![((S)-1-tert-Butoxymethyl-2-methyl-propyl)-[1-[(S)-1-(4-methoxy-benzyl)-3,4,5,6,7,8-hexahydro-1H-isoquinolin-2-yl]-meth-(E)-ylidene]-amine](/Databaselist/images/loading.webp)
30356-07-1Relevant academic research and scientific papers
Imine Reductase-Catalyzed Enantioselective Reduction of Bulky α,β-Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton
Yao, Peiyuan,Xu, Zefei,Yu, Shanshan,Wu, Qiaqing,Zhu, Dunming
, p. 556 - 561 (2019)
The morphinan skeleton is an important sub-structure in many medicines such as dextromethorphan, and can be constructed from 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-benzyl-OHIQ) derivatives. 1-Benzyl-3,4,5,6,7,8-hexahydroisoquinolines (1-benzyl-HHIQs), the precursors of 1-benzyl-OHIQs, constitute a type of bulky α, β-unsaturated imines. Until now, the application of imine reductases (IREDs) to α, β-unsaturated imines has only rarely been reported. In this study, through evaluation of 48 IREDs, both enantiomers of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-(4-methoxybenzyl)-OHIQ) were obtained in high yield and excellent optical purity. Among the enzymes, the most steric hindrance-tolerant IRED from Sandarearacinus amylolyticus (IR40) was able to convert various phenyl substituted 1-benzyl-HHIQ to the corresponding 1-benzyl-OHIQ derivatives with excellent enantiometric excess. These results provide an effective route to synthesize these important compounds via enantioselective reduction of bulky α, β-unsaturated imine precursors, which can be readily prepared from 2-(1-cyclohexenyl)ethylamine and corresponding aryl acetic acids. (Figure presented.).
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
, 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.
A (S) or (R)- 1 - (4 - methoxybenzyl) - 1, 2, 3, 4, 5, 6, 7, 8 - quinoline of eight hydrogens different preparation method
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Paragraph 0064; 0066; 0072; 0074; 0076, (2018/03/01)
The invention discloses a preparation method of (S) or (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate, wherein the method includes the steps: (1) mixing an aromatic solution of a compound having a structure represented by the formula III with acetic acid, to obtain a solution 1; (2) adding a (S)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate seed crystal or a (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate seed crystal into the solution 1, to obtain a solution 2; and (3) cooling the solution 2 to 0-5 DEG C, crystallizing to obtain (S)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate or (R)-1-(4-methoxy benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline acetate.
Method for preparing (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline
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Paragraph 0009; 0013; 0015; 0017, (2018/09/08)
The invention discloses a method for preparing (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline which is a dextromethorphan intermediate. The method includes selectively hydrogenating 1-(4-methoxy benzyl)-3, 4, 5, 6, 7, 8-octahydro isoquinoline (II) under the condition of (R)-N-(5-fluorine-2-hydroxyl benzyl)-2-methylpropane-2-sulfinamide and trichlorosilane to obtain the (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline (I). The 1-(4-methoxy benzyl)-3, 4, 5, 6, 7, 8-octahydro isoquinoline (II) is used as a raw material, and the (R)-N-(5-fluorine-2-hydroxyl benzyl)-2-methylpropane-2-sulfinamide is used as an organic chiral ligand. The method has the advantages that the organic chiral ligand is used, and the raw material is inexpensive, safe, simpleand easily available; the reaction temperatures range from -20 DEG C to -15 DEG C, and accordingly the method can be implemented in industrial production; an ee (enantiomeric excess) value of the (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline which is a product can reach 63%.
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),
COMPOSITIONS AND METHODS FOR THE TREATMENT OF RESPIRATORY DISORDERS
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, (2015/03/31)
The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of respiratory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants, upper respiratory infections, (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis, neuropathic pain and pain associated with fibromyalgia.
COMPOSITIONS AND METHODS FOR THE TREATMENT OF RESPIRATORY DISORDERS
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, (2013/12/03)
The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of respiratory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants, upper respiratory infections, (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis, neuropathic pain and pain associated with fibromyalgia.
General asymmetric synthesis of isoquinoline alkaloids. Enantioselective hydrogenation of enamides catalyzed by BINAP-ruthenium(II) complexes
Kitamura,Hsiao,Ohta,Tsukamoto,Ohta,Takaya,Noyori
, p. 297 - 310 (2007/10/02)
In the presence of a small amount of RuX2[(R)- or (S)-BINAP] (X = anionic ligand) a wide range of (Z)-2-acyl-1-benzylidene-1,2,3,4- tetrahydroisoquinolines are hydrogenated to give the saturated products in nearly quantitative yields and in high (up to 100%) optical yields. The enamide substrates are selectively prepared by N-acylation of the corresponding 1-benzylated 3,4-dihydroisoquinolines under suitable acylation conditions; some crystalline materials having low solubility are obtained by a second-order Z/E stereomutation technique utilizing the double-bond photolability and lattice energy effects. This asymmetric hydrogenation sets the key stereogenic center in a predictable manner, either R or S flexibly, at the C(1) position of the benzylated tetrahydroisoquinolines. The chiral products are converted by standard functional group modification to tetrahydropapaverine, laudanosine, tretoquinol, norreticuline, etc. Hydrogenation of the simple 1-methylene substrate is used for synthesis of salsolidine. This enantioselective hydrogenation is applied to the synthesis of morphine and its artificial analogues such as morphinans and benzomorphans of either chirality. A mnemonic device is presented for predicting the reactivity and enantiofacial selection of the BINAP-Ru catalyzed hydrogenation. Reaction with BINAP-Rh catalyst proceeds with a lower enantioselectivity and an opposite sense of asymmetric induction.
