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CAS No. : | 1151802-22-0 | MDL No. : | MFCD16659007 |
Formula : | C12H19BN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NLWYVKHISUTBMY-UHFFFAOYSA-N |
M.W : | 234.10 | Pubchem ID : | 59327133 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 67.46 |
TPSA : | 36.28 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.54 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.68 |
Log Po/w (WLOGP) : | 1.45 |
Log Po/w (MLOGP) : | 0.87 |
Log Po/w (SILICOS-IT) : | 0.78 |
Consensus Log Po/w : | 0.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.44 |
Solubility : | 0.859 mg/ml ; 0.00367 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.06 |
Solubility : | 2.06 mg/ml ; 0.00878 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.62 |
Solubility : | 0.567 mg/ml ; 0.00242 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.04 |
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: |
* 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 |
---|---|---|
83% | Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.75 h; Stage #2: at 0 - 20℃; for 1 h; |
Step 2 In a flask 1-cyclopropyl-4-iodo-1H-pyrazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution cooled to 0° C. Isopropylmagnesium chloride (2.0 M in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture stirred at 0° C. for 45 min, after which 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 2.60 mmol) was added and the mixture allowed to warm to room temperature over 1 h. The mixture was quenched with 50percent sat aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with sat. NaCl, dried over MgSO4 and the solution was concentrated. The residue was purified by SiO2 chromatography (20-50percent EtOAc/heptane) to afford 405 mg (83percent) of 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester as a colorless viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 0.166667h; | Example 6; Synthesis of 2-(3-chloro-5-( 1 -cyclopropyl- 1 H-pyrazol-4-yl)phenyl)-N-(4-(2-methylpyridin-4- yl)phenyl)propanamideA clear microwave vial was charged with 2-(3-bromo-5-chlorophenyl)-N-(4-(2- methylpyridin-4-yl)phenyl)propanamide (0.150 g, 0.349 mmol), l-cyclopropyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.0981 g, 0.419 mmol), tetrakis(triphenylphosphine)palladium (0.0202 g, 0.0175 mmol), sodium carbonate (0.349 ml, 0.698 mmol) and dioxane (4 mL). The vial was flushed with nitrogen and capped. The vial was heated in a Personal Chemistry SmithSynthesizer to 1100C for 10 minutes. The reaction mixture was diluted with ethyl acetate and water. The organic portion was washed with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, reduced and purified by RP-HPLC using a gradient of 5percentACN 0.1percent TFA to 95percent ACN 0.1percent TFA in water 0.1percent TFA. The pure fractions were neutralized with ammonium hydroxide and the volatiles were removed under reduced pressure. The solid that crashed out of the aqueous layer was filtered off, washed with water and dried in <n="112"/>a vacuum oven at 45 degrees to give 2-(3-chloro-5-(l-cyclopropyl-lH-pyrazol-4-yl)phenyl)-N- (4-(2-methylpyridin-4-yl)phenyl)propanamide as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Step 2In a flask 1-cyclopropyl-4-iodo-1H-pyrazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution cooled to 0° C.Isopropylmagnesium chloride (2.0 M in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture stirred at 0° C. for 45 min, after which 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 2.60 mmol) was added and the mixture allowed to warm to room temperature over 1 h.The mixture was quenched with 50percent sat aqueous NH4Cl and extracted with EtOAc.The organic extract was washed with sat.NaCl, dried over MgSO4 and the solution was concentrated.The residue was purified by SiO2 chromatography (20-50percent EtOAc/heptane) to afford 405 mg (83percent) of 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester as a colorless viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
407 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 20 - 90℃;Inert atmosphere; | 3-Chloro-6-(l-cyclopropy -lH-pyrazol-4-yl)pyridazine To a 100 mL round bottom flask is added the above solid (6.64 g, 28.4 mol), 3,6-dichoropyridazine (8.46 g, 56.8 mmol), Pd(dppf)Cl2 (1.04 g, 1.42 mol) potassium phosphate (18.1 g, 85.2 mmol), water (5 mL), and 1,4-dioxane (50 g) at room temperature under nitrogen. The reaction mixture is stirred at 90 °C overnight. After cooled to 30 °C, water (20 mL) is added. The aqueous phase is isolated and extracted with ethyl acetate (3 X 30 mL). The combined organic phases are concentrated and the residue is purified on a silica gel flash chromatography to provide a yellow solid (4.07 g, 65percent yield). (MS: [M+l] 222) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 235 N-(5-((2S,5R,6S)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1-cyclopropyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 235 Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> gave 235. 1H NMR (400 MHz, DMSO-d6) delta 9.75 (s, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 4.92-4.83 (m, 1H), 4.59-4.40 (m, 1H), 4.32 (dd, J=22.2, 15.0 Hz, 1H), 4.19-3.93 (m, 1H), 3.80 (dd, J=7.4, 3.7 Hz, 1H), 3.77 (s, 3H), 3.38-3.31 (m, 1H), 2.12-2.03 (m, 1H), 1.87-1.66 (m, 5H), 1.17-0.96 (m, 4H). LCMS (ES+) m/z 446 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 2h; | Step 2. (S)-l-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-3,4- dihydroquinolin-l(2H)-yl)ethanone [0344] A mixture of (S)-l-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-l(2H)- yl)ethanone (0.025 g, 0.061 mmol), l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (0.017 g, 0.073 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l, - biphenyl)(2'-amino-l,r-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (2.4 mg, 0.003 mmol), and cesium carbonate (0.059 g, 0.182 mmol) in 1 ,4-dioxane (2.0 mL) and water (0.40 mL) was heated at 100 °C for 2 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100percent ethyl acetate-hexane) to afford (S)-l-(6-(l- cyclopropyl- 1 H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin- 1 (2H)- yl)ethanone (0.012 g, 45percent) as a white solid. MS (ESI, pos. ion) m/z 440. 