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[ CAS No. 154057-58-6 ] {[proInfo.proName]}

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Chemical Structure| 154057-58-6
Chemical Structure| 154057-58-6
Structure of 154057-58-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 154057-58-6 ]

CAS No. :154057-58-6 MDL No. :MFCD19440813
Formula : C37H30BrFNP Boiling Point : -
Linear Structure Formula :- InChI Key :NLIQETRDGNRDCT-UHFFFAOYSA-M
M.W : 618.52 Pubchem ID :46897064
Synonyms :

Calculated chemistry of [ 154057-58-6 ]

Physicochemical Properties

Num. heavy atoms : 41
Num. arom. heavy atoms : 34
Fraction Csp3 : 0.11
Num. rotatable bonds : 7
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 177.59
TPSA : 26.48 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -3.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : -0.46
Log Po/w (XLOGP3) : 9.66
Log Po/w (WLOGP) : 5.62
Log Po/w (MLOGP) : 7.81
Log Po/w (SILICOS-IT) : 9.48
Consensus Log Po/w : 6.42

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -9.91
Solubility : 0.0000000757 mg/ml ; 0.0000000001 mol/l
Class : Poorly soluble
Log S (Ali) : -10.13
Solubility : 0.0000000457 mg/ml ; 0.0000000001 mol/l
Class : Insoluble
Log S (SILICOS-IT) : -14.94
Solubility : 0.0 mg/ml ; 0.0 mol/l
Class : Insoluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.88

Safety of [ 154057-58-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 154057-58-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 154057-58-6 ]

[ 154057-58-6 ] Synthesis Path-Downstream   1~30

  • 1
  • [ 1044518-75-3 ]
  • [ 154057-58-6 ]
  • [ 147489-06-3 ]
  • [ 154170-27-1 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium 1.) THF, -78 deg C, 30 min, 2.) THF, a) -78 deg C, 2 h, b) -78 deg C to 20 deg C, overnight; Yield given. Multistep reaction. Yields of byproduct given;
  • 2
  • [ 154057-56-4 ]
  • [ 603-35-0 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In toluene; at 110℃; for 1h; Example 1:Preparation of Triphenyl[2-cyclopropyI-4-(4-fluorophenyl)-quinoline-3-ylmethyl)- phosphonium] bromide compound of formula-3; Added a solution of 16.1 grams of triphenyl phosphine in 50 ml of toluene to 15grams of 3-(bromomethyl)-2-(l-cylclopropyl)-4-(4'-fluorophenyl)quinoline compound of formula-2. Heated the reaction mixture to 110C. Stirred the reaction mixture for 60 minutes at 110C. Cooled the reaction mixture to 25-35C. Filtered the solid and washed with hexanes to get the title compound. Yield: 20 gramsM.R: 218 - 225C (decomposed)
In isopropyl alcohol; toluene; at 25 - 50℃; for 4h;Industry scale; 1 Kg of <strong>[154057-56-4]3-(bromomethyl)-2-cyclopropyl-4-(4'-flourophenyl)quinoline</strong>, 10 L of toluene and 300 mL of isopropanol were taken in reactor and heated at 50C. 0.874 Kg of triphenyl phosphine solution in 2 L toluene was added slowly and stirred for 3 hours. The reaction mixture was cooled to 25C and stirred for 1 hour. The product was filtered and washed with toluene. The product was dried in tray dryer at 55C for 8 hours to obtain phosphonium bromide compound of formula (IV).
In isopropyl alcohol; toluene; at 50℃; for 3h;Industry scale; 1 Kg of <strong>[154057-56-4]3-(bromomethyl)-2-cyclopropyl-4-(4'-fluorophenyl)quinoline</strong>, 10 L of toluene and 300 mL of isopropanol were taken in reactor and heated at 50 C. 0.874 Kg of triphenyl phosphine solution in 2 L toluene was added slowly and stirred for 3 hours. The reaction mixture was cooled to 25 C. and stirred for 1 hour. The product was filtered and washed with toluene. The product was dried in tray dryer at 55 C. for 8 hours to obtain phosphonium bromide compound of formula (IV).
