Preparation of 2-Cl-5-F-nicotinate and nicotonic acid

Abstract

Production of 2-chlorine-5-fluorine-nicotinate and acid is carried out by 2-chlorine-5-fluorine-nicotinate and related carboxylic acid selective dechlorinating, and 2-chlorine-5-fluorine-nicotinate hydrolyzing 2-chlorine-5-fluorine-niacin under the exist of alkaline substances. It can be used for 2-chlorine-5-fluorine-nicotinate and 2-chlorine-5-fluorine-niacin medicine intermediate.

Description

Technical field: [0001] The invention relates to a preparation method of nicotinic acid ester with chlorine and fluorine groups and nicotinic acid drug intermediates, in particular to a preparation method of 2-chloro-5-fluoro-nicotinic acid ester and acid. Background technique: [0002] 2-Chloro-5-fluoro-nicotinic acid ester and 2-chloro-5-fluoro-nicotinic acid are relatively important drug intermediates, but so far there is no effective synthetic method to prepare this product, and it has been reported in the literature Two preparation methods, one method is to use 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester to react with methyl mercaptan first, and then use Raney nickel as a catalyst to hydrogenate and remove methyl mercapto to obtain 2-chloro- 5-Fluoro-nicotinic acid ethyl ester, and then hydrolyzed to obtain 2-chloro-5-fluoro-nicotinic acid (J.Med.Chem.1993.2678-2688); another method is to start from 2-hydroxy-nicotinic acid and first nitrate Then chlorinated to gi...

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Problems solved by technology

[0002] 2-Chloro-5-fluoro-nicotinic acid ester and 2-chloro-5-fluoro-nicotinic acid are relatively important drug intermediates, but so far there is no effective synthetic method to prepare this product, and it has been reported in the literature Two preparation methods, one method is to use 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester to react with methyl mercaptan first, and then use Raney nickel as a catalyst to hydrogenate and remove methyl mercapto to obtain 2-chloro- 5-Fluoro-nicotinic acid ethyl ester, and then hydrolyzed to obtain 2-chloro-5-fluoro-nicotinic acid (J.Med.Chem.1993.2678-2688); another method is to start from 2-hydroxy-nicotinic acid and first nitrate Then chlorinated to give 2-chloro-5-nitro-nicotinic acid, which was reduced by iron powder to give 2-chloro-5-amino-nicotinic acid, 2-chloro-5-amino-nicotinic acid was diazotized in fluoboric acid The obtained diazonium fluoroborate is heated to obtain 2-chloro-5-fluoro-nicotinic acid (EP0634413A1)

[0007] In the literature synthesis route 1, one must replace 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester with the smelly methyl mercaptan, and at the same time use Raney nickel as the catalyst to selectively remove the methyl mercapto group, Yield is only about 30%, and this reaction has higher requirements on the type of Raney nickel, and the product cannot be obtained with general Raney nickel; and the synthesis process of document synthesis route 2 is too long, and the final diazonium fluoroborate is heated The yield of fluorination reaction is too low and difficult to operate

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