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Medical intermediate and preparation method thereof

A technology for intermediates and medicines, applied in the field of medicine synthesis, can solve the problems of uneconomical industrial scale production, low reaction yield, difficult realization, etc., and achieve the effects of cheap raw materials, simple operation and easy availability of raw materials

Inactive Publication Date: 2017-07-18
YANCHENG DESANO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction yield of this method is low, which is uneconomical in industrial scale production, and a low temperature of -78°C is required when using metal catalysts, which is also difficult to achieve in industrial large-scale production

Method used

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  • Medical intermediate and preparation method thereof
  • Medical intermediate and preparation method thereof
  • Medical intermediate and preparation method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0031] A preparation method of a pharmaceutical intermediate, firstly add 1.2~2.2eq strong base to the reaction bottle under the protection of argon, cool to -78°C, add dropwise a benign solvent of 1.05~1.5eq 1,4-butyrolactone, Incubate at -78°C for 2h; add 1eq ethyl chloroacetate benign solvent dropwise, and incubate at -78°C for 2h; add 6N hydrochloric acid aqueous solution to wash, and then wash with brine; (3) Concentrate the oil phase under reduced pressure to obtain a light yellow oil; then, Dissolve the above oil in acetone, slowly add 1.1~1.5eq aromatic acid or alkyl acid; slowly add 1.1~2.0eq triethylamine dropwise under ice bath, after the dropwise addition, raise the temperature to reflux; until a large amount of white solids are precipitated , filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid; finally, ethyl acetate and saturated sodium bicarbonate solution were added, separated, extracted, washed, and dried to obtain the in...

Embodiment 1

[0035]

[0036] a) Add methyllithium (1.5L, 1.5mol) to the reaction flask under the protection of argon, cool the system to -78°C, add 1,4-butyrolactone (94.78g, 1.1mol) in 2 -Methyl tetrahydrofuran solution 300mL, after dripping, keep warm at -78°C for 2 hours; add 200mL of 2-methyltetrahydrofuran solution containing ethyl chloroacetate (122.60g, 1.0mol) dropwise, after dropwise keep warm, stir at -78°C for 2 hours Hours; 80 mL of 6N hydrochloric acid aqueous solution was added to stir and wash, washed with 150 mL of saturated brine, and the oil phase was concentrated under reduced pressure to obtain 156.88 g of a light yellow oil (compound of formula III), with a molar yield of 96.5% and an HPLC purity of 98.1%.

[0037]b) Dissolve the compound of formula III (15.61g, 0.096mol) in 40mL of acetone, slowly add benzoic acid (13.50g, 0.11mol); slowly add triethylamine (15.18g, 0.15mol) dropwise under ice-cooling, dropwise After completion, the temperature was raised to reflux...

Embodiment 2

[0039]

[0040] The compound of formula III (32.4g, 0.20mol) prepared according to the method in Example 1 was dissolved in 100mL acetone, and acetic acid (13.2g, 0.22mol) was slowly added; triethylamine (30.36g, 0.22mol) was slowly added dropwise under ice-cooling. 0.3mol), the dropwise addition was completed, the temperature was raised to the reflux reaction and then down to room temperature, a large amount of white solid was precipitated, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid, which was stirred and dissolved by adding 50mL ethyl acetate and 40mL saturated sodium bicarbonate solution, Stand for liquid separation, extract the aqueous phase with ethyl acetate (50mL×2), combine the organic phases, wash with 40mL saturated brine and concentrate the filtrate under reduced pressure to obtain 33.36g of a light yellow oil (compound of formula IIb), with a molar yield of 89.6% , HPLC purity is 98.6%.

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Abstract

The invention discloses a medical intermediate. The medical intermediate has the chemical structure shown as a formula II shown in the description, wherein the R is selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, tertiary butyl, sec-butyl, phenyl and naphthyl. The invention also discloses a preparation method of the intermediate; the operation is simple; the cost is low; the preparation method is suitable for scale production. The intermediate can be used for preparing a key intermediate of darunavir; important significance and practical values are realized on the industrial production of the darunavir.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate and a preparation method thereof, belonging to the technical field of pharmaceutical synthesis. Background technique [0002] The (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-oxyl group is an important pharmacological moiety present in the structure of protease inhibitors of retroviruses and is the Important synthetic fragments. Darunavir is developed by Tibotec Pharmaceuticals Co., Ltd. (Tibotec Pharmaceuticals), also known as TMC114, trade name Prezista, approved by the FDA on June 23, 2006, the drug can selectively inhibit the HIV encodes Gag-Polpolyproteins that prevent the formation of mature virions. [0003] An important precursor for the synthesis of the above-described protease inhibitors containing hexahydrofuro[2,3-b]furan-3-oxyl groups is hexahydrofuro[2,3-b]furan-3-ol (compound of formula I): . Wherein the enantiomer (3R, 3aS, 6aR) hexahydrofuro[2,3-b]furan-3-ol (compound of formula I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D493/04
CPCC07D307/33C07D493/04
Inventor 汪守军刘江涛
Owner YANCHENG DESANO PHARMA CO LTD
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