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Chemical Structure| 38222-83-2 Chemical Structure| 38222-83-2

Structure of 38222-83-2

Chemical Structure| 38222-83-2

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Product Details of [ 38222-83-2 ]

CAS No. :38222-83-2
Formula : C14H23N
M.W : 205.34
SMILES Code : CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1
MDL No. :MFCD00006305
InChI Key :HVHZEKKZMFRULH-UHFFFAOYSA-N
Pubchem ID :98898

Safety of [ 38222-83-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 38222-83-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 6
Fraction Csp3 0.64
Num. rotatable bonds 2
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 67.74
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

12.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

3.29
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

4.63
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.99
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

3.21
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

4.25
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.87

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-4.19
Solubility 0.0131 mg/ml ; 0.000064 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-4.63
Solubility 0.00485 mg/ml ; 0.0000236 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.84
Solubility 0.00298 mg/ml ; 0.0000145 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

Yes
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-4.27 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<2.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.93

Application In Synthesis of [ 38222-83-2 ]

* 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 [ 38222-83-2 ]

[ 38222-83-2 ] Synthesis Path-Downstream   1~54

  • 1
  • 2,6-di-t-butyl-4-methylpyrylium perchlorate [ No CAS ]
  • [ 38222-83-2 ]
  • 2
  • [ 421-20-5 ]
  • [ 38222-83-2 ]
  • [ 78020-53-8 ]
  • 3
  • [ 421-20-5 ]
  • [ 38222-83-2 ]
  • 2,6-di-tert-butyl-4-methylpyridinium fluorosulfate [ No CAS ]
  • [ 78008-53-4 ]
  • 4
  • [ 421-20-5 ]
  • [ 38222-83-2 ]
  • [ 78008-53-4 ]
  • 5
  • [ 421-20-5 ]
  • [ 38222-83-2 ]
  • 2,6-Bis(1,1-dimethylethyl)-1,4-dimethylpyridiniumperchlorat [ No CAS ]
  • 6
  • [ 38222-83-2 ]
  • [ 612-12-4 ]
  • [ 118066-99-2 ]
  • 7
  • [ 38222-83-2 ]
  • [ 2926-30-9 ]
  • [ 135182-72-8 ]
  • 8
  • [ 38222-83-2 ]
  • [ 107-30-2 ]
  • [ 107082-94-0 ]
  • 9
  • [ 38222-83-2 ]
  • [ 81142-32-7 ]
YieldReaction ConditionsOperation in experiment
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A3) To a mixture of 2,6-di-t-butyl-4-methylpyridine (Aldrich, 2.0 g, 9.73 mmol) in 25 ml of dry CCl4 was added benzoyl peroxide (24 mg, 0.097 mmol) and NBS (1.9 g, 10.7 mmol). The reaction mixture was refluxed for 16 hours. After it cooled to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, hexane) to give an oil (1.957 g) which contained 82percent of the desired product and 18percent of the starting material. 1 H NMR delta 7.09 (s, 2H), 4.39 (s, 2H), 1.35 (s, 18H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A) To a mixture of 2,6-di-t-butyl-4-methylpyridine (Aldrich, 2.0 g, 9.73 mmol) in 25 ml of dry CCl4 was added benzoyl peroxide (24 mg, 0.097 mmol) and NBS (1.9 g, 10.7 mmol). The reaction mixture was refluxed for 16 hours. After it cooled to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, hexane) to give an oil (1.957 g) which contained 82percent of the desired product and 18percent of the starting material. 1 H NMR delta 7.09 (s, 2H), 4.39 (s, 2H), 1.35 (s, 18H).
  • 11
  • [ 630-18-2 ]
  • [ 41792-83-0 ]
  • [ 38222-83-2 ]
  • 12
  • [ 75-85-4 ]
  • [ 1538-75-6 ]
  • [ 38222-83-2 ]
  • [ 108154-12-7 ]
  • [ 108154-13-8 ]
  • 15
  • [ 38222-83-2 ]
  • [ 615-43-0 ]
  • [ 143321-89-5 ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic anhydride; In dichloromethane; water; Example 6B 2,2,2-Trifluoro-N-(2-iodophenyl)acetamide 2-Iodo-phenylamine (Aldrich, 1.09 g, 5 mmol) was treated with trifluoroacetic anhydride (Aldrich, 1.26 g, 6 mmol) and 2,6-di-tert-butyl-4-methyl-pyridine (Aldrich, 1.23 g, 6 mmol) in CH2Cl2 (10 mL)at room temperature overnight. It was then quenched with with water (5 mL) and extracted with EtOAc (3*10 mL). The extracts were combined and washed with brine (5 mL). The organic solution was concentrated and the title compound was purified by flash chromatography (SiO2, Hexanes/EtOAc, 80:20, Rf. 0.50) as a solid (1.1 g, yield, 70percent). 1H NMR (300 MHz, CD3OD) delta 7.07-7.12 (m, 1H), 7.39-7.47 (m, 2H), 7.95 (dd, J=7.8, 1.3 Hz, 1H) ppm. MS (DCI): m/z 316 (M+H)+.
  • 16
  • [ 38222-83-2 ]
  • [ 358-23-6 ]
  • [ 1879-06-7 ]
  • 1-methyl-4-[1-(trifluoromethylsulphonyloxy)vinyl]-1-cyclohexene [ No CAS ]
  • 17
  • [ 38222-83-2 ]
  • 2,6-di-tert-4-(fluoromethyl)pyridine [ No CAS ]
  • 18
  • [ 38222-83-2 ]
  • [ 862009-38-9 ]
  • 19
  • [ 38222-83-2 ]
  • [ 862009-40-3 ]
  • 20
  • [ 38222-83-2 ]
  • [ 862009-39-0 ]
  • 21
  • [ 38222-83-2 ]
  • 4,4'-bis[3,5-bis(2,6-di-tert-butylpyridin-4-ylmethoxy)benzyloxy]biphenyl [ No CAS ]
  • 22
  • [ 38222-83-2 ]
  • [ 81869-04-7 ]
  • 23
  • [ 38222-83-2 ]
  • C28H44N2*2FHO3S [ No CAS ]
  • 24
  • [ 38222-83-2 ]
  • [ 81142-34-9 ]
  • 25
  • [ 3282-30-2 ]
  • [ 38222-83-2 ]
  • 26
  • [ 38222-83-2 ]
  • [ 17159-79-4 ]
  • [ 122948-57-6 ]
YieldReaction ConditionsOperation in experiment
