147489-06-3

Basic information

• Product Name: (4R,6S)-6-[(1E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester
• Synonyms: (4R,6S)-6-[(1E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester;(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-2,2-Dimethyl-1,3-dioxane-6- heptenoic acid,1,1-dimethylethyl ester;t-Butyl-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-isopropylidenedioxy-6-heptenoate;t-Bytyl(3R,5S)-7-[2-cyclopropyl-4-(4-fluoropenyl)quinolin-3-yl]-3,5-isopropylidenedioxy-6-heptenoate;(3R,5S,E)-tert-butyl7-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxyhept-6-enoate;t-Butyl (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-isopropylidenedioxy-6-hepte;1,3-Dioxane-4-acetic acid,6-[(1E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-,1,1-dimethylethyl ester,(4R,6S)-;-7-[2-cyclopropyl-4-(4-fluorophenyl)
• CAS NO: 147489-06-3
• Molecular Formula: C₃₂H₃₆FNO₄
• Molecular Weight: 517.637
• EINECS: 1592732-453-0
• Mol File: 147489-06-3.mol
• Article Data: 21

Chemical Properties

• Melting Point: 105-116 °C(Solv: hexane (110-54-3))
• Boiling Point: 604.559 °C at 760 mmHg
• Flash Point: 319.426 °C
• Appearance: white or almost white power
• Density: 1.184 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.604
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• PKA: 4.61±0.50(Predicted)
• CAS DataBase Reference: (4R,6S)-6-[(1E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: (4R,6S)-6-[(1E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester(147489-06-3)
• EPA Substance Registry System: (4R,6S)-6-[(1E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester(147489-06-3)

Safety Data

• Hazardous Substances Data: 147489-06-3(Hazardous Substances Data)

Usage

Uses

t-Butyl (3R,5S)-7-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-isopropylidenedioxy-6-heptenoate is an impurity from the synthesis of HMG-CoA reductase inhibitor Pitavastatin [P531040, (Z)-Pitavastatin Calcium Salt].

InChI:InChI=1/C32H36FNO4/c1-31(2,3)38-28(35)19-24-18-23(36-32(4,5)37-24)16-17-26-29(20-12-14-22(33)15-13-20)25-8-6-7-9-27(25)34-30(26)21-10-11-21/h6-9,12-17,21,23-24H,10-11,18-19H2,1-5H3/b17-16+/t23-,24-/m1/s1

Synthetic route

C21H28N2O6S2 + 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (121660-37-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With sodium t-butanolate In tetrahydrofuran at -10 - 25℃; for 4h;	89.6%

C15H24N2O6S2 + 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (121660-37-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 25℃; for 4h;	89.3%

tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) + diethyl <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methylphosphonate (154057-57-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With lithium chloride In tetrahydrofuran at 0 - 35℃; for 5.66667h; Reagent/catalyst; Inert atmosphere;	89%
With n-butyllithium In tetrahydrofuran at -80 - -10℃; for 1h; Solvent; Temperature; Inert atmosphere;	71%

C16H26N2O6S2 + 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (121660-37-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 25℃; for 4h; Temperature;	88.3%

2-({[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl}sulfonyl)benzo[d]thiazole (1234331-54-4) + tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -30 - 20℃; Product distribution / selectivity;	86%

C18H28N2O6S2 + 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (121660-37-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 25℃; for 4h;	82.5%

((2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methyl)triphenylphosphoniumchloride + tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 30 - 50℃; for 3h; Large scale;	80.2%

2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (153968-97-9) + t-butyl (3R,5S,6E)-3,5-isopropylidenedioxy-7-chlorodimethylsilyl-6-heptenoate (153968-91-3) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With bis(η3-allyl-μ-chloropalladium(II)); tetrabutyl ammonium fluoride In tetrahydrofuran at 60℃; for 0.5h;	80%

C31H38O4P(1+)*Cl(1-) + 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (121660-37-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 80 - 85℃; for 1h; Temperature; Reagent/catalyst; Solvent; Inert atmosphere;	79.2%

tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) + <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Stage #1: tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate; <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide In dimethyl sulfoxide at 35℃; Large scale; Stage #2: With potassium carbonate In dimethyl sulfoxide at 70℃; for 4h; Solvent; Time; Temperature; Large scale;	72.3%
With potassium carbonate In dimethyl sulfoxide at 70℃; for 3h; Inert atmosphere;	55.8%
With potassium carbonate In dimethyl sulfoxide at 70℃; for 3h; Wittig Reaction;

