Unlock instant, AI-driven research and patent intelligence for your innovation.

A kind of preparation method of pregabalin chiral intermediate

A chiral intermediate, pregabalin technology, applied in the field of organic synthesis, can solve the problems of easy generation of chiral isomers, difficult to obtain qualified optically pure products, etc., and achieves safe and environmentally friendly reaction process, short route, and overall yield. high effect

Active Publication Date: 2021-08-13
RAFFLES PHAMRMATECH CO LTD
View PDF4 Cites 0 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of preparation method of pregabalin chiral intermediate
  • A kind of preparation method of pregabalin chiral intermediate
  • A kind of preparation method of pregabalin chiral intermediate

Examples

Experimental program
Comparison scheme
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, stirred and cooled to -5°C, and then the 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 (400 MHz, CDCl 3 )δ 3.72 (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 40ml THF). 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 1.0 M sodium bicarbonate solution (200ml) to the reaction system, stir for 10min, let stand, separate the organic layer, and extract the aqueous layer with dichloromethane (150ml); the combined organic layer is dried over anhydrous sodium sulfate, and 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.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a preparation method of a pregabalin chiral intermediate, the chiral intermediate is (S)-4-isobutyl-dihydro-3 H‑ Furan ‑ 2-ketone, the preparation method includes the following steps: S1. S-propylene oxide compound 2 is opened under Grignard reagent conditions to form a chiral hydroxyl compound 3; S2: in the chiral hydroxyl compound 3 synthesized in S1 Sulfonylation protection of the hydroxyl group forms compound 4 with a chiral leaving group; S3: Substitution of compound 4 with acetate or malonate, followed by hydrolysis, decarboxylation, and ring closure under acidic conditions to generate compounds 1. The raw materials used in the preparation of the pregabalin chiral intermediate of the present invention are cheap and easy to obtain, the route is short, the operation is simple, the reaction process is safe and environmentally friendly, the overall yield is high, and it is easy to scale up production, providing an economical and feasible route for the production of high-purity pregabalin route.

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-3 H- Furan - 2-keto. 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-3 H- Furan - 2-keto (1), the intermediate can be obtained by the following route to optically pure pregabalin. [0004] [0005] However, there are still very few convenient preparation methods for this chiral intermediate. [0006] In 2005, Belliotti, Thomas R. et al. reported the following route in Scheme 1, which uses β-c...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/33C07C227/04C07C229/08
CPCC07C67/03C07C67/307C07C227/04C07C247/12C07D307/33C07C69/63C07C229/08
Inventor 黄志宁孙家强费安杰叶伟平徐俊烨
Owner RAFFLES PHAMRMATECH CO LTD