Methods for the preparation of diastereomerically pure phosphoramidate prodrugs

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

• 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)carbocyclyl alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C 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;
• each n is independently 0, 1, or 2;
• each Ra 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, heterocyclyl or heteroaryl;
• each R4 is phenyl;
• 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, 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, 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),- 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, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R5, R6, R7, R11 or R12 or the phenyl of R4 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 la, or
• (c) treating the compound of Formula II with a compound of Formula Illb and a base
• thereby forming a compound of Formula lb;
• wherein:
• each Ar is 3,5-dichlorophenyl.