With trifluorormethanesulfonic acid; In dichloromethane; at 25℃; (1) To a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (8.0 g) and 2,6-di(tert-butyl)-4-methylpyridine (14.4 g) in dichloromethane (200 ml) is added trifluoromethanesulfonic anhydride (8.73 ml) at -78°C, and the mixture is gradually warmed to 25°C, and the mixture is stirred at the same temperature overnight.. The reaction solution is poured into aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate.. The organic layer is washed with saturated brine, and the solvent is evaporated under reduced pressure to give 4-trifluoromethanesulfonyloxy-3-cyclohexenecarboxylic acid ethyl ester.
  • 27
  • [ 38222-83-2 ]
  • [ 53123-88-9 ]
  • [ 1111-92-8 ]
  • [ 3283-12-3 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In dichloromethane; ethyl acetate; Dimethyl-phosphinic acid C-43 rapamycin ester To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1*100 mL), saturated NaHCO3(1*100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.5 (m, 6H); 31P NMR (121 MHz, CDCl3) d 53.6; 1013 m/z (M+Na).
With sodium hydrogencarbonate; In dichloromethane; ethyl acetate; Dimethyl-phosphinic acid C-43 rapamycin ester To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1*100 mL), saturated NaHCO3(1*100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H); 31P NMR (121 MHz, CDCl3) d 53.6; 1013 m/z (M+Na).
With sodium hydrogencarbonate; In dichloromethane; ethyl acetate; EXAMPLE 2Dimethyl-Phosphinic Acid C-43 Rapamycin EsterTo a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane.The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC).The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a reparatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL).Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1*100 mL), saturated NaHCO3(1*100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated.The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) delta4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H); 31P NMR (121 MHz, CDCl3) delta 53.6; 1013 m/z (M+Na).
  • 28
  • [ 38222-83-2 ]
  • [ 503464-97-9 ]
  • [ 1025373-45-8 ]
  • [ 503464-98-0 ]
YieldReaction ConditionsOperation in experiment
75% In dichloromethane; EXAMPLE 3 Synthesis of Trifluoromethanesulfonic Acid 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2H-1-benzopyran-4-yl ester A three-necked 50-ml flask (equipped with a thermometer and a dropping funnel) was charged with 1.0 g (3.6 mmol) of 2,2-bis(fluoromethyl)-3,4-dihydro-6-(trifluoromethyl)-2H-1-benzopyran-4-one, 1.8 g (8.9 mmol) of <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong>, and 10 ml of methylene chloride. Then, 2.0 g (7.1 mmol) of trifluoromethanesulfonic acid anhydride were added in a dropwise manner by spending 5 minutes to the mixture under cooling in an iced water bath at 5-10° C., while the mixture was stirred. After completing the dropping, the temperature of the mixture was gradually increased to room temperature, followed by stirring for 140 hr at room temperature. Then, the methylene chloride was distilled off by an evaporator. The resulting residue was purified by silica gel column chromatography (developing liquid: ethyl acetate/n-hexane=1/8), thereby obtaining 1.1 g (2.7 mmol) of trifluoromethanesulfonic acid 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2H-1-benzopyran-4-yl ester (yield: 75percent). This product was found to have the following properties. 1H-NMR (standard substance: TMS; solvent: CDCl3) sigma (ppm): 4.51-4.73 (m, J=46.4 Hz, 4H), 5.78 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.58 (dd, J=8.8, 2.0 Hz, 1H) 19F-NMR (standard substance: CCl3F; solvent: CDCl3) sigma (ppm): -62.85 (s, 3F), -73.51 (s, 3F), -232.91 (t, J=46.4 Hz, 2F)
  • 29
  • [ 38222-83-2 ]
  • [ 374753-43-2 ]
  • [ 1493-13-6 ]
  • [ 374753-44-3 ]
YieldReaction ConditionsOperation in experiment
95% With sodium hydrogencarbonate; In dichloromethane; water; EXAMPLE 7 Preparation of 4-[6-(4-methoxyphenyl)benzo[b]thiophen-3-yl]pyridine Anhydrous trifluoromethane sulfonic acid (Tf2O; 0.14 ml, 0.8322 mmol) was added to a suspension of 3-(4-pyridyl)benzo[b] thiophen-6-ol (164 mg, 0.7216 mmol) obtained in Example 6 and 2,6-di-t-butyl-4-methylpyridine (180 mg, 0.8766 mmol) in dichloromethane (5 ml) under cooling with ice. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate. The organic layer was washed with 5percent citric acid aqueous solution, saturated aqueous solution of sodium bicarbonate, water, and then saturated brine, sequentially, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained was submitted to silica gel column chromatography (hexane:ethyl acetate=17:3) to obtain a colorless oily product of 3-(4-pyridyl)benzo[b]thiophen-6-yl=trifluoromethane sulfonate (247 mg, 95percent). 1H-NMR(CDCl3) delta: 7.33(dd, J=2.4, 8.9 Hz, 1H), 7.46(d, J=6.0 Hz, 2H), 7.65(s, 1H), 7.85(d, J=2.2 Hz, 1H), 7.93(d, J=8.9 Hz, 1H), 8.73(d, J=6.0 Hz, 2H).
  • 30
  • [ 491-37-2 ]
  • [ 38222-83-2 ]
  • [ 461666-59-1 ]
YieldReaction ConditionsOperation in experiment
94% With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; (34a) Trifluoromethanesulfonic anhydride (1.2 mL, 7.4 mmol)was added drop wise to a stirring solution of chroman-4-one (1.0 g, 6.7 mmol), 2,6-di-t-butyl-4-methyl pyridine (1.59 g, 7.7 mmol) in dichloromethane (40 mL), under nitrogen atmosphere. The reaction was heated to reflux for 2 h, allowed to cool to room temperature and was concentrated in vacuo to give a semi solid residue. This was treated with hexane and the solids were filtered off. The filtrate was concentrated to give 4-[(trifluoromethyl)sulfonyl]-2H-chromene (1.78 g, 94percent) as an orange oil.
