Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340.
The practical synthesis of a mixed phenoxy-amidate derivative of PMPA with high oral bioavailability and favorable pharmacokinetics is described. The non-stereoselective synthetic route produces a 1:1 mixture of two diastereomers at phosphorous. Simulated moving bed chromatography using Chiralpak AS enabled kilo-scale isolation of the more potent diastereomer (GS-7340). The GS-7340 phosphorous chiral center was found to be (S) by X-ray crystallography.
Chapman
H
H
Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, USA.
Kernan
M
M
Prisbe
E
E
Rohloff
J
J
Sparacino
M
M
Terhorst
T
T
Yu
R
R
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D000409:Alanine; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D013237:Stereoisomerism; D000068698:Tenofovir / Q000031:analogs & derivatives
D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine