[Cl:1][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.Cl.[CH:21]12[NH:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][O:23][CH2:22]2.C(N(C(C)C)CC)(C)C>C(#N)C.C(Cl)Cl.Cl.C(OCC)C>[ClH:1].[CH:25]12[N:28]([CH2:2][C:3]3[N:7]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=4)[N:6]=[N:5][N:4]=3)[CH:21]([CH2:27][CH2:26]1)[CH2:22][O:23][CH2:24]2
To a solution of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 1.70 g, 5.91 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (Intermediate 27, 0.884 g, 5.91 mmol) in acetonitrile (25 mL) was added di-isopropylethylamine (2.06 mL, 11.8 mmol). The reaction was heated to 85° C. and stirred for 6 hours. The reaction was cooled and the solvent removed under vacuum. The residue was partitioned between DCM (100 mL) and water (50 mL). The aqueous layer was separated and extracted with DCM (50 mL). The DCM layers were combined and the solvent removed. The residue was purified by silica chromatography (Biotage SP4, eluting a gradient of ethyl acetate in iso-hexane) to yield a colourless gum. The product was dissolved in a minimum of DCM before the addition of 1N HCl in diethyl ether (10 mL). The solvent was removed from the resulting suspension. The solid obtained was triturated with diethyl ether (5 mL), the ether decanted and the solid dried under vacuum at 40° C. for 18 hours to yield the title compound as a white solid (1.43 g).
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