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Chemical Structure| 262587-05-3 Chemical Structure| 262587-05-3

Structure of 262587-05-3

Chemical Structure| 262587-05-3

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Product Details of [ 262587-05-3 ]

CAS No. :262587-05-3
Formula : C7H5BrF2O
M.W : 223.02
SMILES Code : FC(F)OC1=CC(Br)=CC=C1
MDL No. :MFCD00236233
Boiling Point : No data available
InChI Key :NWBDGKNKAFGQQL-UHFFFAOYSA-N
Pubchem ID :2737006

Safety of [ 262587-05-3 ]

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

Computational Chemistry of [ 262587-05-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 2
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 40.74
TPSA ?

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

9.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.17
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

3.98
Log Po/w (WLOGP)?

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

3.89
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.

2.88
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

2.91
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.17

Water Solubility

Log S (ESOL):?

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

-4.0
Solubility 0.0222 mg/ml ; 0.0000996 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.

-3.88
Solubility 0.0297 mg/ml ; 0.000133 mol/l
Class?

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

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

-3.6
Solubility 0.0555 mg/ml ; 0.000249 mol/l
Class?

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

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

Yes
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

No
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.

-4.83 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)

1.65

Application In Synthesis of [ 262587-05-3 ]

* 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 [ 262587-05-3 ]

