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CAS No. : | 847818-74-0 | MDL No. : | MFCD05861380 |
Formula : | C10H17BN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HLXOVAMYQUFLPE-UHFFFAOYSA-N |
M.W : | 208.07 | Pubchem ID : | 4912908 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.7 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 59.97 |
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) : | -6.68 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.25 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | 0.3 |
Log Po/w (SILICOS-IT) : | 0.29 |
Consensus Log Po/w : | 0.51 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.1 |
Solubility : | 1.66 mg/ml ; 0.00798 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.61 |
Solubility : | 5.1 mg/ml ; 0.0245 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.4 |
Solubility : | 0.823 mg/ml ; 0.00395 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.02 |
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 |
---|---|---|
77% | Stage #1: With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: at -78 - 0℃; for 1.25 h; Stage #3: With ammonium chloride In tetrahydrofuran |
To a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction <n="32"/>was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 ml_), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). |
77% | Stage #1: With n-butyllithium In tetrahydrofuran at 0 - 20℃; Stage #2: at -78℃; |
Preparation 2 Preparation of 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazoleTo a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). |
76% | Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 1 h; Stage #2: at -78 - 0℃; for 1.25 h; |
To a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 76percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78 - 20℃; for 1 h; Stage #2: for 1 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexanes |
EXAMPLE 27; 2-r4-ri-methyl-lH-pyrazol-5-vnphenyll-N-fflRVl-r5-r2.2.2-trifluoroethoxy')pyridin-2- yli ethyl > acetamide; To a 5°C solution of 5.00 mL (60.9 mmol) n-methylpyrazole in 100 ml THF was added dropwise 381 mL (60.9 mmol) 1.6M n-BuLi in hexanes. The reaction mixture was warmed to room temperature, and after lhr at room temperature, the reaction mixture was cooled to -78°C. 18.4 mL (79.0 mmol) isopropyl borate was added. After 1.00 h at -78°C, the reaction mixture was quenched with 12.OmL of 2N HCl. The resulting solution was concentrated in vacuo and azotroped with toluene. The resulting crude material was dissolved in 11 ImL THF.6.57g (55.6mmol) pincol and 1.0Og of molecular sieves were added. After 24.0 hr at room temperature, the reaction mixture was filtered and concentrated. The resulting residue was dissolved in 10OmL hexanes, washed twice with water, dried over NaSO4, filtered, and concentrated in vacuo to afford 5.9Og (51percent) l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- <n="64"/>2-yl)-lH-pyrazole. IH NMR (CD3OD, 400 MHz) 7.45(d, IH, J = 1-92); 7.67 (d, 2H, J = 1.92Hz); 4.04 (s, 3H); 1.35 (s, 12H). ESMS+1 for Ci0HnBN2O2: 209.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | at 20℃; for 48 h; Molecular sieve | A solution of 1-methylpyrazole (25.0 g, 305 mmol) in tetrahydrofuran (THF) (600 mL) was cooled to 0 °C. n-Butyl lithium (1.6 M in hexanes, 209 mL, 335 mmol) was added drop-wise over 1 h, keeping the temperature below 7 °C. The solution was stirred at room temperature (rt) for 3 h before cooling to −70 °C. B(OMe)3 (44.4 mL, 0.40 mol) was slowly added, keeping the reaction temperature below −65 °C. The resulting mixture was allowed to warm to rt, before it was quenched with 15percent aqueous (aq) NH4Cl (450 mL). The mixture was extracted with THF (3 × 500 mL), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a yellowish solid (15.6 g, 41percent). The aq layer was concentrated in vacuo, and the resulting solid was repeatedly extracted with THF (5 × 250 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo, yielding a yellow solid (20.3 g, 52percent). The combined yield of (1-methyl-1H-pyrazol-5-yl)boronic acid was 35.9 g (93percent), and 20.3 g (161 mmol) of this material was esterified with pinacole (28.4 g, 240 mmol) in THF (200 mL). 4 Å molecular sieves (6.0 g dried in vacuo at 50 °C) were added, and the resulting mixture was stirred at rt for 2 days. The sieves were filtered off, and the filtrate was concentrated in vacuo. The resulting crude product was dissolved in heptane (500 mL) and washed with water (2 × 250 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a white solid. This material was recrystallized from acetonitrile yielding white crystals (22.5 g, 67percent). Mp 71.0–71.6 °C (Ivachtchenko et al.,21 74–76 °C). 1H NMR (500 MHz, DMSO-d6): δ, 7.46 (d, J = 1.9 Hz, pyrazole H-3), 6.62 (d, J = 1.9 Hz, pyrazole H-4), 3.98 (s, N-methyl), 1.30 (s, pinacol methyl groups, 12H). 13C NMR (126 MHz, DMSO-d6): δ, 138.3, 115.9, 84.4 (2C), 41.9, 24.9 (4C). Anal. calcd for C10H17BN2O2: C, 57.73; H, 8.24; N, 13.46. Found: C, 57.72; H, 8.08; N, 13.40.#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 74℃; for 12 h; Inert atmosphere | A solution of 10 (0.20 g, 0.43 mmol, 1.0 equiv.) in a mixture of toluene(18 mL), ethanol (6 mL) and H2O (6 mL) was treated with Na2CO3(0.09 g, 0.86 mmol, 2.0 equiv.) and 1-methyl-1H-pyrazole-5-boronicacid pinacol ester (0.10 g, 0.47 mmol, 1.1 equiv.) and the mixture waspurged with nitrogen for 20 min. Pd(PPh3)4 (60 mg) was added andthe mixture was stirred at 74 °C for 12 h. After monitoring by TLC,the reaction mixture was cooled to room temperature and diluted withDCM. The organic portion was washed with sat. sodium chloridesolution, and dried over anhydrous Na2SO4 and concentrated underreduced pressure. The resulting residue was purified by flash silica gelchromatography (dichloromethane/MeOH, 30:1) to provide Taladegibas a yellow foam. Yield 0.20 g, 92percent; m.p. 95 °C; 1H NMR (300 MHz,CDCl3) δ 8.09 (dd, J = 7.6, 7.7 Hz, 2H), 7.90–7.80 (m, 2H), 7.65 (d,J = 1.8 Hz, 1H), 7.47–7.28 (m, 3H), 6.59 (d, J = 1.8 Hz, 1H), 4.97–4.89(m, 1H), 4.21–4.08 (m, 2H), 4.05 (s, 3H), 3.44–3.35 (m, 2H), 2.76 (s,3H), 2.35–2.11(m, 2H), 2.04–1.88 (m, 2H); 13C NMR (75 MHz, CDCl3)δ 168.0, 163.8, 159.9, 147.4, 138.2, 136.7, 132.0, 131.9, 131.5, 129.4,129.0, 128.0, 126.3, 124.6, 121.4, 119.5, 114.5, 109.1, 56.9, 51.4, 38.3,31.8, 29.7, 28.4; MS calcd for C26H24F4N6O [M + H]+: 513.2026; found:513.2018. |
92% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 74℃; for 12 h; Inert atmosphere | Compound 10 (0.2 g, 0.429 mmol, 1 eq.) Was dissolved in a mixed solution of 18 mL of toluene, 6 mL of ethanol and 6 mL of water,To the solution were added 0.091 g (0.858 mmol, 2 eq.) Of sodium carbonate and 0.098 g (0.472 mmol, 1.1 eq.) Of 1 -methyl- lH-pyrazole-5-boronic acid pinacol ester (CAS No. 847818- 74-0),After degassing with nitrogen for 20 min, 60 mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was degassed with nitrogen for 10 min. After the reaction was stirred uniformly, the reaction was refluxed at 74 ° C. for 12 h.After the reaction was completed, the mixture was cooled to room temperature, diluted with dichloromethane, washed three times with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.Purification by column chromatography (eluent dichloromethane / methanol, 30: 1 by volume) gave LY-2940680 (0.202 g, 92percent yield) as a pale yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In tetrahydrofuran; at 20℃; for 48h;Molecular sieve; | A solution of 1-methylpyrazole (25.0 g, 305 mmol) in tetrahydrofuran (THF) (600 mL) was cooled to 0 C. n-Butyl lithium (1.6 M in hexanes, 209 mL, 335 mmol) was added drop-wise over 1 h, keeping the temperature below 7 C. The solution was stirred at room temperature (rt) for 3 h before cooling to -70 C. B(OMe)3 (44.4 mL, 0.40 mol) was slowly added, keeping the reaction temperature below -65 C. The resulting mixture was allowed to warm to rt, before it was quenched with 15% aqueous (aq) NH4Cl (450 mL). The mixture was extracted with THF (3 × 500 mL), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a yellowish solid (15.6 g, 41%). The aq layer was concentrated in vacuo, and the resulting solid was repeatedly extracted with THF (5 × 250 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo, yielding a yellow solid (20.3 g, 52%). The combined yield of <strong>[720702-41-0](1-methyl-1H-pyrazol-5-yl)boronic acid</strong> was 35.9 g (93%), and 20.3 g (161 mmol) of this material was esterified with pinacole (28.4 g, 240 mmol) in THF (200 mL). 4 A molecular sieves (6.0 g dried in vacuo at 50 C) were added, and the resulting mixture was stirred at rt for 2 days. The sieves were filtered off, and the filtrate was concentrated in vacuo. The resulting crude product was dissolved in heptane (500 mL) and washed with water (2 × 250 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a white solid. This material was recrystallized from acetonitrile yielding white crystals (22.5 g, 67%). Mp 71.0-71.6 C (Ivachtchenko et al.,21 74-76 C). 1H NMR (500 MHz, DMSO-d6): delta, 7.46 (d, J = 1.9 Hz, pyrazole H-3), 6.62 (d, J = 1.9 Hz, pyrazole H-4), 3.98 (s, N-methyl), 1.30 (s, pinacol methyl groups, 12H). 13C NMR (126 MHz, DMSO-d6): delta, 138.3, 115.9, 84.4 (2C), 41.9, 24.9 (4C). Anal. calcd for C10H17BN2O2: C, 57.73; H, 8.24; N, 13.46. Found: C, 57.72; H, 8.08; N, 13.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 12h; | To a sealed vessel containing 9.20 g (19.8mmol) 2-(4-iodophenyl)-N-{(lR)-l-[5-(2,2,2-trifluoroethoxy)pyridin-2- yl]ethyl}acetamide, 4.95 g (23.8mmol) l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole, .133 g (.476mmol) tricyclohexylphosphine, and .181 g (.198mmol) Pd2(dba)3 was added 52.8 mL dioxane and 26.5 mL of 1.27M K3PO4. After 12.0 h at 1000C, the reaction mixture was cooled to room temperature and extracted three times with CH2Cl2 and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1 x 14 cm silica gel, linear gradient 50 - 100percent EtOAc+/-exane). The resulting solid was recrystallized from n-butylchloride to afford 5.00 g (60percent) 2-[4-(l-methyl-lH- pyrazol-5-yl)phenyl]-N-{(lR)-l-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. IH NMR (CDC13, 400 MHz) 8.23 (d, IH3 J = 2.74Hz); 7.51 (d, IH, J = 1.83Hz); 7.38 (m, 4H); 7.22 (m, 2H); 6.79 (br d, IH, J = 7.15Hz); 6.30 (d, IH, J = 2.01Hz); 5.13 (m, IH); 4.38 (q, 2H, J = 8.05Hz); 3.90 (s, 3H); 3.63 (s, 2H); 1.43 (d, 3H, J = 6.78). HRMS (ES) exact mass calcd for C2IH2IF3N4O2: 419.1682, Found: 419.1690. