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A kind of preparation method of 4-isobutylpyrrolidin-2-one

A technology for the reaction of isobutylpyrrolidine, which is applied in the field of medicine and chemical industry, can solve the problems of long route of pregabalin intermediate 19, unsuitability for commercial production, and low conversion rate, and achieve environmental friendliness, low production cost, and high conversion rate. high rate effect

Active Publication Date: 2015-09-09
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0006] 4-isobutylpyrrolidin-2-one is a key intermediate in the synthesis of pregabalin. The method for preparing pregabalin intermediate 19 has a long route, low yield, cumbersome operation, and is not suitable for commercial production.
[0007] CN102102114A discloses a preparation method of pregabalin, in which pregabalin is obtained from compound 24 through a two-step reaction, and the conversion rate is low

Method used

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  • A kind of preparation method of 4-isobutylpyrrolidin-2-one
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  • A kind of preparation method of 4-isobutylpyrrolidin-2-one

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Embodiment 1

[0031] In a closed container, 90g of ethyl 3-cyano-5-methylhexanoate and 360ml of ethanol-ammonia solution with an ammonia content of 2% were mixed, 5g of industrial-grade palladium carbon was added, hydrogen was introduced to pressurize to 5.5MPa, and the temperature was raised to The reaction was carried out at 30-40°C, and the end point of the reaction was detected by TLC. After the reaction was completed, the temperature was cooled to room temperature, palladium carbon was recovered, and the filtrate was concentrated to obtain 67.9 g of the pregabalin intermediate 4-isobutylpyrrolidin-2-one (GC purity 98 More than %), yield 97.9%.

[0032] 4-isobutylpyrrolidin-2-one 1 H NMR data (400MHz, CDCl 3 ):d6.30(s, 1H), 3.48(dd, J1 / 48.8Hz, 1H), 2.99(dd, J1 / 47.2, 2.4Hz, 1H), 2.50e2.58(m, 1H), 2.42(dd , J1 / 48.8, 8Hz, 1H), 1.97(dd, J1 / 48.8, 8Hz, 1H), 1.53e1.61(m, 1H), 1.31e1.37(m, 2H), 0.89e0.92(m, 6H).

Embodiment 2

[0034] Mix 90 g of benzyl (S)-3-cyano-5-methylhexanoate in a closed container with 360 ml of ethyl acetate-triethylamine solution with a triethylamine content of 10%, add 23 g of Raney nickel , feed hydrogen gas to pressurize to 0.1MPa, heat up to 55-65°C for reaction, TLC detects the end point of the reaction, after the reaction, cool down to room temperature, recover Raney nickel, and concentrate the filtrate to obtain the pregabalin intermediate (S)- 68.8 g of 4-isobutylpyrrolidin-2-one, yield 99.2%.

Embodiment 3

[0036] Mix 90g of methyl 3-cyano-5-methylhexanoate with 360ml of tetrahydrofuran-pyridine solution with a pyridine content of 0.5% in a closed container, add 18g of Raney nickel recovered in Example 2, and pressurize to 2.5 MPa, heat up to 75-85°C to react, TLC to detect the end of the reaction, after the reaction, cool down to room temperature, filter to remove Raney nickel, and concentrate the filtrate to obtain the pregabalin intermediate 4-isobutylpyrrolidin-2-one 68.2g, yield 98.3%.

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Abstract

The invention relates to a preparation method of a pregabalin intermediate 4-isobutyl pyrrolidine-2-ketone, belonging to the field of pharmaceutical chemical engineering, which comprises the following steps of: taking 3-cyan-5-methyl hexanoate as a raw material, and performing hydrogenation reaction in an ammonia and / or organic amine containing organic solvent under the action of a catalyst, thereby obtaining 4-isobutyl pyrrolidine-2-ketone. The method disclosed by the invention is easy in raw material obtaining, simple in operation, low in production cost, high in conversion rate, high in equipment utilization rate, environment-friendly, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pregabalin intermediate, in particular to a preparation method of 4-isobutylpyrrolidin-2-one, which belongs to the field of medicine and chemical industry. Background technique [0002] Pregabalin, whose chemical name is 3-(aminomethyl)-5-methylhexanoic acid, has the following structural formula: [0003] [0004] A substance having a structure similar to γ-aminobutyric acid (GABA). Pregabalin competitively binds to GABA receptors to inhibit excitatory conduction, so it is clinically used as an anti-epileptic and neuroma drug. [0005] CN200680020739.2 discloses a preparation method of pregabalin. Pregabalin is obtained from compound 15 through a three-step reaction. The specific route is as follows: [0006] 4-isobutylpyrrolidin-2-one is a key intermediate in the synthesis of pregabalin. The method for preparing pregabalin intermediate 19 has a long route, low yield, cumbersome operation, and i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/267
Inventor 张拥军朱勇华庄程翰禇运波何俊勇靳小舜徐洪良
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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