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Novel method for preparing dextromethorphan

A compound and reaction technology, which is applied in the field of synthetic route design and preparation of raw materials and intermediates, can solve problems such as difficult to obtain, a large amount of waste liquid and residue, unsuitable for industrial production, etc.

Active Publication Date: 2014-10-29
SHANGHAI TIANCI INT PHARMA
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AI Technical Summary

Problems solved by technology

[0007] In the traditional synthetic route, the synthetic route with optically pure intermediate (VII) is via the racemic 1-(4-methoxy)benzyl-1,2,3,4,5,6,7, 8-hexahydroisoquinoline (Ⅴ-1) is obtained by chiral resolution. This method not only greatly reduces the yield, but also is complex and cumbersome to operate, and produces a large amount of waste liquid and waste residue, which is not conducive to environmental protection; Phenolic hydroxyl methylation treatment, commonly used highly toxic methylation reagents such as methyl iodide and dimethyl sulfate
It has also been reported to use special methylation reagents with good selectivity, such as trimethylphenylammonium hydroxide, but the special methylation reagents are expensive, difficult to obtain, low yield, and produce toxic substances N,N-dimethyl Aniline and other shortcomings, so it is not suitable for industrial production

Method used

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  • Novel method for preparing dextromethorphan
  • Novel method for preparing dextromethorphan
  • Novel method for preparing dextromethorphan

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preparation example Construction

[0098] In the method, the raw material can be obtained by any method, for example, it is prepared by the prior art, or it is purchased through commercial channels. In the present invention, the preferred preparation method comprises steps:

[0099] (1) In an inert solvent, react with a compound of formula (II) and a compound of formula (III) to obtain a compound of formula (IV):

[0100]

[0101] (2) In an inert solvent, carry out a ring-closing reaction with a compound of formula (IV) to obtain a compound of formula (V):

[0102]

[0103] Wherein, in the step (1), the reaction is preferably carried out in the presence of a condensing agent; and the condensing agent is selected from the group consisting of: O-(7-azabenzotriazole-1 -yl)-bis(dimethylamino)carbenium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbenium hexafluorophosphate (HBTU ), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbod...

Embodiment 1

[0178] (1) Preparation of N-(2-(1-ene-1-cyclohexyl)ethyl)-2-p-methoxyphenylacetamide (Ⅳ):

[0179] Add 4-methoxyphenylacetic acid (50.0g, 300.9mmol), cyclohexeneethylamine (37.7g, 300.9mmol) and dichloromethane (300ml) in a 500ml three-neck round bottom flask, stir for 15min, then place on ice The temperature was lowered to 0° C. in a water bath, and DIC (41.8 g, 331.0 mmol) and 4-N,N-lutidine (40.4 g, 331.0 mmol) were added. After stirring at room temperature for 10 h, the reaction was completed. Washed successively with 5% aqueous hydrochloric acid solution (30ml), 5% aqueous sodium carbonate solution (30ml), water (3x50ml) and brine (30ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give a light gray solid as N-(2 -(1-ene-1-cyclohexyl)ethyl)-2-p-methoxyphenylacetamide 78.2g, yield 95.0%

[0180] (2) Preparation of 1-(4-methoxy)benzyl-3,4,5,6,7,8-hexahydroisoquinoline (Ⅴ):

[0181] Add N-(2-(1-ene-1-cyclohexyl)ethyl)-2-p-methoxyphenylacetamide (IV)...

Embodiment 2

[0189] (1) Preparation of N-(2-(1-ene-1-cyclohexyl)ethyl)-2-p-methoxyphenylacetamide (Ⅳ):

[0190] Add 4-methoxyphenylacetic acid (30.0g, 180.5mmol), cyclohexeneethylamine (22.6g, 180.5mmol) and dichloromethane (200ml) in a 500ml three-neck round bottom flask, stir for 15min, then place on ice The temperature was lowered to 0° C. in a water bath, and DCC (40.9 g, 198.6 mmol) and 4-N,N-lutidine (24.3 g, 198.6 mmol) were added. After stirring at room temperature for 8 h, the reaction was completed. Washed successively with 5% aqueous hydrochloric acid (20ml), 5% aqueous sodium carbonate (20ml), water (3x30ml) and brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated to give off-white solid as N-(2 -(1-ene-1-cyclohexyl)ethyl)-2-p-methoxyphenylacetamide 44.4 g, yield 90.0%.

[0191] (2) Preparation of 1-(4-methoxy)benzyl-3,4,5,6,7,8-hexahydroisoquinoline (Ⅴ):

[0192]Add N-(2-(1-ene-1-cyclohexyl)ethyl)-2-p-methoxyphenylacetamide (Ⅳ) (30.0g, 109.7mmol) in ...

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Abstract

The invention relates to a novel method for preparing dextromethorphan. When the method is used for preparing an intermediate (+)-1-(4-methoxy) benzyl-1,2,3,4,5,6,7,8-hexahydroisoquinoline (VI), a catalytic reducing method is adopted to carry out chiral reduction on 1-(4-methoxy) benzyl-3,4,5,6,7,8-hexahydroisoquinoline (VI), so that the intermediate is prepared with high selectivity. The novel method disclosed by the invention can cancel complex operations such as chiral resolution, is simple to operate, gentle in reaction condition, short in total time, wide in material source, and very suitable for industrially producing dextromethorphan.

Description

technical field [0001] The invention relates to the technical field of synthetic route design and preparation of raw materials and intermediates, in particular, to a preparation method of a central antitussive drug dextromethorphan and an intermediate thereof. Background technique [0002] Dextromethorphan is a non-opioid central antitussive drug, which is the dextrorotary form of morphine-like levomorphol. Dextromethorphan inhibits reflex cough by directly acting on the cough center of the brain. It is a powerful central antitussive. It has the advantages of strong sex, quick onset, long duration and less side effects. In 1958, the U.S. Food and Drug Administration approved dextromethorphan to be sold as an antitussive without a doctor's prescription. At the same time, dextromethorphan is also one of the drugs that my country needs to focus on development. Its chemical structure is as follows: [0003] [0004] Chinese patent application CN201310041846, CN201310051880...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20C07C235/34C07C231/02C07D221/28
CPCC07C231/02C07C2601/16C07D217/20C07D221/28C07C235/34
Inventor 李新涓子李健之马西来池王胄刘海胡旭华郑肖利翟志军李建勋
Owner SHANGHAI TIANCI INT PHARMA
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