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Chemical Structure| 56621-89-7 Chemical Structure| 56621-89-7

Structure of 56621-89-7

Chemical Structure| 56621-89-7

5-Amino-2-methoxypyrimidine

CAS No.: 56621-89-7

4.5 *For Research Use Only !

Cat. No.: A136098 Purity: 98%

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Product Details of [ 56621-89-7 ]

CAS No. :56621-89-7
Formula : C5H7N3O
M.W : 125.13
SMILES Code : C1=C(N)C=NC(=N1)OC
MDL No. :MFCD08234878
InChI Key :HKHRENFWPKWVML-UHFFFAOYSA-N
Pubchem ID :352904

Safety of [ 56621-89-7 ]

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

Computational Chemistry of [ 56621-89-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 32.93
TPSA ?

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

61.03 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.14
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

-0.17
Log Po/w (WLOGP)?

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

0.08
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.

-0.9
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

0.2
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.07

Water Solubility

Log S (ESOL):?

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

-0.94
Solubility 14.5 mg/ml ; 0.116 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-0.66
Solubility 27.6 mg/ml ; 0.221 mol/l
Class?

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

Very 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

-1.38
Solubility 5.24 mg/ml ; 0.0419 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

No
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

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.

-7.18 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<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)

1.89

Application In Synthesis of [ 56621-89-7 ]

* 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 [ 56621-89-7 ]