1H NMR (300 MHz, DMSO-i/e) delta ppm 0.81 - 0.91 (m, 5 H), 1.07 (d, J=6.74 Hz, 3 H), 1.47 (m, 1 H), 2.03 (br dd, J=13.34, 6.89 Hz, 1 H), 2.18 (s, 3 H), 2.44 (m, 1 H), 3.55 - 3.67 (m, 1 H), 4.63 (m, 1 H), 7.41 (br s, 1 H), 7.51 - 7.70 (m, 3 H), 7.72 (s, 1 H), 7.91 (ddd, J=8.50, 7.04, 1.47 Hz, 1 H), 8.06 (s, 1 H), 8.10 (d, J=8.21 Hz, 1 H), 9.54 (s, 1 H). MS (ESI, pos. ion) m/z 440 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; 1,2-dichloro-ethane; at 80℃;Inert atmosphere; | Step 2. (S)-l-(5-cyclopropoxy-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone. [0392] A 1.5 mL reaction vial was charged with (S)-l-(6-bromo-5-cyclopropoxy-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone (0.019 g, 0.06 mmol) and 1 ,4-dioxane (50 \iL). 1 -cyclopropyl- 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.2 M solution in 1 ,4-dioxane, 540 \iL, 0.108 mmol) and potassium carbonate (1 M solution in water, 180 \iL, 0.18 mmol) were added, and the reaction mixture was purged with nitrogen. [1 ,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 300 \iL, 0.006 mmol) was added, and the reaction was purged with nitrogen and heated to 80 °C on a heater shaker overnight. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous layer was separated and washed with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford (S)-l-(5-cyclopropoxy-6-(l- cyclopropyl-lH-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-l(2H)-yl)ethanone (0.0039 g, 19percent). MS (ESI, pos. ion) m/z 352 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; | Step 2. (S)-4-(l-acetyl-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-l,2,3,4-tetrahydroquinolin- 5-yloxy)benzamide [0496] A 50-mL, round-bottom flask was charged with (S)-4-(l-acetyl-6-bromo-2-methyl-l,2,3,4- tetrahydroquinolin-5-yloxy)benzamide (0.068 g, 0.17 mmol), l-cyclopropyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.059 g, 0.25 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.014 g, 0.02 mmol), potassium carbonate (0.070 g, 0.50 mmol), 1 ,4-dioxane (20 mL) and water (2 mL). The resulting mixture stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was passed through a short pad of celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1 : 1 , ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge Prep CI 8 OBD Column, 19x150mm 5um 13nm; mobile phase, water (0.05percent ammonium bicarbonate) and acetonitrile (15.0percent to 95percent acetonitrile in 12 min; flow rate: 20 mL/min); Detector, UV 254/220nm. This afforded (S)-4-(l-acetyl-6-(l-cyclopropyl- lH-pyrazol-4-yl)-2-methyl-l,2,3,4-tetrahydroquinolin-5-yloxy)benzamide (0.029 g, 40percent) as an off- white solid. 1H NMR(300 MHz, CD3OD) delta ppm 0.93-1.03 (m, 4 H), 1.15 (d, J=6.60 Hz, 3 H, 1.19- 1.42 (m, 1 H), 2.18-2.27 (m, 5 H), 2.67-2.75 (m, 1 H), 3.56-3.63 (m, 1 H), 4.77-4.79 (m, 1 H), 6.85- 6.88 (m, 2 H), 7.37 (m, 1 H), 7.63 (d, J=8.40 Hz, 1 H), 7.77 (s, 1 H), 7.81-7.85 (m, 2 H), 7.94 (s, 1 H). MS (ESI, pos. ion) m/z 431 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | Step 2. l-[(2S)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]- l,2,3,4-tetrahydroquinolin-l-yl]ethaii-l-one [0539] A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and charged with l-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-l, 2,3,4- tetrahydroquinolin-l-yl]ethan-l-one (11 1 mg, 0.30 mmol), 1,4-dioxane (15 mL), 1 -cyclopropyl-4- (tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (139 mg, 0.59 mmol), [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04 mmol), potassium carbonate (124 mg, 0.90 mmol), and water (5 mL). The resulting mixture stirred overnight at 100 °C. After cooling to room temperature, the solution was diluted with ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1 : 1 , ethyl acetate/petroleum ether). The collected fractions were combined and concentrated under vacuum. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5um, 19x100mm; mobile phase, water (0.05percent ammonium bicarbonate) and acetonitrile (65percent to 85percent acetonitrile in 7 min, flow rate 20 mL/min); Detector, UV 220&254nm. This afforded l-[(2S)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-[(4- methylpyridin-2-yl)oxy]-l,2,3,4-tetrahydroquinolin-l-yl]ethan-l-one (63.6 mg, 53percent) as an off-white solid. 1H NMR (300 MHz, CD3OD) delta ppm 0.95-1.01 (m, 4H), 1.14 (d, J=6.30 Hz, 3H), 1.30-1.45 (m, 1H), 2.10-2.30 (m, 5H), 2.34 (s, 3H), 2.55-2.70 (m, 1H), 3.55-3.65 (m, 1H), 4.68-4.85 (m, 1H), 6.75 (s, 1H), 6.85-6.95 (m, 1H), 7.20-7.32 (m, 1H), 7.55-7.58 (m, 1H), 7.72 (s, 1H), 7.89-7.93 (m, 2H). MS (ESI, pos. ion) m/z 403[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 15h;Inert atmosphere; | Step 2. (S,E)-l-(5-(2-chlorovinyloxy)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone [0575] A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with l-[(2S)-6-bromo-5-(2,2-dichloroethoxy)-2-methyl- 1,2,3,4- tetrahydroquinolin-l-yl]ethan-l-one (43 mg, 0.11 mmol), 1 -cyclopropyl-4-(tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole (40 mg, 0.17 mmol), [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol), potassium carbonate (31 mg, 0.22 mmol), 1,4-dioxane (24 mL), and water (4 mL). The resulting mixture stirred for 15 h at 100 °C in an oil bath. After cooling to room temperature, the reaction mixture was passed a short pad of celite and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with dichloromethane/methanol, 50: 1 then 20: 1) to afford (S,E)-l-(5-(2- chlorovinyloxy)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-l(2H)- yl)ethanone (12 mg, 26percent) as a white solid. 