355806-00-7

Basic information

• Product Name: tert-Butyl rosuvastatin
• Synonyms: (3R,5S,6E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[(methanesulfonyl)methylamino]pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid tert-butyl ester;tert-butyl rosuvastatin;tert-Butyl (6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate;(+)-(3R, 5S)-7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N-METHYL-N-METHANESULFONYLAMINO)PYRIMIDIN-5-YL]-(3, 5)-DIHYDROXY-6(E)-HEPTENOATE;Rosuvastatin intermediate R-3;tert-Butyl(+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-Isopropyl-2-(N-Methyl-N-Methanesul fonylamino)pyrimidin-5-yl]-3,5-Dihydroxy-6(E)-Heptenoate;ZD-8;Tert-butyl-(+)7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidine-5-yl] -(3R,5S) -dihydroxy -(E)-6-Heptena
• CAS NO: 355806-00-7
• Molecular Formula: C₂₆H₃₆FN₃O₆S
• Molecular Weight: 537.64
• EINECS: 609-144-4
• Product Categories: Rosuvastatin Calcium and its intermediates;Rosuvastatin intermediates
• Mol File: 355806-00-7.mol
• Article Data: 29

Chemical Properties

• Boiling Point: 704.158 °C at 760 mmHg
• Flash Point: 379.661 °C
• Appearance: white to off-white crystal powder
• Density: 1.259
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.564
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly, Heated), Methan
• PKA: 13.38±0.20(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: tert-Butyl rosuvastatin(CAS DataBase Reference)
• NIST Chemistry Reference: tert-Butyl rosuvastatin(355806-00-7)
• EPA Substance Registry System: tert-Butyl rosuvastatin(355806-00-7)

Safety Data

• Hazardous Substances Data: 355806-00-7(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 355806-00-7 differently. You can refer to the following data:
1. Rosuvastatin tert-Butyl Ester, is a metabolite of Rosuvastatin (R700500) a selective, competitive HMG-CoA reductase inhibitor.
2. tert-Butyl Rosuvastatin is an impurity of Rosuvastatin (287714-41-4 #CAS), which is a HMG-?CoA reductase inhibitor. In combination of pemafibrate or a salt, it can function as cardiovascular disease medication.

InChI:InChI=1/C26H36FN3O6S/c1-16(2)23-21(13-12-19(31)14-20(32)15-22(33)36-26(3,4)5)24(17-8-10-18(27)11-9-17)29-25(28-23)30(6)37(7,34)35/h8-13,16,19-20,31-32H,14-15H2,1-7H3/b13-12+/t19-,20-/m1/s1

Synthetic route

2-[(4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(isopropyl)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert butyl ester (289042-12-2) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 10℃; for 4h; Temperature;	95%
With water; trifluoroacetic acid at 30 - 40℃;	86%
With camphor-10-sulfonic acid In water; acetonitrile at 20℃; for 0.5h;	57%

tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2-phenyl-1,3-dioxan-4-yl)acetate (1235588-97-2) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Stage #1: tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2-phenyl-1,3-dioxan-4-yl)acetate With water; acetic acid at 40 - 60℃; for 3h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	95%
With hydrogenchloride In tetrahydrofuran; water at 20℃; for 1h;	95%

tert-butyl 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 20℃; for 1h;	95%

tert-butyl 2-((7R,9S)-9-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-6,10-dioxaspiro[4.5]decan-7-yl)acetate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 20℃; for 1h;	95%

(+)-(3R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3-hydroxy-5-oxo-(6E)-heptenoic acid tert-butyl ester → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Stage #1: (+)-(3R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3-hydroxy-5-oxo-(6E)-heptenoic acid tert-butyl ester With triethyl borane In tetrahydrofuran; methanol at -78℃; for 0.25h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at -78℃; for 0.5h; Inert atmosphere;	90.6%
Stage #1: (+)-(3R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3-hydroxy-5-oxo-(6E)-heptenoic acid tert-butyl ester With diethyl methoxy borane In tetrahydrofuran; methanol at -78℃; for 0.5h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol for 3h;	86%
With sodium hydroxide; water In ethanol at 20℃; for 2h;
With sodium tetrahydroborate; diethyl methoxy borane In tetrahydrofuran; methanol at -78 - -75℃; for 1.5h;	10.5 g

