Related tolvaptan impurity, and synthesis method and application thereof

A synthesis method and compound technology, applied in the related impurities of tolvaptan, its synthesis field, can solve the problems such as no method to remove, difficulty in purity, etc., to achieve the effect of ensuring safety and effectiveness, simple method, and cost saving

Pending Publication Date: 2021-06-22
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] For the impurities generated during the synthesis of intermediates, if they cannot be removed in time, they will be further derivatized into other impurities during the subsequent reaction with the process, and there is almost no way to remove them after derivation, so it is not easy to obtain API with higher purity

Method used

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  • Related tolvaptan impurity, and synthesis method and application thereof
  • Related tolvaptan impurity, and synthesis method and application thereof
  • Related tolvaptan impurity, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: the influence of the amount of pyridine on the synthetic formula I compound

[0059]

[0060]Dissolve 15.0 g of 2-methyl-4-(2-methylbenzamido)benzoyl chloride (formula V) in 150 g of dichloromethane, and divide the solution into three parts: A, B and C: Add 1.38 g (1.0 equivalent) of pyridine, add 2.06 g (1.5 equivalent) of pyridine to B, and add 2.75 g (2.0 equivalent) of pyridine to C. React at room temperature (15-20°C) for 10 hours.

[0061] The reaction system was washed with 1 mol / L hydrochloric acid (50 mL) and saturated brine (20 mL), dried and concentrated over sodium sulfate, and the product was separated by column chromatography.

[0062] 1 H-NMR (400MHz, d 6 -DMSO): δ10.72(s,2H),8.09(d,J=8.8Hz,2H),7.85-7.78(m,4H),7.51-7.31(m,8H),2.80(s,2H), 2.61(s,6H),2.40(s,6H)ppm.

[0063] LC-MS: quasi-molecular ion 559.1621, [M+K] +

[0064] Each group of experimental formula I compound productive rate compares the following table:

[0065] Produc...

Embodiment 2

[0068] Embodiment 2: the influence of the amount of triethylamine on the synthetic formula I compound

[0069] Add 185.6 g of dichloromethane to 18.2 g of 2-methyl-4-(2-methylbenzamido)benzoyl chloride (Formula V), and dissolve the solution in three parts: A, B and C: A 2.14 g (1.0 equivalent) of triethylamine was added to B, 3.22 g (1.5 equivalent) of triethylamine was added to B, and 4.28 g (2.0 equivalent) of triethylamine was added to C. React at room temperature (20-25°C) for 8 hours.

[0070] The reaction system was washed with 1 mol / L hydrochloric acid (50 mL) and saturated brine (20 mL), dried and concentrated over sodium sulfate, and the product was separated by column chromatography.

[0071] Each group of experimental formula I compound productive rate compares the following table:

[0072] Table 2 different triethylamine consumption yield contrast

[0073] Experimental group Triethylamine equivalents Formula I Yield molar yield A 1.0 2.36g ...

Embodiment 3

[0075] Embodiment 3: the influence of the amount of N-methylmorpholine on the synthetic formula I compound

[0076] Add 220.6 g of dichloromethane to 21.3 g of 2-methyl-4-(2-methylbenzamido)benzoyl chloride (Formula V), and dissolve the solution, and divide the solution into three parts A, B and C: A 2.51 g (1.0 equivalent) of N-methylmorpholine was added to B, 3.80 g (1.5 equivalent) of N-methylmorpholine was added to B, and 5.02 g (2.0 equivalent) of N-methylmorpholine was added to C. React at room temperature (20-25°C) for 8 hours.

[0077] The reaction system was washed with 1mol / L hydrochloric acid (50ml) and saturated brine (20ml) respectively, dried over sodium sulfate, and the product was separated by column chromatography.

[0078] Each group of experimental formula I compound productive rate compares the following table:

[0079] Table 3 different N-methylmorpholine dosage yield contrast

[0080] Experimental group N-methylmorpholine equivalents Form...

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PUM

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Abstract

The invention discloses a related tolvaptan impurity formula I and a synthesis method thereof. The related tolvaptan impurity formula I can be used as a raw material for synthesizing tolvaptan impurities in a formula VI and a formula VII. The impurity disclosed by the invention provides a new reference substance for detection of impurities in a tolvaptan bulk drug and a preparation thereof, and is more beneficial to quality research and quality control of the tolvaptan bulk drug and the preparation thereof. The tolvaptan impurity prepared by the method provided by the invention has the characteristics of simple steps, low cost, small impurity amount and high yield.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a related impurity of tolvaptan, its synthesis method and application. Background technique [0002] Tolvaptan (Tolvaptan, trade name: Samsca, Sumac), chemical name: N-[4-[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1 - Benzazepine 1-formyl]-3-methylphenyl]-2-methylbenzamide. It is a non-peptide selective antidiuretic hormone V2 receptor antagonist developed by Otsuka Pharmaceutical Co., Ltd., which can selectively block renal tubular arginine vasopressin receptors, and can Raise the concentration of sodium ions in blood plasma and help excrete excess water from urine. Tolvaptan can enhance the ability of the kidneys to process water, and can significantly reduce the patient's body weight and edema, without increasing electrolyte excretion, without disrupting blood electrolyte balance, and has the characteristics of water drainage and sodium excretion. In September 2011, it was approv...

Claims

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Application Information

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IPC IPC(8): C07C237/52C07C231/08C07D223/16G01N30/02G01N30/72G01N30/90G01N30/04
CPCC07C231/08C07C237/52C07D223/16G01N30/02G01N30/04G01N30/72G01N30/90G01N2030/047
Inventor 蔡华生黄祺陈洪黄浩喜苏忠海
Owner CHENGDU BRILLIANT PHARMA CO LTD
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