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Chemical Structure| 102877-78-1 Chemical Structure| 102877-78-1

Structure of 102877-78-1

Chemical Structure| 102877-78-1

4-(Pyridin-4-yloxy)aniline

CAS No.: 102877-78-1

4.5 *For Research Use Only !

Cat. No.: A209500 Purity: 95%

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Product Details of [ 102877-78-1 ]

CAS No. :102877-78-1
Formula : C11H10N2O
M.W : 186.21
SMILES Code : NC1=CC=C(OC2=CC=NC=C2)C=C1
MDL No. :MFCD06825431
InChI Key :IHAFMSZIVGDZTC-UHFFFAOYSA-N
Pubchem ID :11564589

Safety of [ 102877-78-1 ]

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

Computational Chemistry of [ 102877-78-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 12
Fraction Csp3 0.0
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 55.16
TPSA ?

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

48.14 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.8
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

1.7
Log Po/w (WLOGP)?

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

2.46
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.

1.13
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

1.8
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.78

Water Solubility

Log S (ESOL):?

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

-2.57
Solubility 0.504 mg/ml ; 0.00271 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.33
Solubility 0.879 mg/ml ; 0.00472 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

-3.92
Solubility 0.0222 mg/ml ; 0.000119 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

Yes
Log Kp (skin permeation)?

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

-6.23 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.

1.0 alert
Brenk?

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

1.0 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<1.0
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)

1.53

Application In Synthesis of [ 102877-78-1 ]

* 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 [ 102877-78-1 ]

