Premium
Atorvastatin, an HMG‐COA reductase inhibitor and efficient lipid‐regulating agent. Part I. Synthesis of ring‐labeled [ 14 C 6 ]atorvastatin
Author(s) -
Woo Peter W. K.,
Hartman Jon,
Huang Yun,
Nanninga Thomas,
Bauman Kelvin,
Butler Donald E.,
Rubin John R.,
Lee Helen T.,
Huang Che C.
Publication year - 1999
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(199902)42:2<121::aid-jlcr173>3.0.co;2-z
Subject(s) - chemistry , atorvastatin , triethylamine , knoevenagel condensation , medicinal chemistry , bromide , acetanilide , ring (chemistry) , stereochemistry , catalysis , organic chemistry , medicine , endocrinology
Pyrrole‐ring labeled [ 14 C]atorvastatin (Lipitor ® , CI‐981), [R‐(R*,R*)]‐2‐(4‐fluorophenyl)‐β,γ‐dihydroxy‐5‐(1‐methylethyl)‐3‐phenyl‐4‐[(phenylamino)‐carbonyl]‐1H‐[3‐ 14 C]pyrrole‐1‐heptanoic acid calcium salt (2:1) ( 15 ), was synthesized in a 5‐step synthesis from [7‐ 14 C]benzaldehyde ( 5 ) with an overall yield of 6.9 to 9.6%. Thus, Knoevenagel condensation of 5 with isobutyryl‐acetanilide ( 6 ) gave 4‐methyl‐3‐oxo‐N‐phenyl‐2‐(phenyl[ 14 C]methylene)‐pentamide ( 7 ). Stetter condensation of ( 7 ) with p ‐fluorobenzaldehyde ( 8 ), in the presence of the catalyst 3‐ethyl‐5‐(2‐hydroxyethyl)‐4‐methylthiazolium bromide ( 9 ) and triethylamine, gave the key labeled intermediate diketone, 4‐fluoro‐α‐(2‐methyl‐1‐oxopropyl)‐γ‐oxo‐N,β‐diphenylbenzene[3‐ 14 C]butaneamide ( 10 ). Reaction of 10 with the protected chiral dihydroxyaminoheptanoic ester, [4R‐cis]]‐1,1‐dimethylethyl‐6‐(2‐aminoethyl)‐2,2‐dimethyl‐1,3‐dioxane‐4‐acetate ( 11 ), synthesized separately, gave atorvastatin in its protected form, [4R‐cis]‐1,1‐dimethylethyl‐6‐[2[2‐(4‐fluorophenyl)‐5‐(1‐methylethyl)‐3‐phenyl‐4‐[(phenylamino)carbonyl]‐1H‐[3‐ 14 C]pyrrol‐1‐yl]ethyl]‐2,2‐dimethyl‐1,3‐dioxane‐4‐acetate ( 12 ). Deprotection of 12 led to the sodium salt 13 . Subsequent calcium salt formation gave the ring‐labeled atorvastatin 15 . Copyright © 1999 John Wiley & Sons, Ltd.