Process for preparing substituted benzimidazole compounds

A process for preparing a compound of formula VI:

• 36
• wherein:
• R is halo;
• R1 is hydrogen;
• and
• each of R2, R3, R4, R5, R6 and R7 is independently selected from the group consisting of H, hydroxy and protected hydroxy group;
• and pharmaceutically acceptable derivatives and prodrugs thereof;
• said process comprising the steps of:
• (a) cyclizing 4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield a compound of formula II:
• 37
• (b) reacting the compound of formula II with PO(X)3 wherein X is halo, to prepare a compound of formula I:
• 38
• (c) reacting the compound of formula I with a pyranoside of formula IV:
• 39
• to prepare a compound of formula VI and pharmaceutically acceptable derivatives and prodrugs thereof.

A process for preparing 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole and pharmaceutically acceptable derivatives and prodrugs ref, said process comprising:

• (a) reacting 5,6-dichlorobenzimidazol-2-one with phosphorous oxybromide to produce 2-bromo-5,6-dichlorobenzimidazole;
• (b) reacting 2-bromo-5,6-dichlorobenzimidazole with 1,2,3,4-tetra-O-acetyl-β-D-ribopyranose to produce 2-bromo-5,6-dichloro-11-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazole;
• and
• (c) deprotecting 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazole to produce 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole and pharmaceutically acceptable derivatives and prodrugs thereof.

A process for preparing compounds of formula VII:

• 40
• wherein:
• R is —NR8R9 where R8 and R9 are each independently selected from the group consisting of H, C1-6alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, C3-7cycloalkyl, C1-6alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-6alkyl, C2-6alkynyl, aryl, arylC1-6alkyl, and COC1-6alkyl;
• and
• each R10 is independently selected from the group consisting of hydroxy and protected hydroxy group;
• and pharmaceutically acceptable derivatives and prodrugs thereof;
• said process comprising the steps of:
• (a) cyclizing 4,5-dichloro-o-phenylenediamine with carbonyl d i-imidazole to yield a compound of formula II:
• 41
• (b) reacting the compound of formula II with PO(X)3 wherein X is halo, to prepare a compound of formula I:
• 42
• (c) reacting the compound of formula I with a furanosyl of formula III:
• 43
• to prepare a compound of formula V:
• 44
• (d) reacting the compound of formula V with an amine of formula H—NR8R9;
• to prepare a compound of formula VII and pharmaceutically acceptable derivatives and prodrugs thereof.

A process for preparing compounds of formula X:

• 46
• wherein:
• R is selected from the group consisting of halo, hydroxy, azido, C1-8alkyl, trihalomethyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl,
• —NR25R26 wherein R25 and R26 may be the same or different and are each independently selected from the group consisting of H, halo, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-6alkyl, heterocyclylC1-8alkyl, C1-8alkylcarbonyl, and C6-14arylsulfonyl;
• —NHNR30R31 wherein R30 and R31 are the same or different and are each independently C1-6alkyl;
• —N═NNC1-6alkyl;
• —NHOC1-6alkyl;
• —OR27 wherein R27 is selected from the group consisting of C1-8alkyl, C3-7cycloalkyl, and C6-14aryl;
• —SR28 wherein R28 is selected from the group consisting of H, C1-8alkyl, hydroxyC1-8alkyl, C3-cycloalkyl, C6-14aryl, and C6-14arylC1-6alkyl;
• R15 is selected from the group consisting of H, halo, C1-6alkyl or C2-6alkenyl;
• R16 and R17 may be the same or different and are each independently selected from the group consisting of H, halo, C1-8alkyl, C6-14aryl, heterocyclyl-C1-8aryl, C1-8alkoxy, haloC1-8alkyl, NO2, and SR29 where R29 is selected from the group consisting of H, C1-8alkyl, C6-14aryl or C6-14arylC1-8alkyl;
• and
• R20 is a D- or L-sugar moiety selected from the group consisting of:
• 47
• wherein
• R21 and R22 may be the same or different and are each independently selected from the group consisting of H, hydroxy, protected hydroxy group, halo, C1-8alkyl, C1-8alkylhydroxy, haloC1-8alkyl, or C1-8alkoxy;
• and
• R23 is selected from the group consisting of H, hydroxy, protected hydroxy group, C1-8alkyl, C1-8alkoxy, CH2R32 wherein R32 is hydroxy, protected hydroxy group, halo, or azido;
• and C(R33)3. wherein each R33 is halo;
• and wherein R21, R22 and R23 may be in the α- or β-position;
• and pharmaceutically acceptable derivatives and prodrugs thereof;
• said process comprising the steps of:
• (a) cyclizing a phenylenediamine of formula XI:
• 48
• with carbonyl-di-imidazole yield a compound of formula XII:
• 49
• (b) reacting the compound of formula XII with PO(X)3, wherein X is halo, to prepare a compound of formula XIII:
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• (c) reacting the compound of formula XIII with a 5- or 6-membered, D- or L-sugar selected from the group consisting of:
• 51
• wherein
• L is a leaving group in the α- or β-position to prepare compounds of formula X:
• 52
• wherein R15, R16, R17, and R20 are as defined above and R is halo, and pharmaceutically acceptable derivatives and prodrugs thereof;
• and
• (d) optionally converting the compound of formula X or pharmaceutically acceptable derivative or prodrug thereof into a further compound of formula X or pharmaceutically acceptable derivative or prodrug thereof by nucleophilic substitution.