cas 118864-75-8, (1S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline

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Asymmetric Transfer Hydrogenation of 1-Aryl-3,4-Dihydroisoquinolines Using a Cp*Ir(TsDPEN) Complex
We report herein a simple alternative method for the asymmetric transfer hydrogenation (ATH) of 1-aryl-3,4-dihydroisoquinolines (1-Ar-DHIQs) that are known to be challenging substrates owing to their poor reactivity. The hydrogenation protocol employs the
Václavíková Vilhanová, Bea,Budinská, Alena,Václavík, Ji?í,Matou?ek, Václav,Kuzma, Marek,?erveny, Libor
p. 5131 - 5134
(2017)
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Stereoselective Total Syntheses of Solifenacin and N -Acetyl-1-(4-chloro-phenyl)-6,7-dimethoxytetrahydroisoquinoline
A highly stereoselective synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinoline drugs such as solefinacin (muscarinic acetylcholine receptor antagonist) and N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxytetrahydroisoquinoline (AMPA receptor antagonist) has been accomplished using (R)-tert-butanesulfinamide as a chiral source. Chiral tetrahydroisoquinolines have been prepared through the aryl Grignard addition to chiral N-sulfinylimines followed by haloamide cyclization.
Babu, R. Anji,Reddy, N. Siva Senkar,Reddy, B. Jagan Mohan,Reddy, B. V. Subba
p. 2794 - 2798
(2014)
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The development of an asymmetric hydrogenation process for the preparation of solifenacin
The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4- dihydroisoquinoline to 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl] 2-(S)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1-2 equiv of H3PO4, 60 °C, 20 bar H2, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).
Ruzic, Milos,Pecavar, Anica,Prudic, Darja,Kralj, David,Scriban, Corina,Zanotti-Gerosa, Antonio
p. 1293 - 1300
(2012)
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Directed evolution of artificial metalloenzymes: Genetic optimization of the catalytic activity
Artificial metalloenzymes (ArMs) based on the incorporation of a biotinylated metal cofactor within a streptavidin (Sav) combine attractive features of both enzymatic and homogeneous catalysis. To speed up their optimization, we present a directed evolution of an artificial transfer hydrogenase (ATHase) based on a streamlined and optimized protocol for the design, overexpression and screening of Sav isoforms. Ten positions have been subjected to mutagenesis to yield two variants with improved catalytic activity and selectivity for the reduction of cyclic imines, along with greater stability in a biphasic medium.
Hestericová, Martina
p. 189 - 192
(2018)
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Enantioselective synthesis of 1-Aryl-substituted tetrahydroisoquinolines employing imine reductase
Tetrahydroisoquinolines (THIQs) with a C1-aryl-substituted groups are common in many natural and synthetic compounds of biological importance. Currently, their enantioselective synthesis are primarily reliant on chemical catalysis. Enzymatic synthesis using imine reductase is very attractive, because of the cost-effectiveness, high catalytic efficiency, and enantioselectivity. However, the steric hindrance of the 1-aryl substituents make this conversion very challenging, and current successful examples are mostly restricted to the simple alkyl-THIQs. In this report, through extensive evaluation of a large collection of IREDs (including 88 enzymes), we successfully identified a panel of steric-hindrance tolerated IREDs. These enzymes are able to convert meta- and para-substituted chloro-, methyl-, and methoxyl-benzyl dihydroisoquinolines (DHIQs) into corresponding R- or S- THIQs with very high enantioselectivity and conversion. Among them, the two most hindrance-tolerated enzymes (with different stereospecificity) are also able to convert ortho-substituted chloro-, methyl-, and methoxyl-benzyl DHIQs and dimethoxyl 1-chlorobenzyl-DHIQs with good enantiometric excess. Furthermore, using in silico modeling, a highly conserved tryptophan residue (W191) was identified to be critical for substrate accommodation in the binding cavity of the S-selective IRED (IR45). Replacing W191 with alanine can dramatically increase the catalytic performance by decreasing the Km value by 2 orders of magnitude. Our results provide an effective route to synthesize these important classes of THIQs. Moreover, the disclosed sequences and substrate binding model set a solid basis to generate more-efficient and broad-selective enzymes via protein engineering.
Zhu, Jinmei,Tan, Hongqun,Yang, Lu,Dai, Zheng,Zhu, Lu,Ma, Hongmin,Deng, Zixin,Tian, Zhenhua,Qu, Xudong
p. 7003 - 7007
(2017)
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Synthesis and characterization of S(-)1-phenyl-1,2,3,4-tetrahydro isoquinoline acetamide analogues
S(-)1-Phenyl-1,2,3,4-tetrahydro isoquinoline acetamide analogues are prepared by sequence of reactions which involve a metal hydride reduction of 3,4-dihydroisoquinoline followed by separation of S-form with mandelic acid (chiral reagent) by resolution. The product S(-)1-phenyl-1,2,3,4-tetrahydro isoquinoline is treated with halosubstituted acetyl chlorides to obtain tetrahydro isoquinoline acetyl chloride which is further employed to synthesize acetamide derivatives of tetrahydro isoquinoline using various substituted aryl amines. The products were characterized by advanced spectroscopic techniques.
Krishna Rao,Surendra Babu,Basaveswara Rao,Keshavi,Sundara Rao,Eswara Prasad,Murthy
p. 1035 - 1038
(2017)
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Ferritin encapsulation of artificial metalloenzymes: Engineering a tertiary coordination sphere for an artificial transfer hydrogenase
Ferritin, a naturally occuring iron-storage protein, plays an important role in nanoengineering and biomedical applications. Upon iron removal, apoferritin was shown to allow the encapsulation of an artificial transfer hydrogenase (ATHase) based on the streptavidin-biotin technology. The third coordination sphere, provided by ferritin, significantly influences the catalytic activity of an ATHase for the reduction of cyclic imines.
Hestericová, Martina,Heinisch, Tillmann,Lenz, Markus,Ward, Thomas R.
p. 10837 - 10841
(2018)
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The absolute configuration of (1S)-(+)- and (1R)-(-)1-phenyl-1,2,3,4-tetrahydroisoquinoline. A revision of the literature assignment
The title compounds (S)-(+)-8 and (R)-(-)-8 have been prepared by an asymmetric synthesis that is based on stereoselective additions to the chiral N-acylisoquinoliniumion 3. The absolute configuration of these compounds has been determined by an X-ray analysis performed on the intermediate 5. According to the results of this study the stereochemical assignment for (S)-(+)-8 and (R)-(-)-8 described in the literature has to be revised.
Ludwig, Matthias,Beer, Herbert,Lotter, Hermann,Wanner, Klaus Th.
p. 2693 - 2695
(1997)
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Low-Temperature Nickel-Catalyzed C?N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand
The transition-metal-catalyzed C?N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as ?50 °C), enantioselective Ni-catalyzed C?N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2-symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.
Hong, Xin,Shi, Shi-Liang,Wang, Zi-Chao,Xie, Pei-Pei,Xu, Youjun
supporting information
p. 16077 - 16084
(2021/06/17)