C19H15BrFNZn + tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With potassium carbonate In tetrahydrofuran at 0 - 30℃; for 16.5h; Reagent/catalyst; Wittig Olefination;	66.7%

tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) + <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyl(diphenyl)phosphine oxide (146578-99-6) → tert-butyl (3R,5S,6Z)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl}-3,5-isopropylidenedioxy-6-heptenoate + (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran for 3h; Ambient temperature; Yield given. Yields of byproduct given;

2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (153968-97-9) + t-butyl (3R,5S)-3,5-dihydroxy-6-heptynoate (160375-25-7) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With bis(η3-allyl-μ-chloropalladium(II)); dimethylmonochlorosilane; tetrabutyl ammonium fluoride; triethyl phosphite; t-Bu3P*Pt(CH2=CH)SiMe2)2O 1.) 1 h, room t., 2.) THF, 60 deg C, 0.5 h; Yield given. Multistep reaction;

tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) + <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyl(diphenyl)phosphine oxide (146578-99-6) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With 2,2,6,6-tetramethylpiperidinyl-lithium 1.) THF, RT, 30 min, 2.) THF, 3 h; Yield given. Multistep reaction;

2-cyclopropyl-4-(4-fluorophenyl)-3-{[(1-methyl-1H-benzo[d]imidazol-2-yl)sulfonyl]methyl}quinoline + tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (124752-23-4) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
With caesium carbonate In dimethyl sulfoxide at 25 - 35℃; for 3h;

bromoacetic acid tert-butyl ester (5292-43-3) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: 60 percent / Zn / tetrahydrofuran / 1 h / 80 °C 2: 1.) diethylmethoxyborane, 2.) sodium borohydride / 1.) THF, methanol, -78 deg C, 10 min, 2.) THF, methanol, -78 deg C, 3 h 3: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 4: p-toluenesulfonic acid / 2 h / Ambient temperature 5: t-Bu3P*Pt(CH2=CHSiMe2)2O / 1 h / Ambient temperature 6: 80 percent / (η3-allylPdCl)2, TBAF / tetrahydrofuran / 0.5 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1: 1.) Zn, 2.) HCl aq. / 1.) THF, 1 h, reflux, 2.) 0.5 h 2: 82 percent / NaBH4, Et2BOMe / tetrahydrofuran; methanol / 6 h / -78 °C 3: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 4: 1.) ClMe2SiH, 2.) <(allyl)PdCl>2, TBAF, P(OEt)3 / 1.) t-Bu3P*Pt(CH2=CH)SiMe2)2O / 1.) 1 h, room t., 2.) THF, 60 deg C, 0.5 h View Scheme

(3S)-5-(t-butyldimethylsilyl)-3-hydroxy-4-pentynenitrile (153968-98-0) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: 60 percent / Zn / tetrahydrofuran / 1 h / 80 °C 2: 1.) diethylmethoxyborane, 2.) sodium borohydride / 1.) THF, methanol, -78 deg C, 10 min, 2.) THF, methanol, -78 deg C, 3 h 3: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 4: p-toluenesulfonic acid / 2 h / Ambient temperature 5: t-Bu3P*Pt(CH2=CHSiMe2)2O / 1 h / Ambient temperature 6: 80 percent / (η3-allylPdCl)2, TBAF / tetrahydrofuran / 0.5 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1: 1.) Zn, 2.) HCl aq. / 1.) THF, 1 h, reflux, 2.) 0.5 h 2: 82 percent / NaBH4, Et2BOMe / tetrahydrofuran; methanol / 6 h / -78 °C 3: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 4: 1.) ClMe2SiH, 2.) <(allyl)PdCl>2, TBAF, P(OEt)3 / 1.) t-Bu3P*Pt(CH2=CH)SiMe2)2O / 1.) 1 h, room t., 2.) THF, 60 deg C, 0.5 h View Scheme

