【精选】fficient Synthesis of 1,4-Diaryl-5-methyl-1,2,3-triazole, A Potential mGluR1 Antagonist, and th.pdf

Organic Process Research Development 2009, 13, 1407–1412 Efficient Synthesis of 1,4-Diaryl-5-methyl-1,2,3-triazole, A Potential mGluR1 Antagonist, and the Risk Assessment Study of Arylazides Takayuki Tsuritani,*,† Hiroo Mizuno,*,† Nobuaki Nonoyama,† Satoshi Kii,† Atsushi Akao,† Kimihiko Sato,† Nobuyoshi Yasuda,‡ and Toshiaki Mase† Process Research, PreClinical Department, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan, and Process Research, Merck Research Laboratories, Merck Co. Inc., Rahway, New Jersey 07065, U.S.A. Abstract: Scheme 1. Retrosynthetic analysis A concise and practical synthesis of a 1,4-diaryl-5-methyl- 1,2,3-triazole is described. A mGluR1 antagonist 1 was prepared with one-pot operation by the Negishi coupling reaction between two building blocks, 5-bromophthalimidine (2) and 1-aryl-5-methyl-4-triazolylzinc (3-Zn). Bromide 2 was synthesized via N -selective cyclization of o-hydroxymethyl- benzamide 8 easily prepared from phthalide 4. Zinc species 3-Zn was generated in situ by transmetalation of 1-aryl-4- magnesio-5-methyltriazole (3-Mg), which in turn was gener- ated by the regioselective click chemistry between 2,4- difluorophenylazide (5) and propynylmagnesium bromide. The risk assessment of potentially explosive arylazides is also mentioned. 1. Introduction efficient approach to 1 appeared to be the coupling reaction Schizophrenia is one of the most common psychiatric between N-isopropyl-5-bromophthalimidine (2) and 1-aryl-4- diseases. Prevalence of the disease is about 1% of the total metala-5-methyltriazole 3. As to the preparation of N-isopropyl- population over the age of 18. The patient population is 2.2