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Preparation process for key intermediate 1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer) of dextromethorphan hydrobromide serving as cough relieving medicine

A technology of octahydroisoquinoline and medicinal hydrobromic acid, applied in the direction of organic chemistry and the like, can solve the problems of high cost and low utilization rate, and achieve the effect of reducing cost, simple and safe operation

Active Publication Date: 2011-10-19
JIANGSU BAOZONG & BAODA PHARMACHEM
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  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0003] At present, the key intermediate of dextromethorphan hydrobromide is 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (heteromorph) In the utilization process of this step, the general yield is only about 50%. The 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8 obtained in the resolution process -Octahydroisoquinoline (L-isomer) is discarded, which results in a generally low utilization rate of the key intermediate of dextromethorphan at this step, resulting in higher costs

Method used

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  • Preparation process for key intermediate 1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer) of dextromethorphan hydrobromide serving as cough relieving medicine
  • Preparation process for key intermediate 1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer) of dextromethorphan hydrobromide serving as cough relieving medicine
  • Preparation process for key intermediate 1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer) of dextromethorphan hydrobromide serving as cough relieving medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Step 1: Preparation of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (L-isomer):

[0023] In a 500ml four-neck flask equipped with a thermometer and a stirring device, start stirring, and add 150g of 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-octahydro Isoquinoline (L-isomer), 1.1 times molar amount of acetic anhydride, nitrogen protection, heating up to 80°C, heat preservation reaction for 3 hours, after heat preservation reaction is completed, vacuum distillation, after distillation is complete, add 2 mole amount of absolute ethanol Recrystallized, centrifuged, and dried to obtain light yellow solid 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline ( L-isomer) 142.8 g, the yield was 81.8%.

[0024] Step 2: Preparation of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (heteromorph):

[0025] In a 500ml four-neck flask equipped with a thermometer and a stirring device, start stirring, and add 142.8g of 1-(4-methoxy)be...

Embodiment 2

[0029] Step 1: Preparation of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (L-isomer).

[0030] In a 500ml four-neck flask equipped with a thermometer and a stirring device, start stirring, and add 150g of 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-octahydro Isoquinoline (L-isomer), 1.1 times molar amount of acetic acid, nitrogen protection, heating to 80 ° C, heat preservation reaction for 4 hours, heat preservation reaction is completed, vacuum distillation, after distillation, add 2 mole weight of absolute ethanol Crystallized, centrifuged, and dried to obtain light yellow solid 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (Levorotatory body) 143.4 g, the yield was 82.1%.

[0031] Step 2: Preparation of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (heteromorph):

[0032] In a 500 ml four-necked flask with a thermometer and a stirring device, start stirring, and add 143.4 g of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5...

Embodiment 3

[0036] Step 1: Preparation of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (L-isomer):

[0037] In a 500ml four-neck flask equipped with a thermometer and a stirring device, start stirring, and add 150g of 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-octahydro Isoquinoline (L-isomer), 1.1 times the molar amount of formic acid, pass through nitrogen protection, heat up to 80 ° C, heat preservation reaction for 3 hours, heat preservation reaction is completed, vacuum distillation, after distillation is completed, add 2 moles of anhydrous methanol Crystallized, centrifuged, and dried to give light yellow solid 1-(4-methoxy)benzyl-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (Levorotatory body) 134.4 g, the yield was 80.8%.

[0038]Step 2: Preparation of 1-(4-methoxy)benzyl-2-acetyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (heteromorph):

[0039] In a 500 ml four-necked flask with a thermometer and a stirring device, start stirring, and add 134.4 g of 1-(4-methoxy)be...

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Abstract

The invention discloses a preparation process for a key intermediate 1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer) of dextromethorphan hydrobromide serving as a cough relieving medicine, which comprises the following steps of: performing acylation reaction to obtain 1-(4-methoxyl)benzyl-2-alkylacyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (laevo isomer); and racemizing under the alkaline condition to obtain 1-(4-methoxyl)benzyl-2-alkylacyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer); and hydrolyzing under the alkaline condition to obtain the 1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydro isoquinoline (mixed isomer). The process aims to overcome the defect of the synthetic process and reduce cost, so that the process is simply and safely operated, the industrial production is qualified, and the yield of products is between 55 and 69 percent.

Description

technical field [0001] The invention relates to a new process for the preparation of antitussive drugs, in particular to the key intermediate 1-(4-methoxy)benzyl-1,2,3,4, A new process for the preparation of 5,6,7,8-octahydroisoquinoline (heteromorph). Background technique [0002] Dextromethorphan hydrobromide, also known as dextromethorphan hydrobromide, chemically named 3-methoxy-17-methyl-9α, 13α, 14α morphinan hydrobromide hydrate, is a central Antitussives mainly inhibit the cough center of the medulla medulla and exert their effects. Colds, acute and chronic bronchitis, pharyngitis, bronchial asthma, tuberculosis and other upper respiratory tract infections caused by less phlegm cough. [0003] At present, the key intermediate of dextromethorphan hydrobromide is 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (heteromorph) In the utilization process of this step, the general yield is only about 50%. The 1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8 obtained in the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
Inventor 朱志勇陈荣王琳张鹏
Owner JIANGSU BAOZONG & BAODA PHARMACHEM
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