General Papers ARKIVOC 2008 (xvii) 287-294
spectrum of this precipitate showed that Et3N·HCl had coprecipitated along with urea 6. Then, we tried to remove the ammonium salt by washing the precipitate with H2O and several organic solvents, but all attempts were unsuccessful.
In view of the significant improvement in the yield of 6 achieved using triphosgene, and to avoid the formation of the ammonium chloride, we studied the methodology using a traceless HCl-acceptor, such as propylene oxide. This replacement gave an excellent result, as the urea 6 was isolated by precipitation from the reaction medium in 91% yield and in a HPLC purity higher than 95%. The excess of the starting 6-aminoindazole 4 was recovered from the filtrate of the reaction mixture.
F
N N NCO N Cl Cl 8(CCl3 O)2CO TEA or O CH3 N N N H N N H (S) H N (S) N H O Cl Cl O NHR O F F 6:R = Boc 7: R = H (RWJ-58259) NH2 (S) H N (S) N Ph H O NHBoc O F 5HCl Ph
Scheme 2. Improved formation and N-Boc deprotection of urea 6.
Trying to optimize the reaction efficacy, the influence of the molar ratio 4/5 (1/0.5, 1/0.7 and 1/0.9) was also studied. The results showed that while the reaction yield was not significantly affected, when the molar proportion of the dipeptide 5 was higher than 0.5, this compound coprecipitated with the urea 6, and the purification of the reaction mixture required chromatography.
The final N-Boc-deprotection was carried out quantitatively by treatment with a 3 N solution of HCl in MeOH. This last step did not require chromatographic purification, as in the previously described deprotection using TFA/anisole.2a,6 The hydrochloride of RWJ-58259 (7) was obtained in 91% overall yield (from 5, nine-fold higher than by the described methodology) and with higher than 95% HPLC purity.
Conclusions
In summary, we have developed a significant improvement of the described synthesis of the PAR-1 antagonist RWJ-58259 at laboratory scale (0.1-1 g) required to obtain enough quantity to be used as a standard reference in our pharmacological studies. First, replacement of KOH by Cs2CO3 has allowed to double the yield of the N-alkylation of the indazole derivative 1. Second, by using triphosgene in the presence of propylene oxide as traceless reagents for the urea
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