A kind of preparation method of tolvaptan intermediate 2-methyl-4-n-(2-methylbenzoyl)benzoic acid

Abstract

The present invention relates to a kind of new preparation method of tolvaptan intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid, the method is starting raw material with 3-methylaniline, through Formylation, cyanation, cyano hydrolysis, and amidation reactions give intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid. The raw materials of the invention are easy to obtain, the reaction conditions are mild, the yield is high, no special equipment is needed, no highly toxic or expensive reagents are used, the cost is low, and industrial production is convenient.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid of Tolvaptan, a drug for treating hyponatremia . Background technique [0002] Tolvaptan is a non-peptide selective V2 receptor antagonist developed by Japan's Otsuka Company, which can reduce body fluid load without affecting electrolyte balance and renal function, and is suitable for the treatment of diseases such as hyponatremia. treat. The U.S. FDA approved tolvaptan tablets for marketing in 2009. The trade name is samsca, which is used to treat patients with heart failure. The molecular structure of tolvaptan is as follows: [0003] . [0004] There are many reports on the synthesis route of tolvaptan, but they are mainly divided into two categories according to the composition sequence of the molecular skeleton: [0005] One type of synthetic route is shown in Reaction Sch...

AI Technical Summary

Problems solved by technology

[0014] The reaction uses Pd(OAc) 2 / PPh 3 As a catalyst, the cost is high; using CO gas to react, the conditions are harsh, and the requirements for equipment are also high, and CO is poisonous, which poses a great safety hazard

[0015] Invention patent WO2007026971A2 also describes the method for preparing the intermediate 2-methyl-4-N-(2-methylbenzoyl)benzoic acid, which requires Friedel-Crafts acylation to introduce acetyl groups, and then uses hypohalous acid and hypohalite to oxidize acetyl to formic acid, the requirements for reaction conditions and equipment are relatively high, and the route is long, and the overall yield is not high

[0018] The route is simple, and the yield and purity are high, but the amidation reaction needs to be catalyzed by a large amount of silver salt, which increases the cost, and the structure of the starting material is also complicated and difficult to obtain

[0019] Invention patent CN102690211B uses 2-methyl-4-nitrobenzoic acid as the starting material, first esterifies, then reduces the nitro group to amino group by palladium carbon, then reacts with o-toluyl chloride, and then hydrolyzes the ester bond to prepare intermediate body 2-methyl-4-N-(2-methylbenzoyl)benzoic acid, this route needs to use expensive palladium carbon as a catalyst, and the structure of the starting material is complicated, the price is expensive and difficult to obtain, and the overall cost is high

[0020] In addition, there are also some documents that have adjusted the starting materials and reaction conditions, but are generally similar to the above-mentioned literature reports, and need to be improved in terms of cost, reaction conditions or safety.

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