Synthetic background and overview of 2-trifluoromethyl-4-aminopyridine
2-Trifluoromethyl-4-aminopyridine is an organic intermediate that can be prepared through a three-step reaction from 4,4-dimethoxybutan-2-one and ethyl trifluoroacetate.
Synthesis and preparation of 2-trifluoromethyl-4-aminopyridine
Synthesis step 1 of 2-trifluoromethyl-4-aminopyridine, (Z)-6,6,6-trifluoro-5-hydroxy-1,1-dimethoxy-hexyl- 4-en-3-one (compound 16-A)
To the stirred mixture of 4,4-dimethoxybutan-2-one (47.39g) and ethyl trifluoroacetate (76.54g), a methanol solution of sodium methoxide (25 mass) was added dropwise at room temperature. %, 123 mL) and continued stirring at the same temperature for 6 hours. The reaction mixture was then cooled to 10°C and 20% aqueous H3PO4 (150 mL) was added dropwise until pH ~4. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated. The aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain (Z)-6,6,6-trifluoro-5-hydroxy-1,1-dimethoxy-hex-4- as a brown oil. En-3-one (16-A) (64.05g). LCMS: 227.26 (M-H+), retention time 0.53min.
1H NMR (MHz, CDCl3) δppm 5.98 (s, 1H), 4.79 (t, J = 5.7Hz, 1H), 3.39-3.35 (m, 7H), 2.76 (d, J = 5.6Hz, 2H) .
Synthesis step 2 of 2-trifluoromethyl-4-aminopyridine, (Z)-4-amino-1,1,1-trifluoro-6,6-dimethoxy-hexane- 3-en-2-one (compound 17-A):
Purge the stirred (Z)-6,6,6-trifluoro-5-hydroxy-1,1-dimethoxy-hex-4-en-3-one (16-A) with gaseous NH3 ) (8.50g) dioxane solution for 1 hour. The container was sealed and heated at 40°C for 8 hours. The chromium picolinate reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography to give (Z)-4-amino-1,1,1-trifluoro-6,6-dimethoxy-hex-3-en-2-one (Z) as a brown oil. 17-A)(5.92g). LCMS: 226.28(M+H+), retention time 0.88min.
1H NMR(MHz,DMSO-d6)δppm 2.60(d,J＝5.8Hz,2H),3.26(s,6H),4.66(t,J＝5.8Hz,1H),5.35(s,1H) ,8.93(br s,1H),9.88(brs,1H).
Synthesis step 3 of 2-trifluoromethyl-4-aminopyridine, 2-trifluoromethyl-4-aminopyridine (compound 10-A):
To stirred (Z)-4-amino-1,1,1-trifluoro-6,6-dimethoxy-hex-3-en-2-one (17-A) (4.34g ) was added to an acetonitrile solution, NH4OAc (7.35g) was added and then acetic acid (3.1mL) was added. The container was sealed and heated at 150°C for 8 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with sodium percarbonate twice with CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain 2-trifluoromethyl-4-aminopyridine (10-A) as a pale yellow oil (1.86 g). LCMS163.24(M+H+), retention time 0.19min.
1H NMR(MHz,DMSO-d6)δ6.56(br.s.,2H)6.65(dd,J＝5.6,1.96Hz,1H)6.89(d,J＝2.1Hz,1H)8.09(d ,J=5.6Hz,1H).
References
[1] [Chinese invention] CN201780074390.9 Pesticide-active heterocyclic derivatives with sulfur-containing substituents