Asymmetric Transfer Hydrogenation of Unhindered and Non-Electron-Rich 1-Aryl Dihydroisoquinolines with High Enantioselectivity
The use of arene/Ru/TsDPEN catalysts bearing a heterocyclic group on the TsDPEN in the asymmetric transfer hydrogenation (ATH) of dihydroisoquinolines (DHIQs) containing meta- or para-substituted aromatic groups at the 1-position results in the formation of products of high enantiomeric excess. Previously, only 1-(ortho-substituted)aryl DHIQs, or with an electron-rich fused ring gave products with high enantioselectivity; therefore, this approach solves a long-standing challenge for imine ATH.
Barrios-Rivera, Jonathan,Xu, Yingjian,Wills, Martin
supporting information
p. 6283 - 6287
(2020/09/02)

Preparation method of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
The invention discloses a preparation method of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. Benzophenone and aminoacetaldehyde dimethyl acetal are used as raw materials, which carry out a reaction under a heating condition to obtain N-(diphenylmethylene)-2,2-dimethoxyethylamine; N-(diphenylmethylene)-2,2-dimethoxyethylamine carries out cyclization under an acid heating condition to obtain 1-phenylisoquinoline, 1-phenylisoquinoline is reduced by using a Pd/C or Ni catalyst to obtain racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline, and finally 1-phenyl-1,2,3,4-tetrahydroisoquinoline is split byL-mandelic acid to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. Compared with the prior art, benzophenone and aminoacetaldehyde dimethyl acetal are creatively and directly used for reaction,the raw materials are cheap and easy to obtain, and the production cost is greatly reduced. Phosphorus-containing wastewater is not generated, so that the preparation method is safer and more environment-friendly; L-mandelic acid is used for replacing traditional tartaric acid, the crystallization speed is high, the yield is high, the splitting efficiency is improved, and the production period isshortened.
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(2020/11/26)

(S)1-phenyl-1,2,3,4-tetrahydroisoquinoline synthesis method
The invention relates to a (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline synthesis method, wherein the reaction route is defined in the specification. The synthesis method comprises: 1) dissolving a rawmaterial 1 in a solvent, and adding an alkali and a catalyst; and (2) carrying out gas replacement by using hydrogen to form a hydrogen atmosphere, and carrying out an pressurization reaction to obtain (S)1-phenyl-1,2,3,4-tetrahydroisoquinoline 2, wherein the catalyst is a BIAMH system catalyst, a D-BIMAH system catalyst or a P-BIMAH system catalyst.
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Paragraph 0040-0076

(2020/02/08)

Synthesis method of (S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline
The invention relates to a synthetic method of (S) 1-phenyl -1, 2, 3, 4-tetrahydroisoquinoline. The method comprises the following steps: mixing 1-phenyl-3, 4-dihydroisoquinoline, a chiral catalyst, an acid and a solvent, and reacting, wherein the structural formula of the chiral catalyst is shown as a formula (I). further forming (S)-1phenyl -1, 2, 3, 4-tetrahydroisoquinoline with high chiral purity in one step in the hydrogenation reduction process, meanwhile, the product is easy to separate and purify, and the yield is high. In addition, the invention is mild in reaction condition, stable in process, simple, convenient and safe in reaction operation, low in production cost, simple and feasible in three-waste treatment, environment-friendly, simple in equipment used in the reaction process, easily available in raw materials, low in production cost and suitable for industrial production.
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Paragraph 0068; 0073-0075; 0080-0082; 0087-0089; 0094-0096

(2021/01/15)

