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Preparation method of tolvaptan

A technology of tolvaptan and intermediates, applied in the field of chemical pharmacy, can solve problems such as unfavorable workshop safety operation, flammability and explosion of anhydrous ether, serious environmental pollution, etc., to achieve environmental protection and reduce labor protection requirements , The effect of high product yield

Active Publication Date: 2011-05-18
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] (2) During the aftertreatment of process flow 2, the reaction solution is directly poured into water, the pH is adjusted to 8-9 with sodium hydroxide solution, and then extracted with methylene chloride, a large amount of lye is consumed, a large amount of waste water is produced, and the environmental pollution is serious
[0012] (3) During process 2 post-treatment, follow-up treatment is extracted with dichloromethane, emulsification is serious, and extraction is difficult, restricting product yield
Anhydrous ether is flammable and explosive, which is not conducive to safe operation in the workshop

Method used

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  • Preparation method of tolvaptan

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Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1: the synthesis of intermediate III

[0028] 2-Methyl-4-nitrobenzoic acid (purchased from Tianjin Alpha Aisha Chemical Co., Ltd., purity>99%, 25g, 0.14mol) was added to a 250ml reaction bottle, and reacted with thionyl chloride for 3h under reflux conditions , thionyl chloride was distilled off under reduced pressure to obtain 2-methyl-4-nitrobenzoyl chloride (26.8 g, light yellow oily liquid), which was directly used in the next step without purification.

[0029] Intermediate II (20 g, 0.1 mol) and 2-methyl-4-nitrobenzoyl chloride (22.4 g, 0.11 mol) were added to a 250 ml reaction flask. Add dichloromethane (50ml), cool in an ice bath to 0-5°C and stir until dissolved, slowly add N-methylmorpholine (11.2g, 0.11mol) dropwise, stir for a while after dropping, and react at room temperature for 4h. TLC [developing solvent: ethyl acetate-petroleum ether (1:1), the same below] shows that after the reaction is complete, add saturated aqueous sodium bicarbonate (...

Embodiment 2

[0030] Embodiment 2: the synthesis of intermediate IV

[0031] Intermediate III (10g, 28mmol) was added to a 250ml reaction flask, concentrated hydrochloric acid (40ml) and ethanol (50ml) were added, stirred, and an ethanol solution (40ml) of stannous chloride (20g, 88mmol) was slowly added dropwise. After dropping, react at room temperature for 5h. After TLC showed that the reaction was complete, about 70 ml of ethanol was distilled off under reduced pressure, and the residue was cooled at -10°C-0°C overnight. After filtering, the filter cake was washed with water and poured into water (40ml). Add 20% aqueous sodium hydroxide solution (about 60ml) to adjust to pH 9. Filter and recrystallize with absolute ethanol to obtain light yellow powder solid IV (6.3 g, 68.7%), mp 190.4-191.1°C. Purity 97.2% (HPLC normalization method).

Embodiment 3

[0032] Embodiment 3: the synthesis of intermediate V

[0033] Intermediate IV (5g, 15mmol) and triethylamine (2.3g, 23mmol) were sequentially added to a 100ml reaction flask, dichloromethane (30ml) was added, and stirred until completely dissolved. Add o-toluoyl chloride (2.8 g, 18 mmol) dropwise, and react at room temperature for 1 h after dropping. TLC showed that the reaction was complete and then poured into ice water (about 40ml), extracted with dichloromethane (20ml×3), combined the organic phases, and washed successively with 5% hydrochloric acid (25ml×3) and saturated sodium chloride solution (25ml×3 ), washed with anhydrous sodium sulfate, and filtered. The solvent (about 50ml) was recovered from the filtrate under reduced pressure, and the residue was recrystallized from anhydrous methanol-petroleum ether (2:1) to obtain white crystal intermediate V (6.2g, 90.9%), mp 121.1-123.6°C. Purity 98.6% (HPLC normalization method).

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Abstract

The invention relates to a preparation method of tolvaptan as an arginine vessel pitressin V2 receptor antagonist. The tolvaptan and the intermediate thereof with high purity and efficiency can be obtained with the preparation method which can be used as an industrial method for mass production. Meanwhile, the invention has the advantages of reducing the emission of waste liquid, being favorable to labor protection, decreasing the production cost and improving the economic benefits.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a preparation method of tolvaptan for treating hyponatremia caused by congestive heart failure, liver cirrhosis and antidiuretic hormone deficiency syndrome. Background technique [0002] Tolvaptan (Tolvaptan trade name: Samsca), chemical name N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepine -1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide is a new oral selective non-peptide V developed by Otsuka Pharm. 2 receptor antagonists. The US FDA approved it in May 2009 for the treatment of hypercapacity or isovolumic hyponatremia caused by congestive heart failure (CHF), liver cirrhosis, and antidiuretic hormone insufficiency syndrome. Oral administration of tolvaptan tablets can significantly reduce the patient's body weight and edema without disrupting the blood electrolyte balance, and can effectively increase the concurrent hyponatremia in CHF patients. Clinic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 刘登科杨传伟刘颖王平保吴疆
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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