124655-09-0

Basic information

• Product Name: (4R-Cis)-6-Hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester
• Synonyms: D-6 (4R-Cis)-6-HydroxyMethyl-2,2-DiMethyl-1,3-Dioxane-4-AceticAcid,1,1-DiMethylthylEster;tert-Butyl (4R,6S)-6-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-acetate;rosuvastatin intermediatesC-5;T-BUTYL-(3R,5S)-6-HYDROXY 3,5-O-ISOPROPYLIDENE 3,5-DIHYDROXYHEXANOATE;TERT-BUTYL [(4R,6S)-6-(HYDROXYMETHYL)-2,2-DIMETHYL-1,3-DIOXANE-4-YL] ACETATE;TERT-BUTYL (3R,5S)-6-HYDROXY 3,5-O-ISOPROPYLIDENE-3,5-DIHYDROXYHEXANOATE;2-[(4r,6s)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester;(6S-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4R-yl)acetic acid tert-butyl ester
• CAS NO: 124655-09-0
• Molecular Formula: C₁₃H₂₄O₅
• Molecular Weight: 260.33
• EINECS: 432-960-5
• Product Categories: chiral;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 124655-09-0.mol

Chemical Properties

• Boiling Point: 331°C
• Flash Point: 113°C
• Appearance: Colorless to light yellow liquid
• Density: 1.030
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.4500-1.4540
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 14.25±0.10(Predicted)
• CAS DataBase Reference: (4R-Cis)-6-Hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: (4R-Cis)-6-Hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester(124655-09-0)
• EPA Substance Registry System: (4R-Cis)-6-Hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester(124655-09-0)

Safety Data

• Hazardous Substances Data: 124655-09-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
(4R-Cis)-6-Hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester is used as a synthetic intermediate for the preparation of Rosuvastatin (R700500) and its derivatives. (4R-Cis)-6-Hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester plays a crucial role in the development of statin drugs, which are widely used for the treatment of high cholesterol and cardiovascular diseases. Its unique structure allows for the synthesis of various pharmaceutical compounds, making it an essential component in the production process.

InChI:InChI=1/C13H24O5/c1-12(2,3)18-11(15)7-9-6-10(8-14)17-13(4,5)16-9/h9-10,14H,6-8H2,1-5H3/t9-,10+/m1/s1

Synthetic route

tert-butyl 2-((4R,6S)-6-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate (151140-38-4) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethyl acetate at 31 - 33℃; under 7600 Torr; for 5h;	100%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; under 750.075 - 1500.15 Torr; Autoclave;	94%
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; for 5h; Concentration;	94%
With H2; palladium-carbon In ethyl acetate
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 25 - 30℃; under 7500.75 Torr; for 5h; Autoclave;

(4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (154026-95-6) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With potassium carbonate In methanol; water	98%
With methanol; potassium carbonate for 0.5h;	98%
With methanol; potassium carbonate at 20℃;	92%

tert-butyl (3R,5S)-6-(4-methylbenzyloxy)-3,5-O-isopropylidene-3,5-dihydroxyhexanoate → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethyl acetate at 32℃; under 15201 Torr; for 16h;	90%

tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With sodium tetrahydroborate In methanol at 0℃; for 2h;	83%
With sodium tetrahydroborate In methanol at 0℃;

C18H32O6 (1067638-10-1) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With sodium ethanolate In ethanol at 20℃; for 15h;	81%

tert-butyl 2-((4R,6S)-6-((tert-butyldiphenylsilyloxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (124655-08-9) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 0℃; for 3h;	80%

tert-butyl 2-((4R, 6S)-2,2-dimethyl-6-((E)-styryl)-1,3-dioxan-4-yl)acetate (143840-61-3) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With sodium tetrahydroborate; ozone 1.) methanol; Yield given. Multistep reaction;

