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[ CAS No. 182760-06-1 ] {[proInfo.proName]}

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Chemical Structure| 182760-06-1
Chemical Structure| 182760-06-1
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Product Details of [ 182760-06-1 ]

CAS No. :182760-06-1 MDL No. :MFCD00941002
Formula : C22H17F2N5OS Boiling Point : -
Linear Structure Formula :- InChI Key :OPAHEYNNJWPQPX-RCDICMHDSA-N
M.W : 437.47 Pubchem ID :467825
Synonyms :
BMS-207147;ER-30346

Calculated chemistry of [ 182760-06-1 ]

Physicochemical Properties

Num. heavy atoms : 31
Num. arom. heavy atoms : 22
Fraction Csp3 : 0.18
Num. rotatable bonds : 6
Num. H-bond acceptors : 7.0
Num. H-bond donors : 1.0
Molar Refractivity : 111.46
TPSA : 115.86 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.28
Log Po/w (XLOGP3) : 3.54
Log Po/w (WLOGP) : 4.97
Log Po/w (MLOGP) : 2.46
Log Po/w (SILICOS-IT) : 5.2
Consensus Log Po/w : 3.89

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.91
Solubility : 0.00536 mg/ml ; 0.0000123 mol/l
Class : Moderately soluble
Log S (Ali) : -5.66
Solubility : 0.000962 mg/ml ; 0.0000022 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.33
Solubility : 0.0000204 mg/ml ; 0.0000000466 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.22

Safety of [ 182760-06-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P337+P313 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 182760-06-1 ]

* 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 [ 182760-06-1 ]

[ 182760-06-1 ] Synthesis Path-Downstream   1~36

  • 1
  • [ 20099-89-2 ]
  • [ 170863-34-0 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
79.5% In ethanol for 3h; Reflux;
78% In ethanol at 20 - 70℃; for 2h; Inert atmosphere; enantioselective reaction;
38% In ethanol for 2h; Heating;
120 g In methanol at 60 - 65℃; for 3h; 16 Example-16: Preparation of 4-[2-[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile (Formula I, where R1=F and R2 =H): To a solution of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H- 1,2, 4-triazol-1-yl) butanethioamide (100 g) in methanol (1000 ml), 2-bromo-4-cyanoaceto phenone (80 g) was added, heated to 60-65°C and stirred for 3 hrs at the same temperature. After reaction completion, the reaction mass was cooled to 25-30°C, DM water (100 ml) followed by ethyl acetate (1000 ml) was added and stirred for 15 mins. Organic and aqueous layers were separated. Organic layer washed with sodium bicarbonate solution followed by sodium chloride solution and distilled off under reduced pressure at below 50°C. Isopropyl alcohol (250 ml) was added to the reaction mass at 25-30°C, then cooled to 0-5°C and stirred for an hour. The solid obtained was filtered, washed with isopropyl alcohol and dried at 50-55°C for 12 hrs under reduced pressure to get the title compound. Yield: 120 g. Purity by HPLC: 99.5%; Chiral purity: 99.9% e.e.
120 g In methanol at 60 - 65℃; for 3h; 16 Example-16: Preparation of 4-[2-[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile (Formula I, where R1=F and R2 =H): To a solution of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H- 1,2, 4-triazol-1-yl) butanethioamide (100 g) in methanol (1000 ml), 2-bromo-4-cyanoaceto phenone (80 g) was added, heated to 60-65°C and stirred for 3 hrs at the same temperature. After reaction completion, the reaction mass was cooled to 25-30°C, DM water (100 ml) followed by ethyl acetate (1000 ml) was added and stirred for 15 mins. Organic and aqueous layers were separated. Organic layer washed with sodium bicarbonate solution followed by sodium chloride solution and distilled off under reduced pressure at below 50°C. Isopropyl alcohol (250 ml) was added to the reaction mass at 25-30°C, then cooled to 0-5°C and stirred for an hour. The solid obtained was filtered, washed with isopropyl alcohol and dried at 50-55°C for 12 hrs under reduced pressure to get the title compound. Yield: 120 g. Purity by HPLC: 99.5%; Chiral purity: 99.9% e.e.