  • 31
  • [ 38222-83-2 ]
  • [ 374753-45-4 ]
  • [ 374753-52-3 ]
YieldReaction ConditionsOperation in experiment
99% With Tf2O; sodium hydrogencarbonate; In dichloromethane; water; EXAMPLE 13 Preparation of 3-[6-(4-fluorophenyl)benzo[b]thiophen-3-yl]pyridine hydrochloride Tf2O (0.97 ml, 5.766 mmol) was added to a suspension of the 3-(3-pyridyl)benzo[b]thiophen-6-ol (1.14 g, 5.016 mmol) obtained in Example 8 and 2,6-di-t-butyl-4-methylpyridine (1.25 g, 6.087 mmol) in dichloromethane (35 ml) under cooling with ice. The mixture was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with water, 5percent citric acid aqueous solution, saturated aqueous solution of sodium bicarbonate, water, and then saturated brine, sequentially, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was submitted to basic silica gel column chromatography (hexane:ethyl acetate=93:7) to obtain a colorless oily product of 3-(3-pyridyl)benzo[b]thiophen-6-yl=trifluoromethane sulfonate (1.78 g, 99percent). 1H-NMR(CDCl3) delta: 7.32(dd, J=2.3, 8,9 Hz, 1H), 7.42(dd, J=4.9, 7.9 Hz, 1H), 7.57(s, 1H), 7.84-7.86(m, 3H), 8.67(dd, J=2.1, 5.5 Hz, 1H), 8.80(d, J=2.1 Hz, 1H).
  • 32
  • [ 3528-17-4 ]
  • [ 38222-83-2 ]
  • [ 461665-48-5 ]
YieldReaction ConditionsOperation in experiment
51% With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; (33a) Trifluoromethanesulfonic anhydride (2.2 mL, 13.4 mmol) was added dropwise to a stirring solution of thiochroman-4-one (2.0 g, 12.2 mmol), 2,6-di-t-butyl-4-methyl pyridine (2.63 g, 12.8 mmol) in dichloromethane (100 mL), under nitrogen atmosphere. The reaction was heated to reflux for 2 h, allowed to cool to room temperature and was concentrated in vacuo to give a semi-solid residue. This was treated with hexane and the solids were filtered off. The filtrate was concentrated to give 2H-1-benzothiopyran-4-yltrifluoromethyl sulfone (1.84 g, 51percent) as a solid. MS found: (M+H)+=297.
  • 33
  • [ 38222-83-2 ]
  • [ 358-23-6 ]
  • [ 267875-65-0 ]
  • [ 267875-66-1 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; pentane; Step H 2,2-Difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate (1-8) To a stirred -78° C. solution of 50 mg (0.31 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol and 100 mg (0.49 mmol) of 2,6-di-t-butyl-4-methylpyridine in 1.0 ml of CH2Cl2 was added dropwise 79 muL (0.47 mmol) of trifluoromethansulfonic anhydride. After the addition, the cold bath was removed, and stirring continued for 0.5 h. The reaction was diluted with 2 ml of pentane, and the resulting precipitate washed with pentane. The filtrate was evaporated in vacuo to dryness to give as a yellow solid: 1H NMR (CDCl3) delta8.66 (d, 1H, 4.9 Hz), 7.89 (td,1H, 7.7, 1.7 Hz), 7.76 (d, 1H, 7.9 Hz), 7.45-7.49 (m, 1H), 5.12 (t, 2 H, 11.9 Hz).
In dichloromethane; pentane; Step B 2,2-Difluoro-2-(2-pyridyl)ethyl Trifluoromethanesulfonate To a stirred -78° solution of 50 mg (0.31 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol and 100 mg (0.49 mmol) of 2,6-di-t-butyl-4-methylpyridine in 1.0 mL of CH2Cl2 was added 79 muL (0.47 mmol) of trifluoromethansulfonic anhydride dropwise under Ar. After the addition, the cold bath was removed, and stirring continued for 0.5 h. The reaction was diluted with 2 mL of pentane, and the resulting precipitate washed with pentane. The filtrate was evaporated in vacuo to dryness to give the title compound as a yellow solid: 1H NMR (CDCl3) delta 8.66 (d, 1H, 4.9 Hz), 7.89 (td, 1H, 7.7, 1.7 Hz), 7.76 (d, 1H, 7.9 Hz), 7.45-7.49 (m, 1H), 5.12 (t, 2; H, 11.9 Hz).
  • 34
  • [ 38222-83-2 ]
  • [ 40353-34-2 ]
  • [ 358-23-6 ]
  • trifluoromethanesulphonic acid 7-nitro-3,4,4a,8a-tetrahydronaphthalen-1-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; pentane; Step 1 Trifluoromethanesulphonic acid 7-nitro-3,4,4a,8a-tetrahydronaphthalen-1-yl ester 9.8 ml of trifluoromethanesulphonic anhydride are poured at 0° C. into a solution of 10 g of 7-nitrotetralone and 11.8 g of <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> in 365 ml of dichloromethane. After 24 hours at ambient temperature, concentration to dryness and taking up the residue in 200 ml of pentane at reflux for 30 minutes, the precipitate formed is filtered off. The organic phase is washed with a 1N hydrochloric acid solution and then with water, dried over magnesium sulphate and concentrated.
  • 35
  • [ 38222-83-2 ]
  • [ 267875-65-0 ]
  • [ 267875-66-1 ]
YieldReaction ConditionsOperation in experiment
With trifluoromethylsulfonic anhydride; In dichloromethane; pentane; 2,2-Difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate (I-1-4) To a stirred solution of 5 g (31.4 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol I-1-3 and 9.69 g (47.2 mmol) of 2,6-di-t-butyl-4-methylpyridine in 110 mL of methylene chloride at -78° C. under Ar was added 7.93 mL (47.2 mmol) of triflic anhydride dropwise. After 1 h, the reaction was diluted with 100 mL of pentane and filtered. The filtrate was concentrated and treated again with pentane and filtered. Concentration of the filtrate gave I-1-4 as a brown oil, contaminated with 2,6-di-t-butyl-4-methylpyridine: 1H NMR (CDCl3) delta5.12 (t, 2H), 7.45-7.5 (m, 1H), 7.75 (d,1H), 7.86-7.94 (m, 1H), 8.65 (d, 1H).
