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Production technology of 3-hydroxytetrahydrofuran with high optical purity

A technology of hydroxytetrahydrofuran and optical purity, which is applied in the field of preparation of pharmaceutical and pesticide intermediates, can solve the problems of low yield, complex reaction operation, high cost, etc., and achieve the effects of inhibiting racemization, simple and convenient operation, and inhibiting side reactions

Inactive Publication Date: 2017-08-29
SUZHOU HUADAO BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 2. Using ethyl S-4-chloro-3-hydroxybutyrate as a raw material, the target product is obtained by reduction and intramolecular dehydrochlorination and cyclization [US 6359155; Applied Chemical Industry 2008, 37: 191-193]; this method has the advantages of synthesizing The advantages of short route and easy operation; however, the cyclization reaction is carried out in pure water phase, and the product extraction is difficult, which is not conducive to the realization of industrial production. At the same time, the optical purity of the product prepared by this method is only 96.3%, which cannot meet the needs of the production of pharmaceutical products.
[0009] However, the above-mentioned methods generally have disadvantages such as complicated reaction operation, low yield, and high cost, especially the shortcoming of low optical purity of the product, which will lead to low drug effect and side effects

Method used

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  • Production technology of 3-hydroxytetrahydrofuran with high optical purity
  • Production technology of 3-hydroxytetrahydrofuran with high optical purity
  • Production technology of 3-hydroxytetrahydrofuran with high optical purity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Preparation of chiral ethyl 4-chloro-3-hydroxybutyrate:

[0034] Add 500g (3.03mol) ethyl chloroacetoacetate and 2 liters of ethanol in 5 liters of reaction bottles, add chiral catalyst (0.15mol, 0.05eq.) and 250g (3.68mol, 1.2eq.) sodium formate after stirring, heat The temperature was raised to 50°C for reaction; gas phase detection was complete, the solvent was distilled off, and then 485 g of chiral ethyl 4-chloro-3-hydroxybutyrate was obtained by distillation under reduced pressure;

[0035] (2) Preparation of chiral 4-chloro-3-hydroxyl-1-butanol:

[0036] Add 110g (2.9mol, 1eq.) sodium borohydride and 2 liters of tetrahydrofuran into a 5-liter reaction flask, and slowly add 485g (2.9mol, 1eq.) chiral 4-chloro-3-hydroxybutyric acid dropwise at a temperature of 40°C Ethyl ester; after the dropwise addition, heat to reflux for 2 hours, cool down, use dilute hydrochloric acid to extract the reaction, filter with suction, and distill the filtrate to remove the sol...

Embodiment 2

[0040] (1) Preparation of chiral ethyl 4-chloro-3-hydroxybutyrate:

[0041] Add 500g (3.03mol) ethyl chloroacetoacetate and 2 liters of methanol into a 5-liter reaction flask, stir evenly, add a chiral catalyst (0.3mol, 0.1eq.), control the temperature at about 25°C, and add dropwise 400ml of formic acid / Triethylamine (5:2mol / mol) adducts, maintain this temperature to continue the reaction; the gas phase detection reaction is complete, first distill and recover methanol and formic acid / triethylamine adducts, the residue is then distilled under reduced pressure to obtain 488g chiral Ethyl 4-chloro-3-hydroxybutyrate.

[0042] (2) Preparation of chiral 3-hydroxytetrahydrofuran:

[0043] Add 122g (3.21mol, 1.1eq.) sodium borohydride and 2 liters of ethylene glycol dimethyl ether into a 5-liter reaction flask, and slowly add 488g (2.92mol, 1eq.) chiral 4-chloro -3-Hydroxybutyric acid ethyl ester; after the dropwise addition, continue to control the temperature at 50°C for 5 hour...

Embodiment 3

[0045] (1) Preparation of chiral ethyl 4-chloro-3-hydroxybutyrate:

[0046]Add 500g (3.03mol) ethyl chloroacetoacetate and 2 liters of isopropanol in 5 liters of reaction flasks, add chiral catalyst (0.15mol, 0.05eq.) and 286g (4.55mol, 1.5eq.) formic acid after stirring Ammonium, heated to 40 ° C to react; gas phase detection reaction is complete, distilled to remove the solvent, and then distilled under reduced pressure to obtain 501g chiral ethyl 4-chloro-3-hydroxybutyrate;

[0047] (2) Preparation of chiral 4-chloro-3-hydroxyl-1-butanol:

[0048] Add 195g (3.6mol, 1.2eq.) potassium borohydride and 2 liters of tetrahydrofuran into a 5-liter reaction flask, and slowly add 501g (3mol, 1eq.) chiral 4-chloro-3-hydroxybutyric acid dropwise at a temperature of 40°C Ethyl ester; after the dropwise addition, heat to reflux for 4 hours, cool, use dilute hydrochloric acid to extract the reaction, filter with suction, and distill the filtrate to remove the solvent to obtain chiral 4-...

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Abstract

The invention discloses a production technology of3-hydroxytetrahydrofuran with high optical purity. The production technology comprises the following steps: (1) taking chloroacetoacetic acid ethyl ester as a starting raw material, adding appropriate amount of solvents, chiral catalysts and reducing agents, and reacting at an appropriate temperature to obtain chiral ethyl 4-chloro-3-hydroxybutyrate; (2) taking the chiral ethyl 4-chloro-3-hydroxybutyrate obtained in step (1) as a raw material, adding the appropriate amount of solvents and metal borohydride reducing agents, and reacting at the appropriate temperature to obtain chiral 4-chloro-3-hydroxy-1-butanol; (3) taking the chiral 4-chloro-3-hydroxy-1-butanol obtained in step (2) as the raw material, adding appropriate amount of catalysts and solvents, and reacting at the appropriate temperature to obtain chiral 3-hydroxytetrahydrofuran. According to the production technology of the 3-hydroxytetrahydrofuran with the high optical purity, the chiral 3-hydroxytetrahydrofuran can be produced through a three-step reaction, the shortcomings of complicated production operation and high production cost are solved, and products with high optical purity can be produced.

Description

technical field [0001] The invention relates to the field of preparation of medicine and pesticide intermediates, in particular to a production process of high optical purity 3-hydroxytetrahydrofuran. Background technique [0002] Chirality is one of the essential properties of nature and the basis of life activities. Many life phenomena depend on the existence and recognition of chirality. Due to their special properties, optically pure compounds have been widely used and valued in many fields such as medicine, pesticides, materials, etc. Optically active medicines and pesticides have become an important part of the development of the pharmaceutical industry and its pesticide industry due to their unique properties and excellent curative effects. a major trend. [0003] Chiral 3-hydroxytetrahydrofuran is an important chiral intermediate, which can be used in the production of breast cancer drug afatinib, anti-AIDS drugs amprenavir and fosamprenavir, anti-hepatitis C virus ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20
CPCC07D307/20
Inventor 刘明荣陆军
Owner SUZHOU HUADAO BIOLOGICAL PHARMA
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