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In ethanol; water; toluene; at 75℃; for 2h; | Procedure B1c - Suzuki coupling for heterocvcles.; A solution of 7-Bromo-imidazol[1 ,2-a]pyridine (0.5g, 2.54mmol, 1 equivalent, made according to general procedure A1 using 4-bromo-pyridin-2-ylamine instead of 4-chloro-pyridin-2- ylamine) , 1 -methyl-5-(4,4, 5, 5-tetramethyl-[ 1 , 3, 2]dioxaborolan-2-yl)- 1 H-py razole ( 1.1 g, 5.08mmol, 2 equivalents), bis(tri-t-butylphosphine) palladium (0) (66mg, 0.13mmol, 0.05 equivalents) and potassium carbonate (2.1g, 15.24mmol, 6 equivalents) in ethanol (10ml), toluene (10ml) and water (10ml) was heated at 750C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was then washed with a saturated brine solution, dried (MgSO4), filtered and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S, flow rate 25ml/min, gradient 0% to 20% methanol in ethyl acetate) to give 7-(2-methyl-2H-pyrazol-3-yl)- imidazo[1 ,2,a]pyridine as a colourless oil (350mg, 70%). MS: [M+H]+ 199. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 80℃; for 1h; | A solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (2g, 8.51 mmol)[prepared in Preparation 10], potassium carbonate (5.88 g, 42.5 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.124 g, 10.21 mmol)[prepared according to Preparation 7] and bis(tri-t- butylphosphine)palladium(O) (0.217 g, 0.425 mmol) in 1 ,4-Dioxane (35.4 ml) and H2O (7.09 ml) was stirred at 80 0C in a sealed tube for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 25percent EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxylate. This reaction was run in several batches (1g, 3 x 2g) which were combined for workup and purification affording the title compound (5.5 g, 78percent combined yield) as a viscous yellow oil: LCMS (ES) m/e 236 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 0 - 120℃;Inert atmosphere; | General procedure: Tetrakistriphenylphosphane Pd (0) (580mg, 5mol %) was added to a stirred suspension of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5g, 12mmol), K3PO4·3H2O (4.8g, 18mmol) and the corresponding bromide in DMF (100mL) at 0C under nitrogen. The reaction mixture was heated at 80-120C for 8h, then poured into H2O (100mL) and extracted with ethyl acetate (45mL×3). The combined organic layers were washed with brine (50mL×2), dried over Na2SO4, and concentrated under vacuum to afford an off-white semisolid. The crude product was purified by flash silica chromatography to obtain the title compound. 4.1.4.1 Methyl 4-(1-methyl-1H-pyrazol-5-yl)furan-2-carboxylate 12a Reagent: <strong>[58235-80-6]methyl 4-bromofuran-2-carboxylate</strong> 11a (2.05 g, 10 mmol, Supporting Information ). The product was obtained as a white solid (1.63 g, 79%). 1H NMR (500 MHz, CDCl3) delta 7.73 (d, J = 0.8 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 0.8 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H). ESI-MS (m/z): 207 [M + 1]+. |
75% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere; | The <strong>[58235-80-6]4-bromo-furan-2-carboxylic acid methyl ester</strong> (intermediate 2-3) (6.15g, 30mmol), 1-methyl -1H-pyrazole-5-boronic acid pinacone ester (7.5g, 36mmol) and three water potassium phosphate (12g, 45mmol) in sequentially adding a two neck flask, add 100mlN, N-dimethyl formamide, under the protection of nitrogen by adding four (triphenylphosphine) palladium (3.46g, 3mmol), 90 C reaction 12h. After the reaction cooled to room temperature, the reaction solution is poured into water (300 ml) in, extracting reaction solution with ethyl acetate 3 times, washing combined with the phase saturated sodium chloride (200 ml × 3), dried anhydrous sodium sulfate. Pressure reducing and recovering the solvent, silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:1), the white solid obtained after recovering solvent 4.6g, for the 4 - (1-methyl -1H-pyrazol-5-yl) furan-2-carboxylic acid methyl ester (intermediate 2-4), yield 75% |
75% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;Inert atmosphere; | Sequentially adding 4-bromo furan-2-methyl formate (Compound1-1) (4.7g, 22.9mmol), tetra(triphenylphosphine)palladium (0.582g, 1.145mmol), 1-methyl-1H-pyrazol-5-boric acid pinacol ester (5.25g, 25.2mmol) and potassiumcarbonate (7.9g, 57.25mmol) into a 100 mL double-neck flask under the protection of N2, adding 1,4-dioxane(30mL) and water (6mL) thereto, and reacting at 90hfor 12h. After the reaction is finised, the product is cooled toroom temperature, extracting the reaction liquid with ethyl acetate for 3 times, washing the merged organic phasewith saturated sodium chloride once, drying it with anhydrous sodium sulfate. Recycling the solvent under reducedpressure, and carrying out column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =4: 1, increasingthe polarity to 1:1), 3.75g of light yellow solid (Intermediate 1-2) is obtained and the yield is 75% |
26% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 80℃; for 1h; | A solution of <strong>[58235-80-6]methyl 4-bromo-2-furancarboxylate</strong> (470 mg, 2.29 mmol), potassium carbonate (1.58 g, 1 1.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (525 mg, 2.52 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (58.6 mg, 0.1 15 mmol) in 1 ,4-Dioxane (9.5 ml) and water (1.9 ml) was stirred at 80 0C in a sealed tube for 1 h. The solution was partitioned between H2O-DCM and the aqueous phase was <n="219"/>washed several times with DCM. The combined organic fractions were dried over Na2SOphi concentrated and purified via column chromatography (30% EtOAc in hexanes) affording methyl 4-(1-methyl-1 H-pyrazol-5-yl)-2-furancarboxylate (124 mg, 0.60 mmol, 26 % yield) as a white powder: LCMS (ES) m/e 206 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 80℃; for 2h; | A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59 mmol), potassium carbonate (6.63 g, 47.9 mmol), 1-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.19 g, 10.55 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1 ,4- dioxane (40 ml) and water (8 ml) was stirred at 80 0C in a sealed tube for 1 h. 1- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.19 g, 10.55 mmol) and bis(tri-t-butylphospnine)palladium(0) (0.245 g, 0.48 mmol) were added and the reaction stirred an additional 1 h and was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over I^^SOphi concentrated and purified via column chromatography (10-40percent EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl- 1 H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72 mmol, 81 percent yield) as a yellow oil: LCMS (ES) m/e 221 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 75℃; for 2h; | To a solution of 1 ,1-dimethylethyl {2-[[(4-bromo-2- thienyl)carbonyl](hydroxy)amino]-3-phenylpropyl}carbamate (100 mg, 0.22 mmol) in dioxane/H2O (5:1 , 6 mL) was added K2CO3 (91 mg, 0.66 mmol), tetrakistriphenylphosphine Pd(O) (23 mg, 0.022 mmol) and 1-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (68 mg, 0.33 mmol). The reaction mixture was heated to 75° C in a sealed tube. After 2h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 20-40percent) to afford the title compound (87 mg, 87percent).: LC-MS (ES) m/z = 456 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 75℃; for 1.5h; | To a 300 mL sealed flask was added 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (8.14 g, 39.1 mmol). potassium carbonate (12.98 g, 94 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (8 g, 31.3 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.40 g, 0.78 mmol) in 1 ,4-dioxane (50 ml) and H2O (6 ml). After stirring for 90 min at 75 0C, the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered <n="190"/>and concentrated. The reaction residue was purified on silica gel [hexanes/EtOAc, 2:1 ] to give the product [5.7 g, 70percent] as a tan solid: LCMS (ES) m/z 258 (M+H)+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); at 80℃; for 1h; | A solution of methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (300 mg, 1.204 mmol), potassium carbonate (832 mg, 6.02 mmol), 1-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (326 mg, 1.565 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (30.8 mg, 0.060 mmol) were combined in a sealed tube and stirred at 80 0C for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording methyl 5-ethyl-4-(1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxylate (301 mg, 1.204 mmol, 100 percent yield) as a brown oil: LCMS (ES) m/e 251 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); at 80℃; for 1h; | A solution of methyl 4-bromo-5-propyl-2-thiophenecarboxylate (1.0 g, 3.80 mmol), potassium carbonate (2.63 g, 19.00 mmol), 1-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.949 g, 4.56 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.097 g, 0.19 mmol) were combined in a sealed tube and stirred at 80 0C for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated and purified by column chromatography (10-50percent EtOAc in hexanes) affording methyl 4-(1-methyl-1 H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (1.07 g, 3.76 mmol, 99 percent yield) as a yellow oil: LCMS (ES) m/e 265 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | To a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C over 1 hour. The reaction <n="32"/>was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 ml_), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) delta 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). | |
77% | Preparation 2 Preparation of 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazoleTo a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) delta 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). | |
76% | To a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 76%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) delta 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). |
Example 41-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole N-Methylpyrazole (6.0 kg, 1 mol eq, limiting reagent) was charged, followed by anhydrous tetrahydrofuran (84 L, 14 rel vol) and the reaction mixture was cooled to -10 C. n-Hexyllithium (2.3 M solution in hexanes, 23.6 kg, 1.05 mol eq) was charged keeping the temperature below -5 C., followed by a line rinse of iso-hexane (1.2 L, 0.2 rel vol). The reaction mixture was stirred at below -5 C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.9 kg, 1.1 mol eq) was diluted with anhydrous tetrahydrofuran (6.0 L, 1 rel vol) and was charged to the reaction keeping the temperature below 0 C. A line rinse with anhydrous tetrahydrofuran (3.0 L, 0.5 rel vol) was charged and the reaction mixture was stirred for around 30 minutes. The reaction was warmed to 25 C. A solution of glacial acetic acid (6.6 kg, 1.5 mol eq) in water (36 L, 6 rel vol) was charged to the reaction over about 30 minutes. The reaction mixture was stirred for around 30 minutes. The phases were separated and the organic layer retained. Change of solvent to acetonitrile by distillation afforded the title compound as a solution in acetonitrile. The solution yield of the title compound was determined by GC assay; 1H NMR (d6-DMSO): delta 1.31 (s, 12H), 3.98 (s, 3H), 6.62 (d, 1H, J=1.9 Hz), 7.45 (d, 1H, J=2.1 Hz) ppm.Note: if (1,1'-(di-tert-butylphosphino)ferrocene)palladium(II) dichloride is used as catalyst in Example 5 then the solvent change to acetonitrile in the last step of this process is not required. | ||