In isopropyl alcohol; toluene; at 50℃; Preparation-2:Preparation of phosphonium bromide compound of Formula (IV):1 Kg of <strong>[154057-56-4]3-(bromomethyl)-2-cyclopropyl-4-(4'-flourophenyl)quinoline</strong>, 10 L of toluene and 300 mL of isopropanol were taken in reactor and heated at 50C. 0.874 Kg of triphenyl phosphine solution in 2 L toluene was added slowly and stirred for 3 hours. The reaction mixture was cooled to 25C and stirred for 1 hour. The product was filtered and washed with toluene. The product was dried in tray dryer at 55C for 8 hours to obtain phosphonium bromide compound of Formula (IV).
In dichloromethane;Reflux; 3-(Bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline (24 gm) as obtained in step-II was dissolved in methylene chloride (360 ml) and stirred for 15 minutes. To the solution was added triphenylphosphine (17.7 gm) and stirred for 10 minutes. The contents were then heated reflux and maintained for 4 hours at reflux. The reaction mass was cooled to room temperature and then concentrated to obtain a residual mass. To the residual mass was added toluene (240 ml) and stirred for 2 hours at room temperature. The separated solid was filtered and dried to get a solid. The solid obtained was dissolved in methylene chloride (500 ml) and water (250 ml) and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrated to get a solid. The obtained solid was washed with n-hexane and dried to obtain 40 gm of {2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}methyltriphenylphosphonium- bromide.

  • 3
  • [ 124752-23-4 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • [ 147489-06-3 ]
YieldReaction ConditionsOperation in experiment
72.3% To a solution of tert-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (the compound of Formula 3, R=tert-butyl) (1.38 kg) in dimethyl sulfoxide (6 L) was added the compound of Formula 2 (3 kg). The reaction mixture was heated to about 35 C. under stirring. K2CO3 (1 kg) was added to the resulting clear solution, which was washed with DMSO (3 L). The reaction mixture was heated to about 70 C. and then stirred for 4 hours. After confirming with HPLC that the starting material was exhausted, the reaction was quenched. The reaction mixture was cooled to about 45 C. and then methanol (18 L) was added thereto. The reaction mixture was additionally cooled to about 5 C. and then stirred for additional 2 hours. The resulting precipitate was isolated by filtering under reduced pressure, washed with water (3 L), and then dried under reduced pressure at about 50 C. to give the titled compound (1.82 kg) as a white crystalline form (Yield: 72.3%). The HPLC analysis result of the obtained product is shown in FIG. 2.[0048]Melting point: 113 C.-116 C.[0049]HPLC % Area: 99.396 %[0050]1H-NMR (CDCl3): 0.9?1.0 (m, 2H), 1.0?1.03(m, 1H), 1.2?1.3(m, 2H), 1.3?1.38(s, 6H), 1.38?1.4(m, 1H), 1.45(s, 9H), 2.2?2.3(dd, 1H, J=0.015, J=0.038), 2.3?2.4 (m, 2H), 4.1?4.2(m, 1H), 4.3?4.4(m, 1H), 5.5?5.6(dd, 1H, J=0.015, J=0.04), 6.5(d, 1H, J=0.04), 7.0?7.3(m, 6H), 7.5(t, 1H), 7.9(d, 1H, J=0.021)
55.8% With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h;Inert atmosphere; Under the protection of nitrogen, in a 500ml round bottom flask, add 2.7g (0.0104mol) (3R,5S)-6-oxo-3,5-dihydroxy-tert-butyl 3,5, O-isopropylidenohexanoate, 46ml DMSO,5.0g (0.0081mol)triphenyl bromide 2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-ylmethyl) phosphine, 2.88g (0.0208mol) potassium carbonate, turn on the stirring and slowly warm up to 70C , incubate at 70C for 3h, then cool to room temperature, add 200ml water and 200ml toluene, stir for 30 minutes, separate the layers, extract the lower aqueous layer with 200 ml of toluene, and combine the upper toluene layers.Wash with 50ml of water once, the toluene layer was desolvated to dryness under reduced pressure, and 20ml of n-hexane was added,Stir and heat to complete dissolution, lower the temperature and crystallize, suction filter, filter solid and dry,2.60g (0.0050mol) (4R,6S)-(E)-6-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-vinyl]-2, 2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, product purity 90.5%, the pure yield was 55.8%.
