Synthesis Of2-chloro-3-amino-4-(trifluoromethyl) Pyridine

Fluorinated compounds comprise a substantial proportion in thetherapeutic drugs. It is an important strategy to introduce fluorine andfluorinated substitutes in the small molecule for structure-based medicinalchemistry. They can modulate the physicochemical and pharmacokineticproperties to improve bioavailability, alter the conformation of a molecule toenhance the selectivities and binding affinity to target proteins, and blockmetabolically labile sites to increase the metabolic stability of drugs.Pyridine is widely distributed in many types of drugs,2-chloro-3-amino-4-(trifluoromethyl) pyridine is a kind of important intermediate. it was usedin the synthesis of a variety of active pharmaceutical intermediates.Objective:The aim is to establish the synthetic method of2-chloro-3-amino-4-(trifluoromethyl)pyridine and to optimize the syntheticconditions of intermediates and target product.Methods: Cyanoacetamide as the raw material was reacted with ethyl4,4,4-trifluoroacetoacetate to form2,6-dihydroxy-3-cyano-4-(trifluoromethyl)pyridine(2). Chlorination of compound(2) with phosphorus oxychloride andtriethylamine afford2-hydroxy-3-cyano-4-(trifluoromethyl)-6-chloro pyridine(3). And then reduction of the compound(3) with Pd/C and hydrogen produced2-hydroxy-3-cyano-4-(trifluoromethyl)pyridine(4), which was chlorinatedwith phosphorus oxychloride to give2-chloro-3-cyano-4-(trifluoromethyl)pyridine(5). Compound(5) was hydrolyzed with con H2SO4to produce2-chloro-4-(trifluoromethyl)nicotinamide(6), finally compound(6) wasallowed to react with a solution of sodium hydroxide and bromine to providedtarget compound (1,2-chloro-3-amino-4-(trifluoromethyl)pyridine). All intermediates and the target compound were identified with melting point,Mass spectrometry, and1H NMR.Results:1. The target compound is successfully prepared as a white powder withoverall yield26.43%from readily available starting materials and the meltingpoint is52~54℃.2. On the basis of studying the reaction conditions, optimum conditions ofintermediates and target product is obtained as follows:(1) Chlorination of compound(2) with phosphorus oxychloride andtriethylamine afford2-hydroxy-3-cyano-4-(trifluoromethyl)-6-chloropyridine.On the basis of studying the reaction time, temperature, base, we make surethat the optimal reaction conditions of chlorination of the compound(2) arethat the mol ratio of [compound (2)]:(phosphorus oxychloride):(triethylamine) is1:10:2, the reaction temperature is65℃and the reactiontime is19h.the yield was82.2%(2) Reduction of the compound(3) with Pd/C and hydrogen produced2-hydroxy-3-cyano-4-(trifluoromethyl)pyridine. On the basis of studying theamount of10%Pd/C, reaction temperature, base. The optimal reactionconditions of reduction of the compound(3) are that the reaction temperature is35℃, the amount of10%Pd/C was0.05times of compound (3). the yieldwas85.0%.Conclusion: The target compound was conveniently prepared.I has present-ed a highly efficient route by the optimisation of the synthetic conditions ofthe route...