Preparation 4 <n="44"/>Preparation of 5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1 -methyl-1 H-pyrazoleTo a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 ml.) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 ml_, 60 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77%) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) delta 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 17h; | To a solution of 1 ,1-dimethylethyl (2-[(5-bromo-3-thienyl)carbonyl]amino}-2- phenylethyl)carbamate (250 mg, 0.588 mmol) in dioxane/H2O (5:1 , 6 ml.) was added K2CO3 (325 mg, 2.35 mmol), tetrakistriphenylphosphine Pd(O) (34 mg, 29.4 mumol) and 5-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-1-methyl-1 /-/-pyrazole (126 mg, 0.647 mmol). The reaction mixture was heated to 80 C in a sealed tube. After 5h, additional tetrakistriphenylphosphine Pd(O) (34 mg, 29.4 mumol) and 5-(5,5-dimethyl- 1 ,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (126 mg, 0.647 mmol) were added. After 12h, the reaction solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organics were dried (Na2SO4), concentrated under vacuum and purified on silica gel (1 % MeOH in DCM) to give the title compound (250 mg, quant.) as an orange oil: LCMS (ES) m/z = 427. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 75℃; for 13h; | To a solution of 5-bromo-lambda/-((1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2/-/-isoindol-2-yl)-1-[2-(trifluoromethyl)phenyl]methyl}ethyl)-3-furancarboxamide (400 mg, 0.77 mmol) in dioxane/H2O (5:1 , 50 mL) was added K2CO3 (0.32 g, 2.3 mmol), tetrakistriphenylphosphine Pd(O) (20 mg, 40 mumol) and 5-(5,5-dimethyl- 1 ,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (0.19 g, 0.92 mmol). The reaction mixture was heated to 75° C in a sealed tube. After 5h, additional tetrakistriphenylphosphine Pd(O) (20 mg, 40 mumol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1-methyl-1 H-pyrazole (0.19 g, 0.92 mmol) were added. After 8h, the reaction solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organics were dried (Na2SO4), concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 1 :2) to give the title compound (200 mg, 50percent) as white solid: LCMS (ES) m/z = 523. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.8% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 80℃; for 2h; | A solution of methyl 5-bromo-1-methyl-1 H-pyrrole-3-carboxylate (950 mg,4.36 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1088 mg, 5.23 mmol)[prepared according to Preparation 3], potassium carbonate (301 1 mg, 21.78 mmol) and bis(tri-t-butylphosphine)palladium(0) (11 1 mg, 0.218 mmol) in 1 ,4-Dioxane (18.200 ml) and Water (3.64 ml) was stirred at 80 0C in a <n="59"/>sealed tube for 1 h. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (1088 mg, 5.23 mmol) and bis(tri-t-butylphosphine)palladium(0) (1 11 mg, 0.218 mmol) were added and the solution stirred for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SOphi concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 1-methyl-5-(1-methyl-1 H-pyrazol-5-yl)-1 H- pyrrole-3-carboxylate (300 mg, 1.341 mmol, 30.8 % yield) as a clear oil: LCMS m/e ES 220 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<= 100% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 12 - 17h; | To a solution of delta-bromo-S-thiophenecarboxylic acid (875 mg, 4.23 mmol) in dioxane/H2O (5:1 , 21 mL) was added K2CO3 (205 mg, 14.8 mmol), tetrakistriphenylphosphine Pd(O) (297 mg, 0.26 mmol) and 1-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (988 mg, 4.75 mmol). The reaction mixture was heated to 80 C in a sealed tube. After 5h, additional tetrakistriphenylphosphine Pd(O) (108 mg, 0.1 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole (989 mg, 4.75 mmol) were added. After 12h, the reaction solution was then partitioned between H2O- CHCI3, and the aqueous phase was washed several times with CHCI3. The aqueous phase was then adjusted to pH 3 with 2.5M HCI and the aqueous phase extracted with CHCI3. The combined organics were dried (Na2SO4), concentrated under vacuum and dried under high vacuum overnight and used without further purification: LC-MS (ES) m/z = 209 (M+H)+.; To a solution of delta-bromo-S-thiophenecarboxylic acid (414 mg, 2 mmol) in dioxane/H2O (5:1 , 6 mL) was added K2CO3 (828 mg, 6 mmol), tetrakistriphenylphosphine Pd(O) (1 16 mg, 0.1 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1-methyl-1 H-pyrazole (428 mg, 2.2 mmol). The reaction mixture was heated to 80 C in a sealed tube for 12h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ~3 with 3M HCI and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (-100 mg, quant.): LC-MS (ES) m/z = 209 (M+H)+.; To a solution of <strong>[100523-84-0]2-bromo-4-thiophenecarboxylic acid</strong> (104 mg, 0.5 mmol) in dioxane/H2O (4:1 , 10 mL) was added K2CO3 (271 mg, 1.99 mmol), tetrakistriphenylphosphine Pd(O) (28.7 mg, 0.025 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1-methyl-1 H-pyrazole (97 mg, 0.5 mmol). The reaction mixture was heated to 80 C in a sealed tube for 12h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ~3 with 3M HCI and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (104 mg, quant.): LC-MS (ES) m/z = 209 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; industrial methylated spirit; at 140.0℃;Microwave irradiation; | Synthesis 34; 5-(2-Methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid; IMS, delta-Bromo-thiophene-S-carboxylic acid methyl ester (0.193 g, 0.87 mmol) was combined with 1-methyl-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (0.2 g, 0.96 mmol), caesium carbonate (0.424 g, 1.3 mmol), and palladium tetrakis(triphenylphosphine) (0.1 g, 0.09 mmol) in DME (10 ml_), IMS 2 mL) and water (1 mL). The reaction mixture was degassed then heated by microwave irradiation to 1400C for 20 minutes. The mixture was diluted with water then extracted with DCM (* 3) then the organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a 5g silica Il cartridge, - eluting with 5-30% ethyl acetate in cyclohexane to give 5-(2-methyl-2H-pyrazol-3-yl)- thiophene-3-carboxylic acid methyl ester as a brown oil (0.163 g). LCMS m/z 223.24 [M+H]+ RT. = 3.24 min (Analytical Method 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation; Sealed tube; | b) ethyl 2-(1-methyl-1 H-pyrazol-5-yl)-1 ,3-oxazole-4-carboxylate To a solution of ethyl 2-chloro-1 ,3-oxazole-4-carboxylate (2.00 g, 11.39 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole(2.65 g, 13.67 mmol)[prepared in Preparation 2] and potassium carbonate (4.72 g, 34.2 mmol) in 1 ,4-dioxane (16 ml.) and water (4.00 ml.) in a microwave tube was added bis(tri- t-butylphosphine)palladium (0) (0.58 g, 1.14 mmol). The tube was sealed and heated in the microwave reactor at 100 0C for 20 minutes. The mixture was concentrated and purified by column chromatography (silica, 0-40% ethyl acetate / hexane) to generate a yellow solid as the desired product: LC-MS (ES) m/z 222 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; toluene; at 100℃;Inert atmosphere; Sealed glass tube; | A glass tube was charged with 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (0.5 g, 1.4 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.42 g, 2 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (0.081 g, 0.1 mmol) and alternatively purged and backfilled with nitrogen. After addition of anhydrous toluene (10 mL), EtOH (5 mL), and sodium carbonate (2M, 2 mL) the glass tube was sealed and heated at 100° C. under stirring until the reaction was complete as evidenced by the disappearance of starting chloro compound (TLC). The resulting mixture was cooled to a temperature in the range of 15° C. to 40° C., diluted with ethyl acetate (20 mL), filtered through Celite, washed with ethyl acetate, and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford the title compound as a light yellow solid (0.27 g, 48percent).1H NMR (CDCl3, 300 MHz): 8.14 (s, 1H), 8.02 (s, 1H), 7.67 (dd, J=6.6, 1.8 Hz, 2H), 7.32 (dd, J=6.6, 1.8 Hz, 2H), 6.21 (bs, 1H), 3.95 (s, 3H), 3.66 (s, 3H), 3.02-2.74 (m, 6H), 2.58-2.46 (m, 2H), 2.21-1.84 (m, 4H).LC-MSD (ES+): (m/z) 404 [(M+H)+, 100].HPLC: Inertsil ODS-3V C18, 20:80 [KH2PO4 (0.01 M, pH 3.2): CH3CN], gradient, PDA 280 nm, Rt 12.82 min, purity 99.75percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 0.166667h;Inert atmosphere; Microwave irradiation; Sealed tube; | Example 15; 3-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)benzoic acid; Step 1 Preparation of tert-butyl 3-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)benzoate tent-Butyl 3-bromo-5-(trifluoromethyl)benzoate (0.380 g, 1.17 mmol) and <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.250 g, 1.20 mmol) were added to a microwave-safe vial. 1,4-Dioxane (2 mL) and 2.0 M sodium carbonate solution (1.71 mL, 3.42 mmol) were added. The reaction was degassed under an atmosphere of nitrogen for 3 minutes and tetrakis(triphenylphosphine)palladium(0) (0.270 g, 0.234 mmol) was added. The vial was then sealed and irradiated in the microwave at 100° C. for 10 minutes. The reaction vial was unsealed, and the mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, elution with 0-10percent ethyl acetate in dichloromethane) provided a 259 mg of a colorless oil (68percent yield). LC/MS: (FA) ES+ 327. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 74℃;Inert atmosphere; | Preparation 3 tert-Butyl methyl(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)carbamate Place sodium carbonate (3.82 g, 36.09 mmol), tert-butyl 1-(4-chlorophthalazin-1-yl)piperidin-4-yl(methyl)carbamate (6.8 g, 18.04 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (5.63 g, 27 1 mmol) in a flask with a mixture of toluene (50 mL), ethanol (17 mL), and water (17 mL). Degas the mixture for 10 min with nitrogen gas. Add tetrakis(triphenylphosphine)palladium (0.4 g, 0.35 mmol) and heat the mixture at 74° C. overnight. Cool the mixture to ambient temperature and dilute with dichloromethane. Wash the organic portion with brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the title compound as a yellow foam (5.33 g, 70percent). ES/MS m/z 423.2 (M+1). |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 2h; | 0.37 g of the above-mentioned intermediate A was mixed with 0.22 g of 5- (1-methylpyrazole) boronic acid pinacol ester, 0.06 g of tetrakis (triphenylphosphine)Palladium and 0.22 g of sodium carbonate were added to 6 mL of a mixed solvent of toluene / ethanol / water in a volume ratio of 3: 2: 1,Heated to 90 ° C for 2 h. After the end of the reaction, the saturated ammonium chloride solution was quenched to separate the organic phase,The aqueous phase was extracted three times with dichloromethane,The organic phase was combined, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and then dried over anhydrous sodium sulfate,The sodium sulfate was removed by filtration and concentrated to give a crude product. The crude product was purified by column chromatography (200-300 mesh silica gel,Eluting with n-hexane: ethyl acetate = 1: 1) to give pure intermediate B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 90℃;Inert atmosphere; | Preparation 6 tert-Butyl methyl(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)carbamateCharge a reaction tube with tert-butyl 1-(4-bromophthalazin-1-yl)piperidin-4-yl(methyl)carbamate (500 mg, 1 2 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (370 mg, 1.8 mmol), sodium carbonate (252 mg, 2.4 mmol), toluene (3.75 mL), ethanol (1.25 mL), and water (1.25 mL). Degas the reaction mixture with nitrogen for 10 min. Add tetrakis (triphenylphosphine) palladium (137.1 mg, 118.7 mumol). Bubble nitrogen through the reaction mixture for another 10 min. Cap the reaction vial and heat at 90 C. overnight. Cool the reaction and filter through a silica gel pad eluting with 5% MeOH:CH2Cl2. Concentrate the fractions under reduced pressure. Purify the resulting residue using silica gel chromatography (2% 2 N NH3 in MeOH:CH2Cl2) to obtain the final product (345.6 mg, 69%). ES/MS m/z 423.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium carbonate;1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride-chloroform adduct; In water; N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | Example 196 (1R,2R,4R)-4-[2-Chloro-4-(2-methyl-2H-pyrazol-3-yl)-benzenesulfonyl]-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide Mixture of (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4, 130 mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)1H-pyrazole (67 mg), sodium carbonate (66 mg), 1,1'-bis-(diphenylphosphino)ferrocene palladium (II) chloride, 1:1 complex with chloroforme (19 mg) was flushed with argon. Degazed dimethylformamide (4 mL) and water (0.345 mL) were added and the mixture was stirred at 80° C. overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane:methanol (92:2 v/v) as eluant to afford the title compound (114 g, 88percent) as a yellow gum. MS (EI): 566.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 120℃; for 0.75h;Microwave irradiation; | To a mixture of ethyl 2-bromo-1 ,3-thiazole-5-carboxylate (1.01 g, 4.29 mmol), K2CO3 (2.0 g, 14.47 mmol) and Pd(Pt-Bu3)2 (280 mg, 0.548 mmol) in 1 ,4-dioxane (8 ml.) and water (1.6 ml.) was added 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (1.76 g, 8.47 mmol) [prepared in Preparation 2]. The reaction was stirred at 120 0C for 45 min in a microwave reactor and cooled to room temperature. The mixture was partitioned between CHCI3 / H2O and the aqueous layer was washed several times with CHCI3. The combined organic fractions were dried over Na2SO4, concentrated, and purified via column chromatography (silica, 0-50%EtOAc/hexanes) affording the title compound (0.7 g, 61%) as a yellow solid: LC-MS (ES) m/z = 238 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | 9- (3-(isopropylamino)propyl)-8-(6-(l-methyl-lH-pyrazol-5-yl)benzo[d| [l,3]dioxol-5- ylthio)-9H-purin-6-amine [DZ3-44],; 1 -Methyl- l-H-pyrazole-5-boronic acid pinacol ester (18.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90°C for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 2:2:1 :0.5) to give 20.1 mg (74percent) of DZ3-44. 1H NMR (500 MHz, CDC13) delta 8.25 (s, 1H), 7.40 (d, J= 1.8 Hz, lH), 7.05 (s, 1H), 6.80 (s, lH), 6.08 (s, 2H), 6.06 (d, J= 1.8 Hz, 1H), 5.91 (br s, 2H), 4.10 (t, J= 6.7 Hz, 2H), 3.67 (s, 3H), 2.85 (septet, J= 6.3 Hz, 1H), 2.53 (t, J= 6.7 Hz, 2H), 1.97 (m, 2H), 1.13 (d, J= 6.3 Hz, 6H); 13C NMR (125 MHz, CDC13) delta 154.4, 152.7, 151.7, 149.3, 149.0, 147.0, 140.6, 138.5, 127.7, 123.3, 120.0, 113.8, 111.7, 107.4, 102.5, 49.6, 43.2, 41.1, 37.1, 29.1, 22.0; HRMS (ESI) m/z [M+H]+ calcd. for C22H27N802S, 467.1978; found 467.1985; HPLC: method A Rt = 5.74, method B Rt = 5.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | 2-nuoro-9-(2-(isobutylamino)ethyl)-8-((6-(l-methyl-lH-pyrazol-5- yl)benzo[d] [l,3]dioxol-5-yl)methyl)-9H-purin-6-amine [DZ3-45].; 1 -Methyl- 1-H-pyrazole- 5-boronic acidpinacol ester (18.2 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) andNaHC03 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90°C for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 4:7:2:1) to give 26.5 mg (97percent) of DZ3-45. 1H NMR (500 MHz, CDC13) delta 7.49 (d, J= 1.5 Hz, lH), 6.76 (s, 1H), 6.74 (s, 1H), 6.28 (br s, 2H), 6.17 (d, J = 1.5 Hz, 1H), 6.01 (s, 2H), 3.99 (s, 2H), 3.90 (t, J= 6.3 Hz, 2H), 3.66 (s, 3H), 2.76 (t, J= 6.3 Hz, 2H), 2.31 (d, J= 6.8 Hz, 2H), 1.72 (m, 1H), 0.84 (d, J= 6.7 Hz, 6H); 13C NMR (125 MHz, CDC13) delta 159.0 (d, J= 208.7 Hz), 156.4 (d, J= 20.0 Hz), 152.8 (d, J= 18.5 Hz), 151.5, 149.0, 147.1, 141.3, 138.8, 129.4, 123.4, 116.6, 110.7, 109.9, 106.9, 101.9, 57.8, 48.7, 43.1, 36.9, 31.8, 28.3, 20.6; HRMS (ESI) m/z [M+H]+ calcd. for C23H28FN802, 467.2319; found 467.2323; HPLC: method A Rt = 6.37, method B Rt = 6.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 120℃; for 0.333333h;Microwave irradiation; Inert atmosphere; Sealed tube; | Step 1: tert-Butyl 1-(4-(2-(1-methyl-1H-pyrazol-5-yl)- 7-phenylfuro[2, 3-b]pyrazin-6- yl)phenyl)cyclobutylcarbamate: Tetrakis(triphenylphosphine)palladium(0) (6.1 mg, 0.005 mmol) was added to a pre-degassed solution of tert-butyl 1-(4-(2-chloro-7-phenylfuro[2,3- 6]pyrazin-6-yl)phenyl)cyclobutylcarbamate (50.0 mg, 0.105 mmol), 1 -methyl-1 H- pyrazole-5-boronic acid pinacol ester (32.8 mg, 0.158 mmol) and potassium phosphate, tribasic (66.9 mg, 0.315 mmol) in DMF (1.0 ml)/water (0.25 ml) in a microwave vial. The reaction vessel was sealed was subjected to microwave irradiation (CEMExplorer/Discover) at 120 °C for 20 minutes. Analysis by LCMS showed complete conversion to product. The reaction mixture was partitioned between EtOAc and brine, separated, extracted (EtOAc x 2), combined organics were dried (Phase Separator), solvents were removed in vacuo and the remaining residue was purified by flash chromatography (Si02l 0-20percent EtOAc in cyclohexane) to give the title compound (53.7 mg, 98percent). LCMS (Method A): RT = 7.98 min, M+H+ = 522.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 100℃; for 3h;Inert atmosphere; | EXAMPLE 554-{1 -[5-fluoro-2-(1 H-pyrazol-1 -yl)phenyl]ethoxy}-6-(1 -methyl-1 H-pyrazol-5-yl)pyridazin-3- amineH2N To a solution of the chloride of preparation 55 (100 mg, 0.3 mmol) in dimethyl ethylene glycol (4 mL) were added 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (125 mg, 0.6 mmol, 2.0 eq.), 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride (44 mg, 0.06 mmol, 0.2 eq.) and cesium fluoride (160 mg, 1.05 mmol, 3.5 eq.). The resulting mixture was thoroughly degassed before heating, under an atmosphere of nitrogen, to 100 °C for 3 hr. The crude reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was dried over magnesium sulphate and the mixture filtered and the filtrate evaporated under reduced pressure. The resulting residue was purified by chromatography on silica (50 g) eluting with ethyl acetate. Clean fractions were combined and evaporated under reduced pressure to give the title compound as a purple solid. (35 mg, 31percent)1H N R (400 MHz, CDCI3): delta ppm 1.62 (d, 3H), 4.20 (s, 3H), 5.27 (br s, 2H), 5.77 (q, 1 H), 6.56 (m, 1 H), 6.57 (d, 1 H), 7.10 (m, 1 H), 7.22 (dd, 1 H), 7.26 (m, 1 H), 7.32 (dd, 1 H), 7.46 (d, 1 H), 7.66 (d, 1 H), 7.83 (d, 1 H)MS: ESI+, m/z = 380.1 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere; | EXAMPLE 303-{(1 R)-1-[5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)phenyl]ethoxy}-5-(1-methyl-1 H-pyrazol-5- l)pyridin-2-amineTo a solution of the bromide of preparation 45 (690 mg, 1.82 mmol) in 1 , 4-dioxane (100 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (949 mg, 4.56 mmol, 2.5 eq.) followed bytetrakis(triphenylphosphine)palladium(0) (105 mg, 0.091 mmol, 0.05 eq.) and aqueous sodium hydrogen carbonate (1 M, 4.6 mL, 2.5 eq.). The resulting mixture was heated to 110 °C, under an atmosphere of nitrogen, for 2 hr. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to a brown oily residue. The oily residue was partitioned between tert-butyl methyl ether (100 mL) and aqueous hydrochloric acid (4M, 100 mL). The aqueous layer was washed with tert-butyl methyl ether (3 x 100 mL), then made basic with aqueous ammonium hydroxide (0.880, 100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate phases were washed with water (5 x 20 mL) and dried over magnesium sulphate. The mixture was filtered and the filtrate evaporated under reduced pressure. The resulting residue was purified by chromatography on silica (50 g) eluting with ethyl acetate. The clean fractions were combined and evaporated under reduced pressure. The resulting gum was azeotroped with diethyl ether (3 x 100 mL) to give the title compound as a white foam. (220 mg, 32percent)1H NMR (400 MHz, CDCI3): delta ppm 1.61 (d, 3H), 3.67 (s, 3H), 4.92 (bs, 2H, NH2), 5.78 (q, 1 H), 6.16 (d, 1 H), 6.80 (d, 1 H), 7.12 (ddd, 1 H), 7.29 (dd, 1 H), 7.44 (d, 1 H), 7.62 (dd, 1 H), 7.71 (d, 1 H), 7.87 (s, 2H) Optical purity: 97.0percent e.e. (Chiral column conditions: Chiralpak AD-H (250*4.6 mm i.< eluent 100percent methyl alcohol, 1 ml_ / min, Rt = 4.77 min (opposite enantiomer Rt = 4 min)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate;bis(tri-tert-butylphosphine)palladium(0); In 1,4-dioxane; water; at 150℃; for 0.666667h;Microwave irradiation; | EXAMPLE 254-(dimethylamino)-/V-methyl-3-[3-(1-methyl-1 H-pyrazol-5-yl)-1 H-pyrazo4-yl]amino}benzenesulfonamideA mixture of 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4- (dimethylamino)-/\\/-methylbenzenesulfonamide (200 mg, 0.47 mmol), 1 -methyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (586 mg, 2.81 mmol), Pd(f-Bu3P)2 (48 mg, 0.09 mmol) and 2 M aq. K2C03 (1.17 ml_, 2.34 mmol) in 1 ,4-dioxane (4 mL) was heated at 150 °C under microwave conditions for 40 min. The organic layer was separated and concentrated onto Celite.