[ 56621-89-7 ] Synthesis Path-Downstream   1~31

  • 1
  • [ 50-84-0 ]
  • [ 56621-89-7 ]
  • 2-chloro-4-(2-methoxy-pyrimidin-5-ylamino)-benzoic acid [ No CAS ]
  • 2
  • [ 56621-89-7 ]
  • [ 98-74-8 ]
  • [ 71119-37-4 ]
  • 3
  • [ 56621-89-7 ]
  • [ 121-60-8 ]
  • [ 71119-37-4 ]
  • 4
  • [ 10031-82-0 ]
  • [ 56621-89-7 ]
  • [1-(4-Ethoxy-phenyl)-meth-(E)-ylidene]-(2-methoxy-pyrimidin-5-yl)-amine [ No CAS ]
  • 5
  • [ 123-11-5 ]
  • [ 56621-89-7 ]
  • [1-(4-Methoxy-phenyl)-meth-(E)-ylidene]-(2-methoxy-pyrimidin-5-yl)-amine [ No CAS ]
  • 6
  • [ 5736-94-7 ]
  • [ 56621-89-7 ]
  • [1-(4-Hexyloxy-phenyl)-meth-(E)-ylidene]-(2-methoxy-pyrimidin-5-yl)-amine [ No CAS ]
  • 7
  • [ 50262-46-9 ]
  • [ 56621-89-7 ]
  • (2-Methoxy-pyrimidin-5-yl)-[1-(4-nonyloxy-phenyl)-meth-(E)-ylidene]-amine [ No CAS ]
  • 8
  • [ 56621-89-7 ]
  • [ 5736-91-4 ]
  • [1-(4-Butoxy-phenyl)-meth-(E)-ylidene]-(2-methoxy-pyrimidin-5-yl)-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With copper; In methanol; at 150℃; for 24h;Sealed tube; General procedure: To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150C in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.13 g, 67%). LCMS (ES+) 126 (M+H)+, RT 1.06 minutes (method 1).
With copper; In methanol; at 150℃; for 24h;Sealed tube; General procedure: Intermediate 22 5-Methoxypyrazin-2-amine [0242] To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150 C. in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH: DCM 2-3%) to afford the title compound (0.13 g, 67%). LCMS (ES+) 126 (M+H)+, RT 1.06 minutes (method 1).
  • 10
  • [ 14001-69-5 ]
  • [ 56621-89-7 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 635.0 Torr; for 18h; Example 40Synthesis of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(2-methoxy-5-pyrimidinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineThe compound was synthesized according to Method A.To a solution of sodium methoxide (0.090 g of sodium) in MeOH (12 mL) was added 0.486 g (3.03 mmol) of 2-chloro-5-nitropyrimidine, and the mixture was heated under reflux for 1 hr. After cooling, the mixture was concentrated in vacuo, extracted with EtOAc, and washed with water. The aqueous layer was extracted with CHCl3 and the combined organic layers were dried (Na2SO4), and concentrated, to give 0.347 g (75% yield) of 2-methoxy-5-nitropyrimidine as a yellow powder: 1H NMR (CDCl3) delta9.31 (s, 2H), 4.17 (s, 3H); LCMS (APCI+) m/z: 156 (MH+, 100%).To 0.342 g (2.20 mmol) of the above nitro compound in MeOH (20 mL) was added 0.30 g of 10% Pd/C and the mixture was stirred under hydrogen (25 in/Hg) for 18 hrs. The reaction mixture was filtered through celite, and concentrated, to give 0.274 g (100% yield) of 5-amino-2-methoxypyrimidine as a colorless oil: 1H NMR (DMSO-d6) delta 8.05 (s, 2H), 3.94 (s, 3H); LCMS (APCI+) m/z: 126 (MH+, 100%).To 0.274 g (2.19 mmol) of the above amino compound in THF (3 mL) was added 1.25 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.31 g (0.78 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 90 min. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, dried, and concentrated. Recrystallization from EtOH/CH2Cl2 gave 0.098 g (26% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(2-methoxy-5-pyrimidinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 255-258 C.; 1H NMR (DMSO-d6) 810.07 (s, 1H), 8.88-8.74 (m, 2H), 8.15-7.42 (m, 3H), 6.97 (d, J=8.0 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.82-3.72 (m, 8H); Anal. Calcd. for C21H21F2N6O3: C, 52.0; H, 4.4; N, 26.0. Found: C, 52.1; H, 4.5; N, 26.0%.
  • 11
  • [ 1379860-81-7 ]
  • [ 56621-89-7 ]
  • [ 1253574-90-1 ]
  • 12
  • [ 56621-89-7 ]
  • [ 1253574-91-2 ]
  • 13
  • [ 56621-89-7 ]
  • [ 1253574-92-3 ]
  • 14
  • [ 56621-89-7 ]
  • C35H40N10O3 [ No CAS ]
  • 15
  • [ 70-34-8 ]
  • [ 56621-89-7 ]
  • [ 1420044-40-1 ]
  • 16
  • [ 56621-89-7 ]
  • [ 1420044-52-5 ]
  • 17
  • [ 56621-89-7 ]
  • [ 1420044-65-0 ]
  • 18
  • [ 56621-89-7 ]