tert-butyl (6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(isopropyl)pyrimidin-5-yl]-3,5-dioxohept-6-enoate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
With glucose dehydrogenase; D-Glucose; carbonyl reductase; NADP; sodium carbonate In ethanol; water at 30 - 50℃; pH=6.9 - 7.2; Enzymatic reaction;	86.7%

tert-butyl-6-[(1E)-2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate (1007871-85-3) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Stage #1: tert-butyl-6-[(1E)-2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate With hydrogenchloride; water In tetrahydrofuran at 20℃; for 2.5h; Stage #2: With sodium hydroxide; water In water at 0 - 15℃; pH=6; Product distribution / selectivity;	81%
Stage #1: tert-butyl-6-[(1E)-2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate With hydrogenchloride; water In tetrahydrofuran at 20℃; for 1 - 2.5h; Stage #2: With sodium hydroxide In tetrahydrofuran; water at 15℃; pH=6; Product distribution / selectivity;	81%

(5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-5-(hydroxy)-3-oxo-(6E)-heptenoic acid tert-butyl ester (910867-13-9) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Stage #1: (5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-5-(hydroxy)-3-oxo-(6E)-heptenoic acid tert-butyl ester With diethyl methoxy borane In tetrahydrofuran; methanol at -78℃; for 0.583333h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at -78℃; for 3 - 4h; Stage #3: With methanol; water; acetic acid In tetrahydrofuran; ethyl acetate at -78℃; for 0.166667h;
Stage #1: (5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-5-(hydroxy)-3-oxo-(6E)-heptenoic acid tert-butyl ester With diethyl methoxy borane In tetrahydrofuran; methanol at -78 - -75℃; for 1.16667h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at -78 - -75℃; for 2.25h; Stage #3: With acetic acid In tetrahydrofuran; methanol at -78℃;
Stage #1: (5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-5-(hydroxy)-3-oxo-(6E)-heptenoic acid tert-butyl ester With diethyl methoxy borane In tetrahydrofuran; methanol at -78 - -75℃; for 1.16667h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at -78 - -75℃; Inert atmosphere;
Stage #1: (5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-5-(hydroxy)-3-oxo-(6E)-heptenoic acid tert-butyl ester With diethyl methoxy borane In tetrahydrofuran; methanol at -78℃; for 0.583333h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at -78℃; for 3 - 4h; Stage #3: With acetic acid In tetrahydrofuran; methanol; water; ethyl acetate at -78 - 28℃; for 0.166667h;
Stage #1: (5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-5-(hydroxy)-3-oxo-(6E)-heptenoic acid tert-butyl ester With sodium tetrahydroborate; diethyl methoxy borane In tetrahydrofuran; methanol at -90 - 85℃; for 14.5h; Stage #2: With acetic acid In tetrahydrofuran; methanol

tert-butyl 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylsulfonyl)methyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate (1054627-26-7) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / tetrahydrofuran / 1.75 h / -80 - 45 °C 2: hydrogenchloride; water / acetonitrile / 25 - 55 °C / pH 2.5 View Scheme
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0 - 35 °C 2: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(4-nitrophenylsulfonyloxy)methyl]-1,3-dioxan-4-yl]acetate (141942-89-4) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 4-methyl-morpholine / 80 - 90 °C 2: dihydrogen peroxide; hexaammonium heptamolybdate tetrahydrate / dichloromethane; isopropyl alcohol / 16.5 h / 0 - 30 °C 3: potassium tert-butylate / tetrahydrofuran / 1.75 h / -80 - 45 °C 4: hydrogenchloride; water / acetonitrile / 25 - 55 °C / pH 2.5 View Scheme