(R).. The residue was purified by flash column chromatography using 30-80percent (1 percent NH4OH / 9percent MeOH / 90percent CHCI3) / CHCI3 as eluent. The resulting solid was triturated with CH2CI2 to afford the title compound (79 mg, 39percent) as light yellow solid. LCMS(ES) m/e 428 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) delta ppm14.27 (br. s, 1 H), 9.25 (d, J = 2.02 Hz, 1 H), 8.73 (s, 1 H), 8.61 (s, 1 H), 7.78 (d, J = 2.02 Hz, 1 H), 7.36 - 7.50 (m, 3H), 6.81 (d, J = 1.77 Hz, 1 H), 3.86 (s, 3H), 2.45 (d, J = 5.05 Hz, 3H), 2.42 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate;bis(tri-tert-butylphosphine)palladium(0); In 1,4-dioxane; water; at 150℃; for 0.666667h;Microwave irradiation; | EXAMPLE 6/V-methyl-4-(methyloxy)-3-[5-(1^yl]amino}benzenesulfonamideA mixture of 3-[(5-bromo-1 /-/-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-/\\/-methyl-4- (methyloxy)benzenesulfonamide (0.30 g, 0.73 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.15 g, 0.73 mmol), Pd(f-Bu3P)2 (0.037 g, 0.073 mmol) and 2 M aq. K2C03 (1.82 ml_, 3.64 mmol) in 1 ,4-dioxane (10 ml.) was heated at150 °C under microwave conditions for 40 min. The reaction material was purified by flash column chromatography (1 percent NH4OH / 9percent MeOH / 90percent CHCI3). The resulting solid was triturated with MeOH to afford the title compound (120 mg, 30percent) as an off-white solid. Reverse phase HPLC (5-90percent H20/CH3CN) was used for final purification.LCMS (ES) m/e 414 (M+H)+; 1H NMR (400 MHz, DMSO-d6) delta ppm 12.12 (s, 1 H), 9.28 (s, 1 H), 8.42 (s, 1 H), 8.06 (s, 1 H), 7.94 (s, 1 H), 7.41 (s, 1 H), 7.39 (m, 1 H), 7.33 (m, 1 H), 7.29 (s, 1 H), 7.19 (d, J = 8.8 Hz, 1 H), 6.72 (m, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 2.44 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere; | Example 344-( Cyclohexyloxy)-3-( 1 -methyl- 1 H-pyrazol-5-yl)- 1 H-pyrazolo[4, 3-c]pyridine Step 14-( Cyclohexyloxy)-3-( 1 -methyl- 1 H-pyrazol-5-yl)- 1 -trityl- 1 H-pyrazolo[4, 3-c]pyridineIntermediate 11 (120 mg, 0.21 mmol), Pd(dppf)CI2 (16 mg, 0.02 mmol), 2M Na2C03 (aq) (358 muIota, 0.72 mmol) and 1-methyl-1 H-pyrazole-5-boronic acid pinacol ester (64 mg, 0.31 mmol) were combined in dioxane (1 ml) and the solution degassed with nitrogen. The vial was then flushed out with nitrogen and heated at 90 °C for 18 h. The solution was partitioned between DCM and water and filtered through a phase separation cartridge. The solvents were evaporated and the crude material purified by column chromatography eluting with 10percent ethyl acetate/petroleum ether to 100percent ethyl acetate to give a white solid (54 mg, 49percent). 1H N R (400 MHz, DMSO-d6) delta ppm 1.23 - 1.42 (m, 2 H), 1.45 - 1.56 (m, 4 H), 1.63 - 1.72 (m, 2 H), 1.95 - 2.03 (m, 2 H), 3.76 (s, 3 H), 5.07 - 5.29 (m, 1 H), 5.88 (d, J=6.0 Hz, 1 H), 6.89 (d, J=1.8 Hz, 1 H), 7.09 - 7.26 (m, 6 H), 7.30 - 7.41 (m, 9 H), 7.50 (d, 1,8 Hz, 1 H), 7.61 (d, J=6.4 Hz, 1 H); Rf = 0.72 (1 :1, petroleum ether : ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 12h;Sealed tube; | Example 3Preparation of /V-(2-amino-1-benzylethyl)-5-(1-methyl-1 H-pyrazol-5-yl)pyrimidine-2- carboxamidea) 5-(1-methyl-1 H-pyrazol-5-yl)pyrimidine-2-carboxylic acidTo a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (1.35 g, 6.5 mmol) in dioxane/H2O (5:1 , 59 ml.) was added K2CO3 (2.8g, 20.3 mmol), tetrakistriphenylphosphine Pd(O) (340 mg, 0.3 mmol), and 5-bromo-2- pyrimidinecarboxylic acid (1.2 g, 5.9 mmol). The reaction mixture was heated to 80° C in a sealed tube for 12h. The reaction solution was poured onto H2O (100 ml.) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum to give the title compound (0.9 g, 36percent) as a tan solid: LC-MS (ES) m/z = 437 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 70℃; for 10h;Sealed tube; | b) 1 ,1-dimethylethyl [3-[3-(1-methyl-1H-pyrazol-5-yl)phenyl]amino}-3-oxo-2- (phenylmethyl)propyl]carbamateTo a solution of 1 ,1-dimethylethyl [3-[(3-bromophenyl)amino]-3-oxo-2- (phenylmethyl)propyl]carbamate (230 mg, 0.53 mmol) in dioxane/H2O (5:1 , 6 ml.) was added K2CO3 (220 mg, 1.59 mmol), tetrakistriphenylphosphine Pd(O) (61 mg, 52 mumol) and 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (164 mg, 0.79 mmol). The reaction mixture was heated to 70° C in a sealed tube. After 10h, the reaction mixture was concentrated under vacuum and purified on silica (hexanes/EtOAc, 30-60percent) to afford the title compound (0.17 g, 74percent) as a light yellow solid: LC-MS (ES) m/z = 435 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
>95% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 100℃;Inert atmosphere; | General procedure: The boronic acid or ester (2 equiv), aryl bromide 5a/5b (1 equiv, 0.5?2.1 mmol) and Pd(Ph3P)4 (5 mol percent based on 5a/5b) were vigorously mixed in a 5 mL microwave vial. The vial was capped, evacuated and back-filled with argon three times. Toluene (3 mL) and 2 M aq Na2CO3 (2 mL) were added, and the reaction was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc (5 mL) and extracted with water (3 × 5 mL). The organic layer was dried (Na2SO4), evaporated in vacuo, and purified by column flash chromatography (EtOAc/Et3N 95:5, 0?10percent MeOH gradient as eluent, unless stated otherwise). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 100℃;Inert atmosphere; | General procedure: The boronic acid or ester (2 equiv), aryl bromide 5a/5b (1 equiv, 0.5?2.1 mmol) and Pd(Ph3P)4 (5 mol percent based on 5a/5b) were vigorously mixed in a 5 mL microwave vial. The vial was capped, evacuated and back-filled with argon three times. Toluene (3 mL) and 2 M aq Na2CO3 (2 mL) were added, and the reaction was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc (5 mL) and extracted with water (3 × 5 mL). The organic layer was dried (Na2SO4), evaporated in vacuo, and purified by column flash chromatography (EtOAc/Et3N 95:5, 0?10percent MeOH gradient as eluent, unless stated otherwise).#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 20℃; for 70h; | EXAMPLE 7Synthesis of Obtained [2-(1-methyl-1H-pyrazol-3-yl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine (no. 35) and [2-(2-Methyl-2H-pyrazol-3-yl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine (no. 36) To a solution of 10.6 g (54.7 mmol) <strong>[844501-71-9]3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole</strong> in 100 ml acetonitrile, 17.8 g (54.7 mmol) caesium carbonate were added and the mixture stirred at ambient temperature for 70 hrs. The reaction mixture was filtered and the residue washed with acetonitrile. The combined filtrates were evaporated and taken into tert.butylmethylether. Undissolved material was filtered off; the filtrate was dried over sodium sulfate and evaporated. One got a mixture of 1-methyl-<strong>[844501-71-9]3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole</strong> und 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole as colorless, slowly crystallizing oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 60℃; for 12h;Inert atmosphere; Sealed tube; | A round-bottom flask was charged with l-bromo-2-iodo-4- (trifluoromethyl)benzene (5.00 g, 14.25 mmol), 1 -methyl- lh-pyrazole-5-boronic acid pinacol ester (3.41 g, 16.39 mmol), potassium phosphate (6.05 g, 28.5 mmol) and PdCl2(dppf)-CH2Cl2 (1.164 g, 1.425 mmol). The flask was flushed with Ar , and DMF (47.5 ml) was then added. The flask was sealed, heated to 60 C for 12 h, then stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EtOAc (3x). The combined organics were washed with brine, dried, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 100% EtO Ac/Heptane) to yield 5-(2-bromo-5-(trifluoromethyl)phenyl)-l -methyl- IH-pyrazole (2.956 g, 9.69 mmol, 68.0 % yield) as a brown solid. .H NMR (400MHz, DMSO-de) delta = 8.06 (td, J= 0.7, 8.1 Hz, 1 H), 7.86 - 7.73 (m, 2 H), 7.53 (d, J = 2.0 Hz, 1 H), 6.41 (d, J = 2.0 Hz, 1 H), 3.64 (s, 3 H). m z (ESI) 305.0 (M+H)+. |
1.001 g | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; Sealed tube; | Intermediate C: 5-(2-Bromo-5-(trifluoromethyl)phenyl)-l-methyl-lH-pyrazole A 75-mL pressure vessel was charged with l-bromo-2-iodo-4- (trifluoromethyl)benzene (2.015 g, 5.74 mmol), l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (Aldrich, St. Louis, MO, 1.374 g, 6.60 mmol), potassium phosphate (2.438 g, 11.48 mmol), and PdCi2(dppf)-CH2Ci2 adduct (Strem Chemicals Inc., Newburyport, MA, 0.469 g, 0.574 mmol). The vessel was flushed with Ar (g), then DMF (19.14 ml) was added. The vial was sealed and placed in an 80 C oil bath for 2 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on an 80 g silica gel column to give 5-(2-bromo-5-(trifluoromethyl)phenyl)-l-methyl-lH-pyrazole +H]+ = 307.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.36% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; | A round-bottom flask was charged with <strong>[57946-63-1]2-bromo-4-(trifluoromethyl)aniline</strong> (4.115 g, 17.14 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH- pyrazole (4.64 g, 22.29 mmol), potassium phosphate (10.92 g, 51.4 mmol), and Pd(AmPhos)2Ci2 (0.607 g, 0.857 mmol). Dioxane (30 mL) and water (10 mL) were added to give a thick suspension. The flask was fitted with a reflux condenser and placed in a 90 °C oil bath for 4 h. The mixture was removed from the heat, then diluted with water and extracted with EtOAc (3x). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was partially purified twice by chromatography on silica gel, first with 25 to 75percent EtO Ac/Heptane, then with 20 to70percent EtO Ac/Heptane. The partially purified material thus obtained was dissolved in methanol and loaded onto a lOg SCX-2 ion exchange column. The column was eluted with methanol, then with 2N ammonia in methanol. The basic fractions were combined and concentrated to give 2-(l-methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)aniline (0.5526 g, 2.291 mmol, 13.36 percent yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) delta = 7.52 (d, J = 1.9 Hz, 1 H), 7.43 (ddd, J = 0.5, 2.3, 8.6 Hz, 1 H), 7.26 (d, J = 1.9 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.32 (d, J = 1.9 Hz, 1 H), 5.62 (s, 2 H), 3.64 (s, 3 H). m/z (ESI) 242.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-chloro-succinimide; In tetrahydrofuran; at 70℃; for 3h; | Step 1. 4-Chloro-l-methyl-5-(4, 4, 5, 5- borolan-2-yl)-lH-pyrazole A mixture of l-methyl-5-(4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-lH-pyrazole (1.3 g, 6.3 mmol), N-chlorosuccinimide (0.93 g, 7.0 mmol) and THF (6.6 mL) was stirred at 70 °C for 3 h. The mixture was extracted with EtOAc, dried and concentrated under reduced pressure. The sub-title compound was purified by chromatography on silica gel using 40percent EtOAc in hexanes gave the desired compound, 1.456 g, 95percent. |
