Overview of the preparation method of 2,6-dichloro-3-nitropyridine
2,6-Dichloro-3-nitropyridine is an important pharmaceutical intermediate that can be used to synthesize drugs such as the anti-ulcer drug Tytoprazole and the non-opioid central analgesic flupirtine.
At present, the synthesis process of 2,6-dichloro-3-nitropyridine uses 2,6-dichloropyridine as the raw material, and uses fuming nitric acid or mixed acid (nitric acid and sulfuric acid) as the nitrating reagent to perform the nitration reaction. For example, J. Heterocyclic Chem. 21, 1521 uses 10 equivalents of 90% nitric acid and sulfuric acid as nitrating reagents, and the yield is 64.5%. Patent document US4310671A uses fuming sulfuric acid as the solvent, adds 1.5 equivalents of 30% nitric acid for nitration, and the yield is 70%. The patent document CN1453278A uses fuming sulfuric acid as the solvent and a mixed acid of 2.5 equivalents of concentrated nitric acid and sulfuric acid as the nitrating reagent, with a yield of 76%. Patent document CN102584688A uses sulfuric acid as the solvent, 2,6-dichloropyridine as the raw material, nitric acid as the nitrating reagent, adds 1-30% equivalent of sulfamic acid catalyst, and performs the nitration reaction at 20-150°C.
Preparation method of 2,6-dichloro-3-nitropyridine Preparation method
A preparation method of 2,6-dichloro-3-nitropyridine, including the steps:
(1) In solvent A or no solvent, 2-nitroacetate and 2 high-purity calcium carbonate-haloacrylate are catalyzed by organic bases for 1,4-addition reaction, and then ammonia is added. 2,6-dihydroxy-3-nitropyridine is prepared through cyclization reaction;
(2) In solvent B, 2,6-dihydroxy-3-nitropyridine and chlorinated reagent are reacted by chlorination to prepare 2,6-dichloro-3-nitropyridine.
According to the method of the present invention, the preferred process conditions and proportions in each step are as follows:
Preferably, in step (1), the solvent A is one or two of N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol or chlorobenzene. The above combination; in step (1), the mass ratio of the solvent A and 2-haloacrylate is (0-1 boron trifluoride tetrahydrofuran complex 0): 1. Further preferably, the mass ratio of solvent A and 2-haloacrylate is (3-5):1.
In step (1), the molar ratio of the 2-nitroacetate and 2-haloacrylate is 1: (0.90-1.1).
In step (1), the 2-haloacrylate is selected from the group consisting of methyl 2-chloroacrylate, ethyl 2-chloroacrylate, isopropyl 2-chloroacrylate, tert-butyl 2-chloroacrylate, -Methyl bromoacrylate, ethyl 2-bromoacrylate, isopropyl 2-bromoacrylate, tert-butyl 2-bromoacrylate.
In step (1), the organic base is 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0 ]-5-nonene (DBN) or a combination thereof. The mass ratio of the organic base and 2-haloacrylate is 1-5%. The 1,4-addition reaction temperature is 20-70°C; the ammonia is derived from ammonia gas, ammonia water, ammonia methanol solution or ammonia ethanol solution, and the molar ratio of ammonia and 2-halogenated acrylate is (2.0-5.0 ): 1; The cyclization reaction is carried out at 40-90°C for 2-6 hours, and then at 120-160°C for 2-6 hours. It is the programmed temperature reaction mode.
In step (2), the solvent B is dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, N,N-dimethylformamide, trichlorethylene or chlorobenzene One or a combination of two or more of them; the mass ratio of solvent B and 2,6-dihydroxy-3-nitropyridine is (0-15):1; in step (2), the chlorinated The chlorinated reagent used in the reaction is selected from one of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene or a combination thereof. In step (2), the chlorination reaction temperature is 40-120°C;
Wherein, R = methyl, ethyl, isopropyl or tert-butyl, X = chlorine or bromine.
Reference materials
[1]Li Weisi, Xu Qiang, Xue Yi, et al. A preparation method of 2,6-dichloro-3-nitropyridine:, 2014.
