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Preparation method of dimemorfan phosphate intermediate

A technology of dimethylphenone phosphate and an intermediate, applied in the field of chemical pharmacy, can solve the problems of unfavorable operation, easy moisture absorption, difficult white flocs and the like, and achieves the effects of ingenious conception, cost reduction and simple process

Inactive Publication Date: 2013-09-11
SICHUAN BAILI PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] After a lot of experiments, we found that the method of the patent US3786054 is not conducive to industrial production: 1. The quaternary ammonium salt (II) in the route is very easy to absorb moisture in the air, which is not conducive to operation, and the moisture has a great influence on the next step of the Grignard reaction 2. After the Grignard reaction is completed, a large number of complicated operations such as filtration, extraction, pickling, and alkali washing are required, and a large amount of insoluble white flocs are formed during extraction, which is difficult to separate layers, and the obtained compound ( III) The yield is very low; 3, the yield of this method is low, only 22.6%

Method used

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  • Preparation method of dimemorfan phosphate intermediate

Examples

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Embodiment 1

[0032] Example 1: Under the protection of nitrogen, 30kg (225mol) of 5,6,7,8-tetrahydroisoquinoline and 193kg of tetrahydrofuran were added to the reaction kettle, the temperature was lowered to -15~-10°C, and the reaction solution was directly passed 25.7 kg (270 mol) of methyl bromide was added and reacted for 4 hours. The solvent in the upper layer was extracted, and tetrahydrofuran was added for replacement twice, 49 kg each time. 270 mol of newly prepared p-methylbenzylmagnesium chloride was added, and the reaction was stirred for 4 hours. Add 160kg of methanol to the reaction solution, and then add 7kg of sodium borohydride, and react at 10-30°C for 8 hours. The reaction solution was centrifugally filtered, the filtrate was concentrated to dryness, 160kg of water and 70kg of ethyl acetate were added, the layers were stirred, the water layer was extracted with ethyl acetate 60kg×3, the organic phases were combined, washed with saturated brine 20kg×2, and 30kg of anhydrou...

Embodiment 2

[0033] Example 2: Under the protection of nitrogen, 20.3kg (152.2mol) of 5,6,7,8-tetrahydroisoquinoline and 90kg of tetrahydrofuran were added to the reactor, cooled to -5~0°C, and directly added to the reaction solution 30 kg (273 mol) of methyl bromide was introduced and reacted for 5 hours. The solvent in the upper layer was drawn off, and tetrahydrofuran was added to replace it 3 times. 182 mol of newly prepared p-methylbenzylmagnesium chloride was added, and the reaction was stirred for 3.5 hours. Add 120kg of methanol to the reaction solution, and then add 4.7kg of sodium borohydride, and react at 10-30°C for 8 hours. The reaction solution was centrifugally filtered, the filtrate was concentrated to dryness, 120kg of water and 60kg of ethyl acetate were added, the layers were stirred, the water layer was extracted with 40kg of ethyl acetate x 3, the organic phases were combined, washed with 12kg of saturated brine, and 20kg of anhydrous Dry over sodium sulfate, filter,...

Embodiment 3

[0035] Under the protection of nitrogen, 30.2kg (225mol) of 5,6,7,8-tetrahydroisoquinoline and 120kg of tetrahydrofuran were added to the reaction kettle, and the temperature was lowered to -15~-10°C. 27.8 kg (292 mol) of methyl bromide was introduced and reacted for 5 hours. The solvent in the upper layer was drawn off, and tetrahydrofuran was added for replacement 3 times until TLC showed that there was no raw material point. Add 405 mol of newly prepared p-methylbenzylmagnesium chloride, and stir for 4 hours. Add 162kg of methanol to the reaction solution, then add 7.1kg of sodium borohydride, and react overnight at 10-30°C (about 16 hours). The reaction solution was centrifugally filtered, the filtrate was concentrated to dryness, 120kg of water and 80kg of ethyl acetate were added, the layers were stirred, the water layer was extracted with 40kg of ethyl acetate × 3, the organic phases were combined, washed with 20kg of saturated brine, and 30kg of anhydrous sodium sulfa...

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Abstract

The invention discloses a preparation method of an dimemorfan phosphate intermediate, which comprises the following steps: reacting 5,6,7,8-tetrahydroisoquinoline with bromomethane to obtain quaternary ammonium salt; without separating the product from the solvent, directly carrying out Grignard reaction on the product and p-methylbenzyl magnesium chloride in the solvent to obtain 1-(4-methylbenzyl)-2-methyl-1,2,5,6,7,8-hexahydroisoquinoline; without separating the product from the solvent, directly reducing the product with sodium borohydride, centrifuging, concentrating, extracting, drying and the like to obtain dl(4-methylphenyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (IV); and resolving with L-tartaric acid to obtain the intermediate d-(4-methylbenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline L-tartrate (V). The invention can easily implement industrial production, and greatly enhances the yield; and the obtained intermediate has higher purity, and can be continuously reacted to obtain high-purity dimemorfan phosphate.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a preparation method of a non-addictive central antitussive drug dimethylorphin phosphate intermediate. Background technique [0002] Dimemorfan phosphate, the chemical name is (9α,13α,14α)-3,17-dimethylmorphinan phosphate, and its structural formula is as follows: [0003] . [0004] Dimethorphan phosphate is a non-addictive central antitussive drug, and its antitussive effect is slightly better than that of dextromethorphan, which is about twice that of codeine. It has the advantages of low toxicity, high safety, no inhibition of respiration in the therapeutic dose, and no side effects such as constipation. Dimethylorphantyl phosphate has been on the market in Japan for more than 30 years and no serious adverse reactions have been reported. It has a definite curative effect and is safe and reliable. It is suitable for children to take. Because the dosage of this pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04
Inventor 王一茜戚太林
Owner SICHUAN BAILI PHARM CO LTD
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