Preparation method of fluorine-containing primary amine intermediate

Abstract

The invention discloses a preparation method of a fluorine-containing primary amine intermediate. The method comprises the following steps: directly fluorinating an N-hydroxyalkyl phthalimide compound serving as a raw material under the action of an organic solvent and a Lewis acid catalyst to obtain an N-fluoroalkyl phthalimide intermediate, and reducing the intermediate to obtain the fluorine-containing primary amine. According to the method, the raw materials are cheap and easy to obtain, the process route is simple and easy to control, the N-hydroxyalkylphthalimide can be effectively promoted to generate the corresponding fluoride at a high conversion rate, meanwhile, the dehydrofluorination reaction in the fluorination process can be avoided, the yield of the fluoride intermediate is 85% or above, the purity reaches 97% or above, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a fluorine-containing primary amine intermediate, belonging to the technical field of organic fluorine chemistry. Background technique [0002] Fluorine-containing primary amines are important chemical raw materials, widely used in the synthesis and production of fine chemicals such as pharmaceuticals, pesticides, and dyes. Monofluoro primary amines are usually used in drug synthesis, such as 2-fluoroethylamine and its hydrochloride can be used to prepare anticancer drugs, 3-fluoropropylamine hydrochloride can be used to prepare drugs that regulate dopamine neurotransmission for the treatment of central nervous disorders, 5-Fluoropentylamine can be used to synthesize 1H-1,2,4-triazole-3-carboxamide derivatives with antagonistic effects on cannabinoid receptor 1 (CB1). [0003] In the prior art, monofluoro primary amines can be prepared from corresponding fluorine-containing alcohols and fluorine-contain...

AI Technical Summary

Problems solved by technology

Document J.Med.Chem., 1966, 9 (6) 892-911 and Chinese patent CN104496825A disclose a kind of 2-fluoroethanol as raw material, adopt 2-fluoroethanol and p-toluenesulfonyl chloride to generate p-toluenesulfonate fluorine Ethyl ester, which is then reacted with phthalimide potassium salt to generate N-(2-fluoroethyl)phthalimide, and then acidified with hydrazine hydrate to reduce concentrated hydrochloric acid to obtain 2-fluoroethylamine Hydrochloride, this method has disadvantages such as expensive raw materials, long route, and large amount of three wastes

[0004] Monofluoro primary amines can also be prepared by reducing raw materials such as monofluoroamides or nitriles. For example, 2-fluoroethylamine can be prepared by reducing 2-fluoroacetamide or 2-fluoroacetonitrile, or using 1-bromo-2-fluoroacetonitrile Alkanes, 1-chloro-2-fluoroethane functional group conversion preparation, related literature can be found in J. Chem. Soc., 1948, 2174-2177, J. Org. Chem. 1964, 29, 2870-2872, J.Am. . Soc. 1968, 90(10) 2455-2462, etc. The raw materials or intermediates used in these methods are relatively special, the preparation is difficult, and the yield is also unsatisfactory

Except for 2-fluoroethylamine and its hydrochloride, other monofluoro primary amines such as 3-fluoropropylamine, 4-fluorobutylamine, 5-fluoropentylamine, etc. have almost no preparation methods reported in the literature

[0005] In summary, the main problem that the existing fluorine-containing primary amines, especially monofluoro primary amines, cannot be prepared on a large scale is that there is a big problem in the preparation of intermediates. Either the raw materials are not easy to obtain and require special preparation, or the route is long and requires multiple steps. conversion, or a lower yield