Process for the preparation of 4,6-disubstituted-tetrahydro-furo, thieno, pyrrolo and cyclopenta-[3,4][1,3]dioxoles

A process for preparing a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof,

• comprising the steps of:
• (a) obtaining a compound of Formula II, which is a mixture of cis and trans-diastereomers;
• (b) chemically decomposing the compound of Formula II in a solution comprising a solvent and an acid that is a hydrogen donor or an electron pair acceptor, whereby the cis diastereomer is decomposed and the compound of Formula I is obtained;
• wherein D1 is CH2, NR3, O, or S;
• R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, and substituted heterocycle, with the proviso that R1 and R2 are not both hydrogen;
• A is
• wherein;
• n and p are 0, 1, or 2 such that the sum of n+p is from 0 to 3;
• each M is independently hydrogen, NH4+, Na+ or other pharmaceutically acceptable inorganic or organic counterions;
• T1, V and W are each independently selected from O or S;
• X1 and X2 are independently O, NH, CH2, CHF, CHCl, CF2 or CCl2;
• G is M, or
• G is
• wherein:
• L, Q and T are each independently R1, (CO), O, S, NHR1, NR1R3, [NR1(CO)], N[(CO)R1], with the proviso that a stable compound or structure is created by the selection;
• or
• Q and T is absent;
• or
• T is a heterocycle or substituted heterocycle;
• each B is independently —NHR3, alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heterocycle and substituted heterocycle;
• or
• each B is independently a purine residue linked through the 9-position, as in Formula III:
• or a pyrimidine residue linked through the 1-position, as in Formula IV:
• wherein:
• R6 and R10 are hydroxy, oxo, amino, mercapto, alkylthio, alkyloxy, aryloxy, alkylamino, cycloalkylamino, aralkylamino, arylamino, diaralkylamino, diarylamino, or dialkylamino, where the alkyl groups are optionally linked to form a heterocycle;
• or
• R6 and R10 are independently acylamino, acyl(alkyl)amino, acyl(alkenyl)amino, acyl(alkynyl)amino acyl(cycloalkyl)amino, acyl(aryl)amino, acyl(aralkyl)amino, acyl(heteroaryl)amino, or acyl(heteroarylalkyl(amino);
• or
• R6 and R10 are di-acylamino, with the acylamino moieties optionally linked to form a heterocycle;
• or
• when R6 in a purine or R10 in a pyrimidine has as its first atom nitrogen, R6 and R7 or R10 and R11 are taken together to form a 5-membered fused imidazole ring, optionally substituted on the etheno ring with hydrogen, alkyl, cycloalkyl, acyl, substituted acyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
• J is carbon or nitrogen, with the provision that when nitrogen, R8 is not present;
• R7 is hydrogen, or is absent;
• R8 is hydrogen, alkyl, bromo, azido, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio, or R14(C1-6-alkyl)R13—;
• where R9 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio;
• R11 is hydrogen or acyl;
• R12 is hydrogen, alkyl, cycloalkyl, halo, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
• R13 is amino, mercapto, oxo, or carbonyl;
• and
• R14 is amino, mercapto, hydroxyl, or carboxyl.