51072-36-7Relevant academic research and scientific papers
Racemization recovery method of dextromethorphan hydrobromide intermediate byproducts
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, (2021/01/25)
A racemization recovery method of dextromethorphan hydrobromide intermediate byproducts comprises the following steps: 1) performing mother liquor treatment: under a stirring condition, carrying out reduced pressure distillation until methanol is basically evaporated completely, when the temperature of the concentrated mother liquor is lower than 40 DEG C, adding a sodium hydroxide solution, stirring, standing, detecting that the pH value is greater than 12, layering, recovering mandelic acid by using the obtained water phase, concentrating the obtained oil phase under reduced pressure until toluene is completely evaporated, and cooling to 65-80 DEG C; 2) performing N-chlorination: adding isopropanol, and dropwise adding a sodium hypochlorite solution; 3) performing racemization: adding liquid caustic soda into the reaction system, and stirring for reaction; 4) reducing: dropwise adding a sodium borohydride solution, and reacting completely; 5) performing chiral resolution: adding methanol and D-mandelic acid into the toluene solution of a compound (I), and carrying out chiral resolution; and (6) refining the mother liquor: treating the mother liquor obtained in step (5) as a raw material according to the treatment methods in steps (1)-(4) to obtain a mother liquor prepared compound (I) methylbenzene solution, and adding oxalic acid for refining.
Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight
Chen, Fener,Huang, Zedu,Li, Zhining,Lin, Juan,Wang, Jiaqi,Wang, Zexu,Wu, Xiaofan
supporting information, p. 5598 - 5614 (2020/05/19)
(S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline [(S)-1-(4-methoxybenzyl)-OHIQ, (S)-1a] is a key synthetic intermediate in the industrial production of dextromethorphan, one of the most widely used over-the-counter antitussives. We report here that a new cyclohexylamine oxidase discovered by genome mining, named CHAOCCH12-C2, was able to completely deracemize 100 mM 1a under Turner's deracemization conditions to afford (S)-1a in 80% isolated yield and 99% ee at a semipreparative scale (0.4 mmol). When this biocatalytic reaction was scaled up to a gram scale (5.8 mmol), without reaction optimization (S)-1a was still isolated in 67% yield and 96% ee. The relatively higher kcat determined for CHAOCCH12-C2 was rationalized as one major factor rendering this enzyme capable of oxidizing 1a effectively at elevated substrate concentrations. Protein sequence alignment, analysis of our co-crystal structure of CHAOCCH12-C2 complexed with the product 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline [1-(4-methoxybenzyl)-HHIQ, 2a], and the structure-guided mutagenesis study together indicated L295 is one of the critical residues for this efficient enzymatic oxidation process and supported the presence of two cavities as well as a catalytically important "aromatic cage" formed by F342, Y433, and FAD. The synthetic applicability of CHAOCCH12-C2 was further underscored by the stereoselective synthesis of various enantioenriched 1-benzyl-OHIQ derivatives of potential pharmaceutical importance at a semipreparative scale.
AN IMPROVED PROCESS FOR THE PREPARATION OF BUTORPHANOL TARTRATE
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, (2017/11/03)
The present invention relates to an improved process for the preparation of Butorphanol tartrate of formula (I),
Method for preparing levallorphan tartrate
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, (2017/08/29)
The invention provides a method for preparing levallorphan tartrate and belongs to the technical field of drug and chemical synthesis. The method takes methoxyphenylacetic acid and 2-(cyclohexenyl)ethylamine as initial raw materials, and comprises nine reaction steps such as acylation condensation, Bischler-Napieralski ring formation reaction, imine reduction, ether bond hydrolysis, resolution, N-alkylation, Grewe cyclization reaction, and salifying. According to the method, the levallorphan tartrate and each intermediate can be obtained at high yield and high purity, and the method can serve as an industrial method for performing large-scale production.
Racemization recycling method for byproduct in resolution mother liquor of dextromethorphan hydrobromide midbody
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Paragraph 0059; 0060, (2017/01/17)
The invention relates to a racemization recycling method for a resolution byproduct in a dextromethorphan hydrobromide midbody 1,2,3,4,5,6,7,8-octahydro-1-[(4-methoxy phenyl) methyl] isoquinoline. The racemization recycling method is characterized by comprising the following steps: (1) resolving racemic 1,2,3,4,5,6,7,8-octahydro-1-[(4-methoxy phenyl) methyl] isoquinoline by using D-mandelic acid or D-tartaric acid so as to obtain D-mandelic acid or D-tartrate and 1,2,3,4,5,6,7,8-octahydro-R-1-[(4-methoxy phenyl) methyl] isoquinoline of a 1,2,3,4,5,6,7,8-octahydro-S-1-[(4-methoxy phenyl) methyl] isoquinoline compound; (2) oxidizing the 1,2,3,4,5,6,7,8-octahydro-R-1-[(4-methoxy phenyl) methyl] isoquinoline so as to obtain 1,2,3,4,5,6,7,8-octahydro-1-[(4-methoxy phenyl) methyl] isoquinoline; (3) reducing the 1,2,3,4,5,6,7,8-octahydro-1-[(4-methoxy phenyl) methyl] isoquinoline, thereby obtaining the dextromethorphan midbody 1,2,3,4,5,6,7,8-octahydro-1-[(4-methoxy phenyl) methyl] isoquinoline. The racemization recycling method for the byproduct, namely, a levogyration midbody of dextromethorphan, is gentle in condition, simple and convenient to operate and small in material consumption.
Process for the optical resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline
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Paragraph 0032, (2013/09/11)
The resolution of racemic 1-(4-methoxybenzyl)-octahydro-isoquinoline, a key intermediate in the synthesis of the antitussive agent dextromethorphan, is reported using (R)-2-(6-methoxy-2-naphthyl) propionic acid in good yields. The resolving agent and the undesired isomer of the octahydro-isoquinoline have been recovered in good yield.
Resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline
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Page/Page column 9, (2012/04/10)
The resolution of racemic 1-(4-methoxybenzyl)-octahydro-isoquinoline, a key intermediate in the synthesis of the antitussive agent dextromethorphan, is reported using (R)-2-(6-methoxy-2-naphthyl) propionic acid in good yields. The resolving agent and the undesired isomer of the octahydro-isoquinoline have been recovered in good yield.
Optically active 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinolinium acetates
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, (2008/06/13)
Racemic 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline can be resolved by seeding the supersaturated solution of racemic 1-(4-methoxybenzyl)-octahydroisoquinolinium acetate with its enantiomeric forms and crystallizing the optically active acetate corresponding to the configuration of the seed crystals. The continuous form of the process permits obtaining the two enantiomers together.
Process of N-demethylating (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
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, (2008/06/13)
N-Alkyl allylic tertiary amines are dealkylated as illustrated by treatment of (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline in cold methylene chloride with m-chloroperbenzoic acid followed by the addition of aqueous ferrous chloride to provide a good yield of (+)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline with substantial if not complete retention of optical activity. The product is an intermediate in a synthesis of the analgesic known as butorphanol.