  • C14H15N5O [ No CAS ]
  • 19
  • 2-chloro-4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]benzonitrile [ No CAS ]
  • [ 1885-14-9 ]
  • [ 56621-89-7 ]
  • [ 1372927-80-4 ]
YieldReaction ConditionsOperation in experiment
81% General procedure: To a mixture of <strong>[56621-89-7]2-methoxypyrimidine-5-amine</strong> (120 mg) and pyridine (4 ml) was added phenyl chlorocarbonate (0.132 ml) under ice bath cooling, followed by stirring at room temperature for 1.5 hours. Thereafter, a mixture of 2-chloro-4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]benzonitrile (200 mg) and pyridine (3 ml) was added thereto, followed by stirring at 100 C. for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, and toluene (15 ml×2) was added to the residue and the azeotrope was evaporated. Ethyl acetate (20 ml) was added to the residue, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 96/4), to afford 258 mg (81%) of (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-methoxypyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide
  • 20
  • 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]acetic acid [ No CAS ]
  • [ 56621-89-7 ]
  • 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% Example 82 Preparation of 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide. TBTU (244 mg; 0.74 mmol; 1.5 eq) and DIPEA (170 muL; 0.99 mmol; 2 eq) were added to a solution of 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]acetic acid (1-21) (200 mg; 0.50 mmol; 1 eq) in anhydrous dioxane (8 mL). The reaction mixture was stirred at room temperature for 30 minutes. 2-Methoxypyrimidin-5-amine (124 mg; 0.99 mmol; 2 eq) was added and the reaction mixture was stirred at room temperature for 18 hours. Saturated ammonium chloride (20 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated sodium chloride (1 x 20 mL), filtered and evaporated to dryness. The crude was purified on silica gel using dichloromethane/methanol (98/2) as an eluent. After trituration in diethyl ether, the title compound 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylidene imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide was obtained in 25 % yield (79 mg) as a white solid. 1H-NMR (Acetone-d6): delta (ppm) delta 2.96 (m, 1H), 3.09 (m, 1H), 3.24 (m, 1H), 3.43 (m, 1H), 3.75 (s, 3H), 3.78 (m, 1H), 3.92 (s, 3H), 4.30 (m, 1H), 4.65 (s, 1H), 6.86 (m, 2H), 7.25 (m, 4H), 7.45 (m, 2H), 8.75 (m, 2H) 9.62 (m, 1H); MS (ESI+): m/z = 509.9 [M+H]+.
25% Example 82: Preparation of2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5- oxo-2-mlfanylideneimid zolidin-4-yl]-N-{2-methoxypyrim TBTU (244 mg; 0.74 mmol; 1.5 eq) and DIPEA (170 mu 0.99 mmol; 2 eq) were added to a solution of 2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2- sulfanylideneimidazolidin-4-yl]acetic acid (1-21) (200 mg; 0.50 mmol; 1 eq) in anhydrous dioxane (8 mL). The reaction mixture was stirred at room temperature for 30 minutes. 2-Methoxypyrimidin-5-amine (124 mg; 0.99 mmol; 2 eq) was added and the reaction mixture was stirred at room temperature for 18 hours. Saturated ammonium chloride (20 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated sodium chloride (1 x 20 mL), filtered and evaporated to dryness. The crude was purified on silica gel using dichloromethane/methanol (98/2) as an eluent. After trituration in diethyl ether, the title compound 2-[l-(4-fluorophenyl)-3-[2-(4- methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]-N-(2- methoxypyrimidin-5-yl)acetamide was obtained in 25% yield (79 mg) as a white solid. 1H-NMR (Acetone-d6): delta (ppm) delta 2.96 (m, 1H), 3.09 (m, 1H), 3.24 (m, 1H), 3.43 (m, 1H), 3.75 (s, 3H), 3.78 (m, 1H), 3.92 (s, 3H), 4.30 (m, 1H), 4.65 (s, 1H), 6.86 (m, 2H), 7.25 (m, 4H), 7.45 (m, 2H), 8.75 (m, 2H) 9.62 (m, 1H); MS (ESI+): m/z = 509.9 [M+H]+ .
  • 21
  • 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)acetic acid [ No CAS ]
  • [ 56621-89-7 ]
