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Resolution method of 3-(carbamoylmethyl)-5-methylhexanol

A technology of carbamoylmethyl and methylhexanoic acid, applied in the field of splitting of 3-(carbamoylmethyl)-5-methylhexanoic acid, can solve the problem of high price, high environmental pollution, high toxicity, etc. problem, to achieve the effect of simple method, high yield and high selectivity

Inactive Publication Date: 2010-10-13
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The chiral resolving agent ephedrine and norephedrine used in this resolution method are highly toxic, expensive and difficult to buy
[0012] The resolution preparation method of above-mentioned 3-(carbamoylmethyl)-5-methylhexanoic acid has many problems such as high toxicity, large environmental pollution, or difficult acquisition of resolving agent and high price

Method used

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  • Resolution method of 3-(carbamoylmethyl)-5-methylhexanol
  • Resolution method of 3-(carbamoylmethyl)-5-methylhexanol
  • Resolution method of 3-(carbamoylmethyl)-5-methylhexanol

Examples

Experimental program
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Effect test

Embodiment 1

[0048]9.35 g (50 mmol) 3-(carbamoylmethyl)-5-methylhexanoic acid, 12 g (50 mmol) (1R,2S)-N,N-dimethyl-1-p-nitro Phenyl-2-amino-1,3-propanediol (dimethylated L-chloramphenicol), 50 ml of water was added to a 100 ml three-necked flask, heated to reflux, all solids were dissolved, stirred for 5 minutes, and slowly cooled to 50°C , kept warm for 3 hours, then lowered to 30°C, filtered, washed with 5 ml of water to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and (1R,2S)-N , N-dimethyl-1-p-nitrophenyl-2-amino-1,3-propanediol amine salt 9.8 g, yield 46%.

[0049] diastereoisomeric salts 1 H-NMR (DMSO-d6, 300MHz): δ0.81-0.83 (d, 6H, J=6.4), δ1.08-1.12 (m, 2H), 1.60 (m, 1H), δ1.99-2.22 ( m, 5H), δ2.39(s, 6H), δ2.59-2.61(m, 1H), δ3.36-3.45(m, 2H), δ4.68-4.70(d, 1H, J=7.47) , 5.2 (s, (broad), 3H) δ6.75 (s, 1H), δ7.30 (s, 1H), 7.62-7.64 (d, 2H, J=7.44), 8.16-8.19 (d, 2H, J = 8.54).

[0050] The salt was dissociated by adding 18 ml of water and 25 ml of concentrated hydro...

Embodiment 2

[0052] 9.35 g (50 mmol) 3-(carbamoylmethyl)-5-methylhexanoic acid, 12 g (50 mmol) (1R,2S)-N,N-dimethyl 1-p-nitrobenzene Base-2-amino-1,3-propanediol (dimethylated L-chloramphenicol), 50 ml of water was added to a 100 ml three-necked flask, heated to reflux, all solids were dissolved, stirred for 5 minutes, and slowly cooled to 60 ℃, heat preservation for 1.5 hours, then lowered to 30 ℃, filtered, washed with 5 ml of water to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and (1R, 2S)- 10.2 g of N,N-dimethyl-1-p-nitrophenyl-2-amino-1,3-propanediol amine salt, yield 47.8%. After dissociation with hydrochloric acid, (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is the majority, and the enantioselectivity is 79.0% ee.

[0053] Take 5 grams of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and (1R,2S)-N,N-dimethyl-1-p-nitrophenyl- 2-Amino-1,3-propanediol amine salt, recrystallized with water to obtain 4.1 g, yield 82%, after dissociation with hydrochloric acid, o...

Embodiment 3

[0055] 9.35 g (50 mmol) 3-(carbamoylmethyl)-5-methylhexanoic acid, 9.6 g (40 mmol) (1R,2S)-N,N-dimethyl 1-p-nitrobenzene Base-2-amino-1,3-propanediol (dimethylated L-chloramphenicol), 50 ml of water was added to a 100 ml three-necked flask, heated to reflux, all solids were dissolved, stirred for 5 minutes, and slowly cooled to 60 ℃, heat preservation for 3 hours, then lowered to 30 ℃, filtered, washed with 5 ml of water to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and (1R, 2S)- 10.5 g of N,N-dimethyl-1-p-nitrophenyl-2-amino-1,3-propanediol amine salt, yield 55%. After dissociation with hydrochloric acid, (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is the majority, and the enantioselectivity is 65.3%ee.

[0056] Resolution of racemic 3-( Carbamoylmethyl)-5-methylhexanoic acid

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Abstract

The invention discloses a resolution method of 3-(carbamoylmethyl)-5-methylhexanol, which takes racemized 3-(carbamoylmethyl)-5-methylhexanol as a raw material and comprises the following steps: adding the alkamine derivative of a resolving agent to generate diastereoisomer salt with the raw material and then carrying out recrystallization and acid or basic dissociation on the salt to obtain the 3-(carbamoylmethyl)-5-methylhexanol of optical voidness, wherein the enantioselectivity is greater than 99%ee, and the yield can be stabilized to be about 37 percent (by 100 percent racemate). The invention is characterized in that a used solvent in the resolution process is environmental-friendly water, alcohol or ketone.

Description

technical field [0001] The present invention relates to the preparation of optically pure (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, a key intermediate of novel gamma-aminobutyric acid (GABA) receptor agonist drug method. Background technique [0002] Many compounds with the structure of inhibitory neurotransmitter γ-aminobutyric acid (GABA) have pharmacological effects of analgesia and auxiliary treatment of epilepsy, such as gabapentin 1-(aminomethyl)-cyclohexaneacetic acid, especially its The follow-up drug, pregabalin (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, is a novel γ-aminobutyric acid (GABA) receptor agonist that blocks voltage-dependent It can reduce the release of neurotransmitters and is mainly used in the treatment of peripheral neuralgia and auxiliary treatment of localized partial seizures. Therefore, the research on the synthesis process of pregabalin has broad application prospects. [0003] Optically pure (R)-(-)-3-(carbamoylmethyl)-5-methyl...

Claims

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Application Information

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IPC IPC(8): C07C231/20C07C233/05
Inventor 邓金根黄晴菲马海锋廖建朱槿
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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