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 0 - 5 °C 1.2: 10 - 15 °C 2.1: potassium tert-butylate / tetrahydrofuran / 1.75 h / -80 - 45 °C 3.1: hydrogenchloride; water / acetonitrile / 25 - 55 °C / pH 2.5 View Scheme
Multi-step reaction with 5 steps 1: triethylamine / toluene / 3 h / 0 - 30 °C / Inert atmosphere 2: 4-methyl-morpholine / 80 - 90 °C 3: dihydrogen peroxide; hexaammonium heptamolybdate tetrahydrate / dichloromethane; isopropyl alcohol / 16.5 h / 0 - 30 °C 4: potassium tert-butylate / tetrahydrofuran / 1.75 h / -80 - 45 °C 5: hydrogenchloride; water / acetonitrile / 25 - 55 °C / pH 2.5 View Scheme
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane 2: N,N-dimethyl-formamide / 25 - 130 °C 3: hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide / isopropyl alcohol 4: sodium hydride / tetrahydrofuran / 0 - 35 °C 5: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

(4R,6S)-6-(benzothiazol-2-mercapto)methyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (1353750-24-9) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: dihydrogen peroxide; hexaammonium heptamolybdate tetrahydrate / dichloromethane; isopropyl alcohol / 16.5 h / 0 - 30 °C 2: potassium tert-butylate / tetrahydrofuran / 1.75 h / -80 - 45 °C 3: hydrogenchloride; water / acetonitrile / 25 - 55 °C / pH 2.5 View Scheme

(R)-tert-butyl 4-cyano-3-(tert-butyldimethylsilyloxy)butyrate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: dihydrogen peroxide; sodium hydroxide / ethanol; water / 20 h / 10 - 30 °C 2.1: sodium hypochlorite / dichloromethane / 8 h / 0 - 5 °C 3.1: triethylamine / toluene / 4 h / -45 - 0 °C / Inert atmosphere 4.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 4.2: 1.5 h / -60 - 0 °C 5.1: cyclohexane / 30 h / 20 - 82 °C 6.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 7.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

(R)-tert-butyl 4-carbamoyl-3-(tert-butyldimethylsilyloxy)butyrate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium hypochlorite / dichloromethane / 8 h / 0 - 5 °C 2.1: triethylamine / toluene / 4 h / -45 - 0 °C / Inert atmosphere 3.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 3.2: 1.5 h / -60 - 0 °C 4.1: cyclohexane / 30 h / 20 - 82 °C 5.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 6.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

(R)-5-tert-butoxy-3-(tert-butyldimethylsilyloxy)-5-oxopentanoic acid → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triethylamine / toluene / 4 h / -45 - 0 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 2.2: 1.5 h / -60 - 0 °C 3.1: cyclohexane / 30 h / 20 - 82 °C 4.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 5.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: dicyclohexyl-carbodiimide / dichloromethane / 25 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 2.2: -78 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere 5.1: triethyl borane / tetrahydrofuran; methanol / 0.25 h / -78 °C / Inert atmosphere 5.2: 0.5 h / -78 °C / Inert atmosphere View Scheme

(R)-3-(tert-butyldimethylsilyloxy)-5-ethoxycarbonyloxy-5-oxopentanoic acid tert-butyl ester → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 1.2: 1.5 h / -60 - 0 °C 2.1: cyclohexane / 30 h / 20 - 82 °C 3.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 4.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

(R)-ethyl 4-cyano-3-hydroxybutyrate (141942-85-0) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: 1H-imidazole / dichloromethane / 21 h / 20 - 30 °C 2.1: sodium hydroxide; water / methanol / 3 h / 0 - 15 °C 3.1: sodium hydroxide; dmap / tert-butyl alcohol / 8 - 30 °C 4.1: dihydrogen peroxide; sodium hydroxide / ethanol; water / 20 h / 10 - 30 °C 5.1: sodium hypochlorite / dichloromethane / 8 h / 0 - 5 °C 6.1: triethylamine / toluene / 4 h / -45 - 0 °C / Inert atmosphere 7.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 7.2: 1.5 h / -60 - 0 °C 8.1: cyclohexane / 30 h / 20 - 82 °C 9.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 10.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

tert-butyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphorylidenehexanoate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: cyclohexane / 30 h / 20 - 82 °C 2: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 3: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

tertiary butyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenoate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
With sodium tetrahydroborate; diethyl methoxy borane In tetrahydrofuran; methanol at -80 - 25℃; for 4h; Inert atmosphere;

