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CAS No. : | 64517-88-0 | MDL No. : | MFCD02055826 |
Formula : | C5H9N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AXLKRXWNAFFPDB-UHFFFAOYSA-N |
M.W : | 111.15 | Pubchem ID : | 4431056 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.86 |
TPSA : | 43.84 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.01 cm/s |
Log Po/w (iLOGP) : | 1.09 |
Log Po/w (XLOGP3) : | -0.05 |
Log Po/w (WLOGP) : | 0.32 |
Log Po/w (MLOGP) : | -0.27 |
Log Po/w (SILICOS-IT) : | 0.08 |
Consensus Log Po/w : | 0.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.96 |
Solubility : | 12.2 mg/ml ; 0.11 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.42 |
Solubility : | 42.3 mg/ml ; 0.38 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.76 |
Solubility : | 19.1 mg/ml ; 0.172 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.44 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 20℃; for 18h; | [7]; DMA was used as the reaction solvent. The reaction product was purified by trituration in a saturated aqueous sodium bicarbonate solution. The resultant solid was isolated, washed with water and dried under vacuum. The product gave the following characterising data :- 1HNMR Spectrum: (DMSOd6) 1.45 (t, 3H), 2.12 (s, 3H)5 3.69 (s, 3H)5 3.81 (s, 3H)5 3.84 (q, 2H)5 4.29 (q5 2H), 6.84 (d, IH), 7.46 (d, IH)5 7.79 (d, IH)5 7.81 s, IH), 8.03 (d, IH), 8.73 (s, IH)5 8.74 (d, IH)5 9.52 (s, IH); Mass Spectrum: M+H+ 449. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | [5]; 2-(6-Chlorobenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate(V) as the coupling agent. The product gave the following characterising data :- 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 3.66 (s, 2H), 3.70 (s, 3H), 3.78 (s, 3H), 6.77 (d, IH), 6.91 (m, IH), 7.06 (d, IH), 7.37 (d, IH), 7.81 (s, IH)5 8.08 (s, IH), 8.92 (s, IH), 9.44 (s, IH), 9.57 (d, IH); Mass Spectrum: M+H+ 438 and 440. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | [6]; 2-(6-Chlorobenzotriazol-l-yl)-l,l,353-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol-l-yl)-l,l,353-tetramethyluronium hexafluorophosphate(V) as the coupling agent. The product gave the following characterising data :- 1H NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 3.66 (s, 2H), 3.7 (s, 3H), 3.78 (s, 3H)5 4.02 (s, 3H)5 6.51 (d, IH), 6.88 (m, IH)5 7.03 (d, IH), 7.22 (s, IH)5 7.35 (d, IH)5 7.81 (s, IH), 8.77 (d, IH)5 9.43 (s, 2H); Mass Spectrum: M+H+ 434. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere; | 2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide (3.36 g, 10.19 mmol), l,3-dimethylpyrazol-4-amine (1.133 g, 10.19 mmol), palladium(II) acetate (0.183 g, 0.82 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.943 g, 1.63 mmol) and cesium carbonate (3.98 g, 12.23 mmol) were mixed together in dioxane (60 mL). The reaction was degassed with argon and was stirred at 90 0C for 3 hours under argon. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with <n="186"/>2 to 8 % MeOH in DCM. The solvent was evaporated to dryness to give an orange solid. This solid was recrystallised from acetonitrile and the resulting crystalline solid was collected by filtration, washed with acetonitrile and dried to a constant weight in a vacuum oven at 600C to afford the title compound (1.875 g, 4.64 mmol, 45.5 %) as a clear orange crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 24h;Inert atmosphere; | Example 1.012- [ [5-C yano-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll amino I -N-methyl- benzamide 2-[(2-Chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (200 mg, 0.70 mmol), palladium(II) acetate (12.53 mg, 0.06 mmol), l,3-dimethylpyrazol-4-amine (155 mg, 1.40 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (48.4 mg, 0.08 mmol) and cesium carbonate (273 mg, 0.84 mmol) were suspended in dioxane (5 mL). The mixture was purged for 5 minutes with nitrogen and then heated at 900C for 24 hours. