Structure of 49607-51-4
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CAS No. : | 49607-51-4 |
Formula : | C3H6N4 |
M.W : | 98.11 |
SMILES Code : | NC1=NN(C)C=N1 |
MDL No. : | MFCD02853162 |
InChI Key : | CNSCXLZIKKHZND-UHFFFAOYSA-N |
Pubchem ID : | 566503 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 25.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
56.73 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.6 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-1.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.59 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.76 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.54 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.5 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.23 |
Solubility | 58.2 mg/ml ; 0.593 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.49 |
Solubility | 305.0 mg/ml ; 3.11 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.02 |
Solubility | 102.0 mg/ml ; 1.04 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 |
-7.74 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 |
2.0 |
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) |
1.69 |
* 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 |
---|---|---|
99% | With hydrazine;palladium 10% on activated carbon; In methanol; for 1.5h;Heating / reflux; | EXAMPLE H; 1-Methyl-1H-[1,2,4]triazol-3-ylamine; Methyl-3-nitro-1H-1,2,4-triazole (synthesized as desribed in R. W. Middleton et al, Synthesis 1984, 740-3) (613 mg, 4.8 mmol) was dissolved in 6 ml methanol. Palladium on charcoal (10%, 51 mg) and hydrazine monohydrate (543 mg, 11 mmol) were added. The reaction mixture was refluxed for 1.5 h. Palladium on charcoal was filtered off and washed with methanol. The solvent was evaporated off to yield the title compound (469 mg, 99%) as a white solid |
92.5% | With 10 % Pd/C; hydrogen; In ethanol; at 20℃; for 3h; | 1-methyl-3-nitro-1H-1,2,4-triazole (97 mg, 0.76 mmol) was dissolved in ethanol (5.0 mL). 10% Palladium/carbon (10 mg) was added, stirred at room temperature under hydrogen atmosphere for 3 hours. Cerite filtration was carried out after the reaction. The solvent was distilled off to obtain title compound (a yellow solid, 69 mg, 92.5%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | 33). Synthesis of 4-[(3,5-bis-trifluoromethyl-benzoyl)-(1-methyl-1H-{1;2.4]triazol-3-y.)- amino]-2,6-diethyl-piperidine-1-carboxylic acid isopropyl ester; <n="190"/>To a solution of 2,6-diethyl-4-oxo-piperidine-1-carboxylic acid isopropyl ester (1 mmol, 240 mg), 1-methyl-1H-[1 ,2,4]triazol-3-ylamine (2 mmol, 200 mg) and acetic acid (2 mmol, 114 uL) in dichloroethane (2 mL) is added sodium triacetoxyborohydride (2 mmol, 424 mg) at room temperature and stirred for 15 hours. The reaction is quenched by addition of saturated aq. sodium hydrogen carbonate. The mixture is extracted with dichloromethane and the combined organic layer is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: DCM / MeOH) to give 2,6- diethyl-4-(1 -methyl- 1H-[1 ,2,4}triazol-3-ylamino)-piperidine-1-carboxylic acid isopropyl ester (168 mg, 52percent); ESI-MS m/z: 324 [M+1]\\ Retention time 2.06 min (condition A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | EXAMPLE 5 3-[2-(Dimethylamino)ethyl]-5-[(1-methyl -1,2,4-triazol-3-yl) aminomethyl]-1H-indole. Oxalate The title compound free base was prepared in 17percent isolated yield from Intermediate I and 3-amino-1-methyl-1,2,4-triazole (Bull. Soc. Chim. Fr., 1973, 1849) using a similar method to that described for Example 4. The oxalate salt was prepared and recrystallized from methanol; mp 185° C.; deltaH (360 MHz, D2 O)8.09 (1H, s, Ar--H), 7.62 (1H, s, Ar--H), 7.49 (1H, d, J=8.3 Hz, Ar--H), 7.53 (1H, s, At--H), 7.26 (1H, dd, J=8.3 and 1.4 Hz, Ar--H), 4.49 (2H, s, Ar--CH2 --N), 3.71 (3H, s, --NMe), 3.47 (2H, t, J=7.4 Hz, --CH2 --), 3.22 (2H, t, J=7.4 Hz, --CH2 --), 2.90 (6H, s, --NMe2); m/z (EI) 298 (M+). (Found: C, 55.30; H, 6.22; N, 21.23. C16 H21 N6 *1.0C2 H2 O4 *0.2H2 O requires: C, 55.29; H, 6.03; N, 21.49percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.8% | In N,N-dimethyl-formamide; at 80℃; | 4-chloro-7-isothiocyanate-7-de (acetamide)colchicine (54 mg, 0.12 mmol) was dissolved in DMF (1 mL). <strong>[49607-51-4]3-amino-1-methyl-1H-1,2,4-triazole</strong> (15 mg, 0.12x1.2mmol) was added, and stirred at 80 degrees C overnight. The solvent was distilled off after the reaction. Chloroform was added and washed with saturated sodium bicarbonate solution, dried with magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform/methanol) to obtain title compound (a yellow solid, 42 mg, 65.8percent) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.4% | Triphosgene (0.588 g, 1.982 mmol) was added to a stirred solution of (4S)-7-(2- methylpyridin-4-yl)-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3-b][l,4]diazepine (0.5g, 1.982 mmol) in tetrahydrofuran (20 mL) at 0 C and stirred for 30min. Triethylamine (0.829 mL, 5.94 mmol) and 1 -methyl- lH-l,2,4-triazol-3 -amine (0.486 g, 4.95 mmol) was added at 0 C. The reaction mixture was stirred for 48h at 70 C. The reaction mixture was cooled to 28 C, and was partitioned between water (50 mL) and DCM (50 mL). The separated organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SC"4, filtered and filtrate was evaporated to afford crude yellow solid (TLC eluent: 10% MeOH in EtOAc: Rr0.3; UV active). The crude compound was purified by (100-200 mesh) silica gel and was eluting with 5% MeOH in ethyl acetate to afford (4S)-N-(1 -methyl- H- 1 ,2,4-triazol-3 -yl)-7-(2-methylpyridin-4-yl)-3,4-dihydro- 1 ,4- methanopyrido[2,3-6][l,4]diazepine-5(2H)-car-boxamide (0.215g, 0.563 mmol, 28.4 % yield) as light yellow solid, LCMS (m/z): 377.28 [M+H]+.1H NMR (400 MHz, DMSO-i): delta 13.44 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.86 - 7.61 (m, 3H), 5.44 (dd, J = 5.8, 3.0 Hz, 1H), 3.83 (s, 3H), 3.27 (d, J = 30.5 Hz, 3H), 2.95 (dd, J= 12.0, 3.2 Hz, 1H), 2.59 (s, 3H), 2.23 (ddt, J= 16.9, 9.7, 4.4 Hz, 1H), 1.91 (dt, J= 14.7, 7.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.4% | Triphosgene (0.588 g, 1.982 mmol) was added to a stirred solution of (4S)-7-(2-methylpyridin-4-yl)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepine (0.5 g, 1.982 mmol) in tetrahydrofuran (20 mL) at 0° C. and stirred for 30 min. Triethylamine (0.829 mL, 5.94 mmol) and <strong>[49607-51-4]1-methyl-1H-1,2,4-triazol-3-amine</strong> (0.486 g, 4.95 mmol) was added at 0° C. The reaction mixture was stirred for 48 h at 70° C. The reaction mixture was cooled to 28° C., and was partitioned between water (50 mL) and DCM (50 mL). The separated organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and filtrate was evaporated to afford crude yellow solid (TLC eluent: 10percent MeOH in EtOAc: Rf-0.3; UV active). The crude compound was purified by (100-200 mesh) silica gel and was eluting with 5percent MeOH in ethyl acetate to afford (4S)?N-(1-methyl-1H-1,2,4-triazol-3-yl)-7-(2-methylpyridin-4-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-car-boxamide (0.215 g, 0.563 mmol, 28.4percent yield) as light yellow solid, LCMS (m/z): 377.28 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta 13.44 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.86-7.61 (m, 3H), 5.44 (dd, J=5.8, 3.0 Hz, 1H), 3.83 (s, 3H), 3.27 (d, J=30.5 Hz, 3H), 2.95 (dd, J=12.0, 3.2 Hz, 1H), 2.59 (s, 3H), 2.23 (ddt, J=16.9, 9.7, 4.4 Hz, 1H), 1.91 (dt, J=14.7, 7.