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h; Example -3:Preparation of (4R, 6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyI) quinoline-3-yl)- vinyl]-2, 2-dimethyl-l, 3-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula-5; Added a solution of 2.7 grams tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l,3- dioxan-4-yl)acetate compound of formula-4 in 46 ml of dimethylsulfoxide to a mixture of 5 grams of triphenyl[2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-ylmethyl)- phosphonium]bromide compound of formula-3 and 2.88 grams of potassium carbonate. Heated the reaction mixture to 70C. Stirred the reaction mixture for 3 hours at 70C. Quenched the reaction mixture with water. Extracted the reaction mixture with toluene. Concentrated the organic phase and isolated the title compound using hexanes. Yield: 13 gram M.R: 105 - 1160C
With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 10h; To the solution of 0.751 Kg of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l ,3- dioxan-4-yl)acetate (III) in 7 L of dimethylsulphoxide was added 1 Kg of phosphonium bromide compound of formula (IV) and 0.67 Kg of potassium carbonate. The reaction mixture was stirred at 25C for 10 hours. The reaction mixture was quenched with water and extracted with toluene. The organic layer was concentrated and the title compound was isolated using isopropanol as crude solid. The crude product thus obtained was recrystallized in methanol as shown below.Purification of Olefin compound of formula IIPitavastatin Olefin compound (II) (100 g) and methanol (600 mL) were heated to 60C to 65C to obtain the clear solution and stirred for 10 mins. Activated Carbon (10 g) were added at 60C to 65C and stirred for 10 min. The reaction mixture was filtered and washed with methanol (100 mL). The filtrate was cooled to 25C and gradually to 10C followed by stirring for 2 hours at 10C. The resulting slurry was filtered and washed with chilled methanol (100 mL). The wet-cake was heated in methanol (480 mL) at 60C to 65C to obtain the clear solution. Activated Carbon (10 g) were added at 60C to 65C and stirred for 10 min. The reaction mixture was filtered and washed with methanol (100 mL). The filtrate was cooled to 25C and gradually to 10C followed by stirring for 2 hours at 10C. The resulting slurry was filtered and washed with chilled methanol (100 mL). The wet-cake was dried under vacuum for 30 minutes followed by drying in hot air oven at 50C to 55C for 12 hours to obtain crystalline olefin compound (II) characterized by X-ray powder diffraction substantially as same as shown in FIG.3 and DSC thermogram having endothermic peak at about 1 16.04C as shown in FIG.4.
With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 10h;Industry scale; To the solution of 0.751 Kg of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-1,3-dioxan-4-yl)acetate (III) in 7 L of dimethylsulphoxide was added 1 Kg of phosphonium bromide compound of formula (IV) and 0.67 Kg of potassium carbonate. The reaction mixture was stirred at 25 C. for 10 hours. The reaction mixture was quenched with water and extracted with toluene. The organic layer was concentrated and the title compound was isolated using isopropanol as crude solid. The crude product thus obtained was recrystallized in methanol as shown below.
With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 10h;Inert atmosphere; Industry scale; Example-1:Preparation of (4R,6S)-(E)-6-f2-(2-cvclopropyI-4-(4-flourophenyl)quinoline-3-yl)- vinyl-2,2-dimethyl-l,3-dioxane-4-yllacetic acid tertiary butyl ester compound of Formula PiTo a solution of 0.751 Kg of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l,3- dioxan-4-yl)acetate (III) in 7 L of dimethylsulphoxide, was added 1 Kg of phosphonium bromide compound of Formula (IV) and 0.67 Kg of potassium carbonate. The reaction mixture was stirred at 25C for 10 hours under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with toluene. The organic layer was concentrated and the compound of Formula (II) was isolated using isopropanol. The product thus obtained was recrystallized in methanol.

