with suction, and dry to obtain 35g (3R )-(-)-3-(2-acetylamino)-5-methylhexanoic acid, e.e. value 99.5%.

Embodiment 3

[0035] Embodiment 3: Preparation of 4-isobutyl-2,6-piperidone

[0036]

[0037] (3S)-(+)-3-(2-Acetamido)-5-methylhexanoic acid (prepared in Example 1) 200g, urea 60g, heat up to 160~180°C, and keep warm for 1 hour. Cool, add 400g of 60°C hot water at 80°C, cool to 0~5°C, and filter with suction to obtain 250g of 4-isobutyl-2,6-piperidone.

[0038] The test confirmed that this product is 4-isobutyl-2,6-piperidone. mp 136~138.3°C [Literature (Belsain database): 138~138.5°C]. MS (ESI): 168.9 (M+H).

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PUM

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Abstract

The invention provides a method for preparing an antiepileptic medicament pregabalin intermediate, i.e., (3R)-(-)-3-(2-acetamino)-5-methylhexanol. The method comprises the following steps of: salifying a (+/-)-3-(2-acetamino)-5-methylhexanol racemic body serving as a raw material and (S)-(-)-1-phenylethylamine in a mixed solvent of alcohol and halogenated hydrocarbon, precipitating unnecessary S-shaped chiral isomer salts out, filtering, concentrating a filtrate, dissolving into water, and reacting by using an acid to obtain (3R)-(-)-3-(2- acetamino)-5-methylhexanol of which the e.e. value is 80-90 percent; and refining to obtain a (3R)-(-)-3-(2-acetamino)-5-methylhexanol product of which the e.e. value is 98-99 percent. The method has the advantages of high chiral monomer purity, wide reaction temperature range, convenience in operating and suitability for industrial production. The invention further provides a method for preparing a racemate, i.e., (+/-)-3-(2-acetamino)-5-methylhexanol. The racemic body can be taken as a raw material for repeated use, so that the consumption of raw materials is lowered, environmental protection is promoted, and the method has high application value.

Description

technical field [0001] The present invention relates to medicines, in particular to the preparation of pharmaceutical intermediates, in particular to the preparation of antiepileptic drug pregabalin chiral intermediate (3R)-(-)-3-(2-acetylamino)-5-methylhexanoic acid method. Background technique [0002] Epilepsy (commonly known as epilepsy) is a chronic disease in which the sudden abnormal discharge of brain neurons leads to transient brain dysfunction. Epileptic seizures refer to clinical phenomena caused by abnormal brain neurons and excessive hypersynchronized discharges. Depending on where in the brain the abnormally firing neurons are located, epilepsy can have a variety of manifestations, mostly motorsensory or autonomic, with or without changes in consciousness or alertness. According to relevant data, there are currently more than 50 million epilepsy patients in the world, with an average of 1 person per 100 people with epilepsy. On average, 20-70 cases of epileps...

Claims

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Application Information

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IPC IPC(8): C07C233/05C07C231/08
Inventor 褚定军张毅
Owner AURISCO PHARMACEUTICAL CO LTD
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