(R)-(-)-ethyl 4-cyano-3-(tert-butyldimethylsilyloxy)butyrate (141942-82-7) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: sodium hydroxide; water / methanol / 3 h / 0 - 15 °C 2.1: sodium hydroxide; dmap / tert-butyl alcohol / 8 - 30 °C 3.1: dihydrogen peroxide; sodium hydroxide / ethanol; water / 20 h / 10 - 30 °C 4.1: sodium hypochlorite / dichloromethane / 8 h / 0 - 5 °C 5.1: triethylamine / toluene / 4 h / -45 - 0 °C / Inert atmosphere 6.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 6.2: 1.5 h / -60 - 0 °C 7.1: cyclohexane / 30 h / 20 - 82 °C 8.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 9.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

(R)-4-cyano-3-(tert-butyldimethylsilyloxy)butyric acid (105876-28-6) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sodium hydroxide; dmap / tert-butyl alcohol / 8 - 30 °C 2.1: dihydrogen peroxide; sodium hydroxide / ethanol; water / 20 h / 10 - 30 °C 3.1: sodium hypochlorite / dichloromethane / 8 h / 0 - 5 °C 4.1: triethylamine / toluene / 4 h / -45 - 0 °C / Inert atmosphere 5.1: n-butyllithium / tetrahydrofuran / 1.5 h / -60 - 0 °C 5.2: 1.5 h / -60 - 0 °C 6.1: cyclohexane / 30 h / 20 - 82 °C 7.1: hydrogenchloride; water / methanol / 4.5 h / 10 - 25 °C 8.1: diethyl methoxy borane; sodium tetrahydroborate / methanol; tetrahydrofuran / 4 h / -80 - 25 °C / Inert atmosphere View Scheme

3-oxo-propionic acid tert-butyl ester (108350-21-6) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 25 - 30 °C 2: sodium hydroxide / ethanol; water / 25 - 30 °C 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide / water; dichloromethane / 5 - 10 °C 4: sodium carbonate; D-Glucose; NADP; glucose dehydrogenase; carbonyl reductase / ethanol; water / 30 - 50 °C / pH 6.9 - 7.2 / Enzymatic reaction View Scheme

3-hydroxy-5-oxo-hexanoic acid t-butyl ester → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol; water / 25 - 30 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide / water; dichloromethane / 5 - 10 °C 3: sodium carbonate; D-Glucose; NADP; glucose dehydrogenase; carbonyl reductase / ethanol; water / 30 - 50 °C / pH 6.9 - 7.2 / Enzymatic reaction View Scheme

tert-butyl (6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(isopropyl)pyrimidin-5-yl]-3-hydroxy-5-oxohept-6-enoate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide / water; dichloromethane / 5 - 10 °C 2: sodium carbonate; D-Glucose; NADP; glucose dehydrogenase; carbonyl reductase / ethanol; water / 30 - 50 °C / pH 6.9 - 7.2 / Enzymatic reaction View Scheme

(3R,5S)-6-<(methylsulfonyl)oxy>-3,5-O-isopropylidene-3,5-dihydroxyhexanoic acid tert-butyl ester (135054-68-1) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 25 - 130 °C 2: hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide / isopropyl alcohol 3: sodium hydride / tetrahydrofuran / 0 - 35 °C 4: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

[(4R,6S)-2,2-dimethyl-6-(1-phenyl-1H-tetrazol-5-ylsulfanylmethyl)[1,3]dioxan-4-yl]acetic acid tert-butyl ester (380460-39-9) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide / isopropyl alcohol 2: sodium hydride / tetrahydrofuran / 0 - 35 °C 3: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

