Preparation method for asymmetric synthesis of pregabalin

A pregabalin, asymmetric technology, applied in the preparation of organic compounds, chemical instruments and methods, cyanide reaction preparation and other directions, to achieve the effects of improved product yield, novel synthesis route and low cost

Active Publication Date: 2014-06-04
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] In order to solve the problems such as the long synthetic route of pregabalin, the low yield in the production process, and the need for splitting in the preparation process, the present invention provides a kind of synthetic steps less, environmental protection Asymmetric synthetic route with low pollution, high yield and no need for chiral resolution

Method used

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  • Preparation method for asymmetric synthesis of pregabalin
  • Preparation method for asymmetric synthesis of pregabalin
  • Preparation method for asymmetric synthesis of pregabalin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 Preparation of Compound 9

[0063] At room temperature, add 11.3 g of isovaleraldehyde, 50 ml of n-hexane, 0.75 g of acetic acid, and 0.63 g of di(n-)propylamine into a dry 100 mL single-necked flask. Stir well and add 20.0 g of diethyl malonate. Raise the temperature and reflux, connect the water separator to divide the water until no water is produced. Stop heating and stirring, cool to room temperature naturally, add 25mL water to wash, separate the organic phase, wash once with 20mL 1mol / L NaOH aqueous solution, and finally wash with 5% NH 4 The Cl aqueous solution was washed once, and the organic phase was concentrated to obtain the residue as a yellow liquid, and 25.7 g of the target product was distilled out by rectification. Yield: 86.7%.

[0064] 1 HNMR(400MHz,CDCl3): 6.99-7.02(t, 1H, -C=C H ), 4.27-4.32(q, 2H, -OC H 2 CH 3 ), 4.20-4.25(q, 2H, -OC H 2 CH 3 ), 2.17-2.20(t, 2H, -C H 2 C=CH), 1.78-1.84(m, 1H, -C H (CH 3 ) 2 ), 1.25-1...

Embodiment 2

[0065] Example 2 Preparation of Compound 9

[0066] At room temperature, add 11.3g of isovaleraldehyde, 100ml of toluene, 0.75g of acetic acid, and 1.40g of N-methylpiperazine into a 250 mL reaction bottle equipped with a water separator. After stirring evenly, add the material diethyl malonate Esters 20.0 g. Heat up and reflux, connect the water separator to divide the water until no water is produced, and separate the water. Stop heating and stirring, cool to room temperature naturally, add 25mL water to wash, separate the organic phase, wash once with 20mL 1mol / L NaOH aqueous solution, and finally wash with 5% NH 4 The Cl aqueous solution was washed once, the toluene layer was dried with anhydrous magnesium sulfate, the desiccant was filtered off, and the residue was concentrated to obtain a yellow liquid, and 28.0 g of the target product was distilled out by rectification. Yield: 94.4%.

[0067] The 1H NMR spectrum is the same as above.

Embodiment 3

[0068] Example 3 Preparation of Compound 34

[0069] At room temperature, add compound 4 (20.0 g) and nitromethane 26.8 g into a dry 100 mL single-necked flask, stir evenly, cool down to -5°C-0°C, slowly add nitromethane containing DHQ-PYR 4.1 g dropwise 10.0 mL of solvent was added dropwise within 30 minutes, and stirring was continued for 1 hour at -5°C-0°C. The ice bath was removed, and the reaction was stirred at 25-30°C. TLC detected that the starting material disappeared. Add 30mL of 2mol / L hydrochloric acid aqueous solution, under stirring, add 20mL of saturated sodium chloride solution, extract three times with 40mL of ethyl acetate, combine the ethyl acetate layer, wash twice with 10mL of saturated sodium carbonate solution, and then wash twice with 10mL of water , 20.4 g of light yellow oily liquid distilled from the ethyl acetate layer under reduced pressure. Yield: 80.6%, ee value 99.4%, purity 98.3%.

[0070] 1 HNMR(400MHz, CDCl3,):4.50-4.54(q, 1H, -C H 2 NO...

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Abstract

The invention provides a novel method for chiral synthesis of pregabalin. The novel method comprises the following steps that 1, diethyl malonate and 3-methyl butyraldehyde undergo a Knoevenagel reaction to produce an intermediate 2-(3-methylbutenyl)-diethyl malonate, 2, in a nitromethane solution, 2-(3-methylbutenyl)-diethyl malonate and nitromethane undergo an asymmetric addition reaction in the presence of a chiral catalyst to produce an intermediate (S)-2-(3-methyl-2-nitromethyl)diethyl n-butylmalonate, 3, under the acidic conditions, (S)-2-(3-methyl-2-nitromethyl)diethyl n-butylmalonate simultaneously undergoes hydrolysis, decarboxylation and reduction reactions, and pregabalin or its corresponding isomer is separated by alkalization, 4, the pregabalin or its corresponding isomer is subjected to acidity adjustment, decoloration and filtration, the filtrate is subjected to basicity adjustment and crystallization, and the crystals are dried to form the refined pregabalin, and 5, the refined pregabalin is subjected to 1HNMR, 13CNMR, MS and IR identification.

Description

technical field [0001] The invention belongs to the technical field of medicine production, and in particular relates to a new method for asymmetrically synthesizing analgesic pregabalin. Background of the invention [0002] Pregabalin (CAS: 148553-50-8) is a gamma-aminobutyric acid (GABA) analogue, similar in structure and action to gabapentin, with antiepileptic, analgesic and anxiolytic activities. The mechanism of antiepileptic action of this drug is not clear. In laboratory studies, the drug has anticonvulsant activity on various epilepsy models; the activity spectrum of animal models is similar to that of gabapentin, but the activity is 3 to 10 times that of gabapentin. [0003] The drug was applied for registration by Pfizer in 2003, and the FDA approved it for listing in December, 2004, and the preparation is a capsule. This variety is widely used in the treatment of epilepsy, neuropathic pain and anxiety disorders, generalized anxiety disorder, diabetic periphera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/08C07C227/04C07C227/00
Inventor 叶伟平徐俊烨肖诗华黄志宁吴鸿翔郑周何伟健
Owner RAFFLES PHAMRMATECH CO LTD
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