The synthetic method of 2,4-difluorobenzylamine

Abstract

The invention relates to the fields of medicine and agrochemicals, and concretely relates to a synthetic method of an intermediate 2,4-difluorobenzene methylamine. The synthetic method comprises the following steps: 1) m-difluorobenzene, a halogenating agent and paraformaldehyde are reacted under effect of a catalyst to prepare 2,4-difluoro benzyl halide; 2)the prepared 2,4-difluoro benzyl halide and urotropine are reacted to prepare a quaternary ammonium salt compound IV; 3)the prepared quaternary ammonium salt compound is hydrolyzed by concentrated hydrochloric acid to obtain 2,4-difluorobenzene methylamine. The method has the advantages of low cost of the prepared 2,4-difluorobenzene methylamine, convenient operation and high security coefficient, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of medicines and agricultural chemicals, in particular to a synthesis method of an intermediate 2,4-difluorobenzylamine. Background technique [0002] 2,4-Difluorobenzylamine is an important pharmaceutical intermediate, and one of its uses is to synthesize Dolutegravir, a new anti-AIDS drug. In August 2013, the FDA approved Dolutegravir in combination with other antiretroviral agents for previously treated or newly treated HIV-1 adults and children aged 12 and over weighing at least 40 kg. Analysts predict that dolutegravir is expected to become a blockbuster drug with annual sales of billions of dollars. [0003] The existing 2,4-difluorobenzylamine synthesis routes are basically obtained through reduction reactions, as follows: [0004] 1. The synthetic method of 2,4-difluorobenzylamine (US5068371 and Chemistry-AEuropeanJournal, 2013, vol.19, #14p.4437-4440) that has been reported so far, is formed by...

AI Technical Summary

Problems solved by technology

[0004] 1. The synthetic method of 2,4-difluorobenzylamine (US5068371 and Chemistry-AEuropeanJournal, 2013, vol.19, #14p.4437-4440) that has been reported so far, is formed by 2,4-difluorobenzonitrile in It is produced by pressurized hydrogenation in an ammonia atmosphere. The raw materials of this route are expensive, and the yield is only 67%, and it needs to use flammable and explosive Raney nickel, hydrogen and ammonia at high temperature, and the operating conditions are relatively harsh.

[0005] 2. There is another report on the method of reducing benzonitrile with borane-THF complex (Journal of the Chemical Society, Perkin Transactions 1 (2002), (2), 197-206), there is also a reducing agent that is expensive, and 2,4-difluoro The market price of benzonitrile is 500-650 yuan / kg, and it is very toxic and inconvenient to operate

[0006] 3. For the analog fluorobenzaldehyde (J.Med.Chem.2006,49,6197-6208), the oxime is obtained by treatment with hydroxylamine, and then PtO2 hydrogenation reduction method, its raw materials and catalysts are expensive, and the hydrogenation operation is inconvenient

[0007] 4. WO2009100169 reported the preparation of the analogue 5-bromo-6-fluorobenzylamine. This method uses the corresponding benzamide as the raw material, BH3-Me2S as the reducing agent, and heats to 50°C in THF to react, and there is also reduction The agent is expensive, highly toxic, and inconvenient to operate

[0008] 5. WO2012076673 reported using LiAlH4 as a reducing agent, which is also expensive, and the reagent is not safe and not suitable for industrial production

[0009] From the above-mentioned 2,4-difluorobenzylamine synthesis method, although most of the reactions only need one-step reduction to get final product, the yield is low, and the raw material price used is higher, for example, the report of U.S. Patent US5068731 is only The yield is 66%, but the calculated cost price is about 805 yuan / kg

Images