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CAS No. : | 97421-16-4 | MDL No. : | MFCD08700622 |
Formula : | C6H11N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OEXNVHXUPNHOPP-UHFFFAOYSA-N |
M.W : | 125.17 | Pubchem ID : | 13469826 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 37.51 |
TPSA : | 43.84 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.89 cm/s |
Log Po/w (iLOGP) : | 1.32 |
Log Po/w (XLOGP3) : | 0.25 |
Log Po/w (WLOGP) : | 1.05 |
Log Po/w (MLOGP) : | 0.11 |
Log Po/w (SILICOS-IT) : | 0.05 |
Consensus Log Po/w : | 0.56 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.12 |
Solubility : | 9.52 mg/ml ; 0.0761 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.73 |
Solubility : | 23.2 mg/ml ; 0.186 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.83 |
Solubility : | 18.5 mg/ml ; 0.148 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: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
95% | With palladium on activated charcoal; hydrogen In methanol at 20℃; for 3 h; | Into a 25 mL round-bottom flask were placed a solution of intermediate 53.3 (200 mg, 1.29 mmol, 1.00 equiv) in methanol (4 mL) and palladium on charcoal (40 mg). To the above mixture H2 (g) was introduced, and the reaction was stirred for 3 h at room temperature. The solids were filtered and resulting filtrate was concentrated under vacuum to provide 154 mg (95percent) of intermediate 53.3 as pink oil. |
94% | With palladium 10% on activated carbon; hydrogen In ethanol at 25℃; for 12 h; | Under hydrogen (1 atm), to a solution of compound 41-b (1.1 g, 8.8 mmol) in ethanol (20 mL) was added 10percent Pd—C (0.2 g). The mixture was stirred at 25° C. for 12 hours, and then filtrated, the filtrate was concentrated under reduced pressure to give compound 41-a (830 mg, yield: 94percent), which was used directly for the next step without purification. LC-MS (ESI): m/z=126 [M+H]+. |
91% | With palladium on activated charcoal; hydrogen In methanol at 20℃; for 2 h; | Synthesis of Compound 6.2. Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-nitro-l-(propan-2-yl)-lH- pyrazole (6.1) (3.0 g, 19.34 mmol, 1.00 equiv), palladium on carbon (200 mg), and methanol (250 mL). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred 2 h at room temperature under an atmosphere of hydrogen (balloon). The resulting solution was stirred for 2 h at room temperature. The solids were filtered off. Then the resulting mixture was concentrated in vacuo. This provided 2.2 g (91percent) of l-(propan-2-yl)-lH-pyrazol-4-amine (6.2) as red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium 10% on activated carbon; hydrogen; In methanol; under 775.743 Torr; for 2h; | To a solution of 1 -isopropyl -4-nitro-pyrazole (3.0 g, 19.34 mmol) in MeOH (40 ml) under a nitrogen atmosphere was added 10 % Pd/C (600 mg). The RM was purged then stirred under H2 atmosphere at 15 psi for 2 h. The mixture was evaporated under reduced pressure to give the title compound as a brown liquid (Y = 99 %). 'H NMR (400 MHz, methanol-^) d ppm 7.23 (s, 1H), 7.13 (s, 1H), 4.40- 4 .33 (m, 1H), 1.42 (d, J= 6 Hz, 6H). |
95% | With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 3h; | Into a 25 mL round-bottom flask were placed a solution of intermediate 53.3 (200 mg, 1.29 mmol, 1.00 equiv) in methanol (4 mL) and palladium on charcoal (40 mg). To the above mixture H2 (g) was introduced, and the reaction was stirred for 3 h at room temperature. The solids were filtered and resulting filtrate was concentrated under vacuum to provide 154 mg (95%) of intermediate 53.3 as pink oil. |
94% | With palladium 10% on activated carbon; hydrogen; In ethanol; at 25℃; under 760.051 Torr; for 12h; | Under hydrogen (1 atm), to a solution of compound 41-b (1.1 g, 8.8 mmol) in ethanol (20 mL) was added 10% Pd-C (0.2 g). The mixture was stirred at 25 C. for 12 hours, and then filtrated, the filtrate was concentrated under reduced pressure to give compound 41-a (830 mg, yield: 94%), which was used directly for the next step without purification. LC-MS (ESI): m/z=126 [M+H]+. |
