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Optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one preparation method

A technology of dihydrofuran and n-propyl is applied in the field of preparing optically pure -4-n-propyl-dihydrofuran-2-one, and can solve the problems of high price, high cost, harsh reaction conditions and the like

Active Publication Date: 2018-09-07
BEIJING ABLEPHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because enzyme catalysis requires harsh reaction conditions and is expensive, the cost of this route is relatively high

Method used

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  • Optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1: Synthesis of (S)-4-benzyl-3-pentanoyl oxazol-2-one

[0106]

[0107] Add tetrahydrofuran (6.3L) into the reaction flask, add (S)-4-benzyloxazol-2-one (422.0g), cool down to -70°C; under nitrogen protection, keep the internal temperature at -65~-75°C ℃, dropwise add 2.5M n-butyllithium (1.0L) solution, dropwise, keep warm for half an hour; keep the internal temperature at -65~-75°C, dropwise add valeryl chloride (315.9g), dropwise, and react for half an hour After 1 hour, TLC detected that (S)-4-benzyloxazol-2-one disappeared, and treated; warmed to 0°C, added 2L saturated ammonium chloride aqueous solution, quenched butyllithium, and separated phases. Concentrate the organic phase under reduced pressure, concentrate to dryness, dissolve the concentrate with 3L dichloromethane, then wash with water (500mL×2) twice, dry the organic phase with 300.0g anhydrous sodium sulfate for 2 hours; filter, and concentrate to dryness under reduced pressure , to obtain 6...

Embodiment 2

[0109] Example 2: Synthesis of (S)-4-benzyl-3-((R)-2-n-propyl-pent-4-enoyl)oxazol-2-one

[0110]

[0111] Add tetrahydrofuran (50mL) to the reaction flask, add (S)-4-benzyl-3-pentanoyloxazol-2-one (5.2g), cool down to -70°C; under nitrogen protection, keep the internal temperature - 65~-75℃, dropwise add 1.0M LHMDS tetrahydrofuran solution (24mL), dropwise, keep warm for 1 hour; keep the internal temperature at -65~-75℃, add dropwise allyl bromide (3.0g), dropwise, keep warm React for 2 hours, TLC detects that the raw materials disappear, and process; rise to 0 °C, add 50 mL of saturated ammonium chloride aqueous solution, separate phases, extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases, and concentrate under reduced pressure; concentrate to dryness, It was dissolved in 50 mL of dichloromethane, then washed with water (25 mL×2), and the organic phase was dried with 10.0 g of anhydrous sodium sulfate for 2 hours; filtered and concentrated und...

Embodiment 3

[0113] Example 3: Synthesis of (S)-4-benzyl-3-((R)-2-n-propyl-pent-4-ynoyl)oxazol-2-one

[0114]

[0115] Add tetrahydrofuran (50mL) to the reaction flask, add (S)-4-benzyl-3-pentanoyloxazol-2-one (5.2g), cool down to -70°C; under nitrogen protection, keep the internal temperature - 65~-75°C, add 1.0M LHMDS tetrahydrofuran solution (24.0mL) dropwise, after dropping, keep it warm for 1 hour; keep the internal temperature at -65~-75°C, add propargyl bromide (3.1g) dropwise, dropwise, Incubate the reaction for 2 hours, TLC detects that the raw material disappears, and treat it; raise the temperature to 0°C, add 25mL saturated aqueous ammonium chloride solution, separate the phases, and concentrate the organic phase under reduced pressure. The concentrate was dissolved in 50 mL of dichloromethane, then washed with water (25 mL×2), and the organic phase was dried over 10.0 g of anhydrous sodium sulfate for 2 hours; filtered and concentrated under reduced pressure to obtain 6.1 g...

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Abstract

The present invention relates to an optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one preparation method, wherein optically pure (S)-3-n-pentanoyl-4-substituted oxazole-2-one is used as a raw material, alkylation reaction with an olefin or alkyne reagent, reducing removal of a chiral auxiliary group, oxidation of double bond or triple bond and other steps are performed to prepare the opticallypure (R)-4-n-propyl-dihydrofuran-2(3H)-one. According to the present invention, the preparation method has characteristics of easily available raw material, low cost, high total yield, high optical purity of the obtained product, simple reaction conditions and simple operation process.

Description

technical field [0001] The present invention relates to a process for the preparation of optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one. Background technique [0002] The preparation and use of 2-oxo-pyrrolidin-1-yl groups as pharmaceuticals are described in International Patent Application Publication No. WO 01 / 62726, especially for the treatment of neurological disorders. Especially (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (also known as Buvaracetam) is disclosed by European Patent No. EP0162036 as a protective agent for treatment And to prevent central nervous system hypoxia and ischemic damage, the brivaracetam preparation made from it has been approved by the European Medicines Agency (EMA) as an adjuvant drug for partial epilepsy in epilepsy patients over 16 years old seizure treatment. [0003] [0004] (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (R)-4-n-propyl-dihydrofuran-2(3H)-one [0005] Benoit M. Kenda et al. (J. Med. Chem....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33
CPCC07B2200/07C07D307/33
Inventor 马良徐征波
Owner BEIJING ABLEPHARMTECH CO LTD
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