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a solution of 7N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 1.01 (126 mg, 50% yield); 1U NMR spectrum: (300 MHz, DMSO) delta 2.12 (3H, s), 2.84 (3H, d), 3.77 (3H, s), 6.60 (IH, s), 7.21 (IH, ddd), 7.58 (2H, d), 7.79 (IH, d), <n="102"/>7.88 (IH, s), 8.35 (IH, s), 8.66 (IH, s), 8.72 (IH, d), 10.28 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 362.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 4.128- [ [2- [(1 ,3-Dimethylpyrazol-4-yl)aminol -5-fluor o-4-pyridyll aminol -2-methyl-3,4- dihydroisog uinolin- 1-one A mixture of 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4- dihydroisoquinolin- 1-one (100 mg, 0.33 mmol), l,3-dimethylpyrazol-4-amine (48 mg, 0.43 mmol), sodium tert-butoxide (51.5 mg, 0.54 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (41.4 mg, 0.07 mmol) in anhydrous dioxane (3 mL) was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (32.7 mg, 0.057 mmol) was added. The mixture was heated at 15O0C for 30 minutes in a microwave reactor. MeOH was added and the mixture loaded onto an SCX column. The product was eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 4.12 (50.1 mg, 40% yield); 1H NMR spectrum (300 MHz, DMSO): delta 2.09 (3H, s), 2.95 (2H, t), 3.05 (3H, s), 3.55 (2H, t), 3.70 (3H, s), 6.83 - 6.85 (2H, m), 7.38 - 7.43 (2H, m), 7.85 (IH, s), 7.89 (2H, t), 11.24 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 381.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 1h;Inert atmosphere; | Example 1.032- [ [5-C yano-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -N-methoxy-N- methyl-benzamide A mixture of 2- [(2-chloro-5 -cyanopyridin-4-yl)amino] -N-methoxy-N- methylbenzamide (100 mg, 0.32 mmol), palladium(II) acetate (5.67 mg, 0.03 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (21.92 mg, 0.04 mmol), 1,3- dimethylpyrazol-4-amine (70.2 mg, 0.63 mmol) and cesium carbonate (123 mg, 0.38 mmol) were suspended in dioxane (2 mL). The mixture was purged for 5 minutes with nitrogen and then heated at 900C for 1 hour. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then using a solution of 7N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 1.03 (37 mg, 30% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.02 (3H, s), 3.21 (3H, s), 3.47 (3H, s), 3.69 (3H, s), 6.08 (IH, s), 7.28 (IH, td), 7.41 (IH, d), 7.48 - 7.56 (2H, m), 7.77 (IH, s), 8.12 (IH, s), 8.22 (IH, s), 8.49 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 392.49. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 150℃; for 1h;Inert atmosphere; Microwave irradiation; | Example 4.28 7- [ [2- [(1 ,3-Dimethylpyrazol-4-yl)aminol -5-fluor o-4-pyridvH aminol -4-(4- isopropylpiperazin-l-yl)-2-methyl-isoindolin-l-one A mixture of 7-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-4-(4-propan-2- ylpiperazin-l-yl)-3H-isoindol-l-one (150 mg, 0.36 mmol), l,3-dimethylpyrazol-4-amine <n="171"/>(80 mg, 0.72 mmol), cesium carbonate (234 mg, 0.72 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (24.92 mg, 0.04 mmol) and palladium(II) acetate (6.45 mg, 0.03 mmol) was suspended in DMA (2 mL) under an atmosphere of nitrogen. The mixture was heated at 1500C for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was filtered and the filtrate evaporated. The residue was dissolved in MeOH (20 mL) and the solution made acidic (pH6) by the addition of 2M HCl. The mixture was loaded onto an SCX column and the product eluted first wit MeOH and then with a 0.7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated and the residue was then purified by preparative HPLC. Fractions containing product were combined and evaporated to afford example 4.28 (45.4 mg, 26% yield); 1H NMR spectrum (300 MHz, DMSO): delta 1.02 (6H, d), 2.11 (3H, s), 2.60 (4H, t), 2.70 (IH, m), 2.99 (4H,m), 3.06 (3H, s), 3.70 (3H, s), 4.48 (2H, s), 6.92 (IH, d), 7.15 (IH, d), 7.39 (IH, d), 7.86 - 7.93 (3H, m), 9.26 (IH, d); Mass spectrum: m/z (ESI+) (M+H)+ = 493.