93% | With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; for 8h; | The compound (Int-12-b) (6 g, 38.67 mmol) was dissolved in ethanol (50 mL), and palladium / carbon (600 mg) was added, and the mixture was replaced with hydrogen, and reacted at room temperature for 8 hours.The reaction solution was filtered through a celite pad, and the filtrate was concentrated to obtain the title compound (4.5 g, yield: 93%). |
91% | With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 2h; | Synthesis of Compound 6.2. Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-nitro-l-(propan-2-yl)-lH- pyrazole (6.1) (3.0 g, 19.34 mmol, 1.00 equiv), palladium on carbon (200 mg), and methanol (250 mL). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred 2 h at room temperature under an atmosphere of hydrogen (balloon). The resulting solution was stirred for 2 h at room temperature. The solids were filtered off. Then the resulting mixture was concentrated in vacuo. This provided 2.2 g (91%) of l-(propan-2-yl)-lH-pyrazol-4-amine (6.2) as red oil. |
With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; at 17 - 25℃; under 2280.15 Torr; for 2h; | A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for EPO <DP n="125"/>2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material as a colourless oil (0.607 g); 1H NMR: (DMSOd6)1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, IH), 6.88 (s, IH), 7.03 (s, IH). | |
With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h; | A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material as a colourless oil (0.607 g); 1H NMR: (DMSOd6) 1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, IH), 6.88 (s, IH), 7.03 (s, IH). | |
With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h; | A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material as a colourless oil (0.607 g); 1HNMR: (DMSOd6)5 1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, IH), 6.88 (s, IH), 7.03 (s, IH). | |
With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h; | A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material as a colourless oil (0.607 g); 1H NMR: (DMSOd6)1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, IH), 6.88 (s, IH), 7.03 (s, IH). | |
With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h; | A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was, stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material as a colourless oil (0.607 g); 1H NMR: (DMSOd6) 1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, 1H), 6.88 (s, 1H), 7.03 (s, 1H). | |
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 1810.07 Torr; for 1h; | A suspension of impure 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g), from above, in ethanol (50 mL) was treated with 10% palladium on carbon (400 mg, 50% water by weight) and shaken under a hydrogen atmosphere (35 psi) at room temperature for 1 h. After this time, the reaction was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure to afford 1-isopropyl-1H-pyrazole-4-amine (2) (1.15 g) as an impure off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) delta 7.02 (s, 1H), 6.87 (s, 1H), 4.26 (m, 1H), 3.72 (bs, 2H), 1.42 (d, J=6.6 Hz, 6H). | |
With palladium on activated charcoal; hydrogen; In ethanol; at 18 - 25℃; for 2h; | Step 2: preparation of 1-isopropyl-1H-pyrazole-4-amine (0298) (0299) The product obtained in step 1 (250 mg, 1.61 mmol) was dissolved in ethanol (10 mL), followed by the addition of palladium on carbon (25 mg), and reacted under hydrogen atmosphere for 2 hours at room temperature. The reaction solution was filtered and concentrated, and the resulting crude product was used directly in the next step. MS (ESI, m/z): [M+H]+: 125.9. | |
With palladium 10% on activated carbon; hydrogen; In ethanol; at 25℃; under 760.051 Torr; for 12h; | Palladium 10% on carbon (0.2 g) was added to a solution of compound 14-b (1.0 g, 8.8 mmol) in ethanol (20 mL) under hydrogen gas atmosphere (1 atm). The mixture was reacted at 25 C. for 12 hours, filtered and the filtrate was concentrated under reduced pressure to give compound 14-a (830 mg, yield 94%), which was directly used for the next reaction without purification. LC-MS (ESI): m/z=126[M+H]+. | |