t-butyl (3R,5S)-7-(t-butyldimethylsilyl)-3,5-dihydroxy-6-heptynoate (153969-00-7) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 2: p-toluenesulfonic acid / 2 h / Ambient temperature 3: t-Bu3P*Pt(CH2=CHSiMe2)2O / 1 h / Ambient temperature 4: 80 percent / (η3-allylPdCl)2, TBAF / tetrahydrofuran / 0.5 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 2: 1.) ClMe2SiH, 2.) <(allyl)PdCl>2, TBAF, P(OEt)3 / 1.) t-Bu3P*Pt(CH2=CH)SiMe2)2O / 1.) 1 h, room t., 2.) THF, 60 deg C, 0.5 h View Scheme

t-butyl (5S)-7-(t-butyldimethylsilyl)-5-hydroxy-3-oxo-6-heptynoate (153968-99-1) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) diethylmethoxyborane, 2.) sodium borohydride / 1.) THF, methanol, -78 deg C, 10 min, 2.) THF, methanol, -78 deg C, 3 h 2: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 3: p-toluenesulfonic acid / 2 h / Ambient temperature 4: t-Bu3P*Pt(CH2=CHSiMe2)2O / 1 h / Ambient temperature 5: 80 percent / (η3-allylPdCl)2, TBAF / tetrahydrofuran / 0.5 h / 60 °C View Scheme
Multi-step reaction with 3 steps 1: 82 percent / NaBH4, Et2BOMe / tetrahydrofuran; methanol / 6 h / -78 °C 2: 81 percent / TBAF / tetrahydrofuran / 2 h / 0 °C 3: 1.) ClMe2SiH, 2.) <(allyl)PdCl>2, TBAF, P(OEt)3 / 1.) t-Bu3P*Pt(CH2=CH)SiMe2)2O / 1.) 1 h, room t., 2.) THF, 60 deg C, 0.5 h View Scheme

t-butyl (3R,5S)-3,5-dihydroxy-6-heptynoate (160375-25-7) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: p-toluenesulfonic acid / 2 h / Ambient temperature 2: t-Bu3P*Pt(CH2=CHSiMe2)2O / 1 h / Ambient temperature 3: 80 percent / (η3-allylPdCl)2, TBAF / tetrahydrofuran / 0.5 h / 60 °C View Scheme

t-butyl (3R,5S)-3,5-syn-isopropylidenedioxy-6-heptynoate (153969-01-8) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: t-Bu3P*Pt(CH2=CHSiMe2)2O / 1 h / Ambient temperature 2: 80 percent / (η3-allylPdCl)2, TBAF / tetrahydrofuran / 0.5 h / 60 °C View Scheme

3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-quinoline (154057-56-4) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / toluene / 12 h / Heating 2: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol; toluene / 4 h / 25 - 50 °C / Industry scale 2: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol; toluene / 3 h / 50 °C / Industry scale 2: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C / Industry scale View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol; toluene / 50 °C 2: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C / Inert atmosphere; Industry scale View Scheme
Multi-step reaction with 2 steps 1: toluene / 100 - 110 °C 2: n-butyllithium / tetrahydrofuran / 1 h / -80 - -10 °C / Inert atmosphere View Scheme

isopropyl (2S,3R,4S,6R)-7-t-butoxycarbonyl-2,3-dihydroxy-4,6-isopropylidenedioxyheptanoate (147489-02-9) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / sodium metaperiodate, water / diethyl ether / 3 h / Ambient temperature 2: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h View Scheme
Multi-step reaction with 2 steps 1: 85 percent / NaIO4 / diethyl ether; H2O / 2 h / Ambient temperature 2: lithium 2,2,6,6-tetramethylpiperazide / tetrahydrofuran / 3 h / Ambient temperature View Scheme

isopropyl (2S,3R,4S,6R)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-dihydroxyheptanoate (147489-00-7) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

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: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h 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: lithium 2,2,6,6-tetramethylpiperazide / tetrahydrofuran / 3 h / Ambient temperature View Scheme

isopropyl (2S,3R,4S,6R)-7-t-butpxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-isopropylidenedioxyheptanoate (147489-01-8) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

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: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h 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: lithium 2,2,6,6-tetramethylpiperazide / tetrahydrofuran / 3 h / Ambient temperature View Scheme

isopropyl (2S,3S,6R)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-6-hydroxy-4-oxoheptanoate (147488-99-1) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

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: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h 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: lithium 2,2,6,6-tetramethylpiperazide / tetrahydrofuran / 3 h / Ambient temperature View Scheme

isopropyl (2S,3S)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-dioxoheptanoate (147488-98-0) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

