Method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone

Abstract

The invention provides a method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone. The method comprises the following steps: (a) dropwise adding acyl chloride (3) into an organic solvent solution of a compound (1), enabling reaction to obtain an acyl chloride intermediate solution, then dropwise adding an organic solvent solution of a compound (2) and enabling reaction to obtain a compound (4); (b) dropwise adding a bis(trimethylsilyl)amide alkali metal salt solution into an organic solvent solution of the compound (4), enabling reaction, dropwise adding a compound (5) into the obtained reaction liquid and enabling reaction to obtain a compound (6); (c) enabling reaction between the compound (6) and alkali to obtain a compound (7); (d) enabling reaction between the compound (7) and a reducing agent to obtain a compound (8), wherein R is selected from aryl, arylmethyl or alkyl, R1, R2 and R3 are independently selected from alkyl, and X is selected from Cl, Br or I. The method is simple in process, strong in operability and easy for industrial production. The reaction route is shown in the description.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of chiral 4-substituent dihydrofuran-2(3H)-one. Background technique [0002] There are several methods for preparing chiral 4-substituted dihydrofuran-2(3H)-ones in the prior art. However, these methods have more or less disadvantages and are not suitable for industrial applications. The existing methods for preparing chiral 4-substituent dihydrofuran-2(3H)-one mainly include the following: [0003] Method 1: The paper (Journal of Organic Chemistry, 65(18), 5623-5631, 2000) discloses a method for preparing chiral 4-substituted dihydrofuran-2(3H)-one. This method mainly has the following disadvantages: the starting material of the first step needs to use (1R, 2S, 5R)-(-)-menthol (S)-p-toluenesulfinate, which does not have a supplier on the market, And the preparation cost is high, and the process is difficult; the used noble metal rhodium ca...

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Problems solved by technology

This method mainly has the following disadvantages: the starting material of the first step needs to use (1R, 2S, 5R)-(-)-menthol (S)-p-toluenesulfinate, which does not have a supplier on the market, And the preparation cost is high, and the process is difficult; the used noble metal rhodium catalyst RhCl(PPh) 3 Expensive; final step requires tributyltin hydride, a highly toxic liquid with a very unpleasant smell

This method has the following disadvantages: the starting material (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine in the first step is expensive, and allyl dichloride There is no supplier in the phosphine market; the third step requires the use of ozone, which is highly oxidizing and dangerous, requires very high production equipment, and is extremely expensive

There is following shortcoming in this method: the starting material 2 (5H)-furanone of the first step reaction of this method is expensive; There is no supplier on the starting material allyl p-toluene sulfinate market, if oneself prepares, its The preparation cost is high, the process is complicated, and the properties are unstable, so it needs to be prepared and used immediately, which brings uncertainty to production

Therefore, considering the cost of raw materials and the operability of the process, although this method can finally obtain (R)-4-propyldihydrofuran-2(3H)-one with high optical purity, its application still remains in the field of academic research. Sexual level, it is difficult to apply to industrial production

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