[CH3:1][C:2]([CH:4]1[CH2:7][CH2:6][CH2:5]1)=O.Br.BrBr.[CH2:11]([O:13][P:14]([CH2:19][C:20]([NH2:22])=[S:21])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[OH-].[NH4+]>C(O)(=O)C.C(OCC)(=O)C.CO.O.CO>[CH2:11]([O:13][P:14]([CH2:19][C:20]1[S:21][CH:1]=[C:2]([CH:4]2[CH2:7][CH2:6][CH2:5]2)[N:22]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]A 250-mL round-bottom flask equipped with a thermometer, drying tube (calcium chloride) was charged with 10.0 g (0.1019 mol) of cyclobutyl methyl ketone (SEA C Lot 01) and 80 mL of methanol. The mixture was cooled to 5° C., and 0.8 mL of a 30% solution of hydrogen bromide in acetic acid was added, followed by 5.0 mL (0.09705 mol) of bromine, during a period of 10 min, while the temperature of the slight exotherm was maintained at about 5° C. The mixture was stirred for 4 hours at 5° C. (Decolorization from dark brown to light orange occurred after 75 minutes). To this mixture was added dropwise 10.0 mL of water, with cooling in an ice bath (the temperature rose from 5° to 10° C.). After the addition, the mixture was stirred at room temperature for a period of 45 minutes. To this mixture was added 20.45 g (0.0968 mol) of crude compound of Example 1 as a powdered solid which dissolved gradually with concomitant decolorization of the yellow solution. The reaction temperature during the addition of the compound of Example 1 was maintained at 30° C. by an ice bath. The mixture was stirred at room temperature overnight. At that time, the compound of Example 1 was no longer detectable (TLC, Merck silica gel 60, F-254; 95:5 ethyl acetate-methanol). The mixture was rendered basic with concentrated ammonium hydroxide solution while the temperature was maintained at 20° C. with an ice bath and was then evaporated. The residue was taken up in 150 mL of ethyl acetate. This solution was washed with 100 mL of water and the aqueous phase was reextracted with 75 mL of ethyl acetate. 50 mL of brine was used to wash, in succession, the first and the second ethyl acetate solutions. The ethyl acetate solutions were combined and dried over sodium sulfate. After solvent evaporation and drying at 60° C. at 10 torr, there was obtained 28 g of crude [(4-cyclobutyl-2-thiazolyl)methyl]phosphonic acid diethyl ester as a dark oil, 99.83% pure (HPLC); 100% yield based on the compound of Example 1 used.
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