[(4R,6S)-2,2-dimethyl-6-(1-phenyl-1H-tetrazole-5-sulfonylmethyl)[1,3]dioxan-4-yl]acetic acid tert-butyl ester (380460-37-7) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0 - 35 °C 2: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (147118-37-4) → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0 - 35 °C 2: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl(methyl)amino)pyrimidin-5-yl-methyl]triphenylphosphonium triflate → rosuvastatin tert-butyl ester (355806-00-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / -15 - 0 °C 2: hydrogenchloride / water; acetonitrile / 35 - 40 °C View Scheme

rosuvastatin tert-butyl ester (355806-00-7) → rosuvastatin sodium

Conditions	Yield
With sodium hydroxide; water In tetrahydrofuran at 30 - 50℃; for 1 - 2h; Product distribution / selectivity;	100%
With water; sodium hydroxide In acetonitrile at 20℃; for 7h; Temperature;	97%
With sodium hydroxide In ethanol at 0 - 20℃; for 1h;	92%

rosuvastatin tert-butyl ester (355806-00-7) → (E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(methylsulfonyl)amino)pyrimidin-5-yl)-(3R,5S)-3,5-dihydroxyhept-6-enoic acid, calcium salt

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide In ethanol; water at 20℃; for 1h; Stage #2: With calcium chloride In ethanol; water at 0 - 20℃;	94%
Stage #1: rosuvastatin tert-butyl ester With lithium hydroxide In ethanol at 60℃; for 8h; Stage #2: With calcium chloride In water for 0.5h;	90%
Stage #1: rosuvastatin tert-butyl ester With water; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 50℃; for 2h; Stage #2: With calcium chloride In water at 0℃; for 0.25h; Product distribution / selectivity;
Stage #1: rosuvastatin tert-butyl ester With water; isopropylamine In tetrahydrofuran at 95 - 100℃; for 2h; Stage #2: With calcium hydroxide In water at 20℃; for 1h; Product distribution / selectivity;

sodium hydroxide (1310-73-2) + rosuvastatin tert-butyl ester (355806-00-7) → rosuvastatin sodium

Conditions	Yield
With ethanol; water at 20 - 60℃; for 4.5h; Product distribution / selectivity;	91%

rosuvastatin tert-butyl ester (355806-00-7) + rac-methylbenzylamine (618-36-0) → C30H37FN4O5S

Conditions	Yield
In toluene at 100 - 110℃; for 12h;	91%

rosuvastatin tert-butyl ester (355806-00-7) + diisobutylamine (110-96-3) → rosuvastatin diisobutylamine salt

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide In tetrahydrofuran; water at 5 - 10℃; for 5h; Stage #2: With citric acid In dichloromethane; water at 5 - 20℃; for 0.5h; Stage #3: diisobutylamine In acetonitrile at 45 - 50℃; for 0.5h;	90%

rosuvastatin tert-butyl ester (355806-00-7) + tert-butylamine (75-64-9) → (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid-2-methylpropan-2-amine (917805-74-4)

Conditions	Yield
In water; acetonitrile at 25 - 80℃; Product distribution / selectivity;	85%
With water at 95 - 100℃; for 2 - 4h; Product distribution / selectivity;
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide In water; acetonitrile at 17 - 22℃; for 3h; Stage #2: tert-butylamine In dichloromethane for 1h; Temperature; Solvent; Reflux;	9.3 g

rosuvastatin tert-butyl ester (355806-00-7) → crestor

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide In methanol; water at 0 - 10℃; for 5h; Stage #2: With calcium chloride In water at 10 - 15℃;	83.5%
Stage #1: rosuvastatin tert-butyl ester With water; sodium hydroxide at 40 - 45℃; Inert atmosphere; Stage #2: With calcium chloride at 15 - 20℃; Micron filter;	38%
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide; water In acetonitrile at 20℃; for 2h; Stage #2: With calcium chloride In water at 20℃; for 15h; Product distribution / selectivity;

rosuvastatin tert-butyl ester (355806-00-7) → (+)-(3R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3-hydroxy-5-oxo-(6E)-heptenoic acid tert-butyl ester

