Preparation technology of solifenacin succinate

A technology of solifenacin and solifenacin succinate, applied in the field of medicine, can solve the problems of helpless conversion rate, low transesterification reaction conversion rate, difficult industrialized production, etc., and achieves rapid and mild reaction process. , the effect of increasing the conversion rate

Active Publication Date: 2015-05-20
CHENGDU SINO STRONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the experiment, it was found that the conversion rate of the transesterification reaction carried out by these two methods is extremely low, and it is difficult to be used in industrial production
In addition, US2009 / 0099365 reported using NaH as the base and DMF as the solvent for transesterification, but it hardly contributed to the improvement of the conversion rate
The reason for the low conversion rate of this type of reaction is related to the nucleophilicity of the by-product ethanol generated by the condensation reaction

Method used

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  • Preparation technology of solifenacin succinate
  • Preparation technology of solifenacin succinate
  • Preparation technology of solifenacin succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The preparation method of Solifenacin Succinate of the present embodiment is as follows:

[0022] 1. First add 10.0g (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 6.3mL triethylamine into 40mL THF (tetrahydrofuran), and drop into the dissolved Add 6.0g of triphosgene to 20mL of toluene solution, add dropwise under ice-water bath, remove the ice-water bath after dropwise addition, and continue to react for 30 minutes. The organic layer was washed twice with 50 mL of water, and concentrated to obtain 12 g of oily (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbamoyl chloride;

[0023] 2. Add 5.6g (R)-3-quinuclidinol to 50mL DMF (dimethylformamide), stir to dissolve, then add 1.2g sodium hydride in an ice-water bath, stir for 5 minutes after adding, remove Ice-water bath, and continue stirring for 1 hour to obtain a DMF solution of sodium (R)-3-quinuclidinate. Dissolve 12g (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbamoyl chloride oil in 50mL DMF, and drop the soluti...

Embodiment 2

[0029] The preparation method of Solifenacin Succinate of the present embodiment is as follows:

[0030] 1. First add 10.0g (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 6.3mL N-methylmorpholine into 40mL tetrahydrofuran, and then drop into the dissolved Add 6.0g of phosgene to 20mL of toluene solution, add dropwise under ice-water bath, remove the ice-water bath after dropwise addition, and continue to react for 30 minutes. The organic layer was washed twice with 50 mL of water, and concentrated to obtain 12 g of oily (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbamoyl chloride;

[0031] 2. Add 5.6g (R)-3-quinuclidinol into 50mL tetrahydrofuran, stir to dissolve, add 2.0g potassium hydride under ice-water bath, stir for 5 minutes after adding, remove the ice-water bath, and continue stirring for 1 hour A DMF solution of potassium (R)-3-quinuclidinate was obtained. Dissolve 12g (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbamoyl chloride oil in 50mL DMF, and drop the sol...

Embodiment 3

[0037] The preparation process steps in Example 1 were adopted, but the reaction solvent therein was replaced for experimentation, and one solvent component was changed each time.

[0038] (1) (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carbamoyl chloride (Ⅱ) reacts with (R)-3-quinuclidinol metal salt (Ⅲ) to form a Phenacin base reaction solvent adopts THF, DMF, dioxane, dichloromethane respectively, and the productive rate of the Solifenacin succinate finally prepared is respectively THF (42%), DMF (58%), dioxane Cyclo(37%), Dichloromethane (31%).

[0039] (2) Synthesis of (R)-3-quinuclidinol metal salt (Ⅲ) is obtained by reacting sodium hydride, potassium hydride and (R)-3-quinuclidinol respectively, and the final prepared solifenacin succinate Yields were consistent. When using DMF as the solvent for condensation, the yields are all about 58%.

[0040] (3) Reaction of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline with phosgene, diphosgene or triphosgene to generate (S)-1-p...

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Abstract

The invention relates to a preparation technology of solifenacin succinate. According to the preparation technology, (S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline carbamyl chloride (II) and (R)-3-quinuclidine alcohol metal salt (III) are reacted to generate solifenacin alkali, and then the solifenacin alkali is prepared into solifenacin succinate. With the adoption of the preparation technology provided by the invention, nucleophilic species which lead to a reverse reaction can be avoided during condensation process, namely, the reverse reaction cannot be generated in the preparation technology, therefore, a transformation rate of the solifenacin succinate is improved, a reaction is greatly promoted, a reaction process is quickly carried out under a mild condition, and the preparation technology is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation process of solifenacin succinate. Background technique [0002] Solifenacin succinate, chemical name (3R)-1-azabicyclo[2.2.2]octane-3-yl(1S)-1-phenyl-3,4-dihydro Isoquinoline-2-(1H)-carboxylate succinate is a selective muscarinic M3 receptor antagonist developed by Japan Astellas Company. This product can selectively relax the detrusor muscle of the bladder and reduce the systemic adverse reactions of anticholinergic drugs in the past, such as dry mouth, constipation, dilated pupils and tachycardia. The structural formula is as follows: [0003] [0004] EP0801067 Condensation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline with ethyl chloroformate followed by (R)-3-quinuclidinol in the presence of sodium hydride Solifenacin was obtained by the transesterification reaction; the transesterification was carried out under reflux in toluene, and the ethanol prod...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D453/02
Inventor 叶丁高建刘力超刘平
Owner CHENGDU SINO STRONG PHARMA
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