[ 102877-78-1 ] Synthesis Path-Downstream   1~32

  • 1
  • [ 626-61-9 ]
  • [ 102877-78-1 ]
  • 2
  • [ 4783-86-2 ]
  • [ 102877-78-1 ]
  • 5
  • [ 7379-35-3 ]
  • [ 123-30-8 ]
  • [ 102877-78-1 ]
YieldReaction ConditionsOperation in experiment
94% With sodium hydroxide; In dimethyl sulfoxide; at 100℃; for 18h; A solution of 4-chloropyridine hydrochloride (Aldrich, 3.0 g, 20.0 mmol) in dimethyl sulfoxide (40 mL) was treated with 4-aminophenol (Aldrich, 2.1 g, 20.0 mmol) and sodium hydroxide pellets (2.0 g, 50.0 mmol) and the mixture was heated at 100 C. for 18 h. The mixture was cooled to room temperature, poured onto a mixture of ice-water (300 g) and extracted with Et2O (3×150 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give the 4-(4-aminophenoxy)aniline as a pale yellow solid (3.5 g, 94%). 1H NMR (DMSO-d6) delta 8.38 (dd, 2H, J=5.5, 1.5 Hz), 6.83-6.79 (m, 4H), 6.63-6.59 (m, 2H), 5.13 (br s, 2H); MS (ESI+) m/z 187.2 (M+H)+.
67% With sodium hydroxide; In dimethyl sulfoxide; at 100℃; for 16h; Step 1. 4-(Pyridin-4-yloxy) aniline. To a solution of 4-chloropyridine hydrochloride (1.0 g, 6.67 mmol), 4-aminophenol (0.73 g, 6.67 mmol) in 15 niL of DMSO was added NaOH (0.67 g, 16.67 mmol). The reaction mixture was stirred at 100C for 16 hr and cooled to r.t. The resulting mixture was diluted with water and extracted with EtOAc. Combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography to give 4-(pyridin-4-yloxy)aniline (0.83 g, 67% yield) as a pale yellow solid. LC-MS: m/z: 187(M+H)+.
With potassium tert-butylate; In DMF (N,N-dimethyl-formamide); 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)pyrimidinone; at 20 - 100℃; for 24h; A solution of 4-aminophenol (15 g, 0.135 [MOL),] 4-chloropyridine hydrochloride (22.5 g, 0.148 [MOL),] and [KOTBU] (45.8 g, 0.404 mol) in DMPU (208 ml) and DMF (52 ml) is stirred at 100 [C] for 24 h, cooled to rt, poured into [H20] (0.6 L), and extracted with AcOEt (150 [ML,] 6x). The combined organic phases are washed with H20 (100 ml, 2x), brine (100 [MI,] 2x), dried [(NA2SO4),] concentrated under reduced pressure, and flash chromatographed (silica gel, 4.5 x 25 cm; [ACOET/HEXANE] = 1: [9-] 3: 7) to give the title compound of Stage 1.1 as a colorless solid : M+H = 187.2 [; 1H-NMR] (400 MHz, DMSO-d6) : 8.37 (d, 6.5 Hz, 2H, pyridinyl), 6.79 (d, 9.5 Hz, 2H, phenyl), 6.78 (d, 9.5 Hz, 2H, pyridinyl) 5.12 (s, 2H, NH2); Rf [(ACOEVCH2C12 =] 3: 7): 0.23 ; m. p. = 165.8-166. 6 C.
  • 6
  • [ 102877-78-1 ]
  • [ 101094-85-3 ]
  • [ 325781-24-6 ]
YieldReaction ConditionsOperation in experiment
40% In butan-1-ol; at 130℃; for 18h; Example 9: Preparation of 1-[4-(4-pyridyloxy)phenylamino]-4-(4-pyridylmethyl)phthalazine [44.1] A mixture of 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see Novartis patent WO98/35958, 11.02.98) (0.540 g, 2.11 mmol) and <strong>[102877-78-1]4-(4-aminophenoxy)pyridine</strong> (1.18 g, 6.33 mmol) in anhydrous 1-butanol (8.4 mL) was stirred under argon at 130C for 18h. The reaction mixture was quenched with saturated aqueous potassium carbonate (~50 mL) and then extracted with dichloromethane (3 x 100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography in 7: 11: 2 v/v acetone-dichloromethane-methanol provided the title compound as an oil (0.340 g, 0.84 mmol, 40% yield). 1H-NMR (DMSO-d6) 9.26 (s, 1H), 8.58 (d, J = 8.3, 1H), 8.41 to 8.44 (m, 4H), 8.10 (d, J = 8.2, 1H), 7.90 to 8.03 (m, 4H), 7.30 (d, J = 5.9, 2H), 7.17 (d, J = 9.2, 2H), 6.91 (d, J = 5.8, 2H), 4.56 (s, 2H); MS ES 406 (M+H)+, calc. 405; TLC (1:7:12 v/v methanol-acetone-dichloromethane) Rf= 0.08.
40% In butan-1-ol; at 130℃; for 18h; EXAMPLE 9 Preparation of 1-[4-(4-pyridyloxy)phenylamino]-4-(4-pyridylmethyl)phthalazine A mixture of 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see Novartis patent WO98135958, 11.02.98) (0.540 g, 2.11 mmol) and <strong>[102877-78-1]4-(4-aminophenoxy)pyridine</strong> (1.18 g, 6.33 mmol) in anhydrous 1-butanol (8.4 mL) was stirred under argon at 130 C. for 18 h. The reaction mixture was quenched with saturated aqueous potassium carbonate (~50 mL) and then extracted with dichloromethane (3*100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography in 7:11:2 v/v acetone-dichloromethane-methanol provided the title compound as an oil (0.340 g, 0.84 mmol, 40% yield). 1H-NMR (DMSO-d6) 9.26 (s, 1H), 8.58 (d, J=8.3, 1H), 8.41 to 8.44 (m, 4H), 8.10 (d, J=8.2, 11H), 7.90 to 8.03 (m, 4H), 7.30 (d, J=5.9, 2H), 7.17 (d, J=9.2, 2H), 6.91 (d, J=5.8, 2H), 4.56 (s, 2H); MS ES 406 (M+H)+, calc. 405; TLC (1:7:12 v/v methanol-acetone-dichloromethane) Rf=0.08.