CATALYSTS
A compound, e.g. a diamine ligand, represented by the following general formula (1): (Formula (1)) wherein each * represents an asymmetric carbon atom; X represents a group selected from one of an ester (e.g. a t-butyl ester); a thioester; an amide; a heterocyclic moiety (e.g. a five-membered heterocyclic ring) comprising one or more of O, S, Se, and/or P (e.g. a furan, a tetrahydrofuran, a thiophene, an isoxazole, a bromo-furan, or a thiazole); a moiety (e.g. a five-membered heterocyclic ring) comprising a nitrogen atom, wherein the nitrogen atom is protected with a protecting group containing an electron-withdrawing group, preferably the protecting group is selected from one of a carbamate protecting group, an amide protecting group, an aryl sulphonamide protecting group, or an alkyl sulphonamide protecting group; and optionally X may additionally comprise a solid support, e.g. a polymeric or a silica particle; Y represents or is CtT'T'' where 't' is 0 or 1 and when 't' is 1 T' and T'' may individually represent a substituent, e.g. if t is 1, T' and/or T'' may each be hydrogen or deuterium atom, or a halogen atom; for example, Y may represent a carbon atom comprising two further substituents; Z represents a hydrogen atom or a deuterium atom; R1 represents an alkyl group (e.g. a functionalised alkyl group) preferably having between 1 to 100 carbon atoms, for example, between 1 to 30 carbon atoms (e.g. 1 to 20 carbon atoms, or 1 to 10 carbon atoms), a halogenated alkyl group preferably having between 1 to 100 carbon atoms (e.g. CF3), for example, between 1 to 30 carbon atoms (e.g. 1 to 20 carbon atoms, or 1 to 10 carbon atoms), an aryl group preferably having between 5 to 100 carbon atoms, e.g. 6 to 30 carbon atoms and optionally having one or more substituents selected from alkyl groups preferably having 1 to 100 carbon atoms, e.g. 1 to 10 carbon atoms, halogenated alkyl groups preferably having 1 to 100 carbon atoms, e.g. 1 to 10 carbon atoms, and/or halogen atoms; or R1 represents a solid support, e.g. a silica particle or a polymeric particle; R2 and R3 each independently represent a group selected from alkyl groups preferably having between 1 to 100 carbon atoms, for example 1 to 20 carbon atoms (e.g. 1 to 10 carbon atoms), aryl groups (e.g. phenyl groups), and cycloalkyl groups preferably having 3 to 8 carbon atoms, the aryl group or phenyl group optionally having one or more substituents selected from alkyl groups preferably having between 1 to 100 carbon atoms, e.g. between 1 to 20 carbon atoms (e.g. 1 to 10 carbon atoms), alkoxy groups preferably having between 1 to 100 carbon atoms, for example, between 1 to 20 carbon atoms (e.g. 1 to 10 carbon atoms), and halogen atoms, and each hydrogen atom of the cycloalkyl groups being optionally replaced by an alkyl group preferably having between 1 to 100 carbon atoms, e.g. 1 to 20 carbon atoms (e.g. 1 to 10 carbon atoms), or R1 represents a polyethylene glycol (PEG) moiety having the formula C2nH4n+2On+1 wherein n is an integer between 1 and 100; or R2 and R3 form a ring together with carbon atoms to which R2 and R3 are bonded; R4 represents a hydrogen atom or a deuterium atom.
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Page/Page column 32-33; 38

(2020/12/11)

Josiphos-Type Binaphane Ligands for Iridium-Catalyzed Enantioselective Hydrogenation of 1-Aryl-Substituted Dihydroisoquinolines
Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.
Nie, Huifang,Zhu, Yupu,Hu, Xiaomu,Wei, Zhao,Yao, Lin,Zhou, Gang,Wang, Pingan,Jiang, Ru,Zhang, Shengyong
supporting information
p. 8641 - 8645
(2019/10/17)

Breaking Symmetry: Engineering Single-Chain Dimeric Streptavidin as Host for Artificial Metalloenzymes
The biotin-streptavidin technology has been extensively exploited to engineer artificial metalloenzymes (ArMs) that catalyze a dozen different reactions. Despite its versatility, the homotetrameric nature of streptavidin (Sav) and the noncooperative binding of biotinylated cofactors impose two limitations on the genetic optimization of ArMs: (i) point mutations are reflected in all four subunits of Sav, and (ii) the noncooperative binding of biotinylated cofactors to Sav may lead to an erosion in the catalytic performance, depending on the cofactor:biotin-binding site ratio. To address these challenges, we report on our efforts to engineer a (monovalent) single-chain dimeric streptavidin (scdSav) as scaffold for Sav-based ArMs. The versatility of scdSav as host protein is highlighted for the asymmetric transfer hydrogenation of prochiral imines using [Cp*Ir(biot-p-L)Cl] as cofactor. By capitalizing on a more precise genetic fine-tuning of the biotin-binding vestibule, unrivaled levels of activity and selectivity were achieved for the reduction of challenging prochiral imines. Comparison of the saturation kinetic data and X-ray structures of [Cp*Ir(biot-p-L)Cl]·scdSav with a structurally related [Cp*Ir(biot-p-L)Cl]·monovalent scdSav highlights the advantages of the presence of a single biotinylated cofactor precisely localized within the biotin-binding vestibule of the monovalent scdSav. The practicality of scdSav-based ArMs was illustrated for the reduction of the salsolidine precursor (500 mM) to afford (R)-salsolidine in 90% ee and >17 ?000 TONs. Monovalent scdSav thus provides a versatile scaffold to evolve more efficient ArMs for in vivo catalysis and large-scale applications.
Wu, Shuke,Zhou, Yi,Rebelein, Johannes G.,Kuhn, Miriam,Mallin, Hendrik,Zhao, Jingming,Igareta, Nico V.,Ward, Thomas R.
supporting information
p. 15869 - 15878
(2019/10/11)

Asymmetric Transfer Hydrogenation in Thermomorphic Microemulsions Based on Ionic Liquids
A thermomorphic ionic-liquid-based microemulsion system was successfully applied for the Ru-catalyzed asymmetric transfer hydrogenation of ketones. On the basis of the temperature-dependent multiphase behavior of the targeted microemulsion, simple product separation as well as catalyst recycling could be realized. The use of water-soluble ligands improved the immobilization of the catalyst in the microemulsion phase and significantly decreased the catalyst leaching into the organic layer upon extraction of the product. Eventually, the optimized microemulsion system could be applied to a wide range of aromatic ketones that were reduced with good isolated yields (up to 98%) and enantioselectivities (up to 97%), while aliphatic ketones were less successful.
Hejazifar, Mahtab,Pálv?lgyi, ádám Márk,Bitai, Jacqueline,Lanaridi, Olga,Bica-Schr?der, Katharina
p. 1841 - 1851
(2019/10/11)

