Preparation methods of varenicline intermediate, varenicline and its salt

Abstract

The invention discloses preparation methods of a varenicline intermediate, varenicline and its salt. The invention provides a preparation method of a compound shown in a formula I. The preparation method comprises the following steps: carrying out a cyclization reaction on the compound 2 and glyoxal in the presence of a solvent and alkaline acid salt by using or not using inert gas protection to generate the compound as shown in the formula I, wherein R is an amino protecting group. The method can greatly shorten the reaction time of the cyclization reaction under the condition of ensuring the product yield and the product purity, obviously improve the production efficiency of the cyclization product, and greatly reduce the production cost and the time cost of the unit product; and meanwhile, the content of the impurity I in the varenicline intermediate product can be controlled within a relatively low level range, so that the product quality of the drug intermediate and the crude drug can be better guaranteed.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a varenicline intermediate, a varenicline and a salt thereof. Background technique [0002] Varenicline tartrate is a smoking cessation drug that can effectively relieve nicotine craving and / or withdrawal symptoms. It is now on the market in many countries or regions, and has a large market demand. [0003] At present, the market supply of varenicline and varenicline tartrate is affected and restricted by the process routes, one of the more popular synthetic routes is: 2,3,4,5-tetrahydro-7,8-dinitro- 3-(Trifluoroacetyl)-1,5-methylbridge-1H-3-benzazepine (CAS: 230615-59-5), reduced by hydrogen to generate 2,3,4,5-tetrahydro -3-(trifluoroacetyl)-1,5-methylbridge-1H-3-benzazepine-7,8-diamine (CAS: 230615-69-7), and then in bicarbonate (carbonic acid Sodium hydrogen, potassium bicarbonate, etc.) react with glyoxal to generate an intermediate: 7,8,9,...

AI Technical Summary

Problems solved by technology

[0005] However, in the research process of laboratory preparation and / or industrial batch production, we found that the reaction time required by the above-mentioned method is very long; especially, 2,3,4,5-tetrahydro-3-(three The reaction time of fluoroacetyl)-1,5-methylbridge-1H-3-benzazepine-7,8-diamine and glyoxal is as high as more than 20 hours, and the reaction should be controlled in two stages temperature, not only seriously restricts the production efficiency of the method, but also increases the complexity of the operation, which is not conducive to industrial application, nor is it conducive to reducing the production cost and time cost of the unit product.

[0006] And if 2,3,4,5-tetrahydro-3-(trifluoroacetyl)-1,5-methylbridge-1H-3-benzazepine-7,8-diamine and glyoxal The acid salts such as sodium bicarbonate used in the reaction are replaced by organic amines such as triethylamine. Although the reaction time can be shortened and the production efficiency can be improved, since triethylamine and the target drug product belong to organic matter, it is relatively difficult to completely remove it from the product. Difficult, which may cause the target drug prepared by it to have a greater safety risk due to the residue of triethylamine (toxic and highly irritating), which is not conducive to the product quality control of the target drug

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