→ 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / sodium metaperiodate, water / diethyl ether / 3 h / Ambient temperature 2: 83 percent / sodium borohydride / methanol / 2 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 2: NaBH4 / methanol / 0 °C View Scheme

isopropyl (2S,3R,4S,6R)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-dihydroxyheptanoate (147489-00-7) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 99 percent / p-toluenesulfonic acid / 2 h / Ambient temperature 2: 99 percent / tetrabutylammonium fluoride / tetrahydrofuran / 3 h / Ambient temperature 3: 85 percent / sodium metaperiodate, water / diethyl ether / 3 h / Ambient temperature 4: 83 percent / sodium borohydride / methanol / 2 h / 0 °C View Scheme
Multi-step reaction with 4 steps 1: 98 percent / p-TsOH / 2 h / Ambient temperature 2: 99 percent / (n-Bu)4NF / tetrahydrofuran / 3 h / Ambient temperature 3: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 4: NaBH4 / methanol / 0 °C View Scheme

isopropyl (2S,3R,4S,6R)-7-t-butpxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-isopropylidenedioxyheptanoate (147489-01-8) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 percent / tetrabutylammonium fluoride / tetrahydrofuran / 3 h / Ambient temperature 2: 85 percent / sodium metaperiodate, water / diethyl ether / 3 h / Ambient temperature 3: 83 percent / sodium borohydride / methanol / 2 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1: 99 percent / (n-Bu)4NF / tetrahydrofuran / 3 h / Ambient temperature 2: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 3: NaBH4 / methanol / 0 °C View Scheme

isopropyl (2S,3S,6R)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-6-hydroxy-4-oxoheptanoate (147488-99-1) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) diethyl(methoxy)borane, 2.) sodium borohydride / 1.) THF, methanol, RT, 15 min, 2.) THF, methanol, a) -78 deg C, 4 h, b) from -78 deg C to RT, 8 h 2: 99 percent / p-toluenesulfonic acid / 2 h / Ambient temperature 3: 99 percent / tetrabutylammonium fluoride / tetrahydrofuran / 3 h / Ambient temperature 4: 85 percent / sodium metaperiodate, water / diethyl ether / 3 h / Ambient temperature 5: 83 percent / sodium borohydride / methanol / 2 h / 0 °C View Scheme
Multi-step reaction with 5 steps 1: 76 percent / Et2BOMe, NaBH4 / tetrahydrofuran; methanol / -78 deg C to RT, 12 h 2: 98 percent / p-TsOH / 2 h / Ambient temperature 3: 99 percent / (n-Bu)4NF / tetrahydrofuran / 3 h / Ambient temperature 4: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 5: NaBH4 / methanol / 0 °C View Scheme

isopropyl (2S,3S)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-dioxoheptanoate (147488-98-0) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 60 percent / DIBAL / tetrahydrofuran; hexane / 4 h / -78 °C 2: 1.) diethyl(methoxy)borane, 2.) sodium borohydride / 1.) THF, methanol, RT, 15 min, 2.) THF, methanol, a) -78 deg C, 4 h, b) from -78 deg C to RT, 8 h 3: 99 percent / p-toluenesulfonic acid / 2 h / Ambient temperature 4: 99 percent / tetrabutylammonium fluoride / tetrahydrofuran / 3 h / Ambient temperature 5: 85 percent / sodium metaperiodate, water / diethyl ether / 3 h / Ambient temperature 6: 83 percent / sodium borohydride / methanol / 2 h / 0 °C View Scheme
Multi-step reaction with 6 steps 1: 60 percent / diisobutylaluminium hydride / tetrahydrofuran; hexane / 4 h / -78 °C 2: 76 percent / Et2BOMe, NaBH4 / tetrahydrofuran; methanol / -78 deg C to RT, 12 h 3: 98 percent / p-TsOH / 2 h / Ambient temperature 4: 99 percent / (n-Bu)4NF / tetrahydrofuran / 3 h / Ambient temperature 5: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 6: NaBH4 / methanol / 0 °C View Scheme

tert-butyl acetoacetate (1694-31-1) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions

Yield

Multi-step reaction with 7 steps 1: 74 percent / NaH, n-BuLi / 20 h / -78 °C 2: 60 percent / diisobutylaluminium hydride / tetrahydrofuran; hexane / 4 h / -78 °C 3: 76 percent / Et2BOMe, NaBH4 / tetrahydrofuran; methanol / -78 deg C to RT, 12 h 4: 98 percent / p-TsOH / 2 h / Ambient temperature 5: 99 percent / (n-Bu)4NF / tetrahydrofuran / 3 h / Ambient temperature 6: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 7: NaBH4 / methanol / 0 °C View Scheme