[ 262587-05-3 ] Synthesis Path-Downstream   1~32

  • 1
  • [ 262587-05-3 ]
  • {4-[4-benzyloxy-3-(4,5-dimethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-3,5-dichloro-phenyl}-acetic acid methyl ester [ No CAS ]
  • [4-(6-benzyloxy-3'-difluoromethoxy-biphenyl-3-yloxy)-3,5-dichloro-phenyl]-acetic acid methyl ester [ No CAS ]
  • 2
  • [ 57260-71-6 ]
  • [ 262587-05-3 ]
  • [ 756752-48-4 ]
YieldReaction ConditionsOperation in experiment
palladium diacetate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; for 16h;Heating / reflux; A mixture of commercially available 1-boc piperazine (500.1 mg, 2.685 mmol) and commercially available <strong>[262587-05-3]3-difluoromethoxybromobenzene</strong> (598.8 mg, 2.685 mmol) in toluene (20 ml) is placed in a 50 ml three-necked round-bottomed flask made inert with argon, and then the ligand (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (56.850 mg, 91.2 mumol) and palladium(II)acetate (20.4 mg, 91.2 mumol) are added. The reaction mixture is stirred and brought to reflux for 16 hours. After returning to 20 C., the reaction mixture is diluted with water (20 ml) and then extracted with ethyl acetate (2*30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, Ref. FC-25 Si-BP-SUP, 20-40 mum, eluent dichloromethane, flow rate 20 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure. The expected tert-butyl 4-(3-difluoromethoxyphenyl)piperazin-1-ylcarboxylate is isolated (253 mg), the characteristics of which are as follows: LC/MS analysis: tr=4.18 min, M+H+ 329.31
palladium diacetate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; for 16h;Heating / reflux; Step1: A mixture of 500.1 mg of 1-boc piperazine and 598.8 mg of commercial <strong>[262587-05-3]3-difluoromethoxybromobenzene</strong> is placed in 20 ml of toluene in a 50 ml three-necked flask under an inert atmosphere of argon, followed by addition of 56.85 mg of (R)(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 20.4 mg of palladium(II) acetate. The reaction mixture is stirred at reflux for 16 hours. After cooling to 20 C., the reaction mixture is diluted with water (20 ml) and then extracted with ethyl acetate (2×30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, ref. FC-25 Si-BP-SUP, 20-40 mum, dichloromethane eluent, flow rate of 20 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure. 253 mg of tert-butyl 4-(3-difluoromethoxyphenyl)piperazine-1-carboxylate are thus isolated, the characteristics of which are as follows: LC/MS: RT=4.18 min, M+H+ 329.31 (Micromass machine, LCT model, connected to an HP 1100 machine, HP G1315A diode array detector (200-600 nm), Sedex 65 light-scattering detector; data analyzed with the Micromass MassLynx software; separation on a Hypersil BDS C18, 3 mum (50×4.6 mm) column, eluting with a linear gradient of from 5% to 90% of acetonitrile containing 0.05% (v/v) of trifluoroacetic acid (TFA) in water containing 0.05% (v/v) TFA, over 3.5 minutes at a flow rate of 1 ml/min).
  • 3
  • [ 591-20-8 ]
  • [ 1895-39-2 ]
  • [ 262587-05-3 ]
YieldReaction ConditionsOperation in experiment
61% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; Intermediates T18A and T18BT18.1 [0412] l-Bromo-3-(difluoromethoxy)benzene (T18.1). To a solution of 3- bromophenol (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (commercially available from Sigma-Aldrich, St. Louis, MO, USA) (2.82 g, 18.49 mmol) and Cs2CO3 (4.82 g, 14.79 mmol). The reaction mixture was heated at 100C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re- extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T18.1 as an oil that was used without further purification (yield 61%).
61% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; l-Bromo-3-(difluoromethoxy)benzene (T7.1). To a solution of 3- bromophenol (available from Sigma Aldrich) (1.28 g, 7.39 mmol) in DMF (12.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (available from Sigma Aldrich )(2.82 g, 18.49 mmol) and cesium carbonate (4.82 g, 14.79 mmol). The reaction mixture was heated at 100C. Gas was released from the reaction so care should be taken. After 2 hours, the reaction was cooled to room temperature then diluted with EtOAc, washed with water and then brine and re-extracted three times with EtOAc. The combined organic layers were dried over magnesium sulfate and then filtered, concentrated, and purified with silica gel chromatography (0-5% EtOAc in hexanes) to yield T7.1 as an oil that was used without further purification (yield 61%).
