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

A technology of dihydrofuran and substituents, which is applied in the field of preparation of chiral 4-substituent dihydrofuran-2-one, can solve problems such as difficult industrial production, complex process, and difficult process, and achieve easy industrial production, The effect of simple preparation process and strong operability

Inactive Publication Date: 2016-10-12
PHARORGSYN LAB
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  • Abstract
  • Description
  • Claims
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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, a...

Method used

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

Examples

Experimental program
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Embodiment 1

[0045] Synthesis of (S)-4-benzyl-3-pentanoyloxazolidin-2-one (compound 4a)

[0046]

[0047]Add 1 L of tetrahydrofuran, 70.47 g of valeric acid (compound 1a), and 155.83 g of triethylamine into the reaction flask, and cool to -10°C under nitrogen protection. 83.49 g of pivaloyl chloride (compound 3a) was slowly added dropwise. Keep stirring at -10°C for 0.5 hour, and add 31.37 g of anhydrous lithium chloride. A tetrahydrofuran solution of 100.89 g of (S)-4-benzyloxazolidin-2-one (compound 2a) was slowly added dropwise. The temperature was naturally raised to room temperature (20-25)°C, and stirring was continued for 16 hours. After filtration, 1.2 L of 10% potassium carbonate was added to the filtrate, stirred for 10 minutes, THF was distilled off under reduced pressure, and extracted with tertiary methyl ether. The tertiary methyl ether layer was washed successively with 500 mL of 5% dilute hydrochloric acid and 500 mL of saturated sodium bicarbonate. It was dried, fil...

Embodiment 2

[0049] Synthesis of tert-butyl (R)-3–((S)--4-benzyl-2-oxazolidinone-3-carbonyl)hexanoate (compound 6a)

[0050]

[0051] 140 g of (S)-4-benzyl-3-pentanoyloxazolidin-2-one (compound 4a) was dissolved in 1 L of tetrahydrofuran, protected by nitrogen, and cooled to -70°C to -65°C. 290 mL of 2 mol / L sodium bis(trimethylsilyl)amide (NaHMDS) was added dropwise, and the temperature was controlled below -65°C. After the dropwise addition, keep warm for 0.5 hours. 134.4 g of tert-butyl bromoacetate (compound 5a) were added dropwise. After the dropwise addition, the temperature was naturally raised to room temperature (20-25° C.), and stirring was continued for 10 minutes. Add 500 mL of saturated ammonium chloride to quench. The reaction solution was extracted with tertiary methyl ether (800 mL×3), dried, filtered, and concentrated to dryness under reduced pressure. Then recrystallize (methyl tert-ether:petroleum ether=1:5) to obtain 143 grams of (R)-3-((S)--4-benzyl-2-oxazolidin...

Embodiment 3

[0053] Synthesis of (R)-2-(2-(tert-butoxy)-2-oxoethyl)pentanoic acid (Compound 7a)

[0054]

[0055] 318 grams of (R)-3-((S)--4-benzyl-2-oxazolidinone-3-carbonyl) tert-butyl hexanoate (compound 6a) was dissolved in 2.25 L tetrahydrofuran and 0.75 L water In the mixed solvent, stir in an ice bath. 428 grams of hydrogen peroxide was added dropwise while keeping below 5°C. 70.4 g of lithium hydroxide hydrate was added. Stir at room temperature (20-25° C.) for 15 hours. Add water for dilution, and add sodium sulfite solution (476 g of sodium sulfite in 2 L of water) dropwise under ice-cooling, keeping the temperature below 10°C. Add 1.5L of ethyl acetate, stir and separate the layers, and wash the water layer once with 800mL of ethyl acetate. Add 400 g of citric acid to adjust the aqueous layer to pH = 3, and extract with ethyl acetate (600 mL×3). It was dried, filtered, and concentrated to obtain 165 g of oily (R)-2-(2-(tert-butoxy)-2-oxoethyl)pentanoic acid (compound 7a,...

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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...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33C07B2200/07
Inventor 范朋高饶卫军江荣英
Owner PHARORGSYN LAB
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