134395-00-9

Basic information

• Product Name: Atorvastatin tert-Butyl Ester
• Synonyms: (4R-cis)-1,1-diMethylethyl-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(phenylaMino)carbonyl]-1H-pyrro-1-yl]ethyl]-2,2-diMethyl-1,3-dihydroxy-4-acetate;Atorvastatin t-butyl ester;(βR,δR)-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(phenylaMino)carbonyl]-1H-pyrrole-1-heptanoic Acid 1,1-DiMethylethyl Ester;(3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid tert-butyl ester;(R,dR)-2-(4-Fluorophenyl)-,d-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(phenylaMino)carbonyl]-1H-pyrrole;(3R,5R)-tert-Butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl);(3R,5R)-tert-Butyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbaMoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate;1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(phenylaMino)carbonyl]-, 1,1-diMethylethyl ester, (βR,δR)-
• CAS NO: 134395-00-9
• Molecular Formula: C₃₇H₄₃FN₂O₅
• Molecular Weight: 614.7461232
• Product Categories: Chiral Reagents;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Atorvastatin intermediates;Pfizer compounds
• Mol File: 134395-00-9.mol
• Article Data: 38

Chemical Properties

• Melting Point: 66-68°C
• Boiling Point: 721.0±60.0 °C(Predicted)
• Appearance: /
• Density: 1.16
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slig
• PKA: 13.57±0.70(Predicted)
• CAS DataBase Reference: Atorvastatin tert-Butyl Ester(CAS DataBase Reference)
• NIST Chemistry Reference: Atorvastatin tert-Butyl Ester(134395-00-9)
• EPA Substance Registry System: Atorvastatin tert-Butyl Ester(134395-00-9)

Safety Data

• Hazardous Substances Data: 134395-00-9(Hazardous Substances Data)

Usage

Chemical Properties

Off-white to pale yellow solid

Uses

An impurity arising in the synthesis of Atorvastatin

Synthetic route

tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (125971-95-1) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
With hydrogenchloride; water In acetonitrile for 13h; Product distribution / selectivity;	98.9%
With hydrogenchloride In methanol; water at 50 - 55℃;	98%
With hydrogenchloride In methanol; water at 0 - 30℃; Industrial scale;	96.7%

4-methyl-3-oxo-N-phenylpentanamide (124401-38-3) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: β-alanine; glacial acetic acid / hexane / Heating 2: 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; triethylamine / ethanol / Heating 3: pivalic acid / tetrahydrofuran; toluene; heptane / Heating 4: HCl / tetrahydrofuran; H2O / 20 °C View Scheme

benzaldehyde (100-52-7) + HI, I2 → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: β-alanine; glacial acetic acid / hexane / Heating 2: 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; triethylamine / ethanol / Heating 3: pivalic acid / tetrahydrofuran; toluene; heptane / Heating 4: HCl / tetrahydrofuran; H2O / 20 °C View Scheme

4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (125971-57-5) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; triethylamine / ethanol / Heating 2: pivalic acid / tetrahydrofuran; toluene; heptane / Heating 3: HCl / tetrahydrofuran; H2O / 20 °C View Scheme

2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (125971-96-2) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: pivalic acid / tetrahydrofuran; toluene; heptane / Heating 2: HCl / tetrahydrofuran; H2O / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 75 percent / pivalic acid / toluene; heptane; tetrahydrofuran / Heating 2: aq. HCl / methanol View Scheme
Multi-step reaction with 2 steps 1.1: cyclohexane / 0.5 h / 20 °C / Inert atmosphere; Large scale 1.2: Reflux; Large scale 2.1: hydrogenchloride / acetonitrile; water / 1.5 h / 20 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: Trimethylacetic acid / toluene / 1 h / 105 - 110 °C / Industrial scale 2: hydrogenchloride / methanol; water / 0 - 30 °C / Industrial scale View Scheme

aniline (62-53-3) + Wang resin-bound styrene 4 → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: 96 percent / toluene / Heating 2: β-alanine; glacial acetic acid / hexane / Heating 3: 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; triethylamine / ethanol / Heating 4: pivalic acid / tetrahydrofuran; toluene; heptane / Heating 5: HCl / tetrahydrofuran; H2O / 20 °C View Scheme

isobutyryl Meldrum's acid → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: 96 percent / toluene / Heating 2: β-alanine; glacial acetic acid / hexane / Heating 3: 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; triethylamine / ethanol / Heating 4: pivalic acid / tetrahydrofuran; toluene; heptane / Heating 5: HCl / tetrahydrofuran; H2O / 20 °C View Scheme

