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Method for preparing tolterodine and tartrate thereof

A technology of tartrate and tolterodine, applied in the field of compounds, can solve the problems of increased production cost, high price of cinnamon chloride, difficult availability of raw materials, etc., and achieves the effects of easy operation, simple post-processing and stable product quality

Active Publication Date: 2009-06-03
2Y CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this route is that the raw materials are not easy to get, and the synthesis of 3-bromo-N, N-diisopropyl-3-phenylpropanamide will be 4 steps, and the total yield is low
The price of raw material cinnamon chloride used in this method is relatively high, which increases the production cost, and the step of amine substitution is easy to generate etherified by-products under its reaction conditions, so the application is limited

Method used

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  • Method for preparing tolterodine and tartrate thereof
  • Method for preparing tolterodine and tartrate thereof
  • Method for preparing tolterodine and tartrate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] in N 2 Under protection, Mg scraps (1.0g, 0.042mol) were heated to 65°C in a 100ml three-necked flask. After half an hour, 30ml of tetrahydrofuran was added, and bromoethane (4.6g, 0.042mol) was diluted with 10ml of tetrahydrofuran (2 drops of bromine Ethane triggers the reaction), slowly drop into the reaction flask, and keep the reflux temperature (65°C). Diisopropylamine (6.4 g, 0.063 mol) was added after the Mg scraps completely disappeared, and refluxed for 1 hour, then a solution of compound 2 in THF (5 g, 0.021 mol dissolved in 10 ml THF) was added, and the temperature (65° C.) was kept at reflux overnight. After the reaction was complete, 10 ml of water was added to quench the reaction, and the pH value was adjusted to 3 with HCl, and 50 ml of ethyl acetate was added to separate the layers, the organic phase was washed with water (30 ml*3), and dried. The solvent was distilled off under reduced pressure, and the residue was crystallized by adding 10 volumes of ...

Embodiment 2

[0037] in N 2 Under protection, diisopropylamine (0.85g, 0.0084mol) was dissolved in 10ml of tetrahydrofuran in a 50ml three-necked flask, cooled to -80°C, and butyl lithium (3.36ml, 0.0084mol) was added to keep the temperature below -60°C and stirred for 30 Minutes to prepare the LDA solution. Compound 2 (1 g, 0.0042 mol) was dissolved in 10 ml of tetrahydrofuran, and added to the prepared LDA solution, and the reaction was complete after 3 hours. Add 5ml NH 4 Quench the reaction with Cl, adjust the pH value to 3 with HCl, add 10ml of ethyl acetate to separate the liquid, wash the organic phase with water (10ml*3), dry, evaporate the solvent under reduced pressure, and crystallize the residue from methanol to obtain the product.

Embodiment 3

[0039] AlCl was placed in a 50ml three-necked bottle at room temperature 3 (1.7g, 0.013mol) was dissolved in 10ml of dichloromethane and cooled to 0°C. And diisopropylamine (2.8g, 0.028mol) was dissolved in 10ml of dichloromethane and AlCl was added 3In the dichloromethane solution, the temperature is controlled to be less than 20°C. Naturally rise to room temperature. Compound 2 (2 g, 0.0084 mol) was dissolved in 10 ml of dichloromethane and added to the reaction flask. After the reaction was complete, 50ml of water was added to quench, filtered, separated, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized by methanol to obtain the product.

[0040] (2), the synthesis of compound 1 tolterodine free base:

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Abstract

The invention relates to a method for preparing tolterodine and tartrate thereof, which comprises the steps: A) diisopropylamine and compound 2 (3, 4- dihydro-6- methyl-4-phenyl-2H-chromene-2- ketone can be activated and react, and then are decompressed and concentrated after being quenched, acidulated and extracted by organic solvent; after that, the mixture is added with crystallization solvent to be crystallized, and compound 3 is prepared; B) the compound 3 is deacidized by reducing agent, and then is quenched, separated and purified to obtain compound 1 tolterodine free alkali; C) the compound 1 tolterodine free alkali is dissolved by L-(+) tartaric acid, and compound 4 tolterodine tartrate is prepared. The method has short steps, low cost, high yield coefficient, easy operation and simple post treatment, and is stable in the quality of the prepared products and convenient for commercial process.

Description

technical field [0001] The present invention relates to compound tolterodine [(R)-N, N-diisopropyl-3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylamine] and its L-tartrate Preparation. Background technique [0002] Tolterodine (tolterodine, 1) is the common name of compound (R)-N, N-diisopropyl-3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylamine, its structural formula for: [0003] [0004] Tolterodine (1) [0005] Tolterodine (tolterodine) is a highly selective competitive M (muscarinic acid) receptor antagonist to the bladder developed by the company Pharmacia of the United States, which can competitively bind to the M receptor, thereby preventing Blocking the combination of neurotransmitter acetylcholine and M receptors can effectively inhibit the contraction of detrusor muscle, thereby relieving symptoms such as frequent urination, urgency and urgency urinary incontinence, and its metabolites are more selective for M receptors. It is widely used because of its good cu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/54C07C213/10C07C213/00A61P13/06A61P13/00
CPCC07C231/10C07C213/00C07B2200/07A61P13/00A61P13/06C07C215/54C07C235/34
Inventor 王刚张景忠何训贵王元
Owner 2Y CHEM
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