Preparation method of dimemorfan phosphate, and preparation methods of dimemorfan phosphate intermediates

A technology of dimethylorphinyl phosphate and dimethylarphane, which is applied in the field of medicine and chemical industry, can solve the problems of cumbersome filtration, extraction, pickling, alkali washing operation, complicated processing operation, affecting Grignard reaction, etc. Simple handling, simple reaction system, and the effect of improving reactivity

Active Publication Date: 2019-12-31
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After repeating this route, it is found that there are the following disadvantages: 1) The starting material 5,6,7,8-tetrahydroisoquinoline is not easy to obtain, there is no domestic supplier, and the import price is high
2) The more toxic methyl bromide is used in the route, and methyl bromide is a gas at room temperature, which is not conducive to scale-up production
3) The quaternary ammonium salt in the route is very easy to absorb moisture, and it is difficult to fully dry, and the moisture will seriously affect the next step of the Grignard reaction
4) Grignard reaction conditions are harsh, requiring anhydrous and oxygen-free, not suitable for industrial production, and the post-processing operations of Grignard reaction and sodium borohydride reduction reaction are complicated, requiring cumbersome filtration, extraction, pickling, and alkali washing operations, two steps The reaction yield is also low, about 35%
The starting material of this route is not easy to obtain and is a pipe product, and the industrial production is difficult

Method used

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  • Preparation method of dimemorfan phosphate, and preparation methods of dimemorfan phosphate intermediates
  • Preparation method of dimemorfan phosphate, and preparation methods of dimemorfan phosphate intermediates
  • Preparation method of dimemorfan phosphate, and preparation methods of dimemorfan phosphate intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Preparation of 2-(4-methylphenyl)-N-[(cyclohexen-1-yl)ethyl]acetamide

[0064] The reaction formula is as follows:

[0065]

[0066] At room temperature, 15.00 g of 2-(1-cyclohexenyl)ethylamine, 14.39 g of p-tolueneacetic acid and 86 mL of toluene were sequentially added to a 250 mL one-necked bottle, and the reaction solution was heated to 60° C. for 30 h. The reaction of the raw materials was detected by HPLC, and the reaction solution was concentrated under reduced pressure at 55° C. to obtain 23.58 g of an orange oil with a yield of 95.6%, which was directly used in the next reaction without purification.

Embodiment 2

[0068] Preparation of 2-(4-methylphenyl)-N-[(cyclohexen-1-yl)ethyl]acetamide

[0069] The reaction formula is as follows:

[0070]

[0071] At room temperature, 15.00 g of 2-(1-cyclohexenyl)ethylamine, 53.97 g of p-tolueneacetic acid and 345 mL of toluene were sequentially added to a 250 mL one-necked bottle, and the reaction solution was heated to 150° C. for reflux and water separation for 10 h. The reaction of the raw materials was detected by HPLC, and the reaction solution was concentrated under reduced pressure at 55° C. to obtain 30.70 g of an orange oil with a yield of 99.6%, which was directly used in the next reaction without purification.

Embodiment 3

[0073] Preparation of 1-(4-methylbenzyl)-3,4,5,6,7,8 hexahydroisoquinoline

[0074] The reaction formula is as follows:

[0075]

[0076] At room temperature, 15.00 g of 2-(1-cyclohexenyl)ethylamine, 21.59 g of p-tolueneacetic acid and 150 mL of toluene were sequentially added to a 250 mL one-necked bottle, and the reaction solution was heated to 135° C. for 15 h under reflux and water separation. It was detected by HPLC that the reaction of the raw materials was complete, the temperature of the reaction solution was lowered to 80° C., and 50.51 g of phosphorus oxychloride was added to the reaction solution. The reaction solution was warmed up to 105°C and refluxed for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 55° C. to obtain 28.50 g of an orange oil with a yield of 99.4%, which was directly used in the next reaction without purification.

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Abstract

The invention relates to a preparation method for dimemorfan phosphate and preparation methods of dimemorfan phosphate intermediates, and belongs to the field of pharmaceutical chemicals. The invention provides the synthesis method of the dimemorfan phosphate intermediate 2-(4-methylphenyl)-N-[(cyclohexen-1-yl)ethyl]acetamide. The 2-(4-methylphenyl)-N-[(cyclohexen-1-yl)ethyl]acetamide is preparedby reacting 2-(1-cyclohexenyl)ethylamine with p-methylphenylacetic acid. The invention also provides the synthesis method of the other dimemorfan phosphate intermediate 1-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline. The 1-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline is prepared by reducing 1-(4-methylbenzyl)-3,4,5,6,7,8-hexahydroisoquinoline. The invention also provides the preparation method for preparing dimemorfan phosphate from (9alpha,13alpha,14alpha)-3-methylmorphinan-17-carboxaldehyde. The invention further provides a total synthesis method for preparing dimemorfanphosphate from the intermediates. The methods have the advantages of mild reaction conditions, no dangerous reagents, obtaining of high-purity dimemorfan phosphate through a common salt forming reaction and recrystallization, simplicity in post-treatment, and suitableness for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and more specifically relates to a preparation method of dimethylorphane phosphate and an intermediate thereof. Background technique [0002] Dimemorfanphosphate is a non-addictive central cough suppressant listed by Japan Astellas Pharmaceutical Co., Ltd. The chemical name is (9α, 13α, 14α)-3,17-dimethylmorphinan phosphate, and its structural formula is as follows: [0003] [0004] The process listed in Japan uses 5,6,7,8-tetrahydroisoquinoline as the starting material, first reacts with methyl bromide to form quaternary ammonium salt, and then undergoes Grignard reaction, sodium borohydride reduction of double bonds, chiral resolution points, and finally prepared by Grewe cyclization reaction to obtain dimethylorphinyl phosphate. After repeating this route, the following disadvantages are found: 1) The starting material 5,6,7,8-tetrahydroisoquinoline is not easy to obtain, th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/11
CPCC07C231/02C07D217/02C07D221/28C07C2601/16C07C233/11Y02P20/55
Inventor 陈磊黎利军王仲清彭辉邓忠富罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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