  • 2
  • [ 182760-06-1 ]
  • [ 368421-60-7 ]
YieldReaction ConditionsOperation in experiment
With O,S-diethyl-dithiophosphoric acid In water; isopropyl alcohol for 0.5h; Ambient temperature;
  • 3
  • [ 182760-06-1 ]
  • [ 207224-81-5 ]
YieldReaction ConditionsOperation in experiment
60% With 1-methyl-pyrrolidin-2-one; sodium azide; triethylamine hydrochloride at 100℃; for 8h;
  • 4
  • [ 45952-56-5 ]
  • [ 182760-06-1 ]
  • 1-[(2R,3R)-3-[4-(4-Cyano-phenyl)-thiazol-2-yl]-2-(2,4-difluoro-phenyl)-2-hydroxy-butyl]-4-(4-hydroxy-3,5-dimethyl-benzyl)-1H-[1,2,4]triazol-4-ium; bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% In acetonitrile at 20℃;
  • 5
  • [ 182760-06-1 ]
  • [ 241479-84-5 ]
  • 4-{4-[(<i>tert</i>-butoxycarbonyl-methyl-amino)-acetoxy]-3,5-dimethyl-benzyl}-1-[3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,4-difluoro-phenyl)-2-hydroxy-butyl]-1<i>H</i>-[1,2,4]triazol-4-ium; bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In acetonitrile Heating;
  • 7
  • [ 182760-06-1 ]
  • [ 229625-50-7 ]
  • [ 351227-63-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: ravuconazole With iodine; sodium hydride In tetrahydrofuran Stage #2: di-tert-butyl chloromethyl phosphate In tetrahydrofuran
Stage #1: ravuconazole With iodine; sodium hydride In tetrahydrofuran at -5 - 20℃; for 3.65h; Stage #2: di-tert-butyl chloromethyl phosphate In tetrahydrofuran at -5 - 20℃; Stage #3: With sodium hydroxide; phosphoric acid more than 3 stages; 1 Example 1; Di-tert-butyl-[(1R,2R)-2-(4-cynophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy] methyl phosphate; In a 2L 4-neck flask, 17.77g of 62% sodium hydride (0.46 mol) was weighed and tetrahydrofuran (113mL) was added under a nitrogen atmosphere. The bath temperature was set to -5°C and stirring was carried out for 12 minutes, then, a solution of 20.44g of iodide (0.080 mol) dissolved in tetrahydrofuran (113mL) was added dropwise thereto. The bath temperature was set to 20°C and stirring was carried out for 78 minutes, then, the bath temperature was set again to -5°C and stirring was carried out for 65 minutes. A solution of 70.5g 4-{2-[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl} benzonitrile (0.16 mol) dissolved in tetrahydrofuran (289mL) was added dropwise over 16 minutes, followed by stirring for 48 minutes at a bath temperature of -5°C. A solution containing 64.36g of di-tert-butyl chloromethyl phosphate in tetrahydrofuran (7mL) was added thereto followed by stirring overnight with the bath temperature set to 20°C. The bath temperature was set to -5°C, and after cooling, 3.2g of phosphoric acid contained in tert-butyl methyl ether (529mL) was added thereto dropwise over 24 minutes. After stirring for 90 minutes, 352mL of water was added thereto, and a further 352mL of water was added to carry out liquid separation. Next, after sequentially washing with 704mL of an aqueous solution of 2% NaOH, sodium chloride water and water, 3.20g of N-methyl morpholine was added to the separated organic layer and concentrated at a bath temperature of 30°C under a reduced pressure to obtain196g of the title compound (containing net 100g).