With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h; | A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material as a colourless oil (0.607 g); 1H NMR Spectrum: (DMSOd6) 1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, IH), 6.88 (s, IH), 7.03 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 3h; | A mixture of impure <strong>[97421-16-4]1-isopropyl-1H-pyrazole-4-amine</strong> (2) (1.00 g), from above, 6,8-dibromoimidazo[1,2-a]pyrazine (3) (750 mg, 2.71 mmol), and N,N-diisopropylethylamine (526 mg, 4.16 mmol) in DMF (20 mL) was stirred at 100 C. for 3 h. After this time, the reaction was cooled to room temperature and poured into ice water (200 mL). The resulting suspension was filtered and the filter cake dried to a constant weight under vacuum to afford impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (1.26 g) as an off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) delta 10.26 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 4.49 (m, 1H), 1.40 (d, 6H); ESI MS m/z 323.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 98A 1-isopropyl-1H-pyrazol-4-amine The title compound was prepared as described in Example 55A substituting 2-iodopropane for 2-chloro-N,N-dimethylacetamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 98B (1S,2S,3R,4R)-3-({5-chloro-2-[(1-isopropyl-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>[97421-16-4]1-isopropyl-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 (300 MHz, DMSO-D6) ppm 1.39 (d, J=6.74 Hz, 7H) 2.12 (d, J=8.33 Hz, 1H) 2.88 (s, 1H) 4.14 (t, J=7.54 Hz, 1H) 4.34-4.49 (m, 1H) 6.27 (d, J=3.17 Hz, 1H) 6.37 (d, J=5.16 Hz, 1H) 7.25 (s, 1H) 7.51 (s, 1H) 7.65 (s, 1H) 7.76 (d, J=5.95 Hz, 3H) 7.89 (s, 1H) 9.08 (s, 1H); MS (ESI(+)) m/e 388 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 112 (1S,2S,3R,4R)-3-({5-bromo-2-[(1-isopropyl-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>[97421-16-4]1-isopropyl-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 (300 MHz, DMSO-d6) ppm 1.39 (d, J=6.78 Hz, 6H) 2.12 (d, J=8.82 Hz, 1H) 2.75 (s, 1H) 2.75 (s, 1H) 2.87 (s, 1H) 2.87 (s, 1H) 4.15 (t, J=7.97 Hz, 1H) 4.31-4.49 (m, 1H) 6.28 (s, 1H) 6.38 (s, 1H) 7.23 (s, 1H) 7.51 (s, 1H) 7.58 (s, 1H) 7.74 (s, 2H) 7.95 (s, 1H) 9.07 (s, 1H); MS (ESI(+)) m/e 432 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen; In methanol; at 10 - 35℃; for 12h; | General procedure: To a suspension of 4-nitro-lH-pyrazole (500 mg) and potassium carbonate (1.22 g) in DMF (5 mL) was added dropwise 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (1.54 g) . The reaction mixture was stirred at room temperature for 4 hr, treated with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue obtained above and 10% palladium on carbon (1 g) in methanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 12 hr, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (490 mg) . 1 NMR (300 MHz, DMSO-d6) delta 3.97 (2H, brs) , 4.88 (2H, q, J = 9.1 Hz), 7.04 (1H, s) , 7.10 (1H, s) . | |
With hydrogen; In ethanol; ethyl acetate; for 5h; | General procedure: The 1 - (2 - methoxy ethyl) -4 - nitro - 1H - pyrazole (5 g, 29.21 mmol) dissolved in ethanol (25 ml) and ethyl acetate (25 ml) in, add Raney nickel (500 mg), under the hydrogen environment reaction 5 hours. Diatomite filter, evaporating the filtrate, a brown solid 3.6 g, yield 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 140℃; for 0.5h;microwave tube; | To a microwave tube was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4- amine (112 mg, 0.53 mmol), l-isopropyl-lH-pyrazol-4-amine (55 mg, 0.44 mmol), cesium carbonate (0.287 g, 0.88 mmol), XPhos (21 mg, 0.044 mmol), Pd2(dba)3 (20 mg, 0.02 mmol) and dioxane (2.5 mL). The tube was sealed and the reaction was irradiated in the microwave at 140 C for 30 minutes. The reaction mixture was then filtered and concentrated. The crude product was purified by reverse phase HPLC to give N2-(l-isopropyl-lH-pyrazol-4-yl)-N4-methyl-5- (trifluoromethyl)pyrimidine-2,4-diamine (22 mg, 16%). LCMS (Method A): [MH+] = 301.1 at 3.2 min. 