  • 4
  • [ 73183-34-3 ]
  • [ 262587-05-3 ]
  • [ 1035690-56-2 ]
YieldReaction ConditionsOperation in experiment
34% With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 21h;Inert atmosphere; 2-(3-(Difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (T18.2). A stirred mixture of T18.1 (1.00 g, 4.50 mmol), bis(pinacolato)diboron (1.26 g, 4.95 mmol), potassium acetate (1.34 g, 13.70 mmol), and dichloro[l,l'-bis(diphenylphosphino)ferrocene]dichloride palladium(II) DCM adduct (0.17 g, 0.23 mmol) in dry 1,4-dioxane (10.0 mL)was purged three times with argon and placed under vacuum three times. The mixture was heated to 100C and monitored with LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then filtered through Celite filter aid. The organic solvent was removed under reduced pressure, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield T18.2 as a colorless oil (0.41 g, 34%). 1H NMR (400 MHz, CDCl3) delta ppm 7.67 (1 H, d, J=7.4 Hz), 7.56 (1 H, d, J=2.3 Hz), 7.41 (1 H, m), 7.22 (1 H, dd, J=7.8, 2.3 Hz), 6.73 (1H, t, J= 74 Hz), 1.36 (12 H, s).
34% With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 21h;Inert atmosphere; 2-(3-(Difluoromethoxy)phenyl)-4,4,5,5-tetramethyI-1,3,2- dioxaborolane (T7.2). A stirred mixture of T7.1 (1.00 g, 4.50 mmol), bis(pinacolato)diboron (1.26 g, 4.95 mmol), potassium acetate (1.34 g, 13.70 mmol), and dichloro[l,r-bis(diphenylphosphino)ferrocene]dichloride palladium(II) DCM adduct (0.17 g, 0.23 mmol) in dry 1,4-dioxane (10.0 mL)was purged three times with argon and placed under vacuum three times. The mixture was heated to 100C and monitored with LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then filtered through Celite filter aid. The organic solvent was removed under reduced pressure, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield T7.2 as a colorless oil (0.41 g, 34%). 1H NMR (400 MHz, CDCl3) delta ppm 7.67 (1 H, d, J=7.4 Hz), 7.56 (1 H, d, J=2.3 Hz), 7.41 (1 H, m), 7.22 (1 H, dd, J=7.8, 2.3 Hz), 6.73 (1H, t, J= 74 Hz), 1.36 (12 H, s).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90℃; for 21h;Inert atmosphere; A stirred mixture of l-bromo-3-(difluoromethoxy)benzene (0.56 mL, 4 mmol), bis(pinacolato)diboron (1.21 g, 4.8 mmol), l,l'-bis(diphenylphosphino)ferrocene- palladium dichloride (0.32 g, 0.4 mmol), and potassium acetate (1.18 g, 12 mmol) in dry 1,4-dioxane (10.0 mL) was purged three times with argon and placed under vacuum three times. The mixture was heated to 90 C and monitored with LC- MS and TLC. After 21 h, the reactions were cooled to rt then filtered through celite. The organic solvent was removed under reduced pressure, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield a yellow liquid as 2- (3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane. 1H NMR (400 MHz, CDC13) delta ppm 7.66 (1 H, d, J=7.2 Hz), 7.54 (1 H, d, J=2.3 Hz), 7.38(1 H, t, J=7.7 Hz), 7.25 (1 H, m), 6.54 (1 H, t), 1.36 (12 H, s).
  • 5
  • [ 262587-05-3 ]
  • [ 1354286-44-4 ]
  • 6
  • [ 262587-05-3 ]
  • [ 1361046-27-6 ]
  • 7
  • [ 262587-05-3 ]
  • [ 1361044-69-0 ]
  • 8
  • [ 38405-48-0 ]
  • [ 262587-05-3 ]
  • [ 1361046-19-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydride;copper; copper(l) chloride; In N,N-dimethyl-formamide; at 0 - 150℃; for 1h; EXAMPLE 1; Preparation of 2-nitro-5- (3-difluoromethoxyphenylthio) - p-xylene [nitroderivative of formula (III) ]; 4.36 g (0.109 moles) of sodium hydride are sus¬ pended in 80 ml of N, N-dimethylformamide at 0C. 20 g of 4-nitro-2 , 5-dimethylthiophenol (0.109 moles) dis¬ solved in 67 ml of N, N-dimethylformamide are added dropwise under stirring. 24.4 g of l-bromo-3- (difluoromethoxy) benzene (0.109 moles) dissolved in 20 ml of N, N-dimethylformamide are then added dropwise; catalytic Cu and CuCl are subsequently added and the reaction temperature is brought to 150 C for 1 h.After GC control, the reaction mixture is cooled to room temperature, filtered on a celite bed, diluted with water and extracted with ethyl acetate. The or¬ ganic phase is anhydrified with sodium sulfate, and then filtered and evaporated.The product thus obtained is purified on silica gel eluting with hexane/ethyl acetate 9:1. 30 g of the desired product are obtained. GC-MS : M+ = 325