Stage #1: ravuconazole With iodine; sodium hydride In tetrahydrofuran at -5 - 20℃; for 3.65h; Stage #2: di-tert-butyl chloromethyl phosphate In tetrahydrofuran at -5 - 20℃; Stage #3: With phosphoric acid In tetrahydrofuran; tert-butyl methyl ether at -5℃; for 1.9h; 1 Production Example 1; Di-tert-butyl-[(1R,2R)-2-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy]methyl phosphate; 17.77 g (0.46 mol) of 62% sodium hydride was weighed out in a 2 L fourneck flask, and 113 mL of tetrahydrofuran was added under a nitrogen atmosphere. The bath temperature was set to -5°C, and then stirred for 12 minutes, after which 113 mL of a tetrahydrofuran solution in which 20.44 g (0.080 mol) of iodine had been dissolved was added dropwise thereto. The bath temperature was set to 20°C, and then stirred for 78 minutes, after which the bath temperature was brought back down to -5°C, and then stirred for 65 minutes. 289 mL of a tetrahydrofuran solution in which 70.5 g (0.16 mol) of 4-{2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile had been dissolved was added dropwise over a period of 16 minutes, after which the reaction mixture was stirred for 48 minutes at a bath temperature of -5°C. 7 mL of a tetrahydrofuran solution containing 64.36 g of di-tert-butyl chloromethyl phosphate was added, the bath temperature was set to 20°C, and then stirred overnight. The bath temperature was then set to -5°C to cool the system, after which 529 mL of tert-butyl methyl ether containing 3.2 g of phosphoric acid was added dropwise over a period of 24 minutes. After 90 minutes of stirring, 352 mL of water was added, then another 352 mL of water was added, and liquid separation occurred. This product was then washed with 704 mL of a 2% NaOH aqueous solution, saline, and then water, after which 3.20 g of N-methylmorpholine was added to the separated organic layer, and this product was concentrated under a reduced pressure at a bath temperature of 30°C, which gave 196 g (net weight 100 g content) of the titled compound.
97 %Chromat. Stage #1: ravuconazole With sodium hydride In tetrahydrofuran at 20℃; for 1.08333h; Stage #2: With iodine In tetrahydrofuran at 20℃; for 0.166667h; Stage #3: di-tert-butyl chloromethyl phosphate In tetrahydrofuran at 20 - 41℃; for 4.25h; 1.A Step A: An oven dried, IL round-bottom flask equipped with a mechanical stirrer, nitrogen inlet adapter, pressure- equalizing addition funnel fitted with a rubber septum and temperature probe was charged with sodium hydride (2.89 g, 0.069 mol, 60%) and THF (50 mL) . To this stirred suspension, (2R, 3R) -3- [4- (4-cyanophenyl) thiazol-2-yl] -2- (2,4- difluorophenyl) -1- (IH-I, 2, 4-triazol-l-yl) butan-2-ol (formula B) (10 g, 0.023 mol) in 30 mL of THF was added dropwise over 20 minutes at room temperature. After stirring for 45 minutes, a solution of iodine (2.99 g, 0.0115 mol) in THF(30 mL) ) was added dropwise over 10 minutes followed by dropwise addition of compound di-tert-butyl chloromethyl phosphate (formula III') (13.29 g, 0.035 mol, -68% purity) over 15 minutes. The reaction mixture was stirred for 4 hours at about 41°C to complete the reaction. The completion of the reaction was judged by in-process HPLC. The reaction mixture was poured into ice-cold water (100 mL) . The aqueous phase was separated and extracted with ethyl acetate (3 x 50 mL) and the combined organic extract was washed with 10% sodium thiosulfite (50 mL) , water (50 mL) , brine (50 mL) , dried over magnesium sulfate and concentrated under reduced pressure to give pale yellow oil (22.8 g, In- process HPLC: ~ 97 area percent) . The crude product (formula IV) was used "as is" in Step B.
Stage #1: ravuconazole With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: di-tert-butyl chloromethyl phosphate In tetrahydrofuran at 50℃; for 16h; Step A: To a solution of (2R, 3R) -3- [4- (4-cyanophenyl) thiazol-2- yl] -2- (2, 4-difluorophenyl) -1- (IH-I, 2, 4-triazol-l-yl) butan-2- ol, 2, (8.74 g, 20 mmol) in THF (40 inL) under a nitrogen atmosphere was added sodium hydride (0.80 g, 60% in oil, 20 mmol) at rt . The resulting mixture was stirred at rt for0.25 h and then di-tert-butyl chloromethyl phosphate, 3(10.3 g, 40 mmol) is added. The reaction mixture was heated at 500C for 16 h. The reaction mixture was then allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in Et2O and is washed with H2O and brine. The organic layer was dried over MgSO4 and is concentrated under reduced pressure to obtain 17.0 g of crude compound, 4, as a gum. A small portion of this crude compound was purified by reverse phase chromatography on C- 18. The column was eluted with 30% CH3CN/H2O, 38% CH3CN/H2O, 45% CH3CN/H2O and then 50% CH3CN/H2O. The product containing fractions are concentrated under reduced pressure in order to remove CH3CN. The resulting aqueous .layer was then extracted with Et2O. The Et2O layers are washed with brine, dried and concentrated under reduced pressure to afford purified compound, 4, as a white solid. The spectra data is as follows: IH NMR (300' MHz, CDC13) : δ 8.35 (s, IH), 7.98 (d, 2H, J=9), 7.76 (s, IH), 7.71 (d, 2H, J=9) , 7.63 (s, IH), 7.36-7.27 (m, IH), 6.86-6.78 (m, 2H), 5.53 (dd, IH,J=28,6), 5.53 (dd, IH, J=9,6), 5.17 (d, IH, J=15) , 5.03 (d, IH, J=15), 4.01 (q, IH, J=7), 1.47 (s, 9H), 1.45 (s, 9H), 1.37 (d, 3H, J=7) . MS [ESI+ (M+H) +] 660.2 obs .

