Stereoselective synthesis of phosphorus containing actives

1. 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 —(CH 2 ) n SC(O)C(CH 3 ) m (CH 2 OH) 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 C 1-30 alkyl, a substituted or unsubstituted C 3-10 cycloalkyl, a substituted or unsubstituted C 1-30 alkylaryl, a substituted or unsubstituted C 2-10 alkenyl, a substituted or unsubstituted —OC 1-30 alkyl, a substituted or unsubstituted C 6-12 aryl; and

wherein R′ is a substituted or unsubstituted C 1-30 alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted C 1-30 alkylaryl, or a substituted or unsubstituted C 6-12 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.

2. The process of claim 1 , wherein the Active is a nucleoside.

3. The process of claim 1 , wherein R′ is a C 1-6 alkyl or C 3-7 cycloalkyl.

4. The process of claim 1 , wherein R is methyl or isopropyl and R′ is a C 1-6 alkyl or C 3-7 cycloalkyl.

5. The process of claim 1 , wherein LG is an aryloxide substituted with at least one electron withdrawing group.

6. The process of claim 1 , wherein LG is selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.

7. The process of claim 1 , wherein the Active is a nucleoside analog.

8. The process of claim 1 , wherein the Active is a non-nucleoside.

9. The process of claim 1 , wherein the enantiomerically- or diastereomerically enriched phosphorous-containing active, salt, or pharmaceutically acceptable salt thereof of formula I-1 has at least 90 mol % of one enantiomer or diastereomer and at most about 10 mol % of the other enantiomer or diastereomer.

10. The process of claim 9 , wherein no chiral purification technique is used.

11. The process of claim 1 , wherein the enantiomerically- or diastereomerically enriched phosphorous-containing active, salt, or pharmaceutically acceptable salt thereof of formula I-1 has at least 95 mol % of one enantiomer or diastereomer and at most about 5 mol % of the other enantiomer or diastereomer.

12. The process of claim 1 , wherein LG is 2,4-dinitrophenoxide, 4-nitrophenoxide, 2-nitrophenoxide, 2-chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, or pentafluorophenoxide.

13. The process of claim 12 , wherein LG is 4-nitrophenoxide or pentafluorophenoxide.

14. The process of claim 12 , wherein the non-nucleophilic base is triethylamine.

15. The process of claim 1 , wherein the crystallization occurs at a temperature between about −10° C. and about 40° C.

16. The process of claim 1 , wherein the non-nucleophilic base is potassium carbonate, cesium carbonate, di-isopropropylamine, di-isopropylethylamine, triethylamine, quinuclidine, napthalene-1,8-diamine, 2,2,6,6-tetramethylpiperidine, 1,8-diazabicycloundec-7-ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-C 1-6 -alkyl-pyridine, a 2,4,6-tri-C 1-6 -alkyl-pyridine, or a mixture thereof.