Gefarnate key intermediate refining or reaction solution direct post-processing method

An intermediate, gefar ester technology, which is applied in the field of medicine, can solve the problems of cumbersome operation, low yield, and low purity of gefar ester, and achieve the effects of increasing yield, reducing losses, and simplifying operations

Inactive Publication Date: 2015-02-25
NANJING REAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In actual operation, it was found that the two representative methods could not remove E-farnesic acid impurities very well, especially fat-soluble impurities, resulting in low purity of the finished gefar ester, and the intermediate process was through solid precipitation, centrifugation, and cumbersome operation , the yield is low, the molar yield is about 60%
[0014] Based on the pharmaceutical value and good market prospect of gefar ester, and the existing technology can not remove the impurity of the key intermediate E-farnesic acid in the previous step of gefar ester, especially the fat-soluble impurities, resulting in the finished product of gefar ester The purity is not high

Method used

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  • Gefarnate key intermediate refining or reaction solution direct post-processing method
  • Gefarnate key intermediate refining or reaction solution direct post-processing method
  • Gefarnate key intermediate refining or reaction solution direct post-processing method

Examples

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Effect test

Embodiment 1

[0032] Post-treatment of the reaction solution: refer to the patent CN101805260A: add 292.5g (1.0mol) of intermediate (IV), 96.0g (1.7mol) of potassium hydroxide, and 1900ml of 95% ethanol to a 3000mL three-necked glass reaction bottle, heat up to reflux reaction, TLC Track the completion of the reaction (developer: ethyl acetate:petroleum ether=1:9; iodine color development), after the reaction is complete, concentrate under reduced pressure until no ethanol drips out. At room temperature, add 500ml of purified water and stir to dissolve evenly, add acetic acid Wash 250ml of ethyl ester for 3 times (remove fat-soluble impurities), remove the ethyl acetate layer, add 2.0g of medicinal charcoal to the water layer, stir at room temperature for 20 minutes for decolorization, filter for decarburization, remove water-insoluble impurities, adjust the pH of the water layer with dilute hydrochloric acid The value is 2, add 250ml of ethyl acetate to extract 3 times, combine the ethyl ac...

Embodiment 2

[0034]Aftertreatment of the reaction solution: refer to the patent CN1O1805260A: add 292.5g (1.0mol) of intermediate (IV), 96.0g (1.7mol) of potassium hydroxide, and 1900ml of 95% ethanol in a 3000mL three-necked glass reaction bottle, heat up and reflux, TLC Track the completion of the reaction (developer: ethyl acetate:petroleum ether=1:9; iodine color development), after the reaction is complete, concentrate under reduced pressure until no ethanol drips out. At room temperature, add 800ml of purified water and stir to dissolve evenly. Wash 3 times with 400ml of propyl ether (to remove fat-soluble impurities), remove the isopropyl ether layer, add 2.0g of medicinal charcoal to the water layer, stir at room temperature for 20 minutes for decolorization, filter for decarburization, remove water-insoluble impurities, and adjust the pH of the water layer with dilute hydrochloric acid value is 1, add 400ml of isopropyl ether to extract 3 times, combine the isopropyl ether layer, w...

Embodiment 3

[0036] Refining: Add formula (I) compound E-farnesic acid crude product 200g in 3000mL three-necked glass reaction flask, add 15% potassium hydroxide 400ml under room temperature, stir and dissolve evenly, add ethyl acetate 250ml and wash 3 times (degreasing soluble impurities), remove the ethyl acetate layer, add 2.0 g of medicinal charcoal to the water layer, stir at room temperature for 20 minutes for decolorization, decarburize by filtration, remove water-insoluble impurities, adjust the pH value of the water layer to 3 with dilute hydrochloric acid, add 200 ml of ethyl acetate Extract 3 times, combine the ethyl acetate layers, wash 3 times with 200ml of water (to remove water-soluble impurities), add anhydrous sodium sulfate to the organic layer, dry, filter, and concentrate the filtrate under reduced pressure until no ethyl acetate is present, to obtain the compound of formula (I) E-farnesic acid was 227.6g, and the molar yield was 86.1%.

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Abstract

The invention discloses a gefarnate key intermediate (E-farnesyl acid) refining or reaction solution post-processing method, and belongs to medicines. The method is as follows: according to the fact that E-farnesyl acid is water-soluble in alkaline conditions and insoluble in water in acidic conditions, through washing and filtering, fat soluble impurities can be removed in alkaline conditions, and water soluble impurities can be removed in acidic conditions; and the step is as follows: dissolving the E-farnesyl acid with an alkali solution, washing and filtering with an organic solvent, then adjusting filtrate to acidic, adding an organic solvent for extraction, and concentrating to obtain high purity E-farnesyl acid. Finally, gefarnate is prepared from the E-farnesyl acid and geraniol by the method well-known by technical personnel in the field. The gefarnate key intermediate (E-farnesyl acid) refining method can well improve the E-farnesyl acid purity, and especially removes the fat soluble impurities to enable finished product gefarnate after esterification reaction to fully meet and be higher than Japanese Pharmacopoeia standards, the purity can reach 99.5%, and the method is simple in operation, and is more suitable for industrial production.

Description

technical field [0001] The present invention relates to the refining method of formula (I) compound E-farnesic acid or the method for direct aftertreatment of E-farnesic acid reaction liquid, its chemical name is (4E,8E)-5,9,13-trimethyl Base-4,8,12-tetratrienoic acid, the compound is a key intermediate in the previous step of preparing the gastric mucosa protective drug gefarate, and belongs to the field of medicine. [0002] Background technique [0003] Gefate is an isoprene compound, which was originally extracted from cabbage heart and then synthesized by Adami et al. For the treatment of gastric and duodenal ulcers, acute and chronic gastritis, colitis, stomach cramps, etc. It has the effects of accelerating metabolism, regulating gastrointestinal function and gastric acid secretion, and strengthening mucosal protection. The mechanism of action may be to act directly on gastric mucosal epithelial cells to enhance their ability to resist ulcer factors. [0004] Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/03C07C51/42
CPCC07C51/42
Inventor 时文祥叶靖赵允华
Owner NANJING REAL PHARMA
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