4-fluorobenzaldehyde (459-57-4) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2) NEt3 / 1) ethyl thiazolium catalyst / or with methyl thiazolium catalyst; 1) EtOH 2: 75 percent / pivalic acid / toluene; heptane; tetrahydrofuran / Heating 3: aq. HCl / methanol View Scheme

tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / pivalic acid / toluene; heptane; tetrahydrofuran / Heating 2: aq. HCl / methanol View Scheme
Multi-step reaction with 2 steps 1: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 2: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: Acidic conditions 2: hydrogenchloride; methanol View Scheme

2-((4R, 6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid tert-butyl ester (125971-94-0) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / H2, ammonia / Molybdenum doped Raney nickel / methanol / 2585.7 Torr 2: 75 percent / pivalic acid / toluene; heptane; tetrahydrofuran / Heating 3: aq. HCl / methanol View Scheme
Multi-step reaction with 3 steps 1: hydrogen; nickel; ammonia / methanol 2: Acidic conditions 3: hydrogenchloride; methanol View Scheme
Multi-step reaction with 3 steps 1: hydrogen; ammonia / cyclohexane; water / 30 - 40 °C / 3750.38 Torr / Autoclave 2: Trimethylacetic acid; diisopropylamine; tetra(n-butyl)ammonium hydrogensulfate / 40 h / 78 - 85 °C 3: hydrogenchloride; water / methanol / 25 - 30 °C View Scheme

7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, tert-butyl ester → C37H43FN2O5 + (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
With formic acid; triethylamine; [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-ruthenium In toluene for 24h;

C42H49FN2O5 (1035204-85-3) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Stage #1: C42H49FN2O5 With hydrogenchloride In methanol; tert-butyl methyl ether; water at 50℃; for 5h; Stage #2: With sodium hydroxide In methanol; tert-butyl methyl ether; water at 50℃; for 1h; pH=> 13; Product distribution / selectivity;

tert-butyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate (1035204-90-0) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Stage #1: tert-butyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate With hydrogenchloride In methanol; water for 18h; Heating / reflux; Stage #2: With sodium hydroxide In methanol; tert-butyl methyl ether; water at 47 - 52℃; for 1h; Product distribution / selectivity;

tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (125971-95-1) → atorvastatin lactone (125995-03-1) + (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
With hydroxylamine hydrochloride; water In methanol; acetone at 55 - 65℃; for 0.833333 - 1.25h; Product distribution / selectivity;
With hydrogenchloride; water In etanol; acetone at 55 - 65℃; for 0.833333 - 1.25h; Product distribution / selectivity;

5-(4-fluorophenyl)-2-(1-methylethyl)-1-(cis-t-butyl-2-ethoxy-3,5-dioxane-7-amido-heptanoate)-N,4-diphenyl-1H-pyrrole-3-carboxamide → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
With hydrogenchloride; water In methanol at 20℃; for 1.5h;

cis-t-butyl-7-nitro-3,5-dihydroxy-heptanoate (1370478-51-5) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 6 steps 1: methanesulfonic acid / tetrahydrofuran / 0 °C 2: hydrogen; ammonia / palladium 10% on activated carbon / water; tetrahydrofuran; methanol / 6 h / 20 °C 3: triethylamine / acetonitrile / 0 - 20 °C / Inert atmosphere 4: triethylamine / dichloromethane / 0 °C / Inert atmosphere 5: acetic anhydride / 5 h / 75 - 80 °C / Inert atmosphere 6: hydrogenchloride; water / methanol / 1.5 h / 20 °C View Scheme

cis-t-butyl-2-methoxy-3,5-dioxane-6-amino-(N-ethyl-(4-fluorobenzene)-acetate)-heptanoate → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 °C / Inert atmosphere 2: acetic anhydride / 5 h / 75 - 80 °C / Inert atmosphere 3: hydrogenchloride; water / methanol / 1.5 h / 20 °C View Scheme

cis-t-butyl-2-ethoxy-3,5-dioxane-6-amino(N,N-((4-fluorobenzene)isobutyryl)-acetic acid)-heptanoate → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic anhydride / 5 h / 75 - 80 °C / Inert atmosphere 2: hydrogenchloride; water / methanol / 1.5 h / 20 °C View Scheme

cis-t-butyl-2-methoxy-3,5-dioxane-7-nitro-heptanoate → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogen; ammonia / palladium 10% on activated carbon / water; tetrahydrofuran; methanol / 6 h / 20 °C 2: triethylamine / acetonitrile / 0 - 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 0 °C / Inert atmosphere 4: acetic anhydride / 5 h / 75 - 80 °C / Inert atmosphere 5: hydrogenchloride; water / methanol / 1.5 h / 20 °C View Scheme

cis-t-butyl-2-methoxy-3,5-dioxane-7-amino-heptanoate → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / acetonitrile / 0 - 20 °C / Inert atmosphere 2: triethylamine / dichloromethane / 0 °C / Inert atmosphere 3: acetic anhydride / 5 h / 75 - 80 °C / Inert atmosphere 4: hydrogenchloride; water / methanol / 1.5 h / 20 °C View Scheme

