Details for Patent: 8,859,756
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Title: | Stereoselective synthesis of phosphorus containing actives |
Abstract: | Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same. |
Inventor(s): | Ross; Bruce S. (Plainsboro, NJ), Sofia; Michael Joseph (Doylestown, PA), Pamulapati; Ganapati Reddy (Plainsboro, NJ), Rachakonda; Suguna (Twinsburg, OH), Zhang; Hai-Ren (Ellicott City, MD) |
Assignee: | Gilead Pharmasset LLC (Foster City, CA) |
Filing Date: | Mar 31, 2011 |
Application Number: | 13/076,842 |
Claims: | 1. A process for preparing an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-1: ##STR00204## 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 ##STR00205## wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside; wherein the nucleoside is selected from ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## wherein the nucleoside-analog is selected from ##STR00211## ##STR00212## wherein the non-nucleoside is selected from ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## wherein W is an aryl or --(CH.sub.2).sub.nSC(O)C(CH.sub.3).sub.m(CH.sub.2OH).sub.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.sub.1-30 alkyl, a substituted or unsubstituted C.sub.3-10 cycloalkyl, a substituted or unsubstituted C.sub.1-30 alkylaryl, a substituted or unsubstituted C.sub.2-10 alkenyl, a substituted or unsubstituted --OC.sub.1-30 alkyl, a substituted or unsubstituted C.sub.6-12 aryl; and wherein R' is a substituted or unsubstituted C.sub.1-30 alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted C.sub.1-30 alkylaryl, or a substituted or unsubstituted C.sub.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.sub.1-6alkyl or C.sub.3-7cycloalkyl. 4. The process of claim 1, wherein R is methyl or isopropyl and R' is a C.sub.1-6alkyl or C.sub.3-7cycloalkyl. 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.degree. C. and about 40.degree. 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.sub.1-6-alkyl-pyridine, a 2,4,6-tri-C.sub.1-6-alkyl-pyridine, or a mixture thereof. |