Sodium hydride → Hydrogen Bromide

Participants

Reaction Steps

The synthesis route to prepare nifrolidine 9 is shown in FIG. 2. Starting with 3,5-dibromopyridine 1,3-bromo-5-methoxypyridine 2 was prepared in approximately 60%-89% yield by treatment with sodium hydride in methanol. Using an alternate procedure of sodium methoxide in N,N-dimethylformamide, more reproducible results were obtained in this reaction. Demethylation of 2 with refluxing hydrogen bromide provided 3-bromo-5-pyridinol 3 in 82% yield. The mixture generally had to be refluxed for longer times than reported (36 h rather than 16 h) for the high yields. Protection of (S)-pyrrolidinemethanol 4 was performed with di-tert-butyldicarbonate to provide 1-BOC-2-(S)-pyrrolidinemethanol 5 in 88% yield (alternatively, 5 is also available from Aldrich Chemical Co.). Mitsonobu reaction coupling of 3 and 5 was performed by diethyl azodicarboxylate in the presence of triphenylphosphine to provide the bromopyridyl ether 6 in 44% yield, which is somewhat lower than reported. To introduce a 3′-propanolic group at the 5-position, an allyl group was introduced. Using reported procedures, allylation of this bromo derivative 6 was first performed by allyltributyl tin in the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium to provide the 5-allylpyridyl ether derivative 7 in 57% yield. Hydroboration of the allyl group followed by alkaline hydrogen peroxide treatment using previously described conditions led to the important alcohol intermediate, 8 in 26% yield. The low yield in this step was probably a result of the formation of a BH3 complex of the alcohol 8. Some preliminary efforts to neutralize this BH3 complex were not successful. Similar BH3-complex formation has recently been reported for other amines. The substituted alcohol 8 was treated with DAST to convert the alcohol to the corresponding fluoride using methods that we have previously used. Removal of the N—BOC group was achieved by treating with TFA to provide 9 in 25% yield. Final product 9, nifrolidine, was used as a p-toluenesulfonate salt for in vitro binding assays. For radiolabeling with 18F, the tosylate 10 was prepared from the BOC-protected key alcohol intermediate 8 by reacting with toluenesulfonyl chloride in yields of 40%-50%. The tosylate 10 was found to be stable and suitable for 18F radiolabeling and was stored at 0° C. to 20° C.

Provenance & Evidence