125971-95-1

Basic information

• Product Name: tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate
• Synonyms: tert-butyl (4r,6r)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate;(4R-CIS)-1,1-DIMETHYLETHYL-6-[2-[2-(4-FLUOROPHENYL)-5-(1-ISOPROPYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROL-1-YL]ETHYL]-2,2-DIMETHYL-1,3-DIOXANE-4-ACETATE;(4R-CIS)-[1,1-DIMETHYLETHYL-6-[(2-FLUOROPHENYL)-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO) CARBONYL]-1H-PYRROL-1-YL]ETHYL]-2, 2-DIMETHYL-1, 3-DIOXANE-4-ACETATE;(4R-CIS)-6-[2-[2-(4-FLUOROPHENYL)-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROL-1-YL]ETHYL]-2,2-DIMETHYL-1,3-DIOXANE-4-ACETIC ACID, 1,1-DIMETHYLETHYL ESTER;L-1(4R-Cis)-1,1-DiMethylethyl-6- 2- 2-(4-Fluorophenyl)-5-(1-Isopropyl)-3-Phenyl-4 (PhenylaMino)carbonyl -1H-pyrrol-1-yl Ethyl -2,2-DiMethyl-1,3-Dioxane-4-Acetate;tert-Butyl (4R,6R)-6-[2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1-pyrrolyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate ;tert-Butyl 2-[(4R,6R)-6-[2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamo
• CAS NO: 125971-95-1
• Molecular Formula: C₄₀H₄₇FN₂O₅
• Molecular Weight: 654.81
• EINECS: 258-925-2
• Product Categories: Intermediates & Fine Chemicals. Pfizer compounds;INTERMEDIATES OF ATORVASTATIN;(intermediate of atorvastatin);Chiral Reagents;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals;Asymmetric Synthesis;Chiral Building Blocks;Complex Molecules
• Mol File: 125971-95-1.mol
• Article Data: 45

Chemical Properties

• Melting Point: 144-148 °C(lit.)
• Boiling Point: 678.035 °C at 760 mmHg
• Flash Point: 363.863 °C
• Appearance: /
• Density: 1.15 g/cm³
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 13.57±0.70(Predicted)
• CAS DataBase Reference: tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate(CAS DataBase Reference)
• NIST Chemistry Reference: tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate(125971-95-1)
• EPA Substance Registry System: tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate(125971-95-1)

Safety Data

• Safety Statements: 24/25
• RIDADR: UN 2811 6.1 / PGII
• WGK Germany: 3
• Hazardous Substances Data: 125971-95-1(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

Different sources of media describe the Uses of 125971-95-1 differently. You can refer to the following data:
1. Atorvastatin intermediate
2. Atorvastatin Acetonide tert-Butyl Ester (Atorvastatin EP Impurity I) is an Atorvastatin intermediate.

InChI:InChI:1S/C40H47FN2O5/c1-26(2)36-34(27-14-10-8-11-15-27)35(38(45)42-30-16-12-9-13-17-30)37(28-18-20-29(41)21-19-28)43(36)23-22-31-24-32(47-40(6,7)46-31)25-33(44)48-39(3,4)5/h8-21,26,31-32H,22-25H2,1-7H3,(H,42,45)

Synthetic route

C40H45FN2O5 → 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)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen	97%

tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) + 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (125971-96-2) → 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)

Conditions	Yield
With Trimethylacetic acid In toluene at 105 - 110℃; for 1h; Industrial scale;	96.5%
With tetra(n-butyl)ammonium hydrogensulfate; diisopropylamine; Trimethylacetic acid at 78 - 85℃; for 40h; Paal-Knorr Pyrrole Synthesis;	82.3%
With Trimethylacetic acid In tetrahydrofuran; n-heptane; toluene Heating;	75%

C26H22FNO3 (1331869-19-2) + tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) → 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)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Trimethylacetic acid In cyclohexane at 80 - 84℃; for 25h; Concentration; Reagent/catalyst; Paal-Knorr Pyrrole Synthesis; Dean-Stark; Reflux;	79%
With Trimethylacetic acid In tetrahydrofuran; hexane; toluene at 110℃; for 30h; Paal-Knorr pyrrole synthesis; Inert atmosphere;

tert-butyl 2-((4R,6S)-6-(2-iodoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (1173184-80-9) + 5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide → 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)

Conditions	Yield
With 18-crown-6 ether; potassium carbonate In acetonitrile Reflux;	65%

t-butyl 2-((4R,6R)-6-(2-(2-isopropyl-4-phenyl-3-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate + 1-Bromo-4-fluorobenzene (460-00-4) → 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)

Conditions	Yield
With potassium acetate; palladium diacetate at 150℃; for 15h; Heck Reaction; Inert atmosphere;	44%