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 1h;Inert atmosphere; | Example 1.096-[(l.,3-Dimethylpyrazol-4-yl)aminol-4-[[7-(4-isopropylpiperazin-l-yl)-2-methyl-3- oxo-isoindolin-4-yll aminol pyridine-3-carbonitrile 6-Chloro-4-[[2-methyl-3-oxo-7-(4-propan-2-ylpiperazin-l-yl)-lH-isoindol-4- yl]amino]pyridine-3-carbonitrile (100 mg, 0.24 mmol), palladium(II) acetate (4.23 mg, 0.02 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (16.34 mg, 0.03 mmol), l,3-dimethylpyrazol-4-amine (52.3 mg, 0.47 mmol) and cesium carbonate (92 mg, 0.28 mmol) were suspended in dioxane (2 mL). The mixture was purged for 5 minutes with <n="112"/>nitrogen and then heated at 900C for 1 hour. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a solution of 7N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 1.09 (31 mg, 26% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.02 (6H, d), 2.09 (3H, s), 2.60 (4H, t), 2.68 - 2.73 (IH, m), 3.01 (4H, t), 3.06 (3H, s), 3.72 (3H, s), 4.49 (2H, s), 6.72 (IH, s), 7.14 (IH, d), 7.39 (IH, d), 7.86 (IH, s), 8.30 (IH, s), 8.65 (IH, s), 9.26 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 500.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In tetrahydrofuran; 1,4-dioxane; at 140℃; for 0.666667h;Microwave irraidiation; | Example 48 2-({5-Chloro-2-[(1,3-dimethyl-1H-pyrazol-4-yl)-amino]-4-pyridinyl}amino)-N-(methyloxy)benzamide A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (250 mg, 0.8 mmol), <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (187 mg, 1.68 mmol), cesium carbonate (783 mg, 2.4 mmol) and dioxane/THF (3:1 ml). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (9 mg, 0.04 mmol) and BINAP (50 mg, 0.08 mmol) were added. The mixture was stirred in a microwave at 140 C. for 40 min. It was evaporated and the residue dissolved in MeOH was filtered thru celite and thru an Acrodisc and purified further using preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. Ether was added to the residue and a tan precipitate crashed out. It was filtered off and dried under vacuum at 40 C. for 2 days to afford the desired product (55 mg, 18%) as a tan solid. LC-MS (ES) m/z=387.1, [M+H]+=389.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.93 (br. s., 1H) 9.51 (br. s., 1H) 8.03 (s, 1H) 7.96 (s, 1H) 7.82 (s, 1H) 7.51-7.61 (m, 3H) 7.07-7.15 (m, 1H) 6.68 (s, 1H) 3.70 (d, J=4.29 Hz, 6H) 2.07 (s, 3H). |
5% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 3.01 l-rrS-Chloro-l-rfU-dimethylpyrazoM-vDaminol^-pyridyllaminol-N-methoxy- benzamide 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxybenzamide (0.1 g, 0.32 mmol), 1,3- dimethylpyrazol-4-amine (0.053 g, 0.48 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.037 g, 0.06 mmol) and sodium tert-butoxide (0.046 g, 0.48 mmol) were suspended in dioxane (5 mL) and purged with nitrogen. Bis(dibenzylideneacetone)palladium (0.029 g, 0.050 mmol) was added and the mixture was heated at 1500C for 30 minutes in a microwave reactor. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a solution of 0.35N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 3.01 (6.0 mg, 5% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.06 (3H, s), 3.69 - 3.71 (6H, m), 6.66 (IH, s), 7.08 - 7.13 (IH, m), 7.50 - 7.60 (4H, m), 7.80 (IH, s), 7.95 - 7.99 (2H, m), 9.43 (IH, s), 11.87 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 387.03 and 389.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 3.226-[[5-Chloro-2-[(l,3-dimethylpyrazol-4-yl)aminol-4-pyridyllaminol-4-methyl-2,3- dihydro- 1 ,4-benzoxazepin-5-one 6-[(2,5-Dichloropyridin-4-yl)amino]-4-methyl-2,3-dihydro- 1 ,4-benzoxazepin-5- one (118mg, 0.35 mmol), l,3-dimethylpyrazol-4-amine (58.2 mg, 0.52 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (40.4 mg, 0.07 mmol) and sodium tert- butoxide (50.3 mg, 0.52 mmol) were suspended in dioxane (5 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (32.0 mg, 0.056 mmol) was added. The mixture was heated at 1500C for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product was eluted first with MeOH and then using a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC. Fractions containing product were combined and evaporated to afford example 3.22 (39.0 mg, 27 % yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.06 (3H, s), 3.12 (3H, s), 3.50 (2H, t), 3.69 (3H, s), 4.32 (2H, t), 6.66 (IH, s), 6.77 - 6.80 (IH, m), 7.32 - 7.34 (IH, m), 7.46 (IH, t), 7.80 (IH, s), 7.93 (IH, s), 7.98 (IH, s), 9.00 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 413.05 and 415.