Preparation method for (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline
The invention relates to a medical intermediate, in particular to a preparation method for (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. Benzoyl chloride or benzoic acid, phenylethylamine, alkali metalhydroxide and water are mixed to react, N-(2-phenethyl)benzamide, phosphorus pentoxide and phosphorus chloride at a certain ratio are mixed and heated with organic solvent, obtained 1-phenyl-3,4-dihydroisoquinoline, a first alcohol solvent and borohydride are mixed to react, the obtained 1-phenyl-1,2,3,4-dihydroisoquinoline, a second alcohol solvent, water and D-tartaric acid are mixed and heatedto react, the obtained (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline tartrate, alkali metal hydroxide and water are mixed to obtain a target product. The preparation method for (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline has the advantages of simpleness in operation and aftertreatment.
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(2019/03/31)

Asymmetric synthesis method of solifenacin intermediate
The invention discloses a preparation method of a Solifenacin intermediate. The Solifenacin intermediate is prepared by subjecting 1-phenyl-3,4-dihydroisoquinoline as a raw material, a chiral diphosphine ligand metal complex as a catalyst, and an organic acid or an inorganic acid as an additive to an asymmetric hydrogenation reaction; the chiral diphosphine ligand metal complex is a catalyst solution obtained by in-situ complexation of a chiral diphosphine ligand and a metal precursor. The preparation method of the invention is simple, efficient and practical, and the catalyst used is high inefficiency, and the method is suitable for industrial production.
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Paragraph 0015

(2019/08/06)

Dual Stereocontrol for Enantioselective Hydrogenation of Dihydroisoquinolines Induced by Tuning the Amount of N-Bromosuccinimide
An efficient dual stereocontrol in iridium-catalyzed hydrogenation of 1-substituted 3,4-dihydroisoquinolines was realized by tuning the amount of N-bromosuccinimide using chiral ligand of single configuration, providing both enantiomers of 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 89% ee (S) and 98% ee (R), respectively. Dual activation role of N-bromosuccinimide is proposed to be responsible for the reversal of enantioselectivity under two hydrogenation conditions.
Ji, Yue,Wang, Jie,Chen, Muwang,Shi, Lei,Zhou, Yonggui
supporting information
p. 139 - 142
(2018/01/05)

Directed Evolution of an Artificial Imine Reductase
Artificial metalloenzymes, resulting from incorporation of a metal cofactor within a host protein, have received increasing attention in the last decade. The directed evolution is presented of an artificial transfer hydrogenase (ATHase) based on the biotin-streptavidin technology using a straightforward procedure allowing screening in cell-free extracts. Two streptavidin isoforms were yielded with improved catalytic activity and selectivity for the reduction of cyclic imines. The evolved ATHases were stable under biphasic catalytic conditions. The X-ray structure analysis reveals that introducing bulky residues within the active site results in flexibility changes of the cofactor, thus increasing exposure of the metal to the protein surface and leading to a reversal of enantioselectivity. This hypothesis was confirmed by a multiscale approach based mostly on molecular dynamics and protein–ligand dockings.
Hestericová, Martina,Heinisch, Tillman,Alonso-Cotchico, Lur,Maréchal, Jean-Didier,Vidossich, Pietro,Ward, Thomas R.
supporting information
p. 1863 - 1868
(2018/01/27)

A method catalyzed by iridium and used for bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline
A method catalyzed by iridium and used for bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline is provided. A catalysis system adopted by the method is a chiral diphosphine complex of iridium. By utilizing a single chiral source and
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Paragraph 0035-0041

(2018/03/01)

Genetic Engineering of an Artificial Metalloenzyme for Transfer Hydrogenation of a Self-Immolative Substrate in Escherichia coli's Periplasm
Artificial metalloenzymes (ArMs), which combine an abiotic metal cofactor with a protein scaffold, catalyze various synthetically useful transformations. To complement the natural enzymes' repertoire, effective optimization protocols to improve ArM's performance are required. Here we report on our efforts to optimize the activity of an artificial transfer hydrogenase (ATHase) using Escherichia coli whole cells. For this purpose, we rely on a self-immolative quinolinium substrate which, upon reduction, releases fluorescent umbelliferone, thus allowing efficient screening. Introduction of a loop in the immediate proximity of the Ir-cofactor afforded an ArM with up to 5-fold increase in transfer hydrogenation activity compared to the wild-type ATHase using purified mutants.
Zhao, Jingming,Rebelein, Johannes G.,Mallin, Hendrik,Trindler, Christian,Pellizzoni, Michela M.,Ward, Thomas R.
supporting information
p. 13171 - 13175
(2018/10/23)

Solifenacin succinate raw medicine synthesis process
The invention discloses a solifenacin succinate raw medicine synthesis process. 2-phenylethylamine and 3-quinuclidinone hydrochloride are respectively used as starting raw materials for synthesizing afragment A and a fragment B; then, condensation reaction occurs to generate solifenacin; through salt formation, the solifenacin succinate is obtained. The process is characterized in that straight-chain paraffin and water are used as reaction solvents; alkali metal hydroxides or carbonate and bicarbonates of the alkali metal hydroxides are used as acid-binding agents; phenylethylamine and benzoyl chloride take acylation reaction to generate midbodies 1 of solid precipitation fragments A insoluble in reaction solvents; in the post treatment process, filtering is directly performed; isomers ofthe fragment A are subjected to catalytic racemization through alkali metal hydroxides by using dimethylsulfoxide as a solvent, so that the byproduct isomers can be recovered and utilized; in the second-step reaction post treatment of the fragment B, a conventional pressure reduced distillation method is used for obtaining high-purity and high-yield 3-acetoxyquinine acetate. The invention provides a novel synthesis process with the advantages of high yield and economic and environment-friendly effects, and is suitable for industrial mass production.
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(2018/08/28)

Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-Catalyzed Enantioselective C?H Functionalization
Reported is an achiral CpxRhIII/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one. Secondary
Lin, Luqing,Fukagawa, Seiya,Sekine, Daichi,Tomita, Eiki,Yoshino, Tatsuhiko,Matsunaga, Shigeki
supporting information
p. 12048 - 12052
(2018/09/11)

A one-pot process for the enantioselective synthesis of tetrahydroquinolines and tetrahydroisoquinolines: Via asymmetric reductive amination (ARA)
Asymmetric reductive amination for the synthesis of both chiral tetrahydroquinolines (THQs) and tetrahydroisoquinolines (THIQs) has been realized with an Ir/ZhaoPhos catalytic system via a one-pot N-Boc deprotection/intramolecular asymmetric reductive amination (ARA) sequence. Control experiments reveal that HCl plays a vital role to the success of this transformation. The HCl acid assists the removal of the N-Boc protecting group and also provides chloride ions to interact with the thiourea moiety in ZhaoPhos, thus leading to excellent reaction enantiocontrol.
Yang, Tao,Yin, Qin,Gu, Guoxian,Zhang, Xumu
p. 7247 - 7250
(2018/07/05)

One-Pot N-Deprotection and Catalytic Intramolecular Asymmetric Reductive Amination for the Synthesis of Tetrahydroisoquinolines
A one-pot N-Boc deprotection and catalytic intramolecular reductive amination protocol for the preparation of enantiomerically pure tetrahydroisoquinoline alkaloids is described. The iodine-bridged dimeric iridium complexes displayed superb stereoselectivity to give tetrahydroisoquinolines, including several key pharmaceutical drug intermediates, in excellent yields under mild reaction conditions. Three additives played important roles in this reaction: Titanium(IV) isopropoxide and molecular iodine accelerated the transformation of the intermediate imine to the tetrahydroisoquinoline product; p-toluenesulfonic acid contributed to the stereocontrol.
Zhou, Huan,Liu, Yuan,Yang, Suhua,Zhou, Le,Chang, Mingxin
supporting information
p. 2725 - 2729
(2017/02/26)

Identification of an Imine Reductase for Asymmetric Reduction of Bulky Dihydroisoquinolines
A new imine reductase from Stackebrandtia nassauensis (SnIR) was identified, which displayed over 25- to 1400-fold greater catalytic efficiency for 1-methyl-3,4-dihydroisoquinoline (1-Me DHIQ) compared to other imine reductases reported. Subsequently, an efficient SnIR-catalyzed process was developed by simply optimizing the amount of cosolvent, and up to 15 g L-1 1-Me DHIQ was converted completely without a feeding strategy. Furthermore, the reaction proceeded well for a panel of dihydroisoquinolines, affording the corresponding tetrahydroisoquinolines (mostly in S-configuration) in good yields (up to 81%) and with moderate to excellent enantioselectivities (up to 99% ee).
Li, Hao,Tian, Ping,Xu, Jian-He,Zheng, Gao-Wei
supporting information
p. 3151 - 3154
(2017/06/23)

Simultaneous engineering of an enzyme's entrance tunnel and active site: The case of monoamine oxidase MAO-N
A new directed evolution approach is presented to enhance the activity of an enzyme and to manipulate stereoselectivity by focusing iterative saturation mutagenesis (ISM) simultaneously on residues lining the entrance tunnel and the binding pocket. This combined mutagenesis strategy was applied successfully to the monoamine oxidase from Aspergillus Niger (MAO-N) in the reaction of sterically demanding substrates which are of interest in the synthesis of chiral pharmaceuticals based on the benzo-piperidine scaffold. Reversal of enantioselectivity of Turner-type deracemization was achieved in the synthesis of (S)-1,2,3,4-tetrahydro-1-methyl-isoquinoline, (S)-1,2,3,4-tetrahydro-1-ethylisoquinoline and (S)-1,2,3,4-tetrahydro-1-isopropylisoquinoline. Extensive molecular dynamics simulations indicate that the altered catalytic profile is due to increased hydrophobicity of the entrance tunnel acting in concert with the altered shape of the binding pocket.
Li, Guangyue,Yao, Peiyuan,Gong, Rui,Li, Jinlong,Liu, Pi,Lonsdale, Richard,Wu, Qiaqing,Lin, Jianping,Zhu, Dunming,Reetz, Manfred T.
p. 4093 - 4099
(2017/07/10)

Enantioselective hydrogenation of cyclic imines catalysed by Noyori-Ikariya half-sandwich complexes and their analogues
A method for enantioselective hydrogenation of cyclic imines with gaseous hydrogen has been developed. Easily accessible Noyori-Ikariya Ru(ii) and Rh(iii) complexes can be used directly without an inert atmosphere. Substrate activation has been achieved by trifluoroacetic acid. A new hydroxyl-functionalized complex is reported, showing high activity in transfer hydrogenation.
Vilhanová,Václavík,?ot,Pechá?ek,Zápal,Pa?out,Maixner,Kuzma,Ka?er
supporting information
p. 362 - 365
(2016/01/09)

Method for preparing chiral amine compound and its application
The invention discloses a preparation method of a chiral amine compound. In presence of a semi-sandwich type complex and an acid additive, an asymmetrization reaction is carried out on a prochiral amine compound in a hydrogen atmosphere, and postprocessin
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Paragraph 0046; 0049; 0050; 0051; 0052

(2017/04/11)