Conditions	Yield
With manganese(IV) oxide In dichloromethane at 40℃; for 18h; Temperature;	80%
With manganese(IV) oxide for 20h; Reflux;	17.6 g

rosuvastatin tert-butyl ester (355806-00-7) → rosuvastatin (287714-41-4)

Conditions	Yield
With sodium hydroxide; ethanol; water at 20℃; for 2h; Product distribution / selectivity;
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide; water In tetrahydrofuran at 50 - 55℃; for 1h; Stage #2: With phosphoric acid; water Product distribution / selectivity;
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide; water In tetrahydrofuran at 30℃; for 2h; Stage #2: With hydrogenchloride; water at 20℃; Product distribution / selectivity;

rosuvastatin tert-butyl ester (355806-00-7) + diethylamine (109-89-7) → C4H11N*C22H28FN3O6S (917805-73-3)

Conditions	Yield
With water at 95 - 100℃; for 3.5h;

rosuvastatin tert-butyl ester (355806-00-7) + N-methylpropan-2-amine (4747-21-1) → C4H11N*C22H28FN3O6S (917805-72-2)

Conditions	Yield
With water at 95 - 100℃; for 2h;

rosuvastatin tert-butyl ester (355806-00-7) + tetramethyl ammoniumhydroxide (75-59-2) → rosuvastatin tetramethyl ammonium salt (917805-79-9)

Conditions	Yield
With water at 40 - 45℃; for 1h;

rosuvastatin tert-butyl ester (355806-00-7) + diisopropylamine (108-18-9) → E-7-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid diisopropylamine salt (862994-56-7)

Conditions	Yield
With water at 95 - 100℃; for 3h;

rosuvastatin tert-butyl ester (355806-00-7) + isopropylamine (75-31-0) → (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(isopropyl)pyrimidine-5-yl]-3,5-dihydroxyhept-6-enoic acid isopropylamine (852820-97-4)

Conditions	Yield
With water at 95 - 100℃; for 2 - 3h; Product distribution / selectivity;
In water at 98 - 100℃; for 2h;

rosuvastatin tert-butyl ester (355806-00-7) + SEC-BUTYLAMINE (33966-50-6) → (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl}-(3R,5S)-3,5-dihydroxy-hept-6-enoic acid sec-butylammonium salt (917805-75-5)

Conditions	Yield
With water at 95 - 100℃; for 4h;

rosuvastatin tert-butyl ester (355806-00-7) → Rosuvastatin lactone (503610-43-3)

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With potassium hydroxide; water In tetrahydrofuran at 40 - 45℃; for 1.5h; Stage #2: With phosphoric acid; water In ethyl acetate for 0.333333h; Heating / reflux; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate

rosuvastatin tert-butyl ester (355806-00-7) → rosuvastatin triol t-butyl ester (1058749-22-6)

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With boron dimethyl-trifluoro sulphide In tetrahydrofuran at 20℃; for 3h; Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 50℃; for 0.5h;

rosuvastatin tert-butyl ester (355806-00-7) + rosuvastatin triol t-butyl ester (1058749-22-6) → rosuvastatin triol calcium + crestor

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester; rosuvastatin triol t-butyl ester With sodium hydroxide; water In ethanol at 20℃; for 2h; Stage #2: With calcium chloride In water at 20 - 40℃; for 1h;

rosuvastatin tert-butyl ester (355806-00-7) + N,N'-dibenzylethylenediamine diacetate (122-75-8) → N,N'-dibenzylethylenediamine rosuvastatin (1045601-12-4)

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide In ethanol; water at 25 - 30℃; for 1h; Stage #2: N,N'-dibenzylethylenediamine diacetate In water for 2h;

rosuvastatin tert-butyl ester (355806-00-7) + N,N'-dibenzylethylenediamine diacetate (122-75-8) → (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)]-2-[methyl(methylsulfonyl)amino-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid N,N'-dibenzylethylenediamine

Conditions	Yield
Stage #1: rosuvastatin tert-butyl ester With sodium hydroxide; ethanol; water at 25 - 30℃; for 1h; Stage #2: N,N'-dibenzylethylenediamine diacetate In water for 2h; Product distribution / selectivity;