5-(4-fluorophenyl)-2-(1-methylethyl)-1-(cis-t-butyl-2-ethoxy-3,5-dioxane-7-amido-heptanoate)-N-4-diphenyl-1H-pyrrole-3-carboxamide → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
With hydrogenchloride; water In methanol at 20℃; for 1.5h;

(R)-N,N-diallyl-5-(benzyloxy)-3-hydroxypentanethioamide (1331869-16-9) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 12 steps 1.1: 2,6-dimethylpyridine / dichloromethane / 3 h / 0 - 20 °C 2.1: diethyl ether / 4.5 h / 0 - 20 °C 3.1: tetrahydrofuran; diethyl ether / -78 °C 3.2: -78 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3.5 h / 0 - 20 °C 5.1: sodium tetrahydroborate; diethyl methoxy borane / tetrahydrofuran; methanol / 10 h / -80 °C 6.1: toluene-4-sulfonic acid / acetone / 4 h / 20 °C 7.1: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 8.1: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 9.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 10.1: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 11.1: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 12.1: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

(R)-N,N-diallyl-5-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)pentanethioamide (1347738-07-1) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 11 steps 1.1: diethyl ether / 4.5 h / 0 - 20 °C 2.1: tetrahydrofuran; diethyl ether / -78 °C 2.2: -78 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3.5 h / 0 - 20 °C 4.1: sodium tetrahydroborate; diethyl methoxy borane / tetrahydrofuran; methanol / 10 h / -80 °C 5.1: toluene-4-sulfonic acid / acetone / 4 h / 20 °C 6.1: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 7.1: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 8.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 9.1: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 10.1: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 11.1: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

CF3O3S(1-)*C25H42NO2SSi(1+) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: tetrahydrofuran; diethyl ether / -78 °C 1.2: -78 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3.5 h / 0 - 20 °C 3.1: sodium tetrahydroborate; diethyl methoxy borane / tetrahydrofuran; methanol / 10 h / -80 °C 4.1: toluene-4-sulfonic acid / acetone / 4 h / 20 °C 5.1: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 6.1: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 7.1: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 8.1: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 9.1: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 10.1: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

(R)-tert-butyl 7-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-3-oxoheptanoate (1331869-20-5) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 9 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3.5 h / 0 - 20 °C 2: sodium tetrahydroborate; diethyl methoxy borane / tetrahydrofuran; methanol / 10 h / -80 °C 3: toluene-4-sulfonic acid / acetone / 4 h / 20 °C 4: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 5: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 6: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 7: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 8: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 9: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

C18H26O5 → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 8 steps 1: sodium tetrahydroborate; diethyl methoxy borane / tetrahydrofuran; methanol / 10 h / -80 °C 2: toluene-4-sulfonic acid / acetone / 4 h / 20 °C 3: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 4: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 5: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 6: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 7: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 8: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

C18H28O5 → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 7 steps 1: toluene-4-sulfonic acid / acetone / 4 h / 20 °C 2: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 3: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 4: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 5: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 6: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 7: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

tert-butyl 2-((4R,6R)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (1331869-21-6) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions

Yield

Multi-step reaction with 6 steps 1: 20% palladium hydroxide on carbon; hydrogen / ethyl acetate / 24 h / 60 °C / 760.05 Torr 2: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 4: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 5: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 6: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

tert-butyl 2-((4R,6R)-6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (1173184-84-3) → (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: dmap; triethylamine / dichloromethane / 4 h / 0 - 20 °C 2: sodium azide / N,N-dimethyl-formamide / 6 h / 20 °C 3: water; triphenylphosphine / tetrahydrofuran / 2 h / 50 °C 4: Trimethylacetic acid / tetrahydrofuran; hexane; toluene / 30 h / 110 °C / Inert atmosphere 5: hydrogenchloride / tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C View Scheme

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin hemicalcium salt trihydrate

Conditions	Yield
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide In acetonitrile at 45 - 60℃; for 3h; Stage #2: With water In acetonitrile at 45 - 60℃; Stage #3: With calcium(II) nitrate for 4.5h; Reagent/catalyst; Solvent;	99.62%