With trifluoromethylsulfonic anhydride; In dichloromethane; pentane; Step E 2,2-Difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate (5a) To a stirred solution of 5 g (31.4 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol 5 and 9.69 g (47.2 mmol) of 2,6-di-t-butyl-4-methylpyridine in 110 mL of methylene chloride at -78° C. under Ar was added 7.93 mL (47.2 mmol) of triflic anhydride dropwise. After 1 h, the reaction was diluted with 100 mL of pentane and filtered. The filtrate was concentrated and treated again with pentane and filtered. Concentration of the filtrate gave 5a as a brown oil, contaminated with 2,6-di-t-butyl-4-methylpyridine: 1H NMR (CDCl3) delta5.12 (t, 2H), 7.45-7.5 (m, 1H), 7.75 (d, 1H), 7.86-7.94 (m, 1H), 8.65 (d, 1H).
With trifluoromethylsulfonic anhydride; In dichloromethane; pentane; 2,2-Difluoro-2-(2-pyridyl)ethyl Trifluoromethanesulfonate (1-4). To a stirred solution of 5 g (31.4 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol 1-3 and 9.69 g (47.2 mmol) of 2,6-di-t-butyl-4-methylpyridine in 110 mL of methylene chloride at -78° C. under Ar was added 7.93 mL (47.2 mmol) of triflic anhydride dropwise. After 1 h, the reaction was diluted with 100 mL of pentane and filtered. The filtrate was concentrated and treated again with pentane and filtered. Concentration of the filtrate gave 1-4 as a brown oil, contaminated with 2,6-di-t-butyl-4-methylpyridine: 1H NMR (CDCl3) delta 5.12 (t, 2H), 7.45-7.5 (m, 1H), 7.75 (d, 1H), 7.86-7.94 (m, 1H), 8.65 (d, 1H).
  • 36
  • [ 38222-83-2 ]
  • [ 247568-68-9 ]
  • [ 420-37-1 ]
  • [ 247567-42-6 ]
YieldReaction ConditionsOperation in experiment
In 1,2-dichloro-ethane; EXAMPLE 64(3) To a solution of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide (200 mg) in 1,2-dichloroethane (10 mL) were added trimethyloxonium tetrafluoroborate (91.2 mg) and <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (158 mg), and the mixture was heated for 3 hours under reflux. The mixture was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluding with a mixture of hexane and ethyl acetate (3:1 to 1:1). The obtained product was triturated with diisopropyl ether to give (R)-N-(3,4-dimethoxybenzyl)-2-(2-methoxy-1-methylethylamino)-5-nitrobenzamide as yellow powders (145 mg). NMR (DMSO-d6, delta): 1.17 (3H, d, J=7 Hz), 3.29 (3H, s), 3.42 (2H, br), 3.73 (3H, s), 3.74 (3H, s), 3.88-4.00 (1H, br), 4.37 (2H, d, J=7 Hz), 6.85-6.96 (4H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.29 (1H, br); Mass m/z: 402(M+).
  • 37
  • [ 38222-83-2 ]
  • 4'-5' dibromomethylfluorescein di-t-butyldiphenylsilyl ether [ No CAS ]
  • 4',5'-Dinitrooxymethylfluorescein Di-t-butyldiphenylsilyl Ether [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With silver nitrate; In 1,4-dioxane; water; l) 4',5'-Dinitrooxymethylfluorescein Di-t-butyldiphenylsilyl Ether (Formula 28) Silver nitrate (20 mg, 0.12 mmol) was dissolved in a minimal portion of water (~1 mL) and added to a stirring solution of 4',5'-dibromomethylfluorescein di-t-butyldiphenylsilyl ether (Formula 27) (25 mg, 25 mumol) and 2,6-di-t-butyl-4-methylpyridine (10 mg, 49 mumol) in 5 mL of dioxane. The reaction mixture was stirred for 12 h at room temperature. The gray silver precipitate was removed by filtration and the solvents were removed. Flash chromatography (7:3 hexanes/EtOAc) yielded the product as a white solid (15 mg, 62percent). TLC Rf=0.56 (7:3 hexanes/EtOAc). 1H NMR (CDCl3) delta 111(18H, s), 6.06 (4H, s), 6.16 (2H, d, J=9.0 Hz), 6.35 (2H, d, J=9.0 Hz), 7.13 (1H, d, J=7.5 Hz), 7.33-7.60 (14H, m), 7.65-7.70 (8H, m), 7.85 (1H, d, J=7.5 Hz). FTIR (KBr, cm-1) 2957, 2931, 2859, 1764, 1633, 1607, 1575, 1491, 1472, 1428, 1392, 1363, 1276, 1228, 1109, 971, 942, 910, 858, 837, 823, 745, 701, 615, 546, 501, 440, 418.
  • 38
  • [ 38222-83-2 ]
  • 3-benzyloxy-estrone [ No CAS ]
  • 3-Benzyloxy-17-(trifluoromethanesulfonyl)estra-1,3,5(10),16-tetraene [ No CAS ]
YieldReaction ConditionsOperation in experiment
84.5% With trifluoromethylsulfonic anhydride; In dichloromethane; Synthesis of 3-Benzyloxy-17-(trifluoromethanesulfonyl)estra-1,3,5(10),16-tetraene (compound 3) To a solution of compound 2, comprising 4.8 g (13 mmol) of compound 2 in CH2Cl2 (70 ml) was added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (3 g, 14 mmol) and triflic anhydride (6 g, 27 mmol) at 0° C. The mixture was stirred for 5 hrs at room temperature and the mixture was filtered and the filtrate was washed with 10percent sodium bicarbonate solution. The solution was then dried (Na2SO4), filtered and evaporated and chromatographed (petroleum ether:ethyl acetate, 2:1) to give a yellowish solid (5.2 g, 84.5percent) (compound 3).
  • 39
  • [ 202648-54-2 ]
  • [ 38222-83-2 ]
  • [ 420-37-1 ]
  • [ 202648-55-3 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; PREPARATION 108 Methyl 2-O-Benzyl-3-O-p-methoxybenzyl-6-O-methyl-alpha-D-glucopyranoside (122) Compound 121 (26.4 g) is dissolved in dichloromethane (263 ml) under a nitrogen atmosphere. Trimethyloxonium tetrafluoroborate (11.6 g) and <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (17.4 g) are added at room temperature. After 4 hours, the mixture is poured onto ice-water and extracted with dichloromethane. The organic phase is washed with sodium hydrogen carbonate and concentrated. Purification of the crude product by chromatography on a column of silica gel allows 18.5 g of compound 122 to be obtained. TLC: Rf=0.25, silica gel, 7/3 v/v toluene/ethyl acetate