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 3.357- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -2-methyl- isoindolin-1-one <n="144"/>7-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3H-isoindol-l-one (156 mg, 0.51 mmol), l,3-dimethylpyrazol-4-amine (84 mg, 0.76 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (58.6 mg, 0.10 mmol) and sodium tert-butoxide (73.0 mg, 0.76 mmol) were suspended in dioxane (5 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (46.4 mg, 0.081 mmol) was added and the mixture heated at 1500C for 30 minutes in a microwave reactor. The mixture was allowed to cool to room temperature and then loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC. Fractions containing product were combined and evaporated to afford example 3.35 (27.0 mg, 14% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.11 (3H, s), 3.07 (3H, s), 3.71 (3H, s), 4.47 (2H, s), 7.00 (IH, s), 7.15 (IH, d), 7.44 - 7.47 (IH, m), 7.54 (IH, d), 7.87 (IH, s), 8.00 (IH, s), 8.14 (IH, s), 9.53 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 383.05 and 385.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 3.387- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -4-(4- 5 isopropylpiperazin-l-yl)-2-methyl-isoindolin-l-one A mixture of 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-4-(4-propan-2- ylpiperazin-l-yl)-3H-isoindol-l-one (0.20 g, 0.46 mmol), l,3-dimethylpyrazol-4-amine (0.061 g, 0.55 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.053 g, 0.0910 mmol) and sodium te/t-butoxide (0.066 g, 0.69 mmol) was suspended in dioxane (5 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (0.042 g, 0.073 mmol) was added. The mixture was heated at 1500C for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first using MeOH and then with a 0.35M <n="148"/>solution ofNH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 3.38 (0.050 g, 21% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.00 - 1.03 (6H, m), 2.10 (3H, s), 2.55 - 2.62 (4H, m), 2.65 - 2.72 (IH, m), 2.98 - 3.01 (4H, m), 3.06 (3H, s), 3.71 (3H, s), 4.48 (2H, s), 6.91 (IH, s), 7.14 (IH, d), 7.41 (IH, d), 7.85 (IH, s), 7.95 (IH, s), 8.07 (IH, s), 9.32 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 509.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 3.392- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -3-fluoro-N- methyl-benzamide l,3-Dimethylpyrazol-4-amine (53.1 mg, 0.48 mmol), 2-[(2,5-dichloropyridin-4- yl)amino]-3-fluoro-N-methylbenzamide (lOOmg, 0.32 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (36.8 mg, 0.06 mmol) and sodium tert-butoxide (45.9 mg, 0.48 mmol) were suspended in dioxane (3 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (28 mg, 0.049 mmol) was added and the mixture was heated at 1500C for 30 minutes in a microwave reactor. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The product was eluted first with MeOH and then with a 0.7M solution OfNH3 in MeOH and pure fractions were evaporated. The residue was purified by preparative HPLC to afford example 3.39 (37.7 mg, 30% yield); 1H NMR spectrum: (300 MHz, DMSO) delta IH NMR (300.132 MHz, DMSO) delta 2.02 (3H, s), 2.75 (3H, s), 3.67 (3H, s), 5.84 (IH, d), 7.31 (IH, td), 7.45 - 7.54 (2H, m), 7.74 (IH, s), 7.88 (IH, s), 7.91 (IH, s), 8.63 - 8.95 (2H, m); Mass spectrum: m/z (ESI+) (M+H)+ = 389.3 and 391.