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 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 90℃;Inert atmosphere; | General procedure: To a solution of 9 (88 mg, 0.5 mmol) in DMF (10 mL) was added Cs2CO3 (179 mg, 0.55 mmol) and 1-(chloromethyl)-3-iodobenzene (151 mg, 0.52 mmol). The resulting reaction mixture was stirred at 40-50 C for 3 h, and then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (30 mL). The organic layer was washed with brine (10 mL 3) and then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by using column chromatography to afford the corresponding product 10a in 75percent yield. To a solution of 10a (102 mg, 0.26 mmol), the corresponding amines (0.31 mmol) in 1, 4-dioxane (15 mL) was added Pd2(dba)3 (7.3 mg, 0.008 mmol), Xantphos (5 mg, 0.008 mmol) and Cs2CO3(101 mg, 0.31 mmol) under nitrogen atmosphere. The reaction mixture was heated to 90 C with stirring overnight. The solution was concentrated under reduced pressure, and then the residue was purified by column chromatography on silica gel to afford compounds .4.3.1. 2-(3-((1-Methyl-1H-1,2,4-triazol-3-yl)amino)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (14)white solid (76percent). 1HNMR (300 MHz, DMSO-d6) d 9.11 (s, 1H),8.20 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.78 (d, J 9.6 Hz, 1H), 7.48 (s,1H), 7.43 (d, J 8.1 Hz, 1H), 7.14 (t, J 7.8 Hz, 1H), 7.01 (d, J 9.6 Hz,1H), 6.71 (d, J 7.5 Hz, 1H), 5.16 (s, 2H), 3.85 (s, 3H), 3.70 (s, 3H).13CNMR (126 MHz, DMSO-d6) d 160.7, 159.0, 143.3, 142.7, 140.0, 137.7,137.1, 131.7, 130.5, 129.7, 129.2, 118.8, 118.5, 115.1, 54.77, 39.2, 36.0.MS (ESI) m/z 363.2 [MH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 150℃; for 1h; | 5 ml of toluene were added to 100 mg (0.22 mmol) of 5-[4-chloro-3-(trifluoromethyl)phenoxy]-2-(methylsulphonyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (Example 40A) and 57 mg (0.67 mmol) of 4-amino-1H-pyrazole, and the mixture was then re-concentrated under reduced pressure. A drop of DMSO was added to the residue, and the mixture was then stirred at 150° C. for 1 h. The mixture was then purified directly by preparative HPLC [column: Chromatorex C18 10 mum, 250×30 mm; flow rate: 50 ml/min; run time: 45 min; detection: 210 nm; injection after 3 min of run time; mobile phase A: acetonitrile, mobile phase B: water; gradient: 10percent A (5.00 min)?95percent A (35.00-40.00 min)?10percent A (40.50-45.00 min)]. This gave 30 mg (31percent of theory) of the title compound.LC-MS (Method 1): Rt=1.03 min; MS (ESpos): m/z=440.0 (M+H)+1H-NMR (400 MHz, DMSO-d6): delta=7.37 (m, 1H), 7.48 (d, 1H), 7.64 (m, 2H), 7.92 (br. s, 1H), 9.10 (br. s, 1H), 11.98 (br. s, 1H), 12.66 (br. s, 1H). The Exemplary compounds below were prepared analogously to Example 104 from the appropriate 2-methylsulphonyl-substituted pyrimidinones and the respective amine components: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | In toluene; at 150℃; for 1h; | General procedure: 5 ml of toluene were added to 100 mg (0.22 mmol) of 5-[4-chloro-3-(trifluoromethyl)phenoxy]-2-(methylsulphonyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (Example 40A) and 57 mg (0.67 mmol) of 4-amino-1H-pyrazole, and the mixture was then re-concentrated under reduced pressure. A drop of DMSO was added to the residue, and the mixture was then stirred at 150° C. for 1 h. The mixture was then purified directly by preparative HPLC [column: Chromatorex C18 10 mum, 250×30 mm; flow rate: 50 ml/min; run time: 45 min; detection: 210 nm; injection after 3 min of run time; mobile phase A: acetonitrile, mobile phase B: water; gradient: 10percent A (5.00 min)?95percent A (35.00-40.00 min)?10percent A (40.50-45.00 min)]. This gave 30 mg (31percent of theory) of the title compound.The Exemplary compounds below were prepared analogously to Example 104 from the appropriate 2-methylsulphonyl-substituted pyrimidinones and the respective amine components:(20percent of theory; without addition of DMSO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | (2S,3S)-2-(Fluoromethyl)-7-(methylcarbamoyl)-3-phenyl-2,3-d ihyd robenzofuran-5-carboxylic acid (80 mg, 