  • 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% Example 79 Preparation of 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide. TBTU (177.2 mg; 0.54 mmol; 1.5 eq) and DIPEA (126 muL; 0.72 mmol; 2 eq) were added to a solution of 2-(3- {2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)acetic acid (1-37) (150 mg; 0.36 mmol; 1 eq) in dioxane (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. A solution of <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (90.3 mg; 0.72 mmol; 2 eq) in dimethylformamide (2 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to dryness. Saturated ammonium chloride was added (15 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride (3 x 20 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate (25/75 to 0/100) as an eluent. After trituration in diethyl ether/dichloromethane, the title compound 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-5-oxo-2-sulfanylidene imidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide was obtained in 28 % yield (52 mg) as an off-white solid. 1H-NMR (DMSO-d6): delta (ppm) 2.75 (m, 1H), 2.84 (s, 6H), 2.94 (m, 1H), 3.15 (d, 1H), 3.28 (m, 1H), 3.64 (m, 1H), 3.89 (s, 3H), 4.13 (m, 1H), 4.73 (m, 1H), 6.65 (d, 2H), 7.07 (d, 2H), 7.37 (m, 4H), 8.72 (d, 2H), 10.5 (s, 1H); MS (ESI+): m/z = 522.9 [M+H]+.
28% Example 79: Preparation of 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-l-(4- fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)-N-(2-methoxypyrim yl)acetamide. TBTU (177.2 mg; 0.54 mmol; 1.5 eq) and DIPEA (126 mu 0.72 mmol; 2 eq) were added to a solution of 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-l-(4-fluorophenyl)- 5-oxo-2-sulfanylideneimidazolidin-4-yl)acetic acid (1-37) (150 mg; 0.36 mmol; 1 eq) in dioxane (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. A solution of <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (90.3 mg; 0.72 mmol; 2 eq) in dimethylformamide (2 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to dryness. Saturated ammonium chloride was added (15 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride (3 x 20 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate (25/75 to 0/100) as an eluent. After trituration in diethyl ether/dichloromethane, the title compound 2-(3-{2-[4-(dimethylamino) phenyl]ethyl}-l-(4-fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)-N-(2- methoxypyrimidin-5-yl)acetamide was obtained in 28% yield (52 mg) as an off- white solid. 1H-NMR (DMSO-d6): delta (ppm) 2.75 (m, IH), 2.84 (s, 6H), 2.94 (m, IH), 3.15 (d, IH), 3.28 (m, IH), 3.64 (m, IH), 3.89 (s, 3H), 4.13 (m, IH), 4.73 (m, IH), 6.65 (d, 2H), 7.07 (d, 2H), 7.37 (m, 4H), 8.72 (d, 2H), 10.5 (s, IH); MS (ESI+): m/z = 522.9 [M+H]+ .
  • 22
  • 2-[1-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]acetic acid [ No CAS ]
  • [ 56621-89-7 ]
  • 2-[1-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 20℃; Example 80 Preparation of 2-[1-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide. TBTU (265.8 mg; 0.83 mmol; 1.5 eq), followed by DIPEA (288 muL; 1.66 mmol; 3 eq) and after 10 minutes, <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (103.6 mg; 0.83 mmol; 1.5 eq) were added to a solution of 2-[1-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2-yl)ethyl] imidazolidin-4-yl] acetic acid (1-17) (200 mg; 0.55 mmol; 1 eq) in dioxane/dimethylformamide (3 mL/300 muL). The reaction mixture was stirred at room temperature overnight. Saturated sodium hydrogenocarbonate (15 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated sodium chloride (3 x 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol (100/0 to 97/3) as an eluent. After washing in hydrochloric acid 1M and trituration in diethyl ether, the title compound, 2-[1-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2-yl)ethyl] imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide, was obtained in 55% yield (143 mg) as beige solid. 1H-NMR (CDCl3): delta (ppm) 2.83 (m, 1H), 2.96 (m, 1H), 3.25 (m, 2H), 3.5 (m, 1H), 4.01 (m, 4H), 4.31 (m, 1H), 6.92 (m, 2H), 7.16 (m, 3H), 7.39 (m, 2H), 7.61 (s, 1H), 8.66 (m, 2H); MS (ESI+): m/z = 469.9 [M+H]+.
55% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 20℃; Example 80: Preparation of 2-[l-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2- l)ethyl]imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide. TBTU (265.8 mg; 0.83 mmol; 1.5 eq), followed by DIPEA (288 mu 1-66 mmol; 3 eq) and after 10 minutes, <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (103.6 mg; 0.83 mmol; 1.5 eq) were added to a solution of 2-[l-(4-fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2- yl)ethyl]imidazolidin-4-yl] acetic acid (1-17) (200 mg; 0.55 mmol; 1 eq) in dioxane/dimethylformamide (3 mL/300 mu). The reaction mixture was stirred at room temperature overnight. Saturated sodium hydrogenocarbonate (15 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated sodium chloride (3 x 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol (100/0 to 97/3) as an eluent. After washing in hydrochloric acid 1M and trituration in diethyl ether, the title compound, 2-[l-(4- fluorophenyl)-2,5-dioxo-3-[2-(thiophen-2-yl)ethyl]irnidazolidin-4-yl]-N-(2- methoxypyrimidin-5-yl)acetamide, was obtained in 55% yield (143 mg) as beige solid. 1H-NMR (CDC13): delta (ppm) 2.83 (m, 1H), 2.96 (m, 1H), 3.25 (m, 2H), 3.5 (m, 1H), 4.01 (m, 4H) , 4.31 (m, 1H) , 6.92 (m, 2H), 7.16 (m, 3H) , 7.39 (m, 2H), 7.61 (s, 1H) , 8.66 (m, 2H); MS (ESI+): m/z = 469.9 [M+H]+ .
  • 23
  • 2-[1-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]acetic acid [ No CAS ]
  • [ 56621-89-7 ]
  • 2-[1-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 20℃; Example 81 Preparation of 2-[1-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide. TBTU (254.5 mg; 0.79 mmol; 1.5 eq), followed by DIPEA (276 muL; 1.59 mmol; 3 eq) and after 10 minutes, <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (99.12 mg; 0.79 mmol; 1.5 eq) were added to a solution of 2-[1-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2-(thiophen-2-yl) ethyl]imidazolidin-4-yl]acetic acid (I-19) (200 mg; 0.53 mmol; 1 eq) in dioxane/dimethylformamide (3 mL/300 muL). The reaction mixture was stirred at room temperature overnight. Saturated sodium hydrogenocarbonate (15 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated sodium chloride (3 x 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol (100/0 to 98/2) as an eluent. After washing with 1M hydrochloric acid and trituration in diethyl ether, the title compound, 2-[1-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2-(thiophen-2-yl) ethyl]imidazolidin-4-yl]-N-(2-methoxypyrimidin-5-yl)acetamide, was obtained in 28 % yield (71 mg) as beige solid. 1H-NMR (DMSO-d6): delta (ppm) 3.2 (m, 4H), 3.75 (m, 1H), 3.88 (s, 3H), 4.26 (m, 1H), 4.75 (m, 1H), 6.97 (m, 2H), 7.37 (m, 5H), 8.71 (m, 2H), 10.47 (s, 1H); MS (ESI+): m/z = 485.8 [M+H]+.
28% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 20℃; Example 81: Preparation of 2-[l-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2- (thiophen-2-yl)ethyl]imidazolidin-4-yl]-N-(2-methoxypyrim TBTU (254.5 mg; 0.79 mmol; 1.5 eq), followed by DIPEA (276 mu 1-59 mmol; 3 eq) and after 10 minutes, <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (99.12 mg; 0.79 mmol; 1.5 eq) were added to a solution of 2-[l-(4-fluorophenyl)-5-oxo-2-sulfanylidene-3-[2- (thiophen-2-yl)ethyl]imidazolidin-4-yl]acetic acid (1-19) (200 mg; 0.53 mmol; 1 eq) in dioxane/dimethylformamide (3 mL/300 mu). The reaction mixture was stirred at room temperature overnight. Saturated sodium hydrogenocarbonate (15 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated sodium chloride (3 x 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol (100/0 to 98/2) as an eluent. After washing with 1M hydrochloric acid and trituration in diethyl ether, the title compound, 2-[l-(4- fluorophenyl)-5-oxo-2-sulfanylidene-3-[2-(thiophen-2-yl)ethyl]imidazolidin-4-yl]-N- (2-methoxypyrimidin-5-yl)acetamide, was obtained in 28% yield (71 mg) as beige solid. 1H-NMR (DMSO-d6): delta (ppm) 3.2 (m, 4H), 3.75 (m, 1H), 3.88 (s, 3H) , 4.26 (m, 1H), 4.75 (m, 1H), 6.97 (m, 2H) , 7.37 (m, 5H) , 8.71 (m, 2H) , 10.47 (s, 1H); MS (ESI+): m/z = 485.8 [M+H]+ .