78% | With N-chloro-succinimide; In tetrahydrofuran; at 70℃; for 2h; | 4-Chloro-<strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> A solution of <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.00 g, 4.81 mmol) and N-chlorosuccinimide (0.671 g, 5.05 mmol) in tetrahydrofuran (10 mL, 100 mmol) was stirred at 70° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (10-80percent). The purification afforded 1.08 g (78percent yield) of the desired product as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 1 DMethyl 6-methyl-5-(6-(1 -methyl-1 H-pyrazol-5-yl)pyrazolo[1 ,5-a]pyridine-3- carboxamido)nicotinateStep 1 : Ethyl 6-(1-methyl-1 H-pyrazol-5-yl)pyrazolo[1 ,5-a]pyridine-3-carboxylate A mixture comprising ethyl 6-bromopyrazolo[1 ,5-a]pyridine-3-carboxylate (1.5 g, 5.57 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .218 g, 5.85 mmol), cesium carbonate (7.26 g, 22.30 mmol) and PdCI2(dppf).CH2CI2 adduct (91 mg, 0.1 1 1 mmol) in DME (10 ml) and water (4.00 ml) was heated using microwave radiation at 70 C for 1 hr. Further PdCI2(dppf).CH2CI2 adduct (91 mg, 0.1 1 1 mmol) was added and the mixture was heated at 80 C for 1 hr. 1-Methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.218 g, 5.85 mmol) and PdCI2(dppf).CH2CI2 adduct (91 mg, 0.1 1 1 mmol) were added and heating continued at 100 C for 3 hrs. The mixture was diluted with 10% MeOH in EtOAc (200 ml) and washed with sat. NaHC03. The organic solvent was removed under vacuum and azeotroped with toluene. The resulting solid was loaded onto silica and purified by chromatography eluting with 0 - 100% EtOAc in iso-hexane to afford the title compound;LC-MS: Rt 0.92 mins; MS m/z 271.4 {M+H}+; Method 2minl_owpH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; phosphate potassium salt; In 1,4-dioxane; water; at 100.0℃; for 1.5h;Inert atmosphere; | Dioxane (2.12 mL), water (0.24 mL), tribasic potassium phosphate (300 mg, 1.41 mmol), and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (120 mg, 0.58 mmol) were added to <strong>[73895-98-4]6-bromo-4-methylpyridin-2-amine</strong> (88 mg, 0.47 mmol) in a scintillation vial. The vial was purged with argon 3 times before PdCl2(dppf)-CH2Cl2 adduct (34 mg, 0.047 mmol) was added. The vial was purged 3 times with argon, sealed, and heated to 100C. After 1.5 hours, the reaction was cooled to room temperature, filtered through CELITE (washed with dichloromethane), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-70% acetone/hexanes, linear gradient) to afford 4-methyl-6-(l- methyl-lH-pyrazol-5-yl)pyridm-2-amine. MS ESI calc'd. for C10H13N4 [M + H]+ 189, found 189. 'H NMR (500 MHZ, CDCI3) delta 7.46 (s, 1H), 6.77 (s, 1H), 6.48 (d, J = 1.8 Hz, 1H), 6.30 (s, 1H), 4.15 (s, 3H), 2.28 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With [1,4-bis(diphenylphosphino)butane] palladium(ll) dichloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; Microwave irradiation; | In a 20 mL microwave vial was added methyl2,5-dichloro-3-iodobenzoate (500mg, I.5II mmol), I-methyl-5-( 4,4,5,5-tetramethyl-I ,3,2-dioxaborolan-2-yl)-IH-pyrazole (500 mg, 2.403 mmol), sodium bicarbonate (38I mg, 4.53 mmol), N,NDimethylformamide(DMF) (20 mL) and water (2 mL). The mixture was stirred andpurged with N2 . To the reaction was added PdCb(PPh3) 2 (60 mg, 0.085 mmol). The vialwas capped and stirred at 90 oc for 2 hr. The reaction turned black after ~ I.5 hrs. LCMSshowed after 2 hr the reaction was complete. The reaction was evaporated to dryness under vacuum and purified by silica gel chromatography (Analogix, SF25-60g, 0 to 30percentEtOAc in hexanes) (loaded with CH2Cb onto a DASi column). The pure fractions werecombined and evaporated to dryness to give the product methyl2,5-dichloro-3-(I-methylIH-pyrazol-5-yl)benzoate (0.36 g, I.263 mmol, 84 percentyield) as a clear oil. 1H NMR(400MHz, DMSO-d6) 8 = 7.98 (d, J= 2.8 Hz, I H), 7.8I (d, J= 2.5 Hz, I H), 7.54 (d, J=1.8 Hz, I H), 6.42 (d, J = 1.8 Hz, I H), 3.90 (s, 3 H), 3.66 (s, 3 H). MS(ES) [M+H]+285.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; 1,2-dimethoxyethane; at 150℃; for 0.166667h;Microwave irradiation; | Preparation 121 2-Chloro-4-(1-methyl-1H-pyrazol-5-yl)aniline Prepared using Method C (Preparation 85) using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-2-chloroaniline in DME/MeOH 2/1 for 10 minutes at 150 C. under microwave irradiation. Purified using silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a white powder (77 mg, 74%). 1H-NMR (500 MHz, CDCl3): delta 3.86 (s, 3H), 4.26 (s, br, 2H), 6.22 (d, J=2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 7.1 (dd, J=2 Hz, 8.3 Hz. Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.48 (d, J=2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 100℃; for 16h; | To a stirred solution of<strong>[6942-36-5]methyl 2-bromo-5-nitrobenzoate</strong> (10 g, 38.46 mmol) was treated 1 -methyl-5-(4,4,5 ?5-tetramethyl- 1,3 ?2-dioxaboroan-2-y)- 1 H-pyrazole (6.2 g, 46.15 mmol) using K3P04 (16.3 g, 76.92 mmol), Pd(PPh3)4 (2.2 g, 1.92 mmol) in 300mL of 1,4 dioxane and water (9:1) at rt to 100 C. TLC after 16 h indicated absence of starting materia and a new poar spot was seen. After completion, the reaction mass was filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, eluent EtOAc and petroleum ether 30:70%) to methyl 2-(1-methyl-1H-pyrazol-5-yl)-5- nitrobenzoate (5 g, 50%, LC-MS 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 75℃; for 24h; | [00466] Without wishing to be bound by theory, the ability to generate nonsymmetrical c s-imidazolines from a host of halogenated arenes may provide a platform for further derivatization using metal catalyzed functionalizations. For example, it was postulated that bromoaryl derivative 18.1 (Scheme 21) might be functionalized selectively, as oxidative addition should be accelerated compared to the neighboring chloroarene. Traditional palladium cross-couplings under various conditions to generate new sp2-sp2 C-C bonds or sp2 carbon-heteroatom bonds should be substrate compatible (Altman, R. A. and Buchwald, S. L. (2007) Nat. Protoc. 2, 3115; Martin, R. and Buchwald, S. L. (2008) Acc. Chem. Res. 41, 1461). Traditional Suzuki cross coupling conditions were employed using Pd(0)-tetrakis and an aryl boronic ester (21.1) to test this hypothesis (Scheme 11) (see WO 2008/98104 Al, col. 173). After stirring for 24 hours at 75 °C, formation of the desired pyrazole adduct 21.2 was confirmed and isolated in 62percent yield. The aryl chloride subunit was clearly intact (as confirmed by HRMS) and oxidation to the imidazole was not observed. Without wishing to be bound by theory, this data demonstrates the feasibility of late stage, site-selective functionalization from differentiated halo-arenes to access novel heterocyclic derivatives within this family. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; water; toluene; at 95℃;Inert atmosphere; | tert-Butyl N-[1 -(4-chlorophthalazin-1 -yl)-4-piperidyl]carbamate (2.Og, 5.Smmol) was dissolved in toluene (45mL) (required heating) and a solution of catalyst generated from triphenylphosphine (0.52g, 2.Ommol) and palladium acetate (112mg, 0.Smmol) in toluene (5mL) and ethanol (l5mL)was added. 1-Methyl-i H-pyrazole-5-boronic acid, pinacolester (1 .67g, 8.Ommol) was then added followed by water (1 5mL) and the sodium carbonate (1 .75g 1 6.Smmol). The solution was de-gassed under vacuum and purged with nitrogen three times before heating to 95C overnight. LCMS confirmed the presence of the desired product hence the reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic and aqueous layers were separated and theorganic layer washed with brine, dried (Mg504) and then concentrated in vacuo to afford a dark brown oil/gum. Purification by silica flash chromatography using 10% 3M NH3/MeOH: 30% ethyl acetate: 60% heptane afforded tert-butyl N-[1 -[4-(2-methylpyrazol-3-yl)phthalazin- 1 -yl]-4- piperidyl]carbamate (1 .99 g 4.87mmol, 88%) as an off-white solid.1H NMR (400MHz, ODd3) s/ppm: 8.11-8.06 (m,2H), 7.90-7.81 (m,2H), 7.67 (d, J1.9Hz, 1H), 6.60(d, J 1 .9Hz, 1 H), 4.61 (s (br), 1 H), 4.07 (s, 3H), 4.00 (m(br), 2H), 3.82 (s(br), 1 H), 3.32 (m(br), 2H),2.24-2.17 (m, 2H), 1 .84-1 .73 (m, 2H), 1 .50 (s, 9H).MS Method 1: RT: 3.65mm, ES÷ m/z 409.4 [M÷H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.8% | With tetrakis(triphenylphosphine) palladium(0); potassium dihydrogen phosphate; In 1,2-dimethoxyethane; at 120℃; for 4h;Microwave irradiation; Sealed tube; Inert atmosphere; | The reaction was carried out in 3 x 2OmL microwave tubes: i-methyl-i H-pyrazole-5-boronic acid,pinacolester (5.28g, 25.4mmol), tert-butyl N-[i -(6-chloro-4,5-dimethyl-pyridazin-3-yl)-4-piperidyl]-N-methyl-carbamate (6.Og, i 6.9mmol), palladium(0) tetrakis(triphenylphosphine) (0.98g, 0.8Smmol) were combined in i ,2-dimethoxyethane (30.mL, i 6.9i mmol) and a solution of potassium hydrophosphate (5.9g, 33.8mmol in i 5mL water) was added, The vessels were sealed, the reaction mixture degassed with nitrogen and heated to i 20C in the microwave for 2hrs. Further i-methyl30H-pyrazole-5-boronic acid, pinacolester (2.i 4g, i2.7mmol), palladium(0)tetrakis(triphenylphosphine) (0.49g, 0.425mmo1) and potassium hydrophosphate (2.85g, i 6.9mmol in 7.5mL water) were added and the vessels were resealed, the reaction mixture was again degassed with nitrogen and heated to i 20C in the microwave for 2hrs. The reaction was cooled to room temperature, the organic and aqueous layers were separated and the aqueous layer wasextracted with ethyl acetate (x3). The organic layers were combined, dried over brine and sodium sulphate. Filtered and evaporated in vacuo to a dark brown gum. . The crude material was purified by silica flash chromatography using 1 00% heptane with a gradient to 40% ethyl acetate in heptane then an isocratic flow of 40% ethyl acetate in heptane for 4 column volumes before increasing the gradient to 1 00% ethyl acetate. Fractions containing the product were combined and evaporated in vacuo to afford tert-butyl N-[1 -[4,5-dimethyl-6-(2-methylpyrazol-3-yl)pyridazin-3-yl]-4-piperidyl]-N-methyl-carbamate (5.2g, l3mmol, 76.8%)1H NMR (400MHz, ODd3) s/ppm: 7.56 (d, J1.9Hz, 1H), 6.35 (d, J1.9Hz, 1H), 4.36-3.93 (m(br), 1H),3.92 (s, 3H), 3.68-3.61 (m(br), 2H), 3.09 (t, Ji 2.1 Hz, 2H), 2.81 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H),1 .97-1 .85 (m, 2H), 1 .83-1 .76 (m(br),2H), 1 .49 (s, 9H).MS Method 2: RT: 1 .66 mi m/z 401 .3 [M÷H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 120℃; for 2h;Microwave irradiation; | tert-Butyl 4-[(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1 -yl)-methyl-amino]piperidine-1 - carboxylate (627.8mg, 1 .71 mmol), 1 -methyl-1 H-pyrazole-5-boronic acid, pinacol ester (0.71 g, 3.42mmol) and potassium carbonate (0.47g, 3.42mmol) were combined in toluene (9ml_), ethanol (3ml_) and water (3ml_) and the mixture was degassed. Palladium (0) tetrakis(triphenylphosphine) (0.1 g, 0.090mmol) was quickly added and the vial capped and heated using microwave irradiation at 120°C for 1 hour. LCMS analysis showed the reaction had not gone to completion. Further 1 - methyl-1 H-pyrazole-5-boronic acid, pinacol ester (0.36g, 1 .7mmol), potassium carbonate (0.24g, 1 .7mmol) and palladium (0) tetrakis(triphenylphosphine) (0.1 g, 0.09mmol) were added and the reaction heated using microwave irradiation at 120°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water (x3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica flash column chromatography eluting with 20percent ethyl acetate in heptane with a gradient to 100percent ethyl acetate to afford tert-butyl 4-[methyl-[1 -(2-methylpyrazol-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-4-yl]amino]piperidine-1 -carboxylate (545mg,1 .32mmol, 77percent yield) as a yellow orange oil which was used immediately in the next step. MS Method 2: RT: 1 .45min, ES+ m/z 413.