1H- MR (DMSO): delta 9.43 (m, 2H), 8.08 (s, 1H), 7.89 (s, 1H), 7.54 (s, 1H), 6.96 (m, 2H), 4.43 (m, 1H), 2.92 (d, J= 8.0, 3H), 1.39 (d, J= 6.6, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With toluene-4-sulfonic acid; In 1,4-dioxane; at 100℃; for 3h; | Example 30: Synthesis of 1 -(2-(2-(5-chloro-2-((1 -isopropyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (30) 1-(2-(2-(5-Chloro-2-((1-isopropyl- 1H-pyrazol-4-yI) amino)pyrimidin-4-yI)ethyl)phenyl)cyclopropanecarboxamide (30)A mixture of <strong>[97421-16-4]1-isopropylpyrazol-4-amine</strong> (0.083 g, 0.66 mmol), 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A 14 (0.110 g, 0.327mmol) and TsOH.H20 (0.013 g, 0.066 mmol) in 1,4-dioxane (2.0 mL) was heated in the microwave to 100 00 for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60 C then 0-10% MeOH in EtOAc) to give the title compound30 (0.094 g, 68%). LCMS-D: rt 3.355 mm; m/z 425.3 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | [00303] Example 9: Synthesis of 10-N-[l-(propan-2-yl)-lH-pyrazol-4-yl]-12-N-[trans-4- (morpholin-4-yl)cyclohexyl]-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll- tetraene-10,12-diamine (1-9). [00304] A suspension of 3.4 (120 mg, 0.31 mmol, 1.00 equiv), l-(propan-2-yl)-lH-pyrazol-4- amine (46.5 mg, 0.372 mmol, 1.20 equiv) and hydrochloric acid (0.5 mL, 4 M in hexane) in dry isopropanol (5 mL) was heated in the microwave at 140 C for 1.5 h. After cooling to rt, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol/ammonia (20: 1 :0.1) to give 66.1 mg (45%) of 1-9 as a white solid. MS (ES): m/z 482 (M+H)+. 1H NMR (300 MHz, CD3OD): delta 7.84 (s, 1H), 7.56 (s, 1H), 4.49-4.40 (m, 1H), 4.04-3.95 (m, 1H), 3.71-3.68 (m, 4H), 2.94 (t, 2H), 2.83 (t, 2H), 2.78- 2.62 (m, 4H), 2.50-2.45 (m, 2H), 2.39-2.25 (m, 1H), 2.25-2.14 (m, 2H), 2.11-1.99 (m, 2H) , 1.47 (d, 6H), 1.46-1.32 (m, 4H). | |
45% | With hydrogenchloride; In isopropyl alcohol; at 140℃; for 1.5h;Microwave irradiation; | A suspension of 3.4 (120 mg, 0.31 mmol, 1.00 equiv), l-(propan-2-yl)-lH-pyrazol-4- amine (46.5 mg, 0.372 mmol, 1.20 equiv) and hydrochloric acid (0.5 mL, 4 M in hexane) in dry isopropanol (5 mL) was heated in the microwave at 140 C for 1.5 h. After cooling to rt, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol/ammonia (20:1 :0.1) to give 66.1 mg (45%) of 1-10 as a white solid. MS (ES): m/z 482 (M+H)+. 1H NMR (300 MHz, CD3OD): delta 7.84 (s, 1H), 7.56 (s, 1H), 4.49-4.40 (m, 1H), 4.04-3.95 (m, 1H), 3.71-3.68 (m, 4H), 2.94 (t, 2H), 2.83 (t, 2H), 2.78- 2.62 (m, 4H), 2.50-2.45 (m, 2H), 2.39-2.25 (m, 1H), 2.25-2.14 (m, 2H), 2.11-1.99 (m, 2H) , 1.47 (d, 6H), 1.46-1.32 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; at 140℃; for 3h;Microwave irradiation; | Into a 5 mL microwave vial were placed a solution of intermediate 45.4 (150 mg, 0.42 mmol, 1.00 equiv) in isopropanol (3.5 mL), intermediate 53.3 (106.2 mg, 0.85 mmol, 2.00 equiv) and a solution of hydrogen chloride in dioxane (0.1 mL). The final reaction mixture was irradiated with in a microwave reactor for 3 h at 140 C. The solution was adjusted to pH 9 with sodium carbonate (1 M). The resulting mixture was concentrated under vacuum. The crude product was purified using preparative HPLC to furnish 66.7 mg (3 6%) of compound 1-53 as a brown solid. LCMS (ES, m/z): 443 [M+H] ?H NMR: (400 MHz, d6- DMSO): oe 9.086 (s, 1H), 8.736 (s, 1H), 7.879 (s, 1H), 7.660-7.619 (s, 1H), 7.478 (s, 1H), 4.482- 4.416 (m, 1H), 4.038-4.012 (t, 1H), 3.578 (s, 4H), 2.502 (s, 4H), 2.268-2.235 (d, 1H), 2.019-1.894 (m, 4H), 1.559-1.521 (d, 2H), 1.479-1.423 (d, 3H), 1.401-1.345 (d, 3H), 1.307-1.266 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium phosphate; (2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2-amino-1,1?