  • 7
  • [ 102877-78-1 ]
  • [ 6160-65-2 ]
  • [ 52024-72-3 ]
  • 8
  • [ 102877-78-1 ]
  • [ 17738-61-3 ]
  • N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-(4-pyridinyloxy)phenyl]ethanediamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; 50 mg (0.19 MMOL) of 10,31. 7 mg (0.17 MMOL) of 2,71 mg of TBTU (0.22 mmol) and 7.8 mg (0.05 mmol) of HOBT were dissolved in dimethylformamide, 0.12 ml (0.68 MMOL) of N-ethyldiisopropylamine was added at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted a number of times with ethyl acetate. The combined organic phases were washed with water, dried using NA2SO4, filtered and evaporated. A little ethyl acetate and n- heptane were added to the residue, and the deposited crystals were filtered off with suction and dried. Yield : 26 mg (35%), beige solid
  • 9
  • [ 2849-93-6 ]
  • [ 102877-78-1 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% 0.064 mmol of benzimidazolecarboxylic acid 41 was dissolved in DMF together with 0.064 mmol of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0. 026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. A further 0. 25 eq. of acid was added, and the mixture was stirred for 4 hours. The reaction mixture was diluted with water and extracted a number of times with ethyl acetate. The combined organic phases were washed 2 x with water, dried, filtered and evaporated. Yield : 99%, colourless solid
  • 10
  • [ 39811-14-8 ]
  • [ 102877-78-1 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5-chloro-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% 0.064 MMOL of benzimidazolecarboxylic acid 4a was dissolved in DMF together with 0.064 mmol of the amine 5a, a solution of TBTU (0.096 MMOI) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2.5 hours, 0.2 eq. of acid was added, and the mixture was stirred overnight. After a further addition of 0.16 EQ. of acid, the reaction mixture was diluted with water after 1.5 hours, and the resulting precipitate was filtered off with suction, washed with water and digested with diethyl ether. Yield : 75%, pale-brown solid
  • 11
  • [ 827029-04-9 ]
  • [ 102877-78-1 ]
  • N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-(pyridine-4-yloxy)phenyl]-malonamid [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With O-benzotriazol-1-yl-N,N,N',N'-bis(tetramethylene)uronium tetrafluoroborate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; 30 MG (0. 107 MMOL) OF 21, 18.1 mg (0. 097 MMOL) OF 2, 41 mg of TBTU (0.127 MMOL) and 4.5 mg (0.029 MMOL) of HOBT are dissolved in 3 ML DIMETHYLFORMAMIDE, 0.07 ML (0.39 MMOL) of N-ethyldiisopropylamine is added at room temperature, and the mixture is stirred overnight. The reaction mixture is diluted with water and extracted several times with ethyl acetate. The combined organic phases are washed with water, dried over NA2SO4, filtered and evaporated. The residue is put on silica gel and purified by column chromatography (4 G silica gel, eluent : ethyl acetate/n- heptane). Yield : 25 mg (57%), colourless solid.
  • 12
  • [ 102877-78-1 ]
  • [ 2107-39-3 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71.5% 0.064 mmol of BENZIMIDAZOLECARBOXYLIC acid 4b was dissolved in DMF together with 0.064 MMOL of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 mmol) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, A further 0.4 EQ. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield: 71.5%, beige solid
  • 13
  • [ 102877-78-1 ]