  • 5
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C 2.1: hydrogenchloride; water / methanol / 8 h / 25 °C 2.2: 15 °C 2.3: 0.5 h / 25 °C
Multi-step reaction with 2 steps 1.1: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C / Industry scale 2.1: hydrogenchloride / water; methanol / 8 h / 25 °C 2.2: 4 h / 25 °C 2.3: 0.5 h / 25 °C
  • 6
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C 2.1: hydrogenchloride; water / methanol / 8 h / 25 °C 2.2: 15 °C 2.3: 0.5 h / 25 °C
Multi-step reaction with 2 steps 1.1: potassium carbonate / dimethyl sulfoxide / 10 h / 25 °C / Industry scale 2.1: hydrogenchloride / water; methanol / 8 h / 25 °C 2.2: 4 h / 25 °C 2.3: 0.5 h / 25 °C
  • 7
  • [ 603-35-0 ]
  • [ 121660-11-5 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example-6Preparation of triphenyl (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-phosphonium bromideTo 100 g of (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)methanol added dichloromethane (400 ml). Stirred the reaction mixture for 30 minutes. To this reaction mixture added a solution of phosphorous tribromide (16.2 ml) in dichloromethane (100 ml) slowly at 25 C. and stirred for 1 hr at same temperature. Quenched the reaction mixture with 10% sodium bicarbonate solution and adjusted the pH to neutral at 20 C. Stirred the reaction mixture to 15 minutes. Separated the both aqueous and organic layers. Extracted the aqueous layer with dichloromethane (100 ml). Washed the organic layer with 10% hypo solution. Then again washed the organic layer with saturated sodium chloride solution. Heated the reaction mixture to 40 C. To the reaction mixture added triphenyl phosphene (90 g) in dichloromethane (100 ml) and stirred. Distilled off the solvent completely under reduced pressure. Added toluene (100 ml) to the reaction mixture and stirred for 15 minutes. Distilled off the toluene completely. Cooled the reaction mixture to 40 C., added toluene (500 ml) and heated for 1 hr at 75 C. Cooled the reaction mixture to 25 C. and stirred for 1 hr. Filtered the reaction mixture and washed the compound with toluene and dried. The compound obtained as a crystalline solid.Yield: 200 g. MR: 215-218 C.; Purity by HPLC: 99.61%, desfluoro-0.08%;
  • 8
  • [ 603-35-0 ]
  • [ 121659-86-7 ]
  • [ 154057-58-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: methyl 4-(4'-fluorophenyl)-2-cyclopropylquinoline-3-carboxylate In toluene at 25℃; for 5h; Inert atmosphere; Stage #2: With phosphorus tribromide In dichloromethane for 3h; Stage #3: triphenylphosphine In dichloromethane at 40℃; for 2h; 7 Example-7Preparation of triphenyl (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-phosphonium bromide (One pot process)To 50 g of methyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate added toluene (500 ml) and stirred for 15 minutes at 25° C. Added 145 ml of vitride (65% solution in toluene) to the reaction mixture slowly in 45 minutes at the same temperature under nitrogen atmosphere. Stirred the reaction mixture for 4 hrs at 25° C. Quenched the reaction mixture with hydrochloric acid (55 ml) solution and stirred for 30 minutes. Separated the both aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Neutralized the reaction mixture with 10% sodium bicarbonate solution. Washed the organic layer with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure. To the above obtained compound, 250 ml of dichloromethane was added. To this reaction mixture phosphorous tri bromide was slowly added and stirred for 3 hrs. Adjusted the pH with 10% sodium bicarbonate solution. Separated the both aqueous and organic layers. Aqueous layer was extracted with dichloromethane and washed with hypo solution. Again the reaction mixture was washed with sodium chloride solution. Heated the reaction mixture to 40° C. To this added a solution of triphenyl phosphene (38.4 g) in dichloromethane (50 ml). Stirred the reaction mixture for 2 hrs. Distilled off the solvent completely under reduced pressure. To this added 250 ml of toluene and stirred for 2 hrs. Filtered the solid precipitated and dried it. The title compound obtained as a crystalline solid.Yield: 88 g.; M.R: 215-218° C.