  • 40
  • [ 38222-83-2 ]
  • [ 267875-74-1 ]
  • [ 267875-75-2 ]
YieldReaction ConditionsOperation in experiment
With trifluoromethanesulfonic acid anhydride; In dichloromethane; pentane; Step C 3-Cyclopropyl-2,2-difluoropropyl trifluoromethanesulfonate To a 0° C. solution of 952 mg (7.0 mmol) of 3-cyclopropyl-2,2-difluoropropanol and 5.0 g (18 mmol) of 2,6-di-t-butyl-4-methylpyridine in 7 mL of CH2Cl2 was added 5.0 g of trifluoromethanesulfonic anhydride dropwise under Ar. The cold bath was removed and the mixture stirred overnight. The reaction mixture was diluted with 100 mL of pentane, and the precipitate removed by filtration. The filter cake was washed with pentane, and the filtrate washed with two portions of cold 1M HCl, brine, dried over Na2SO4 and the solvents removed at reduced pressure to give the title compound as an oil: 1H NMR (CDCl3) delta 4.62 (t, 2H, 11.4 Hz), 1.91 (td, 2H, 15.6, 7.1 Hz), 0.79-0.88 (m, 1H), 0.58-0.63 (m, 2H), 0.17-0.23 (m, 2H).
  • 41
  • [ 38222-83-2 ]
  • [ 32707-89-4 ]
  • [ 159707-06-9 ]
YieldReaction ConditionsOperation in experiment
With trifluoromethanesulfonic acid anhydride; In tetrachloromethane; Step A 3,5-Bis(trifluoromethyl)benzyl alcohol, trifluoromethane-sulfonate ester A solution of 1.00 g (4.1 mmole) of 3,5-bis(trifluoro-methyl)benzyl alcohol and 1.05 g (5.12 mmole) of 2,6-di-t-butyl-4-methylpyridine in 45 mL of dry carbon tetrachloride under a nitrogen atmosphere was treated with 0.74 mL (4.38 mmole) of trifluoromethanesulfonic anhydride at room temperature. A white precipitate formed shortly after the addition of the anhydride. After 90 min, the slurry was filtered under nitrogen with a Schlenk filter, and the filtrate was concentrated in vacuo. The residue, which was a two-phase oil, was dissolved under nitrogen in 10 mL of dry toluene. The resulting clear solution was used immediately in Step B below.
With trifluoromethanesulfonic acid anhydride; In tetrachloromethane; Step B 3,5-Bis(trifluoromethyl)benzyl alcohol, trifluoromethane-sulfonate ester A solution of 1.00 g (4.1 mmole) of 3,5-bis(trifluoromethyl)benzyl alcohol and 1.05 g (5.12 mmole) of 2,6-di-t-butyl-4- methylpyridine in 45 mL of dry carbon tetrachloride under a nitrogen atmosphere was treated with 0.74 mL (4.38 mmole) of trifluoromethanesulfonic anhydride at room temperature. A white precipitate formed shortly after the addition of the anhydride. After 90 min, the slurry was filtered under nitrogen with a Schlenk filter, and the filtrate was concentrated in vacuo. The residue, which was a two-phase oil, was dissolved under nitrogen in 10 mL of dry toluene. The resulting clear solution was used immediately in Step E below.
With trifluoromethanesulfonic acid anhydride; In tetrachloromethane; Step A 3,5-Bis(trifluoromethyl)benzyl alcohol, trifluoromethane-sulfonate ester A solution of 1.00 g (4.1 mmole) of 3,5-bis(trifluoromethyl)benzyl alcohol and 1.05 g (5.12 mmole) of 2,6-di-t-butyl-4-methylpyridine in 45 mL of dry carbon tetrachloride under a nitrogen atmosphere was treated with 0.74 mL (4.38 mmole) of trifluoromethanesulfonic anhydride at room temperature. A white precipitate formed shortly after the addition of the anhydride. After 90 min, the slurry was filtered under nitrogen with a Schlenk filter, and the filtrate was concentrated in vacuo. The residue, which was a two-phase oil, was dissolved under nitrogen in 10 mL of dry toluene. The resulting clear solution was used immediately in Step B below.
  • 42
  • [ 38222-83-2 ]
  • [ 217978-01-3 ]
  • [ 345963-90-8 ]
YieldReaction ConditionsOperation in experiment
85% With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6) A stirred, cooled (ice bath) solution of ethyl-2-fluoro-4-hydroxy-benzoate (Intermediate 5, 0.368 g, 2 mmol) and 2,6-di-tert-butyl-4-methyl-pyridine (0.81 g, 8 mmol) in 8 mL of dichloromethane was treated with trifluoromethanesulfonic anhydride (0.1 g, 4 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10percent ethyl acetate in hexane as the eluent to afford the title compound (0.53 g, 85percent). 1H-NMR (300 MHz, CDCl3): delta1.41 (t, J=7.3 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 7.12-7.20(m, 2H), 8.08(t, J=8.3 Hz, 1H).
85% With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6) A stirred, cooled (ice bath) solution of ethyl-2-fluoro-4-hydroxy-benzoate (Intermediate 5, 0.368 g, 2 mmol) and 2,6-di-tertbutyl-4-methyl-pyridine (0.81 g, 8 mmol) in 8 mL of dichloromethane was treated with trifluoromethanesulfonic anhydride (0.1 g, 4 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10percent ethyl acetate in hexane as the eluent to afford the title compound (0.53 g, 85percent). 1H-NMR (300 MHz, CDCl3): delta 1.41 (t, J=7.3 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 7.12-7.20(m, 2H), 8.08(t, J=8.3 Hz, 1H).
  • 43
  • [ 38222-83-2 ]
  • N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)-benzamide [ No CAS ]