  • [ 827042-59-1 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5-chloro-4-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% 0.064 mmol of benzimidazolecarboxylic acid 4c was dissolved in DMF together with 0.064 MMO . of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, 0.3 eq. of acid was added, and the mixture was stirred for 2 hours. After further addition of 0.3 eq. of acid, the reaction mixture was diluted with water after 2 hours, and the resulting precipitate was filtered off with suction, washed with water and digested with diethyl ether and ethyl acetate. Yield : 96%, pale-beige solid
  • 14
  • [ 102877-78-1 ]
  • [ 827042-60-4 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-4-bromo-6-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% 0.064 MMOL of BENZIMIDAZOLECARBOXYLIC acid 4d was dissolved in DMF together with 0.064 mmol of the amine 5a, a solution of TBTU (0.096 mmol) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, a further 0.2 eq. of acid was added, and the mixture was stirred overnight. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 68%, pale-beige solid
  • 15
  • [ 102877-78-1 ]
  • [ 827042-61-5 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5-chloro-6-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% 0.064 MMOL of benzimidazolecarboxylic acid 4e was dissolved in DMF together with 0.064 mmol of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, A further 0. 2 eq. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield: 61 %, beige solid
  • 16
  • [ 102877-78-1 ]
  • [ 673487-32-6 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-4-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% 0.064 MMOL of BENZIMIDAZOLECARBOXYLIC acid 4f was dissolved in DMF together with 0.064 MMOL of the amine 5a, a solution of TBTU (0.096 mmol) in DMF, HOBT (0.026 MMOL) in DMF and 0. 32 mmol of D1PEA were added successively, and the mixture was stirred at room temperature. After 3 hours, a further 0.3 eq. of acid was added, and the mixture was stirred overnight. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 73%, beige solid
  • 17
  • [ 102877-78-1 ]
  • [ 827042-62-6 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-4-chloro-6-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% 0.064 MMOL of benzimidazolecarboxylic acid 4g was dissolved in DMF together with 0.064 mmol of the amine 5a, a solution OF TBTU (0.096 MMOL) in DMF, HOBT (0.026 mmol) in DMF and 0. 32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 65%, pale-beige solid
  • 18
  • [ 102877-78-1 ]
  • [ 827042-63-7 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5-chloro-6-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; 0.064 mmol of benzimidazolecarboxylic acid 4H was dissolved in DMF together with 0. 064 mmol of the amine 5A, A solution of TBTU (0. 096 MMOL) in DMF, HOBT (0. 026 MMOL) in DMF and 0. 32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. The resulting solid was digested a number of times with ethyl acetate, and the combined filtrates were evaporated. Yield : 26%, brown solid
  • 19
  • [ 102877-78-1 ]
  • [ 827042-64-8 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-4,6-bis(tifluoromethyl)-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; 0.064 mmol of BENZIMIDAZOLECARBOXYLIC acid 4i was dissolved in DMF together with 0.064 mmol of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 72%, pale-beige solid
  • 20
  • [ 102877-78-1 ]
  • [ 287730-14-7 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5,6-dichloro-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; 0.064 MMOL of BENZIMIDAZOLECARBOXYLIC acid 4j was suspended in DMF together with 0.064 MMOL of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0. 32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield: 51%, pale-brown solid
  • 21
  • [ 102877-78-1 ]
  • [ 99459-47-9 ]
  • N-[4-(pyridine-4-yloxy)phenyl]-5-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
39.5% 0.064 mmol of BENZIMIDAZOLECARBOXYLIC ACID 4K WAS DISSOLVED in DMF together with 0.064 mmol of the amine 5a, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 4 hours, 0.3 eq. of acid was added, and the mixture was stirred overnight. After further addition of 0.3 eq. of acid, the reaction mixture was diluted with water after 2 hours, and the resulting precipitate was filtered off with suction and washed with water. The resulting crude product was purified by chromatography (ethyl acetate/n-heptane: 9/1). Yield : 39.5%, beige solid