4-methyl-3-oxo-N-phenylpentanamide (124401-38-3) → 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)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1.1: L-proline / Inert atmosphere 2.1: 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide; potassium phosphate / acetonitrile / 16 h / 120 °C / Inert atmosphere; Glovebox; Schlenk technique; Sealed tube 2.2: 4 h / 120 °C / Inert atmosphere; Gas phase; Schlenk technique; Sealed tube 3.1: potassium acetate; palladium diacetate / 15 h / 150 °C / Inert atmosphere View Scheme

benzaldehyde (100-52-7) + HI, I2 → 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)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide (125971-57-5) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; triethylamine / ethanol / Heating 2: pivalic acid / tetrahydrofuran; toluene; heptane / Heating View Scheme
Multi-step reaction with 2 steps 1.1: 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide; potassium phosphate / acetonitrile / 16 h / 120 °C / Inert atmosphere; Glovebox; Schlenk technique; Sealed tube 1.2: 4 h / 120 °C / Inert atmosphere; Gas phase; Schlenk technique; Sealed tube 2.1: potassium acetate; palladium diacetate / 15 h / 150 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide; triethylamine / Reflux 2: Trimethylacetic acid / toluene; hexane; tetrahydrofuran / Reflux View Scheme

aniline (62-53-3) + Wang resin-bound styrene 4 → 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)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

isobutyryl Meldrum's acid → 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)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

4-fluorobenzaldehyde (459-57-4) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2) NEt3 / 1) ethyl thiazolium catalyst / or with methyl thiazolium catalyst; 1) EtOH 2: 75 percent / pivalic acid / toluene; heptane; tetrahydrofuran / Heating View Scheme
Multi-step reaction with 2 steps 1: 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide; triethylamine / Reflux 2: Trimethylacetic acid / toluene; hexane; tetrahydrofuran / Reflux View Scheme

2-((4R, 6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid tert-butyl ester (125971-94-0) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / H2, ammonia / Molybdenum doped Raney nickel / methanol / 2585.7 Torr 2: 75 percent / pivalic acid / toluene; heptane; tetrahydrofuran / Heating View Scheme
Multi-step reaction with 2 steps 1: hydrogen; nickel; ammonia / methanol 2: Acidic conditions View Scheme
Multi-step reaction with 2 steps 1: ammonia; hydrogen / methanol / 6 h / 30 - 40 °C / 2250.23 - 3000.3 Torr / Autoclave 2: Trimethylacetic acid / tetrahydrofuran; n-heptane / 60 h / Reflux View Scheme
Multi-step reaction with 2 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 View Scheme

1-[2-((4R,6R)-6-tert-butoxycarbonylmethyl-2,2-dimethyl-[1,3]dioxan-4-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (805242-36-8) + aniline (62-53-3) → 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)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 50 - 60℃; Product distribution / selectivity;

C34H41ClFNO5 + aniline (62-53-3) → 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)

Conditions	Yield
In benzene at 70℃; Product distribution / selectivity;

C39H50FNO8 + aniline (62-53-3) → 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)

Conditions	Yield
With toluene-4-sulfonic acid In tetrahydrofuran at 55 - 60℃; Product distribution / selectivity;

4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide + tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) → 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)

Conditions	Yield
With 2-Methylbutanoic acid In n-heptane; toluene for 22h; Product distribution / selectivity; Heating / reflux;
With Trimethylacetic acid In n-heptane; toluene for 25h; Heating / reflux;
With 2-Methylbutanoic acid In n-heptane; toluene for 48h; Product distribution / selectivity; Heating / reflux;

2-[1-phenyl-2-(4-fluorophenyl)-2-oxoethyl]-4-methyl-N-methyl-N-phenyl-3-oxo-pentanamide + tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) → 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)

Conditions	Yield
In tetrahydrofuran; n-heptane; oenanthic acid; toluene for 8h; Heating / reflux;

(4R-cis)-1,1-dimethylethyl-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate (914222-70-1) + 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (125971-96-2) + isopropyl alcohol (67-63-0) → (4R-cis)-1,1-dimethylethyl 6-[2]2-(-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl ]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate + 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)

Conditions	Yield
In n-heptane; toluene

tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) + 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (125971-96-2) + isopropyl alcohol (67-63-0) → 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)

Conditions	Yield
In n-heptane; toluene

tert-butyl [(4S,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1105067-89-7) + 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (125971-96-2) → tert-butyl (4S,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (1105067-90-0) + 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)

Conditions	Yield
With Trimethylacetic acid In n-heptane; toluene for 19h; Heating; Title compound not separated from byproducts.;

tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) + 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (125971-96-2) → ((4R,6R)-6-{2-[2-((4R,6R)-6-{2-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetylamino]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester (1116118-82-1) + 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 (125971-95-1)