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: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h 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: lithium 2,2,6,6-tetramethylpiperazide / tetrahydrofuran / 3 h / Ambient temperature View Scheme

2-cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)quinoline (121660-11-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 98 percent / phosphorus tribromide / CH2Cl2; toluene / 3 h / Ambient temperature 2: 100 percent / toluene / 12 h / Heating 3: 1.) lithium 2,2,6,6-tetramethylpiperidine / 1.) THF, RT, 30 min, 2.) THF, 3 h View Scheme
Multi-step reaction with 3 steps 1.1: phosphorus tribromide / dichloromethane / 2 h / 0 - 25 °C / Industry scale 1.2: pH 7 - 8 2.1: isopropyl alcohol; toluene / 4 h / 25 - 50 °C / Industry scale 3.1: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1: phosphorus tribromide / dichloromethane / 0 - 25 °C / Industry scale 2: isopropyl alcohol; toluene / 3 h / 50 °C / Industry scale 3: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C / Industry scale View Scheme

tert-butyl acetoacetate (1694-31-1) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

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: lithium 2,2,6,6-tetramethylpiperazide / tetrahydrofuran / 3 h / Ambient temperature View Scheme

Cyclopropyl methyl ketone (765-43-5) → (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 0.25 h / 25 °C 1.2: 14 h / 10 - 75 °C / Inert atmosphere 1.3: 0.75 h / 0 - 25 °C / pH 2.5 2.1: sulfuric acid / water; methanol / 22.25 h / 25 - 65 °C 2.2: 0.75 h / 0 - 25 °C / pH 6 3.1: toluene / 5 h / 25 °C / Inert atmosphere 3.2: 3 h 3.3: 2 h / 40 °C 4.1: potassium carbonate / dimethyl sulfoxide / 7 h / 75 °C View Scheme
Multi-step reaction with 5 steps 1.1: toluene / 0.25 h / 25 °C 1.2: 14 h / 10 - 75 °C / Inert atmosphere 1.3: 0.75 h / 0 - 25 °C / pH 2.5 2.1: sulfuric acid / water; methanol / 22.25 h / 25 - 65 °C 2.2: 0.75 h / 0 - 25 °C / pH 6 3.1: diisobutylaluminium hydride / toluene / 2 h / 0 - 25 °C 3.2: 0.25 h / 10 °C 4.1: phosphorus tribromide / dichloromethane / 1.5 h / 25 °C 4.2: 1 h / 75 °C 5.1: potassium carbonate / dimethyl sulfoxide / 7 h / 75 °C View Scheme

(4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3) → (3R,5S,6E)-7-<2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl>-3,5-dihydroxy-6-heptenoic acid 1,5-lactone

Conditions	Yield
With hydroxylamine hydrochloride In methanol; water; acetone Reflux;	99%
With trifluoroacetic acid	74%
With trifluoroacetic acid In dichloromethane for 16h; Ambient temperature;	67%
With trifluoroacetic acid In dichloromethane for 16h; Ambient temperature;	67%
Stage #1: (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester With hydrogenchloride; water In acetonitrile at 30℃; for 2h; Stage #2: With sodium hydroxide In water; acetonitrile at 35℃; for 2h; Product distribution / selectivity;

(4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3) → (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid tert-butyl ester (586966-54-3)

Conditions	Yield
With hydrogenchloride In water; acetonitrile at 40℃; for 2h;	95.2%
With hydrogenchloride; water In acetonitrile for 3h; Large scale;	88.4%
Stage #1: (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester With water; oxalic acid In methanol at 35℃; for 6h; Stage #2: With sodium carbonate In methanol; water at 10 - 30℃; for 2.75h; pH=7;
With hydrogenchloride; water In acetonitrile at 25 - 55℃; pH=2.5;	27 g
With hydrogenchloride In water; acetonitrile at 13℃; for 2h;

(4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester (147489-06-3) → pitavastatin (147526-32-7)