(3R,5S)-3,5-Dihydroxy-5-((2S,3S)-3-trimethylsilanyl-oxiranyl)-pentanoic acid tert-butyl ester (143827-05-8) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / H(1+) 2: 1.) Bu3SnLi / 2.) Pd(PPh3)4 3: 1.) O3, 2.) NaBH4 / 1.) methanol View Scheme
Multi-step reaction with 3 steps 1: 81 percent / H(1+) 2: 90 percent 3: 1.) O3, 2.) NaBH4 / 1.) methanol View Scheme

(S)-5-Hydroxy-3-oxo-5-((2S,3S)-3-trimethylsilanyl-oxiranyl)-pentanoic acid tert-butyl ester (143840-67-9) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 60 percent / Et2BOMe, NaBH4 2: 81 percent / H(1+) 3: 1.) Bu3SnLi / 2.) Pd(PPh3)4 4: 1.) O3, 2.) NaBH4 / 1.) methanol View Scheme
Multi-step reaction with 4 steps 1: 60 percent / Et2BOMe, NaBH4 2: 81 percent / H(1+) 3: 90 percent 4: 1.) O3, 2.) NaBH4 / 1.) methanol View Scheme

[(4R,6S)-2,2-Dimethyl-6-((2S,3S)-3-trimethylsilanyl-oxiranyl)-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester (143800-10-6) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) Bu3SnLi / 2.) Pd(PPh3)4 2: 1.) O3, 2.) NaBH4 / 1.) methanol View Scheme
Multi-step reaction with 2 steps 1: 90 percent 2: 1.) O3, 2.) NaBH4 / 1.) methanol View Scheme

acetic acid tert-butyl ester (540-88-5) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 100 percent / LDA / tetrahydrofuran / 1.75 h / -70 - -15 °C 2: 1). Et3B; 2.) NaBH4, MeOH / 1.) THF, 23 deg C, 15 min; 2.) -70 deg C 3: 70 percent / p-toluenesulfonic acid / acetone / 2 h / 23 °C 4: 80 percent / Bu4NF / tetrahydrofuran / 3 h / 0 °C View Scheme
Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: sodium hydride / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 2.2: 6 h / 20 °C / Inert atmosphere 3.1: methanol; diethyl methoxy borane; sodium tetrahydroborate / tetrahydrofuran / 2.5 h / -80 - -70 °C / Inert atmosphere 4.1: methanesulfonic acid / 20 °C 5.1: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 750.08 - 1500.15 Torr / Autoclave View Scheme
Multi-step reaction with 3 steps 1.1: (S)-5-benzyl 2,2,3-trimethyl-4-thione / ethanol / 0.5 h / 0 °C 1.2: 3 h / 0 - 30 °C 2.1: camphor-10-sulfonic acid / ethyl acetate / 4 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 5 h / 20 °C View Scheme

(3R,5S)-tert-butyl 6-(tert-butyldiphenylsilyloxy)-3,5-dihydroxyhexanoate (124655-07-8) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / p-toluenesulfonic acid / acetone / 2 h / 23 °C 2: 80 percent / Bu4NF / tetrahydrofuran / 3 h / 0 °C View Scheme

(5S)-6-(tert-butyl-diphenylsilanyloxy)-5-hydroxy-3-oxohexanoic acid tert-butyl ester (124655-06-7) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1). Et3B; 2.) NaBH4, MeOH / 1.) THF, 23 deg C, 15 min; 2.) -70 deg C 2: 70 percent / p-toluenesulfonic acid / acetone / 2 h / 23 °C 3: 80 percent / Bu4NF / tetrahydrofuran / 3 h / 0 °C View Scheme

1-methyl 6-tert.-butyl (2S,4R)-2,4-O-isopropylidene-2,4-dihydroxyadipate (140387-94-6) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
With hydrogenchloride; sodium borohydrid; ammonium chloride In tetrahydrofuran; methanol
With hydrogenchloride; sodium borohydrid; ammonium chloride In methanol

