Structure of 135242-93-2
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CAS No. : | 135242-93-2 |
Formula : | C4H7N3O |
M.W : | 113.12 |
SMILES Code : | C[N]1C=NC(=N1)CO |
MDL No. : | MFCD16710296 |
InChI Key : | WEDYTSQNYJKOPC-UHFFFAOYSA-N |
Pubchem ID : | 10351670 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 27.41 |
TPSA ? Topological Polar Surface Area: Calculated from |
50.94 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.78 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.85 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.98 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.19 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.42 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.4 |
Solubility | 44.8 mg/ml ; 0.396 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.26 |
Solubility | 206.0 mg/ml ; 1.82 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.2 |
Solubility | 72.0 mg/ml ; 0.637 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 |
-7.59 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) |
1.78 |
* 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 |
---|---|---|
49% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 48h; | 3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-alpha]pyrimidin-5-one (77 mg, 0.25 mmol), triphenylphosphine (165 mg, 0.63 mmol) and <strong>[135242-93-2](1-methyl-1H-1,2,4-triazol-3-yl)methanol</strong> (80 mg, 0.63 mmol) were suspended in dry tetrahydrofuran (1.5 ml).. diethyl azodicarboxylate (100 mul, 0.63 mmol) was added and a solution resulted immediately.. The reaction was stirred at room temperature for 48 hours before purification by preparative tlc (40percent EtOAc/hexanes) to give a white solid which was recrystallized from ethyl acetate/hexanes to afford 3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[1,5-alpha]pyrimidine (49 mg, 49percent) as white needles, m.p. 170-171° C.; deltaH (400 MHz, d6-DMSO) 3.84 (3H, s, NCH3), 5.57 (2H, s, OCH2), 7.35-7.41 (2H, m, ArH), 7.43-7.51 (4H, m, ArH), 7.73 (2H, dd, J=8.1 and 1.8 Hz, ArH), 8.14 (1H, td, J=7.5 and 1.8 Hz, ArH), 8.45 (1H, s, triazole CH), 9.51 (1H, s, pyrimidine CH); m/z (ES+) 402 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 48h; | 6-Cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-alpha]pyrimidin-5-one (50 g, 0.18 mmol), triphenylphosphine (120 mg, 0.44 mmol) and <strong>[135242-93-2](1-methyl-1H-1,2,4-triazol-3-yl)methanol</strong> (50 g, 0.44 mmol) were suspended in dry tetrahydrofuran (1.5 ml).. diethyl azodicarboxylate (70 mul, 0.44 mmol) was added and a solution resulted immediately.. The reaction was stirred at room temperature for 48 hours during which time a precipitate formed in the reaction mixture.. The crude reaction mixture was evaporated and recrystallized from EtOAc. The pale pink crystalline solid thus produced was collected by filtration and washed with diethyl ether to afford 6-cyclobutyl-3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-alpha]pyrimidine (40 mg, 60percent) as pale needles, m.p. 202-205° C.; deltaH (400 MHz, CDCl3) 1.84-1.92 (1H, m, CH(CH2)3), 2.06-2.16 (3H, m, CH(CH2)3), 3.67 (1H, quintet, J=9 Hz, CH(CH2)3), 3.94 (3H, s, NCH3), 7.19-7.29 (2H, m, ArH), 7.32-7.36 (1H, m, ArH), 8.04 (1H, s, triazole CH), 8.12 (1H, td, J=7.5 and 1.8 Hz, ArH), 8.55 (1H, d, J=1.5 Hz, pyrimidine CH); m/z (ES+) 380 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In thionyl chloride; | c 3-Chloromethyl-1-methyl-1H-1,2,4-triazole (1-Methyl-1H-1,2,4-triazol-3-yl)methanol (500 mg, 4.4 mmol) (prepared using the conditions described in EP-A-421210) was added portionwise to thionyl chloride (5 ml) at 0° C. Upon complete addition the mixture was allowed to warm to room temperature, then heated at reflux for 45 minutes (gas evolution observed). Upon cooling the thionyl chloride was removed in vacuo. The residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate. The aqueous phase was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated to give the title chloride (570 mg), as an oil. This material was used without further purification. Data for the title compound: 1H NMR (250 MHz, CDCl3) delta 3.92 (3H, s), 4.63 (2H, s), 8.10 (1H, s). MS (ES+) m/e 133 [MH]+, 131 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; N,N-dimethyl-formamide; | f 