  • 8
  • [ 1443-80-7 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 70 percent / Br2, AlCl3 / ethyl acetate / 5 h / 10 °C 2: 38 percent / ethanol / 2 h / Heating
  • 9
  • [ 170862-36-9 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 81 percent / diethyl dithiophosphate / H2O; propan-2-ol / 3 h / Heating 2: 38 percent / ethanol / 2 h / Heating
Multi-step reaction with 2 steps 1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 2: methanol / 3 h / 60 - 65 °C
  • 10
  • [ 182760-06-1 ]
  • [ 207224-83-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: diethyl dithiophosphate / propan-2-ol; H2O / 0.5 h / Ambient temperature 2: 1.) iodomethane, 2.) Et3N, H2SO4 / 1.) acetone, 40 deg C, 1 h, 2.) reflux, 1 h
  • 11
  • [ 182760-06-1 ]
  • (2R,3R)-2-(2,4-Difluoro-phenyl)-3-{4-[4-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-thiazol-2-yl}-1-[1,2,4]triazol-1-yl-butan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: diethyl dithiophosphate / propan-2-ol; H2O / 0.5 h / Ambient temperature 2: 1.) iodomethane, 2.) Et3N, H2SO4 / 1.) acetone, 40 deg C, 1 h, 2.) reflux, 1 h 3: 67 percent / K2CO3 / acetone / 18 h / Ambient temperature
  • 12
  • [ 182760-06-1 ]
  • (2R,3R)-2-(2,4-Difluoro-phenyl)-3-{4-[4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-thiazol-2-yl}-1-[1,2,4]triazol-1-yl-butan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 60 percent / NaN3, Et3N*HCl, N-methylpyrrolidone / 8 h / 100 °C 2: 1.) cesium carbonate / 1.) DMF, 60 deg C, 1 h, 2.) DMF, RT, 1 h
  • 13
  • [ 182760-06-1 ]
  • [ 251295-70-2 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran 4 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (5.8 mmol) was added to a suspension of potassium hydride (7 mmol) in THF at 0C and was allowed to stir for 0.5 hours. Choromethyl chloroformate (5.8 mmol, in 2mL THF) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 4 hours. The crude reaction was diluted with EtoAc, and was sequentially washed with H2O, 0.1N HCl, H2O, and brine. The organic layer was dried over MgSO4 and was concentrated to afford 3.43 g of the subtitled product as a pale yellow solid. 1H NMR (DMSO) δ 8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 5.93 (d, 1H, J=6), 5.90 (d, 1H, J=6), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=530).
  • 14
  • chloromethyl ester [ No CAS ]
  • [ 182760-06-1 ]
  • [ 251295-69-9 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran 3 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-chloromethyl]benzoyloxy]methoxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-chloromethyl]benzoyloxy]methoxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl] -2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (13.9 mmol) was added to a suspension of potassium hydride (15.3 mmol) in THF (100 mL) at 0° C. The heterogeneous mixture was stirred for 15 minutes and the chloromethyl ester (16.8 mmol, prepared by the method disclosed in Houben-Weyl, Methoden Der Organischen Chemie, Band E14a/3, 85, 1992) was added. The reaction was allowed to stir at 0° C. for 2 h and then warmed to r.t. and stirred for 2 h. Excess base was carefully quenched with water, and the crude reaction was extracted into ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. Purification of the crude product via flash chromatography (Hexanes/EtOAc) yielded 4.6 g of the subtitled compound as a colorless oil. 1H NMR (CDCl3): δ 1.29 (m, 3H), 4.14 (m, 1H), 5.03 (d, J=16.0, 2H), 5.35 (d, J=18.0, 2H), 6.20 (s, 2H), 6.85 (m, 2H), 7.29(m, 1H), 7.42(m, 2H), 7.56(d, J=7.7, 1H), 7.70(m, 3H), 7.79(d, J=7.8, 1H), 7.88(s, 1H), 7.94(d, J=8.5, 2H), 8.11(s, 1H).