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 3.402- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -6-fluoro-N- methyl-benzamide l,3-Dimethylpyrazol-4-amine (70.8 mg, 0.64 mmol), 2-[(2,5-dichloropyridin-4- yl)amino]-6-fluoro-N-methylbenzamide (100 mg, 0.32 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (36.8 mg, 0.06 mmol) and sodium tert-butoxide (45.9 mg, 0.48 mmol) were suspended in dioxane (3 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (28 mg, 0.049 mmol) was added and the mixture heated at 1500C for 1 hour in a microwave reactor. The mixture was allowed to cool to room temperature and the mixture was acidified with a 2M solution of HCl in MeOH. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 0.7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated to afford example 3.40 (46.4 mg, 38% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.99 (3H, s), 2.71 (3H, d), 3.62 (3H, s), 6.53 (IH, d), 6.92 (IH, m), 7.26 (IH, d), 7.42 (IH, td), 7.73 (IH, s), 7.87 (IH, s), 7.93 (IH, s), 8.49 (IH, m), 8.68 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 389.3 and 391.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 0℃; | Example 4. Compounds of formula IV[0077] 4-Isothiocyanato-l -methyl- lH-pyrazole (Compound 1012), 4-isothiocyanato-l,3- dimethyl-lH-pyrazole (Compound 1013), and l-ethyl-4-isothiocyanato-lH-pyrazole (Compound 1014) were prepared from 1 -methyl- lH-pyrazol-4-amine, l,3-dimethyl-lH-pyrazol-4-amine (from Matrix Chemical Co.), and 1 -ethyl- lH-pyrazol-4-amine (from Oakwood Products), respectively, by reacting the pyrazolamine with thiophosgene at O0C in the presence of pyridine.CH,[1012] [1013] [1014] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 134 (1S,2S,3R,4R)-3-({5-chloro-2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> for 1-methyl-1H-pyrazol-4-amine in Example 1B along with substitution of (+)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4,5-trichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6, T=90 C.) ppm 1.34-1.47 (m, 1H) 2.06-2.16 (m, 4H) 2.73 (s, 1H) 2.87 (s, 1H) 3.71 (s, 3H) 4.03-4.15 (m, 1H) 6.21 (dd, J=5.49, 3.05 Hz, 1H) 6.31 (dd, J=5.65, 2.90 Hz, 1H) 7.42 (d, J=7.63 Hz, 1H) 7.65 (s, 1H) 7.81 (s, 1H) 7.87 (s, 1H); MS (ESI(+)) m/e 374 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 135 (1S,2S,3R,4R)-3-({5-bromo-2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> for 1-methyl-1H-pyrazol-4-amine in Example 1B along with substitution of (+)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4-dichloro-5-bromopyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6) ppm 1.37-1.43 (m, 1H) 2.05-2.17 (m, 4H) 2.49-2.53 (m, 1H) 2.72 (s, 1H) 2.86 (s, 1H) 3.70 (s, 3H) 4.03-4.14 (m, 1H) 6.20 (dd, J=5.80, 3.05 Hz, 1H) 6.30 (dd, J=5.65, 2.90 Hz, 1H) 7.38 (d, J=7.93 Hz, 1H) 7.64 (s, 1H) 7.88 (s, 1H) 7.91 (s, 1H); MS (ESI(+)) m/e 418, 420 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | 4-Bromo-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromobenzenesulfonyl chloride (396 mg, 1.55 mmol) and <strong>[64517-88-0]4-amino-1,3-dimethyl-1H-pyrazole</strong> (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (469 mg, 1.42 mmol, 92%). OH (D-6 DMSO, 300K) 9.44 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.57 (2H, d J 8.7 Hz), 7.39 (1H, s), 3.65 (3H, s), 1.70 (3H, s). m/z (ES+, 70V) 332.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | 4-Bromo-2,6-dichloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and <strong>[64517-88-0]4-amino-1,3-dimethyl-1H-pyrazole</strong> (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a pale pink solid (501 mg, 1.26 mmol, 82%). deltaH (CDCl3, 300K) 7.65 (2H, s), 7.31 (1H, s), 6.77 (1H, s), 3.78 (3H, s), 2.04 (3H, s). m/z (ES+, 70V) 399.9 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | In iso-butanol; at 110℃; | 100367] Step A: (5)-i -(2-(tert-Butyldimethylsilyloxy)- 1 -(4-chloro-3 -fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2( 111)-one (0.100 g, 0.186 mmol) and i,3-dimethyl-1H-pyrazol-4-amine (0.413 g, 3.72 mmol) were placed in s-BuOH (2 mL), heated to 110C overnight, then poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:10 DCMJMeOH) to give the product (5)-i -(2-(tert-butyldimethylsilyloxy)- 1 -(4-chloro-3-fluorophenyl)ethyl)-4-(2-(( 1,3 - dimethyl- 1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2( 1 11)-one (0.070 g, 66.2% yield).