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Synthetic method of pregabalin

A kind of technology of pregabalin and synthesis method, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of side reaction, insufficient time and the like

Inactive Publication Date: 2015-04-08
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, since the condensation and addition reactions are carried out above 50°C, more side reactions are prone to occur
The time of the hydrolysis reaction reported in this patent is nearly 100h, but our experiment shows that this time is still not enough

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-5

[0067] Step 1: Preparation of (±)-3-(carbamoylmethyl)-5-methyl-hexanoic acid (6)

[0068] Add 110g of ethyl cyanoacetate and 1mL of piperidine into a 1000ml flask, and stir until evenly distributed. Slowly add 86g of isovaleraldehyde dropwise, and stir at 20-30°C for 6-10h. After the dropwise addition was completed, when TLC showed that the reaction was qualified, 164 g of diethyl malonate was added, and 10 g of DBU was added and stirred at room temperature for 2 hours. LCMS showed major [M-H] - The ion peak is 258.1250, and the chemical formula is C 12 h 20 NO 5 . Then 350mL of water was added to the organic phase, then transferred to a 1000mL autoclave, heated to 98-102°C, maintained at this temperature and evacuated for 5 minutes, then sealed the autoclave, continued to heat to 260°C and maintained at this temperature After 8 hours, cool to below 40°C, and then pour ammonia water (1.5 equivalents) into the system. Reheat to 180°C and maintain at this temperature for ...

Embodiment 6

[0077] Embodiment 6: Step 1 reacts under flow reactor

[0078] Add 110 g of ethyl cyanoacetate (1.03 mol) and 1 mL of piperidine (as a catalyst) into the flask, and stir until evenly distributed. 86 g (1 mol) of isovaleraldehyde was slowly added dropwise, the dropping temperature was 20°C, and the dropping time was 30 minutes, then stirred at 20-30°C for 6-10 hours until TLC showed that the reaction was complete. The reaction mixture was pumped proportionally into the T-mixer of the first SS capillary reactor as stream A, while stream B consisting of 164 g (1,02 mol) diethyl malonate and 10 g DBU (as catalyst) was proportionally into the T-blender. The length of the reactor is related to the fluid pumping speed, and the reaction liquid is controlled to react at 70° C. for 12 minutes. The obtained reaction fluid continues to enter the second T-mixer, and the T-mixer is pumped into the fluid C (350mL 90°C hot water) in proportion, and then the temperature is controlled at 340°...

Embodiment 7

[0079] Example 7: Step 1 uses cyanoacetamide

[0080] Add (0.22mol) 185g cyanoacetamide, 500mL water and 5gDMF to the flask, cool to 5-15°C, add 86g (0.1mol) 3-methylbutyraldehyde and then stir. After reacting at 5-15° C. for 8 hours, it was cooled, and the reaction mixture was heated in an autoclave. The subsequent steps were the same as the first step in Example 1. The yield was 88%.

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PUM

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Abstract

The invention discloses a synthetic method of pregabalin. According to the synthetic method, isovaleraldehyde and cyanoacetic alkyl ester are used as starting materials; condensation reaction, Michael addition reaction, hydrolysis reaction, amidation reaction and the like are carried out successively to obtain 3-(carbamoyl methyl)-5-methyl-hexanoic acid; and resolution and Hofmann elimination are carried out to obtain pregabalin. The greatest improvement of the synthetic method is to carry out the hydrolysis reaction and the amidation reaction under the condition of near-critical water. Thus, addition of a catalyst is avoided, and yield of the reaction is raised. In addition, a flow reactor can be applied to the reaction so as to obtain a better reaction effect.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of pregabalin and its intermediates. Background technique [0002] The chemical name of pregabalin is (S)-(+)-3-aminomethyl-5-methylhexanoic acid, and its structure is shown in formula (I), which was discovered in the early 1990s. GABA (gamma-aminobutyric acid) analogue-type drugs for the treatment of epilepsy, neuropathic pain, anxiety, and social phobia. Newer studies have shown it to be effective in certain chronic pain conditions, and it has also been found to be useful as an antispasmodic agent. [0003] [0004] There are a lot of documents to report about the preparation method of this compound, disclose a kind of preparation method of this compound in the patent WO 9640617, this preparation method first makes isovaleraldehyde and ethyl cyanoacetate condensation reaction, the condensation intermediate that obtains ...

Claims

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Application Information

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IPC IPC(8): C07C229/08C07C227/04
Inventor 亚罗米尔·托曼姚成志陈为人刘雄丁世雄鲍继胜支浩西廖腾火生
Owner ZHEJIANG MENOVO PHARMA
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