Structure of 56621-89-7
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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 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 |
61.03 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.14 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.17 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.08 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.9 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.2 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.07 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.94 |
Solubility | 14.5 mg/ml ; 0.116 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.66 |
Solubility | 27.6 mg/ml ; 0.221 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.38 |
Solubility | 5.24 mg/ml ; 0.0419 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.18 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.89 |
* 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.
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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%. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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]+ . |
Yield | Reaction Conditions | Operation 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]+ . |
Yield | Reaction Conditions | Operation 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]+ . |
Yield | Reaction Conditions | Operation 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]+ . |
Yield | Reaction Conditions | Operation 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]+ . |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation 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]. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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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