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Preparation method of dimemorfan phosphate

A technology of dimethylphene phosphate and phosphoric acid, which is applied in the field of preparing non-addictive central antitussive drug dimethylphene phosphate, can solve the problems of general yield and the like, and achieves high product purity, low cost and concise process route. Effect

Inactive Publication Date: 2018-09-04
HEFEI IND PHARMA INST +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The starting material of this process, dextromorphan, is rarely commercially available, and two-step reactions are required to produce dimethylmorpholane, resulting in a general yield (about 60-70% of the total yield)

Method used

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  • Preparation method of dimemorfan phosphate
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  • Preparation method of dimemorfan phosphate

Examples

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Embodiment 1

[0036] Under the protection of nitrogen, the starting material 3-methoxy-17-methyldextromorphan (5.71g, 20mmol) and bis(tricyclohexylphosphine)nickel dichloride (0.70g, 1mmol) were added to 100ml of toluene and stirred Dissolve, heat up to 65°C, add methylmagnesium bromide (tetrahydrofuran solution) (1mol / L, 20ml, 20mmol) dropwise, complete the dropwise addition and keep warm for reaction, TLC detects that the raw materials are cooled to room temperature after the reaction is completed, add dropwise a small amount of saturated chloride Quench the reaction with ammonium solution, add water to wash and separate the layers, and separate the organic layer; wash the organic layer with saturated brine, and then dry it, then distill off the toluene under reduced pressure to obtain dimerphane; without purification, directly add 25ml of 95% ethanol and stir at room temperature to dissolve , and then add 85% phosphoric acid (2.3g, 20mmol) to react and precipitate a white solid, which is ...

Embodiment 2

[0038] Under nitrogen protection, the starting material 3-methoxy-17-methyldextromorphan (5.71g, 20mmol) and bis(tricyclohexylphosphine)nickel dichloride (0.14g, 0.2mmol) were added in 100ml of toluene Stir to dissolve, raise the temperature to 65°C, add methylmagnesium bromide (tetrahydrofuran solution) (1mol / L, 20ml, 20mmol) dropwise, and keep warm for reaction after the dropwise addition, after the reaction is detected by TLC. Subsequent reaction was carried out according to the method of Example 1 to obtain 3.76 g of dimethylorphinyl phosphate, with a yield of 53.3% and a purity of 93.7%.

Embodiment 3

[0040] Under the protection of nitrogen, the starting material 3-methoxy-17-methyldextromorphan (5.71g, 20mmol) and bis(tricyclohexylphosphine)nickel dichloride (0.70g, 1mmol) were added to 100ml of toluene and stirred Dissolve, heat up to 65°C, add methylmagnesium bromide (tetrahydrofuran solution) (1mol / L, 60ml, 60mmol) dropwise, complete the dropwise insulation reaction, after TLC detects that the raw materials have reacted, carry out subsequent reactions according to the method of Example 1 to obtain 5.51 g of dimetyl phosphate, yield 78.1%, purity 97.4%.

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a non-addictive central antitussive dimemorfan phosphate. The method is characterized by: taking the basic group dextromethorphan of the drug dextromethorphan hydrobromide marketed for years as the starting raw material, conducting methoxymethylation, and then salifying the product with phosphoric acid to obtain dimemorfan phosphate. The method provided by the invention has the advantages of concise process route, high product purity and low cost, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for preparing the non-addictive central antitussive drug dimethylorphin phosphate. Background technique [0002] Dimethylorphantyl phosphate was developed by Fujisawa Pharmaceutical Co., Ltd. in Japan. It was first launched in Japan in 1974. There have been no reports of serious adverse reactions in clinical application for many years. It has definite curative effect and is safe and reliable. At present, it has not been approved for marketing in China, and there is no import, so there is a certain market prospect for the development of this product in China. The chemical name of dimethylmorphan phosphate is (9S,13S,14S)-3,17-dimethylmorphanophosphate, and its chemical structure is as follows: [0003] [0004] See the original research company literature Chem.Pharm.Bull.1972,20(8),1706-1710 and patent US3786054, the preparation process of dimethylorphin phosphate l...

Claims

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Application Information

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IPC IPC(8): C07D221/28
CPCC07D221/28
Inventor 何广卫刘为中王奎李鑫源
Owner HEFEI IND PHARMA INST
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