  • 9
  • [ 765-43-5 ]
  • [ 154057-58-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 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
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: 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
  • 10
  • [ 32249-35-7 ]
  • [ 154057-58-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sulfuric acid / water; methanol / 22.25 h / 25 - 65 °C 1.2: 0.75 h / 0 - 25 °C / pH 6 2.1: toluene / 5 h / 25 °C / Inert atmosphere 2.2: 3 h 2.3: 2 h / 40 °C
Multi-step reaction with 3 steps 1.1: sulfuric acid / water; methanol / 22.25 h / 25 - 65 °C 1.2: 0.75 h / 0 - 25 °C / pH 6 2.1: diisobutylaluminium hydride / toluene / 2 h / 0 - 25 °C 2.2: 0.25 h / 10 °C 3.1: phosphorus tribromide / dichloromethane / 1.5 h / 25 °C 3.2: 1 h / 75 °C
  • 11
  • [ 121659-86-7 ]
  • [ 154057-58-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: diisobutylaluminium hydride / toluene / 2 h / 0 - 25 °C 1.2: 0.25 h / 10 °C 2.1: phosphorus tribromide / dichloromethane / 1.5 h / 25 °C 2.2: 1 h / 75 °C
  • 12
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 7 h / 75 °C 2.1: water; oxalic acid / methanol / 6 h / 35 °C 2.2: 2.75 h / 10 - 30 °C / pH 7 3.1: sodium hydroxide; water / methanol / 1.67 h / 0 °C 3.2: 0.67 h / 25 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / dimethyl sulfoxide / 7 h / 75 °C 2.1: water; oxalic acid / methanol / 6 h / 35 °C 2.2: 2.75 h / 10 - 30 °C / pH 7 3.1: sodium hydroxide; water / acetonitrile / 1.5 h / 30 °C 3.2: 0.25 h / 0 °C / pH 4 3.3: 0.5 h / 0 °C 4.1: sodium hydroxide / water / 0.75 h / 30 °C 4.2: 0.75 h / 35 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 - 80 °C 2.1: (R)-10-camphorsulfonic acid / acetonitrile; water / 4 h / 20 °C 3.1: hydrogenchloride / acetonitrile; water / 3 h / 20 °C 3.2: 36 h / 20 °C 4.1: sodium hydroxide / ethanol; water / 2 h / 0 °C 4.2: 0 °C
Multi-step reaction with 3 steps 1.1: dimethyl sulfoxide / 35 °C / Large scale 1.2: 4 h / 70 °C / Large scale 2.1: hydrogenchloride; water / acetonitrile / 3 h / Large scale 3.1: water; sodium hydroxide / 1 h / 20 °C / Large scale 3.2: 3 h / 20 °C / Large scale

  • 13
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • [ 147526-32-7 ]
  • 14
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 7 h / 75 °C 2.1: water; oxalic acid / methanol / 6 h / 35 °C 2.2: 2.75 h / 10 - 30 °C / pH 7 3.1: sodium hydroxide; water / methanol / 2.17 h / 25 °C
Multi-step reaction with 3 steps 1.1: potassium <i>tert</i>-butylate / toluene / 0.17 h / 60 °C / Inert atmosphere 1.2: 0.02 h / Inert atmosphere 2.1: tetrabutyl ammonium fluoride; acetic acid / tetrahydrofuran / 0 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; water / 1 h / 30 °C
Multi-step reaction with 3 steps 1.1: sodium hexamethyldisilazane / toluene / 0.17 h / 60 °C / Inert atmosphere 1.2: 0.02 h / Inert atmosphere 2.1: tetrabutyl ammonium fluoride; acetic acid / tetrahydrofuran / 0 - 20 °C 3.1: sodium hydroxide / tetrahydrofuran; water / 1 h / 30 °C
  • 15
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / dimethyl sulfoxide / 7 h / 75 °C 2.1: water; oxalic acid / methanol / 6 h / 35 °C 2.2: 2.75 h / 10 - 30 °C / pH 7 3.1: sodium hydroxide; water / acetonitrile / 1.5 h / 30 °C 3.2: 0.25 h / 0 °C / pH 4 3.3: 0.5 h / 0 °C
  • 16
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • [ 586966-54-3 ]
  • 17