  • 15
  • [ 182760-06-1 ]
  • [ 251295-69-9 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran 2 (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-chloromethyl)benzoyloxy]methoxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-chloromethyl)benzoyloxy]methoxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1.09 mmol) was added to a suspension of potassium hydride (1.31 mmol) in THF at 0° C. The heterogeneous mixture was stirred for 0.25 hours and chloride 8 (1.14 mmol, prepared via the method of Iyer et al, Syn. Comm. 25, 2739, 1995) was added. The reaction was allowed to stir at 0° C. for 2 hours, and then was allowed to warm to room temperature and stirred for 7 hours. The excess base was carefully quenched with water, and the crude reaction was extracted into ethyl acetate. The layers were separated and the organic layer was washed with water, brine, and was dried over Na2SO4. Purification of the crude product via column chromatography yielded 300 mg of the subtitled compound as a colorless oil. 1H NMR (CDCl3) δ 8.11 (s, 1H), 7.94 (d, 2H, J=8.5), 7.88 (s, 1H), 7.79 (d, 1H, J=7.8), 7.70 (m, 3H), 7.56 (d, 1H, J=7.8), 7.42 (m, 2H), 7.29 (m, 1H), 6.85 (m, 2H), 6.20 (s, 2H), 5.35 (d, 2H, J=18), 5.03 (d, 2h, J=18), 4.14 (m, 1H), and 1.29 (m, 3H). MS (M+=619).
  • 16
  • [ 182760-06-1 ]
  • (2R.3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran (2R.3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane (2R.3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (5.8 mmol) was added to a suspension of potassium hydride (7 mmol) in THF at 0° C. and was allowed to stir for 0.5 hours. Choromethyl chloroformate (5.8 mmol, in 2mL THF) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 4 hours. The crude reaction was diluted with EtOAc, and was sequentially washed with H2O, 0.1N HCl, H2O, and brine. The organic layer was dried over MgSO4 and was concentrated to afford 3.43 g of the subtitled product as a pale yellow solid. 1H NMR (DMSO) δ8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 5.93 (d, 1H, J=6), 5.90 (d, 1H, J=6), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=530).
  • 17
  • [ 75-44-5 ]
  • [ 182760-06-1 ]
  • [ 1022985-55-2 ]
YieldReaction ConditionsOperation in experiment
22% With pyridine In dichloromethane; toluene at 20℃;
  • 18
  • [ 22128-62-7 ]
  • [ 182760-06-1 ]
  • [ 1022985-55-2 ]
  • [ 1022985-62-1 ]
YieldReaction ConditionsOperation in experiment
90% With pyridine In dichloromethane at 20℃;
  • 19
  • [ 22128-62-7 ]
  • [ 182760-06-1 ]
  • [ 251295-70-2 ]
YieldReaction ConditionsOperation in experiment
71% Stage #1: ravuconazole With potassium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: carbonochloridic acid, chloromethyl ester In tetrahydrofuran for 1.5h; Further stages.;
3.43 g Stage #1: ravuconazole With potassium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: carbonochloridic acid, chloromethyl ester In tetrahydrofuran for 4h;
  • 20
  • [ 182760-06-1 ]
  • [ 251295-68-8 ]
  • [ 251295-69-9 ]
YieldReaction ConditionsOperation in experiment
300 mg Stage #1: ravuconazole With potassium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: (3-chloromethyl)benzoic acid chloromethyl ester In tetrahydrofuran for 9h;
  • 22
  • 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: acetone; methanol / 20 °C / Reflux 2: sodium hydroxide / dichloromethane; water
  • 23
  • (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In dichloromethane; water 1 To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1R)-10-camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41% yield, 99.1% ee); m.p. 164-166° C.; [α]=-30° (c=1, methanol, 25° C.); NMR (CDCl3): 1.23 (3H, d, J=8 Hz), 4.09 (1H, q, J=8 Hz), 4.26 (1H, d, J=14 Hz), 4.92 (1H, d, J=14 Hz), 5.75 (1H, s), 6.75-6.85 (2H, m), 7.45-7.54 (2H, m), 7.62 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8 Hz), 7.86 (1H, s), 8.03 (1H, d, J=8 Hz). The analytical data were identical with published (U.S. Pat. No. 5,648,372 and Chem. Pharm. Bull. 1998, 46, 623-630).
