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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 preparation of -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

[0097] Example 1: Synthesis of (S)-4-benzyl-3-pentanoyl oxazol-2-one

[0098]

[0099] Add tetrahydrofuran (6.3L) to the reaction flask, add (S)-4-benzyloxazol-2-one (422.0g, 2.38mol), cool down to -70°C; under nitrogen protection, keep the inner temperature at -65°C ~-75°C, dropwise add a solution with a concentration of 2.5M n-butyl lithium (1.0L, 2.5mol, 1.05eq). 315.9g, 2.62mol, 1.1eq), after dropping, reacted for 1 hour, TLC detected that (S)-4-benzyloxazol-2-one disappeared, treated; warmed to 0°C, added 2L saturated ammonium chloride aqueous solution, The butyllithium was quenched and the phases were separated. 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 621.3 g of the target compound as a white solid, with ...

Embodiment 2

[0101] Example 2: (S)-4-phenyl-3-pentanoyloxazol-2-one

[0102]

[0103] Add tetrahydrofuran (50mL) to the reaction flask, add (S)-4-phenyloxazol-2-one (5.0g, 30.6mmol), cool down to -70°C; under nitrogen protection, keep the internal temperature at -65~ -75°C, dropwise add n-butyllithium solution (12.9mL, 32.2mmol, 1.05eq) with a concentration of 2.5M, after dropping, keep warm for half an hour; keep the internal temperature at -65~-75°C, add dropwise valeryl chloride ( 4.1g, 34.0mmol, 1.11eq), dropwise, reacted for 1 hour, TLC detection (S)-4-phenyloxazol-2-one disappeared, treated; raised to 0°C, added 20mL saturated ammonium chloride aqueous solution, Butyllithium was quenched, the phases were separated and the organic phase was concentrated 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 with 10.0 g of anhydrous sodium sulfate for 2 hours; filtered and concentrated und...

Embodiment 3

[0105] Example 3: (S)-4-isopropyl-3-pentanoyl oxazol-2-one

[0106]

[0107] Add tetrahydrofuran (50mL) into the reaction flask, add (S)-4-isopropyloxazol-2-one (5.0g, 38.7mmol), cool down to -70°C; under nitrogen protection, keep the inner temperature at -65°C ~-75°C, dropwise add n-butyl lithium solution (16.2mL, 40.5mmol, 1.05eq) with a concentration of 2.5M, after dropping, keep warm for half an hour; keep the internal temperature at -65~-75°C, add valeryl chloride dropwise (5.1g, 42.3mmol, 1.09eq), after dripping, react for 1 hour, TLC detects that (S)-4-isopropyloxazol-2-one disappears, treat; rise to 0°C, add 20mL saturated ammonium chloride aqueous solution, quenched with butyllithium, separated the phases, and concentrated 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 with 10.0 g of anhydrous sodium sulfate for 2 hours; filtered and concentrat...

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Abstract

The invention relates to an optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one preparation method, and belongs to the field of chemical synthesis. According to the method, optically pure (S)-3-n-pentanoyl-4-substituted oxazole-2-one is used as a raw material, and alkylation, reduction, cyano hydrolysis, esterification and other steps are performed to obtain the optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one. According to the present invention, the preparation method has advantages of easily available raw materials, low cost, high total yield, high optical purity of the obtained product, simple reaction conditions and simple operation process.

Description

technical field [0001] The invention relates to a preparation method 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. 2004, 47, 530-54...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D263/26C07D263/24C07D263/22C07C253/30C07C255/12
CPCC07C253/30C07D263/22C07D263/24C07D263/26C07D307/33C07C255/12
Inventor 马良
Owner BEIJING ABLEPHARMTECH CO LTD