Stereoselective synthesis of phosphorus containing actives

A process for preparing an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-1:

• which comprises the steps of:
• (a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or a diastereomerically enriched compound of formula II-1
• wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside;
• wherein the nucleoside is selected from
• wherein the nucleoside-analog is selected from
• wherein the non-nucleoside is selected from
• wherein W is an aryl or —(CH2)nSC(O)C(CH3)m(CH2OH)3-m;
• wherein n is 2 or 3 and m is 0, 1, 2, or 3;
• wherein LG is selected from the group consisting of halogen, tosylate, mesylate, triflate, acetate, trifluoromethylacetate, camphorsulfonate, 2-thioxobenzo[d]thiazol-3(2H)-yl, aryloxide, and aryloxide substituted with at least one electron withdrawing group;
• wherein R is a substituted or unsubstituted C1-30 alkyl, a substituted or unsubstituted C3-10 cycloalkyl, a substituted or unsubstituted C1-30 alkylaryl, a substituted or unsubstituted C2-10 alkenyl, a substituted or unsubstituted —OC1-30 alkyl, a substituted or unsubstituted C6-12 aryl;
• and
• wherein R′ is a substituted or unsubstituted C1-30 alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted C1-30 alkylaryl, or a substituted or unsubstituted C6-12 aryl;
• and
• (b) optionally deprotecting the compound obtained in step (a) to obtain the enantiomerically- or diastereomerically-enriched phosphorous-containing active, salt, or pharmaceutically acceptable salt thereof of formula I-1,
• wherein the enantiomerically- or diastereomerically-enriched compound of formula II-1 is obtained by crystallization from a composition comprising:
• i. a first composition;
• ii. a leaving group precursor;
• iii. a non-nucleophilic base;
• and
• iv. a liquid composition;
• wherein the first composition comprises Rp-II-1 and Sp-II-1;
• and
• wherein the leaving group precursor is 2,4-dinitrophenol, 4-nitrophenol, 2-nitrophenol, 2-chloro-4-nitrophenol, 2,4-dichlorophenol, or pentafluorophenol.