Method for preparing solifenacin intermediate
The invention belongs to the field of medicine and particularly relates to a method for preparing a solifenacin intermediate. After 2-halogenated diphenyl ketone is used for carbonyl protection, n-butyllithium is used for removing bromine, then the formyl group is added; a condensation reaction with nitromethane and catalytic hydrogenation for reduction are carried out, and then acidification is conducted; later, cyclization is carried out, and a solifenacin intermediate compound I is obtained through alkaline hydrolysis after reduction and chiral resolution. The structural formula of the solifenacin intermediate is shown in the description. According to the method for preparing the solifenacin intermediate, the initial raw materials easy to obtain are utilized, and the production cost is reduced. The process route is advanced, the reaction conditions are mild, the reaction yield is high, less three wastes are caused, expensive and toxic reagents do not exist, reaction solvents can be used repeatedly after distillation, industrial production is facilitated, and implementation value and social, economic and environmental protection benefits are high.
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(2016/11/24)

1-phenyl -1, 2, 3, 4-isoquinoline method for the preparation of
The invention provides a 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method. The 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method comprises the following steps of: mixing benzoyl chloride or benzoic acid, phenethylamine and alkali metal hydroxide with water, and reacting to obtain N-(2-phenethyl) benzamide; then mixing the N-(2-phenethyl) benzamide with phosphorus pentoxide, chloride phosphorus and a benzene solvent, heating and reacting to obtain 1-phenyl-3, 4-dihydro-isoquinoline; and further mixing the 1-phenyl-3, 4-dihydro-isoquinoline with a first alcohol solvent and hydroboron, and reacting to obtain the product. Compared with the prior art, the 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline preparation method has the advantages that firstly, no organic solvents are added, the product N-(2-phenethyl) benzamide is insoluble in an aqueous solution, and therefore, the steps of skimming and the like are avoided in the after-treatment process, and the after-treatment operation is simplified; secondarily, as the organic solvents are not added, the cost is reduced, and the pollution to environments is avoided; and thirdly, as the phosphorus pentoxide and the chloride phosphorus are subjected to oxidization cyclization reaction, polyphosphoric acids are prevented from being heated and decomposed to generate hypertoxic phosphorus oxide exhaust gas.
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(2017/01/26)

Enantioselective Synthesis of 1-Aryl-Substituted Tetrahydroisoquinolines Through Ru-Catalyzed Asymmetric Transfer Hydrogenation
A convenient and general asymmetric transfer hydrogenation of a wide array of 1-aryl-3,4-dihydroisoquinoline derivatives using a [RuIICl(η6-benzene)TsDPEN] complex in combination with a 5:2 HCOOH-Et3N azeotropic mixture as a hydrogen source was developed. Under mild reaction conditions, the described catalytic transformation secured a practical synthetic access to the corresponding valuable chiral 1-aryltetrahydroisoquinoline units with high atom economy, a broad substrate scope, high isolated yields (up to 97%) and good to excellent enantioselectivities (up to 99% ee). It was found that the stereochemical outcome of the reaction was strongly influenced by both the structure of the catalyst and the substituents present on the substrate. The synthetic utility of the present protocol has been demonstrated through the asymmetric synthesis of several biologically important alkaloids including the antiepileptic drug agent 1c, as well as (-)-nor-cryptostyline alkaloids I and II.
Perez, Marc,Wu, Zi,Scalone, Michelangelo,Ayad, Tahar,Ratovelomanana-Vidal, Virginie
supporting information
p. 6503 - 6514
(2015/10/19)

Concise Redox Deracemization of Secondary and Tertiary Amines with a Tetrahydroisoquinoline Core via a Nonenzymatic Process
A concise deracemization of racemic secondary and tertiary amines with a tetrahydroisoquinoline core has been successfully realized by orchestrating a redox process consisted of N-bromosuccinimide oxidation and iridum-catalyzed asymmetric hydrogenation. This compatible redox combination enables one-pot, single-operation deracemization to generate chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 98% ee in 93% yield, offering a simple and scalable synthetic technique for chiral amines directly from racemic starting materials.
Ji, Yue,Shi, Lei,Chen, Mu-Wang,Feng, Guang-Shou,Zhou, Yong-Gui
supporting information
p. 10496 - 10499
(2015/09/28)

Enhancing effects of salt formation on catalytic activity and enantioselectivity for asymmetric hydrogenation of isoquinolinium salts by dinuclear halide-bridged iridium complexes bearing chiral diphosphine ligands
Asymmetric hydrogenation of 1- and 3-substituted and 1,3-disubstituted isoquinolinium chlorides using triply halide-bridged dinuclear iridium complexes [{Ir(H)(diphosphine)} 2(μ -Cl)3]Cl has been achieved by the strategy of HCl salt formation of isoquinolines to afford the corresponding chiral 1,2,3,4-tetrahydroisoquinolines (THIQs) in high yields and with excellent enantioselectivities after simple basic workup. The effects of salt formation have been investigated by time-course experiments, which revealed that the generation of isoquinolinium chlorides clearly prevented formation of the catalytically inactive dinuclear trihydride complex, which was readily generated in the catalytic reduction of salt-free isoquinoline substrates. Based on mechanistic investigations, including by 1H and 31P{1H} NMR studies and the isolation and characterization of several intermediates, the function of the chloride anion of the isoquinolinium chlorides has been elucidated, allowing us to propose a new outer-sphere mechanism involving coordination of the chloride anion of the substrates to an iridium dihydride species along with a hydrogen bond between the chloride ligand and the N-H proton of the substrate salt.
Kita, Yusuke,Yamaji, Kenta,Higashida, Kosuke,Sathaiah, Kandula,Iimuro, Atuhiro,Mashima, Kazushi
p. 1915 - 1927
(2015/01/30)