-biphenyl)]palladium(ll) methanesulfonate; In tert-butyl alcohol; at 20℃; for 3h; | Into a 50 mL round-bottom flask, were placed a solution of intermediate 55.1 (200 mg, 0.54 mmol, 1.00 equiv) in tert-butanol (4 mL), compound 53.3 (135.87 mg, 1.09 mmol, 2.00 equiv), potassium phosphate (345.65 mg, 1.63 mmol, 3.00 equiv) and 3rd Generation Xphos precatalyst (22.99 mg, 0.05 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum and resulting crude was purified using preparative HPLC to furnish 101.8 mg (41%) of compound 1-57 as a pink solid. LCMS (ES, m/z): 458 [M+H] ?H NMR (400 MHz, d6-DMSO): oe 9.481 (s, 1H), 7.876 (s, 1H), 7.505 (s, 1H), 5.184-5.117 (m, 1H), 4.511-4.422 (m, 1H), 3.595-3.567 (m, 4H), 2.753(s, 3H),2.496 (s, 4H), 2.325-2.196 (m, 3H), 1.956-1.916 (d, 2H), 1.454-1.617 (m, 2H), 1.355-1.483 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 110℃; for 2h; | [0483j To a solution of N-(2-(2-chloropyrimidin-4-yl)-6,7,8 ,9-tetrahydro-5H- benzo [7] annulen-5 -yl)-3 -isopropoxyazetidine- 1 -carboxamide (130 mg, 0.32 mmol) in 1,4- dioxane (5 mL) were added 1-ethyl-1H-pyrazol-4-amine (36 mg, 0.32 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), S-Phos (26 mg, 0.064 mmol) and Cs2CO3 (312 mg, 0.96 mmol). The mixture was stirred at 100 C for 2 h. After diluted with water (50 mL), the mixture was extracted with EtOAc (60 mL x 2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by prep-HPLC (CH3CN/H20 with 0.05% NH4OH as mobile phase) to give N-(2-(2-(( 1-ethyl-i H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8 ,9-tetrahydro-5H- benzo[7]annulen-5-yl)-3-isopropoxyazetidine-1-carboxamide as a yellow solid (129 mg, yield:73%). [0564j Synthesis of 3 -(tert-butoxy)-N-(4-(2-(( 1 -isopropyl- 1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine- 1 -carboxamide was similar to that of Example 161. The crude product was purified by prep-HPLC (CH3CN/H20 with 0.05% NH4OH as mobile phase) to give 3-(tert-butoxy)-N-(4-(2-((1-isopropyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-2-(trifluoromethyl)benzyl)azetidine- 1 -carboxamide as a yellow solid (67 mg, yield: 37%). ESI-MS (M+H) : 532.3. ?H NMR (400 MHz, CD3OD) 5: 8.42 (s, 1H), 8.37 (d, J 4.8 Hz, 1H), 8.21 (d, J 8.0 Hz, 1H), 7.95 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.53 (s, 1H), 7.17 (d, J= 4.8 Hz, 1H), 4.53-4.47 (m, 1H), 4.49 (s, 2H), 4.44-4.37 (m, 1H), 4.11-4.08 (m, 2H), 3.73-3.69 (m, 2H), 1.42 (d, J= 6.4 Hz, 6H), 1.10 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With toluene-4-sulfonic acid; In butan-1-ol; at 115℃; for 18h; | Compound 41-a (71 mg, 0.57 mmol) and compound 5 (80 mg, 0.19 mmol) were dissolved in n-butanol (2 mL), p-toluene sulfonic acid monohydrate (71 mg, 0.38 mmol) was added. The mixture was heated to 115 C. and stirred for 18 hours, then cooled to room temperature. The mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (10 mL×3). The organic layers were combined, washed with water (10 mL×3) and saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated. The residue was purified by preparation HPLC (mobile phase:acetonitrile/methanol (1:1), water (0.05% trifluoroacetic acid); gradient: 75%-95%-10%) to give compound T-41 (48 mg, yield: 49%). LC-MS (ESI): m/z=512 [M+H]+. (0305) 1H-NMR (400 MHz, CDCl3) delta: 8.65 (s, 1H), 8.30 (d, J=3 Hz, 1H), 8.15 (d, J=5 Hz, 1H), 8.00 (d, J=3 Hz, 1H), 7.67 (d, J=3 Hz, 1H), 7.36 (d, J=6 Hz, 1H), 4.63 (t, J=6 Hz, 2H), 4.53 (m, 1H), 4.28 (d, J=9 Hz, 1H), 3.60 (s, 3H), 3.18 (q, J=7 Hz, 2H), 1.39 (t, J=7 Hz, 3H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In tert-butyl alcohol; at 110℃; | Synthesis of Compound 1-6. Into a 25-mL round-bottom flask, was placed 1.1 (50 mg, 0.15 mmol, 1.00 equiv), l-(propan-2-yl)-lH-pyrazol-4-amine (6.2) (37 mg, 0.30 mmol, 2.00 equiv), K3PO4 (152 mg, 0.75 mmol, 5.00 equiv), and 3rd Generation XPhos precatalyst (846 mg, 1.00 mmol, 0.20 equiv) in tert-butanol (10 mL). The reaction was stirred overnight at 110 C in an oil bath. The residue was purified by silica gel column chromatography with dichloromethane/methanol (10: 1). This afforded 53.5 mg (85%) of 1-6 as a white solid. LC-MS (ESI, m/z): 425 [M+H]+ MR (400 MHz, DMSO^) delta 8.39 (s, 1H), 7.86 (s, 1H), 7.66 (d, J= 8.1 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J = 2.1 Hz, 1H), 6.77 (dd, J = 4.4, 1.7 Hz, 1H), 6.36 (dd, J = 4.3, 2.5 Hz, 1H), 4.42 (p, J = 6.7 Hz, 1H), 3.61-3.54 (m, 4H), 3.33 (s, 2H), 2.49 (s, 1H), 2.31-2.20 (m, 1H), 2.03 (d, J = 11.6 Hz, 2H), 