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Asymmetric synthesis method of Solifenacin intermediate

A technology for solifenacin and intermediates, which is applied in the field of preparation of solifenacin intermediates, can solve the problems of cumbersome splitting steps, unsatisfactory enantioselectivity control and the like, and achieves a simple preparation method and high efficiency Effect

Pending Publication Date: 2019-07-23
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1. First prepare the racemate 1-phenyl-1,2,3,4-tetrahydroisoquinoline, and then split to obtain optically pure I. This is the method used in the current drug synthesis process, but the steps of split More cumbersome, but also for R Isomers undergo racemization and re-resolution
[0006] 2. Chiral catalyst catalyzed the asymmetric hydrogenation reaction of latent chiral imine II to obtain I, among which Zhang Xumu group (Chang, M.; Li, Wei.; Zhang, X. Angew. Chem. Int. Ed. 2011, 50 , 10679) reported Ir-( S , S )-(f)-binaphane catalyzed the asymmetric hydrogenation of II with the best results, but the control of enantioselectivity is still not ideal, ee Value is 95%

Method used

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  • Asymmetric synthesis method of Solifenacin intermediate
  • Asymmetric synthesis method of Solifenacin intermediate
  • Asymmetric synthesis method of Solifenacin intermediate

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Experimental program
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Effect test

Embodiment 1

[0027]

[0028] Under nitrogen protection, [Ir(COD)Cl] 2 (1.6 mg, 0.0024 mmol) and the above bisphosphine ligand (3.6 mg, 0.0055 mmol) and 1 mL of tetrahydrofuran were placed in a Schlenk reaction tube, stirred for 30 min, the catalyst solution was transferred to the hydrogenation reaction tube, and 104 mg Imine substrate and 7 μL hydrobromic acid aqueous solution (40%), then add 1 mL tetrahydrofuran, hydrogen replacement three times, at room temperature and 50 atm H 2 After the reaction was completed, the solvent was evaporated to dryness, and the residue was dissolved in 10 mL of dichloromethane, washed with saturated sodium bicarbonate solution, water and brine successively, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, and then a short silica gel column Column chromatography obtains solifenacin intermediate I, 1 H NMR detection reaction conversion > 99 %, chiral HPLC detection enantiomeric excess > 99 % ee . 1 H NMR (400 MHz, CDCl 3...

Embodiment 2

[0030]

[0031] Under nitrogen protection, [Ir(COD)Cl] 2 (1.6 mg, 0.0024 mmol) and the above bisphosphine ligand (4.2 mg, 0.0055 mmol) and 1 mL of tetrahydrofuran were placed in a Schlenk reaction tube, stirred for 30 min, the catalyst solution was transferred to the hydrogenation reaction tube, and 104 mg Imine substrate and 7 μL hydrobromic acid aqueous solution (40%), then add 1 mL tetrahydrofuran, hydrogen replacement three times, at room temperature and 50 atm H 2 After the reaction was completed, the solvent was evaporated to dryness, and the residue was dissolved in 10 mL of dichloromethane, washed with saturated sodium bicarbonate solution, water and brine successively, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, and then a short silica gel column Column chromatography obtains solifenacin intermediate I, 1 H NMR detection reaction conversion rate > 99 %, chiral HPLC detection enantiomeric excess > 84 % ee .

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Abstract

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.

Description

technical field [0001] The invention relates to a preparation method of a solifenacin intermediate, which belongs to the field of medicine. Background technique [0002] Overactive bladder (OAB) is a common clinical manifestation of voiding dysfunction, characterized by urgency, incontinence, frequency and nocturia, etc. OAB greatly reduces the quality of life of patients. Solifenacin succinate (Solifenacin succinate, trade name: Weixikang), is a new generation of cholinergic receptor (M3) blocker, developed by Japan Astellas Company, compared with similar drugs, it has higher selectivity, The curative effect is better, and its structural formula is: [0003] [0004] ( S )-1-phenyl-1,2,3,4-tetrahydroisoquinoline I is an important intermediate for preparing solifenacin succinate, and its preparation method mainly includes the following two kinds: [0005] 1. First prepare the racemate 1-phenyl-1,2,3,4-tetrahydroisoquinoline, and then split to obtain optically pure I. T...

Claims

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Application Information

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IPC IPC(8): C07D217/02
CPCC07B2200/07C07D217/02
Inventor 张生勇聂慧芳朱钰璞周晓伟
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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