30 g With copper; sodium hydride; copper(l) chloride; In N,N-dimethyl-formamide; mineral oil; at 0 - 150℃; for 1h; EXAMPLE 1 Preparation of 2-nitro-5-(3-difluoromethoxyphenylthio)-p-xylene [nitroderivative of formula (III)] 4.36 g (0.109 moles) of sodium hydride are suspended in 80 ml of N,N-dimethylformamide at 0 C. 20 g of 4-nitro-2,5-dimethylthiophenol (0.109 moles) dissolved in 67 ml of N,N-dimethylformamide are added dropwise under stirring. 24.4 g of <strong>[262587-05-3]1-bromo-3-(difluoromethoxy)benzene</strong> (0.109 moles) dissolved in 20 ml of N,N-dimethylformamide are then added dropwise; catalytic Cu and CuCl are subsequently added and the reaction temperature is brought to 150 C. for 1 h. After GC control, the reaction mixture is cooled to room temperature, filtered on a celite bed, diluted with water and extracted with ethyl acetate. The organic phase is anhydrified with sodium sulfate, and then filtered and evaporated. The product thus obtained is purified on silica gel eluting with hexane/ethyl acetate 9:1. 30 g of the desired product are obtained. GC-MS: M+=325
  • 12
  • [ 321745-86-2 ]
  • [ 262587-05-3 ]
  • [ 1439400-61-9 ]
YieldReaction ConditionsOperation in experiment
With bis(tri-t-butylphosphine)palladium (0); In 1,4-dioxane; diethyl ether; at 20℃;Inert atmosphere; General procedure: To a mixture of l-bromo-3-(difluoromethoxy) benzene (1 g, 4.5 mmol), bis(tri-tert- butylphosphine) palladium(O) (460 mg, 0.9 mmol) in 1,4-dioxane (30 ml) under argon atmosphere was added 0.5 M of 2-tert-butoxy-2-oxoethyl zinc chloride in ether (22.5 ml). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between saturated NH4C1 and EtOAc. The organic extract was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% EtOAc in Hexane to afford 1119.
  • 13
  • [ 262587-05-3 ]
  • [ 262587-06-4 ]
  • 14
  • [ 262587-05-3 ]
  • [ 1439399-52-6 ]
  • 15
  • [ 262587-05-3 ]
  • [ 1439399-54-8 ]
  • 16
  • [ 73183-34-3 ]
  • [ 262587-05-3 ]
  • 2-[3-bromo-5-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tetrahydrofuran; at 80℃; for 14h;Inert atmosphere; To a stirred solution of <strong>[262587-05-3]1-bromo-3-(difluoromethoxy)benzene</strong> (1000.00 mg, 4.48 mmol, 1.00 equiv) in tetrahydrofuran (1.5 mL) was added4,4,5,5-tetramethyl-2- (tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1,3 ,2-dioxaborolane (797.06 mg,3.14 mmol, 0.70 equiv) , 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (24.07 mg, 0.09 mmol,0.02 equiv) and bis(( 1Z,5Z)-cycloocta- 1 ,5-diene)dimethyl-2,4-dioxa- 1 ,3-diiridabicyclo[ 1.1 .0]butane-2,4-diium- 1 ,3-diuide (30 mg, 0.05 mmol,0.01 equiv) under nitrogen. The resulting solution was stuffed for 14 hours at 80 C, diluted with ethyl acetate, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to give 703 mg (45%) of the title compound as a yellow oil.
  • 17
  • [ 73183-34-3 ]
  • [ 262587-05-3 ]
  • [ 866607-09-2 ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; water; potassium acetate; In 1,4-dioxane; at 100℃; for 17h;Inert atmosphere; [1603j KOAc (26.4 g, 269 mmol), bisQ,inacolato)diboron (30 g, 116 mmol), 3- (difluoromethoxy)bromobenzene (20 g, 90 mmol) and PdC12(dppf) (7.3 g, 9 mmol) were suspended in dry 1,4- dioxane (280 ml) and heated at 100 C under N2 for 17 h. After cooling to room temperature, the mixture was diluted with EtOAc (600 mL) and water (200 mL). The mixture was then filtered via Celite, and washed with EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was used for the next step without further purification.
  • 18
  • [ 262587-05-3 ]
  • 6-(2-(3-(difluoromethoxy)phenyl)pyridin-3-yl)-4-methoxyquinazoline [ No CAS ]
  • 19
  • [ 262587-05-3 ]
  • 6-(2-(3-(difluoromethoxy)phenyl)pyridin-3-yl)quinazolin-4(3H)-one [ No CAS ]
