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Preparation method of pregabalin chiral intermediate

A chiral intermediate, pregabalin technology, applied in the field of organic synthesis, can solve problems such as difficulty in obtaining qualified optically pure products, easy generation of chiral isomers, etc., achieving a short route, easy to scale up production, and high overall yield Effect

Active Publication Date: 2016-04-13
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses cheap chiral materials as starting materials, and there are fewer steps, but since chiral epoxides have two reaction sites, strict control conditions are required to obtain the target chiral five-membered ring and three-membered ring structure , so it is easy to produce chiral isomers; in addition, there are more reaction sites when the Grignard reagent attacks the three-membered ring, and the reaction temperature needs to be strictly controlled, which makes it difficult to obtain qualified optically pure products in scale-up production

Method used

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  • Preparation method of pregabalin chiral intermediate
  • Preparation method of pregabalin chiral intermediate
  • Preparation method of pregabalin chiral intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Synthesis of (S)-1-tert-butoxy-4-methyl-2-pentanol (3a)

[0035]

[0036] Under nitrogen protection, a THF solution of isopropylmagnesium bromide (220ml, 1mol / L, 0.22mol) was added to a 1L three-necked flask, cooled to -5°C under stirring, and then a THF solution of compound 2a (26.04g dissolved in 40ml THF). After the dropwise addition, keep the temperature between -10°C and 0°C for 4 hours. After the reaction was completed, 200ml of water was added dropwise to the reaction system, and HOAc was used to adjust the pH to between 6-8. EA extraction (100mlx3), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 32.21 g of compound 3a as a colorless oily liquid with a yield of 92.4%. 1 HNMR (400MHz, CDCl 3 )δ3.72(dd,1H),3.59-2.64(m,1H),3.42(dd,1H),1.92(t,2H,),1.62-1.66(m,1H),1.23(S,9H), 0.87(d,6H).

Embodiment 2

[0038] Synthesis of (S)-1-tert-butoxy-4-methyl-2-pentanol (3a)

[0039]

[0040] Under nitrogen protection, a THF solution of isopropylmagnesium chloride (220ml, 1mol / L, 0.22mol) was added to a 1L three-necked flask, stirred and cooled to -5°C, and then the THF solution of compound 2a (26.04g dissolved in 40mlTHF). After the dropwise addition, keep the temperature between -10°C and 0°C for 6 hours. After the reaction was completed, 200ml of water was added dropwise to the reaction system, and HOAc was used to adjust the pH to between 6-8. EA extraction (100mlx3), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 29.88g of a colorless oily liquid of compound 3a, with a yield of 85.7%.

Embodiment 3

[0042] Synthesis of (S)-1-tert-butoxy-4-methyl-2-pentyl trifluoromethanesulfonate (4a)

[0043]

[0044] Add 3a (34.85g, 0.20mol) and dichloromethane (340ml) into a 1L three-necked flask, stir and cool to -10°C under nitrogen protection, then add triethylamine (24.29g, 0.24mol). Keep warm and slowly add trifluoroacetic anhydride (59.25 g, 0.21 mol) dropwise. After the dropwise addition, keep the temperature at -10°C for 1 hour. Add 1.0M sodium bicarbonate solution (200ml) to the reaction system, stir for 10min, then let stand, separate the organic layer, and extract the aqueous layer with dichloromethane (150ml); the combined organic layer is dried over anhydrous sodium sulfate, in The solvent was removed under reduced pressure at less than 35°C to obtain compound 4a as a light yellow oily liquid, which was directly used in the next reaction.

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Abstract

The invention provides a preparation method of a pregabalin chiral intermediate. The pregabalin chiral intermediate is (S)-4-isobutyl-dihydro-3H-furan-2-one. The preparation method comprises following steps: S1, a chiral hydroxyl compound 3 is obtained from an S-epoxypropane compound 2 via ring-opening reaction under Grignard reagent conditions; S2, sulfonylation protection of hydroxy groups in the chiral hydroxyl compound 3 is carried out so as to obtain a compound 4 with chiral leaving groups; and S3, the compound 4 and an acetate compound or malonic ester are subjected to substitution reaction, and a compound 1 is obtained via hydrolysis, decarboxylation, and ring closing reaction under acidic conditions. The raw materials used in preparation of the pregabalin chiral intermediate are cheap and easily available; reaction route is short; operation is simple; reaction process is safe and is friendly to the environment; the entire yield is high; the preparation method is convenient for large scale production; and an economical feasible route is provided for production of high purity pregabalin.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and more specifically relates to a preparation method of a pregabalin chiral intermediate, which is (S)-4-isobutyl-dihydro-3H -furan-2-one. Background technique [0002] Pregabalin is a new type of calcium ion channel regulator, which can block voltage-dependent calcium channels and reduce the release of neurotransmitters. It was approved by the FDA in 2004 and is mainly used for the treatment of localized partial seizures. [0003] There are many synthetic routes of pregabalin, so there are many key intermediates, one of which is (S)-4-isobutyl-dihydro-3H-furan-2-one (1), the intermediate Optically pure pregabalin can be obtained by the following route. [0004] [0005] However, there are still very few convenient preparation methods for this chiral intermediate. [0006] In 2005, Belliotti, ThomasR. et al. reported the following route in Scheme 1, which uses β-chiral acid ester...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07C227/04C07C229/08
CPCC07C67/03C07C67/307C07C227/04C07C247/12C07D307/33C07C69/63C07C229/08
Inventor 孙家明费安杰叶伟平徐俊烨
Owner RAFFLES PHAMRMATECH CO LTD
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