C13H25ClO4Si → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 1 h / 0 °C 2.1: sodium tetrahydroborate / water / 14 h / 0 °C 3.1: acetone / 0.25 h / 25 °C 3.2: 6 h / 48 - 50 °C 4.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 5.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 1 h / 0 °C 2.1: diethyl methoxy borane / tetrahydrofuran; methanol / 1 h / 25 °C / Inert atmosphere 2.2: 4 h / -78 °C / Inert atmosphere 3.1: acetone / 0.25 h 3.2: 6 h / 48 - 50 °C 4.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 5.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 1 h / 0 °C 2.1: sodium tetrahydroborate; sodium dodecyl-sulfate / water / 14 h / 0 °C 3.1: acetone / 0.25 h 3.2: 6 h / 48 - 50 °C 4.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 5.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 5 steps 1: hydrogenchloride / water / 1 h / 0 °C 2: sodium tetrahydroborate / water / 14 h / 0 °C 3: (R)-10-camphorsulfonic acid / dichloromethane / 3 h / 40 °C 4: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 5: potassium carbonate; methanol / 0.5 h View Scheme

(5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (406680-96-4) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetone / 0.25 h / 25 °C 1.2: 6 h / 48 - 50 °C 2.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 3.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 3 steps 1: (R)-10-camphorsulfonic acid / dichloromethane / 3 h / 40 °C 2: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 3: potassium carbonate; methanol / 0.5 h View Scheme

tert-butyl 2-((6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 85 °C 2: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / water; dichloromethane / 24 h / 20 °C 2: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 3: potassium carbonate; methanol / 0.5 h View Scheme

Tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate (154026-92-3) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / water / 14 h / 0 °C 2.1: acetone / 0.25 h / 25 °C 2.2: 6 h / 48 - 50 °C 3.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 4.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 4 steps 1.1: diethyl methoxy borane / tetrahydrofuran; methanol / 1 h / 25 °C / Inert atmosphere 1.2: 4 h / -78 °C / Inert atmosphere 2.1: acetone / 0.25 h 2.2: 6 h / 48 - 50 °C 3.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 4.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; sodium dodecyl-sulfate / water / 14 h / 0 °C 2.1: acetone / 0.25 h 2.2: 6 h / 48 - 50 °C 3.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 4.1: potassium carbonate; methanol / 0.5 h View Scheme

1,1-dimethylethyl (3R,5S)-6-chloro-3,5-dihydroxy-4-hexanoate (154026-93-4) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetone / 0.25 h 1.2: 6 h / 48 - 50 °C 2.1: 1-methyl-pyrrolidin-2-one / 24 h / 25 - 95 °C 3.1: potassium carbonate; methanol / 0.5 h View Scheme
Multi-step reaction with 3 steps 1: (1S)-10-camphorsulfonic acid / acetone / 6 h / 48 - 50 °C 2: 1-methyl-pyrrolidin-2-one / 24 h / 95 °C 3: methanol; potassium carbonate / 20 °C View Scheme

tert-butyl 2-((6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water; dichloromethane / 48 h / 25 °C 2: potassium carbonate; methanol / 0.5 h View Scheme

(4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid,1,1-dimethylethyl ester (154026-94-5) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-methyl-pyrrolidin-2-one / 24 h / 95 °C 2: methanol; potassium carbonate / 20 °C View Scheme

tert-butyl (S)-4-(propylene oxide-2-yl)-3-oxobutanoate (623566-51-8) → 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 1.2: 6 h / 20 °C / Inert atmosphere 2.1: methanol; diethyl methoxy borane; sodium tetrahydroborate / tetrahydrofuran / 2.5 h / -80 - -70 °C / Inert atmosphere 3.1: methanesulfonic acid / 20 °C 4.1: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C / 750.08 - 1500.15 Torr / Autoclave View Scheme

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetic acid (154877-92-6)

Conditions	Yield
Stage #1: 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate With water; sodium hydroxide In methanol at 40 - 50℃; Stage #2: With hydrogenchloride In water at 15 - 20℃; pH=4 - 4.2;	100%
With sodium hydroxide In tetrahydrofuran Reflux;
With sodium hydroxide In tetrahydrofuran Reflux;

1H-imidazole (288-32-4) + ethyl acetate dichloromethane + 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → (3R,5S)-6-iodo-3,5-O-isopropylidene-3,5-dihydroxyhexanoic acid tert-butyl ester (134742-42-0)