1H NMR(300 MHz, CD3OD) delta ppm 1.05-1.15 (m, 7 H), 1.35-1.58 (m, 1 H), 2.21 (s, 3 H), 2.25-2.50 (m, 2 H), 2.80-2.93 (m, 1 H), 3.65-3.75 (m, 1 H), 4.61 (s, 1 H), 4.70-4.85 (m, 1 H), 5.52 (d, J=4.20 Hz, 1 H), 6.52 (d, J=4.20 Hz, 1 H), 7.15-7.25 (m, 1 H), 7.54 (d, J=8.40 Hz, 1 H),7.89 (s, 1 H), 8.07 (s, 1 H). MS (ESI, pos. ion) m/z 372[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; | Step 3. (S)-l-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4- dihydroquinolin-l(2H)-yl)ethanone [0602] A 100-mL, round-bottom flask was charged with (S)-l-(6-bromo-2-methyl-5-(3- methylpyridin-2-yloxy)-3,4-dihydroquinolin-l(2H)-yl)ethanone (0.129 g, 0.34 mmol), [Iota, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.025 g, 0.03 mmol), potassium carbonate (0.142 g, 1.03 mmol), l-cyclopropyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.243 g, 1.04 mmol), 1.4-dioxane (10 mL) and water (2 mL). The resulting mixture stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was passed through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50percent ethyl acetate-petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18,19xl50mm; mobile phase, water (0.05percent ammonium bicarbonate) and acetonitrile (54percent to 80percent acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254nm. This afforded (S)- 1 -(6-( 1 -cyclopropyl- 1 H-pyrazol-4-yl)-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4- dihydroquinolin-l(2H)-yl)ethanone (0.0285 g, 21percent) as an off-white solid. 1H NMR(300 MHz, CD3OD) delta ppm 1.00-1.03 (m, 4 H), 1.16 (d, J=6.60 Hz, 3 H), 1.32-1.42 (m, 1 H), 2.20-2.28 (m, 5 H), 2.48 (s, 3 H), 2.54-2.59 (m, 1 H), 3.57-3.64 (m, 1 H), 4.75-4.80 (m, 1 H), 6.95-7.00 (m, 1 H), 7.22-7.27 (m, 1 H), 7.54 (d, J=8.40 Hz, 1 H), 7.63 (s, 1 H), 7.72-7.77 (m, 2 H), 7.80 (s, 1 H). MS (ESI, pos. ion) m/z 403[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; | Step 3. l-((S)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H- purin-2-yloxy)-3,4-dihydroquinoliii-l(2H)-yl)ethanone [0608] A 100-mL, round-bottom flask was charged with l-((S)-6-bromo-2-methyl-5-(7-(tetrahydro- 2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-l(2H)-yl)ethanone (0.200 g, 0.41 mmol), [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.030 g, 0.04 mmol), potassium carbonate (0.170 g, 1.23 mmol), l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (0.288 g, 1.23 mmol), 1 ,4-dioxane (20 mL), and water (2 mL). The resulting mixture stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was passed through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1 :2, ethyl acetate/petroleum ether) to afford 1- ((S)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2- yloxy)-3,4-dihydroquinolin-l(2H)-yl)ethanone (0.150 g, 71percent) as light yellow oil. MS (ESI, pos. ion) m/z 514[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h; | Step 3. (E/Z)-(S)-6-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methyl-5-((l-(prop-l-en-l-yl)-lH- benzo[d]imidazol-2-yl)oxy)-l,2,3,4-tetrahydroquinoline [0726] A mixture of (S)-5-(l-allyl-lH-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-l ,2,3,4- tetrahydroquinoline (0.115 g, 0.29 mmol), l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole (0.269 g, 1.15 mmol), potassium carbonate (0.118 g, 0.85 mmol), and [Iota, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.023 g, 0.03 mmol) in 1,4-dioxane (10 mL) and water (3 mL) stirred for 3 h at 100 °C. The reaction mixture was cooled to room temperature, filtered through a short pad of Celite and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1 :2, ethyl acetate/petroleum ether) to afford (S)-6-(l -eye lopropyl-lH-pyrazol-4-yl)-2-methyl-5-((l -(prop- 1-en- l-yl)-lH-benzo[d]imidazol-2-yl)oxy)-l ,2,3,4-tetrahydroquinoline (0.106 g, 86percent) as a red oil which is mixture of E and Z isomers. MS (ESI, pos. ion) m/z 426 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 16h; | A mixture of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.500 g, 1.858 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (0.457 g, 1.951 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (0.146 g, 0.186 mmol), and cesium carbonate (1.816 g, 5.57 mmol) in 1,4-dioxane (7.5 mL) and water (1.50 mL) was heated at 100 °C for 16 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100percent ethyl acetate-hexane) to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.335 g, 61percent) as an off-white solid. MS (ESI, pos. ion) m/z 297 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 17h; | A mixture of (S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4- dihydroquinoxaline-1(2H)-carboxylate (0.250 g, 0.574 mmol), 1-cyclopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.148 g, 0.632 mmol), tris(dibenzylideneacetone)dipalladium (0.026 g, 0.029 mmol), X-Phos (0.027 g, 0.057 mmol) and cesium carbonate (0.561 g, 1.723 mmol) in 1,4-dioxane (5.0 mL) and water (1.0 mL) was heated at 100 °C for 17 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100percent ethyl acetate-hexane) to afford (S)- cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)- carboxylate (0.124 g, 59 percent) as a yellow solid. MS (ESI, pos. ion) m/z 367 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; 1,2-dichloro-ethane; at 80℃; for 4h;Inert atmosphere; | A reaction vial was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydropyrido[2,3- b]pyrazin-1(2H)-yl)ethanone (0.1 M solution in 1,2-dichloroethane, 0.30 mL, 0.03 mmol) and N,N-diisopropylethylamine (0.052 mL, 0.300 mmol) was added. 1-Fluoro-4-isocyanatobenzene (0.017 mL, 0.150 mmol) was added neat, followed by the addition of a catalytic amount of DMAP (~1 mg), and the reaction was shaken at 50 °C overnight. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen and vacuum to yield (S)-1-acetyl-6-bromo-N-(4- fluorophenyl)-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. The crude product was dissolved in 1,4-dioxane (100 L), and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.2 M solution in 1,4-dioxane, 0.27 mL, 0.054 mmol), potassium carbonate (1.0 M solution in water, 0.090 mL, 0.090 mmol) and [1,1?- bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 150 muL, 0.003 mmol) were added. The reaction was purged with nitrogen, and heated to 80 °C on a heater shaker for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution and brine. The combined organic layers were concentrated in a Genevac. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(4-fluorophenyl)-2-methyl-2,3- dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. MS (ESI, pos. ion) m/z 435 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In 1,4-dioxane; water; N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | General procedure: A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1- (6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2- trifluoroethanone (0.626 g, 1.5 mmol), 1,4-dioxane (15 mL), 4-(methylsulfonyl)phenylboronic acid (0.360 g, 1.8 mmol), and sodium bicarbonate as a 1M solution in water (4.5 mL, 4.5 mmol). The reaction mixture was purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (0.01 M solution in DMF, 7.5 mL, 0.075 mmol) was added, and the reaction mixture was purged with nitrogen and heated to 80 °C overnight. The reaction was diluted with ethyl acetate (30 mL) and washed with brine (15 mL). The aqueous layer was separated and washed with ethyl acetate (30 mL) and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 1:1 hexanes? ethyl acetate) to afford (S)-furan-2-yl(3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4- dihydroquinoxalin-1(2H)-yl)methanone (0.33 g, 55 percent yield) as a viscous yellow oil. MS (ESI, pos. ion) m/z 397 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 1.5h; | A mixture of (S)-(4-(benzo[d]oxazol-2-yl)-6-bromo-2-methyl-3,4-dihydroquinoxalin- 1(2H)-yl)(cyclopropyl)methanone (0.019 g, 0.046 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.012 g, 0.051 mmol), tris(dibenzylideneacetone) dipalladium (2.1 mg, 2.3 mumol), 2-dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (XPhos) (2.2 mg, 4.6mumol) and cesium carbonate (0.045 g, 0.138 mmol) in dioxane (1.0 mL) and water (0.20 mL) was heated in the microwave at 100 °C for 1.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100percent ethyl acetate- hexane) to afford (S)-(4-(benzo[d]oxazol-2-yl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4- dihydroquinoxalin-1(2H)-yl)(cyclopropyl)methanone (0.014 g, 69percent) as an off-white solid.1H NMR (300 MHz, DMSO-d6) delta ppm 0.65 - 1.05 (m, 11 H), 1.85 - 2.02 (m, 1 H), 3.58 - 3.80 (m, 1 H), 3.90 - 4.16 (m, 2 H), 5.02 - 5.18 (m, 1 H), 7.01 - 7.26 (m, 2 H), 7.31 (dd, J = 8.21, 1.76 Hz, 1 H), 7.35 - 7.58 (m, 3 H), 7.79 (s, 1 H), 8.18 (s, 1 H), 8.36 (d, J = 2.05 Hz, 1 H). MS (ESI, pos. ion) m/z 440 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; 1,2-dichloro-ethane; at 80℃;Inert atmosphere; | A 1.5 mL reaction vial was charged with (S)-1-(4-(benzo[d]isoxazol-3-yl)-6-bromo- 2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.012 g, 0.03 mmol), 1-cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 M in 1,4-dioxane, 225 muL, 0.03 mmol), and dioxane (0.1 mL). Potassium carbonate (1 M solution in water, 90 muL, 0.09 mmol) was added, and the reaction mixture was purged with nitrogen. [1,1?- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.02 M solution in 1,2-dichloroethane, 150 muL, 0.003 mmol) was added, the reaction was purged with nitrogen, and heated overnight at 80 °C on a heater shaker. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous layer was separated and washed with ethyl acetate and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford 1-[(2S)-4-[(furan-2- yl)carbonyl]-6-(5-methanesulfonylpyridin-2-yl)-2-methyl-1,2,3,4-tetrahydroquinoxalin-1- yl]ethan-1-one (0.0026 g, 22percent). MS (ESI, pos. ion) m/z 414 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; | A 100-mL round-bottom flask was purged with an inert atmosphere of nitrogen and charged with (S)-1-(6-bromo-4-(7-fluoro-1-methyl-1H-indazol-3-yl)-2-methyl-3,4-dihydro quinoxalin-1(2H)-yl)ethan-1-one (46 mg, 0.11 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77.6 mg, 0.33 mmol), [1,1?-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol), potassium carbonate (46 mg, 0.33 mmol), 1,4-dioxane (20 mL) and water (2 mL). The resulting mixture stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered through a short pad of celite and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether) to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4- yl)-4-(7-fluoro-1-methyl-1H-indazol-3-yl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (13.1 mg, 27percent) as a white solid.1H NMR(300 MHz, CDCl3) delta ppm 1.01-1.14 (m, 4H), 1.26 (d, J = 6.90 Hz, 3H), 2.32 (s, 3H), 3.55-3.65 (m, 1H), 3.67-3.75 (m, 1H), 3.90-4.01 (m, 1H), 4.23 (s, 3H), 6.76 (s, 1H), 6.85-6.98 (m, 2H), 7.01-7.15 (m, 3H), 7.49 (s, 1H), 7.56 (s, 1H). MS (ESI, pos. ion) m/z 445 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; 1,2-dichloro-ethane; at 80℃;Inert atmosphere; | A reaction vial was charged with (S)-isopropyl 7-bromo-3-methyl-4- (methylcarbamoyl)-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.015 g, 0.04 mmol), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (0.2 M solution in 1,4-dioxane, 0.40 mL, 0.080 mmol), potassium carbonate (1.0 M solution in water, 0.120 mL, 0.120 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 0.200 mL, 0.004 mmol). The reaction was purged with nitrogen and heated to 80 °C on a heater shaker overnight.. The reaction was diluted with ethyl acetate and washed with brine. The combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-isopropyl 7-(1- cyclopropyl-1H-pyrazol-4-yl)-3-methyl-4-(methylcarbamoyl)-3,4-dihydropyrido[2,3-b]pyrazine- 1(2H)-carboxylate. MS (ESI, pos. ion) m/z 399 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; 1,2-dichloro-ethane; at 80℃; | A reaction vial was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydropyrido[2,3- b]pyrazin-1(2H)-yl)ethanone (0.1 M solution in 1,2-dichloroethane, 0.30 mL, 0.03 mmol), 1,4- dioxane (100 L), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (0.2 M solution in 1,4-dioxane, 0.27 mL, 0.054 mmol), potassium carbonate (1.0 M solution in water, 0.090 mL, 0.090 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 150 muL, 0.003 mmol). The reaction was purged with nitrogen, and heated to 80 °C on a heater shaker overnight. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution and brine. The combined organic layers were concentrated under a stream of nitrogen and vacuum to yield (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydropyrido[2,3- b]pyrazin-1(2H)-yl)ethanone. The crude product was dissolved in 1,2-dichloroethane (200 L), and N,N-diisopropylethylamine (0.052 mL, 0.300 mmol) was added. 2-Isocyanatopropane (0.020 mL, 0.200 mmol) was then added along with a catalytic amount of DMAP (~1 mg), and the reaction was shaken at 80 °C for 3 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate and the combined organic layers were concentrated in a Genevac. The crude product was purified by mass triggered preparatory HPLC. The product- containing fractions were combined and concentrated to afford (S)-1-acetyl-6-(1-cyclopropyl- 1H-pyrazol-4-yl)-N-isopropyl-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. MS (ESI, pos. ion) m/z 383 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; water; at 90℃; for 16h; | A mixture of isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4- dihydroquinoxaline-1(2H)-carboxylate (0.131 g, 0.327 mmol), 1-cyclopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.092 g, 0.392 mmol), cesium carbonate (0.319 g, 0.980 mmol), XPhos (0.016 g, 0.033 mmol) and tris(dibenzylideneacetone)dipalladium (0.015 g, 0.016 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was heated for 16 h at 90 C. The reaction was cooled to rt and concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-7-(1- cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 428 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With (chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Microwave irradiation; | A mixture of (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydro quinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (0.100 g, 0.256 mmol), 1-cyclopropyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.066 g, 0.281 mmol), chloro(2-dicyclohexyl phosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (XPhos Precatalyst 2nd Generation) (10.06 mg, 0.013 mmol), and cesium carbonate (0.250 g, 0.767 mmol) in dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100 °C for 16 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100percent ethyl acetate-hexane) to afford (S)-cyclopropyl(7-(1-cyclopropyl-1H- pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone (0.065 g, 79percent) as a yellow solid. MS (ESI, pos. ion) m/z 323 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With tris-(dibenzylideneacetone)dipalladium(0); potassium dihydrogenphosphate; In 1,4-dioxane; water; at 90℃; for 15h; | Pd2(dba)3 (0.087 g, 0.095 mmol) and X-phos (0.018 g, 0.047 mmol) was added to degassed solution of (4S)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (0.3 g, 0.947 mmol), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (0.333 g, 1.421 mmol) and potassium dihydrogen phosphate (0.258 g, 1.894 mmol) in 1,4-dioxane (5 mL): water (1 mL) and heated to 90 C. for 15 hours. Cooled to room temperature and filtered through pad of celite. The filtrate was diluted with water (25 mL) and ethyl acetate (50 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude (TLC eluent: 10% MeOH in ethyl acetate; UV active; Rf0.30). The crude compound was purified by column chromatography using neutral alumina and eluted in 75% ethyl acetate in hexane to afford (4S)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3b][1,4]diazepine-5(2H)-carboxamide (0.13 g, 0.332 mmol, 35.0% yield) off-white solid, LCMS (m/z): 389.32 [M+H]+. 1H NMR (400 MHz, CDCl3): delta ppm 14.14 (s, 1H), 9.60 (d, J=1.10 Hz, 1H), 8.61 (s, 1H), 8.29-8.33 (m, 2H), 8.03 (s, 1H), 7.47-7.58 (m, 1H), 7.13 (d, J=8.11 Hz, 1H), 5.66 (dd, J=6.03, 3.18 Hz, 1H), 3.73 (tt, J=7.43, 3.75 Hz, 1H), 3.08-3.34 (m, 3H), 2.99 (dd, J=11.95, 3.18 Hz, 1H), 2.32 (dddd, J=14.11, 10.00, 6.03, 4.06 Hz, 1H), 2.02-2.11 (m, 1H), 1.22-1.32 (m, 2H), 1.07-1.18 (m, 2H). |
35% | With tris-(dibenzylideneacetone)dipalladium(0); potassium dihydrogenphosphate; XPhos; In 1,4-dioxane; water; at 90℃; for 15h; | Pd2(dba)3 (0.087 g, 0.095 mmol) and X-phos (0.018 g, 0.047 mmol) was added to degassed solution of (4,S)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-l,4-methanopyrido[2,3- b][,4] diazepine-5(2H)-carboxamide (0.3 g, 0.947 mmol), l-cyclopropyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.333 g, 1.421 mmol) and potassium dihydrogen phosphate (0.258 g, 1.894 mmol) in 1,4-dioxane (5 mL):water (1 mL) and heated to 90 C for 15 hours. Cooled to room temperature and filtered through pad of celite. The filtrate was diluted with water (25 mL) and ethyl acetate (50 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude (TLC eluent: 10% MeOH in ethyl acetate; UV active; Rf-0.30). The crude compound was purified by column chromatography using neutral alumina and eluted in 75%) ethyl acetate in hexane to afford (4,S)-7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(pyrazin- 2-yl)-3,4-dihydro-l,4-methanopyrido [2,3b][l,4]diazepine-5(2H)-carboxamide (0.13 g, 0.332 mmol, 35.0 % yield) off-white solid, LCMS (m/z): 389.32 [M+H]+.1H NMR (400 MHz, CDC13): delta ppm 14.14 (s, 1H), 9.60 (d, J= 1.10 Hz, 1H), 8.61 (s, 1H), 8.29 - 8.33 (m, 2H), 8.03 (s, 1H), 7.47 - 7.58 (m, 1H), 7.13 (d, J = 8.11 Hz, 1H), 5.66 (dd, J = 6.03, 3.18 Hz, 1H), 3.73 (tt, J = 7.43, 3.75 Hz, 1H), 3.08 - 3.34 (m, 3H), 2.99 (dd, J = 11.95, 3.18 Hz, 1H), 2.32 (dddd, 7 =14.11, 10.00, 6.03, 4.06 Hz, 1H), 2.02 - 2.11 (m, 1H), 1.22 - 1.32 (m, 2H), 1.07 - 1.18 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.4% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 16h;Inert atmosphere; | Tripotassium phosphate (6.51 g, 30.7 mmol) and l-cyclopropyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.87 g, 12.27 mmol) were added to a stirred solution of (4S)-7-chloro-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3-b][l,4]diazepine (2 g, 10.22 mmol) in mixture of 1,4-Dioxane (40 mL), Water (10.00 mL) at RT. Purged with argon for 5 min, then added PdCl2(dppf)-CH2Cl2 adduct (0.835 g, 1.022 