147489-06-3

Usage

Uses

Used in Pharmaceutical Industry:
(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 is used as an impurity in the synthesis of HMG-CoA reductase inhibitors, such as Pitavastatin. Its presence is crucial for the development and optimization of these cholesterol-lowering drugs, as it can impact the efficacy and safety of the final product.
Used in Research and Development:
(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 is also used in research and development for the study of HMG-CoA reductase inhibitors and their mechanisms of action. Understanding the role of this specific compound in the synthesis process can lead to improvements in drug design and the development of more effective treatments for hypercholesterolemia and related conditions.

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 
• 5292-43-3 bromoacetic acid tert-butyl ester 
• 154057-56-4 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-quinoline 
• 147489-02-9 isopropyl (2S,3R,4S,6R)-7-t-butoxycarbonyl-2,3-dihydroxy-4,6-isopropylidenedioxyheptanoate 
• 147489-00-7 isopropyl (2S,3R,4S,6R)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-dihydroxyheptanoate 
• 147489-01-8 isopropyl (2S,3R,4S,6R)-7-t-butpxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-isopropylidenedioxyheptanoate 
• 147488-99-1 isopropyl (2S,3S,6R)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-6-hydroxy-4-oxoheptanoate 
• 147488-98-0 isopropyl (2S,3S)-7-t-butoxycarbonyl-2,3-bis(t-butyldimethylsilyloxy)-4,6-dioxoheptanoate 
• 1234331-54-4 2-({[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl}sulfonyl)benzo[d]thiazole 
• 1234331-56-6 3-(chloromethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline 
• 121660-37-5 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline 

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 academic research and scientific papers

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 of pitavastatin tert-butyl ester

The invention discloses a synthesis method of pitavastatin tert-butyl ester, which comprises the following steps: carrying out a reaction on (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing the substance B with an oxidizing agent to obtain a substance C; carrying out a reaction with 2-Cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; and finally, performing acid deprotection to obtain the pitavastatin tert-butyl ester. The method has the advantages of mild and controllable reaction conditions, wherein the reaction conditions of Julia olefination are free of requirement of ultralow-temperature reaction, so that the synthesis method has advantages of convenience and simplicity in operation, good stereoselectivity and high yield, and the synthesized pitavastatin tert-butyl ester is completely free of cis-isomer and high in purity.

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.

A process for preparing pitavastatin calcium key intermediate of

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a pitavastatin calcium key intermediate. The method comprises a step of preparing an organic zinc reagent by using high-activity zinc and 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline methylene bromide. The organic zinc reagent generates a Witting reaction with (3R, 5S)-6-oxo-3,5-dihydroxyl-3,5-O-isopropylidene tert-butyl caproate to generate (3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolone-3-yl]-3,5-dihydroxyl-3,5- O-isopropylidene-6-tert-butyl heptenate which is recrystallized to obtain the pitavastatin calcium key intermediate. The synthesis method provided by the invention has the characteristics of high purity of E construction, simple process, high yield and the like.

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.

For production of the precursor [...]

PROBLEM TO BE SOLVED: To provide a precursor compound of pitavastatin calcium excellent in safety and cost with high yield and high selectivity in a mild condition.SOLUTION: A method for producing a precursor compound of pitavastatin calcium of formula 1 is characterized by reacting a compound of formula 2 with a compound of formula 3 in the presence of an alkali metal salt selected from alkali metal carbonate, alkali metal acetate, and alkali metal propionate. (In the formulae, Ris a C-Calkyl group, and Ris an aryl group, an aralkyl group, or an alkyl group.)

Pitavastatin calcium method for the preparation of

The invention relates to a preparation method of a cholesterol reduction drug, particularly relates to a preparation method of pitavastatin calcium as a crude drug of the cholesterol reduction drug, and aims at the problems that the pitavastatin calcium synthetic technology in the prior art is long in steps and complicated in operation, and uses strongly corrosive reagents which is environmentally unfriendly, causes serious corrosion to equipment, and may not facilitate industrial production. The invention provides the new preparation method of the pitavastatin calcium, the new preparation method is as follows: 3-bromomethyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline is prepared from 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde by a one step reaction, and then reacts with an organophosphorus reagent to obtain pitavastatin calcium intermediate phosphorus ylide, on the basis of improving of the yield to 80%, the reaction steps are reduced, and the reaction difficulty is reduced, and hydroxylamine hydrochloride is selected as a deprotection reagent, so that the new preparation method is mild in reaction conditions, environmentally friendly, high in yield, and beneficial to industrial production.

A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE

The present invention provides a process of preparation of an intermediate useful for the preparation of statins more particularly the present invention relates to an eco-friendly and cost effective process for the preparation of tert -butyl (3R,5S)-6-oxo-3,5-dihydroxy- 3,5-O-isopropylidene-hexanoate [I].

AN IMPROVED PROCESS FOR THE PREPARATION OF CHIRAL DIOL SULFONES AND STATINS

The present invention relates to an improved process to prepare chiral diol sulfones of formula (I), wherein R1 and R2 each independently represent group selected from C1-4 alkyl, C1-4 alkenyl, C3-6 cycloalkyl, C6-10 aryl or C7-12 aralkyl, each of R1 and R2 may be substituted and wherein R1 and R2 may form a ring together with the C-atom; R3 represents group selected from C1-5 alkyl, aryl or aralkyl.

METHOD FOR PREPARING AN INTERMEDIATE OF PITAVASTATIN OR OF THE SALT THEREOF

The present invention relates to a method for preparing (4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-fluorophenyl)quinolin-3-yl)-vinyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid ester derivative, which is an intermediate of pitavastatin or of the salt thereof, into a crystalline solid form. In addition, the present invention relates to a novel solvate of the intermediate, and to a method for preparing pitavastatin or the salt thereof using the intermediate.