Conditions	Yield
With iodine; triphenylphosphine In benzene	99%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → C13H24O5

Conditions	Yield
With toluene-4-sulfonic acid In acetone at 50℃;	99%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4)

Conditions	Yield
Swern oxidation; (further oxidizing agents);	97%
Stage #1: 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate With dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at -5 - 0℃; for 0.5h; Stage #2: With pyridine; sulfur trioxide pyridine complex; dimethyl sulfoxide In dichloromethane at -5 - 20℃; for 1.16667h;	93%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide In dichloromethane; water at 5 - 10℃; for 0.166667h; Temperature; Flow reactor;	93.5%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) + methanesulfonyl chloride (124-63-0) → (3R,5S)-6-<(methylsulfonyl)oxy>-3,5-O-isopropylidene-3,5-dihydroxyhexanoic acid tert-butyl ester (135054-68-1)

Conditions	Yield
With pyridine In dichloromethane at 0℃; for 0.5h;	90%
With pyridine In dichloromethane; toluene
With triethylamine In dichloromethane	100 g

C20H19FN2O3 (906645-38-3) + 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → C33H41FN2O7 (906645-40-7)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at -5 - 20℃; Mitsunobu reaction;	88%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) + benzoyl chloride (98-88-4) → ((4S,6R)-6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)methyl benzoate (131666-50-7)

Conditions	Yield
Stage #1: 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate With pyridine In dichloromethane at 20℃; for 0.5h; Stage #2: benzoyl chloride In dichloromethane at 20℃; for 1h;	88%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) + acetyl chloride (75-36-5) → (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (154026-95-6)

Conditions	Yield
Stage #1: 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate With pyridine In dichloromethane at 20℃; for 0.5h; Stage #2: acetyl chloride In dichloromethane at 20℃; for 1h;	86%
With pyridine In dichloromethane at 20℃; for 0.5h;	15.9 g

2-methyl-2-phenylpropionic acid (826-55-1) + 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → C22H34O5

Conditions	Yield
With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve;	52%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) + ethyl (triphenylphosphoranylidene)acetate (1099-45-2) → C17H28O6 (707542-98-1)

Conditions	Yield
With manganese(IV) oxide In toluene for 17h; Heating / reflux;	41%

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → C40H44F2N2O5

Conditions	Yield
Multi-step reaction with 2 steps 1: 46 percent / n-BuLi / 2 h / -78 - 25 °C View Scheme

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → (6-{2-[3-(4-fluorophenyl)-1-isopropyl-5-(4-methoxybenzylcarbamoyl)-4-phenyl-1H-pyrrol-2-yl]vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)acetic acid tert-butyl ester (855249-03-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / NaHMDS / tetrahydrofuran / 2 h / -78 - 25 °C View Scheme

1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (124655-09-0) → C42H51FN2O6

Conditions	Yield
Multi-step reaction with 3 steps 1: 75 percent / NaHMDS / tetrahydrofuran / 2 h / -78 - 25 °C 2: hydrogen / Pd/C / methanol / 3 h / 25 °C / 2585.81 Torr View Scheme

Upstream product

• 124655-08-9 tert-butyl 2-((4R,6S)-6-((tert-butyldiphenylsilyloxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 124752-23-4 tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 143840-61-3 tert-butyl 2-((4R, 6S)-2,2-dimethyl-6-((E)-styryl)-1,3-dioxan-4-yl)acetate 
• 151140-38-4 tert-butyl 2-((4R,6S)-6-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate 
• 1694-31-1 tert-butyl acetoacetate 
• 143840-67-9 (S)-5-Hydroxy-3-oxo-5-((2S,3S)-3-trimethylsilanyl-oxiranyl)-pentanoic acid tert-butyl ester 
• 540-88-5 acetic acid tert-butyl ester 
• 124655-07-8 (3R,5S)-tert-butyl 6-(tert-butyldiphenylsilyloxy)-3,5-dihydroxyhexanoate 
• 140387-94-6 1-methyl 6-tert.-butyl (2S,4R)-2,4-O-isopropylidene-2,4-dihydroxyadipate 
• 154026-95-6 (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester 
• 1067638-10-1 C₁₈H₃₂O₆ 
• 406680-96-4 tert-butyl (5S)-6-chloro-3,5-dihydroxyhexanoate 
• 521973-99-9 tert-butyl 2-((6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 154026-92-3 Tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate 