  • [ 895129-27-8 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • [ 147489-06-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 75℃; for 7h; Example-8Preparation of (4R,6S)-(E)-6-{2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-vinyl]-2,2-dimethyl-[1,3]-dioxan-4-yl}-acetic acid tertiary butyl esterTo the solution of triphenyl (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-phosphonium bromide (60 g) in DMSO (100 ml) added a solution of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (25 g) in DMSO (50 ml). Heated the reaction mixture to 75 C. and added potassium carbonate (20 g) to it. Stirred the reaction mixture for 7 hrs at 75 C. Cooled the reaction mixture to 25 C., added water (250 ml) and stirred for 90 minutes at same temperature. Filter the solid precipitated and washed with water (200 ml). To the obtained wet solid added methanol (250 ml) and stirred for 45 minutes at 65 C. Cooled the reaction mixture to 25 C. and stirred for 90 minutes. Filtered the compound and washed with methanol (25 ml) and dried. The compound obtained as a crystalline solid.Yield: 35 g.; M.R: 111-113 C.;Purity by HPLC: 97.65%; Impurity-A: 0.40%, Impurity-J: 0.90%
  • 18
  • [ 121660-37-5 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • 19
  • [ 124752-23-4 ]
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; 1.IV {2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}methyltriphenylphosphonium- bromide (50 gm) as obtained in step-Ill was dissolved in dimethylformamide (750 ml) and stirred for 15 minutes to obtain a solution. To the solution was added potassium carbonate (22.3 gm) and then added a solution of tert-butyl-2-(4R,6S)-6-formyl-2,2- dimethyl-l,3-dioxan-4-yl)acetate (25.1 gm) in dimethylformamide (50 ml) slowly at room temperature. The reaction mixture was heated to 80°C and stirred for 5 hours. The reaction mass was then cooled to room temperature and then added toluene (300 ml) and water (300 ml). Then the layers were separated and the aqueous layer was extracted with toluene. The combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual mass. To the residual mass was added n-hexane (220 ml) and stirred for 1 hour. The reaction mass was filtered to remove unwanted solid and then concentrated the n-hexane layer to obtain a residual solid. To the residual solid obtained was added 30% aqueous acetonitrile (500 ml) and then cooled to 0°C. The reaction mass was maintained for 3 hours 30 minutes and filtered. The solid obtained was dried to give 32 gm of tert-butyl-(3R, 5S, 6Z)-7-{2-cyclopropyl-4-(4- fluorophenyl)quinoline-3-yl}-3,5-isopropylidenedioxy-6-heptenoate.
Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With triphenylphosphine In dimethyl sulfoxide at 50℃; for 3h; Stage #2: 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 25 - 30℃; for 5h; 1; 6; 9 Example 1 In a 3L reaction flask, add 100.00g (280.71mmol) of the parent nucleus bromide and 700ml (7v) of dimethyl sulfoxide, stir and heat to 50°C, add 87.40g (1.18eq, 333.21mmol) of triphenylphosphorus, keep the reaction for 3h After cooling to about 25°C, add 100.00g (1.35eq, 378.95mmol) side chain aldehyde and 128.25g (3.00eq, 842.13mmol) DBU, stir at 30°C for 5h, add water after the reaction to quench the reaction, add toluene for extraction, organic The phase was concentrated and crystallized with isopropanol to obtain 118.4 g of pitavastatin calcium intermediate with a yield of 81%.
