Process for the preparation of solifenacin and salts thereof

A solifenacin and diastereomeric technology, which is applied in the field of preparation of solifenacin and its salts, can solve the problems of expensive and difficult preparation, and achieve the effects of mild conditions, short time and reduced total cost

Inactive Publication Date: 2014-04-02
ISOCHEM SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specifically, all of the above routes involve the use of the key homochiral intermediate compound (1S)-phenyl-1,2,3,4-tetrahydroisoquinoline, which is expensive and difficult to prepare

Method used

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  • Process for the preparation of solifenacin and salts thereof
  • Process for the preparation of solifenacin and salts thereof
  • Process for the preparation of solifenacin and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Preparation of (R)-quinuclidin-3-yl phenethylcarbamate (Compound III), Method A.

[0093] 14 g (86.17 mmol) 1,1′-carbonyldiimidazole was added to a suspension of 10 g (78.51 mmol) 3(R)-quinine alcohol in 150 mL THF at 0° C. under nitrogen atmosphere. The reaction mixture was left under stirring at 0 °C for 4 h until cleared by TLC (CH 2 Cl 2 :MeOH:NH 3 Aq. 9:1:0.1) Complete conversion to (R)-imidazole-1-carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester (Compound Ia) was observed. To the obtained solution was added dropwise a mixture of 9.9 mL (78.51 mmol) of 2-phenethylamine and 10.0 mL (78.51 mmol) of triethylamine at 0°C. After 30 minutes at 0 °C, the reaction mixture was allowed to reach room temperature and left to stir overnight under nitrogen atmosphere. The solvent was distilled off in vacuo and the residue was dissolved in 100 mL of dichloromethane and extracted twice with 50 mL of 1N HCl. The aqueous extract was basified to pH 10 with potassium carbonate...

Embodiment 2

[0096] Preparation of (R)-quinuclidin-3-yl phenethylcarbamate (Compound III), Method B.

[0097] a) Preparation of phenethylurethane (compound IIa).

[0098] At 0° C., 13.9 mL (145 mmol) of ethyl chloroformate was added dropwise to a solution of 14.72 g (145 mmol) of triethylamine and 15.99 g (132 mmol) of 2-phenethylamine in 300 mL of dichloromethane. After stirring the mixture at room temperature for 3 hours, it was washed successively with water, HCl 1M and brine, and evaporated to dryness under reduced pressure. The crude product was obtained as a pale yellow oil (27.77 g) and used in the next step without further purification.

[0099] RMN1H(CDCl3),δ(ppm):1.26(t,3H,CH3);2.84(t,2H,CH2);3.3-3.5(m,2H,CH2-N);4.13(q,2H,CH2-O );4.72(s,1H,NH);7.1-7.4(m,5H,Ar).

[0100] b) Preparation of (R)-quinuclidin-3-yl phenethylcarbamate (compound III).

[0101] To a solution of 1.33 g (7.56 mmol) of crude phenethylurethane in a mixture of 1 mL of DMF and 20 mL of toluene was added 1....

Embodiment 3

[0103] Preparation of (R)-quinuclidin-3-yl phenethylcarbamate (Compound III), Method B.

[0104] a) Preparation of N-phenethyl-1H-imidazole-1-carboxamide (compound lib).

[0105] 5.0 g (30.8 mmol) of 1,1′-carbonyldiimidazole was added to a solution of 3.13 g (25.8 mmol) of 2-phenethylamine in 70 mL of dichloromethane under a nitrogen atmosphere. After stirring the mixture at room temperature for 3.5 hours, 70 mL of water was added. The aqueous layer was separated, the organic layer was washed with 70 mL of water and evaporated to dryness under reduced pressure. 5.11 g (92%) of N-phenethyl-1H-imidazole-1-carboxamide were obtained as a white solid and used in the next step without further purification.

[0106] RMN1H(CDCl3),δ(ppm):3.00(t,2H,CH2Ar);3.72(m,2H,CH2N);6.50(s,1H,NH);7.08(s,imidazole);7.00-7.45(m, 6H,Ar+imidazole);8.28(s,1H,imidazole).

[0107] b) At room temperature, 2.36 g (18.6 mmol) of 3(R)-quinine alcohol was slowly added to a suspension of 0.82 g (20.5 mmol...

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Abstract

The invention provides a new process for the preparation of solifenacin or a pharmaceutically acceptable acid addition salt thereof, comprising reacting (R)-quinuclidin-3-yl phenethylcarbamate with benzaldehyde in the presence of an acid to obtain a diasteroisomeric mixture (S,R)-((R)-quinuclidin-3-yl)1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate of formula (IV) which can be resolved and the solifenacin or a pharmaceutically acceptable acid addition salt thereof recovered. The invention also provides the new key intermediate (R)-quinuclidin-3-yl phenethylcarbamate involved in the process. Further the invention provides a method for the transformation of (R)-((R)-quinuclidin-3-yl)1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate into a diasteroisomeric mixture (S,R)-((R)-quinuclidin-3-yl)1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate.

Description

technical field [0001] The present invention relates to obtaining (S)-1-phenyl-3,4-dihydroisoquinoline-2 (1H)-carboxylic acid ((R)-quinuclidin-3-yl) ester (sofenacin ( solifenacin)) or an acid addition salt thereof, in particular an improved method of a pharmaceutically acceptable acid addition salt thereof. The present invention also relates to novel intermediate compounds for the synthesis of solifenacin. The present invention also relates to the conversion of (R)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ((R)-quinuclidin-3-yl)ester into diastereomeric Method for isomerizing mixture (S,R)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ((R)-quinuclidin-3-yl)ester. Background technique [0002] Solifenacin, namely (3R)-1-azabicyclo[2.2.2]oct-3-yl-(1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H )-carboxylic acid ((R)-quinuclidin-3-yl) ester or 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3(R)- The quinuclidinyl ester, also known as YM-905 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02A61P13/02A61P13/10
Inventor J.贝萨贝尔芒特M.科贝拉莫拉托
Owner ISOCHEM SA
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