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A kind of tetrahydrofuran-2-formic acid industrialized racemization process

A technology of tetrahydrofuran formic acid and tetrahydrofuran, which is applied in the field of pharmaceutical synthesis, can solve problems such as increased production cost, harsh reaction conditions, and cannot be recycled, and achieves the effects of good racemization effect, stable product properties, and mild reaction conditions.

Active Publication Date: 2018-01-09
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, tetrahydrofuran-2-carboxylic acid with high optical purity is mainly obtained by splitting the racemate of tetrahydrofuroic acid. After splitting, another configuration of tetrahydrofuran-2-carboxylic acid cannot be recycled, and the waste of materials increases the production cost. At the same time, it also brings pressure on disposal and environmental protection
Hu Yu et al. (Chemical World, 2009, 50, 160-162) reported a method for racemating optically pure tetrahydrofuran-2-carboxylic acid with a strong base and high temperature, but the method used a large excess of base (100:1) to To achieve complete racemization, if the method reduces the amount of alkali used, it needs to use a high-boiling organic solvent, and the reaction conditions are harsh, which is not conducive to industrialization

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] A kind of industrialized racemization process of S-tetrahydrofuran-2-formic acid, comprising the following steps:

[0017] Pump 200 Kg of S-tetrahydrofuran-2-carboxylic acid, 100 Kg of water, and 340 Kg of 30% sodium hydroxide into the high-pressure reactor, heat in an oil bath, keep stirring at 160-165°C, and keep increasing the pressure in the kettle to 0.5-0.6 Mpa , take a sample to monitor the e.e. value, the racemization is complete in about 5 hours, then lower to room temperature, adjust the pH=1 to 2 with concentrated hydrochloric acid, extract three times with 200 Kg dichloromethane, combine the dichloromethane layers, and dry with anhydrous sodium sulfate. Concentrate to obtain tetrahydrofuran-2-carboxylic acid racemate: 184 Kg. Yield: 92%, optical purity: 0.2%.

Embodiment 2

[0019] A kind of industrialization racemization process of R-tetrahydrofuran-2-formic acid, comprises the following steps:

[0020] Pump 200 Kg of R-tetrahydrofuran-2-carboxylic acid, 100 Kg of ethanol, and 318 Kg of 30% sodium carbonate solution into the autoclave, heat in an oil bath, keep stirring at 120-135°C, and keep increasing the pressure in the autoclave to 0.5-0.6 Mpa, take a sample to monitor the e.e. value, the racemization is complete in about 5 hours, then lower to room temperature, adjust the pH=1~2 with concentrated hydrochloric acid, extract three times with 200 Kg dichloromethane, combine the dichloromethane layers, and dry with anhydrous sodium sulfate , concentrated to give tetrahydrofuran-2-carboxylic acid racemate: 181 Kg. Yield: 90.5%, optical purity: 0.3%.

Embodiment 3

[0022] A kind of industrialized racemization process of S-tetrahydrofuran-2-formic acid, comprising the following steps:

[0023] Pump 200 Kg of S-tetrahydrofuran-2-carboxylic acid, 100 Kg of water, and 500 Kg of 30% sodium bicarbonate into the high-pressure reaction kettle, heat in an oil bath, keep stirring at 180-185 ° C, and the pressure in the kettle will continue to rise to 0.5-0.6Mpa , take a sample to monitor the e.e. value, the racemization is complete in about 5 hours, then reduce to 65-85°C and concentrate under reduced pressure to remove 70% of water, then use concentrated hydrochloric acid to adjust the pH=1~2, and then concentrate under reduced pressure at 65-85°C to remove 80% water. % water, add 150Kg of toluene, heat up and divide the water, stop the water division when the temperature rises to 100°C, cool down to room temperature, filter, wash the kettle and filter cake with 50Kg of toluene, concentrate the filtrate under reduced pressure, and flash evaporate ...

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Abstract

The invention discloses an industrial racemization technology for tetrahydrofuran-2-formic acid and belongs to the field of chemical synthesis. The industrial recemization technology comprises the following steps: by taking tetrahydrofuran-2-formic acid (II) as a raw material, in the presence of inorganic alkali and a solvent, reacting for 0.1-20 hours at the temperature of 100-200 DEG C, and carrying out recemization to obtain recemized tetrahydrofuran formic acid, wherein the molar ratio of inorganic alkali to tetrahydrofuran-2- formic acid (II) is (0.1-20):1, and the solvent is low-boiling point alcohol or water or mixture of low-boiling point alcohol and water. The technology has the advantages that the alkali usage amount is greatly reduced, a high-boiling point solvent is not needed, and reaction conditions are mild; and practical industrial production verifies that the operation is safe and reliable, product characters are stable, the purity can reach more than 99%, the optical purity can be less than 0.5%, the yield can reach more than 90%, the repeatability is good, and the recemization effect is good, thereby being a reliable industrial recemization technology for tetrahydrofuran-2-formic acid.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to an industrial racemization process of tetrahydrofuran-2-carboxylic acid. Background technique [0002] Tetrahydrofuran-2-carboxylic acid is an important chemical intermediate widely used in many fields such as medicine and chemical industry. The derivatives of chiral tetrahydrofuran-2-carboxylic acid have been widely used in the synthesis of drugs including diuretics, alfuzosin for the treatment of prostatic hypertrophy, terazosin for antihypertensive drugs, and furopenem for antibiotics. An important ligand synthon in asymmetric reactions and an intermediate in the synthesis of acetyltetrahydrofuran with high optical purity. At present, tetrahydrofuran-2-carboxylic acid with high optical purity is mainly obtained by splitting the racemate of tetrahydrofuroic acid. After splitting, another configuration of tetrahydrofuran-2-carboxylic acid cannot be recycled, and the wast...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/24C07B55/00
CPCC07B55/00C07D307/24
Inventor 袁伟成邢志奎徐小英牟行彦李宗林欧仁树葛真真陈诚张小祥季红清
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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