S(Cl)(N=C=O)(=O)=O.C1(CO)C=CC=CC=1.Cl.[CH3:17][CH:18]1[CH2:21][NH:20][CH2:19]1.Cl[S:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:25])=[O:24]>C(OC(C)C)(=O)C.C(N(CC)CC)C.C(#N)C>[CH3:17][CH:18]1[CH2:21][N:20]([S:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:24])=[O:25])[CH2:19]1
Isopropyl acetate (300 mL) was charged into a 1000 ml 3-neck flask and cooled to −10˜−5° C. Sulfurisocyanatidic chloride (44.5 mL) was added at −5˜10° C. followed by the addition of phenylmethanol (50.5 mL) in isopropyl acetate (60 mL) at −5˜10° C. over 60 minutes. The mixture reacted at −5˜10° C. and was monitored by HPLC until the content of benzyl alcohol was <2% (after 1 hour at 0° C.). A mixture of acetonitrile (300 mL), 3-methylazetidine hydrochloride (50 g) (Intermediate C, either commercially available or prepared as set out below) and triethylamine (162 mL) was stirred in a 2000 mL 3-neck flask and to this was added the solution of the intermediate benzyl chlorosulfonylcarbamate in isopropyl acetate (360 mL) dropwise at <−5° C. over 90 minutes. The mixture was allowed to warm to RT overnight. The reaction was quenched with acetic acid and pH was adjusted to 4˜5. The mixture was separated and the aqueous phase was washed with isopropyl acetate (500 ml) and then separated. The organic phase was combined and washed with 10% brine (2×120 ml), dried with anhydrous magnesium sulphate, filtered and the filter cake washed with isopropyl acetate (30 ml) and filtered to afford the sub-title product (145 g) as a red oil.
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