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The present invention provides a 1-phenyl -1, 2, 3, 4-isoquinoline method for the preparation of, the, benzoyl chloride or benzoic acid, phenethylamine, alkali metal hydroxide is mixed with water, after the reaction, to obtain N-(2-phenethyl) benzamide; then with the phosphorus pentoxide, phosphorus chloride and benzene solvent mixed, the heating reaction, to obtain 1-phenyl -3,4-dihydro-quinoline; further and 1st alcohol solvent and borohydride mixing, the product is obtained after the reaction. Compared with the prior art, first of all, the invention does not add any organic solvent and the product N-(2-phenethyl) benzamide not dissolved in aqueous solution, therefore in post-treatment process in the steps such as the liquid does not need to be, the advantages of simplifying the post-processing operation; secondly, without the added organic solvent the cost is also reduced, to avoid the pollution of the environment; once again, adopts a phosphorus pentoxide and phosphorus chloride oxidation reaction loop, avoiding poly phosphoric acid is heated and decomposed to produce the hypertoxic the phosphorus oxide is flue gas. (by machine translation)

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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.

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The present invention relates to a process for the preparation of Solifenacin succinate by condensing a compound of formula (IVb) with (RS)-3-quinuclidinol, wherein, R represents methyl, ethyl, isopropyl; to produce a diastereomeric mixture of ( 1S)-3,4-dihydro- 1 -phenyl-2( 1 H)-isoquinolinecarboxylic acid (3RS)- 1 – azabicyclo[2.2.2]oct-3-yl ester, which is treated with succinic acid in a solvent or mixture of solvents to produce optically pure Solifenacin succinate, Formula (X).

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The present invention relates to an improved process for the preparation of solifenacin compound of formula (1) and its succinate salt compound of formula (1a), comprising the condensation of (R)-3- quinuclidinol with (S)-ethyl- 1 -phenyl- 1,2,3,4-tetrahydro-2-isoquinoline carboxylate in presence of a suitable hydroxide base in a suitable solvent.

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A method of preparing (lS)-(3R)-l-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-l-phenyl-2(lH)- isoquinoline carboxylate (solifenacin) or its pharmaceutically acceptable salts with high optic purity, wherein the crude solifenacin base is transformed to the hydrogen tartrate, which is then optionally transformed to another pharmaceutically acceptable salt or the base of solifenacin. A crystalline salt of solifenacin hydrogen tartrate.

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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).

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A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to the PCP binding site of the NMDA receptor complex. The (S)-configured tetrahydroisoquinoline derivative (S)-4 e x HCl bearing a 2-methylphenyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the derivatives with a K(i)-value of 0.0374 microM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times more potent than the corresponding (R)-enantiomer (R)-4 e x HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives is described.

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To provide a novel method for producing a composition comprising solifenacin or a salt thereof, and a composition comprising solifenacin or a salt thereof as produced by the method, wherein an optionally substituted lower alkyl is added to the 2-position of the quinuclidine of solifenacin. The composition of the present invention contains a highly pure solifenacin, while the unexpected compounds specific to the method in an extremely low content, so that it has very preferable properties as a bulk for pharmaceutical products.

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In this paper, we have reported the synthesis and biological evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives as novel candidate antidepressant and anticonvulsant agents. Compounds 2h, 2k, 2r, and 2s exhibited better potent antidepressant activity and displayed the antidepressant effects in a dose-dependent manner from 10 to 30 mg/kg in the FST and TST. And, we found that the best antidepressant effect of compounds 2r and 2s are likely mediated by an increase in central nervous system 5-HT and NE. In addition, compounds 2r and 2s also exhibited the anticonvulsant activity against MES-induced seizures. Thus, compounds 2r and 2s may be a useful antidepressant adjunct therapy for treating depression in patients with epilepsy. In addition, compounds 2r and 2s showed the anti-inflammatory activity and the excellent analgesic activity. Several scholars have postulated the anti-inflammatory and analgesic effects of antidepressant drugs, suggesting that they may be possess a similar mechanism of action.

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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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