Patent ID: 6576786
Filing Date: 2003-06-10
Classification: A61P,C07B,C07C,C07D

Abstract:
A process for preparing a compound of the formula (Ib): whereinR1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and aralkyl; R2 is selected from the group consisting of hydrogen; alkyl, cycloalkyl, halogen substituted alkyl, aryl and substituted aryl; R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkylene, cycloalkyl, aryl and substituted aryl, provided that at least one of R3 or R4 is alkyl; X is NHC(&boxH;NH)NH2; and pharmaceutically acceptable salts thereof; comprising reacting an N-protected compound of formula (II), wherein W is an N-protecting group, â€ƒwith a nitride oxide of formula (III), â€ƒat a temperature which prevents uncontrolled decomposition of the compound of formula (III), â€ƒto yield the compounds of formula (IV) and (IVâ€²); reacting the mixture of the compounds of formula (IV) and (IVâ€²) with alkali or tetra alkyl ammonium hydroxides to form the corresponding alkali metal salts of formula (V) and (Vâ€²), where M+ represents an alkali metal cation or a tetra-alkyl-ammonium cation; reacting the mixture of the compounds of formula (V) and (Vâ€²) with an acid to form the corresponding acids of formula (VI) and (VIâ€²); reacting the compounds of formula (VI) and (VIâ€²) with ammonia or an amine to precipitate the corresponding salt of formula (VII), where Qâ€² represents NH4+ or substituted ammonium cation; reacting the compound of formula (VII) with R1OH and treating with a nonaqueous acid, to yield the compound of formula (IVa), and when the N-protecting group on compound (VII) is t-butoxycarbonyl (Boc), the solution is further treated with di-tert-butyl dicarbonate and a tertiary amine; reducing the compound of formula (IVa) using sodium borohydride and NiCl2 to yield the corresponding aminoalcohol of formula (IX); recrystallizing the compound of formula (IX) from an organic solvent or an alcohol/water mixture, to isolate the corresponding compound of formula (IXa); reacting the compound of formula (IXa) with a compound of formula (X), (R2CO)2O, or a compound of formula (XI), R2COV, where R2 is as described above and V is chlorine or bromine, to produce the corresponding compound of formula (XII); removing the N-protecting group from the compound of formula (XII) to produce the corresponding compound of formula (XIII), or salt thereof, reacting compound of formula (XIII) with a base to produce the corresponding acid salt of formula (XIV); reacting the compound of formula (XIII) with guanylating agent, to produce compound (Ib) when R1=alkyl, cycloalkyl and aralkyl and reacting the compound (XIV) with a guanylating agent, to produce the corresponding compound of formula (Ib), when R1=H.