6-(1-Methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-phenyl-3-(pyrazin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine To a solution of <strong>[135242-93-2](1-methyl-1H-1,2,4-triazol-3-yl)methanol</strong> (prepared using the conditions described in EP-A-421210; 0.044 g, 0.39 mmol) in dimethyl formamide (10 ml) was added sodium hydride (0.016 g of a 60percent dispersion in oil, 0.390 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 0.5 h. After this time, the product from Example 1 step e) (0.1 g, 0.325 mmol) was added and the reaction mixture stirred for 2.5 h. The solvent was removed under high vacuum. Water (5 ml) was added to the residue and the solid produced was collected by filtration. The solid was recrystallized from ethyl acetate/ethanol to give the required product (0.049 g, m.p. 256.9-257.8° C.). 1H NMR (360 MHz, CDCl3) delta 3.94 (3H, s), 5.62 (2H, s), 7.47 (3H, m), 7.67 (2H, m), 8.04 (1H, s), 8.10 (1H, s), 870 (1H, s), 8.84 (1H, s), 9.80 (1H, s) MS (ES+) m/e 386 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With ammonium hydroxide; thionyl chloride; | a 1-Methyl-1,2,4-triazole-3-methylamine hydrochloride 1-Methyl-1,2,4-triazole-3-methanol (500 mg, 4.4 mmol) was added to ice-cold thionyl chloride (5 ml, 69 mmol). The mixture was heated at reflux for 0.75 h, then cooled to room temperature and evaporated in vacuo. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution and the aqueous layer separated and further extracted with dichloromethane (*2). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was treated with 33percent w/w aqueous ammonia (5 ml) and the mixture heated in a sealed tube at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was evaporated in vacuo and azeotroped with ethanol to give the title-amine (600 mg, 92percent), 1H NMR (250 MHz, d6-DMSO) delta 3.88 (3H, s, Me), 4.04 (2H, s, CH2), 8.36 (2H, br s, NH2), 8.58 (1H, s, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | In N,N-dimethyl-formamide; | b N,N-Diethyl-N-[6-(1-methyl-1 H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-7-yl]amine To a solution of N-(6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-7-yl)-N,N-diethylamine (180 mg, 0.33 mmol) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (68 mg) in dry DMF (5 ml) was added sodium hydride (60percent dispersion in oil, 34 mg, 0.36 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3*25 ml). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The solid was recrystallized from ethyl acetate, and collected by filtration to afford the title pyridazine (81 mg, 36percent). 1H NMR (500 MHz, DMSO-d6) delta1.08 (6 H, t, J=8.5 Hz), 3.31 (4 H, q, J=8.5 Hz), 3.87 (3 H, s), 5.50 (2 H, s), 7.22 (1 H, s), 7.47-7.59 (3 H, m), 8.37 (2 H, d, J=8.5 Hz), 8.51 (1 H, s). MS (ES+) 379 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
c) 6-(2-Methyl-1,2,4-triazol-5-yl)methyloxy-3-(isoxazol-3-yl)imidazo[5,1-a]phthalazine The title compound was prepared from 6-chloro-3-(isoxazol-3-yl)-imidazo[5,1-a]phthalazine (Part b) and (2-methyl-1,2,4-triazol-5-yl)methanol as described in Example 1, Part c. 1H NMR (360 MHz, CDCl3) delta 3.96 (s, 3H), 5.7 (s, 2H), 7.40 (s, 1H), 7.52 (t, J=8 Hz, 1H), 7.76 (t, J=8 Hz, 1H), 7.89 (s, 1H), 8.0 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 8.56 (s, 1H). MS (ES+) m/e 348 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 1h; | To a solution of (1-methyl-1 H-1 ,2,4-triazol-3-yl)methanol (489 mg, compound D24) in dry DCM (0.6 ml) are added tetrabromomethane (1 .87 g) and triphenylphosphane (1.48 g). The mixture is stirred for 1 h at RT to give 3-(bromomethyl)-1-methyl-1 H-1 ,2,4-triazole. The reaction mixture is directly used in step 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h; | To a cooled (ice bath) solution of (1-methyl- 1H-1 ,2,4-triazol-3-yl)methanol (400 mg, 3.54 mmol) and DIEA (0.98 mL, 7.1 mmol) in CH2CI2 (35 mL) wasadded MsCI (0.41 mL, 5.3 mmol). The reaction was stirred at roomtemperature for 3 h then quenched with NaHCO3 (sat) (20 mL). The layers wereseparated and the aqueous layer was back-extracted with CH2CI2 (15 mL x 2).The combined organic layers were washed with brine (20 mL x 2) then dried over anhydrous Na2504, filtered and concentrated to give(1-methyl- 1H-1 ,2,4-triazol-3-yl)methyl methanesulfonate (650 mg, 96percent) asyellow oil. 1H NMR (400 MHz, ODd3) O [ppm] 8.05 (s, 1H), 5.29(s, 2H), 3.93(s,3H), 3.09 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid; In chloroform; at 20℃; for 4h; | In the third step, 153.1 g (0.443 mol, 1.0 eq) of N-formyl-2-trityloxyacetamide was added to a 1L three-necked flask with a mechanical stirrer and a thermometer.30.6 g (0.664 mol, 1.5 eq) of methyl hydrazine and 800 mL of chloroform, stirring was started, 1.5 g (8.9 mmol, 0.02 eq) of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 4 h. The remaining material in the HPLC control was less than 1percent.225mL2mol/L hydrochloric acid, stirring at room temperature for 2 hours, saturated sodium carbonate solution to adjust the pH value of 6-7, layering, the aqueous layer extracted with chloroform(100mL×2), the organic layer was combined with the solvent under reduced pressure to obtain a crude product, and the crude product was recrystallized from ethanol/water (1:2), suction-filtered and dried.Colorless needle crystals (1-methyl-1H-[1,2,4]triazol-3-yl)-methanol 43.0 g, yield 85percent, purity 97.0percent (HPLC),Mp 73-75°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In dichloromethane; at 15 - 20℃; for 2h; | To a mixture of (l-methyl-l/-/-l,2,4-triazol-3-yl)methanol (400 mg, 3.54 mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane (10 mL) was added TEMPO ((2, 2,6,6- tetramethylpiperidin-l-yl)oxyl) (56 mg, 354 pmol). The mixture was stirred at 15-20C for 2h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ethenethyl acetate = 1:2) to give l-methyl-l/-/-l,2,4-triazole-3-carbaldehyde (300 mg, 2.70 mmol, 76% yield). XH NMR (chloroform-d 400 MHz) d 10.01 (s, 1H), 8.19 (s, 1H), 4.06 (s, 3H). |
76% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In dichloromethane; at 15 - 20℃; for 2h; | To a mixture of <strong>[135242-93-2](1-methyl-1H-1,2,4-triazol-3-yl)methanol</strong> (400 mg, 3.54 mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane (10 mL) was added TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (56 mg, 354 mumop. The mixture was stirred at 15-20 C. for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:2) to give 1-methyl-1H-1,2,4-triazole-3-carbaldehyde (300 mg, 2.70 mmol, 76% yield). 1H NMR (chloroform-d 400 MHz) delta 10.01 (s, 1H), 8.19 (s, 1H), 4.06 (s, 3H). |
76% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In dichloromethane; at 15 - 20℃; for 2h; | To a mixture of 176 <strong>[135242-93-2](1-methyl-1H-1,2,4-triazol-3-yl)methanol</strong> (400 mg, 3.54 mmol) and 177 iodobenzene diacetate (1.25 g, 3.89 mmol) in 68 dichloromethane (10 mL) was added 178 TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (56 mg, 354 mumol). The mixture was stirred at 15-20 C. for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:2) to give 179 1-methyl-1H-1,2,4-triazole-3-carbaldehyde (300 mg, 2.70 mmol, 76% yield). 1H NMR (chloroform-d 400 MHz) delta 10.01 (s, 1H), 8.19 (s, 1H), 4.06 (s, 3H |
76% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; [bis(acetoxy)iodo]benzene; In dichloromethane; at 15 - 20℃; for 2h; | To a mixture of (l-methyl-l/-/-l,2,4-triazol-3-yl)methanol (400 mg, 3.54 mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane (10 mL) was added TEMPO ((2, 2,6,6- tetramethylpiperidin-l-yl)oxyl) (56 mg, 354 pmol). The mixture was stirred at 15-20C for 2h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ethenethyl acetate = 1:2) to give l-methyl-l/-/-l,2,4-triazole-3-carbaldehyde (300 mg, 2.70 mmol, 76% yield). XH NMR (chloroform-d 400 MHz) d 10.01 (s, 1H), 8.19 (s, 1H), 4.06 (s, 3H). |
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; iodobenzene diacetic acid; In dichloromethane; at 15 - 20℃; for 2h; | To a mixture of <strong>[135242-93-2](1-methyl-1H-1,2,4-triazol-3-yl)methanol</strong> (400 mg, 3.54 mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane (10 mL) was added TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (56 mg, 354 mumol. The mixture was stirred at 15-20 C. for 2h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:2) to give 1-methyl-1H-1,2,4-triazole-3-carbaldehyde. | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In dichloromethane; at 15 - 20℃; for 2h; | To a mixture of (1 -methyl-1 H-1 ,2, 4-triazol-3-yl)methanol (400 mg, 3.54 mmol) and iodobenzene diacetate (1 .25 g, 3.89 mmol) in dichloromethane (1 0 mL) was added TEMPO ((2,2,6,6-tetramethylpiperidin-1 -yl)oxyl) (56 mg, 354 muetaiotaomicronIota). The mixture was stirred at 1 5- 20C for 2h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1 :2) to give 1 -methyl-1 H-1 ,2,4-triazole-3- carbaldehyde (300 mg, 2.70 mmol, 76% yield).1H NMR (chloroform-c 400 MHz) delta 1 0.01 (s, 1 H), 8.1 9 (s, 1 H), 4.06 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere; | To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.2 mmol), (1 -methyl- l,2,4-triazol-3-yl)methanol (45.83 mg, 0.41 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (ImL) was added the DIAD (81.92 mg, 0.41 mmol), and the mixture was stirred at 20 °C under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL x 2). Then the combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by purified by prep-HPLC [Kromasil (150 mm x 25 mm, 5 muiotaeta) A = H20 (0.05percent NH4OH) and B = CH3CN; 47-87percentB over 7 minutes] to give the product (21.81 mg, 0.06 mmol, 28percent yield) as a solid. 1H NMR (DMSO-c 400MHz) deltaH = 8.40 (s, 1H), 8.12 (d, 2H), 7.87 (d, 1H), 7.80 (d, 1H), 7.47 (d, 2H), 5.13 (s, 2H), 3.80 (s, 3H). LCMS Rt = 1.12 min in 2 min chromatography, MS ESI calcd. for C17H13F3N5O3 [M+H]+ 392.1, found 392.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | A mixture of carbonyldiimidazole (CDI, 4.62 g, 28.5 mmol), ( 1 -methyl- 1,2, 4-triazol- 3-yl)methanol (3.45g, 30.53 mmol), and 2-MeTHF (50 mL) was stirred at room temperature (20 C) for 3 hours. To the mixture was added methyl (5)-l-amino-7-fluoro-2,3-dihydro-lH- indene-4-carboxylate hydrochloride [lOa.HCl] (5.0 g, 20.35 mmol) followed by N,N- diisopropylethylamine (6.58 g, 50.9 mmol). The contents were heated to 60 C and stirred for 15 hours. The mixture was cooled to 20 C, charged with water (50 mL), and stirred for 30 min. The slurry was filtered, washed with 2-MeTHF (2 x 5 mL) and dried under vacuum to give methyl fV)-7-riuoro- 1 -(((( 1 -methyl- 1 H- 1.2.4-triazol-3-yl)methoy)carbonyl)amino)- 2,3-dihydro-lH-indene-4-carboxylate [11a] as white crystalline solid (5.8g, 81.8% yield). 'H NMR (400 MHz, DMSO-d6) d 8.41 (s, 1H), 7.87 (dd, J = 8.6, 5.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.11 (t, J = 8.8 Hz, 1H), 5.28-5.22 (m, 1H), 4.98 (q, J = 10 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.31 (ddd, J = 17.6, 8.8, 5.5 Hz, 1H), 3.06 (ddd, J = 17.6, 8.7, 6.3 Hz, 1H), 2.44- 2.35 (m, 1H), 1.94-1.81 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
144.5 g | A mixture of carbonyldiimidazole (CDI) (97 g, 0.6 mol), (l-methyl-l,2,4-triazol-3- yl)methanol [8] (67.7 g, 0.6 mol), and 2-MeTHF (1150 mL) was stirred at room temperature (20 C) for 2 hours. The reaction mixture was added to a stirred mixture of (S)- 1 -amino-N- (3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide hydrochloride [7.HC1] (143.3 g, 0.4 mol), 2-MeTHF (860 mL), and N,N-diisopropylethylamine (129 g, 1 mol). The mixture was heated to 60 C and the contents maintained at 60 C for 6 hours. (0248) The contents were cooled to 20 C, water (285 mL) was added, and the mixture was stirred for 15 min. The layers were separated and the organic layer was washed with water two times (285 mL each time). The organic layer was filtered through a pad of CELITE, and rinsed with 145 mL 2-MeTHF (1 volume). The solution was concentrated to about 700 mL under vacuum. 2-propanol (710 mL) was added and the mixture concentrated to about 700 mL. Additional 2-propanol (710 mL) was added and the mixture concentrated to (0249) approximately 1000 mL. The slurry was heated at 45 C for 2 hours and cooled to 20 C over 1 hour. The slurry was stirred at 20 C for 2 hours, and the product filtered. The product was washed with 2-propanol two times (286 mL each wash), and the wet product was dried under vacuum to give (l-methyl-lH-l,2,4-triazol-3-yl)methyl fV)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9] as solid (144.5 g, 78.4% yield). XH NMR (400 MHz, DMSO-d6) d 10.39 (s, 1H), 8.42 (s, 1H), 8.06-7.99 (m, (0250) 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71-7.59 (m, 2H), 7.39 (t, J = 9.1 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 5.26 (q, J = 7.7 Hz, 1H), 4.99 (dd, J = 20.0, 12.0 Hz, 1H), 3.83 (s, 2H), 3.21 (ddd, J = 17.1, 8.8, 5.1 Hz, 1H), 3.04-2.96 (m, 1H), 2.46-2.33 (m, 1H), 1.92-1.83 (m, 1H). mp: 185.9- 186.9 C. |
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