Method for synthesizing Teprenone

A teprenone and catalyst technology, applied in chemical instruments and methods, preparation of organic compounds, separation/purification of carbonyl compounds, etc., can solve the problems of increased impurities, high water solubility, low conversion rate, etc., and achieve inhibition of alcohol The generation of similar by-products, the improvement of product purity, and the effect of realizing industrialization

Active Publication Date: 2014-02-05
CHONGQING HEALTHY MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, in the existing reported Carroll reaction, due to the presence of organoaluminum catalysts, alcohol by-products are inevitably produced, and the generated alcohol by-products are difficult to separate, and in the post-treatment process, emulsification after solvent extraction, separation and washing Seriously, high-purity products cannot be obtained, and the conversion rate of the reaction is low, which leads to a low yield of the final product
And the Carroll reaction uses nitrogen or atmospheric distillation to eliminate the lower alcohols (methanol, ethanol, etc.) and carbon dioxide produced during the reaction. The reaction temperature exceeds 170°C, and high-temperature distillation will also lead to an increase in impurities.
Japanese Eisai Patent WO0203981A1 discloses that n-hexane is used as the extraction and separation solvent, and methanol, ethanol or isopropanol is continuously added. The solvent system has a low boiling point and is easy to distill, but has a large water solubility and the demulsification effect is not ideal, so it cannot be well realized. industrialization

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  • Method for synthesizing Teprenone
  • Method for synthesizing Teprenone
  • Method for synthesizing Teprenone

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Embodiment 1 The synthesis and separation method of teprenone of the present invention

[0035] Dissolve 5.0g (24.5mmol) of aluminum isopropoxide in 20g (0.172mol) of methyl acetoacetate at 40-100°C, then distill under negative pressure at 40-120°C with a pressure of 0.03MPa, discard Slip out of the liquid to get a pretreated catalyst. Add 120g (0.413mol) of geranyl linalool, 38g (0.327mol) of methyl acetoacetate, 40g of cyclohexanone and pretreated catalyst in the three-necked flask, stir and heat up, react at 125°C for 30-60 minutes, and then increase to React at 135°C for 30-60 minutes, then react at 150°C for 2-4 hours, while the water pump 0.03MPa vacuum distills methanol and removes CO 2 , stop reaction, rapid cooling, get the crude product of teprenone, residual raw material geranyllinalool 0.85% in GC measurement reaction solution, product 95.76% (double peak), alcohols by-product accounts for 0.12% (double peak), reaction Liquid was directly added to a 1L sep...

Embodiment 2

[0037] Embodiment 2 The synthesis and separation method of teprenone of the present invention

[0038]Dissolve 5.0g (24.5mmol) of aluminum isopropoxide in 38.4g (0.330mol) of methyl acetoacetate at 40-100°C, then distill under negative pressure at 40-120°C with a pressure of 0.03MPa, discard Slip out of the liquid and get the pretreated catalyst. Add 120 g (0.413 mol) of geranyl linalool, 38.4 g (0.330 mol) of methyl acetoacetate, 100 g of methyl amyl ketone and a pretreated catalyst in a three-necked flask, stir and heat up, and react at 125° C. for 30 minutes, then increase React at 135°C for 60 minutes, then react at 150°C for 3 hours, while the water pump 0.03MPa vacuum distills methanol and removes CO 2 , stop reaction, rapid cooling, get the thick product of teprenone, 0.65% of residual raw material geranyllinalool is measured in the reaction liquid by GC, product 95.9% (double peak), alcohols by-product accounts for 0.09% (double peak), reaction Liquid was directly ad...

Embodiment 3

[0040] Embodiment 3 The synthesis and separation method of teprenone of the present invention

[0041] Dissolve 5.0g (24.5mmol) of aluminum isopropoxide in 19g (0.165mol) of methyl acetoacetate at 40-100°C, then distill under negative pressure at 40-120°C with a pressure of 0.03MPa, discard Slip out of the liquid and get the pretreated catalyst. Add 120g (0.413mol) of geranyl linalool, 77g (0.661mol) of methyl acetoacetate, 20g of heptanone and the pretreated catalyst in the three-necked flask, react at 125°C for 30-60 minutes, and then raise the temperature to 135°C for 30 minutes. -60 minutes, and then react at 150°C for 2-4 hours, while the water pump 0.03MPa vacuum distills methanol and removes CO 2 , stop reaction, rapid cooling, get the thick product of teprenone, residual raw material geranyllinalool 0.98% in GC measurement reaction solution, product 95.3% (double peak), alcohols by-product accounts for 0.16% (double peak), reaction Add liquid directly into a 1L separ...

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Abstract

The invention discloses an improved process for synthesizing Teprenone with Carroll reaction and a separation and purification method. In the method, aiming at the condition that alcohol byproducts which are difficult to separate are always produced in reaction, a treated organic aluminum catalyst is adopted, a ketone solvent is added for diluting; and low vacuum is adopted in the reaction process for rapidly transferring the low-level alcohol and the carbon dioxide generated in the reaction, and therefore, the reaction temperature is reduced, the side reaction is well controlled, the generation of the alcohol byproducts is decreased and the reaction conversion rate is higher than 95%. According to the invention, the emulsification problem in the purification process is solved so that the yield of the product before the rectification is increased to be higher than 87%, the short-distance distillation is well realized, the separated Teprenone completely meets the standards on the marketed drugs, the purity is not less than 99.0% and the yield of the high-purity product is above 66%. The improved process and the post-treatment and separation technology are simple for operation, easy for control, good in stability, achieve high reaction conversion rate and stable quality and are easy for industrialized production.

Description

technical field [0001] The invention relates to a method for synthesizing teprenone, in particular to a technique for synthesizing teprenone by Carroll reaction and a separation and purification technology. Background technique [0002] Teprenone, geranylgeranylacetone, is a kind of terpene, also known as pentacentrone, chemical name is 6, 10, 14, 18-tetramethyl-5, 9, 13, 17-nineteen Carbon tetraenyl 2-ketone, the structural formula is as follows: [0003] [0004] Launched in Japan in 1984, approved by FDA in 1994, imported capsules from Japan in 2000, imported raw materials in 2006, Eisai (China) Pharmaceutical Co., Ltd. approved capsules in 2009, exclusive production. Teprenone is a broad-spectrum anti-ulcer drug, which has strong anti-ulcer effect and improvement effect on various experimental ulcers and gastric mucosal lesions. This drug can promote the synthesis and secretion of main regenerative defense factors, high molecular glycoproteins and phospholipids in g...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/203C07C45/65C07C45/80C07C45/82
Inventor 周武春李仕林吴刚桂亚华严强
Owner CHONGQING HEALTHY MEDICINE CO LTD
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