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The preparation method of tolvaptan intermediate

A technology for tolvaptan and intermediates, applied in the field of drug synthesis, can solve problems such as high cost, lack of market competitiveness, and large quantities, and achieve the effects of improving product quality and yield, simple and feasible process methods, and simplified processing methods

Active Publication Date: 2015-12-09
ZHENGZHOU MINGZE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method is simple and feasible, it needs to use a large amount of silver salt compound in the synthesis process, which leads to high cost and lack of market competitiveness.

Method used

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  • The preparation method of tolvaptan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Preparation of methyl 4-nitro-2-methylbenzoate (general formula 4)

[0038] Weigh 18.1g of 4-nitro-2-methylbenzoic acid, add 181g of anhydrous methanol, stir to dissolve, then slowly add 1.81g of concentrated sulfuric acid, heat up to the boiling point of methanol, reflux reaction, TLC (thin layer chromatography) tracking to The raw material (4-nitro-2-methylbenzoic acid) disappeared, cooled to below 30°C, concentrated under negative pressure to recover methanol to dryness, added 181mL ethyl acetate, stirred to dissolve, added 180mL water and stirred to separate layers, and the organic layer solution was re- Wash twice with saturated brine (90mL×2), add an appropriate amount of anhydrous sodium sulfate and dry for 1.5 hours; filter off the desiccant, and seal the filtrate for later use.

Embodiment 2

[0039] Embodiment 2: Preparation of ethyl 4-nitro-2-methylbenzoate (general formula 4)

[0040] Weigh 18.1g of 4-nitro-2-methylbenzoic acid, add 181g of absolute ethanol, stir and dissolve, then slowly add 1.81g of concentrated sulfuric acid, heat up to the boiling point of ethanol, reflux reaction, TLC tracking to the raw material (4-nitrate base-2-methylbenzoic acid) disappeared, lowered the temperature to below 30°C, concentrated under negative pressure to recover ethanol to dryness, added 180mL ethyl acetate, stirred to dissolve, added 180mL water and stirred to separate layers, and the organic layer solution was washed with saturated saline ( 90mL×2) was washed twice, added an appropriate amount of anhydrous sodium sulfate, dried for 1.5 hours, filtered off the desiccant, and the filtrate was sealed for later use.

Embodiment 3

[0041] Embodiment 3: Preparation of methyl 4-amino-2-methylbenzoate (general formula 3)

[0042] In the solution obtained in Example 1, add 1.45g (on a dry basis) of 10% palladium carbon and 108g ammonium formate, stir and react at 45°C until the raw materials disappear, filter off the palladium carbon, wash and filter with a small amount of ethyl acetate Cake once, combine the organic layer solution, wash with saturated brine (60mL×2 times), separate layers, dry over anhydrous sodium sulfate for 1 hour, filter off the desiccant, concentrate under negative pressure to recover ethyl acetate, and obtain light yellow crystal 4 -Methyl amino-2-methylbenzoate.

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Abstract

The invention relates to a method for preparing a tolvaptan intermediate. The method comprises the following steps of: reacting 2-methyl-4-nitrobenzoic acid used as an initial raw material and alcohols under the action of a catalyst to generate 2-methyl-4-nitrobenzoate, and reacting under the action of palladium-carbon catalyst by using ammonium formate as hydrogen donor to obtain 2-methyl-4-aminobenzoate compounds; and reacting the 2-methyl-4-aminobenzoate compounds and o-toluoyl chloride under the alkaline condition to generate 2-methyl-4-N-(2-methylbenzoyl)benzoate, adding alkali and a catalyst at presence of water to perform hydrolysis, extracting a water layer by using an organic reagent for one to two times, after layering, collecting a water-layer solution, adjusting the pH of the water-layer solution to be 5 to 6 to separate solid out, filtering an aqueous solution out to obtain solid remnant, and drying to obtain a target product. By the method, the quality and yield of a product are improved; a method for treating the intermediate is simplified; and a simple and feasible process method is provided for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a method for preparing a tolvaptan intermediate used for treating hyponatremia caused by congestive heart failure, liver cirrhosis, and antidiuretic hormone deficiency syndrome, more specifically, a tolvaptan intermediate. A preparation method of vaptan intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid (general formula 1). Background technique [0002] Tolvaptan is a non-peptide selective antidiuretic hormone V2 receptor antagonist developed by Otsuka Company. It has a strong diuretic effect and is not accompanied by an increase in electrolyte excretion. It was approved by the US FDA in May 2009 and can be used to treat various diseases. Patients with edematous diseases, hyponatremia and heart failure. Tolvaptan is the only oral selective vasopressin antagonist approved for the treatment of hyponatremia caused by congestive heart failure, liver cirrhosis, and hyponatr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/81C07C231/12
Inventor 李海涛张英斌李春风徐贡杰徐培明
Owner ZHENGZHOU MINGZE MEDICAL TECH
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