mmol) stirred the reaction mixture at 1 10 C for 16 h. Allowed the reaction mixture to RT, diluted with water (150 mL) extracted with Ethyl acetate (2x300 mL), washed with brine (200 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to obtain crude compound. The crude product was purified by flash column chromatography (silica-gel: 100-200 mesh) and was eluted with 10% MeOH-DCM to afford (4S)-7-(l-cyclopropyl-lH-pyrazol-4-yl)-2,3,4,5-tetrahydro-l,4-methanopyrido[2,3- b][l,4]diazepine (1 g, 3.52 mmol, 34.4 % yield), LCMS (m/z): 268.13 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; | Dissolved (S)-7-chloro-3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5- (phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine (47.3 mg, 0.1 mmol) and l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (46.8 mg, 0.200 mmol) in 1.7 mL of dioxane. Added PdCl2(dppf CH2Cl2Adduct (8.2 mg, 10.0 muetaiotaomicron) and 0.3 mL of sodium carbonate (300 mu, 0.300 mmol). Bubbled in argon for 2 min while sonicating. Heated at 100 °C for 2 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 ACN: water with 0.1 percent trifluoroacetic acid; Mobile Phase B : 95 : 5 ACN: water with 0.1 percent trifluoroacetic acid; Gradient: 35-75percent B over 20 min, then a 5-min hold at 100percent B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.0 mg (61percent), and its estimated purity by LCMS analysis was 98percent. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7-muiotaeta particles; Mobile Phase A: 5:95 ACN:water with 10 mM NlrUOAc; Mobile Phase B: 95:5 ACN:water with 10 mM NH4OAc; Temperature: 50 °C; Gradient: 0-100percent B over 3 min, then a 0.5-min hold at 100percent B; Flow: 1.0 mL/min; Detection: UV at 220 nm. RT = 1.81 min, M+H = 545. Injection 2 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7-mupiiota particles; Mobile Phase A: 5:95 methanol: water with 10 mM NHiOAc; Mobile Phase B: 95:5 methanol: water with 10 mM NEUOAc; Temperature: 50 °C; Gradient: 0-100percent B over 3 min, then a 0.5-min hold at 100percent B; Flow: 0.5 mL/min; Detection: UV at 220 nm. RT = 3.15 min, M+H = 545. H NMR (500MHz, DMSO-de) delta 8.63 (s, 1H), 8.58 - 8.53 (m, 2H), 8.51 (br. s., 1H), 8.26 (s, 1H), 7.84 (d, J=7.7 Hz, 2H), 7.70 (d, J=8.1 Hz, 1H), 7.31 (t, J=7.5 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 5.93 (br. s., 1H), 4.03 (s, 3H), 3.90 (dd, J=7.5, 3.5 Hz, 2H), 3.76 (d, J=10.6 Hz, 2H), 3.26 (t, J=l 1.4 Hz, 1H), 2.30 (s, 3H), 1.56 (d, J=10.6 Hz, 1H), 1.51 - 1.38 (m, 1H), 1.36 - 1.24 (m, 1H), 1.24 - 1.14 (m, 3H), 1.14 - 0.95 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
495 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 85℃; for 24h;Inert atmosphere; | (A) (2E)-Ethyl 3-(4-(1-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)acrylate A mixture of (2E)-ethyl 3-(4-chloro-5-fluoropyridin-3-yl)acrylate (800 mg), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (923 mg), 2-(dicyclohexylphosphino)biphenyl (160 mg), Pd2(dba)3 (163 mg), cesium carbonate (2.76 g), DME (21 mL) and water (3 mL) was stirred under nitrogen atmosphere at 85° C. for 24 hours. The reaction mixture was filtered through Celite. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (495 mg). MS: [M+H]+302.2. |
495 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 20 - 85℃; for 24h;Inert atmosphere; | In a nitrogen atmosphere,85 ° C,Ethyl (2E) -3- (4-chloro-5-fluoropyridin-3-yl) acrylate (800 mg)1-cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (923 mg)2- (dicyclohexylphosphino) biphenyl (160 mg),Pd2 (dba) 3 (163 mg),Cesium carbonate (2.76 g),DME (21 mL) and water (3 mL) was stirred at room temperature for 24 hours.The reaction mixture was filtered through celite.Water was added to the reaction mixture and the aqueous layer was extracted with ethyl acetate.The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (495 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tris-(dibenzylideneacetone)dipalladium(0); (dicyclohexylphosphino)biphenyl; caesium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 16h; | General procedure: To a solution of 25a (500 mg, 2.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (498 mg, 2.40 mmol), CyJohnPhos (95 mg, 0.27 mmol) and Cs2CO3 (1.77 g, 5.44 mmol) in DME (14 mL)/water (2.0 mL) was added Pd2(dba)3 (100 mg, 0.11 mmol) at rt. The mixture was stirred at 85 °C for 16 h. The mixture was treated with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10?80percent EtOAc/hexane) to yield 26a (450 mg, 75percent) as a pale yellow solid |
3.22 g | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 85℃; for 15h;Inert atmosphere; | (A) (2E)-tert-Butyl 3-(4-(1-cyclopropyl-1H-pyrazol-4-yl)-5-fluoropyridin-3-yl)acrylate A mixture of (2E)-tert-butyl 3-(4-chloro-5-fluoropyridin-3-yl)acrylate (3.51 g), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (3.88 g), 2-(dicyclohexylphosphino)biphenyl (611 mg), Pd2(dba)3 (749 mg), cesium carbonate (10.7 g), DME (70 mL) and water (10 mL) was stirred under nitrogen atmosphere at 85° C. for 15 hours. The reaction mixture was filtered through Celite, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (3.22 g). MS: [M+H]+330.2. |
3.22 g | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 85℃; for 15h;Inert atmosphere; | In a nitrogen atmosphere,85 ° C,(2E) -3- (4-chloro-5-fluoropyridin-3-yl) acrylic acid tert-butyl ester (3.51 g)Cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (3.88 g)2- (dicyclohexylphosphino) biphenyl (611 mg),Pd2 (dba) 3 (749 mg),Cesium carbonate (10.7 g),DME (70 mL) and water (10 mL) was stirred for 15 h.The reaction mixture was filtered through celite and water was added to the filtrate followed by extraction with ethyl acetate.The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.22 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tris-(dibenzylideneacetone)dipalladium(0); (dicyclohexylphosphino)biphenyl; potassium carbonate; In 1,2-dimethoxyethane; water; at 75℃; for 16h; | General procedure: Solid Pd2(dba)3 (0.377 g, 0.41 mmol) was added to a degassed solution of 6 (5.79 g, 27.4 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.28 g, 30.2 mmol), 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos, 0.294 g, 0.84 mmol) and K2CO3 (9.40 g, 68.0 mmol) in DME (100 mL) and water (33 mL) and heated at 75 C for 16 h. Removed insoluble material by filtration and separated layers. Extracted aqueous layer with EtOAc (100 mL), and washed combined organics with sat. aq. NaHCO3 (2 × 100 mL) and brine (2 × 50 mL). Dried organic layer over MgSO4, filtered, and evaporated solvent under vacuum. The crude was triturated with MTBE (30 mL), and product collected by filtration (4.48 g). A second crop was collected by concentrating the resulting filrate and purification by column chromatography (silica gel, eluted with 0-100% EtOAc/hexane). Trituration with MTBE afforded a second crop of product (0.921 g). Compound 8b (overall yield 5.40 g, 77%) was thus obtained as an off-white solid |