  • N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In molecular sieve; xenon difluoride; dichloromethane; EXAMPLE 28 Compound C A solution of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (1 g; that is prepared as described in Example 20) in dichloromethane (100 mL), containing molecular sieve 4A, under nitrogen, is treated with <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (1.28 g). The resulting mixture is stirred at room temperature for 1.5 hours, and then it is cooled to 0° C. (in an ice/salt bath) and treated with xenon difluoride (0.51 g) in one portion. After stirring for a further 2 hours in the cold, the mixture is filtered, and the filtrate is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The resulting residue is subjected to flash chromatography, eluding with a mixture of ethyl acetate and pentane (2:3 v/v), to give impure N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)-benzamide (600 mg). It is further purified by reversed phase HPLC on octadecylsilyl silica gel, eluding with a mixture of methanol and water (7:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)benzamide (519 mg), in the form of a white solid, m.p. 111-113° C. Elemental analysis: C,51.50; H,4.12; N,6.74percent; calculated: C,52.05; H,4.12;[N,6.74percent].
In molecular sieve; xenon difluoride; dichloromethane; EXAMPLE 28 Compound CI A solution of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (1 g; that is prepared as described in Example 20) in dichloromethane (100 mL), containing molecular sieve 4A, under nitrogen, is treated with <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (1.28 g). The resulting mixture is stirred at room temperature for 1.5 hours, and then it is cooled to 0° C. (in an ice/salt bath) and treated with xenon difluoride (0.51 g) in one portion. After stirring for a further 2 hours in the cold, the mixture is filtered, and the filtrate is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The resulting residue is subjected to flash chromatography, eluding with a mixture of ethyl acetate and pentane (2:3 v/v), to give impure N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)-benzamide (600 mg). It is further purified by reversed phase HPLC on octadecylsilyl silica gel, eluding with a mixture of methanol and water (7:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)benzamide (519 mg), in the form of a white solid, m.p. 111°-113° C. Elemental analysis: C,51.50; H,4.12; N,6.74percent; calculated: C,52.05; H,4.12;[N,6.74percent].
  • 44
  • [ 38222-83-2 ]
  • [ 196398-40-0 ]
  • [ 76-83-5 ]
  • [ 144-55-8 ]
  • 2-{4-[(3-O-acetyl-4,6-O-benzylidene-1deoxy-2-O-(4-methoxybenzyl)-β-D-galactopyranosyl)thio]phenoxy}acetic acid [ No CAS ]
  • [ 196398-47-7 ]
YieldReaction ConditionsOperation in experiment
171 mg (81%) With silver trifluoromethanesulfonate; In dichloromethane; 7.30. 2-{4-[(3-O-acetyl-4,6-O-benzylidene-1deoxy-2-O-(4-methoxybenzyl)-beta-D-galactopyranosyl)thio]phenoxy}acetic acid (95) To a solution of 81, prepared as above (139 mg, 0.303 mmol) and 2,6-di-t-butyl-4-methyl pyridine (187 mg, 0.91 mmol) in 5 mL CH2 Cl2, are added chlorotriphenylmethane (101 mg, 0.364 mmol) and silver trifluoromethanesulfonate (78 mg, 0.30 mmol). The reaction mixture is stirred at room temperature for 45 min and then is filtered though celite and washed with 10 mL of aqueous NaHCO3. The aqueous solution is extracted with CH2 Cl2 (2*10 mL) and the organic layers are combined and dried over Na2 SO4, filtered and concentrated. The product is purified by flash chromatography (25percent EtOAc/hexane) to give 171 mg (81percent) of 1-deoxy-3,4-O-isopropylidene-1-{4-[2-(trimethylsilyl)ethoxymethoxy]phenylthio}-6-O-triphenylmethyl-beta-D-galactopyranose 89 as white solid: Rf 0.2 (25percent EtOAc/hexane); 1 H NMR (CDCl3, 300 MHz) delta 7.53-7.40 (m, 8H), 7.31-7.21 (m, 9H), 6.95 (d, J=8.5 Hz, 2H), 5.19 (s, 2H), 4.29 (d, J=10.2 Hz, 1H, H-1), 4.14 (dd, J=5.6, 2.0 Hz, 1H, H-4), 4.02 (dd, J=6.9, 5.6 Hz, 1H, H-3), 3.73 (m, 3H), 3.56 (dd, J=9.6, 6.9 Hz, 1H, H-6), 3.48 (ddd, J=8.9, 6.9, 2.0 Hz, 1H, H-2), 3.36 (dd, J=9.6, 5.3 Hz, 1H, H-6), 2.37 (d, J=2.0 Hz, 1H, OH), 1.37 (s,3H), 1.31 (s, 3H), 0.96 (t, J=7.2 Hz, 2H), 0.00 (s, 9H)
  • 45
  • [ 38222-83-2 ]
  • 1,2-O-Isopropylidene-3-deoxy-3-azido-D-xylofuranose [ No CAS ]
  • 1,2-O-Isopropylidene-3-deoxy-3-azido-5-trifluoromethanesulfonyloxy-D-xylofuranose [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With trifluoromethylsulfonic anhydride; In (CH2 Cl)2; hexane; 1,2-O-Isopropylidene-3-deoxy-3-azido-5-trifluoromethanesulfonyloxy-D-xylofuranose (14). 4-Methyl-2,6-di-t-butylpyridine (1.28 g, 6.3 mmol) was dissolved in 10 mL of dry (CH2 Cl)2 under N2 and then cooled to -78° C. Triflic anhydride (1.05 ml, 6.3 mmol) was added to the solution which was then stirred for 5 minutes. A solution of 13 (1.12 g, 5.2 mmol) in 12 mL of dry (CH2 Cl)2 was added to the triflate solution which was then stirred at -10° C. for 30 minutes. The reaction was warmed to rt, 10 mL of hexane was added, and the solution loaded onto a silica gel column. Elution with 3:7 hexane/CHCl3 afforded triflate 14 (1.41 g, 78percent). FAB HRMS exact mass calcd. for MH+C9 H13 SN3 F3 O6 requires 348.0477, found 348.0477.
  • 46
  • [ 38222-83-2 ]
  • [ 108-95-2 ]
  • 7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-(phenoxymethyl)-1H-1,4-benzodiazepine [ No CAS ]
YieldReaction ConditionsOperation in experiment