1.91 (d, J = 12.0 Hz, 2H), 1.48-1.24 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.4% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; | A mixture of 4-chloro-7-methoxyimidazo F 1,2-a] quinoxaline lOa (0.55 g, 2.360 mmol), 1 -isopropyl- 1 H-pyrazol-4-amine (1.18 g, 9.44 mmol), palladium(II)acetate (0.158 g, 0.708 mmol), BINAP (0.733 g, 1.18 mmol) and cesium carbonate (1.53 g,4.720 mmol) in dioxane (5 mL) was stirred at 100C under N2 for 2h. After cooling to room temperature, the mixture was filtered through Celite and washed with EtOAc (2 x 10 mL). The filtrate was evaporated under reduced pressure and the crude product was purified on basic alumina (15% EtOAc in hexane) giving compound 12b (0.5 g, 65.4%) as a brown liquid. ?H NMR (500 MHz, DMSO-d6) 5 ppm: 8.30 (s, 1H), 8.10(s, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.20 (s, 1H), 7.10 (d,1H), 4.50 (m, 1H), 3.90 (s, 3H), 1.50 (d, 6H). LC-MS FmJz]: 323.2 FM+H], 98.44%purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 mg | With trifluoroacetic acid; In 1,4-dioxane; at 90℃; for 0.5h;pH 5.0;Microwave irradiation; | Step 3: preparation of 1-(3-(((2-((1-isopropyl-1H-pyrazol-4-yl-amino)thieno[3,2-d] pyrimidin-4-yl)amino)methyl)azetidin-1-yl)prop-2-en-1-one (0300) The product obtained in step 3 of Example 61 (30 mg, 0.1 mmol) and <strong>[97421-16-4]1-isopropyl-1H-pyrazole-4-amine</strong> (19 mg, 0.15 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction solution was adjusted to pH 5 with trifluoroacetic acid, and reacted under microwave irradiation at 90C for 0.5 hours. The reaction solution was cooled to room temperature, adjusted with 1N sodium hydroxide solution to pH 8, and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 : 1) to give a yellow solid (15 mg). Yield: 37.8%. MS (ESI, m/z): [M+H]+: 398.3; 1H-NMR (300 MHz, DMSO-d6) delta: 7.81 (s, 1H), 7.64 (d, 1H, J= 5.4 Hz), 7.60 (s, 1H), 7.20 (d, 1H, J= 5.4 Hz), 6.31-6.37 (m, 1H), 6.13-6.22 (m, 1H), 5.66-5.70 (m, 1H), 4.31-4.37 (m, 1H), 4.18-4.24 (m, 1H), 4.00-4.05 (m, 1H), 3.81-3.95 (m, 3H), 3.09 (m, 1H), 1.53 (s, 3H), 1.51 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | 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 110℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube; | A stirred solution of S-66 (0.30 g, 0.74 mmol) in 1,4-dioxane taken in a microwave vial was charged with <strong>[97421-16-4]1-isopropyl-1H-pyrazol-4-amine</strong> S-14g (0.11 g, 0.89 mmol) and Cs2CO3(0.48 g, 1.48 mmol). Argon gas was purged through septum and the reaction was degassed for about 5 min. To this reaction mixture, xantphos (0.042 g, 0.074 mmol) and Pd2(dba)3(0.067 g, 0.074 mmol) were added under inert atmosphere. This reaction mixture was purged with argon gas again for 5 min. The microwave vial was sealed and irradiated at 110 C for 1 h in CEM-microwave instrument. The reaction mixture was filtered, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 0 - 60% EtOAc in hexanes as eluent to afford S-67 (0.16 g, 44%, AMRI lot IN-SKY-C-103) as an off-white solid. The compound was characterized by1H NMR analysis.1H NMR (300 MHz, CD3OD): delta 8.39 (bs, 1H), 7.50 (d, J = 3.54 Hz, 2H), 7.46 (s, 1H), 7.16 (d, J = 3.54 Hz, 2H), 6.99 (d, J = 3.9 Hz, 1H), 6.50 (d, J = 4.2 Hz, 1H), 4.44- 4.35 (m, 1H), 4.26- 4.22 (m, 1H), 2.34- 2.27 (m, 1H), 1.97- 1.84 (m, 2H), 1.78- 1.64 (m, 4H), 1.43 (dd, J = 6.9 Hz, 6H), 1.99 (d, J = 6.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | 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 110℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube; | A stirred solution of S-111 (0.30 g, 0.78 mmol) in 1,4-dioxane (3.0 mL) taken in a microwave vial was charged with <strong>[97421-16-4]1-isopropyl-1H-pyrazol-4-amine</strong> S-14g (0.11 g, 0.94 mmol) and Cs2CO3(0.50 g, 1.56 mmol). Argon gas was purged through septum and the reaction was degassed for about 5 min. To this reaction mixture, xantphos (0.045 g, 0.078 mmol) and Pd2(dba)3(0.071 g, 0.078 mmol) were added under inert atmosphere. This reaction mixture was purged with argon gas again for 5 min. The microwave vial was sealed