  • 22
  • [ 75-44-5 ]
  • [ 102877-78-1 ]
  • C12H8N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; In dichloromethane; toluene; at 0 - 20℃; for 1 - 2h;Product distribution / selectivity; To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH2Cl2 (13 mL) at 0 C was slowly added pyridine (0.105 mL) was added slowly over a 5 min, then <strong>[102877-78-1]4-(4-pyridinyloxy)aniline</strong> (0.250 g, 1.3 mmol) was added in one aliquot causing a transient yellow color to appear. The solution was stirred at 0 C for 1 h, then was allowed to warm to room temp. over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-tert-butyl-N'-(tert-butoxycarbonyl)pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 C for 12 h forming a white precipitate. The solids were dissolved in a 1N HCl solution and allowed to stir at room temp. for 1 h to form a new precipitate. The white solid was washed (50% Et2O/50% pet. ether) to afford the desired urea (0.139 g, 59%): mp >228 C dec; TLC (10% MeOH/ 90% CHCl3) Rf 0.239; 1H-NMR (DMSO-d6) delta 1.24 (s, 9H), 5.97 (s, 1H), 6.88 (d, J=6.25 Hz, 2H), 7.10 (d, J=8.82 Hz, 2H), 7.53 (d, J=9.2 Hz, 2H), 8.43 (d, J=6.25 Hz, 2H), 8.92 (br s, 1H), 9.25 (br s, 1H), 12.00 (br s, 1H); EI-MS m/z rel abundance 351 (M+, 24%).; C4c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline; N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-pyridinyloxy)phenyl)urea:; To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH2Cl2 (5 mL) was added a solution of <strong>[102877-78-1]4-(4-pyridinyloxy)aniline</strong> (0.30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CH2Cl2 (5 mL). The resulting mixture was allowed to warm to room temp. and was stirred for 1 h, then was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (5 mL), then treated with 5-tert-butylthiopheneammonium chloride (Method A4c; 0.206 g, 1.07 mmol), followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for 1 h, then treated with 2-(dimethylamino)ethylamine (1 mL), followed by stirring at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL), sequentially washed with a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 30% EtOAc/70% hexane to 100% EtOAc) to give the desired product (0.38 g , 97%): TLC (50% EtOAc/50% hexane) Rf 0.13; 1H-NMR (CDCl3) delta 1.26 (s, 9H), 6.65 (d, J=1.48 Hz, 1H), 6.76 (dd, J=1.47, 4.24 Hz, 2H), 6.86 (d, J=1.47 Hz, 1H), 6.91 (d, J=8.82 Hz, 2H), 7.31 (d, J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 (d, J=1.47 Hz, 2H); 13C-NMR (CDCl3) delta 32.1 (3C), 34.4, 106.2, 112.0 (2C), 116.6, 121.3 (2C), 121.5 (2C), 134.9, 136.1, 149.0, 151.0 (2C), 154.0, 156.9, 165.2; FAB-MS m/z (rel abundance) 368 ((M+H)+, 100%).
  • 23
  • [ 102877-78-1 ]
  • [ 32315-10-9 ]
  • [ 70338-47-5 ]
  • 1-(4-benzyloxy-3-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; 1 g (3.74 mmol) 56, 697 mg (3.74 mmol) 24 and 3.18 mi (18. 7 mmol) N- Ethyldiisopropylamine in 40 ml THF are cooled to 0 C, treated with 740 mg (2.49 mmol) Bis (trichloromethyl)-Carbonate in 10 ml THF and stirred for 2 h at room temperature. Then, the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by chromatography (silica gel, eluent : petroleum ether/EtOAc) and/or recrystallisation from diethylether. Yield : 305 mg (17 %) 85, colourless crystals
  • 24
  • [ 102877-78-1 ]
  • [ 55809-27-3 ]
  • N-(5-t-butyl-3-isoxazolyl)-2-[4-(4-pyridinyloxy)phenylamino]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
29% With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 4h; A solution of 58.2 mg (0.27 [MMOL)] of compound 10 in dimethylformamide (DMF) is given to a solution of 50 mg (0.27 [MMOL)] of compound 2 and 0.05 ml (0.3 [MMOL)] N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100 [C] for 4 h, then evaporated and the residue is purified by preparative HPLC to yield 28 mg (29 %) colourless solid.
  • 25
  • [ 102877-78-1 ]
  • [ 668980-81-2 ]
  • N-(3-t-butyl-5-isoxazolyl)-2-[4-(4-pyridinyloxy)phenylamino]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