Expanding the chemical diversity in artificial imine reductases based on the biotin-streptavidin technology
We report on the optimization of an artificial imine reductase based on the biotin-streptavidin technology. With the aim of rapidly generating chemical diversity, a novel strategy for the formation and evaluation of biotinylated complexes is disclosed. Tethering the biotin-anchor to the Cp* moiety leaves three free coordination sites on a d6 metal for the introduction of chemical diversity by coordination of a variety of ligands. To test the concept, 34 bidentate ligands were screened and a selection of the 6 best was tested in the presence of 21 streptavidin (Sav) isoforms for the asymmetric imine reduction by the resulting three legged piano stool complexes. Enantiopure α-amino amides were identified as promising bidentate ligands: up to 63 % ee and 190 turnovers were obtained in the formation of 1-phenyl-1,2,3,4-tetrahydroisoquinoline with [IrCp*biotin(L-ThrNH2)Cl]?SavWT as a catalyst. Biotinspired! A new strategy for the generation of chemical diversity in artificial transfer hydrogenases (ATHases) based on the biotin-streptavidin technology is disclosed. By combining a biotinylated MCp* fragment with 34 commercially available ligands in the presence of wild-type streptavidin, promising candidates for the asymmetric reduction of imines are identified. Selected ligands are screened against 21 streptavidin isoforms and the performance of the resulting constructs is evaluated.
Quinto, Tommaso,Schwizer, Fabian,Zimbron, Jeremy M.,Morina, Albert,Koehler, Valentin,Ward, Thomas R.
p. 1010 - 1014
(2014/05/06)

The role of the aromatic ligand in the asymmetric transfer hydrogenation of the CN bond on Noyori's chiral Ru catalysts
Only four types of dimeric precursors [RuCl2(η6-arene)]2 for the synthesis of Noyori's half sandwich diamine catalysts [RuCl(TsDPEN)(η6-arene)] are commercially available, yet so far no study has tried to system
ot, Petr,Vilhanov, Beta,Pechek, Jan,Vclavk, Ji,Zpal, Jakub,Kuzma, Marek,Kaer, Petr
p. 1346 - 1351
(2015/02/02)

Enantioselective and rapid Rh-catalyzed arylation of N -tosyl- and N -nosylaldimines in methanol
Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to N-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt3 as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-d-aspartate (NMDA) receptor.
Chen, Chun-Chih,Gopula, Balraj,Syu, Jin-Fong,Pan, Jhih-Han,Kuo, Ting-Shen,Wu, Ping-Yu,Henschke, Julian P.,Wu, Hsyueh-Liang
p. 8077 - 8085
(2015/03/18)

Development of an R-selective amine oxidase with broad substrate specificity and high enantioselectivity
Amine oxidases are useful bio-catalysts for the synthesis of enantiomerically pure 1°, 2° and 3° chiral amines. Enzymes in this class (e.g., MAO-N from Aspergillus niger) reported previously have been shown to be highly S selective. Herein we report the development of an enantiocomplementary R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity. The engineered 6-HDNO enzyme has been applied to the preparative deracemisation of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee. Nicotine rush: An R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity has been developed. The engineered 6-HDNO enzyme is applied to the preparative deracemization of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee.
Heath, Rachel S.,Pontini, Marta,Bechi, Beatrice,Turner, Nicholas J.
p. 996 - 1002
(2014/05/06)

Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines using Ru(II) diamine catalysts
A new [Ru(II)(η6-p-cymene)(1R,2R)-N-((1S,2S)-borneol-10- sulfonyl)-1,2-diphenylethylenediamine] catalyst for the asymmetric transfer hydrogenation of both 1-alkyl and 1-aryl dihydroisoquinolines has been isolated. For the first time in this type of reaction, the catalyst employs an N-alkylsulfonyl group instead of N-arylsulfonyl.
P?ech, Jan,Václavík, Ji?í,?ot, Petr,Pechá?ek, Jan,Vilhanová, Beáta,Janu??ák, Jakub,Syslová, Kamila,Pa?out, Richard,Maixner, Jaroslav,Zápal, Jakub,Kuzma, Marek,Ka?er, Petr
p. 67 - 70
(2013/06/27)

Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products
The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.
Ghislieri, Diego,Green, Anthony P.,Pontini, Marta,Willies, Simon C.,Rowles, Ian,Frank, Annika,Grogan, Gideon,Turner, Nicholas J.
p. 10863 - 10869
(2013/08/23)

One-pot racemization process of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline: A key intermediate for the antimuscarinic agent solifenacin
(S)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the N-chloroamine into the imine hydrochloride, and reduction of the imine double bond. The racemized amine was successfully resolved by d-(-)-tartaric acid obtaining (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield and with 96.7% ee and, from the crystallization mother liquors, the R enriched form. This was racemized by the same one-pot process and resolved by d-(-)-tartaric acid with the same efficiency. Such an approach to the racemization of 1-phenyl-1,2,3,4- tetrahydroisoquinoline can be industrially useful to recycle the waste R enantiomer resulting from the classical resolution used to obtain the S enantiomer on a large scale.
Bolchi, Cristiano,Pallavicini, Marco,Fumagalli, Laura,Straniero, Valentina,Valoti, Ermanno
p. 432 - 437
(2013/05/09)

Enantioselective iridium-catalyzed hydrogenation of 1- and 3-substituted isoquinolinium salts
Asymmetric hydrogenation: The title reaction provides an efficient and rapid access to chiral 1- and 3-substituted 1,2,3,4-tetrahydroisoquinolines with excellent enantioselectivity (see scheme; L=ligand). A preliminary mechanistic study indicates that the 1,2-hydride addition might be the initial step in the reaction. The method has been used in the synthesis of urinary antispasmodic drug (+)-solifenacin. Copyright
Ye, Zhi-Shi,Guo, Ran-Ning,Cai, Xian-Feng,Chen, Mu-Wang,Shi, Lei,Zhou, Yong-Gui
p. 3685 - 3689
(2013/04/24)

Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation
Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl]2/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.
Berhal, Farouk,Wu, Zi,Zhang, Zhaoguo,Ayad, Tahar,Ratovelomanana-Vidal, Virginie
supporting information; experimental part
p. 3308 - 3311
(2012/08/28)

A highly efficient and enantioselective access to tetrahydroisoquinoline alkaloids: Asymmetric hydrogenation with an iridium catalyst
Efficient and enantioselective: Using the iodine-bridged dimeric iridium complex [{Ir(H)[(S,S)-(f)-binaphane]}2(μ-I)3] +I- (1) a wide range of tetrahydroisoquinoline alkaloids, including the substructure of the pharmaceutical drug solifenacin, were obtained with excellent enantioselectivities and high turnover numbers (see scheme). Copyright
Chang, Mingxin,Li, Wei,Zhang, Xumu
supporting information; experimental part
p. 10679 - 10681
(2011/12/05)

PROCESSES FOR THE PREPARATION OF SOLIFENACIN OR A SALT THEREOF
The present invention describes recovery and racemization of (1R)-Phenyl- 1,2,3,4-tetrahydroisoquinoline of compound of formula (III) to obtain racemic 1- phenyl-1, 2,3,4-tetrahydroisoquinoline of compound of formula (I) and its further resolution to get ( IS)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (intermediate B) in high chemical and chiral purity, which is the key intermediate for the preparation of (3R)-azabicyclo[2.2.2]oct-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)- carboxylate.
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Page/Page column 15

(2011/05/06)

Catalytic kinetic resolution of cyclic secondary amines
The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.
Binanzer, Michael,Hsieh, Sheng-Ying,Bode, Jeffrey W.
supporting information; experimental part
p. 19698 - 19701
(2012/01/13)

PROCESS FOR THE PREPARATION OF SOLIFENACIN AND SOLIFENACIN SUCCINATE
A process for the preparation of solifenacin wherein all the reaction steps, starting from (i) release of (S) -I -phenyl- 1, 2,3, 4 - tetrahydroisoquinoline from its diastereoisomeric salt with D- (-) - tartaric acid, (ii) conversion of (S) - 1 -phenyl - 1, 2, 3, 4 - tetrahydroisoquinoline into 1 - (5) -phenyl - 1, 2, 3, 4 - tetrahydroisoquinolinecarbonyl chloride in the reaction with triphosgene in the presence of pyridine to (iii) the reaction between 1- (5) -phenyl - 1, 2, 3, 4 - tetrahydroisoquinolinecarbonyl chloride and 3- (S) - quinuclidinol in the presence of sodium hydride are carried out without the isolation of intermediates in solid form and the solvents used for the reactions are aprotic solvent. Resulting solifenacin in the free base form is converted into the corresponding succinic acid salt using methods known in the art.
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Page/Page column 10

(2011/08/04)

A PROCESS FOR THE PREPARATION OF SOLIFENACIN SALTS AND THEIR INCLUSION INTO PHARMACEUTICAL DOSAGE FORMS
The invention relates to the synthesis of solifenacin, the preparation of its salts and their inclusion into pharmaceutically acceptable dosage forms.
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Page/Page column 29

(2010/04/03)

Enantioselective synthesis of 1-aryltetrahydroisoquinolines
(Figure presented) 1-Aryltetrahydroisoquinolines (1-arylTHIQs) are important structural motifs in many alkaloids and biologically active compounds. Ligand 2a promotes the enantioselective addition of arylzinc reagents to 3,4-dihydroisoquinoline N-oxide to
Wang, Sa,Onaran, M. Burak,Seto, Christopher T.
supporting information; experimental part
p. 2690 - 2693
(2010/09/03)

Chemical Properties

Appearance/Colour :white solid
Melting Point: 80-82 °C
Boiling Point: 338.4 °C at 760 mmHg
Flash Point:167 °C
Density: 1.065 g/cm³
Solubility:Chloroform (Slightly), Dichloromethane (Slightly), Methanol (Slightly)
Storage Temp.:under inert gas (nitrogen or Argon) at 2–8 °C
Vapor Pressure: 9.87E-05mmHg at 25°C
Refractive Index: 1.589
PKA: 8.91±0.40(Predicted)
PSA: 12.03000
LogP: 3.25050

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118864-75-8

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Chemical Properties

Appearance/Colour :white solid

Melting Point: 80-82 °C

Boiling Point: 338.4 °C at 760 mmHg

Flash Point:167 °C

Density: 1.065 g/cm³

Solubility:Chloroform (Slightly), Dichloromethane (Slightly), Methanol (Slightly)

Storage Temp.:under inert gas (nitrogen or Argon) at 2–8 °C

Vapor Pressure: 9.87E-05mmHg at 25°C

Refractive Index: 1.589

PKA: 8.91±0.40(Predicted)

PSA: 12.03000

LogP: 3.25050

Global suppliers and manufacturers of 118864-75-8total 219 suppliers on LookChem

Article Database

118864-75-8

Articles about 118864-75-8Total 61 be found

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Chemical Properties

Appearance/Colour :white solid

Melting Point: 80-82 °C

Boiling Point: 338.4 °C at 760 mmHg

Flash Point:167 °C

Density: 1.065 g/cm3

Solubility:Chloroform (Slightly), Dichloromethane (Slightly), Methanol (Slightly)

Storage Temp.:under inert gas (nitrogen or Argon) at 2–8 °C

Vapor Pressure: 9.87E-05mmHg at 25°C

Refractive Index: 1.589

PKA: 8.91±0.40(Predicted)

PSA: 12.03000

LogP: 3.25050

Global suppliers and manufacturers of 118864-75-8total 219 suppliers on LookChem

Density: 1.065 g/cm³