Conditions	Yield
Stage #1: tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate; 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide In toluene at 90 - 100℃; for 1 - 1.5h; Heating / reflux; Stage #2: Trimethylacetic acid In toluene Product distribution / selectivity; Heating / reflux;
Stage #1: tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate; 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide In tetrahydrofuran; n-heptane; toluene at 40 - 50℃; for 1 - 1.5h; Heating / reflux; Stage #2: Trimethylacetic acid In tetrahydrofuran; n-heptane; toluene for 35h; Product distribution / selectivity; Heating / reflux;
Stage #1: tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate; 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide In tetrahydrofuran; toluene at 40 - 50℃; for 1 - 1.5h; Heating / reflux; Stage #2: Trimethylacetic acid In tetrahydrofuran; toluene for 24h; Product distribution / selectivity; Heating / reflux;

+/-(4-fluoro-alpha-(2-methyl-1-oxopropyl)-gama-oxo-N-beta-diphenyl benzenebutaneamine) + tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (125971-86-0, 125995-13-3) → 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)

Conditions	Yield
Stage #1: +/-(4-fluoro-alpha-(2-methyl-1-oxopropyl)-gama-oxo-N-beta-diphenyl benzenebutaneamine); tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate With Trimethylacetic acid In tetrahydrofuran; n-heptane; toluene for 40 - 50h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; n-heptane; water; toluene pH=7; Product distribution / selectivity;
Stage #1: +/-(4-fluoro-alpha-(2-methyl-1-oxopropyl)-gama-oxo-N-beta-diphenyl benzenebutaneamine); tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate With Trimethylacetic acid In tetrahydrofuran; hexane; toluene for 40 - 50h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; hexane; water; toluene pH=7; Product distribution / selectivity;

(R)-N,N-diallyl-5-(benzyloxy)-3-hydroxypentanethioamide (1331869-16-9) → 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)

Conditions

Yield

Multi-step reaction with 11 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 View Scheme

(R)-N,N-diallyl-5-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)pentanethioamide (1347738-07-1) → 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 (125971-95-1)

Conditions

Yield

Multi-step reaction with 10 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 View Scheme

CF3O3S(1-)*C25H42NO2SSi(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 (125971-95-1)

Conditions

Yield

Multi-step reaction with 9 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 View Scheme

(R)-tert-butyl 7-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-3-oxoheptanoate (1331869-20-5) → 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)

Conditions

Yield

Multi-step reaction with 8 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 View Scheme

C18H26O5 → 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)

Conditions

Yield

Multi-step reaction with 7 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 View Scheme

C18H28O5 → 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)

Conditions

Yield

Multi-step reaction with 6 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 View Scheme

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%

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) → lipitor (134523-03-8)

Conditions	Yield
Stage #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 With hydrogenchloride; methanol; water at 35℃; for 3h; Stage #2: With calcium hydroxide In methanol; water; toluene at 70℃; for 2h; Stage #3: In methanol; water at 20 - 78℃; for 24.25h;	96%
Stage #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 With hydrogenchloride; water In methanol at 15 - 30℃; for 12h; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; for 6h; pH=12; Stage #3: With hydrogenchloride; calcium acetate Product distribution / selectivity; more than 3 stages;	93.94%
Stage #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 With hydrogenchloride; water In methanol at 15 - 30℃; for 10 - 12h; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; for 4 - 6h; pH=~ 12; Stage #3: With hydrogenchloride; calcium acetate Product distribution / selectivity; more than 3 stages;	86.5%

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) → [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: 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 With hydrogenchloride In methanol; water at 50℃; for 10h; Stage #2: With methanol; sodium hydroxide; water at 20 - 60℃; for 10h; Stage #3: With hydrogenchloride; ammonia Product distribution / selectivity; more than 3 stages;	95%

methanol (67-56-1) + 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 (125971-95-1) → methyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (1353049-81-6)

Conditions	Yield
With sodium hydroxide for 7h; Reflux;	37%

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 (134523-00-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: HCl / tetrahydrofuran; H2O / 20 °C 2: sodium hydroxide / H2O; tetrahydrofuran / 20 °C View Scheme
Stage #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 With hydrogenchloride; water In tetrahydrofuran; methanol at 20℃; Stage #2: With sodium hydroxide; water In tetrahydrofuran; methanol at 0 - 20℃;
Stage #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 With hydrogenchloride; water In tetrahydrofuran at 25℃; for 8h; Stage #2: With sodium hydroxide; water In tetrahydrofuran for 8h; Stage #3: With phosphoric acid In water; ethyl acetate pH=4.0; 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 sodium (134523-01-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. HCl / methanol 2: aq. NaOH / methanol View Scheme
Stage #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 With hydroxylamine hydrochloride In methanol; water; acetone at 55 - 65℃; Industry scale; Stage #2: With sodium hydroxide In methanol; water at 35 - 45℃; Product distribution / selectivity;
Stage #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 With hydrogenchloride; water In tetrahydrofuran at 25℃; for 6.25h; Industry scale; Stage #2: With sodium hydroxide In tetrahydrofuran at 31℃; for 14h; Product distribution / selectivity; Cooling;

