[N:1](OC(C)(C)C)=O.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([NH:24][CH2:25][C@H:26]([OH:28])[CH3:27])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO.C([O-])(=O)C.[NH4+]>O1CCCC1.[Zn].C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:19]([C:20]([NH2:1])=[N:21][N:24]2[CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:22][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Tert-butyl nitrite (759 mL, 6.38 mol) was added to a stirred solution of (R)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (1), prepared according to the methods described in WO 02/98861 A1 and WO 02/98862 A1 (1.20 kg, 4.25 mol) in 12 L of tetrahydrofuran under an atmosphere of nitrogen. After 1 h, the solution was cooled to 15° C., and 2.6 L of methanol was added followed by 10 L of saturated aqueous ammonium acetate solution. Zinc dust (1.1 kg, 17 mol) was added over 1.5 h, keeping the reaction temperature below 40° C. Ethyl acetate (10 L) was added, and the liquid phase was decanted from the solid residue and combined with that from one additional run on the same scale. The combined liquid phases were partitioned between ethyl acetate and brine. The organic solution was dried (Na2SO4), treated with decolorizing charcoal, filtered and concentrated in vacuo to afford 1976 g (78%) of 2.
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