6% With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 2h; A solution of 58.2 mg (0.27 [MMOL)] of compound 11 in dimethylformamide (DMF) is given to a solution of 50 mg (0.27 [MMOL)] of compound 2 and 0.05 ml (0.3 [MMOL) N-ETHYL-DIISOPROPYLAMINE] in DMF. The reaction mixture is heated to 100 [C] for 2 h, then evaporated and the residue is purified by preparative HPLC to yield 5.5 mg (6 %) colourless solid.
  • 26
  • [ 102877-78-1 ]
  • C15H19Cl3N2O3 [ No CAS ]
  • 1-[3-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 10 - 20℃; b) The thus obtained solution is treated with 250 mg (1.34 mmol) 24 in 10 mi THF at 10 C and stirred overnight at room temperature. The reaction mixture is treated with water extracted with ethylacetate. The organic phase is washed with water, dried using Na2SO4, filtered and evaporated. The residue is purified by preparative thin layer-chromatography (eluent : DCM115% MeOH/1 % NH40H). Yield : 100 mg (18 %) 59
  • 27
  • [ 102877-78-1 ]
  • C14H17Cl3N2O3 [ No CAS ]
  • 1-[4-(pyridin-4-yloxy)-phenyl]-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 10 - 20℃; b) The thus obtained solution is treated with 250 mg (1.34 mmol) 24 in 10 mi THF at 10 C and stirred overnight at room temperature. The reaction mixture is treated with water extracted with ethylacetate. The organic phase is washed with water, dried using Na2SO4, filtered and evaporated. The residue is purified by chromatography (silica gel, eluent : DCM/2- 10% MeOH/0-0. 4% NH40H). Yield : 200 mg (41 %) 60
  • 28
  • [ 102877-78-1 ]
  • C16H12Cl4N2O4 [ No CAS ]
  • C26H21ClN4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 10 - 20℃; b) The thus obtained solution is treated with 250 mg (1.34 rnmol) 24 in 10 ml THF at 10 C and stirring is continued overnight at room temperature. The reaction mixture is treated with ethylacetate and water, the organic phase is separated, washed with water, dried using Na2SO4, filtered and evaporated. The residue is crystallised from dichloromethane by addition of methanol. Yield : 52 mg (8 %) 89
  • 29
  • [ 102877-78-1 ]
  • [ 351-33-7 ]
  • N-(4-chloro-3-trifluoromethylphenyl)-2-[4-(4-pyridinyloxy)phenylamino]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
5% With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 6h; A solution of 146.1 mg (0.54 [MMOL)] of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 [MMOL)] of compound 2 and 0.1 mi (0.59 [MMOL)] N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100 [C] for 6 h, then evaporated and the residue is purified by preparative HPLC to yield 10.7 mg (5 %) colourless solid.
  • 30
  • [ 102877-78-1 ]
  • [ 326-06-7 ]
  • [ 64-19-7 ]
  • 0.6C2H4O2*C23H17F3N6O [ No CAS ]
  • 0.6C2H4O2*C23H17F3N6O [ No CAS ]
  • 31
  • [ 102877-78-1 ]
  • [ 864272-25-3 ]
YieldReaction ConditionsOperation in experiment
c) 2 g (10.74 mmol) of 2 were suspended in 20 ml of water, the suspension was cooled to between-5 and 0C, and 40 mi of conc. HCI were added over the course of 10 minutes with stirring. 760 mg (11.01 mmol) of NaN02, dissolved in 12 ml of water, were subsequently added dropwise over the course of 10 minutes, and the reaction mixture was stirred for 30 minutes. 12 g (53.18 mmol) of tin (ll) chloride dihydrate, dissolved in 24 ml of conc. HCI, were added dropwise to the solution over the course of 20 minutes at between-5 and 0C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness, dissolved in a little water and adjusted to pH 2.5 using 2N NaOH, and the suspension was evaporated to dryness. The residue was then suspended in 1 I of EtOH and left to stand at room temperature for 2 hours. The solution was carefully decanted off and evaporated to dryness. The residue was taken up in a little water, neutralised using NaHCO3 and extracted with ethyl acetate. The combined organic phases were dried using Na2SO4, filtered and evaporated. The resultant product was employed in the next step without further purification.
  • 32
  • [ 102877-78-1 ]
  • [ 5147-80-8 ]
  • C16H12N4OS [ No CAS ]
 

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Technical Information

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