Synthesis Of 2-chloro-5-trifluromethylpyridine

2-chloro-5-trifluromethylpyridine (CTFP) is a key intermediate for agrochemical and pharmaceutical synthesis. In this thesis, a novel method of CTFP synthesis derived from 3-methylpyridine was developed in 4 steps, i.e., N-oxidation, chlorination with benzoyl chloride, chlorination with the chlorine, and fluorination with KF, which involved in three intermediates as N-oxide-3-methylpyridine(NOMP), 2-chloro-5-methylpyridine(CMP), and 2-chloro-5-trichloromethylpyridine (CTP) respectively. All the four synthetic processes were optimized by an overall yield of 30.5% CTFP, which show the benefit of cheap materials, mild reaction conditions and controllable operation. Each step of the reactions is described as follows:1. Synthesis of N-oxide-3-methylpyridine(NOMP)3-Methylpyridine was treated with 30% H2O2 in an acetic acid solution under 70℃for 24 hours, where the molar ratio of 3-methylpyridine to 30% H2O2 is 1:1.5 and 84.8% yield of NOMP with 93.9% content in the crude product was obtained;2. Synthesis of 2-chloro-5-methylpyridine(CMP) CMP was prepared by the treatment of NOMP with benzoyl chloride in dichloromethane in the presence of triethylamine as the acid scavenger, where the molar ratio of N-oxide-3-methylpyridine to benzoyl chloride is 1:1.4, and 54.4% yield of CMP was obtained with 81.5% content in the crude product after reluxing for 3 hours with agitating;3. Synthesis of 2-chloro-5-trichloromethylpyridine(CTP)CMP was dealed with chlorine as chlorination reagent and azodiisobutyronitrile(AIBN) as activator in 1,2-dichlorobenzene solvent. 5% AIBN to CMP dosage was introduced and a mixture containing 78.3% CTP was obtained under 140℃for 20 hours. Pure CTP was achieved by silica column separation in 82.7% yield;4. Synthesis of 2-chloro-5-trifluromethylpyridine(CTFP)Fluorination was realized by the treatment of CTP with anhydrous KF as the fluorination reagent and hexadecyl trimethyl ammonium bromide (CTAB) as the phase transfer catalyst in DMSO. 80.0% yield of CTFP was obtained at 99% content in product with a molar ratio of CTP to KF 1:2 and 8% CTBA to CTP dosage after refluxing for 6 hours.NOMP, CMP, CTP, and CTFP were characterized by GC-MS and 1H NMR spectra.