[CH:1]1([NH:4][C:5]2[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=2[C:7]([O:9]CC)=O)[CH2:3][CH2:2]1.ClS([N:23]=[C:24]=[O:25])(=O)=O.C([O-])(=O)C.[Na+].CC(C)([O-])C.[Na+]>ClCCl>[CH:1]1([N:4]2[C:5]3[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=3[C:7](=[O:9])[NH:23][C:24]2=[O:25])[CH2:2][CH2:3]1
A solution of 4.1 g (15.2 mmol) of ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34) in 125 mL of dichloromethane is cooled to −20° C. and treated dropwise with 5.24 g (37 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at −20° C. for 3 hours and allowed to come to room temperature overnight. The mixture is recooled to −20° C. and treated with 6.8 g (80 mmol) of solid sodium acetate. After stirring for 1 hour without cooling, the solvent is removed in vacuo without heating. The residue is triturated with a saturated solution of sodium acetate in brine and extracted with ethyl acetate (3×75 mL). The combined organic layers are dried (MgSO4), filtered and evaporated in vacuo. The residue is suspended in 100 mL of tetrahydrofuran and treated with 3.6 g (32 mmol) of solid sodium tert-butoxide and stirred at room temperature for 36 hours. The solvent is removed in vacuo, the residue triturated with 100 mL of 0.1 M formic acid and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give a residue which is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane to give 0.75 g of the title compound, mp 220–222° C.
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