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Process for the preparation of solifenacin

A process for the preparation of (1S,3’R)-quinielidin-3′-yl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-carboxylate, namely solifenacin, comprising the reaction of a compound of formula (IV) with a compound of formula (V), as herein defined, and the subsequent reaction with 3-quinuclidinol.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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AN IMPROVED PROCESS FOR THE PREPARATION OF SOLIFENACIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

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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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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A process for the preparation of new thorley that succinic acid (by machine translation)

The invention relates to a method for preparing a solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate). The method comprises the following steps: 1) preparing a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III from a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, serving as a raw material, of formula IV; 2) synthesizing a compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an ionic liquid by using the compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III; and 3) salifying the compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an organic solvent to obtain the compound solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate) of formula I. The preparation method has the advantages that the process is simple, the method is suitable for industrialized production, the yield of the product is high and the purity of the product is high.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Properties and Exciting Facts About (S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline

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An Enantioselective Access to 1-Alkyl-1,2-Dihydroisoquinolines and 1-Alkyl-, 3-Alkyl-, and 1,3-Dialkyl-1,2,3,4-tetrahydroisoquinolines

New chiral isoquinolinium salt derivatives 1, 2 or 3 have been treated with Grignard reagents to give as major products, 1-substituted 1,2-dihydroisoquinolines 4a-f, oxazolidine derivatives 10a-f or 21, respectively, in good yield and in moderate to good diastereoisomeric excess. The stereochemistry of these new derivatives has been elucidated, in particular, by X-ray crystallographic studies of 1,2-dihydroisoquinoline 4b and the minor oxazolidine lib. Reduction of all these intermediates gave chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines such as base 8. The enantioselective synthesis of the natural alkaloid (-)-salsonidine in three steps and 38% overall yield from salt 3 is described as an application. Reduction of salt 2 gave a new oxazolidine derivative 15 which is a practical intermediate for the synthesis of 3-alkyl 1,2,3,4-tetrahydroisoquinolines 17a,b, while oxazolidines such as 10 are convenient precursors of 1,3-disubstituted tetrahydroisoquinolines, as illustrated by a synthesis of 1,3-dimethyl tetrahydroisoquinoline 20.

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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 alkylamines as well as nonprotected primary alkylamines underwent the transformation with high enantioselectivities (up to 98.5:1.5 e.r.) by using a newly developed chiral carboxylic acid as the sole source of chirality to achieve enantioselective C?H cleavage by a concerted metalation-deprotonation mechanism.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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SOLIFENACIN SALTS

The invention concerns fumarate salts of solifenacin, as well as pharmaceutical compositions comprising fumarate salts of solifenacin. The invention furthermore concerns a process for preparing solifenacin and salts thereof. The fumarate salt provides improved properties over the known solifenacin salts, especially in terms of its stability. The novel process for its preparation is furthermore improved over known processes for preparing solifenacin in that it provides a higher yield and recovers a greater amount of starting material.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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3-Hydroxypyrroles and 1H-Pyrrol-3(2H)-ones. Part 3. Pyrrolones from Pyrolyses of Aminomethylene Meldrum’s Acid Derivatives: Loss of Chirality at the Site of Hydrogen Transfer.

Pyrolysis of the diastereoisomeric Meldrum’s acid derivatives (4) and (5), or of the chiral derivatives (6), (7), and (9), gives 2,2-disubstituted 1H-pyrrol-3(2H)-ones in which there is loss of configuration at the reaction site .The extent of configuration loss is greater if the reaction site is part of a ring.These results are explained by a two-step, hydrogen-transfer-cyclisation mechanism, following initial generation of a methyleneketene.

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Tetrahydroisoquinoline – Wikipedia,
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Extracurricular laboratory:new discovery of (S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline

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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.

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Tetrahydroisoquinoline – Wikipedia,
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Safe and Efficient Phosgenation Reactions in a Continuous Flow Reactor

Phosgene is widely used in organic synthesis owing to its high reactivity, utility, and cost efficiency. However, the use of phosgene in batch processes on the industrial scale is challenging owing to its toxicity. An effective method to minimize reaction volumes and mitigate the safety risks associated with hazardous chemicals is the use of flow reactors. Consequently, we have established a flow reaction system using triphosgene and tributylamine, which affords a homogeneous reaction that avoids clogging issues. In addition, we have demonstrated that this methodology can be applied to a wide variety of phosgene reactions, including the preparation of pharmaceutical intermediates, in good to excellent yields.

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Tetrahydroisoquinoline – Wikipedia,
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(1 S) -1 – phenyl – 3, 4 – dihydro – 1H – isoquinolin -2 – carbonyl imidazole new crystal and its preparation method (by machine translation)

The invention relates to a (1 S) – 1 – phenyl – 3, 4 – dihydro – 1 H – isoquinoline – 2 – carbonyl imidazole crystalline form A, characterized in that the Cu – Kalpha radiation to, 2 theta ¡À 0.2 diffraction angle expressed in X – ray powder diffraction spectrum, in the 7.6, 8.7, 10.9, 11.9, 19.3, 20.6, 21.5, 22.8 there is a characteristic diffraction peak. The present invention discloses (1 S) – 1 – phenyl – 3, 4 – dihydro – 1 H – isoquinoline – 2 – carbonyl imidazole crystalline form A stability is good, convenient to use, in the production process and the removal of the impurity in the intermediate storage. (by machine translation)

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Reference£º
Tetrahydroisoquinoline – Wikipedia,
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