  • 20
  • [ 154057-58-6 ]
  • [ 147511-70-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 - 80 °C 2.1: (R)-10-camphorsulfonic acid / acetonitrile; water / 4 h / 20 °C 3.1: hydrogenchloride / acetonitrile; water / 3 h / 20 °C 3.2: 36 h / 20 °C
  • 21
  • [ 934263-63-5 ]
  • [ 154057-58-6 ]
  • [ 1391833-21-8 ]
  • [ 1391833-12-7 ]
YieldReaction ConditionsOperation in experiment
1: 83 %Chromat. 2: 11 %Chromat. Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With sodium hexamethyldisilazane In toluene at 60℃; for 0.166667h; Inert atmosphere; Stage #2: (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carboxaldehyde In toluene for 0.0166667h; Inert atmosphere;
  • 22
  • [ 934263-63-5 ]
  • [ 154057-58-6 ]
  • [ 1356998-79-2 ]
  • [ 1391833-21-8 ]
  • [ 1391833-12-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
1: 7 %Chromat. 2: 5 %Chromat. 3: 20 %Chromat. 4: 17 %Chromat. Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With sodium hexamethyldisilazane In acetonitrile at 60℃; for 0.166667h; Inert atmosphere; Stage #2: (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carboxaldehyde In toluene for 0.0166667h; Inert atmosphere;
  • 23
  • [ 934263-63-5 ]
  • [ 154057-58-6 ]
  • [ 1391833-21-8 ]
  • [ 1391833-12-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
1: 41 %Chromat. 2: 7 %Chromat. 3: 13 %Chromat. Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In toluene at 60℃; for 0.166667h; Inert atmosphere; Stage #2: (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carboxaldehyde In toluene for 0.0166667h; Inert atmosphere;
  • 24
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium <i>tert</i>-butylate / toluene / 0.17 h / 60 °C / Inert atmosphere 1.2: 0.02 h / Inert atmosphere 2.1: tetrabutyl ammonium fluoride; acetic acid / tetrahydrofuran / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0.25 h / Cooling with ice 3.2: 18.5 h / 20 °C
Multi-step reaction with 3 steps 1.1: sodium hexamethyldisilazane / toluene / 0.17 h / 60 °C / Inert atmosphere 1.2: 0.02 h / Inert atmosphere 2.1: tetrabutyl ammonium fluoride; acetic acid / tetrahydrofuran / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0.25 h / Cooling with ice 3.2: 18.5 h / 20 °C
  • 25
  • [ 154057-58-6 ]
  • [ 141750-63-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / toluene / 0.17 h / 60 °C / Inert atmosphere 1.2: 0.02 h / Inert atmosphere 2.1: tetrabutyl ammonium fluoride; acetic acid / tetrahydrofuran / 0 - 20 °C
Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / toluene / 0.17 h / 60 °C / Inert atmosphere 1.2: 0.02 h / Inert atmosphere 2.1: tetrabutyl ammonium fluoride; acetic acid / tetrahydrofuran / 0 - 20 °C
  • 26
  • [ 124655-09-0 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • [ 147489-06-3 ]
YieldReaction ConditionsOperation in experiment
5 g With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h; To a solution of tert-butyl-2-((4R,6S)-6-formul-2,2-dimethyl-l,3- dioxan-4-yl)acetate (2.7 g) in 46 ml of dimethylsulfoxide was added triphenyl[2-cyclopropyl-4-(4-fluorophenyl)- quinoline-3-ylmethyl)- phosphonium]bromide (5 g) and potassium carbonate (2.88 g). The reaction mixture was heated to 70C and stirred for 3 hours at 70C. After completion of reaction, reaction was quenched with water and extracted with ethyl acetate (3 X 50 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated to obtain crude product, which was further re-crystallized from methanol to obtain desired product as solid material (5 g).