Downstream Products

• 124752-23-4 tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 141942-87-2 [(4R,6S)-6-(4-Chloro-benzenesulfonyloxymethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester 
• 136006-37-6 (3R,5S)-6-<(p-tolylsulfonyl)oxy>-3,5-O-isopropylidene-3,5-dihydroxyhexanoic acid tert-butyl ester 
• 141942-88-3 [(4R,6S)-6-(4-Bromo-benzenesulfonyloxymethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester 
• 141942-89-4 tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(4-nitrophenylsulfonyloxy)methyl]-1,3-dioxan-4-yl]acetate 
• 855249-03-5 (6-{2-[3-(4-fluorophenyl)-1-isopropyl-5-(4-methoxybenzylcarbamoyl)-4-phenyl-1H-pyrrol-2-yl]vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)acetic acid tert-butyl ester 
• 855249-04-6 (3R,5R)-7-[3-(4-fluoro-phenyl)-1-isopropyl-5-(4-methoxy-benzylcarbamoyl)-4-phenyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester 
• 125971-86-0 tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 125971-94-0 2-((4R, 6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid tert-butyl ester 
• 135054-71-6 4(R)-Hydroxy-6(S)-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)phenoxymethyl]-3,4,5,6-tetrahydro-2H-pyran-2-one 
• 135054-70-5 tert.-Butyl 3(R),5(S)-dihydroxy-6-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)phenoxy]hexanoate 
• 135054-69-2 {(4R,6S)-6-[4'-Fluoro-5-(4-fluoro-phenylsulfanyl)-3-isopropyl-biphenyl-2-yloxymethyl]-2,2-dimethyl-[1,3]dioxan-4-yl}-acetic acid tert-butyl ester 
• 136034-04-3 Sodium 3(R),5(S)-dihydroxy-6-[(2-p-fluorophenyl-4-p-fluorophenylthio-6-isopropyl)phenoxy]hexanoate 
• 129894-42-4 ((4R,6S)-6-{(Z)-2-[4-(4-Fluoro-phenyl)-2-isopropyl-6-phenyl-pyridin-3-yl]-vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester 

Relevant articles and documents

STEREOSELECTIVE REDUCTION OF β,δ-DIKETO ESTERS DERIVED FROM TARTARIC ACID. A FACILE ROUTE TO OPTICALLY ACTIVE 6-OXO-3,5-syn-ISOPROPYLIDENEDIOXYHEXANOATE, A VERSATILE SYNTHETIC INTERMEDIATE OF ARTIFICIAL HMG Co-A REDUCTASE INHIBITORS.

Reduction of β,δ-diketo esters derived from tartaric acid with HAl(i-Bu)2 gave stereoselectively β-hydroxy-δ-keto esters which were reduced with NaBH4 and Et2BOMe to β,δ-syn-dihydroxy esters.This strategy was successfully applied to the synthesis of t-butyl (3R,5S)-6-oxo-3,5-isopropylidenedioxyhexanoate starting from D-tartrate.

A novel process for synthesis of Rosuvastatin

A novel process for the preparation of antihypercholesterolemic drug rosuvastatin calcium using novel intermediates has been described. Novel intermediates have been characterized by using IR, NMR and Mass spectroscopy.

Preparation method of rosuvastatin calcium intermediate

The invention belongs to the technical field of medicinal chemistry and relates to the technical field of drug synthesis, particularly to a preparation method of a high-purity rosuvastatin calcium intermediate. The preparation method of the high-purity rosuvastatin calcium intermediate comprises controlling reaction PH and temperature and applied amount of sodium hypochlorite to control the content of impurities in the high-purity rosuvastatin calcium intermediate shown as the formula I', thereby improving the yield and purity of finished products. The content of impurity compound I' in the high-purity rosuvastatin calcium intermediate prepared through the method is lower than 0.05%. The preparation method of the high-purity rosuvastatin calcium intermediate is highly significant to quality improvement of industrialized production products of the high-purity rosuvastatin calcium intermediate, and further achieves certain assisting and supporting effects on quality improvement as well as registration and declaration of rosuvastatin calcium drugs.