30 mg (49%) With trifluoromethylsulfonic anhydride; In tetrahydrofuran; dichloromethane; mineral oil; D. 7-Bromo-2,3,4,5-tetrahydro-4-(methylsulfonyl)-3-(phenoxymethyl)-1H-1,4-benzodiazepine To a solution of Compound C (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (62 mg, 0.30 mmol). The solution was cooled to -40° C. under N2. Triflic anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred under N2 for 1 h at -40° C. In a separate flask, phenol (100 mg, 1.1 mmol) was added to a solution of sodium hydride (44 mg, 1.1 mmol, 60percent dispersion in mineral oil, prewashed with hexanes) in THF (2.5 mL). The solution was stirred for 20 min at ambient temperature under N2 and was added quickly to the triflate solution. After stirring for 20 minutes, the solution was diluted with methylene chloride (40 mL) and washed with saturated aq sodium bicarbonate solution. The organic layer was dried (Na2SO4), filtered and concentrated to give a solid. This material was chromatographed on flash silica eluding with 1:1 ethyl acetate:hexanes to afford 30 mg (49percent) of Compound D as an off-white solid. MS (M+H)+ 411.
  • 47
  • [ 38222-83-2 ]
  • [ 204716-63-2 ]
  • [ 7143-01-3 ]
  • [ 204716-67-6 ]
YieldReaction ConditionsOperation in experiment
In methanol; dichloromethane; b 3-[1-(3-Methanesulfonyloxymethylbenzyl)-indol-3-yl]-4-(1-methyl-indol-3-yl)-pyrrole-2,5-dione Methanesulfonic anhydride (0.35 g, 2.0 mmol) was added to a stirred solution of the product of step a) (0.234 g, 0.51 mmol) and <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (0.42 g, 2.0 mmol) in dry CH2 Cl2 (15 mL) at room temperature. The reaction mixture was stirred for 16 h, and thereafter quenched by adding methanol (1.5 mL). The solvent was evaporated and the crude product chromatographed (ethyl acetate/heptane: 2/1) to yield 0.285 g of the sub-title product. 1 H-NMR (CDCl3):delta7.76 (1H, s); 7.66 (1H, s); 7.58 (1H, s); 7.38-7.24 (3H, m); 7.22-7.00 (6H, m); 6.82 (1H, d, J=8.05 Hz); 6.77 (1H, t, J=8.30 Hz); 6.68 (1H, t, J=8.05 Hz); 5.34 (2H, s); 5.18 (2H, s); 3.86 (3H, s); 2.83 (3H, s).
  • 48
  • [ 38222-83-2 ]
  • trifluoromethane sulfonic anhydride [ No CAS ]
  • [ 60-29-7 ]
  • [ 302-97-6 ]
  • 3-(Trifluoromethanesulfonyloxy)-3,5-androstadiene-17β-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; formic acid; In tetrahydrofuran; dichloromethane; water; Step A (Route 1) A solution of 3-oxo-4-androstene-17beta-carboxylic acid (4.0 g., 12.5 mmoles), 2,6-di-tert-butyl-4-methyl pyridine (8.304 g., 31 mmoles) and trifluoromethane sulfonic anhydride (9.28 g., 33 mmoles) in 40 ml of methylene chloride was stirred at 22° C. for 2 hours and then was kept at 5° C. for 16 hours. The organic solvent was evaporated and the residue was dissolved in 200 ml of tetrahydrofuran containing 1.0 ml of water and 4.5 g. of 4-dimethylaminopyridine. This mixture was stirred at 22° C. for 20 hours and then acidified with 2N hydrochloric acid. The organic solvent was removed and the residue dissolved in methylene chloride, was applied to a column of 400 g. of silica gel. Elution with a 9:1 mixture of CH2 Cl2: ethyl ether, containing 0.4percent of formic acid (88percent) afforded 6.2 g. of pure product. A portion triturated with acetonitrile gave an analytical sample, m.p. 140°-150° C. with decomposition. Calcd.: C, 56.24; H, 6.07. Found: C, 56.71; H, 6.20.
  • 49
  • [ 38222-83-2 ]
  • trifluoromethane sulfonic anhydride [ No CAS ]
  • [ 6650-44-8 ]
  • 17β-benzoyl-3-trifluoromethanesulfonyloxy-3,5-androstadiene [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; cyclohexane; Step A (Route 3) To a solution of 1.3 g. (3.46 mmoles) of the diketosteroid from Example 9 and 9.92 mg. (4.83 mmoles) of <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> in 15 ml. of methylene chloride was added at 0° C., 1.46 g. of trifluoromethane sulfonic anhydride. The reaction at 24° C. colored and darkened, and a precipitate formed. After 30 minutes, the reaction was diluted with methylene chloride and filtered. The filtrate was quickly washed successively with 5N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The residue obtained on evaporation was chromatographed on 100 g. of silica gel with 9:1 cyclohexane/ethyl acetate to remove a faster moving impurity. Continued elution gave the title compound, 1.21 g., identified by its mass and nmr spectra. This material was used directly in the next Example.
  • 50
  • [ 38222-83-2 ]
  • N-(2-adamantyl)-3-oxo-4-androstene-17β-carboxamide [ No CAS ]
  • trifluoromethane sulfonic anhydride [ No CAS ]
  • N-(2-Adamantyl)-3-(trifluoromethanesulfonyloxy)-3,5-androstadiene-17β-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; acetone; Step A (Route 3) A soluton of the adamantyl amide from Example 24 (350 mg., 0.73 mmole), <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (211 mg., 1.03 mmole) and trifluoromethane sulfonic anhydride (416 mg., 1.48 mmole) in 5 ml. of methylene chloride was prepared at 0° C. The mixture warmed to room temperature and was kept at 24° C. for 2.5 hours. Additional methylene chloride was added and the solution was washed successively with dilute hydrochloric acid, dilute sodium bicarbonate solution and water. The residue obtained on concentration was eluted on 3-2000mu silica gel plates with 5percent acetone in methylene chloride. Starting material and the title compound were isolated. The latter, 376 mg., was identified by its nmr and mass spectra.