  • 24
  • 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-2,5-dioxoimidazolidin-4-yl)acetic acid [ No CAS ]
  • [ 56621-89-7 ]
  • 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-2,5-dioxoimidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% c) 2-(3-{2-[4-(Dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-2,5-dioxoimidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide (example 78). [0255] TBTU (187.1 mg; 0.57 mmol; 1.5 eq) and DIPEA (131 muL; 0.75 mmol; 2 eq) were added to a solution of 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-5-oxo-2-sulfanylideneimidazolidin-4-yl)acetic acid (1-39) (150 mg; 0.38 mmol; 1 eq) in dioxane (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (93.8 mg; 0.75 mmol; 2 eq) in dimethylformamide (2 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to dryness. Saturated ammonium chloride was added (15 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride (3 x 20 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel using cyclohexane/ ethyl acetate (25/75 to 0/100) as an eluent. After trituration in diethyl ether/ dichloromethane/pentane, the title compound 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-1-(4-fluorophenyl)-2,5-dioxoimidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide was obtained in 33% yield (63.8 mg) as an off-white solid. 1H-NMR (DMSO-d6): delta (ppm) 2.69 (m, 1H), 2.80 (m, 1H), 2.83 (s, 6H), 3.02 (d, 1H), 3.12 (d, 1H), 3.28 (m, 1H), 3.68 (m, 1H), 3.88 (s, 3H), 4.51 (m, 1H), 6.64 (d, 2H), 7.05 (d, 2H), 7.36 (m, 4H), 8.71 (s, 2H), 10.39 (s, 1H); MS (ESI+): m/z = 506.9 [M+H]+.
33% c) 2-(3-|2-r4-(Dimethylamino)phenyllethyl)- l-(4-fluorophenyl)-2,5- dioxoimidazolidin-4-yl)-N-(2-methoxypyrimidin-5-yl)acetamide (example 78). TBTU (187.1 mg; 0.57 mmol; 1.5 eq) and DIPEA (131 mu 0.75 mmol; 2 eq) were added to a solution of 2-(3-{2-[4-(dimethylamino)phenyl]ethyl}-l-(4-fluorophenyl)- 5-oxo-2-sulfanylideneimidazolidin-4-yl)acetic acid (T39) (150 mg; 0.38 mmol; 1 eq) in dioxane (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (93.8 mg; 0.75 mmol; 2 eq) in dimethylformamide (2 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to dryness. Saturated ammonium chloride was added (15 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium chloride (3 x 20 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate (25/75 to 0/100) as an eluent. After trituration in diethyl ether/dichloromethane/pentane, the title compound 2-(3-{2-[4- (dimethylamino)phenyl]ethyl}-l-(4-fluorophenyl)-2,5-dioxoimidazolidin-4-yl)-N-(2- methoxypyrimidin-5-yl)acetamide was obtained in 33% yield (63.8 mg) as an off- white solid. 1H-NMR (DMSO-d6): delta (ppm) 2.69 (m, 1H), 2.80 (m, 1H), 2.83 (s, 6H), 3.02 (d, 1H), 3.12 (d, 1H), 3.28 (m, 1H), 3.68 (m, 1H), 3.88 (s, 3H), 4.51 (m, 1H), 6.64 (d, 2H), 7.05 (d, 2H), 7.36 (m, 4H), 8.71 (s, 2H), 10.39 (s, 1H); MS (ESI+): m/z = 506.9 [M+H]+ .
  • 25
  • [ 2905-21-7 ]
  • [ 56621-89-7 ]
  • C11H10FN3O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; at 100℃; 2-[(2-Chloro-6-fluorobenzyl)amino]-N-(2-methoxypyrimidin-5- yl)benzenesulfonamide (lntB2) The title compound (106 mg, impure, used without further purification) was prepared in two steps from 2-fluorobenzenesulfonyl chloride (0.46 mL, 3.5 mmol) and 5-amino- 2-methoxypyrimidine (482 mg, 3.85 mmol) in 1 ,4-dioxane at 100C; followed by 2- chloro-6-fluorobenzyl amine (0.36 mL, 2.8 mmol) in MeCN (1.5 mL) at 180C in a Biotage Initiator microwave reactor using the methods of (IntBI). LCMS (Method A): m/z 421.2, 423.2 (M-H)- (ES-), at 0.13 and 1.13 min, 95% TLC: Rf = 0.64 (iso-hexane:EtOAc)
  • 26
  • [ 1413913-54-8 ]
  • [ 56621-89-7 ]
  • [ 1569514-39-1 ]