0.24 minol) and HATU (111 mg, 0.292 minol) were dissolved in DMSO (0.85 mL), andthe resulting solution was treated with DIPEA (0.127 mL, 0.729 minol) and the reaction minxture wasleft to stir at rt for 5 min 1-Methyl-1H-1,2,4-triazol-3-amine (23.8 mg, 0.243 minol) was added andthe reaction was left to stir for 1 h at rt. Further HATU (111 mg, 0.292 minol) and DIPEA (0.127 mL,0.729 minol) were added and the reaction minxture was left to stir for 5 min then <strong>[49607-51-4]1-methyl-1H-1,2,4-triazol-3-amine</strong> (23.8 mg, 0.243 minol) was added and reaction minxture stirred for 2 h at rt. FurtherHATU (111 mg, 0.292 minol) and DIPEA (0.127 mL, 0.729 minol) were added and the reaction minxturewas left to stir for 5 min then <strong>[49607-51-4]1-methyl-1H-1,2,4-triazol-3-amine</strong> (23.8 mg, 0.243 minol) was addedand reaction minxture stirred for 2 h at rt and was then left to stand overnight. HATU (111 mg, 0.292minol) and DIPEA (0.127 mL, 0.729 minol) were again added and the reaction minxture was left to stirfor 5 min then <strong>[49607-51-4]1-methyl-1H-1,2,4-triazol-3-amine</strong> (23.8 mg, 0.243 minol) was added and reaction minxture stirred for 3 h then left to stand over the weekend. The reaction minxture had separated and become solid and not all of the reactants seemed to have gone into solution therefore further DMSO (1 mL) was added to the reaction minxture and it was left to stir at rt for 3 h. 1-Methyl-1H-1,2,4-triazol- 3-amine (23.8 mg, 0.243 minol) was added and the reaction minxture was left to stir at rt for 1 h thenleft to stand overnight. Further HATU (iii mg, 0.292 minol), DIPEA (0.127 mL, 0.729 minol) and 1- methyl-1H-1,2,4-triazol-3-amine (23.8 mg, 0.243 minol) were added and the reaction left to stir at rt for 1 h. Further HATU (iii mg, 0.292 minol), DIPEA (0.127 mL, 0.729 minol) and 1-methyl-1H-1,2,4- triazol-3-amine (23.8 mg, 0.243 minol) were added and the reaction left to stir at rt for 1 h. The reaction minxture was then purified by MDAP (method high pH) to give (2S,3S)-2-(fluoromethyl)-N7-methyl-N5-( 1-methyl-i H-1,2,4-triazol-3-yl)-3-phenyl-2,3-d ihydrobenzofuran-5,7-dicarboxaminde (24.8 mg 25percent) as a white solid.LCMS (method forminc): Retention time 0.79 min [M+H] = 410 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With acetic acid; for 7h;Reflux; | 3,4-Dimethylfuran-2,5-dione (550 mg, 4.36 mmol, 1.05 equiv) and <strong>[49607-51-4]1-methyl-1H-1,2,4-triazole-3-amine</strong> (407 mg, 4.15 mmol, 1.00 equiv) were dissolved in concentrated acetic acid (15 ml) and stirred under reflux conditions for 7 h. After cooling to room temperature, water and ethyl acetate were added and the mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 3,4-dimethyl 1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-pyrrole-2,5-dione in the form of a colorless solid (90 mg, 10% of theory). 1H-NMR (400 MHz, d6-DMSO delta, ppm) 8.09 (s, 1H), 3.75 (s, 3H), 2.01 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With toluene-4-sulfonic acid; In toluene; at 100℃; for 0.5h;Microwave irradiation; | 3-Chloro-4-methylfuran-2,5-dione (625 mg, 4.27 mmol, 1.00 equiv) and <strong>[49607-51-4]1-methyl-1H-1,2,4-triazole-3-amine</strong> (419 mg, 4.15 mmol, 1.00 equiv) were dissolved in toluene (10 ml), 4-toluenesulfonic acid monohydrate (12 mg, 0.06 mmol, 0.02 equiv.) was added and the mixture was stirred under microwave conditions at a temperature of 100 C. for 30 minutes. After cooling to room temperature, water and ethyl acetate were added and the reaction mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 3-chloro-4-methyl-1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-pyrrole-2,5-dione in the form of a colorless solid (110 mg, 11% of theory). 1H-NMR (400 MHz, d6-DMSO delta, ppm) 8.13 (s, 1H), 3.80 (s, 3H), 2.09 (s, 3H). |
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