and irradiated at 110 C for 1 h in CEM-microwave instrument. The reaction mixture was filtered, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 0 - 60% EtOAc in hexanes as eluent to afford S-112 (0.15 g, 40%, AMRI lot IN-SKY-C- 150) as an off-white solid. The compound was characterized by1H NMR analysis.1H NMR (400 MHz, CD3OD): delta 8.05 (s, 1H), 7.66 (s, 1H), 6.95 (d, J = 3.6 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1H), 5.57 (s, 2H), 4.63- 4.52 (m, 1H), 4.44 (s, 1H), 3.66 (t, J = 8 Hz, 2H), 3.41 (s, 3H), 1.59 (d, J = 6.4 Hz, 6H), 1.42 (d, J = 6.8 Hz, 3H), 1.25- 1.19 (m, 1H), 0.97 (t, J = 8 Hz, 2H), 0.78- 0.73 (m, 1H), 0.59- 0.52 (m, 1H), 0.49- 0.44 (m, 1H), 0.37- 0.31 (m, 1H), 0.0 (s, 9H). |
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 110℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube; | A stirred solution of S-56 (0.30 g, 0.7 mmol) in 1,4-dioxane taken in a microwave vial was charged with <strong>[97421-16-4]1-isopropyl-1H-pyrazol-4-amine</strong> S-14g (0.105 g, 0.84 mmol) and Cs2CO3(0.45 g, 1.4 mmol). Argon gas was purged through septum and the reaction was degassed for about 5 min. To this reaction mixture, xantphos (0.04 g, 0.07 mmol) and Pd2(dba)3(0.064 g, 0.07 mmol) were added under inert atmosphere. This reaction mixture was purged with argon gas again for 5 min. The microwave vial was sealed and irradiated at 110 C for 1 h in CEM-microwave instrument. The reaction mixture was filtered, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 0- 5% MeOH in CH2Cl2as eluent to afford S-57 (0.20 g, 55%, AMRI lot IN-CKB-G-62) as an off-white solid. The compound was characterized by1H NMR and UPLC-MS analysis.1H NMR (400 MHz, CDCl3): delta 8.56 (d, J = 4.80 Hz, 1H), 7.97 (d, J = 8.40 Hz, 2H), 7.66- 7.62 (m, 1H), 7.43 (s, 1H), 7.19 (d, J = 8.40 Hz, 3H), 7.15 (d, J = 4.00 Hz, 1H), 6.66 (s, 1H), 6.40 (d, J = 4.00 Hz, 1H), 6.26 (d, J = 6.80 Hz, 1H), 5.38 (t, J = 6.80 Hz, 1H), 4.57- 4.50 (m, 1H), 2.33 (s, 3H), 1.57- 1.55 (m, 9H); MS-UPLC (MM) m/z 517.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 1 -(6-((dimethyl(oxo)-A6-sulfaneylidene)amino)pyridin-2-yl)-6-(methylthio)-2-(prop- 2-yn-1 -yl)-1 ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (38 mg, 0.098 mmol) in a mixture of toluene (1 mL) and dichloromethane (1 mL) was added m-CPBA, 70% purity (26.5 mg, 0.108 mmol). The reaction mixture was stirred for 30 minutes at RT. LC-MS analysis showed complete oxidation of the starting material. To the reaction mixture were added <strong>[97421-16-4]1-isopropyl-1H-pyrazol-4-amine</strong> (12.2 mg, 0.098 mmol) and DIPEA (0.051 mL, 0.293 mmol). The mixture was heated at 65 00 under a nitrogen atmosphere overnight, then it was loaded directly onto a silica gel cartridge and purified by flash chromatography (0-10% MeOH in EtOAc). The product containing fractions were evaporated under reduced pressure and freeze dried (ACNlwater) yielding the title compound as a beige solid.LCMS (Method C): RT = 0.98 mi m/z = 466 [M+H].1H NMR (300 MHz, DMSO) O 10.42 (5, 1H), 8.96-8.77 (m, 1H), 8.11-7.94 (m, 1H),7.80 (t, J= 8.0 Hz, 1H), 7.57-7.50 (m, 1H), 7.45 (d, J= 7.7 Hz, 1H), 6.63 (d, J= 7.9 Hz, 1H), 4.88 (5, 2H), 4.55-4.40 (m, 1H), 3.37 (5, 6H), 3.23-3.15 (m, 1H), 1.49-1.34 (m, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87 mg | With toluene-4-sulfonic acid; In butan-1-ol; at 108℃; for 6h; | Compound 14-a (94 mg, 0.75 mmol), p-toluenesulfonic acid (150 mg, 0.75 mmol) and compound 13-a (145 mg, 0.5 mmol) were added to n-butanol (10 mL), the mixture was heated to 108 C. and stirred for 6 hours. After cooling to room temperature, the reaction solution was concentrated, the residue was added to a saturated aqueous sodium bicarbonate solution (80 mL) and extracted with dichloromethane (100 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel TLC preparative plate (petroleum ether: ethyl acetate=1:1) to give 14 as a yellow solid (87 mg, yield 46%). LC-MS (ESI): m/z=380[M+H]+. (0259) 1H-NMR (400 MHz, DMSO-d6) delta: 8.67 (s, 1H), 7.74 (s, 1H), 7.36 (t, J=8 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J=8 Hz, 1H), 7.08 (d, J=8 Hz, 1H), 7.03 (t, J=8 Hz, 1H), 4.20 (m, 1H), 3.67 (s, 3H), 2.35 (s, 3H), 1.25 (d, J=8 Hz, 6H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