YieldReaction ConditionsOperation in experiment
60% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation; A mixture of 2-bromo-N-ieri-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide (150 mg, 351 muiotaetaomicron), <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (65.9 mg, 526 muiotaetaomicron), xantphos (60.9 mg, 105 muiotaetaomicron), Pd2(dba)3 (32.1 mg, 35.1 muiotaetaomicron) and cesium carbonate (229 mg, 702 muiotaetaomicron) in dioxane (2 mL) was heated in a microwave at 150C for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 40-80 % ethyl acetate in hexanes) to give N-ieri-butyl- 2-(2-methoxypyrimidin-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide (99 mg, 210 muiotaetaomicron, 60 %) as a yellow solid. (EI/CI) m/z: 484.3 [M + H].
  • 27
  • [ 16885-99-7 ]
  • [ 79-37-8 ]
  • [ 56621-89-7 ]
  • 2-(1-isopropyl-1H-indol-3-yl)-N-(2-methoxypyrimidin-5-yl)-2-oxoacetamide [ No CAS ]
  • 28
  • [ 79-37-8 ]
  • [ 1158209-64-3 ]
  • [ 56621-89-7 ]
  • 2-(1-(2-methoxyethyl)-1H-indol-3-yl)-N-(2-methoxypyrimidin-5-yl)-2-oxoacetamide [ No CAS ]
  • 29
  • (+/-)-methyl 3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate [ No CAS ]
  • [ 7693-46-1 ]
  • [ 56621-89-7 ]
  • (+/-)-3-(4-(diisobutylamino)-2-fluoro-5-(3-(2-methoxypyrimidin-5-yl)ureido)phenyl)pentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% To a homogeneous mixture of (+-)-methyl 3-(5-amino-4-(diisobutylamino)-2-fluorophenyl)pentanoate (compound 1128D, 25.4 mg, 0.07 mmol) in THF (1 mL), at room temperature in a sealable vial, was added 4-nitrophenyl carbonochloridate (25 mg, 0.12 mmol). The resulting mixture was stirred at ambient temperature for one hour before 4-ethoxy-2-fluoroaniline, HCl (41 mg, 0.22 mmol) and TEA (0.10 mL, 0.72 mmol) were added. The mixture was then stirred at 50 C. for 16 hours then at room temperature for two hours before MeOH (0.5 mL) was added to the reaction vial followed by LiOH (aq) (1M solution, 0.5 mL, 0.50 mmol). After 1.5 hours, the reaction was treated with LiOH (aq) (1M solution, 0.5 mL, 0.50 mmol) and stirred for 20 hours before being treated with acetic acid (0.06 mL, 1.05 mmol). The mixture was diluted with DMSO then purified by preparative RP HPLC (MeCN/H2O gradient+10-mM NH4OAc) to afford Example 1137 (22.6 mg, 60% yield); 12385] Example 1140 (25.7 mg, 73% yield) was preparedfollowing a procedure analogous to that for the synthesis ofExample 1137, except that <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong>(27.1 mg, 0.22 mmol) was used instead of 4-ethoxy-2-fluoroaniline, HC1. ?H NMR (500 MHz, DMSO-d5) oe 9.55(s, 1H), 8.66 (s, 2H), 7.85 (s, 1H), 7.80 (d, J=8.1 Hz, 1H),7.03 (d, J=11.9 Hz, 1H), 3.88 (s, 3H), 3.20-3.08 (m, 1H),2.75-2.61 (m, 4H), 2.58-2.54 (m, 2H), 1.71-1.59 (m, 3H),1.54-1.41 (m, 1H), 0.89-0.80 (m, 12H), 0.72 (t, J=7.3 Hz,3H). MS(ES): mlz=490 [M+H]. Tr=1.82 mm (Method C).
  • 30
  • 4-((4-(4-chloroquinolin-6-yl)phenyl)sulfonyl)morpholine [ No CAS ]
  • [ 56621-89-7 ]
  • N-(2-methoxypyrimidin-5-yl)-6-(4-(morpholinosulfonyl)phenyl)quinolin-4-amine [ No CAS ]
  • 31
  • [ 40052-13-9 ]
  • [ 56621-89-7 ]
  • t-butyl 3-((2-methoxypyrimidin-5-yl)amino)-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.12 g With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 2h;Reflux; A solution of 3-(t-butoxy)-3-oxopropionic acid (CAS No. 40052-13-9) (1.41 g, 8.79 mmol, 1.1 equivalents), <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (CAS No. 56621-89-7) (1.00 g, 7.99 mmol, 1.0 equivalents), triethylamine (1.34 mL, 9.59 mmol, 1.2 equivalents) and EDC (1.84 g, 9.59 mmol, 1.2 equivalents) in DCM (20 mL) was heated to reflux for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel, 50%-100% ethyl acetate/n-heptane) to afford the title compound (2.12 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.52 (s, 9H), 3.42 (s, 2H), 4.01 (s, 3H), 8.76 (s, 2H), 9.52 (br. s, 1H).
 

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