Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

A method for preparing a compound of Formula Ia or Ib:

• or a pharmaceutically acceptable salt or acid thereof;
• wherein:
• each R1, R2, R7, R22, R23 or R24 is independently H, OR11, NR11R12, C(O)NR11R12, —OC(O)NR11R12, C(O)OR11, OC(O)OR11, S(O)nRa, S(O)2NR11R12, N3, CN, halogen, (C1-C8)alkyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl;
• or any two R1, R2, R7, R22, R23 or R24 on adjacent carbon atoms when taken together are —O(CO)O— or —O(CR11R12)O— or when taken together with the ring carbon atoms to which they are attached form a double bond;
• each Base is independently a naturally occurring or modified purine or pyrimidine base linked to the furanose ring through a carbon or nitrogen atom;
• provided that Base is not uracil;
• each n is independently 0, 1, or 2;
• each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
• each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl provided that Rc and Rd are not the same;
• each R5 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
• each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl, heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S(O)n— or —NRa—;
• and
• wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R4, R5, R6, R7, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2, NH(Ra), NH2, NO2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O)nRa, S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra:
• said method comprising:
• (a) providing a compound of Formula II
• and
• (b) treating the compound of Formula II with a compound of Formula IIIa and a base
• thereby forming a compound of Formula Ia or
• (c) treating the compound of Formula II with a compound of Formula IIIb and a base
• thereby forming a compound of Formula Ib;
• wherein:
• each Ar is a (C6-C20) aryl or heteroaryl wherein said (C6-C20) aryl or heteroaryl is substituted with one or more halogen, NO2, or (C1-C8)haloalkyl and optionally substituted with with one or more CN, N3, N(Ra)2, C(O)N(Ra)2, OC(O)N(Ra)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O)nRa, S(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4, the method further comprising a method of preparing a compound of Formula IIIa or Formula IIIb
• wherein:
• each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
• each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-(C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl provided that Rc and Rd are not the same;
• each R5 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
• wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl (C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl of each Rc, Rd, R4, R5 or R6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2 NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O)nRaS(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra;
• and
• each Ar is a (C6-C20) aryl or heteroaryl wherein said (C6-C20) aryl or heteroaryl is substituted with one or more halogen, NO2, or (C1-C8)haloalkyl and optionally substituted with with one or more CN, N3, N(Ra)2 C(O)N(Ra)2, OC(O)N(Ra)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O)n RaS(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4;
• said method comprising:
• (d) providing a diastereomeric compound of Formula VIII
• and
• (e) dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by addition of a C5-C8 hydrocarbon or C5-C8 cyclic hydrocarbon;
• thereby forming a pure diasteromer of Formula IIIa or Formula IIIb.