In dichloromethane; acetone; Step A (Route 3) A solution of the adamantyl amide from Example 24 (350 mg., 0.73 mmole), <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (211 mg., 1.03 mmole) and trifluoromethane sulfonic anhydride (416 mg., 1.48 mmole) in 5 ml. of methylene chloride was prepared at 0° C. The mixture warmed to room temperature and was kept at 24° C. for 2.5 hours. Additional methylene chloride was added and the solution was washed successively with dilute hydrochloric acid, dilute sodium bicarbonate solution and water. The residue obtained on concentration was eluted on 3-2000mu silica gel plates with 5percent acetone in methylene chloride. Starting material and the title compound were isolated. The latter, 376 mg., was identified by its nmr and mass spectra.
In dichloromethane; acetone; Step A (Route 3) A solution of the adamantyl amide from Example 24 (350 mg., 0.73 mmole), 2,6di-tert-butyl-4-methylpyridine (211 mg., 1.03 mmole) and trifluoromethane sulfonic anhydride (416 mg., 1.48 mmole) in 5 ml. of methylene chloride was prepared at 0° C. The mixture warmed to room temperature and was kept at 24° C. for 2.5 hours. Additional methylene chloride was added and the solution was washed successively with dilute hydrochloric acid, dilute sodium bicarbonate solution and water. The residue obtained on concentration was eluted on 3-2000mu silica gel plates with 5percent acetone in methylene chloride. Starting material and the title compound were isolated. The latter, 376 mg., was identified by its nmr and mass spectra.
  • 51
  • [ 38222-83-2 ]
  • 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol [ No CAS ]
  • ammonium chloride [ No CAS ]
  • [ 149831-83-4 ]
  • 1,2-cyclohexylidene-3-O-(5-phthalimidopentyl)-4,5,6-tri-O-benzyl-inositol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; B. 1,2-Cyclohexylidene-3-O-(5-phthalimidopentyl)-4,5,6-tri-O-benzyl-inositol(16). To a solution of 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol (9) (10.1 mmol) in dry dichloromethane (100 mL) is added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (2.3 g, 11.1 mmol) and a solution of 5-phthalimido-1-pentyl triflate (15) (10.1 mmol) in dry dichloromethane (100 mL) at 0° C. To the resulting mixture is added sodium hydride (2.0 g, 50.5 mmol) and the reaction is stirred at room temperature for 24 h. The reaction is quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography to afford 1,2-cyclohexylidene-3-O-(5-phthalimidopentyl)-4,5,6-tri-O-benzyl-inositol (16).
  • 52
  • [ 38222-83-2 ]
  • 7-phthalimido-1-heptyl triflate [ No CAS ]
  • 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol [ No CAS ]
  • ammonium chloride [ No CAS ]
  • 1,2-cyclohexylidene-3-O-(7-phthalimidoheptyl)-4,5,6-tri-O-benzyl-inositol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; B. 1,2-Cyclohexylidene-3-O-(7-phthalimidoheptyl) -4,5,6-tri-O-benzyl-inositol (21). To a solution of 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol (9) (10.1 mmol) in dry dichloromethane (100 mL) is added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (2.3 g, 11.1 mmol) and a solution of 7-phthalimido-1-heptyl triflate (20) (10.1 mmol) in dry dichloromethane (100 mL) at 0° C. To the resulting mixture is added sodium hydride (2.0 g, 50.5 mmol) and the reaction is stirred at room temperature for 24 h. The reaction is quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography to afford 1,2-cyclohexylidene-3-O-(7-phthalimidoheptyl)-4,5,6-tri-O-benzyl-inositol (21).
  • 53
  • [ 38222-83-2 ]
  • 6-acetamido-1-hexyltriflate [ No CAS ]
  • 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol [ No CAS ]
  • ammonium chloride [ No CAS ]
  • 1,2-cyclohexylidene-3-O-(6-acetamidohexyl)-4,5,6-tri-O-benzyl-inositol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; B. 1,2-Cyclohexylidene-3-O-(6-acetamidohexyl)-4,5,6-tri-O-benzyl-inositol (26). To a solution of 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol (9) (10.1 mmol) in dry dichloromethane (100 mL) is added <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> (2.3 g, 11.1 mmol) and a solution of 6-acetamido-1-hexyltriflate (25) (10.1 mmol) in dry dichloromethane (100 mL) at 0° C. To the resulting mixture is added sodium hydride (2.0 g, 50.5 mmol) and the reaction is stirred at room temperature for 24 h. The reaction is quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography to afford 1,2-cyclohexylidene-3-O-(6-acetamidohexyl)-4,5,6-tri-O-benzyl-inositol (26).
  • 54
  • [ 38222-83-2 ]
  • 5-acetamido-1-pentyl triflate [ No CAS ]
  • 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol [ No CAS ]
  • ammonium chloride [ No CAS ]
  • 1,2-cyclohexylidene-3-O-(5-acetamidopentyl)-4,5,6-tri-O-benzyl-inositol [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; B. 1,2-Cyclohexylidene-3-O-(5-acetamidopentyl)-4,5,6-tri-O-benzyl-inositol (31). To a solution of 1,2-cyclohexylidene-4,5,6-tri-O-benzyl-inositol (9) (10.1 mmol) in dry dichloromethane (100 mL) is added 2,6 -di-tert-butyl-4 -methylpyridine (2.3 g, 11.1 mmol) and a solution of 5-acetamido-1-pentyl triflate (30) (10.1 mmol) in dry dichloromethane (100 mL) at° C. To the resulting mixture is added sodium hydride (2.0 g, 50.5 mmol) and the reaction is stirred at room temperature for 24 h. The reaction is quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography to afford 1,2-cyclohexylidene-3-O-(5-acetamidopentyl)-4,5,6-tri-O-benzyl-inositol (31).
 

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Technical Information

Categories

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[ 38222-83-2 ]

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