[00368] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | 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), l,3-dimethyl-lH-pyrazol-4-amine (58.5 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, 25-100% ethyl acetate in hexanes) lo give N-iert-butyl- 2-(l,3-dimethyl-lH-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide (89 mg, 194 muiotaetaomicron, 55 %) as a yellow gum. (EI/CI) m/z 458.3 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With toluene-4-sulfonic acid; In 1,4-dioxane; at 120℃; for 6h;Microwave irradiation; | Exam p1e26: Synthesis of I -(2-(2-(5-Chloro-2-((I ,3-di methyl-I H-pyrazol-4- yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (26) (a) 1-(2-(2-(5-Chloro-2-((1, 3-dimethyl- 1H-pyrazol-4-yI)amino)pyrimidin-4- yI)ethyl)phenyl) cyclopropanecarboxamide (26)A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4- yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (0.070 g, 0.63 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.032 mmol) in 1,4-dioxane (1.0 mL) was stirred in the microwave at 12000 for 2 hours. Additional 1 ,4-dioxane (1.5 mL) was added and the reaction mixture was stirred in the microwave at 120 00 for a further 4 hours. The reaction mixture was adsorbed onto Si02 and purified by column chromatography (Biotage Isolera, 24 gSi02 cartridge, 15-100% EtOAc in petroleum benzine 40-60 00). Fractions containing suspected product were combined and adsorbed onto silica and purified by column chromatography (Biotage Isolera, 12 g Si02, 0-5% MeOH in DCM) to give the title compound 26 as a pale yellow solid (0.030 g, 25%). LCMS-D: rt 3.24 mm; m/z 411 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-tri-1-propyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(II); dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine; sodium t-butanolate; In 1,4-dioxane; at 100℃; for 16h; | To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (1 equiv) and sodium tert-butoxide_(2 equiv) in 1,4-dioxane (0.15 M) was added chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-tri-1-propyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (0.06 equiv) and dicyclohexyl(2?,6?-diisopropoxy-[1,1?-biphenyl]-2-yl)phosphine (0.06 equiv). The reaction was stirred at 100 C. for 16 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound (37% yield). MS (ESI) m/z 562.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution 49-a and 49-b (5.7 g, 4.04 mmol) in ethanol (50 mL), 0.8 g of Pd(OH)2 was added and then stirred reaction under H2 gas atm for 14h. After the completion of reaction (TLC monitoring), the solution was filtered through celite bed, washed with methanol.and concentrated the solvent to get a crude mixture precursor-25 (3.0 g, 67% yield) that was carried as such for the next step without further purification. ?HNMR (400 MHz, DMSO-d6): oe 6.81 (s, 11-1), 3.57 (s, 3H), 3.52 (s, 2H), 2.05 (s, 3H). MS: 112.08 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 mg; 86% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere; Microwave irradiation; | General procedure: [0 140j To a solution of tert-butyl 2-methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)benzylcarbamate (3.47 g, 10 mmol) and 2,4-dichloropyrimidine (1.79 g, 12 mmol) in 1,4- dioxane (28 mL) and H20 (7 mL), Pd(dppf)C12.DCM (815 mg, 1.0 mmol) and K2C03 (2.76 g,mmol) were added under N2. The mixture was stirred at 90 C for 2 h. After cooling to rt, the mixture was diluted with H20 (80 mL) and extracted with EA (80 mL x2). The organic layers were dried and concentrated. The residue was purified by column chromatography (silica,petroleum ether/EtOAc = 5:1 to 2:1) to give tert-butyl 4-(2-chloropyrimidin-4-yl)-2- methylbenzylcarbamate (2.67 g, yield 80%) as white solid .