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Pregabalin intermediate and process for preparing same

A technology of isobutylglutarimide and cyclization reaction, which is applied in the field of pregabalin intermediates and its preparation, can solve the problems of long synthetic route, difficult separation, high toxicity of solvent-chloroform, etc., and achieve cost-effective, Mild reaction conditions and easy operation

Active Publication Date: 2006-12-27
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The synthesis route of this method is relatively long, and the splitting operation of intermediates is relatively cumbersome
The transition between the intermediate and the chiral resolving agent is viscous, and it is very difficult to separate from the solvent
In addition, the filtration and washing of chiral intermediates must be carried out at low temperature; and the solvent used for resolution - chloroform is highly toxic
The last step involves chiral synthesis. The strong basicity of the Hoffmann rearrangement changes the optical rotation of the resolved intermediate, and the melting point and optical purity of pregabalin obtained are not ideal.

Method used

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  • Pregabalin intermediate and process for preparing same
  • Pregabalin intermediate and process for preparing same
  • Pregabalin intermediate and process for preparing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1) Preparation of 3-isobutylglutaric acid (refer to Organic Process Research & Development 1997, 1, 26-38)

[0035]Ethyl cyanoacetate (187.2g, 1.65mol), isovaleraldehyde (156.3g, 1.81mol) and 210ml of n-hexane, n-dipropylamine (1.65g, 1.62mmol) were placed in a reaction flask, refluxed to separate water until no water came out, The solvent was concentrated under reduced pressure to dryness, diethylphthalate (317.1g, 1.98mol) and n-dipropylamine (16.8g, 165mmol) were added, stirred at 50°C for 1 hour, then poured into 900ml of 6N hydrochloric acid, and refluxed for 72 hours. Cool the toluene for extraction, and concentrate the extract to dryness to obtain 3-isobutylglutaric acid (261.9g, yield 85%). NMR 1 HNMR and infrared IR (KBr) are consistent with the literature.

[0036] 2) Preparation of 3-isobutylglutarimide

[0037]

[0038] Add 200.0g (1.06mol) of 3-isobutylglutaric acid and 63.8g (1.06mol) of urea into a 1000ml three-necked flask. Heat the oil bath to 160...

Embodiment 2

[0050] 1) Preparation of 3-isobutylglutaric acid

[0051] Same as step 1) in Example 1

[0052] 2) Preparation of 3-isobutylglutarimide

[0053] Add 200.0g (1.06mol) of 3-isobutylglutaric acid and 127.7g (2.12mol) of urea into a 1000ml three-necked flask. Heat the oil bath to 150°C, react at 150-170°C for 2 hours, then cool to 80°C, add 200ml of water, 400ml of ethanol and 15g of activated carbon, heat and reflux for 30 minutes, filter while it is hot, cool the filtrate, filter, and vacuum at 50°C After drying, 166 g (yield: 92.3%) of 3-isobutylglutarimide can be obtained as white flaky crystals with a melting point of 137-138°C.

[0054] Mass spectrum MS: 125.9, 168.0, 168.9

[0055] Nuclear magnetic resonance 1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangeable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H), 1.28-1.24 (t, 2H), 0.92 (s, 6H)

[0056] Infrared IR (KBr): 3198, 3088, 2955, 1735, 1686, 1422, 1384, 1291, 1269cm-1

[0057] 3) Preparation of 3-isobut...

Embodiment 3

[0062] 1) Preparation of 3-isobutylglutaric acid

[0063] With embodiment one.In step 1)

[0064] 2) Preparation of 3-isobutylglutarimide

[0065] Add 200.0 g (1.06 mol) of 3-isobutylglutaric acid and 220 g (3.18 mol) of 25% ammonia water into a 1000 ml three-necked flask. (During the experiment, due to excessive ammonia water, although there was volatilization, it did not affect the reaction) After concentrating the ammonia water to dryness, heat the oil bath to 100°C, react for 2 hours, then cool to 80°C, add 400ml of water, 200ml of ethanol and activated carbon 15g, reheated and refluxed for 30 minutes, filtered while hot, cooled the filtrate, filtered, and dried in vacuum at 50°C to obtain 164g of 3-isobutylglutarimide (yield 91%), white flaky crystals, melting point 137- 138°C.

[0066] Mass spectrum MS: 125.9, 168.0, 168.9

[0067] Nuclear magnetic resonance 1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangeable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H)...

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Abstract

The invention relates to 3-isobutyl glutarimide which is the intermediate of pregabalin treating intermediate and preventing epilepsy, and the method for preparing the same. The method comprises preparation of 3-isobutyl glutarimide by using 3-isobutyl glutaric acid and agent containing nitrogen through cyclocondensation reaction, and preparation of S-(+) - 3- isobutyl gamma- aminobutyric acid through Hoffmann rearrangement and S-amygdalic acid resolution. The method is characterized by simple process, easy separation of intermediate product and end product from reacting dissolvent or recrystallization dissolvent, low cost and suitable for industrial production.

Description

technical field [0001] The invention relates to an intermediate of pregabalin, a drug for antiepileptic and neuralgia treatment, and a preparation method thereof. Background technique [0002] The compound S-(+)-3-isobutyl γ-aminobutyric acid (pregabalin) has been used clinically as an antiepileptic and neuralgia drug. There are many literature reports on the preparation of this compound. [0003] Yuen PW et al. disclosed a method for preparing pregabalin in Bioorganic & Medicinal Chemistry Letters [1994, 4(6) 823-826]. The synthetic route is long, and butyllithium is used in the reaction, the reaction conditions are harsh, and it is difficult to realize industrial production. [0004] Marvin S.Hoekstra etc. disclose several methods for preparing S-(+)-3-isobutyl γ-aminobutyric acid in Organic Process Research & Development (1997,1,26-38), wherein one method is to adopt 3 - Dehydration and cyclization of isobutyl glutaric acid, and then ring-opening with ammonia water to ...

Claims

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Application Information

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IPC IPC(8): C07D211/88
CPCC07C227/12C07D211/88
Inventor 张桂森杨相平马彦琴石绍华段炼朱永超
Owner NHWA PHARMA CORPORATION
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