2.73 g | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 75℃; for 9h;Inert atmosphere; | (A) (2E)-Ethyl 3-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)acrylate A mixture of (2E)-ethyl 3-(4-chloropyridin-3-yl)acrylate (2.22 g), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (2.89 g), 2-(dicyclohexylphosphino)biphenyl (0.19 g), Pd2(dba)3 (0.24 g), potassium carbonate (3.64 g), DME (50 mL) and water (13 mL) was stirred under nitrogen atmosphere at 75 C. for 9 hours. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.73 g). MS: [M+H]+284.0. |
2.73 g | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 75℃; for 9h;Inert atmosphere; | In a nitrogen atmosphere, 75 C,(2E) -3- (4-chloropyridin-3-yl) acrylate (2.22 g)Cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (2.89 g)2- (dicyclohexylphosphino) biphenyl (0.19 g), Pd2 (dba) 3 (0.24 g),Potassium carbonate (3.64 g), DME (50 mL) and water (13 mL) was stirred for 9 hours.Water (50 mL) and ethyl acetate (100 mL) were added to the reaction mixture,And the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.73 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.76 g | (A') (2E)-Ethyl 3-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)acrylate hydrochloride A mixture of (2E)-ethyl 3-(4-chloropyridin-3-yl)acrylate (16.63 g), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (22.99 g), 2-(dicyclohexylphosphino)biphenyl (1.377 g), Pd2(dba)3 (1.799 g), 2 M aqueous potassium carbonate solution (98 mL) and DME (400 mL) was stirred overnight under nitrogen atmosphere at 75 C. Water (200 mL) and ethyl acetate (400 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The insoluble matter was removed by filtration. The organic layer of the filtrate was washed with water (200 mL), a 3% aqueous ammonia solution (100 mL) and brine (200 mL) and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate (800 mL) and NH silica gel (350 g) were added to the residue at room temperature, and the mixture was stirred overnight at the same temperature. NH silica gel was removed by filtration and washed with ethyl acetate (1500 mL), and the solvent in the combined filtrate and washings was distilled off under reduced pressure. Ethyl acetate (800 mL) and NH silica gel (350 g) were added to the residue at room temperature, and the mixture was stirred overnight at the same temperature. NH silica gel was removed by filtration and washed with ethyl acetate (1500 mL), and the solvent in the combined filtrate and washings was distilled off under reduced pressure. Ethyl acetate (800 mL) and NH silica gel (350 g) were added to the residue at room temperature, and the mixture was stirred overnight at the same temperature. NH silica gel was removed by filtration and washed with ethyl acetate (1500 mL), and was the solvent in the combined filtrate and washings was distilled off under reduced pressure. Ethyl acetate (750 mL) and a 4 N solution of hydrogen chloride in ethyl acetate (58.9 mL) were added to the residue at 0 C., and the solvent was distilled off under reduced pressure. Ethyl acetate (150 mL) was added to the residue, and the mixture was stirred at 0 C. for 1 hour. The precipitate was collected by filtration and washed with ethyl acetate to obtain the title compound (19.76 g). MS: [M+H]+284.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 3h; | To a solution of <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (S2, 1 equiv) in DMF/H2O (9:1, 10 vol) was added compound S1 (1 equiv), Cs2CO3(2 equiv), and tetrakis(triphenylphosphine)palladium (0.1 equiv). The reaction mixture was stirred at 90° C. for 3 h and then concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel to give compound S3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 5h; | To a solution of <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (S2, 1 equiv) in DMF/H2O (9:1, 10 vol) was added compound S1 (1 equiv), Cs2CO3(3 equiv), and tetrakis(triphenylphosphine)palladium (0.1 equiv). The reaction mixture was stirred at 90° C. for 5 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH/DCM) to give compound S3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.76 g | In a nitrogen atmosphere, 75 C,(2E) -3- (4-chloropyridin-3-yl)Acrylate (16.63 g),Cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (22.99 g)2- (dicyclohexylphosphino) biphenyl (1.377 g),Pd2 (dba) 3 (1.799 g), 2M aqueous potassium carbonate solution (98 mL) and DME (400 mL) was stirred overnight.Water (200 mL) and ethyl acetate (400 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes.Filter to remove insoluble matter. The organic layer of the filtrate was washed with water (200 mL),3% aqueous ammonia solution (100 mL) and brine (200 mL), followed by distillation under reduced pressure to remove the solvent.Ethyl acetate (800 mL) and NH silica gel (350 g) were added to the residue at room temperature and the mixture was stirred overnight at the same temperature.The NH silica gel was removed by filtration and washed with ethyl acetate (1500 mL), and then the solvent removed in the combined filtrate and the laundry was distilled under reduced pressure. Ethyl acetate (800 mL) and NH silica gel (350 g) were added to the residue