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Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine

A technology of tetrahydrothebaine and acetyl group, which is applied in the field of double bond hydrogenation reaction of thienorphine intermediates, can solve the problems of low product conversion rate, inconvenient operation, and high equipment requirements, and achieve low investment cost and universal equipment Good performance and high benefit

Inactive Publication Date: 2012-03-21
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The existing hydrogenation reduction method of thienorphine hydrochloride intermediates uses high pressure 4-5MPa (see CN01142149.5) to catalyze hydrogenation addition, which requires high equipment, large investment, low product conversion rate, inconvenient operation and poor safety and other issues, and the yield is around 75%

Method used

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  • Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine
  • Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Put 14L of absolute ethanol and 1Kg of thienorphine intermediate 7ɑ-acetyl-6,14-ethylene bridge tetrahydrothebaine into a 20L hydrogenation reaction tank, then add 0.2Kg of 10% palladium carbon and 50mL of pyridine, and turn on hydrogen To a pressure of 0.01MPa, first vacuum the system and replace it with hydrogen. Under the condition of hydrogen, stir and heat up to 56°C for hydrogenation reduction reaction for 8 hours. During the reaction, a small amount of fresh hydrogen is exchanged. TLC detects that the reaction is complete. The reduction reaction solution is filtered hot, the filter cake is washed with ethanol, the obtained filtrate is concentrated to near dryness under reduced pressure, and the concentrated product is added with ethanol equivalent to 0.5 times the amount of 7ɑ-acetyl-6,14-ethylene bridged tetrahydrothebaine After stirring evenly, cool to about 5°C, let stand for more than 4 hours and centrifuge, and then wash the centrifuged product with ethanol e...

Embodiment 2

[0030] Put 280mL of anhydrous methanol and 20g of thienorphine intermediate 7ɑ-acetyl-6,14-ethylene bridge tetrahydrothebaine into a 500mL three-necked hydrogenation reaction bottle, then add 4g of 10% palladium carbon and 1mL of pyridine, and turn on hydrogen To a pressure of 0.01MPa, first vacuum the system and replace it with hydrogen. Under the condition of hydrogen, stir and heat up to 56°C for 12 hours. During the reaction, a small amount of fresh hydrogen is exchanged. TLC detects that the reaction is complete. Filtrate hot, wash the filter cake with methanol, concentrate the obtained filtrate to near dryness under reduced pressure, and then use ethanol for 3 times to remove the methanol, and then add the equivalent of 7ɑ-acetyl-6,14-ethylene bridged tetrahydrodiba to the concentrated product Because the ethanol with a dosage of 1.0 times is stirred evenly, cooled to about 5°C, left to stand for more than 4 hours and centrifuged, and the centrifuged product is then used ...

Embodiment 3

[0032] Put 280mL of absolute ethanol and 20g of thienorphine intermediate 7ɑ-acetyl-6,14-ethylene bridge tetrahydrothebaine into a 500mL three-necked hydrogenation reaction bottle, then add 2g of platinum dioxide and 1mL of pyridine, and turn on the hydrogen to The pressure is 0.01MPa, first vacuumize the system and replace it with hydrogen, under the condition of hydrogen, stir and heat up to 56°C for 12 hours, a small amount of fresh hydrogen is exchanged during the reaction, TLC detects that the reaction is complete, first heat the hydrogenation reduction reaction solution Filtrate, wash the filter cake with ethanol, concentrate the obtained filtrate to near dryness under reduced pressure, add ethanol equivalent to 0.7 times the amount of 7ɑ-acetyl-6,14-ethylene-tetrahydrothebaine, stir evenly, and cool to 5 Centrifuge at about 4 hours, the centrifuged product is then washed with ethanol equivalent to about 1 times the amount of 7ɑ-acetyl-6,14-ethylene bridged tetrahydrotheb...

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Abstract

The invention relates to the field of the double bond hydrogenation reaction of a thenorphine intermediate, in particular to a preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine. The method comprises the following steps of: dissolving 7alpha-acetyl-6,14-ethylene bridge tetrahydrothebaine serving as a raw material into a polar solvent; adding an effective quantity of catalyst and organic alkaline reagent; and introducing an excessive amount of hydrogen at certain temperature and under certain pressure for undergoing a hydrogenation reduction reaction to obtain 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine, wherein the polar solvent is absolute ethyl alcohol or absolute methanol; the catalyst is palladium carbon or platinum dioxide; the organic alkaline reagent is pyridine; and the using amount of the organic alkaline reagent is 1-5 percent (v / w) based on the amount of the 7alpha-acetyl-6,14-ethylene bridge tetrahydrothebaine. The method disclosed by the invention has the advantages of high operating safety, high product yield and low production cost.

Description

technical field [0001] The invention relates to the field of double bond hydrogenation reaction of thienorphine intermediates, in particular to a preparation method of 7ɑ-acetyl-6,14-ethyl-tetrahydrothebaine. Background technique [0002] Thienophine Hydrochloride, the English name is Thenorphine Hydrochloride, [0003] The chemical name is 21-Cyclopropyl-7α-[1-(R)-1-hydroxy-1-methyl-3-(thien-2-yl)propyl]-6,14endoethano-6,7,8,14-tetrahydrooripavine Hydrochloride Monohydrate. Structural formula: [0004] [0005] Thienophine hydrochloride is a national first-class new drug with independent intellectual property rights developed by the Institute of Toxicology and Drugs of the Academy of Military Medical Sciences. The drug has a novel structure and is a partial agonist of opioid receptors. Pharmacodynamic studies have shown that the drug has the advantages of strong analgesic effect, long action time, small effective dose, good oral absorption, no potential for physical d...

Claims

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Application Information

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IPC IPC(8): C07D489/12
Inventor 许东新张宇松应明华
Owner ZHEJIANG XIANJU PHARMA
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