  • 24
  • [ 132507-89-2 ]
  • [ 182760-06-1 ]
  • 25
  • C15H21F2N3O2Si [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydroxide; tetrabutyl ammonium fluoride / 15 h / 20 °C / Inert atmosphere 2: toluene / 22 h / 20 - 50 °C / Inert atmosphere 3: water; isopropyl alcohol / 9 h / 20 - 80 °C / Inert atmosphere 4: ethanol / 2 h / 20 - 70 °C / Inert atmosphere
  • 26
  • 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)-methyl)-1H-1,2,4-triazole [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: toluene / 22 h / 20 - 50 °C / Inert atmosphere 2: water; isopropyl alcohol / 9 h / 20 - 80 °C / Inert atmosphere 3: ethanol / 2 h / 20 - 70 °C / Inert atmosphere
  • 27
  • [ 51336-94-8 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: C6H18NSi2(1-)*Gd(1+); 1,5-anhydro-2,6-dideoxy-3-O-(4,5-difluoro-2-hydroxyphenyl)-6-(diphenylphosphinyl)-D-arabino-hexitol / -30 °C / Inert atmosphere 2: diisobutylaluminium hydride / toluene / -78 °C / Inert atmosphere 3: tetrahydrofuran / 0.67 h / -78 °C / Inert atmosphere 4: tetrabutyl ammonium fluoride / 28 h / 55 °C / Inert atmosphere 5: methanesulfonyl chloride; triethylamine / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere 6: toluene / 22 h / 20 - 50 °C / Inert atmosphere 7: water; isopropyl alcohol / 9 h / 20 - 80 °C / Inert atmosphere 8: ethanol / 2 h / 20 - 70 °C / Inert atmosphere
  • 28
  • C13H19ClF2O2Si [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: tetrabutyl ammonium fluoride / 28 h / 55 °C / Inert atmosphere 2: methanesulfonyl chloride; triethylamine / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere 3: toluene / 22 h / 20 - 50 °C / Inert atmosphere 4: water; isopropyl alcohol / 9 h / 20 - 80 °C / Inert atmosphere 5: ethanol / 2 h / 20 - 70 °C / Inert atmosphere
  • 29
  • [ 861718-83-4 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: diisobutylaluminium hydride / toluene / -78 °C / Inert atmosphere 2: tetrahydrofuran / 0.67 h / -78 °C / Inert atmosphere 3: tetrabutyl ammonium fluoride / 28 h / 55 °C / Inert atmosphere 4: methanesulfonyl chloride; triethylamine / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere 5: toluene / 22 h / 20 - 50 °C / Inert atmosphere 6: water; isopropyl alcohol / 9 h / 20 - 80 °C / Inert atmosphere 7: ethanol / 2 h / 20 - 70 °C / Inert atmosphere
  • 30
  • [ 861718-85-6 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: tetrahydrofuran / 0.67 h / -78 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / 28 h / 55 °C / Inert atmosphere 3: methanesulfonyl chloride; triethylamine / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere 4: toluene / 22 h / 20 - 50 °C / Inert atmosphere 5: water; isopropyl alcohol / 9 h / 20 - 80 °C / Inert atmosphere 6: ethanol / 2 h / 20 - 70 °C / Inert atmosphere
  • 31
  • [ 31618-90-3 ]
  • [ 182760-06-1 ]
  • C27H28F2N5O4PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
82.2% Stage #1: ravuconazole With sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: diethyl (p-toluenesulfonyloxymethane)phosphonate In tetrahydrofuran at 50℃; for 6h; Inert atmosphere; 3.a (a) Preparation of (2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 ,Diethyl 4-triazol-1-yl)-butan-2-yloxy)methylphosphonate An oven-dried 500 mL three-necked flask equipped with a mechanical stirrer,A nitrogen gas-protected, thermometer apparatus was charged with THF (50 mL) and sodium hydride (4.3 g, 0.11 mol, 60%).(2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1) dissolved in 60 mL of THF ,2,4-triazol-1-yl)-butan-2-yloxy)butan-2-ol(Compound of the structure of formula G, Isavuconazole, esaconazole) (15 g, 0.034 mol) was added dropwise at room temperature for 15 minutes.The stirred suspension.After stirring for 45 minutes, diethyl p-toluenesulfonyloxymethylphosphonate (18 g, 0.56 mol) was then added dropwise over 15 minutes.The reaction mixture was stirred at about 50 ° C for 6 hours to complete the reaction.The reaction was quenched by HPLC, and the reaction was quenched by the addition of acetic acid (5.5 g) and water (15 ml), and then concentrated under reduced pressure. The mixture was added with methylene chloride (80 ml) and 50 ml of tap water. The organic layer was separated and the organic layer was washed once with saturated brine.The organic layer was dried over MgSO4 and evaporated(16.4g, 82.2%).