at room temperature and the mixture was stirred overnight at the same temperature.The NH silica gel was removed by filtration and washed with ethyl acetate (1500 mL), and then the solvent removed in the combined filtrate and the laundry was distilled under reduced pressure.Ethyl acetate (800 mL) and NH silica gel (350 g) were added to the residue at room temperature and the mixture was stirred overnight at the same temperature. The NH silica gel was removed by filtration and washed with ethyl acetate (1500 mL), and then the solvent removed in the combined filtrate and the laundry was distilled under reduced pressure.Then, a solution of ethyl acetate (750 mL) and 4N hydrochloric acid in ethyl acetate (58.9 mL) was added to the residue at 0 C, and the solvent was distilled off under reduced pressure. Ethyl acetate (150 mL) was added to the residue, and the mixture was stirred at 0 C for 1 hour.The precipitate was collected by filtration and washed with water to give the title compound (19.76 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | General procedure: 2-Ethylhexyl 3-((3-(1 -cyclopropyl-1 H-pyrazol-4-yl)-5-methoxyphenyl)thio)propanoate was synthesised according to general procedures GP13 - from 2-ethylhexyl 3-((3-bromo-5- methoxyphenyl)thio)propanoate (2.23 g, 5.55 mmol), 1 -cyclopropyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 4.27 mmol), Pd(dppf)CI2 (220 mg, 5 molpercent), CS2CO3 (4.48 g, 13.7 mmol), 1 ,4-dioxane/H20 (5:1 ; 30 mL); 90 °C, 16 h. Chromatographic purification (0?10percent EtOAc/hexane) afforded a yellow oil (1 .46 g, 80percent). NMR (400 MHz, DMSO-c/6) delta 8.23 (s, 1 H), 7.90 (s, 1 H), 7.1 1 (br, 1 H), 6.99 (br, 1 H), 6.68 (t, J = 1 .6 Hz, 1 H), 3.94 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.73-3.71 (m, 1 H), 1 .51 -1 .47 (m, 1 H), 3.23-3.20 (m, 2H), 2.63 (t, J = 6.8 Hz, 2H), 1 .30-1 .22 (m, 8H), 1 .07-1 .04 (m, 2H), 1 .00-0.97 (m, 2H), 0.85-0.81 (m, 6H). LCMS (ESI) m/z 431 (M+ H)+. General procedures GP13 [00693] A mixture of bromide GP13_1 , Pd(PPh3)4, ArB(OR')2, Na2C03, H20, EtOH and toluene was degassed with argon and then stirred at 100 °C for 16 h. After cooling to rt, the mixture was diluted with Et20 and filtered through celite. The organic solution was washed with H20, dried over Na2S04, filtered and the solvent was removed under reduced pressure. The crude was purified by chromatography to afford biaryl GP13_2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(triphenylphosphine)palladium(II) dichloride; potassium carbonate; triphenylphosphine; In propan-1-ol; water; at 100℃; for 3h;Inert atmosphere; | 2-Chloro-5-nitrobenzenesulfonamide (674 mg, 2.85 mmol) and i-cyclopropyl-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 4.27 mmol) were dissolved in npropanol (34 ml) and bis(triphenylphosphine)palladium(l I) dichioride (CAS 13965-03-2)(100 mg, 142 pmol) and triphenylphosphine (37.3 mg, 142 pmol) were added. Thereaction was purged with argon for 5 minutes and aq. potassium carbonate (5.7 ml, 1.0 M,5.7 mmol) was added. The reaction was heated at 100°C for 3h. Afterwards the mixturewas filtered over Celite and the solvent was removed under reduced pressure. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Whatmanfilter and the solvent was removed under reduced pressure.The crude was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | N-(4-Bromo-3-[(d imethylam ino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (500 mg, 1.09 mmol), 1 -cyclopropyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1H-pyrazole (510 mg, 2.18 mmol) and potassium fluoride (139 mg, 2.4 mmol) were dissolved in dry and degased DMF (30 ml) and the solution was purged againwith argon for 5 minutes followed by addition of bis(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (28 mg, 54 pmol). The reaction was heated for2h at 10000. Afterwards the mixture was filtered over Celite, the solvent was removed under reduced pressure and the crude was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.2 mg | With bis(triphenylphosphine)palladium(II) dichloride; potassium carbonate; triphenylphosphine; In propan-1-ol; water; at 120℃; under 1500.15 Torr; for 1h;Inert atmosphere; Microwave irradiation; | N-(4-Bromo-3-[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chloro-4-fluoro- phenyl)acetamide (250 mg, 524 pmol) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1 H-pyrazole (246 mg, 1.05 mmol) were dissolved in n-propanol (9.6 ml) and bis(triphenylphosphine)palladium(l I) dichloride (CAS 13965-03-2) (18.5 mg, 26.2 pmol) and triphenylphosphine (6.88 mg, 26.2 pmol) were added. The solution was purgedwith argon for 5 minutes and aq. potassium carbonate (660 p1, 2.0 M, 1.3 mmol) was added. The reaction was heated at 120°C for lh in the microwave (2 bar I 25W). Afterwards the mixture was filtered over Celite, the solvent was removed under reduced pressure and the crude was dissolved in methanol (5 ml) and treated with 32percent aqueous sodium hydroxide (0.2 ml) at 80°C until completion of the reaction. The solvent wasremoved under reduced pressure, the crude was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried over Whatmanfilter and the solvent was removed under reduced pressure. The crude was purified by HPLC (Waters XBrigde 018 5p lOOx3Omm, acetonitrile/water + 0.2percent aqueous ammonia (32percent)) to yield the title compound (38.2 mg, 95percent purity, 15percentyield over 2 steps).LC-MS (Method B): Rt = 0.98 mm; MS (ESineg): mlz = 447 [M-H]1HNMR (400MHz, DMSO-d6): O [ppm]= 0.94- 1.01 (m, 2H), 1.05- 1.11 (m, 2H), 3.74 (tt,1H), 3.87 (s, 2H), 7.17 - 7.25 (m, 3H), 7.41 - 7.52 (m, 3H), 7.67 (s, 1H), 7.80 (dd, 1H),8.04 (s, 1H), 8.31 (d, 1H), 10.57 (s, 1H). |
Tags: 1151802-22-0 synthesis path| 1151802-22-0 SDS| 1151802-22-0 COA| 1151802-22-0 purity| 1151802-22-0 application| 1151802-22-0 NMR| 1151802-22-0 COA| 1151802-22-0 structure
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P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
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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