134395-00-9

Usage

Uses

Used in Pharmaceutical Industry:
Atorvastatin tert-Butyl Ester is used as an impurity in the synthesis process for the production of Atorvastatin, a cholesterol-lowering drug. Its presence in the synthesis process can affect the purity and efficacy of the final product, making it important to monitor and control its levels during manufacturing.

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

• 100-52-7 benzaldehyde 
• 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 
• 1331869-16-9 (R)-N,N-diallyl-5-(benzyloxy)-3-hydroxypentanethioamide 
• 1347738-07-1 (R)-N,N-diallyl-5-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)pentanethioamide 
• 1331869-20-5 (R)-tert-butyl 7-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-3-oxoheptanoate 
• 1331869-21-6 tert-butyl 2-((4R,6R)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-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 
• 1331869-22-7 tert-butyl 2-((4R,6R)-2,2-dimethyl-6-(2-(tosyloxy)ethyl)-1,3-dioxan-4-yl)acetate 
• 682356-88-3 tert-butyl 2-((4R,6R)-6-(2-azidoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 1331869-19-2 C₂₆H₂₂FNO₃ 
• 1447820-23-6 C₁₈H₂₇NO₄ 
• 1447820-21-4 C₃₀H₃₅NO₂ 

Downstream Products

• 134523-01-6 atorvastatin sodium 
• 125995-03-1 atorvastatin lactone 
• 134523-02-7 atorvastatin potassium 
• 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 academic research and scientific papers

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AN IMPROVED AND COMMERCIALLY VIABLE PROCESS FOR PREPARATION OF PYRROLE DERIVATIVES WITH IMPROVED IMPURITY PROFILE & MINIMISATION OF UNIT OPERATIONS.

The present invention relates to improved process for the preparation of a pyrrole derivative as a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof or a pharmaceutically acceptable salt and hydrates thereof and also intermediates involved therein. Particularly invention is directed to improved processes for the preparation of pyrrole derivatives such as (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(1-methyl-ethyl)-pyrrole-1-yl]-2,2-dimethyl-[1,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV followed by its conversion into [R-(R*, R*]-2-(4-fluorophenyl)- β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic acid particularly calcium salt and its hydrate represented by Formulae I/IA respectively wherein formation of the impurities is either eliminated or minimized in the corresponding intermediaries.

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