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Synthesis method of (R)-4-propyldihydrofuran-2-ketone

A technology of propyl dihydrofuran and synthesis method, which is applied in the direction of organic chemistry, organic chemistry, etc., can solve the problems of low product purity, high price, difficult production and amplification, etc., and achieve high optical purity, low cost, and novel route short effect

Active Publication Date: 2020-12-11
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In order to improve the shortcomings of (R)-4-propyldihydrofuran-2-one, which is expensive in material price, low in product purity, and difficult to produce and scale up, the present invention has developed a new process route, using Michaelis acid and R-epoxy Chloropropane is used as the starting material, and the compound is obtained through the two-step reaction of closing the three-membered ring and ring-opening with the Grignard reagent, and using (1S,5R)-3-oxabicyclo[3.1.0]-2-hexanone as the intermediate

Method used

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  • Synthesis method of (R)-4-propyldihydrofuran-2-ketone
  • Synthesis method of (R)-4-propyldihydrofuran-2-ketone
  • Synthesis method of (R)-4-propyldihydrofuran-2-ketone

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Embodiment 1

[0023] (1) Synthesis of (1S,5R)-2-keto-3-oxabicyclohexane

[0024] Add ethanol (9L), sodium ethoxide (318.6g, 1.2eq.), stir at 0-5°C, add cycloisopropylidene malonate dropwise at 0-5°C (Menten's acid, 675g, 1.2eq. ), the dropwise addition was completed, and the reaction was kept at 0-5°C for 30 minutes; the temperature was naturally raised to 25°C (20-30°C), and R-epichlorohydrin (361g, 1.0eq.) was added dropwise. 20~30℃) to react for 10min; heat up to reflux reaction (78~83℃) to react for 8-12h until R-epichlorohydrin≤5%, drop to room temperature (25℃), dry under reduced pressure (jacket temperature ≤55℃), add 1.8L of water, 1.8L of ethyl acetate, stir, separate the liquids, extract the water phase with ethyl acetate (1.8L*2), combine the organic phases, add 720g of anhydrous sodium sulfate to dry for 30min, and filter with suction , the filter cake was rinsed with ethyl acetate, the filtrate was concentrated and dried under reduced pressure (jacket temperature ≤ 55°C), an...

Embodiment 2

[0028] (1) Synthesis of (1S,5R)-2-keto-3-oxabicyclohexane

[0029] Add ethanol (9L), sodium methoxide (1.2eq.), stir at 0-5°C, add cycloisopropylidene malonate (675g, 1.2eq.) dropwise at 0-5°C, after the addition is complete, Reaction at ~5°C for 30 minutes; naturally warm up to 25°C (20-30°C), add R-epichlorohydrin (361g, 1.0eq.) dropwise, after the addition is complete, react at 25°C (20-30°C) for 10 minutes ;Heat up to reflux reaction (78~83°C) for 8-12h, until R-epichlorohydrin≤5%, drop to room temperature (25°C), dry under reduced pressure (jacket temperature≤55°C), add water 1.8L, 1.8L ethyl acetate, stirring, liquid separation, extract the aqueous phase with ethyl acetate (1.8L*2), combine the organic phase, add 720g of anhydrous sodium sulfate to dry for 30min, filter with suction, and rinse the filter cake with ethyl acetate After washing, the filtrate was concentrated and dried under reduced pressure (jacket temperature≤55° C.), and the concentrated dry matter was s...

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Abstract

The invention discloses a synthesis method of (R)-4-propyldihydrofuran-2-ketone, and belongs to the field of organic chemical synthesis. A new process route is developed to overcome the defects that (R)-4-propyldihydrofuran-2-ketone is relatively high in material price, low in product purity, difficult to produce and amplify and the like. Meldrum's acid and R-epichlorohydrin are used as initial raw materials, and the compound is obtained by taking (1S, 5R)-3-oxabicyclo [3.1. 0]-2-hexanone as an intermediate through a two-step reaction of closing a three-membered ring and opening a ring by using a Grignard reagent. The (R)-4-propyldihydrofuran-2-ketone is synthesized by adopting the synthesis method, a novel process route is adopted in the process, the total molar yield is greater than 50%,and the method has the characteristics of novel and short route, high optical purity, low cost and the like.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a new synthesis method of (R)-4-propyldihydrofuran-2-one. Background technique [0002] (R)-4-Propyldihydrofuran-2-one is the key intermediate of the antiepileptic drug Buvaracetam, and the chemical formulas of the two are as follows: [0003] [0004] There are currently four main synthetic routes for this intermediate. Among them, the synthetic route 1 is shown below, using cheap chiral source (R)-epichlorohydrin, the chiral control is superior, but using potassium cyanide is inconvenient, and the chiral purity is unsatisfactory after repeated experiments. [0005] [0006] Route 1 [0007] Route 2 requires kinetic resolution catalyzed by lipase. Although the undesired enantiomers can be recovered by racemization, additional steps are added; and the enzymatic catalysis has low productivity, and the conditions of the subsequent reduction step are rel...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33C07B2200/07
Inventor 费安杰叶伟平毛彦利周章涛吴春林
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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