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Synthesis methods of teprenone and intermediate thereof

A synthesis method and technology of teprenone, applied in the field of synthesis of teprenone and its intermediates, can solve the problems of difficult industrial application, small difference in boiling point, low yield, etc., and achieve easy industrial production, easy control, Simple operation effect

Active Publication Date: 2018-05-18
ZHEJIANG NHU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] For example, Chen Hairong and Hu Zonglin provided a method for synthesizing all-trans geranyl linalool in "Chinese Journal of Pharmaceutical Industry" 2004,35 (8), 449-450, using trans-nerolidol as raw material and ethyl acetoacetate Ester reaction to obtain 5E-, 5Z-farnesylacetone cis-trans isomer mixture, through rectification to obtain (5E, 9E) farnesylacetone, part of (5E, 9E) farnesylacetone and (5Z, 9E) method The mixture of Nylacetone is isomerized under selenium powder, and then rectified to obtain (5E, 9E) Farnesylacetone, (5E, 9E) Farnesylacetone reacts with vinylmagnesium chloride to obtain all-trans geranyllinalool, However, due to the high boiling point of the cis-trans isomers in farnesyl acetone and the small difference in boiling points between the isomers, more rectification towers with a large number of pedals are needed to achieve the separation effect, and the large number of pedals leads to an increase in the pressure of the rectification tower , even under high vacuum during rectification, the temperature of the still liquid is still high, and more impurities and scraps are produced, resulting in low purity of all-trans farnesyl acetone obtained by separation, and low yield at the same time. content of all-trans farnesyl acetone is difficult to synthesize and obtain qualified teprenone product as raw material, and it is difficult to industrialized application

Method used

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  • Synthesis methods of teprenone and intermediate thereof

Examples

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Effect test

Embodiment 1

[0040] Example 1: Synthesis of a mixture of isomers of (5Z, 9Z)-, (5Z, 9E)-, (5E, 9Z)-, (5E, 9E)-farnesylacetone

[0041] Add 100g of 5Z-, 5E-nerolidol mixture (wherein 5E-nererolidol content is 59.5%) and 2.0g aluminum isopropoxide into a 250ml four-necked flask equipped with a common distillation unit, stir and heat up to 100°C, while Add 80 g of methyl acetoacetate dropwise while raising the temperature, raise the temperature to 200°C, keep it warm for 2 hours, stop heating, let the reaction system cool down to below 100°C naturally, remove methanol and excess methyl acetoacetate by distillation under reduced pressure, distill under reduced pressure, collect The product (5Z, 9Z)-, (5Z, 9E)-, (5E, 9Z)-, (5E, 9E) farnesyl acetone mixture 100g, the reaction yield is 84.7%, of which the all-trans (5E, 9E) The farnesylacetone content is 36%.

Embodiment 2

[0042] Example 2: Synthesis of (5Z, 9Z)-, (5Z, 9E)-, (5E, 9Z)-, (5E, 9E)-isomer mixture of farnesyl acetone

[0043] Add 89g of 5Z-, 5E-nerolidol mixture (59.5% of the 5E-nererolidol content) and 1.5g of aluminum isopropoxide into a 250ml four-necked flask equipped with a common distillation device, stir and heat up to 140°C, drop Add 80 g of ethyl acetoacetate, raise the temperature to 200° C. after dropping, keep the temperature for 2 hours, stop heating, let the reaction system cool down to below 100° C., remove ethanol and excess ethyl acetoacetate by vacuum distillation, and collect the product ( 5Z, 9Z)-, (5Z, 9E)-, (5E, 9Z)-, (5E, 9E) farnesyl acetone mixture 95g, the reaction yield is 90.4%, of which all-trans (5E, 9E) farnes The oxyacetone content was 36%.

Embodiment 3

[0044] Example 3: Synthesis of (5Z, 9Z)-, (5Z, 9E)-, (5E, 9Z)-, (5E, 9E)-isomer mixture of farnesyl acetone

[0045] Add 114g of 5Z-, 5E-nerolidol mixture (wherein 5E-nererolidol content is 59.5%) and 2.0g aluminum isopropoxide into a 250ml four-neck flask equipped with a common distillation device, stir and heat up to 170°C, drop Add 90 g of methyl acetoacetate, keep it warm for 2 hours, stop heating, let the reaction system cool naturally to below 100°C, remove methanol and excess methyl acetoacetate by vacuum distillation, and collect the products (5Z, 9Z)-, (5Z, 9E)-, (5E, 9Z)-, (5E, 9E) farnesyl acetone mixture 103.2g, the reaction yield is 76.7%, wherein the all-trans (5E, 9E) farnesyl acetone content is 36 %.

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Abstract

The invention relates to synthesis methods of teprenone and an intermediate thereof. The synthesis of the intermediate all-trans (5E,9E)-farnesyl acetone comprises: 1) in the presence of a catalyst, carrying out a carroll rearrangement reaction on the mixture of 5E-nerolidol and 5Z-nerolidol and hydrocarbonyl acetoacetate to obtain the isomer mixture of (5Z,9Z)-farnesyl acetone, (5Z,9E)-farnesyl acetone, (5E,9Z)-farnesyl acetone, and (5E,9E)-farnesyl acetone, wherein the content of (5E,9E)-farnesyl acetone in the isomer mixture is controlled at more than 18%; and 2) carrying out low-temperature crystallization separation on the isomer mixture in a moderately polar solvent to obtain the all-trans (5E,9E)-farnesyl acetone. According to the present invention, the high-purity all-trans (5E,9E)-farnesyl acetone is obtained by using the mixture of 5E-nerolidol and 5Z-nerolidol as the raw material through the low-temperature crystallization separation, such that the teprenone with the qualified quality can be conveniently obtained.

Description

technical field [0001] The invention relates to the synthesis field of teprenone, in particular to a synthesis method of teprenone and an intermediate thereof. Background technique [0002] Teprenone (Teprenone), CAS: 6809-52-5, trade name: Shiweishu, other names: pentaerythrone, E0671, Tetraprenylacetrone, Cerbex, Selbex. Chemical name: 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one, which is (5E,9E,13E)-type and (5Z,9E,13E )-type cis-trans isomers (3:2) mixture, a colorless to light yellow oily liquid with a special smell. [0003] Teprenone is mainly used for acute gastritis, acute exacerbation of chronic gastritis, improvement of gastric mucosal lesions (erosion, bleeding, flushing, edema) and strong anti-gastric ulcer effect. Teprenone is mainly synthesized through two different synthetic routes: (1) carroll reaction of geranyl linalool and alkyl acetoacetate; (2) 1-halo-3,7,11,15-tetramethyl- Reaction of hexadeca-2,6,10,14-tetraene with alkyl acetoacetate. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/54C07C49/203C07C29/40C07C33/02C07C45/81
CPCC07B2200/09C07C29/40C07C45/54C07C45/81C07C49/203C07C33/02
Inventor 贺家伟钱洪胜鲁国彬胡瑞君张永钗张洋洋吴可军
Owner ZHEJIANG NHU CO LTD
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