  • 27
  • [ 1449311-25-4 ]
  • [ 154057-58-6 ]
  • [ 1449311-30-1 ]
YieldReaction ConditionsOperation in experiment
91% With lithium hydroxide monohydrate In tetrahydrofuran; acetonitrile at 60℃; for 3h; 6 synthesis of t-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2-benzyl-1,3-dioxane-4-yl)acetate As a mother nucleus of statin [2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]methyltriphenylphosphoniumbromide 30.8g (0.05 mol) THF / acetonitrile (20/1 , it was dissolved in 100ml), and the temperature was raised to 60°C . The reaction solution was charged with lithium hydroxide hydrate 2.8 g, Example 1 was prepared in t-butyl 2-((4R,6S)-6-formyl-2-benzyl-1,3-dioxane-4-yl)acetate 16g (0.05 mol) of the ratio of THF / acetonitrile (10/1, 50ml) After 3 hours reflux agitation while the solution added dropwise dissolved in, allowed to cool to room temperature and vacuum concentrated. It was dissolved concentrated solution in heptane (300 ml), washed with 0.1N HCl (200ml × 2) and saturated brine (200ml). The obtained organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The resulting residue was recrystallized from ethyl acetate and hexane to obtain pitavastatin precursor 26.2g of solid following general formula VI. (91% yield, E / Z = 99/1)
  • 28
  • [ 1636156-91-6 ]
  • [ 154057-58-6 ]
  • [ 1636156-99-4 ]
YieldReaction ConditionsOperation in experiment
4.1 g Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With lithium hexamethyldisilazane In tetrahydrofuran at -45 - -30℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyl 2-[(4R,6S)-6-formyl-2-phenylethyl-[1,3,2]-dioxaboran-4-yl]acetate In tetrahydrofuran at -45 - -30℃; for 10.5h; Inert atmosphere; 12 preparation of tert-butyl 2-[(4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]ethenyl]-2-(2-phenylethyl)-1,3,2-dioxaborinan-4-yl]acetate It cooled in 3hole flask to 40~35after [[2cyclo profile 4(4fluorophenyl)quinoline 3yl]methyl]triphenylphosphonium bromide 3.5gr wasdissolved at the tetrahydrofuran 100mL under thenitrogen condition. 2M lithium hexamethyldisilazide 3.8mL is slowly injected in the reacting solutioncooled. When the input is completed, in the sametemperature, additional cooling is progressed as the state where the inner temperature is 45~40after doing 30 min. mixing and the tertbutyl2((4R,6S) 6formyl2phenethyl[1,3,2] dioxaborane 4yl)acetate 2.3gr which in the above preferred embodiment 8, it manufactures is gradually injected for 30 minutes. When the input is completed, stirred for 10 hours while 35~30is maintained. When reaction is completed, if it reached 10~15 after it left as it is in order to raise temperature the reacting solution as the gradually using the cold water bath, , the acetic acid was injected in the reacting solution and the pH of the reacting solution was maintained with 5.0~6.0. When the pH adjusting is completed, after the water 150mL and ethyl acetate 80mL were injected in the reacting solution and the organic layer was separated after doing 30 minutes the mixing the organic layer was washed with the saturation brine 100mL. After the organic layer was separated it processed as the Magnesium Sulfate Anhydrous and the solution was filtered and the oily product which was concentratedunder reduced pressure and was obtained was obtained and this was done and the subject compound 4.1gr was obtained.
  • 29
  • [ 6399-81-1 ]
  • [ 121660-11-5 ]
  • <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide [ No CAS ]
  • 30
  • [ 124752-23-4 ]
  • [ 154057-58-6 ]
  • [ CAS Unavailable ]
  • [ 147489-06-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: <2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl>methyltriphenylphosphonium bromide With triphenylphosphine In dimethyl sulfoxide at 55℃; for 4h; Stage #2: 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester With anhydrous sodium carbonate In dimethyl sulfoxide at 30℃; for 5h; 1-5; 7-8; 10 Comparative Example 1 In a 1L reaction flask, add 20.00g (56.14mmol) of the parent nucleus bromide and 140ml of dimethyl sulfoxide, stir and heat to 55°C, add 18.40g (70.50mmol) of triphenylphosphorus, and then add 21.75g (1.5g) after the reaction is maintained for 4h. eq, 84.20mmol) side chain aldehyde and 14.87g (2.5eq, 140.33mmol) sodium carbonate, stirred at 30°C for 5h, after the reaction was completed, water was added to quench the reaction, toluene was added for extraction, the organic phase was concentrated and crystallized with isopropanol to obtain 15.10g pitavastatin calcium intermediate, yield 52%.
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