355806-00-7

Usage

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

• 910867-13-9 (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 
• 1007871-85-3 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 
• 141942-85-0 (R)-ethyl 4-cyano-3-hydroxybutyrate 
• 141942-82-7 (R)-(-)-ethyl 4-cyano-3-(tert-butyldimethylsilyloxy)butyrate 
• 105876-28-6 (R)-4-cyano-3-(tert-butyldimethylsilyloxy)butyric acid 
• 108350-21-6 3-oxo-propionic acid tert-butyl ester 
• 135054-68-1 (3R,5S)-6-<(methylsulfonyl)oxy>-3,5-O-isopropylidene-3,5-dihydroxyhexanoic acid tert-butyl ester 
• 380460-39-9 [(4R,6S)-2,2-dimethyl-6-(1-phenyl-1H-tetrazol-5-ylsulfanylmethyl)[1,3]dioxan-4-yl]acetic acid tert-butyl ester 
• 380460-37-7 [(4R,6S)-2,2-dimethyl-6-(1-phenyl-1H-tetrazole-5-sulfonylmethyl)[1,3]dioxan-4-yl]acetic acid tert-butyl ester 
• 147118-37-4 N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 
• 154026-95-6 (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester 
• 154026-93-4 1,1-dimethylethyl (3R,5S)-6-chloro-3,5-dihydroxy-4-hexanoate 

Downstream Products

• 917805-72-2 C₄H₁₁N*C₂₂H₂₈FN₃O₆S 
• 917805-79-9 rosuvastatin tetramethyl ammonium salt 
• 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 
• 503610-43-3 Rosuvastatin lactone 
• 1058749-22-6 rosuvastatin triol t-butyl ester 
• 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 
• 917805-73-3 C₄H₁₁N*C₂₂H₂₈FN₃O₆S 
• 287714-41-4 rosuvastatin 
• 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 

Relevant academic research and scientific papers

PROCESS FOR MANUFACTURE OF ROSUVASTATIN CALCIUM AMORPHOUS

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

Purification method of rosuvastatin calcium key intermediate

The invention provides a purification method of a rosuvastatin calcium intermediate. The rosuvastatin calcium intermediate has a structure of a compound (4). The purification method comprises following steps: adding an alcohol solvent and water into a crude product containing the compound (4), then adding an ether solvent, cooling, and crystallizing to obtain the compound (4). The structure of thecompound (4) is represented in the description. The provided purification method has the advantages of simple operation, high yield, and good selectivity, can obtain high purity rosuvastatin calciumkey intermediate, which is used to prepare high quality rosuvastatin calcium, and improves the drug quality.

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.

Synthesis method of chiral isomer impurities of rosuvastatin calcium

The invention relates to a synthesis method of chiral isomer impurities of rosuvastatin calcium. The invention finds that meso compounds IV (3R, 5R) and (3R, 5S), which are obtained after a compound III is reduced by sodium borohydride, differ greatly in chemical properties, (3R, 5S) compounds, adopting hydroxyl cis-structures, on C-3 and C-5 can be hydrolyzed in a very low-temperature alkaline environment, while (3R, 5R) compounds, adopting hydroxyl trans-structures, on the C-3 and the C-5 can be hydrolyzed at a relatively high temperature and cannot be hydrolyzed at a low temperature, and by virtue of a peculiar phenomenon, two chiral isomers of the meso compound IV are separated to obtain a target compound. The synthesis method is short in route; chiral carbon is not required to be introduced from a side chain source; the synthesis method is simple in process and easy to operate; the purity and the yield of the obtained target product are high, the purity can reach 98.8%, the yield can reach 75%, and the purity and the yield are much higher than those in the prior art; a reference substance is provided for the (3R, 5S) chiral isomer impurities of the rosuvastatin calcium; the synthesis method is of a great significance in researching the quality of the rosuvastatin calcium.

Ruishufatatinggan and wherein the intermediate preparation method

The invention relates to preparation methods for rosuvastatin calcium and intermediates thereof. Specifically, the invention discloses intermediate compounds for preparing rosuvastatin calcium and a preparation method of the intermediate compounds, and the intermediates are the compounds shown as formula V and formula VI. The invention also discloses a preparation method of rosuvastatin calcium or salts thereof, and the preparation method is based on the two intermediate compounds and the preparation method thereof. The preparation is simple and safe in operation, low in production cost and applicable to industrialized production.

PROCESSES FOR THE PREPARATION OF ROSUVASTATIN OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to processes for the preparation of rosuvastatin calcium of formula I and pharmaceutically acceptable salts thereof using novel intermediates, and to a pharmaceutical composition containing the same.

New Statin intermediate, the preparation of the same and the preparation of Rosuvastatin using the same

The present invention provides a novel producing method for producing a core intermediate (chemical formula IV) of rosuvastatin, a novel intermediate used therefor and a producing method of rosuvastatin hemi-calcium salts using the same. The novel intermediate of the present invention can be prepared with high purity and in high yields in mild conditions, and thus the rosuvastatin intermediate and rosuvastatin hemi-calcium salts can be conveniently and efficiently mass-produced without complicated processes.

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.

Method for preparing of chiral intermediate and method for the preparing of HMG-CoA reductase inhibitor using chiral intermadiate

Chiral compounds and manufacturing method of the present invention refers to using the same manufacturing method relates to number of HMG-COa reduction inhibitors, more specifically an HMG-COa-reduction inhibitors number jaws statin compound in number of chiral intermediates that can be used a reaction steps, mild, and endangering a simple method and in high yield and purity can be under trillion number, purity statin compound is mirror number under trillion number on a commercial scale in can manufacturing method and [...] compounds using the same number of HMG-COa reduction inhibitors relates to manufacturing method. (by machine translation)

Ruishufatatinggan and wherein the intermediate preparation method (by machine translation)

This invention involves a kind of Ruishufatatinggan and wherein the intermediate preparation method. In particular, the invention discloses used for preparing rosuvastatin calcium and its method for preparing intermediate compounds, the structure of the specification are as intermediates for Chinese II, formula III, formula IV, formula VI or formula VII is shown in. The invention also discloses switzerland extends down his sandbank or its salt preparation method, the method is based on the aforesaid five intermediate compound and its preparation method, the operation is simple, safe, and the production cost is low, is suitable for industrial production. (by machine translation)