  • 20
  • [ 262587-05-3 ]
  • C20H12ClF2N3O [ No CAS ]
  • 21
  • [ 262587-05-3 ]
  • 6-(2-(3-(difluoromethoxy)phenyl)pyridin-3-yl)quinazolin-4-amine [ No CAS ]
  • 22
  • [ 177-11-7 ]
  • [ 262587-05-3 ]
  • 8-[3-(difluoromethoxy)phenyl]-1,4-dioxa-8-azaspiro[4.5]decane [ No CAS ]
YieldReaction ConditionsOperation in experiment
450 mg With sodium t-butanolate; In 1,4-dioxane; at 100℃;Inert atmosphere; To a flask containing <strong>[262587-05-3]1-bromo-3-(difluoromethoxy)benzene</strong> (350 mg, 1.58 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (249 mg, 1.74 mmol) in dioxane (10 mL) was added t-BuONa (303mg, 3.16 mmol), under N2 After being heated with stuffing at 100 C overnight, the resulting reaction mixture was cooled to rt, diluted with H20 (30 mL) and extracted with EA (30 mL) for three times. The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give 8-[3-(difluoromethoxy)phenyl]-1,4-dioxa-8-azaspiro[4.5]decane (450 mg), which was used in the next step without further purification.
  • 23
  • [ 262587-05-3 ]
  • 1-[3-(difluoromethoxy)phenyl]piperidin-4-one [ No CAS ]
  • 24
  • [ 262587-05-3 ]
  • 6-[3-(difluoromethoxy)phenyl]-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
  • 25
  • methyl 1-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)phenyl]azetidine-3-carboxylate [ No CAS ]
  • [ 262587-05-3 ]
  • methyl 1-[3-[3-(difluoromethoxy)phenyl]-5-methylphenyl]azetidine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; cesium fluoride; In 1,2-dimethoxyethane; at 120℃; for 1h;Microwave irradiation; 93 mg of 1 -bromo-3(dofluoromethoxy)benzene (0.42 mmol; 1.00 eq) and the successively 142 mg of 1 -[3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]azetidine-3-carboxylic acid (preparation 9; 0.42 mmol; 1.00 eq) dissolved in 4 mE of DME, 3.4 mg of Pd(dppf)C12, CH2C12 (0.01 eq.) and finally 127 mg of CsF (0.83 nnol; 2.00 eq) were introduced into a microwave- resistant 10 mE reaction vessel. The reaction mixture was microwave-irradiated for 1 h at 120 C. The reaction medium was then taken up with ethyl acetate and water, while adjusting the pH to 6, and then extracted with ethyl acetate and washed with brine. The organic phase was dried over magnesium suflate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (l3iotage 10 g silica 15-40 jtmlliquid deposit in dichloromethane) using a cyclohexane/0% to 100% dichloromethane gradient. The fractions containing the targeted product were combined and then evaporated, under reduced, pressure to give 99 mg of title compound in the form of a colorless oil,Yld: 33%.10548] ?H NMR (300 MHz, CHC13-d) oeppm 2.24 (s, 3H)3.41-3.49 (m, 1H) 3.62 (s, 3H) 3.92-4.02 (m, 4H) 6.18 (s, 1H) 6.32 (s, 1H) 6.43 (t, J=74 Hz, 1H) 6.68 (s, 1H) 6.93-6.96 (m, 1H) 7.19-7.3 1 (m, 3H).EC-MS mlz (M+H): 348.
  • 26
  • methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate [ No CAS ]
  • [ 262587-05-3 ]
  • methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In toluene; at 70℃;Inert atmosphere; A nitrogen-purged mixture of tris(dibenzylideneacetone)dipalladium(0) (0.0193 g, 0.021 mmol), and di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine (0.0251 g, 0.052 mmol) in toluene (2.2 mL) was stirred for 20 minutes and then added to an nitrogen-purged mixture of methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (0.1760 g, 0.441 mmol, E509), <strong>[262587-05-3]1-bromo-3-(difluoromethoxy)benzene</strong> (0.1179 g, 0.529 mmol), and Cs2CO3 (0.2143 g, 0.658 mmol). The mixture was heated to 70 C overnight, diluted with water, extracted with DCM (3 x 8 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica (30-60% EtOAc/DCM to 4% MeOH/DCM) and re-chromatographed (2.5-4% zPrOH/DCM) to give the titled compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.28 - 8.16 (m, 2H), 7.58 (t, J = 8.2 Hz, 1H), 7.51 - 7.03 (m, 3H), 3.95 (dq, J = 18.1, 9.8, 8.5 Hz, 1H), 3.88 (s, 3H), 3.63 - 3.48 (m, 6H), 2.91 (t, J = 11.9 Hz, 2H), 2.53 - 2.48 (m, 4H), 2.46 - 2.28 (m, 2H), 2.12 - 1.88 (m, 4H), 1.63 (td, J = 13.1, 12.6, 6.4 Hz, 2H).
