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 compounds of Formula II, which is a mixture of cis and trans-diastereomers, wherein cis and trans refer to the positions of R2 vs. the two hydrogens on the 4 and 5 positions of the dioxolane ring;
• (b) reacting the mixture with 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;
• R2═H;
• R1and 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, heterocyclyl, and substituted heterocyclyl, with the proviso that R1 and R2 are not both hydrogen on the dioxolane ring;
• 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 another pharmaceutically acceptable inorganic or organic counterion;
• T1, V and W are each independently O or S;
• X1 and X2 are independently O, NH, CH2, CHF, CHCl, CF2 or CCl2;
• G is M,
• wherein:
• L is R1 when both Q and T are absent;
• or
• L is (CO);
• Q is O, S, or absent;
• and T is R1, NHR1, NR1R3, NHR1(CO), a heterocyclyl or substituted heterocyclyl;
• B is a purine or an azapurine residue linked though the 9-position, as in Formula III:
• or a pyrimidine residue linked though the 1-position, as in Formula IV:
• wherein:
• R6 or R10 is 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 or R10 is 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 or R10 is 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 proviso that when J is nitrogen, R8 is not present;
• R7 is hydrogen, or is absent;
• R8 is absent or is hydrogen, alkyl, bromo, azido, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio, or R14(C1-6-alkyl)R13—;
• 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 (—NH—), sulfide (—S—), oxo (—O—), or carbonyl;
• and
• R14 is amino (—NH2), thiol (—SH), hydroxyl, or carboxyl;
• wherein the substituents of the substituted groups are independently selected from the group consisting of hydroxy, oxo, nitro, methoxy, ethoxy, alkoxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, alkyl, thio, thioalkyl, acyl, carboxyl, alkoxycarbonyl, carboxamido, alkylsulfonyl, alkylsulfinyl, alkylsulfonylamino, sulfonamido, cyano, amino, substituted amino, acylamino, trifluoromethyl, trifluoromethoxy, phenyl, aryl, pyridyl, imidazolyl, heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl, pyrrolidinyl, piperidinyl, morpholino, and heterocyclyl.