Preparation method of (R)-4-propyl-dihydrofuran-2-one

A technology of dihydrofuran and propyl, which is applied in the field of chemical drug synthesis, can solve the problems of limited industrial scale-up, high cost, and low yield, and achieve the effects of low cost, less waste gas, and high optical purity

Active Publication Date: 2019-03-29
JIANGZI QINGFENG PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

When the company reproduced the method of the patent, it was found that a large amount of gas was generated in the reduction step, which limited further industrial scale-up
Moreover, the yield of the two steps of hydrolysis and reduction is low, and the cost is relatively high

Method used

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  • Preparation method of (R)-4-propyl-dihydrofuran-2-one
  • Preparation method of (R)-4-propyl-dihydrofuran-2-one
  • Preparation method of (R)-4-propyl-dihydrofuran-2-one

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Experimental program
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Effect test

Embodiment 1～5

[0074] The preparation of embodiment 1~5 formula B compound

[0075]

Embodiment 1

[0077] Into a 30L reaction kettle, add 428.31g of n-valeric acid and 6.0L of tetrahydrofuran, under stirring, add 951.23g of triethylamine, under the protection of nitrogen, cool down to -15°C, dropwise add 510.77g of pivaloyl chloride, dropwise, React at -20°C for 1.0h, add 187.21g of lithium chloride, keep warm for 10min, add dropwise a tetrahydrofuran solution (2.4L tetrahydrofuran) containing 600.0g of reactant A, and control the temperature at -20°C; , heated to 20°C, stirred for 12.0h, after the reaction, added 6.0L of 10% potassium carbonate aqueous solution, stirred for 10.0min, concentrated under reduced pressure to remove tetrahydrofuran, then added 6L of methyl tert-butyl ether for extraction; the water phase was reused 4.8L of methyl tert-butyl ether was extracted once, and finally the organic layers were combined, and the organic layer was washed once with 3.0L 1M hydrochloric acid and 3.0L aqueous sodium bicarbonate solution, and finally concentrated to remove the...

Embodiment 2

[0079] Into a 30L reactor, add 428.31g of n-valeric acid and 6.0L of 2-methyltetrahydrofuran, under stirring, add 743.54g of pyridine, under the protection of nitrogen, cool down to -15°C, dropwise add 510.77g of pivaloyl chloride, dropwise After completion, react at -5°C for 1.0h, add 187.21g of lithium chloride, keep warm for 10min, add dropwise 2-methyltetrahydrofuran solution (2.4L 2-methyltetrahydrofuran) containing 600.0g of reactant A, and control the temperature at -5°C After the dropwise addition was completed, after 2.0 hours of reaction, the temperature was raised to 20°C and stirred for 12.0 hours. After the reaction was completed, 6.0L of 10% potassium carbonate aqueous solution was added, and after stirring for 10.0 minutes, 2-methyltetrahydrofuran was removed by concentration under reduced pressure, and then added 6L methyl tert-butyl ether extraction; the aqueous phase was extracted once with 4.8L methyl tert-butyl ether, and finally the organic layer was combin...

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Abstract

The invention discloses a preparation method of (R)-4-propyl-dihydrofuran-2-one, key intermediates-a compound as shown in a formula B which is shown in the description and a compound as shown in a formula C which is shown in the description, and a preparation method of the key intermediates. The preparation method of the (R)-4-propyl-dihydrofuran-2-one, disclosed by the invention, is strong in technological operability and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and relates to a preparation method of (R)-4-propyl-dihydrofuran-2-one Background technique [0002] (R)-4-Propyl-dihydrofuran-2-one is a key intermediate in the synthesis of the new antiepileptic drug Brivaracetam. At present, many literatures have reported the synthesis method of this compound. The synthetic method was first seen in, Journal of American Chemical Society, 1985, 107, 4088-4090. Adopting the allyl p-toluene sulfinate that does not have market supply is starting material, and cost is high, has no industrialization value; After that, there are bibliographical reports synthetic method (for example: Journal of American Chemical Society, 2003,125,11253 -11258), the cost is high and has no industrial value. [0003] Patent CN106008411A reports a method with relatively low cost. The synthetic route is as follows: [0004] [0005] The patent describes that after i...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07D263/26
CPCC07D263/26C07D307/33C07B2200/07
Inventor 郭训发付敏赖正茂刘地发何智斌苏绪燕方小军
Owner JIANGZI QINGFENG PHARMACEUTICALS INC
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