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Synthesis method of pregabalin intermediate 2-acetyl-3-nitromethylene-5-methyl-ethyl hexanoate

A technology of nitromethylene and pregabalin, applied in the field of organic synthesis, can solve the problems of high cost, long reaction time, and many intermediates, and achieve the effects of mild reaction conditions, low reaction cost, and simple post-treatment

Active Publication Date: 2020-03-06
SHAANXI UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The structural formula of pregabalin is relatively simple, but there are many intermediates, and the synthetic route is complicated. Most of the solvents used are organic solvents, which are toxic and harmful and cannot be reused. The cost is high, the reaction time is too long, and the yield is low, which affects its large-scale production.

Method used

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  • Synthesis method of pregabalin intermediate 2-acetyl-3-nitromethylene-5-methyl-ethyl hexanoate
  • Synthesis method of pregabalin intermediate 2-acetyl-3-nitromethylene-5-methyl-ethyl hexanoate
  • Synthesis method of pregabalin intermediate 2-acetyl-3-nitromethylene-5-methyl-ethyl hexanoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 Synthesis of 1-nitro-4-methyl-1-pentene:

[0022] In a dry three-necked flask, add 1.4g (1mol) 1 choline chloride and 1.2g (2mol) urea, heat up to 80°C, and magnetically stir until a colorless transparent liquid is obtained, that is, a deep eutectic solvent: DES (choloride chloride) Alkali-urea), cooled to room temperature; then added 0.5375g (1 mol) isovaleraldehyde, 0.457 (1.2 mol) nitromethane, heated to 80°C, stirred the reaction, and monitored by TLC until the reaction was complete. After the reaction was completed, it was cooled to room temperature, and a small amount of water was added to precipitate a pale yellow solid, which was filtered with suction, washed with water, and dried to obtain 1-nitro-4-methyl-1-pentene with a yield of 97%. The DES is recovered by evaporation of the water phase and can be reused.

[0023] 1 H NMR (400MHz, DMSO-d 6 )δ: 5.44(s, 1H), 4.67-4.68(m, 1H), 1.31-1.62(m, 2H), 1.18-1.26(m, 1H), 0.83-0.87(d, 6H).

Embodiment 2

[0024] Example 2 Synthesis of 2-acetyl-3-nitromethylene-5-methyl-hexanoic acid ethyl ester:

[0025] The recovered DES, 0.782 g (1 mol) 1-nitro-4-methyl-1-pentene, and 0.945 g (1.2 mol) ethyl acetoacetate were added to a dry three-necked flask. The temperature was raised to 80°C, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. It was cooled to room temperature, a small amount of water was added, a solid was precipitated, suction filtered, washed with water, and dried to obtain 2-acetyl-3-nitromethylene-5-methyl-hexanoic acid ethyl ester as a white powdery solid in a yield of 97%. The DES is recovered by evaporation of the water phase and can be reused.

[0026] 1 H NMR (400MHz, CDCl 3 )δ: 5.50(d, 1H), 4.32-4.33(d, 1H), 4.15-4.20(t, 2H), 2.28(s, 3H), 1.67-1.72(m, 2H), 1.56-1.62(m, 1H), 1.28-1.30(t, 2H), 1.24-1.26(t, 3H), 0.92-0.97(d, 6H).

Embodiment 3

[0027] Example 3 Synthesis of 2-acetyl-3-nitromethylene-5-methyl-hexanoic acid ethyl ester:

[0028] The recovered DES, 0.782 g (1 mol) 1-nitro-4-methyl-1-pentene, and 0.788 g (1 mol) ethyl acetoacetate were added to a dry three-necked flask. The temperature was raised to 80°C, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. It was cooled to room temperature, a small amount of water was added, a solid was precipitated, suction filtered, washed with water, and dried to obtain a white powdery solid 2-acetyl-3-nitromethylene-5-methyl-hexanoic acid ethyl ester with a yield of 93%. The DES is recovered by evaporation of the water phase and can be reused.

[0029] 1 H NMR (400MHz, CDCl 3 )δ: 5.50(d, 1H), 4.32-4.33(d, 1H), 4.15-4.20(t, 2H), 2.28(s, 3H), 1.67-1.72(m, 2H), 1.56-1.62(m, 1H), 1.28-1.30(t, 2H), 1.24-1.26(t, 3H), 0.92-0.97(d, 6H).

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Abstract

The invention provides a synthesis method of a pregabalin intermediate 2-acetyl-3-nitromethylene-5-methyl-ethyl hexanoate. The method comprises following steps: choline chloride and urea are added toa dry three-neck flask, heated to 80 DEG C and stirred magnetically until a DES (deep-eutectic solvent) is obtained, and the DES is cooled to room temperature; then isovaleraldehyde and nitromethane are added, the temperature is increased to 80 DEG C, and stirring reaction is performed; after the reaction, cooling is performed to reach the room temperature, a small amount of water is added, faintyellow solids are separated out, suction filtration, water washing and drying are performed, and 1-nitro-4-methyl-1-pentene is obtained; the DES is recovered by water phase evaporation and can be recycled; the DES recovered in the first step, 1-nitro-4-methyl-1-pentene and ethyl acetoacetate are added to the dry three-neck flask; the temperature is increased to 80 DEG C, and the stirring reactionis performed; cooling is performed to reach the room temperature, a small amount of water is added, solids are separated out, suction filtration, water washing and drying are performed, and 2-acetyl-3-nitromethylene-5-methyl-ethyl hexanoate is obtained; and the DES is recovered by water phase evaporation and can be recycled.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing a pregabalin-containing intermediate. Background technique [0002] Pregabalin is a 3-substituted analog of γ-aminobutyric acid and is a new type of calcium channel modulator. It can block voltage-dependent calcium channels and reduce the release of neurotransmitters. It is mainly used for local treatment of peripheral neuropathic pain, anxiety disorders and partial epileptic seizures. Pregabalin is the first drug that can be used to treat both types of neuralgia, and in addition to reducing pain, it can significantly improve sleep and quality of life. As a new type of psychotherapeutic drug, pregabalin has a rapid onset of action and few side effects, and has broad market development prospects. The structural formula of pregabalin is relatively simple, but there are many intermediates, and the synthetic route is complicated. Most of the solv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C205/51C07C201/12C07C205/03
CPCC07C205/51C07C201/12C07C205/03
Inventor 刘玉婷党阳尹大伟
Owner SHAANXI UNIV OF SCI & TECH