  • 32
  • C15H17F2N3O3 [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: sodium hydroxide; water / methanol / 25 - 35 °C 2.1: (<i>S</i>)-1-phenyl-ethylamine / ethyl acetate; isopropyl alcohol / 0.5 h / 75 - 80 °C 2.2: pH > 10 3.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 3.2: 2 h / 5 - 10 °C 4.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 5.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 6.1: methanol / 3 h / 60 - 65 °C
Multi-step reaction with 6 steps 1.1: sodium hydroxide; water / methanol / 25 - 35 °C 2.1: (<i>S</i>)-1-phenyl-ethylamine / ethyl acetate; isopropyl alcohol / 0.5 h / 75 - 80 °C 3.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 3.2: 2 h / 5 - 10 °C 4.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 5.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 6.1: methanol / 3 h / 60 - 65 °C
  • 33
  • [ 166948-49-8 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 1.2: 2 h / 5 - 10 °C 2.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 3.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 4.1: methanol / 3 h / 60 - 65 °C
  • 34
  • [ 219872-85-2 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 2: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 3: methanol / 3 h / 60 - 65 °C
  • 35
  • 3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid [ No CAS ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: (<i>S</i>)-1-phenyl-ethylamine / ethyl acetate; isopropyl alcohol / 0.5 h / 75 - 80 °C 1.2: pH > 10 2.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 2.2: 2 h / 5 - 10 °C 3.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 4.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 5.1: methanol / 3 h / 60 - 65 °C
Multi-step reaction with 5 steps 1.1: (<i>S</i>)-1-phenyl-ethylamine / ethyl acetate; isopropyl alcohol / 0.5 h / 75 - 80 °C 2.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 2.2: 2 h / 5 - 10 °C 3.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 4.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 5.1: methanol / 3 h / 60 - 65 °C
  • 36
  • [ 86404-63-9 ]
  • [ 182760-06-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: chloro-trimethyl-silane; zinc; iodine / tetrahydrofuran / 16 h / 50 °C / Inert atmosphere; Reflux 2.1: sodium hydroxide; water / methanol / 25 - 35 °C 3.1: (<i>S</i>)-1-phenyl-ethylamine / ethyl acetate; isopropyl alcohol / 0.5 h / 75 - 80 °C 3.2: pH > 10 4.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 4.2: 2 h / 5 - 10 °C 5.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 6.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 7.1: methanol / 3 h / 60 - 65 °C
Multi-step reaction with 7 steps 1.1: chloro-trimethyl-silane; zinc; iodine / tetrahydrofuran / 16 h / 50 °C / Inert atmosphere; Reflux 2.1: sodium hydroxide; water / methanol / 25 - 35 °C 3.1: (<i>S</i>)-1-phenyl-ethylamine / ethyl acetate; isopropyl alcohol / 0.5 h / 75 - 80 °C 4.1: thionyl chloride / tetrahydrofuran / 35 - 40 °C 4.2: 2 h / 5 - 10 °C 5.1: trichlorophosphate / N,N-dimethyl-formamide / 10 - 35 °C 6.1: O,O-Diethyl hydrogen phosphorodithioate / isopropyl alcohol; water / 16 h / 75 °C / Reflux 7.1: methanol / 3 h / 60 - 65 °C
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