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) → C34H35FN2O3

Conditions	Yield
With hydroxylamine hydrochloride In methanol; water; acetone at 67℃; for 1h; Product distribution / selectivity; Heating / reflux;
With hydroxylamine hydrochloride In water; isopropyl alcohol; acetone at 67℃; for 1h; Product distribution / selectivity; Heating / reflux;

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) → {[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid} hemi-magnesium salt

Conditions	Yield
Stage #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 With hydrogenchloride In methanol; water at 20 - 26℃; for 6.25h; Stage #2: With sodium hydroxide In methanol; water at 25 - 30℃; for 6h; pH=~ 12; Stage #3: With hydrogenchloride; magnesium acetate In methanol; water at 20 - 55℃; pH=7.8 - 8;
Stage #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 With hydrogenchloride; methanol; water at 20 - 25℃; for 3.75h; Stage #2: With sodium hydroxide In methanol; water at 20 - 25℃; for 3h; Stage #3: With hydrogenchloride; magnesium acetate more than 3 stages;

Upstream product

• 125971-86-0 tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 347-84-2 1-(4-fluorophenyl)-2-phenylethanone 
• 124401-38-3 4-methyl-3-oxo-N-phenylpentanamide 
• 74530-57-7 tert-butyl 4-bromoacetoacetate 
• 74530-56-6 tert-butyl 4-chloroacetoacetate 
• 125971-93-9 (3R,5R)-tert-butyl-6-cyano-3,5-dihydroxyhexanoate 
• 7342-02-1 3-phenylpropynoic acid phenylamide 
• 79-30-1 isobutyryl chloride 
• 403-43-0 4-fluorobenzoyl chloride 
• 62-53-3 aniline 
• 42558-54-3 Methyl 4-methyl-3-oxopentanoate 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 1402828-93-6 C₂₇H₂₆FNO₂ 
• 1331869-19-2 C₂₆H₂₂FNO₃ 

Downstream Products

• 134523-00-5 atorvastatin 
• 134523-02-7 atorvastatin potassium 
• 134523-03-8 lipitor 
• 1353049-81-6 methyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 1353048-94-8 (3R,5R)-3,3-dimethyl-5,6-bis(nitrooxy)hexyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 
• 1353049-82-7 3,3-dimethyl-5,6-bis (nitrooxy)hexyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 581772-29-4 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 
• 125995-03-1 atorvastatin lactone 
• 134395-00-9 (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid t-butyl ester 
• 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 
• 134523-01-6 atorvastatin sodium 

Relevant articles and documents

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.

Atorvastatin calcium intermediate as well as preparation method and application thereof

The invention discloses an atorvastatin calcium intermediate as well as a preparation method and application thereof. A synthesis process of the intermediate is environmentally-friendly, simple to operate and low in EHS risk; raw materials are easy to obtain; a used chemical reagent is small in toxicity and low in cost; and the synthesis process is a green synthesis process suitable for the industrial production. Moreover, the intermediate provided by the invention is applied to the synthesis of atorvastatin calcium and a key intermediate thereof, the route is relatively short, the yield is high, the industrial production cost of the atorvastatin calcium is effectively reduced, and the atorvastatin calcium intermediate has a relatively high industrial application prospect.

Separating method for impurity A and impurity B and method for effectively reducing content of impurity A in atorvastatin calcium condensate

The invention discloses a separating method for an impurity A and an impurity B and a method for effectively reducing the content of an impurity A in an atorvastatin calcium condensate, and belongs tothe technical field of impurity separating in medicinal chemistry. The invention specifically discloses the impurity A in the atorvastatin calcium condensate, and a method for separating the impurityA from the atorvastatin calcium condensate, further studies that the impurity A of the atorvastatin calcium condensate is introduced by the impurity B in a starting material ATS-9 crude product, anddiscloses a method for separating the impurity B in the ATS-9 crude product, so as to reduce the content of impurity A in the atorvastatin calcium condensate, and further provide the basis for reducing the content of impurities in atorvastatin calcium diamine. The purity of the impurity A in the atorvastatin calcium condensate obtained by the separating method is at least 99.5%, and the purity ofthe impurity B in ATS-9 is at least 99.5%.