Upstream product

• 124655-08-9 tert-butyl 2-((4R,6S)-6-((tert-butyldiphenylsilyloxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 124655-07-8 (3R,5S)-tert-butyl 6-(tert-butyldiphenylsilyloxy)-3,5-dihydroxyhexanoate 
• 1235588-93-8 tert-butyl 2-((4R,6S)-6-((tert-butyldiphenylsilyloxy)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate 
• 1235588-94-9 tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl)acetate 
• 131666-50-7 ((4S,6R)-6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)methyl benzoate 
• 131666-49-4 (2S,4R)-6-tert-butoxy-2,4-dihydroxy-6-oxohexyl benzoate 
• 1044518-72-0 tert-butyl 2-((4R,6S)-6-[(tert-butyl)dimethylsilyloxymethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 1044518-92-4 (3R,5S)-tert-butyl 6-(tert-butyldimethylsilyloxy)-3,5-dihydroxyhexanoate 
• 124752-23-4 tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 128237-30-9 1-tert-butyl 5-ethyl 3-hydroxypentanedioate 

Downstream Products

• 917805-73-3 C₄H₁₁N*C₂₂H₂₈FN₃O₆S 
• 917805-72-2 C₄H₁₁N*C₂₂H₂₈FN₃O₆S 
• 1045601-12-4 N,N'-dibenzylethylenediamine rosuvastatin 
• 1422619-13-3 7-[4-(4-fluorophenyl)-6-isopropyl-2(N-methyl-N-methanesulfonamido)pyrimidin-5-yl]-(3R)-3-hydroxy-5-carbonyl-6-(E)-heptenoic acid 
• 1094100-06-7 (E)-(3R,5R)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid 
• 1058749-22-6 rosuvastatin triol t-butyl ester 
• 503610-43-3 Rosuvastatin lactone 
• 917805-74-4 (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid-2-methylpropan-2-amine 
• 917805-75-5 (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl}-(3R,5S)-3,5-dihydroxy-hept-6-enoic acid sec-butylammonium salt 
• 852820-97-4 (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(isopropyl)pyrimidine-5-yl]-3,5-dihydroxyhept-6-enoic acid isopropylamine 
• 862994-56-7 E-7-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid diisopropylamine salt 
• 917805-79-9 rosuvastatin tetramethyl ammonium salt 
• 287714-41-4 rosuvastatin 

Relevant articles and documents

PROCESS FOR MANUFACTURE OF ROSUVASTATIN CALCIUM AMORPHOUS

Disclosed here is a process for the preparation of amorphous Rosuvastatin calcium hydrate with high purity.

INTERMEDIATE COMPOUND FOR PREPARING ROSUVASTATIN CALCIUM AND METHOD FOR PREPARING ROSUVASTATIN CALCIUM THEREFROM

Provided are an intermediate compound for preparing rosuvastatin calcium and a preparation method of the rosuvastatin calcium. The method comprises: using the foregoing intermediate compound as a raw material, and subjecting the raw material to a step of Wittig reaction, a step of protecting group removal and hydrolysis and a step of calcium salt formation, so as to obtain the rosuvastatin calcium. The product, which is prepared from the intermediate compound, can be substantially enhanced in stereoselectivity and also notably improved in purity and yield; in addition, the method for preparing rosuvastatin calcium from the intermediate compound is simple, convenient and low in cost.

Ruishufatatinggan known method for the preparation of impurity

The invention relates to a preparation method of known impurities of rosuvastatin. The preparation method comprises the following step: by taking 4-(4-fluorophenyl)-5-triphenyl phosphine bromine-6-isopropyl-2-[(N-methyl-N-methanesulfonamido)]-pyrimidine as a raw material, preparing (bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]-pyrimidine-yl]-3R-3-hydroxyl-5-oxo-6-heptenoic acid] calcium salt through witting reaction, acidification, oxidization, alkaline hydrolysis and salt forming reaction to obtain the known impurities of rosuvastatin. The preparation method is short in synthetic line and simple to operate, and the product obtained is high in purity and can be applied to research of reference substances.