(O252 Synthesis of tert-butyl 4-(2-(( 1,3 -dimethyl- 1 H-pyrazol-4-yl)amino)pyrimidin-4- yl)-2-methylbenzylcarbamate was similar to that of tert-butyl 4-(2-chloropyrimidin-4-yl)-2- methylbenzylcarbamate. The resulting product was purified by column chromatography (petroleum ether/EtOAc =5:1 to 1:2) to give tert-butyl 4-(2-((1 ,3-dimethyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate (116 mg) and tert-butyl 4-(2-(( 1,5 -dimethyl1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-methylbenzylcarbamate as a yellow solid (218 mg, yield: 86%). ESI-MS (M+H) : 409.3. [0253j tert-butyl 4-(2-(( 1,3 -dimethyl- 1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2- methylbenzylcarbamate: ?H NMR (400 MHz, CDC13) oe: 8.41 (d, J 5.2 Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.37 (d, J 7.6 Hz, 1H), 7.05 (d, J= 5.6 Hz, 1H), 6.59 (s, 1H), 4.38 (d, J 5.2 Hz, 2H), 3.85 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H), 1.47 (s, 9H).[0254j tert-butyl 4-(2-(( 1,5 -dimethyl- 1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2- methylbenzylcarbamate: ?H NMR (400 MHz, CDC13) (5: 8.37 (d, J = 5.2 Hz, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.42 (s, 1H), 4.36 (d,J= 5.2 Hz, 2H), 3.81 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | Example 45 Synthesis of N-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2-methyl-9H-pyrimido[4,5-b]indol-4-amine (Cpd. No. 34) S13 (70 mg) and <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-ylamine</strong> (88 mg) were dissolved in isopropanol (5 mL). Four drops of concentrated HCl was added via a glass pipette. The mixture was heated at reflux for overnight. The reaction was concentrated on a rotary evaporator and the remaining residues were purified by HPLC to yield the desired product Cpd. No. 34 in 30 mg as a salt of trifluoroacetic acid. ESI-MS calculated for C22H24N7O2 [M+H]+=418.19; Observed: 418.45. 1H NMR (300 MHz, MeOD) delta 8.0-7.7 (m, 2H), 7.47 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.70 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 2h; | Step 3: A mixture of <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (453 mg, 4.66 mmol), 5- bromo-2-fluoropyrimidine (750 mg, 4.24 mmol) and DWA (1.62 mL, 21.8 mmol) in DM50 (5 mE) was heated with at 120 C for 2 h. The resulting mixture was cooled to it and quenched with water. The yellow solid was collected via filtration, washed with water, and dried in vacuum oven to give 5-bromo-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.08 g, 99%). LC-MS (ESI) m/z 268, 270 (M+Hjb. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 90℃; for 7h;Inert atmosphere; | General procedure: A mixture of compound 7a (212 mg, 0.50 mmol), 1-methyl-1H-pyrazol-4-amine (97 mg, 1.00 mmol), Pd2 (dpa)3 (30 mg, 0.03 mmol), BINAP (60 mg, 0.10 mmol) and Cs2CO3 (446 mg, 1.40 mmol) in DMF (15 mL) was degassed and charged with nitrogen for three times and then heated in an oil bath at 90 C for 7 h under the protection of nitrogen. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The concentrates was purified by flash chromatography on silica gel eluting with EtOAc/CH2Cl2 (8%-100%) to give 8a (90 mg, 45%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 90℃; for 7h;Inert atmosphere; | General procedure: To a solution of 9 (0.50mmol) and corresponding aromatic amine (0.55mmol) in DMF (10mL) was added Cs2CO3 (455mg, 1.40mmol) under N2 protection. Pd2(dpa)3(30mg, 0.033mmol) and BINAP (62mg, 0.10mmol) were added, and the resulting reaction was stirred 90C. After 7h, the mixture was cooled to room temperature, diluted with water (30mL), and extracted with ethyl acetate (60mL×3). The combined organic layer were washed with saturated solution of NaCl (60mL×3), dried over MgSO4, concentrated and purified by flash chromatography eluting with 8-100% ethyl acetate in CH2Cl2 to provide the desired product. 