Conditions	Yield
Stage #1: (4R,6S)-(E)-{6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid tert-butyl ester With trifluoroacetic acid In acetonitrile at 30 - 35℃; Stage #2: With caesium carbonate In acetonitrile at 35 - 40℃;	94%
Multi-step reaction with 3 steps 1.1: water; oxalic acid / methanol / 6 h / 35 °C 1.2: 2.75 h / 10 - 30 °C / pH 7 2.1: sodium hydroxide; water / methanol / 1.67 h / 0 °C 2.2: 0.67 h / 25 °C 3.1: hydrogenchloride / dichloromethane; water / 0.83 h / 0 - 25 °C / pH 3 View Scheme
Multi-step reaction with 4 steps 1.1: water; oxalic acid / methanol / 6 h / 35 °C 1.2: 2.75 h / 10 - 30 °C / pH 7 2.1: sodium hydroxide; water / acetonitrile / 1.5 h / 30 °C 2.2: 0.25 h / 0 °C / pH 4 2.3: 0.5 h / 0 °C 3.1: sodium hydroxide / water / 0.75 h / 30 °C 3.2: 0.75 h / 35 °C 4.1: hydrogenchloride / dichloromethane; water / 0.83 h / 0 - 25 °C / pH 3 View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / acetonitrile; water / 2 h / 13 °C 2: sodium hydroxide / water / 2 h / 10 °C / Large scale View Scheme

Upstream product

• 124752-23-4 tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 146578-99-6 <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyl(diphenyl)phosphine oxide 
• 154057-58-6 <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide 
• 1234331-54-4 2-({[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl}sulfonyl)benzo[d]thiazole 
• 765-43-5 Cyclopropyl methyl ketone 
• 32249-35-7 methyl 3-cyclopropyl-3-oxopropanoate 
• 121659-86-7 methyl 4-(4'-fluorophenyl)-2-cyclopropylquinoline-3-carboxylate 
• 406680-96-4 tert-butyl (5S)-6-chloro-3,5-dihydroxyhexanoate 
• 154026-94-5 (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid,1,1-dimethylethyl ester 
• 154026-95-6 (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester 
• 521973-99-9 tert-butyl 2-((6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 
• 124655-09-0 1,1-dimethylethyl (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate 
• 154026-92-3 Tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate 
• 154026-93-4 1,1-dimethylethyl (3R,5S)-6-chloro-3,5-dihydroxy-4-hexanoate 

Downstream Products

• 147526-32-7 pitavastatin 
• 574705-92-3 sodium (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoate 
• 586966-54-3 (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid tert-butyl ester 
• 147526-32-7 pitavastatin calcium salt 
• 192565-91-6 pitavastatin potassium 

Relevant articles and documents

Preparation method of pitavastatin calcium intermediate

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a pitavastatin calcium intermediate. The preparation method comprises the following steps: 1,carrying out a chemical reaction on a compound II and triphenylphosphine at a temperature of 10-150 DEG C to prepare a compound III; 2, in the presence of triethylamine, with oxalyl chloride and dimethyl sulfoxide as oxidants, subjecting a compound IV to a chemical reaction to prepare a compound V; and 3, subjecting the compound III and the compound V to a chemical reaction at 20-150 DEG C in thepresence of a basic catalyst so as to prepare a compound I. The intermediate prepared by using the method provided by the invention has the advantages of easy availability of raw materials, simple operation, high yield and high purity. The specific synthetic route of the method is shown in the specification.

Synthetic method for pitavastatin calcium intermediate

The invention discloses a synthetic method for a pitavastatin calcium intermediate. The method includes the following steps: reacting 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-bromomethyl with trithiocyanuric acid under catalysis of sodium hydroxide to obtain a substance A; then oxidizing by the effect of an oxidizing agent to obtain a substance B; and reacting with (4R-Cis)-6-aldehyde group-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate under the catalysis of sodium hydride to obtain the pitavastatin calcium intermediate. The synthetic method for the pitavastatin calcium intermediate is cheap and easily available in raw material, is novel in route, is good in atom economy, is green and environmentally friendly, is mild and controllable in reaction condition, is convenient and simple inoperation, is simple in purification treatment, is suitable for industrialization production, is good in stereoselectivity, is high in yield, and is good in purity of the prepared pitavastatin calciumintermediate.

Preparation method of statins intermediate

The invention discloses a preparation method of a statins intermediate, comprising the following steps: a phosphate compound and an aldehyde compound are subjected to a condensation reaction under theaction of a catalyst and alkali; after the reaction, post-treatment is conducted to obtain the statins intermediate. The statins intermediate includes a rosuvastatin intermediate (Compound A) and a pitavastatin calcium intermediate (Compound B). The preparation method has the advantages of low cost, simple operation and good yield, is environmentally friendly, and is suitable for industrial production.