133 mg | With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;Inert atmosphere; | A mixture of 4-chloro-6-(2-(4-fluorophenyl)pyrrolidin-1-yl)pyrimidine compound 6 (200 mg, 0.720 mmol), <strong>[97421-16-4]1-isopropyl-1H-pyrazol-4-amine</strong> (112.68 mg, 0.900 mmol), xantphos (4,5-diphenylphosphanyl-9,9?-dimethyl-9-H-xanthene, 104.17 mg, 0.180 mmol), K2CO3 (497.63 mg, 3.60 mmol) and palladium(II) acetate (24.25 mg, 0.108 mmol) in 1,4-dioxane (10 ml) was purged with argon for 1 hour. The mixture was heated in an oil bath for overnight at 90 C. TLC was checked and the starting material was consumed. After cooling to room temperature, the reaction mixture was passed through a pad of celite using 10% IPA/DCM and was concentrated. The crude product was purified by column chromatography (silica gel, 0-5% MeOH in DCM) to obtain compound 59 as orange solids (133 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.62 (br, 1H), 8.04 (s, 1H), 7.68 (br, 1H), 7.26 (s, 1H), 7.14 (m, 4H), 5.32 (br, 1H), 4.98 (br, 1H), 4.39 (m, 1H), 3.73 (m, 2H), 2.34 (m, 1H), 1.91 (m, 3H), 1.37 (d, J=6.8 Hz, 6H); ESI-MS: calcd for (C20H23FN6) 366, found 367 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.43% | Into a 8-mL vial, was placed l-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6- methanesulfinyl-2-(prop-2-en-l-yl)-lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one (36.5 mg, 0.098 mmol, 1 equiv), toluene (2 mL, 0.022 mmol, 0.22 equiv), l-(propan-2-yl)-lH-pyrazol- 4-amine (14.68 mg, 0.117 mmol, 1.20 equiv), DIEA (37.90 mg, 0.293 mmol, 3 equiv). The resulting solution was stirred for 2 hr at room temperature. The resulting mixture was concentrated. The crude product (23 mg) was purified by Prep-HPLC with the following conditions: Column, X-bridge RP18; mobile phase, 0.05% FA in water and CH3CN (45% CH3CN up to 60% in 5 min); Detector, UV 254 nm. This resulted in 4.8 mg (10.43%) of 1- [6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-l-yl)-6-[[l-(propan-2-yl)-lH-pyrazol- 4-yl]amino]-lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride as a white solid. LC- MS (ES, m/z): 435[M+l] + , 1H NMR (300 MHz, DMSO-d6, ppm) d: 8.80 (s, 1H), 8.06-8.01 (m, 1H), 7.92 (s, 1H), 7.75 (d, / = 8.1 Hz, 1H), 7.65 (d, 7 = 7.5 Hz, 1H), 7.54 (s, 1H), 5.69- 5.60 (m, 1H), 4.99 (d, / = 10.2 Hz, 1H), 4.79 (d, / = 17.1 Hz, 1H), 4.68 - 4.57 (m, 2H), 4.46- 4.41 (m, 1H), 1.55 - 1.28 (m, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.7% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); caesium carbonate; In tert-butyl alcohol; at 160℃; for 1h;Inert atmosphere; | The mixed solution comprising the compound prepared in step 1 above (300 mg, 0.962 mmol), <strong>[97421-16-4]1-isopropyl-1H-pyrazol-4-amine</strong> (133 mg, 1.059 mmol), Cs2CO3 (941 mg, 2.89 mmol) and t-BuOH (9 ml) was degassed using a nitrogen balloon, to which XPhos Pd G2 (76 mg, 0.096 mmol) was added. Then, the reaction mixture was loaded in a microwave reactor. The temperature of the reactor was raised to 160 C., which was maintained for 1 hour. The reaction mixture was filtered with celite and then concentrated. The obtained residue was purified by silica gel chromatography (40-50% ethyl acetate/hexane). As a result, a target compound was obtained (130 mg, 33.7% yield). 1H NMR (400 MHz, Chloroform-d) delta 8.39 (d, 1H), 8.10 (dd, 1H), 7.86 (s, 1H), 7.80 (dd, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.44 (d, 1H), 6.86 (t, 1H), 6.64 (s, 1H), 6.51 (dd, 1H), 4.51 (p, 1H), 2.66 (s, 3H), 1.55 (d, 6H); MS m/z: 401[M+H] |
Tags: 97421-16-4 synthesis path| 97421-16-4 SDS| 97421-16-4 COA| 97421-16-4 purity| 97421-16-4 application| 97421-16-4 NMR| 97421-16-4 COA| 97421-16-4 structure
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P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
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 |
Sorry,this product has been discontinued.
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