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The preparation method of dextromethorphan

A technology of dextromethorphan and white solid, which is applied in the field of preparation of dextromethorphan, can solve the problems of high price of trimethylphenyl ammonium hydroxide, increased production cost of dextromethorphan, and difficulty in obtaining it, so as to promote economic and technological development Effect

Active Publication Date: 2015-08-26
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the high price of trimethylphenylammonium hydroxide and its difficulty in obtaining, the yield of methylation is only about 50%, thus greatly increasing the production cost of dextromethorphan
More prominently, the by-product of this reaction, N,N-dimethylaniline, is a genotoxic substance, and its residual amount will directly affect the quality of raw materials

Method used

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  • The preparation method of dextromethorphan
  • The preparation method of dextromethorphan
  • The preparation method of dextromethorphan

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: Intermediate (II) (25.7 g, 0.1 mol), 40% formaldehyde (15.0 g, 0.2 mol) and 200 mL of methanol were sequentially added into a 500 mL three-necked flask, and reacted with slow stirring for 12 hours. Transfer the reaction solution into a hydrogenation reactor, add 3 g of Raney nickel, keep room temperature and a pressure of 2-4 kg, react for 4 hours, and TLC detects that the reaction is complete. The catalyst was recovered by filtration, the mother liquor was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 22.5 g of off-white solid dextromethorphan (I), with a yield of 83.0%.

Embodiment 2

[0022] Embodiment two: add intermediate (II) (25.7g, 0.1mol), paraformaldehyde (6.0g, 0.2mol), solid potassium carbonate (13.8g, 0.1mol), methanol 150mL and Add 50 mL of water, raise the temperature to 65-75°C, and start stirring to react for 6 hours. The reaction solution was transferred to a hydrogenation reactor, 3 g of palladium carbon was added, the temperature was raised to 40-45° C., and the pressure was maintained at 2-4 kg, and the reaction was carried out for 6 hours, and the reaction was detected by TLC. The catalyst was recovered by filtration, the mother liquor was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 23.8 g of off-white solid dextromethorphan (I), with a yield of 87.8%.

Embodiment 3

[0023] Example 3: Add intermediate (II) (25.7 g, 0.1 mol), sodium methoxide (10.8 g, 0.2 mol), and 150 mL of methyl formate to a 500 mL three-necked flask in sequence, raise the temperature to 50-55 ° C, and stir the reaction 6 After 1 hour, TLC detected that the reaction was over. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol. Sodium borohydride (4.6 g, 0.12 mol) was added in batches, and the reaction was carried out at room temperature for 12 hours, and the reaction was detected by TLC. The mother liquor was concentrated, and the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water to neutrality, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, and recrystallize the residue from methanol to obtain 21.6 g of off-white solid dextromethorphan (I), with a yield of 79.6%.

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Abstract

The invention discloses a method for preparing dextromethorphan (I), which comprises the following steps: performing N-methylation by an intermediate ent-3-methoxymorphinan (II) to generate the dextromethorphan (I). The preparation method is simple and convenient, and favorable for reducing the production cost of the dextromethorphan and can improve the quality of the product.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis method design and preparation of raw materials and intermediates, and in particular relates to a preparation method of dextromethorphan. Background technique [0002] Dextromethorphan ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphan, I) is the dextroisomer of morphine-like levomorphan methyl ether, which inhibits It is a powerful central antitussive drug whose antitussive strength is equal to or slightly stronger than that of codeine. Due to the low drug resistance and addiction of this variety, it is an antitussive drug suitable for long-term use or high-dose use. The drug has been included in the pharmacopoeia of many countries, and it is also one of the varieties that my country needs to focus on in this field. [0003] [0004] The current preparation of dextromethorphan is mostly through the following method: the optically pure intermediate (+)-1-(4-methoxy)benzyl-1,2,3,4,5,6,7,8-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/28
Inventor 许学农苏健王喆冷秀云
Owner SUZHOU LIXIN PHARMA
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