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Preparation method of dimethylmorphinan phosphate used as cough medicine

A technology of dimethylorphantyl phosphate and dichloromethane, which is applied in the direction of organic chemistry, can solve the problems of low chiral resolution yield, high production cost, and many process steps, and achieve the reduction of chiral resolution process and production The effect of short cycle and simple process

Inactive Publication Date: 2011-11-16
HANGZHOU BAOLING GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are many steps in this process, the price of several materials used is relatively expensive, chiral resolution is required in the middle, and the yield is low, and it needs many times in subsequent refining Desalination, extraction, and salt formation lead to high final production costs

Method used

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  • Preparation method of dimethylmorphinan phosphate used as cough medicine
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  • Preparation method of dimethylmorphinan phosphate used as cough medicine

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preparation example Construction

[0029]The preparation method of dimetyl phosphate of the present invention, the method is: (S)-1-(4-methylbenzyl)-1,2,3,4,5,6,7,8-eight De-L-mandelic acid of hydroisoquinoline-L-mandelic acid to obtain (S)-l-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydro Isoquinoline, using (S)-l-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline chiral substance as raw material for methylation , and then undergo a ring-forming reaction with phosphoric acid under heating and reduced pressure to obtain (9S, 13S, 14S)-3,17-dimethylmorphinan monophosphate with three chiral centers, that is, dimethylmorphanyl phosphate , and then go through desalination, rectification, crystallization, salt formation, drying and packaging, and finally obtain the refined product of dimethylorphane phosphate.

[0030] The (S)-l-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline-L-mandelate, the chirality used The protective reagent can also be one of L-tartaric acid, L-(+)-dimethyl tartrate, L-(+)-ethyl ma...

Embodiment 1

[0041] Add 100g of L-D-3 mandelate, 400ml of water and 400ml of dichloromethane into a 1000ml three-necked flask, stir for 0.5h, then add 150g of 10% aqueous sodium bicarbonate solution dropwise, continue stirring for 1h, separate layers and concentrate. Then add 400ml of ethanol, 25g of paraformaldehyde and 8g of 5% palladium carbon, and feed hydrogen to maintain a certain pressure. After reacting for 10 hours, filter and concentrate, then add 200g of phosphoric acid, heat up to 120°C and evaporate water under reduced pressure, keep warm for 50 hours, adjust pH to 8 with ammonia water, extract with 400ml of dichloromethane, and concentrate. In high vacuum, rectification under the condition of 170 ℃. Add 5g of phosphoric acid to finally obtain 25g of white crystals with a content of 99.2%.

Embodiment 2

[0043] Add 100g of L-D-3 mandelate, 400ml of water and 400ml of dichloromethane into a 1000ml three-necked flask, stir for 0.5h, then add 250g of 10% aqueous sodium carbonate solution dropwise, continue stirring for 1h, separate layers and concentrate. Then add 400ml of ethanol, 30g of paraformaldehyde and 7g of 5% palladium carbon, and feed hydrogen to maintain the pressure. After reacting for 22 hours, filter, concentrate, add 300g of phosphoric acid, heat up to 110°C and evaporate water under reduced pressure, keep warm for 40-80h, adjust pH to 9 with ammonia water, extract with 400ml of dichloromethane, and concentrate. In high vacuum, rectification under the condition of 170 ℃. Add 10g of phosphoric acid to finally obtain 52g of white crystals with a content of 99.5%.

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Abstract

The invention discloses a preparation method of dimethylmorphinan phosphate used as a cough medicine. The method comprises the following steps: removing L-mandelic acid from (S)-l-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline-L-mandelate to obtain (S)-l-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, performing methylation by using the (S)-l-(4-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline chiral material as a raw material, and then performing cyclization reaction together with phosphoric acid under the conditions of heating and decompression to obtain (9S,13S,14S)-3,17-dimethylmorphinan monophosphate with three chiral centers, namely dimethylmorphinan phosphate; and desalting, rectifying, crystallizing, salifying, drying, and packaging to obtain the refined dimethylmorphinan phosphate product. The method has the characteristics of simple process, low cost, high yield, high product purity, short production cycle and the like, thereby being a synthetic route suitable for industrial mass production.

Description

technical field [0001] The invention relates to a method for preparing a non-addictive central antitussive drug dimethylorphin phosphate, which inhibits the cough center of the medulla oblongata, and belongs to the technical field of drug synthesis. Background technique [0002] Phosphate ( Dimemorfan 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. The advantages are low toxicity, high safety, no inhibition of respiration in the therapeutic dose, and no side effect of 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 product is small, the syrup made into it has a good taste, and children have good drug compliance. Its chemical na...

Claims

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Application Information

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IPC IPC(8): C07D221/28
Inventor 虞英民陈丹龙沈文忠胡晓岚
Owner HANGZHOU BAOLING GROUP CO LTD
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