Common name: Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor
Tradename: Lipitor (Warner-Lambert); Sortis (Parke-Davis); Torvast (Pfizer); Totalip (Guidotti); Xarator (Parke-Davis)
CAS Registry Number: 125995-03-1 (also see 134523-03-8; 134523-00-5)
CAS Name: 5-(4-Fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1H-pyrrole-3-carboxamide
Molecular Formula: C33H33FN2O4
Molecular Weight: 540.62
SMILES: CC(C)C1=C(C(=O)NC2=CC=CC=C2)C(=C(N1CCC(O)CC(O)CC([O-])=O)C1=CC=C(F)C=C1)C1=CC=CC=C1
InChI Key: XUKUURHRXDUEBC-UHFFFAOYNA-M
InChI: InChI=1/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/p-1
Activity: CARDIOVASCULAR DRUGS, Treatment of Lipoprotein Disorders, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors
Status: Launched 1996
Originator: Pfizer
Atorvastatin synthesis: EP0409281; US5273995
Tradename: Lipitor (Warner-Lambert); Sortis (Parke-Davis); Torvast (Pfizer); Totalip (Guidotti); Xarator (Parke-Davis)
CAS Registry Number: 125995-03-1 (also see 134523-03-8; 134523-00-5)
CAS Name: 5-(4-Fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1H-pyrrole-3-carboxamide
Molecular Formula: C33H33FN2O4
Molecular Weight: 540.62
SMILES: CC(C)C1=C(C(=O)NC2=CC=CC=C2)C(=C(N1CCC(O)CC(O)CC([O-])=O)C1=CC=C(F)C=C1)C1=CC=CC=C1
InChI Key: XUKUURHRXDUEBC-UHFFFAOYNA-M
InChI: InChI=1/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/p-1
Activity: CARDIOVASCULAR DRUGS, Treatment of Lipoprotein Disorders, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors
Status: Launched 1996
Originator: Pfizer
Atorvastatin synthesis: EP0409281; US5273995
Atorvastatin synthesis: Contemporary Drug Synthesis, 2004, Wiley Publications (This book as well as many other citations point it as Pfizer's commercial route)
Central Molecule (Tetrahedron Lett 1992, 33, 2283-2284)
Side Chain (Tetrahedron Lett 1992, 33, 2279-2282)
Finally, Atorvastatin
Atorvastatin (lactone) synthesis: J Med Chem 1991, 34(1), 357-66 (Scheme 1) (also Ref. 6)
Atorvastatin ((+)-lactone): J Med Chem 1991, 34(1), 357-66 (Scheme 2) (also Ref. 6)
Atorvastatin Side Chain (J Org Chem 2014, 79(6), 2723-2728)
References:
1. Graul, A.; Castañer, J.; Atorvastatin Calcium. Drugs Fut 1997, 22(9), 956.
2. Roth, B.D.; et. al. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34(1), 357-66.
3. Radl, S.; et. al.; An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis. Tetrahedron Lett 2002, 43(11), 2087.
4. Roth, B. D. [R-(R*R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof. US5273995A, EP0409281B1.
5. Li, J. J.; et. al. Contemporary Drug Synthesis, 2004, Wiley Publications.
6. Roth, B. D. Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. US4681893A
7. Roth, B. D.; et. al. The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33(17), 2279–2282.
8. Roth, B. D.; et. al. The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33(17), 2283–2284.
9. Krasavin, M.; et. al. An improved kilogram-scale preparation of atorvastatin calcium. Chemistry Central Journal 2015, 9(1), 7. (high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities)
10. Chen, X.; et. al. Asymmetric Synthesis of the HMG-CoA Reductase Inhibitor Atorvastatin Calcium: An Organocatalytic Anhydride Desymmetrization and Cyanide-Free Side Chain Elongation Approach. J Org Chem 2014, 79(6), 2723-2728 (Cyanide-Free Side Chain Elongation Approach ???)
For more drugs and their synthesis: Synayurajan database
2. Roth, B.D.; et. al. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34(1), 357-66.
3. Radl, S.; et. al.; An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis. Tetrahedron Lett 2002, 43(11), 2087.
4. Roth, B. D. [R-(R*R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof. US5273995A, EP0409281B1.
5. Li, J. J.; et. al. Contemporary Drug Synthesis, 2004, Wiley Publications.
6. Roth, B. D. Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. US4681893A
7. Roth, B. D.; et. al. The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33(17), 2279–2282.
8. Roth, B. D.; et. al. The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33(17), 2283–2284.
9. Krasavin, M.; et. al. An improved kilogram-scale preparation of atorvastatin calcium. Chemistry Central Journal 2015, 9(1), 7. (high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities)
10. Chen, X.; et. al. Asymmetric Synthesis of the HMG-CoA Reductase Inhibitor Atorvastatin Calcium: An Organocatalytic Anhydride Desymmetrization and Cyanide-Free Side Chain Elongation Approach. J Org Chem 2014, 79(6), 2723-2728 (Cyanide-Free Side Chain Elongation Approach ???)
For more drugs and their synthesis: Synayurajan database
