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Synthesizing method of (S)-3-hydroxytetrahydrofuran

A technology of hydroxytetrahydrofuran and a synthesis method, applied in directions such as organic chemistry, can solve the problems of high price, unfavorable production efficiency, high reaction temperature, and achieve the effects of improving yield and optical purity, low reaction system requirements, and reducing side reactions

Inactive Publication Date: 2017-10-10
BTC PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, in the production method of (S)-3-hydroxytetrahydrofuran, it is usually necessary to use lithium aluminum hydride, which has strict requirements on the system and is relatively expensive. At the same time, the reaction temperature of the system is relatively high, and the residence time of the product in the system under reduced pressure Longer, easy to produce side reactions, making the subsequent purification operation of the product quite difficult, which is not conducive to the improvement of production efficiency

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] A synthetic method for (S)-3-hydroxytetrahydrofuran, comprising the following steps:

[0015] (1) Add 250g (1.86 mol) of L-malic acid and 500ml of methanol into a 1000ml four-necked reaction flask, start stirring, add 20g (0.1 mol) of concentrated sulfuric acid, after the addition is complete, turn on the condensed water, put the oil bath at 75°C under reflux React for 2 hours, take a sample and send the gas phase to check that the reaction is complete. After cooling down to room temperature, add sodium carbonate to adjust the pH to 8, remove methanol under reduced pressure, add 100ml of water, and extract the water phase with dichloromethane 3 times, 100ml each time, for the third extraction After the water phase, check whether the extraction has been completed. If it is not extracted, extract it again with 100ml of dichloromethane, combine the organic phases, remove the solvent under reduced pressure, and distill 277g of L-dimethyl malate, with a yield of 92%. ;

[0...

Embodiment 2

[0019] A synthetic method for (S)-3-hydroxytetrahydrofuran, comprising the following steps:

[0020] (1) Add 200g (1.49mol) of L-malic acid and 400ml of methanol into a 1000ml four-necked reaction flask, start stirring, add 14.6g (0.149mol) of concentrated sulfuric acid, after the addition is complete, turn on condensed water, oil bath at 75°C, and reflux The reaction was carried out for 2 hours, and the gas phase was sampled to detect that the reaction was complete. After cooling down to room temperature, sodium carbonate was added to adjust the pH to 8. Methanol was removed under reduced pressure, and 100ml of water was added. The aqueous phase was extracted 3 times with 100ml of dichloromethane. After the extraction, the aqueous phase was tested to see if the extraction was clean. If it was not extracted, it was extracted again with 100ml of dichloromethane, the organic phases were combined, the solvent was removed under reduced pressure, and 221g of L-dimethylmalate was eva...

Embodiment 3

[0024] A synthetic method for (S)-3-hydroxytetrahydrofuran, comprising the following steps:

[0025] (1) Add 200g (1.49mol) of L-malic acid and 400ml of methanol into a 1000ml four-necked reaction bottle, start stirring, add 14.6g (0.149mol) of concentrated sulfuric acid, after the addition is complete, turn on condensed water, oil bath at 70°C, and reflux The reaction was carried out for 2.5 hours, and the gas phase was sampled to detect that the reaction was complete. After cooling down to room temperature, sodium carbonate was added to adjust the pH to 9. Methanol was removed under reduced pressure, and 100ml of water was added. The aqueous phase was extracted 3 times with 100ml of dichloromethane. After the first extraction, the aqueous phase was tested to see if the extraction was clean. If it was not extracted, it was extracted again with 100ml of dichloromethane, the organic phases were combined, the solvent was removed under reduced pressure, and 222.2g of L-dimethylmal...

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Abstract

The invention provides a synthesizing method of (S)-3-hydroxytetrahydrofuran. The synthesizing method comprises the following steps of synthesizing of L-dimethyl malate, synthesizing of chiral 1,2,4-butantriol crude product, synthesizing of the (S)-3-hydroxytetrahydrofuran, and the like. The synthesizing method has the advantages that low-cost L-malate is used as a raw material, and is reduced by sodium borohydride to form the L-dimethyl malate under the promoting action of methyl alcohol, so that the requirement of a reaction system is low; remained phosphoric acid in a quenching process is heated to catalyze chiral butantriol to generate the (S)-3-hydroxytetrahydrofuran in a closed ring way, and the product is separated and purified from the system via distillation, so that the economic and environment-friendly effects are realized, and the adding of a catalyst is not needed; the reaction temperature is lower, the staying time of the product in the system is short, the production of side production is greatly reduced, and the yield rate and optical purity of the product are increased.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of (S)-3-hydroxytetrahydrofuran. Background technique [0002] (S)-3-Hydroxytetrahydrofuran is used for the first-line treatment of advanced non-small cell lung cancer and the intermediate of the raw material afatinib for HER2-positive advanced breast cancer patients. At present, in the production method of (S)-3-hydroxytetrahydrofuran, it is usually necessary to use lithium aluminum hydride, which has strict requirements on the system and is relatively expensive. Longer, easy to produce side reactions, making the follow-up purification operation of the product quite difficult, which is not conducive to the improvement of production efficiency. Contents of the invention [0003] The technical problem to be solved by the present invention is to provide a method for synthesizing (S)-3-hydroxytetrahydrofuran (S)-3-h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20
CPCC07D307/20
Inventor 殷亮吴加朋周广徐本全
Owner BTC PHARMA TECH CO LTD
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