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin sodium (134523-01-6)

Conditions	Yield
With sodium hydroxide; water In 1,4-dioxane; tert-butyl methyl ether for 21h; Product distribution / selectivity; Heating / reflux;	97.7%
With methanol; sodium hydroxide; water In tert-butyl methyl ether for 21h; Product distribution / selectivity; Heating / reflux;	91%
With sodium hydroxide; water; tert-butyl alcohol In tert-butyl methyl ether for 21h; Product distribution / selectivity; Heating / reflux;	91%

L-arginine (74-79-3) + (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin arginine

Conditions	Yield
In methanol for 8h; Reflux;	72.9%

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin (134523-00-5)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; water at 20℃; Hydrolysis;
With methanol; potassium hydroxide; water
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With methanol; sodium hydroxide; water In tert-butyl methyl ether for 2.08333 - 7.08333h; Heating / reflux; Stage #2: With hydrogenchloride pH=8.0 - 8.2;

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → lipitor (134523-03-8)

Conditions	Yield
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide In methanol; water at 50℃; for 1h; Stage #2: With calcium acetate In water; ethyl acetate at 50℃; for 1h;
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide; water In acetonitrile at 40 - 45℃; for 2h; Stage #2: With calcium acetate In water; acetonitrile at 40 - 45℃; for 0.5 - 1h; Stage #3: With sodium hydroxide In water; acetonitrile at 70 - 80℃; for 7 - 9h;
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With sodium hydroxide In methanol; water Stage #2: With calcium chloride In water at 55 - 60℃; Product distribution / selectivity;

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid; ammonium salt (340266-37-7)

Conditions	Yield
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With methanol; sodium hydroxide; water at 55℃; for 2.5h; Stage #2: With hydrogenchloride In tert-butyl methyl ether (MTBE); water at 20℃; Stage #3: With ammonia In tert-butyl methyl ether; water for 2 - 3h; Product distribution / selectivity;

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → [R-(R*,R*)]2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid sodium salt

Conditions	Yield
With sodium hydroxide In water; acetonitrile at 45 - 50℃; for 5 - 6h;

atorvastatin lactone (125995-03-1) + (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin sodium (134523-01-6)

Conditions	Yield
With sodium hydroxide; water In methanol at 35 - 45℃; for 0.5 - 0.666667h; Product distribution / selectivity;
With sodium hydroxide; water In ethanol at 35 - 45℃; for 0.5 - 0.666667h; Product distribution / selectivity;

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin lactone (125995-03-1)

Conditions	Yield
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With potassium hydroxide Stage #2: With hydrogenchloride In water Stage #3: With toluene-4-sulfonic acid In toluene Reflux;

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester (134395-00-9) → atorvastatin hemicalcium

Conditions	Yield
Stage #1: (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester With water; sodium hydroxide In methanol; tert-butyl methyl ether Inert atmosphere; Reflux; Stage #2: With calcium chloride hexahydrate In water at 20 - 25℃; Inert atmosphere;

Upstream product

• 1035204-85-3 C₄₂H₄₉FN₂O₅ 
• 1035204-90-0 tert-butyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate 
• 125971-95-1 tert-butyl (4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate 
• 1331869-19-2 C₂₆H₂₂FNO₃ 
• 1447820-23-6 C₁₈H₂₇NO₄ 
• 1447820-21-4 C₃₀H₃₅NO₂ 
• 442851-51-6 tert-butyl 2-((2R,4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetate 
• 1447820-19-0 tert-butyl 2-((2R,4R,6R)-6-(2-(diallylamino)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetate 
• 1447820-18-9 (R)-5-(diallylamino)pentane-1,3-diol 
• 1447820-16-7 (S)-N,N-diallyl-3-hydroxy-5-(trityloxy)pentanethioamide 
• 682356-88-3 tert-butyl 2-((4R,6R)-6-(2-azidoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 1331869-22-7 tert-butyl 2-((4R,6R)-2,2-dimethyl-6-(2-(tosyloxy)ethyl)-1,3-dioxan-4-yl)acetate 
• 1173184-84-3 tert-butyl 2-[(4R,6R)-6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 1331869-21-6 tert-butyl 2-((4R,6R)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 

Downstream Products

• 134523-01-6 atorvastatin sodium 
• 134523-02-7 atorvastatin potassium 
• 125995-03-1 atorvastatin lactone 
• 340266-37-7 [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid; ammonium salt 
• 134523-03-8 lipitor 
• 134523-00-5 atorvastatin 

Relevant articles and documents

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