4.1.8.1 (R)-1-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-N-(4-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (3a) (0050) Compound 9 (225mg, 0.50mmol) was reacted with <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (53mg, 0.55mmol) according to the general procedure C to give compound 3a (128mg, yield: 56%). mp: 108-110C. 1H NMR (400MHz, CDCl3) delta 8.50 (s, 1H), 7.60 (d, J=6.4Hz, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 7.19 (d, J=8.4Hz, 2H), 6.49 (s, 1H), 6.19 (d, J=6.4Hz, 1H), 5.65 (s, 1H), 4.49 (dd, J=6.0, 14.8Hz, 1H), 4.39 (dd, J=5.6, 14.8Hz, 1H), 3.82 (s, 3H), 3.78 (s, 1H), 3.62 (d, J=13.2Hz, 1H), 3.23-3.17 (m, 1H), 2.95 (t, J=11.6Hz, 1H), 2.44-2.39 (m, 1H), 2.13 (s, 3H), 2.02 (s, 1H), 1.98 (s, 1H), 1.88-1.77 (m, 2H), 1.60-1.51 (m, 1H). 13C NMR (101MHz, CDCl3) delta 172.8, 157.4, 157.0, 148.5, 147.6, 144.6, 142.8, 136.9, 129.1, 127.0, 121.2, 118.7, 100.7, 88.5, 49.1, 47.0, 42.6, 42.4, 39.1, 27.9, 23.6, 11.1. ESI-MS m/z: 489.50 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 90℃; for 7h;Inert atmosphere; | General procedure: To a solution of 5 (0.56mmol) and corresponding aromatic amine in DMF (10mL) was added Cs2CO3 (511mg, 1.57mmol) under N2 protection. Pd2(dpa)3(33mg, 0.036mmol) and BINAP (67mg, 0.108mmol) were added, and the resulting reaction was stirred 90C. After 7h, the mixture was cooled to room temperature, diluted with water (30mL), and extracted with ethyl acetate (60mL×3). The combined organic layer were washed with saturated solution of NaCl (60mL×3), dried over MgSO4, concentrated and purified by flash chromatography eluting with 8-100% ethyl acetate in CH2Cl2 to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 90℃; for 7h;Inert atmosphere; | General procedure: To a solution of 5 (0.56mmol) and corresponding aromatic amine in DMF (10mL) was added Cs2CO3 (511mg, 1.57mmol) under N2 protection. Pd2(dpa)3(33mg, 0.036mmol) and BINAP (67mg, 0.108mmol) were added, and the resulting reaction was stirred 90C. After 7h, the mixture was cooled to room temperature, diluted with water (30mL), and extracted with ethyl acetate (60mL×3). The combined organic layer were washed with saturated solution of NaCl (60mL×3), dried over MgSO4, concentrated and purified by flash chromatography eluting with 8-100% ethyl acetate in CH2Cl2 to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 90℃; for 7h;Inert atmosphere; | General procedure: To a solution of 5 (0.56mmol) and corresponding aromatic amine in DMF (10mL) was added Cs2CO3 (511mg, 1.57mmol) under N2 protection. Pd2(dpa)3(33mg, 0.036mmol) and BINAP (67mg, 0.108mmol) were added, and the resulting reaction was stirred 90C. After 7h, the mixture was cooled to room temperature, diluted with water (30mL), and extracted with ethyl acetate (60mL×3). The combined organic layer were washed with saturated solution of NaCl (60mL×3), dried over MgSO4, concentrated and purified by flash chromatography eluting with 8-100% ethyl acetate in CH2Cl2 to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-methyl-4-nitro-1H-pyrazole; methyl iodide In acetone at 60℃; for 20h; Stage #2: With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 6h; | 3 Step 2: Add methyl iodide (2.85g, 20mmol) to the acetone solution (15mL) of 5-methyl-4-nitro-1H-pyrazole (1.3g, 10mmol), heat the reaction at 60 degrees Celsius for 20 hours, and cool , Respectively add ethyl acetate and water to quench, the organic phase is dried and concentrated to obtain yellow-brown oil (1,3-dimethyl-4-nitro-1H-pyrazole and 1,5-dimethyl-4- Nitro-1H-pyrazole) 1.5g was used directly in the next step.Step 3: Dissolve the oil obtained in step B1-2 in methanol (30mL), add wet palladium on carbon (55% humidity, 10% palladium content, 80mg), replace the reaction system with hydrogen, and stir at room temperature under hydrogen conditions. After 6 hours, filter with celite and concentrate the filtrate to obtain colorless oil (1,3-dimethyl-1H-pyrazol-4-amine and 1,5-dimethyl-1H-pyrazol-4-amine) ) 0.96g was used directly in the next step; MS: 112[M+H]+. |
Tags: 64517-88-0 synthesis path| 64517-88-0 SDS| 64517-88-0 COA| 64517-88-0 purity| 64517-88-0 application| 64517-88-0 NMR| 64517-88-0 COA| 64517-88-0 structure
[ 197367-87-6 ]
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Code | Phrase |
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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