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

A technology of ethyl methylhexanoate and nitromethylene, which is applied in the field of synthesis of intermediates containing pregabalin, can solve the problems of high cost, many intermediates, long reaction time, etc. The effect of simple processing and low reaction cost

Active Publication Date: 2020-02-18
SHAANXI UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The structural formula of pregabalin is relatively simple, but there are many intermediates. Among them, the synthesis route of 2-carboxyethyl-3-nitromethylene-5-methylhexanoic acid ethyl ester is complicated, and most of the solvents used are organic solvents, which are toxic and harmful. Unable to reuse, high cost; too long reaction time, low yield, affecting its industrialization

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Synthesis of ethyl 2-carboxyethyl-5-methyl-2-hexanoate:

[0023] In a dry three-necked flask, add 1.4g (1mol) choline chloride and 1.2g (2mol) urea, stir and heat up to 80°C to obtain a colorless transparent liquid, which is the deep eutectic solvent: DES (chlorinated choline-urea); then add 0.5375g (1mol) isovaleraldehyde, 1.0g (1.0mol) diethyl malonate, stir and react at 80°C, monitor by TLC until the reaction is complete. After the reaction, the reaction mixture was cooled to room temperature, distilled water was added, extracted with ethyl acetate, and the organic phase was evaporated to remove the solvent to obtain ethyl 2-carboxyethyl-5-methyl-2-hexanoate, a colorless transparent liquid. Yield 96.6%. The water phase is evaporated to obtain DES, which can be recycled and reused.

[0024] 1 H NMR (400MHz, CDCl 3 )δ:6.99(t,1H),4.17-4.31(m,4H),2.18-2.15(m,2H),1.76-1.82(m,1H),1.31-1.24(m,6H),0.91-0.93( m,6H).

[0025] 13 C NMR (101MHz, CDCl 3 )δ: 165....

Embodiment 2

[0026] Example 2 Synthesis of ethyl 2-carboxyethyl-3-nitromethylene-5-methylhexanoate:

[0027] The second step: add 1.394g (1.0mol) 2-carboxyethyl-5-methyl-2-hexanoic acid ethyl ester, 0.447g (1.2mol) nitromethane, 0.293g (1.0mol) NaOH to the mortar , 1.01g (1.0mol) anhydrous K 2 CO 3 (Wherein E:F:G:H=1:1.2:1:1.1) Grinding reaction, TLC monitoring until the reaction is complete, add appropriate amount of distilled water, extract with ethyl acetate, evaporate the solvent from the organic layer to obtain 2-carboxyethyl-3 -Ethyl nitromethylene-5-methylhexanoate, yellow liquid, yield 96%.

[0028] 1 H NMR (400MHz, CDCl 3 )δ:4.73-4.50(q,2H),4.23-4.20(q,4H),3.62(d,2H),1.62-1.70(q,1H),1.25-1.34(d,8H),0.87-0.95( m, 6H).

Embodiment 3

[0029] Example 3 Synthesis of ethyl 2-carboxyethyl-3-nitromethylene-5-methylhexanoate:

[0030] Step 1: In a dry three-necked flask, add 1.4g (1mol) choline chloride and 1.2g (2mol) urea at room temperature, raise the temperature to 80°C, and stir magnetically until a colorless transparent liquid is obtained, that is, a deep eutectic solvent : DES (choline chloride-urea); then add 0.5375 (1 mol) isovaleraldehyde, 1.2 g (1.2 mol) diethyl malonate, heat up to 80 ° C, stir the reaction, TLC monitoring until the reaction is complete. After the reaction, cool to room temperature, pour into water, extract with ethyl acetate, evaporate the solvent from the organic layer to obtain ethyl 2-carboxyethyl-5-methyl-2-hexanoate, evaporate the water phase to recover DES, which can be reused . The second step: add 1.626g (1.0mol) ethyl 2-carboxyethyl-5-methyl-2-hexanoate, 0.521g (1.2mol) nitromethane, 0.284g (1mol) NaOH in the mortar, 0.980g (1mol) K 2 CO 3 , (wherein E:F:G:H=1:1.2:1:1.1)...

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Abstract

The invention provides a synthesis method of a pregabalin intermediate, namely 2-carboxyethyl-3-nitromethylene-5-methyl ethyl hexanoate. The synthesis method comprises the following steps: 1, adding choline chloride and urea, stirring and heating to 80 DEG C to obtain a colorless transparent solution, and cooling to room temperature; then adding isovaleraldehyde and diethyl malonate, stirring at 80 DEG C to react, and monitoring by TLC (Thin Layer Chromatography) until the reaction is complete; and after the reaction is finished, cooling the reaction mixed liquid to room temperature, adding water, extracting with ethyl acetate, and evaporating an organic layer to remove the solvent, thereby obtaining 2-carboxyethyl-5-methyl-2-ethyl hexanoate; 2, adding the 2-carboxyethyl-5-methyl-2-ethyl hexanoate, nitromethane, NaOH and anhydrous K2CO3 into a mortar, carrying out a grinding reaction, carrying out TLC monitoring until the reaction is complete, adding distilled water, extracting with ethyl acetate, and evaporating an organic layer to remove the solvent in order to obtain the 2-carboxyethyl-3-nitromethylene-5- methyl ethyl hexanoate.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of a pregabalin-containing intermediate. Background technique [0002] Pregabalin is used as an adjuvant therapy for anti-neuralgia and epilepsy. Modern pharmacological experiments have confirmed that pregabalin has good anti-convulsant, anti-anxiety, and analgesic effects. It is used for the treatment of epilepsy, anxiety, and spinal cord injury. The central nervous system pain caused by trauma or multiple sclerosis is widely used clinically. As a new type of psychotherapeutic drug, pregabalin has a rapid onset of action and few side effects, and has broad market development prospects. 2-carboxyethyl-3-nitromethylene-5-methylhexanoic acid ethyl ester is an intermediate in the synthesis of pregabalin, so the research and exploration of its synthesis method has very important practical significance. The structural formula of pregabalin is relatively ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C201/12C07C205/51C07C67/343C07C69/593
CPCC07C67/343C07C201/12C07C69/593C07C205/51Y02P20/584
Inventor 尹大伟党阳刘玉婷
Owner SHAANXI UNIV OF SCI & TECH
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