Preparation method of rosuvastatin calcium intermediate

Preparation method of rosuvastatin calcium intermediateTo the preparation method of the compound CL - 9, the compound CL - 8 is subjected to organic alkali treatment to obtain the compound CL - 9. The compound CL - 9 prepared through the route has the advantages of high yield, high purity, controllable impurities, suitability for industrial production and the like.

Efficient and Practical Deacylation Reaction System in a Continuous Packed-Bed Reactor

The ester deacylation reaction is widely applied in organic synthesis for preparing desired hydroxy compounds, as the acyl group is often used for protecting the hydroxyl group. This reaction is usually performed by acid, base, or enzyme catalysts, which have to be removed by complicated workups such as extraction or filtration in batch mode. Therefore, a simple deacylation process is desirable to improve productivity, especially at the industrial scale. In this work, we established an efficient and practical packed-bed reactor system for undertaking the deacylation reaction using an anion-exchange resin that provides a simple process compared with batch processing. We also demonstrated that this technique is applicable to the preparation of a wide variety of desired pharmaceutical intermediates containing hydroxy groups in good to excellent yields.

Synthesis method of rosuvastatin calcium side chain key intermediate

The invention discloses a synthesis method of a rosuvastatin calcium side chain key intermediate and provides a preparation method of the rosuvastatin calcium side chain key intermediate. (S)-2-(epoxypropane-2-yl)methyl acetate is taken as a starting material and subjected to a condensation reaction, a ring opening reaction, a reduction reaction, a hydroxyl group protecting reaction and a debenzylation reaction. The method is simple and convenient to operate, easy in separation and purification, higher in yield and capable of obtaining the intermediate with higher chemical purity and optical purity.

Preparation method of rosuvastatin calcium medicine intermediate

The invention belongs to the technical field of medicine chemicals, and particularly relates to a preparation method of a rosuvastatin calcium medicine intermediate. The preparation method comprises the following steps of using monochloroacetaldehyde as the raw material; substituting, condensing, and chirally catalyzing, so as to prepare a compound V; protecting by 2,2-dimethoxypropane, and debenzylating, so as to obtain a target compound I. The preparation method has the advantages that the raw materials are easy to obtain; (S)-5-benzyl-2,2,3-trimethyl-4-thioketone is used as a catalyst for stereo selective reduction, the reaction conditions are mild, the yield rate is higher, and the industrialization production of the component I is easy.

Method for preparing heptenoic acid cyclopentyl ester derivative

The invention discloses a method for preparing a heptenoic acid cyclopentyl ester product by taking (4R-cis)-6-[(acetoxy)methyl]-2,2-dimethyl-1,3-dioxane-4-tert butyl acetate as an initial raw material, and the product is prepared through steps of hydrolysis, replacement and oxidation. The synthesis step is simple, an intermediate can be subjected to a next reaction without refining and purifying steps, for a butt-coupling reaction, the conventional mild technology condition can replace ultralow temperature reaction condition, superbase with high danger is simultaneously replaced, reaction security is increased, the route total yield is high, and the method is suitable for large-scale industrial 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.

Method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate

The invention discloses a method for preparing solid (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and belongs to the pharmaceutical and chemical field. The method includes the following steps that a compound III is dissolved in a mixed solvent of methanol and water, potassium carbonate is added for hydrolysis, potassium carbonate is filtered out and removed, methanol is removed through distillation, an organic solvent is added, and an organic solvent solution of a compound II is obtained after washing; secondly, TEMPO, potassium bromide and sodium bicarbonate are added, stirred, mixed and cooled, then a sodium hypochlorite solution is added dropwise, stirring reaction is carried out, after reaction, a sodium thiosulfate solution is quenched, washed, dried and condensed, and a crude product of a compound I is obtained; thirdly, an organic solvent is added, cooled and stirred after being heated and dissolved and is crystallized and filtered to obtain solid crystal of the compound I. The preparation method is safe, environmentally friendly, easy and convenient to operate, high in yield, high in purify and capable of facilitating large-scale production.