With tris-(dibenzylideneacetone)dipalladium(0); bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; In toluene; at 70℃; General procedure: A nitrogen-purged mixture of tris(dibenzylideneacetone)dipalladium(O) (0.0193 g, 0.021 mmol), and di-tert-butyl(2?,4?,6?-triisopropyl-3,4,5,6-tetramethyl-[1,1?-biphenyl]-2-yl)phosphine (0.0251 g, 0.052 mmol) in toluene (2.2 mL) was stirred for 20 minutes and then added to an nitrogen-purged mixture of methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (0.1760 g, 0.441 mmol, E509), <strong>[262587-05-3]1-bromo-3-(difluoromethoxy)benzene</strong> (0.1179 g, 0.529 mmol), and Cs2CO3 (0.2143 g, 0.658 mmol). The mixture was heated to 70 C. overnight, diluted with water, extracted with DCM (3×8 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica (30-60nM EtOAc/DCM to 4nM MeOH/DCM) and re-chromatographed (2.5-4nM iPrOH/DCM) to give methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (E510). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.28-8.16 (m, 2H), 7.58 (t, J=8.2 Hz, 1H), 7.51-7.03 (m, 3H), 3.95 (dq, J=18.1, 9.8, 8.5 Hz, 1H), 3.88 (s, 3H), 3.63-3.48 (m, 6H), 2.91 (t, J=11.9 Hz, 2H), 2.53-2.48 (m, 4H), 2.46-2.28 (m, 2H), 2.12-1.88 (m, 4H), 1.63 (td, J=13.1, 12.6, 6.4 Hz, 2H); MS (APCI+) m/z 542.4 (M+H)+. 1008161A 1 N aqueous solution of sodium hydroxide (0.14 mL, 0.140 mmol) was added to a mixture of methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (E510, 0.0647 g, 0.119 mmol) in methanol (0.14 mL) and tetrahydrofuran (0.40 mL), The mixture was stirred for 2 hours, diluted with water, and extracted with DCM that was back-extracted with water (2×). The aqueous layer was neutralized with 1 N HCl (0.17 mL), and extracted with DCM, dried (Na2SO4), and concentrated to give 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid.
  • 27
  • [ 262587-05-3 ]
  • [ 1142225-18-0 ]
  • [ 1142225-17-9 ]
  • 28
  • [ 262587-05-3 ]
  • [ 1142224-93-8 ]
  • 29
  • [ 262587-05-3 ]
  • [ 1142224-91-6 ]
  • 30
  • [ 262587-05-3 ]
  • [ 1142234-76-1 ]
  • [ 1142234-74-9 ]
  • 31
  • [ 108-86-1 ]
  • 1-(difluoromethoxy)-3-methyl-6-nitro-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-3-ium trifluoromethanesulfonate [ No CAS ]
  • [ 175278-33-8 ]
  • [ 5905-69-1 ]
  • [ 262587-05-3 ]
YieldReaction ConditionsOperation in experiment
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 23℃; for 12h;Irradiation; Glovebox; Sealed tube; Inert atmosphere; In a glovebox, to an oven-dried 20 mL screw cap vial was added 1- (difluoromethoxy) -3-methyl-6-nitro-4- (trifluoromethyl) -lff- benzo [d] [1, 2, 3] triazol-3-ium trifluoromethanesulfonate (la) (92.4 mg, 0.200 mmol, 1.00 equiv), (hetero) arene (2.00 mmol, 10.0 equiv), Ru (bpy) 3 (PF6) 2, (0.860 mg, 1.00 pmol, 0.500 mol%), and MeCM (1.00 mL, 0.200 M, with respect to la) . To this suspension or solution was added a magnetic stir bar. Next, the reaction vial was capped and taken out of the glovebox. The reaction mixture was stirred at ambient temperature (23 C) and irradiated with blue LEDs (30 W, Xmax = 450 nm) which was placed 20.0 m from the vial for 12 h. To determine the yield of the products, an internal standard, trifluorotoluene (PhCF3) (14.6 mg, 12.3 pL, 0.100 mmol, 0.500 equiv) was added to the vial. Then, a 100 pL of the reaction mixture was taken and then dilute with 500 pL CD3CN followed by 19F NMR (the NMR sample was recombined with the rest of the reaction mixture afterward) . The combined reaction mixture was then purified by HPLC on the Luna PFP(2) preparative column (250 x 21.2 mm) column eluting with MeCN:H20 (v/v) with a flow rate of 10.6 mL/min to provide the purified products. In cases of closely-eluting peaks, products were isolated as a mixture of isomers. Afterwards, the products were extracted with CDC13 (3 x 1 mL) , dried with magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the desired product (s). For very volatile compounds, the products were extracted immediately with CDCI3 (l x l mL) and then directly characterized. 1H and 13C NMR of these Compound (s) contains MeCN residue signal (1H NMR: ? 1.94, 13C NMR: u 118.26, 1.32 in CDCI3 )
  • 32
  • [ 133776-41-7 ]
  • [ 262587-05-3 ]
  • C14H11F2NO2 [ No CAS ]
 

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