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 150℃; for 0.916667h;Inert atmosphere; Sealed tube; Microwave irradiation; | Lambda/-(1 -Benzyl-4-piperidyl)-6-chloro-/V,4,5-trimethyl-pyridazin-3-amine (500mg, 1 .45mmol) and potassium carbonate (401 mg, 2.9mmol) were added to toluene (1 .5ml_), ethanol (1 mL) and water (0.50ml_) and degassed by purging with nitrogen for 1 0min. Palladium (0) tetrakis(triphenylphosphine) (252mg, 0.22mmol) and 1 -methyl-1 H-pyrazole-5-boronic acid, pinacolester (452mg, 2.17mmol) were then added, the vial sealed and heated by microwave irradiation at 150°C for 55 mins. The reaction mixture was poured into EtOAc (25ml_) and water (25ml_) and the phases were separated. The aqueous layer was re-extracted with EtOAc (2x25 mL) and the combined organic layers washed with brine, dried (Na2S04), filtered and concentrated in vacuo lo afford brown semi-solid. The residue was taken up in methanol and purified through a 5g SCX cartridge with methanol washings followed by 0.7M ammonia in methanol solution to elute the product. Concentration in vacuo afforded N-(1 -benzyl-4-piperidyl)-N,4,5-trimethyl-6-(2- methylpyrazol-3-yl)pyridazin-3-amine (500mg,1 .28mmol, 88percent yield) as a pale yellow oil which was used immediately in the next step. MS Method 2: RT: 1 .1 Omin, ES+ m/z 391 .3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃;Inert atmosphere; | To a mixture of 18a (81 mg, 0.15 mmol), 19 (38 mg, 0.18 mmol), Na2CO3 (40 mg, 0.38 mmol) and Pd(dppf)Cl2·CH2Cl2 (12 mg, 0.015 mmol) in a round bottom flask, was added DME (6 mL) and water (2 mL) under a nitrogen atmosphere. The resulting mixture was degassed with nitrogen for 5 min, and then stirred at 85 °C until the completion of the reaction. The reaction was cooled to room temperature and extracted with ethyl acetate. The extracts were combined and washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by chromatograph (0-5percent MeOH/DCM) to give the title compound 21 as a white solid (70 mg, 70percent). Mp: 163-165 °C. 1H NMR (300 MHz, CDC13) delta: 9.40 (s, 1H), 9.18 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.56-7.45 (m, 4H), 7.45-7.36 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.29 (J = 1.8 Hz, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 1.76-1.70 (m, 4H); 13C NMR (126 MHz, CDCl3) delta: 169.3, 169.1, 163.7, 157.9, 143.0, 138.7, 137.8, 137.5, 136.8, 134.0, 130.3, 129.8, 129.6, 127.3, 123.7, 121.0, 120.9, 113.1, 109.2, 106.2, 37.6, 29.7, 17.8; MS (ESI, m/z): 491.1 [M-H]-; HRMS (ESI) calcd for C28H23N6O3 [M-H]-: 491.1832; found: 491.1819. |
70% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃;Inert atmosphere; | Compound IA-12 (81 mg, 0.15 mmol), Compound 3a (38 mg, 0.18 mmol) (commercially available) Pd (dppf) CI2CH2CI2 (12 mg, 0.015 mmol) Sodium carbonate (40 mg, 0.38 mmol) was added to a dry round bottom flask. Vacuum, Replace nitrogen for three times. Under the protection of nitrogen, 6 mL of dimethyl ether (DME) H202mL, degassed with nitrogen for 5min, the mixture was heated at 85 ° C, TLC monitoring until the reaction is complete, stop heating and cool to room temperature. Ethyl acetate was added to the layers, The aqueous layer was extracted with ethyl acetate, Combine the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography (0-5percent methanol: dichloromethane) gave the desired product IA-20 as a white solid (52 mg, 70percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium phosphate; ((2-dicyclohexylphosphino-2',4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate); In tetrahydrofuran; water; at 40℃; for 64h;Inert atmosphere; Reflux; | Under argon, tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate (0.20 g, 0.48 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (102 mg, 0.49 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l '-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(II) methanesulfonate (11 mg, 13 muiotaetaomicron) were dissolved in degassed tetrahydrofuran (4 mL). Potassium phosphate solution (1 M in water, degassed) (2.55 mL, 2.55 mmol) was added and the mixture was stirred at 40 C for 48 h. Additional (2-dicyclohexylphosphino-2',4',6'- triisopropyl-l, -biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (11 mg, 13 muiotaetaomicron) was added and the mixture was stirred at reflux for 16 h. The phases were separated and the organic phase was subjected to preparative HPLC (Method 1A) to afford the title compound (140 mg, 70% of theory). LC-MS (Method IB): Rt = 1.05 min, MS (ESIPos): m/z = 449 [M+H]+ |
140 mg | With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In tetrahydrofuran; water; for 16h;Reflux; | Example 145A Tert-butyl 4-[10-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl]piperidine-1-carboxylate Under argon, tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate (0.20 g, 0.48 mmol), <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (102 mg, 0.49 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11 mg, 13 mumol) were dissolved in degassed tetrahydrofuran (4 mL). Potassium phosphate solution (1 M in water, degassed) (2.55 mL, 2.55 mmol) was added and the mixture was stirred at 40 C. for 48 h. Additional (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11 mg, 13 mumol) was added and the mixture was stirred at reflux for 16 h. The phases were separated and the organic phase was subjected to preparative HPLC (Method 1A) to afford the title compound (140 mg, 70% of theory). LC-MS (Method 1B): Rt=1.05 min, MS (ESIPos): m/z=449 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 140℃; for 0.333333h;Inert atmosphere; Microwave irradiation; | To 23-dichoro-5-nitropyridine (0.30 g, 1.56 mrno) in 1,4-dioxane (10.5 m) were added 1-methy-1H-pyrazoe-5-boronic acid pinaco ester (0.32 g, 1.56 rnmo), water (2.4 m) and K2003 (1 29 g, 9.3 mmoD. Under argon, Pd(PPh3)4 (90 mg, 0.078 mmoD was added and the reaction mixture was stirred in microwave at 140C for 20 mm. Water and AcOEt were added, the organic phase was dried over Na2SO4, fitered and evaporated. The crude product was purified by flash chromatography on sHica ge (heptane/AcOEt 85/15 to 15/85) to afford 3-choro-2-(1 -methy- I H-pyrazo5-y-5-nitropyridmne. M/z = 239-241 [M+H]+, Rt = 0.85 mm (U PLC Method 82). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | I nte rmed iate-10 (0.5 g, 0.95 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2-yl )-1H-pyrazole (415 mg, 1.9 mmol), aq. potassium carbonate (1.4 ml, 2 M) and PdCI2(PPh3)2 (67 mg,0.094 mmol) were solubilised in dimethoxyethane (60 ml). The reaction mixture was stirred for 20minutes at 130°C under microwave irradiation. After cooling to rt, the reaction mixture wasfiltered through a silicon filter and concentrated under reduced pressure. The crude material waspurified by flash column chromatography (hexane/ethyl acetate/ethanol mixture). The desiredfractions were concentrated under reduced pressure and solubilised in conc. sulphuric acid (5 ml).The mixture was stirred for 3h at rt. The mixture was then poured into ice and basified using solidsodium hydrogen carbonate. The suspension was filtered and the solid was stirred with ethanol at40°C, filtered and dried under reduced pressure. The title compound was obtained in 78percent yield(0.28 g).?H-NMR (400MHz, DMSO-d5): 6 [ppm]= 1.30 (d, 3H), 3.30 - 3.40 (m, 1H), 3.51 - 3.62 (m, 1H), 3.68 -3.77 (m, 4H), 3.79 - 3.86 (m, 1H), 4.01 - 4.09 (m, 1H), 4.18 - 4.28 (m, 1H), 4.60 -4.69 (m, 1H), 6.59 (d, 1H), 7.27 (d, 1H), 7.42 (s, 1H), 7.60 (s, 1H), 7.63 -7.69 (m, 2H), 8.35 (d, 1H), 13.42 (br. s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 0 - 120℃;Inert atmosphere; | General procedure: Tetrakistriphenylphosphane Pd (0) (580mg, 5mol %) was added to a stirred suspension of <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (2.5g, 12mmol), K3PO4·3H2O (4.8g, 18mmol) and the corresponding bromide in DMF (100mL) at 0C under nitrogen. The reaction mixture was heated at 80-120C for 8h, then poured into H2O (100mL) and extracted with ethyl acetate (45mL×3). The combined organic layers were washed with brine (50mL×2), dried over Na2SO4, and concentrated under vacuum to afford an off-white semisolid. The crude product was purified by flash silica chromatography to obtain the title compound. 4.1.4.3 Methyl 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)furan-2-carboxylate 15 Reagent: methyl 4,5-dibromofuran-2-carboxylate 14 (2.84 g, 10 mmol). The product was obtained as a white solid (2.36 g, 83%). 1H NMR (500 MHz, CDCl3) delta 7.54 (d, J = 2.1 Hz, 1H), 7.29 (s, 1H), 6.92 (d, J = 2.1 Hz, 1H), 4.14 (s, 3H), 3.92 (s, 3H). ESI-MS (m/z): 285 [M + 1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere; | The 4-bromo-1-methyl -1H-pyrrole-2-carboxylic acid methyl ester (intermediate 1-1) (2.2g, 10mmol), four (triphenylporphyrin phosphorus) palladium (1.1g, 1mmol), 1-methyl -1H-pyrazole-5-boronic acid pinacone ester (2.5g, 12mmol) and K3PO4 3H2O (4.0g, 15mmol) in sequentially adding a two neck flask, add N, N-dimethyl formamide (DMF) 30 ml, nitrogen protection, 90 C reaction under 12h. After the reaction cooled to room temperature, ethyl acetate extraction reaction solution 3 times, saturated sodium chloride washing combined with the phase 1 times, dry anhydrous sodium sulfate. Pressure reducing and recovering the solvent, silica gel column chromatography (petroleum ether: ethyl acetate = 4:1-1:1), and recovering the solvent to obtain pale yellow solid 1.64g, as 1-methyl-4 - (1-methyl -1H-pyrazol-5-yl) - 1H-pyrrole-2-carboxylic acid methyl ester (intermediate 1-2), yield 75% |
68% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 0 - 120℃;Inert atmosphere; | General procedure: Tetrakistriphenylphosphane Pd (0) (580mg, 5mol %) was added to a stirred suspension of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5g, 12mmol), K3PO4·3H2O (4.8g, 18mmol) and the corresponding bromide in DMF (100mL) at 0C under nitrogen. The reaction mixture was heated at 80-120C for 8h, then poured into H2O (100mL) and extracted with ethyl acetate (45mL×3). The combined organic layers were washed with brine (50mL×2), dried over Na2SO4, and concentrated under vacuum to afford an off-white semisolid. The crude product was purified by flash silica chromatography to obtain the title compound. 4.1.4.2 Methyl 1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-2-carboxylate 12b Reagent: <strong>[1196-90-3]methyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate</strong> 11b (2.18 g, 10 mmol, Supporting Information ). The product was obtained as a white solid (1.49 g, 68%). H NMR (500 MHz, CDCl3) delta 7.45 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.85 (s, 3H). ESI-MS (m/z): 220 [M + 1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 0 - 120℃;Inert atmosphere; | General procedure: Tetrakistriphenylphosphane Pd (0) (580mg, 5mol %) was added to a stirred suspension of <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (2.5g, 12mmol), K3PO4·3H2O (4.8g, 18mmol) and the corresponding bromide in DMF (100mL) at 0C under nitrogen. The reaction mixture was heated at 80-120C for 8h, then poured into H2O (100mL) and extracted with ethyl acetate (45mL×3). The combined organic layers were washed with brine (50mL×2), dried over Na2SO4, and concentrated under vacuum to afford an off-white semisolid. The crude product was purified by flash silica chromatography to obtain the title compound. 4.1.4.4 Methyl 4-(1-methyl-1H-pyrazol-5-yl)benzoate 18 Reagent: methyl 4-bromobenzoate 17 (2.15 g, 10 mmol). The product was obtained as a white solid (2.05 g, 95%). 1H NMR (500 MHz, CDCl3) delta 8.12 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 1.9 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H). ESI-MS (m/z): 217 [M + 1]+. |
85% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | Sequentially adding 4-methyl bromobenzoate (Compound 6-1) (2.2g, 10mmol), tetra(triphenylphosphine)palladium(1.15g, 1 mmol), 1-methyl-1H-pyrazol-5-boric acid pinacol ester (2.5g, 12 mmol) and potassium phosphatetrihydrate (4.0 g, 15 mmol) to 100ml of three-neck flask with 50mL of DMF under the protection of N2, fully stirring thereaction system at 90C and reacting overnight. Cooling the product to room temperature after the reaction is completed,pouring the reaction liquid into 100ml of water, extracting the reaction liquid with ethyl acetate 3 times, merging theorganic layer, washing with saturated sodium chloride twice, drying it with anhydrous sodium sulfate, concentratingunder reduced pressure, and purify the obtained primary product by column chromatography on silica gel, 1.83g of lightyellow solid (Intermediate 6-2) is obtained and the yield is 85%; 1H NMR (500 MHz, CDCl3) delta 8.12 (d, J = 8.3 Hz, 2H),7.54 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 1.9 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃; | Under the protection of nitrogen, the 4-bromo-2-thiophene formaldehyde (intermediate 3-1) (1.9g, 10mmol), four (triphenylphosphine) palladium (1.1g, 1mmol), 1-methyl -1H-pyrazole-5-boronic acid pinacone ester (2.5g, 12mmol) and potassium phosphate ( trihydrate ) (4.0g, 15mmol) is sequentially adding 50mLN, -dimethyl formamide N 100 ml in three-necked bottle, reaction system over 90 C fully stirring the reaction overnight. After the reaction cooled to room temperature, the reaction solution is poured into 100 ml water, extracting with ethyl acetate 3 times, combined with the organic layer, used after washing twice with saturated sodium chloride, dried anhydrous sodium sulfate, concentrated under reduced pressure, the resulting crude product by silica gel column chromatography (eluant: petroleum ether: ethyl acetate = 7:1) purified to obtain light yellow solid 1.7g (intermediate 3-2), yield 88% |
81% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 6h;Inert atmosphere; | 4.1.1 4-(1-Methyl-1H-pyrazol-5-yl)thiophene-2-carbaldehyde 2 To a solution of 4-bromothiophene-2-carbaldehyde 1 (3.82 g, 20 mmol) in 1,4-dioxane/H2O (v/v = 3/1, 60 mL) was added K2CO3 (5.52 g, 40 mmol) and <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (5.0 g, 24 mmol), followed by tetrakistriphenylphosphane Pd (0) (1.16 g, 5 mol %). The reaction mixture was heated at reflux under nitrogen for 6 h. After cooling to r.t., the reaction solution was poured into H2O (50 mL) and extracted with ethyl acetate (15 mL * 3). The combined organic layers were dried over Na2SO4, concentrated under vacuum and purified on silica gel to afford the title compound 2 as a pale yellow solid (3.11 g, 81%), mp: 70-72 C. 1H NMR (500 MHz, CDCl3) delta 9.98 (d, J = 1.1 Hz, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J = 1.9 Hz, 1H), 6.39 (d, J = 1.9 Hz, 1H), 3.97 (s, 3H). ESI-MS: m/z = 193 [M + 1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃; | Under the protection of nitrogen, the 4-bromo thiophene-2-aldehyde (intermediate 4-1) (2.1g, 10mmol), four (triphenylporphyrin phosphorus) palladium (1.1g, 1mmol), 1-methyl -1H-pyrazole-5-boronic acid pinacone ester (2.5g, 12mmol) and potassium phosphate trihydrate (4.0g, 15mmol) is sequentially adding 50mLN, -dimethyl formamide N 100 ml in three-necked bottle, reaction system over 90 °C fully stirring the reaction overnight. After the reaction cooled to room temperature, the reaction solution is poured into 100 ml water, extracting with ethyl acetate 3 times, combined with the organic layer, used after washing twice with saturated sodium chloride, dried anhydrous sodium sulfate, concentrated under reduced pressure, the resulting crude product by silica gel column chromatography (eluant: petroleum ether: ethyl acetate = 8:1) purified to obtain light yellow solid 3.6g (intermediate 4-2), yield 83percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | The title compound is prepared according to General Procedure 16 described in Example 62, using 4-bromo-2-fluoro-1-methanesulfonylbenzene (100 mg; 0.40 mmol; 1 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- 1 H-pyrazole (164 mg; 0.79 mmol; 2 eq.), cesium carbonate (407 mg; 1.19 mmol; 3 eq.), Pd(dppf)2*CH2CI2 (17 mg; 0.02 mmol; 0.05 eq.), dioxane (2 mL) and water (1 mL). Conditions: 100 °C, overnight. Purification by FCC (0percent to 50percent EtOAc gradient in hexane) affords 5-(3-fluoro-4-methanesulfonyl- phenyl)-1-methyl-1 H-pyrazole (95 mg; 0.37 mmol; 94percent; UPLC purity: 99.5percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 74℃; for 12h;Inert atmosphere; | A solution of 10 (0.20 g, 0.43 mmol, 1.0 equiv.) in a mixture of toluene(18 mL), ethanol (6 mL) and H2O (6 mL) was treated with Na2CO3(0.09 g, 0.86 mmol, 2.0 equiv.) and 1-methyl-1H-pyrazole-5-boronicacid pinacol ester (0.10 g, 0.47 mmol, 1.1 equiv.) and the mixture waspurged with nitrogen for 20 min. Pd(PPh3)4 (60 mg) was added andthe mixture was stirred at 74 C for 12 h. After monitoring by TLC,the reaction mixture was cooled to room temperature and diluted withDCM. The organic portion was washed with sat. sodium chloridesolution, and dried over anhydrous Na2SO4 and concentrated underreduced pressure. The resulting residue was purified by flash silica gelchromatography (dichloromethane/MeOH, 30:1) to provide Taladegibas a yellow foam. Yield 0.20 g, 92%; m.p. 95 C; 1H NMR (300 MHz,CDCl3) delta 8.09 (dd, J = 7.6, 7.7 Hz, 2H), 7.90-7.80 (m, 2H), 7.65 (d,J = 1.8 Hz, 1H), 7.47-7.28 (m, 3H), 6.59 (d, J = 1.8 Hz, 1H), 4.97-4.89(m, 1H), 4.21-4.08 (m, 2H), 4.05 (s, 3H), 3.44-3.35 (m, 2H), 2.76 (s,3H), 2.35-2.11(m, 2H), 2.04-1.88 (m, 2H); 13C NMR (75 MHz, CDCl3)delta 168.0, 163.8, 159.9, 147.4, 138.2, 136.7, 132.0, 131.9, 131.5, 129.4,129.0, 128.0, 126.3, 124.6, 121.4, 119.5, 114.5, 109.1, 56.9, 51.4, 38.3,31.8, 29.7, 28.4; MS calcd for C26H24F4N6O [M + H]+: 513.2026; found:513.2018. |
92% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 74℃; for 12h;Inert atmosphere; | Compound 10 (0.2 g, 0.429 mmol, 1 eq.) Was dissolved in a mixed solution of 18 mL of toluene, 6 mL of ethanol and 6 mL of water,To the solution were added 0.091 g (0.858 mmol, 2 eq.) Of sodium carbonate and 0.098 g (0.472 mmol, 1.1 eq.) Of 1 -methyl- lH-pyrazole-5-boronic acid pinacol ester (CAS No. 847818- 74-0),After degassing with nitrogen for 20 min, 60 mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was degassed with nitrogen for 10 min. After the reaction was stirred uniformly, the reaction was refluxed at 74 C. for 12 h.After the reaction was completed, the mixture was cooled to room temperature, diluted with dichloromethane, washed three times with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.Purification by column chromatography (eluent dichloromethane / methanol, 30: 1 by volume) gave LY-2940680 (0.202 g, 92% yield) as a pale yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 110℃; for 16h;Inert atmosphere; | To a mixture of 1-chloro-5-iodo-4-methoxy-2-methyl-benzene (500 mg, intermediate Bi, step2), 1 -methyl-5-(4,4 ,5 ,5 -tetramethyl- [1,3,2] dioxaborolan-2-yl)- 1 H-pyrazole (442 mg, CAS:847818-74-0) and K2C03 (733 mg) in dioxane (12 ml) and water (4 ml) was added PdC12(PPh3)2-CH2C12 (25 mg) and the reaction mixture was heated to 110°C for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml), filtered through celite and the filtrate was evaporated. The resulting residue was purified by column chromatography over silica gel (0-20percent EtOAc/hexane) to obtain 5-(5-chloro-2-methoxy-4-methyl-phenyl)- 1-methyl- 1H-pyrazole (365 mg, 87percent) as brown sticky solid. MS (ESI): mlz = 236.7 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 3h;Inert atmosphere; | A mixture of Intermediate E, ((E)-1-(4-bromophenyl)-2-(4-(hexyloxy)phenyl)diazene) (2.77 mmol), <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (3.6 mmol), a solution of sodium carbonate (7 mmol) in water (3 mL), tetrakis(triphenylphosphine)palladium(0) (0.139 mmol), ethanol (12 mL), and toluene (25 mL) was stirred under argon and heated at 100° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and stirred for 1 hour. Finally, the reaction mixture was extracted with ethyl acetate (100 mL), and the volatiles were removed under reduced pressure. The residue was chromatographed using silica gel and hexane/ethyl acetate (1:1) as an eluent to give 0.38 g (75percent) of Chromophore 6, [(E)-5-(4-((4-(hexyloxy)phenyl)diazenyl)phenyl)-1-methyl-1H-pyrazole]. It was further purified by recrystallization. 1H-NMR (CDCl3): delta 7.95 (2H, d), 7.91 (2H, d), 7.56 (3H, m), 7.02 (2H, d), 6.38 (H, d), 4.04 (2H, t), 3.94 (3H, s), 1.82-1.24 (8H, m), 0.91 (3H, m). LC-MS: MH+ 363. UV-Vis in ethyl acetate 359 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 3h;Inert atmosphere; | A mixture of ((E)-4-((4-bromophenyl)diazenyl)phenyl 2-ethylbutanoate (Intermediate H) (2.77 mmol), <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (3.6 mmol), a solution of sodium carbonate (7 mmol) in water (3 mL), tetrakis(triphenylphosphine)palladium(0) (0.139 mmol), ethanol (12 mL), and toluene (25 mL) was stirred under argon and heated at 100° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and stirred for 1 hour. Finally, the reaction mixture was extracted with ethyl acetate (100 mL), and the volatiles were removed under reduced pressure. The residue was chromatographed using silica gel and hexane/ethyl acetate (1:1) as an eluent to give 0.4 g (80percent) of Chromophore 20, (E)-4-((4-(1-methyl-1H-pyrazol-5-yl)phenyl)diazenyl)phenyl 2-ethylbutanoate. The compound was further purified by recrystallization. 1H-NMR (CDCl3): delta 7.99 (4H, m), 7.58 (4H, m), 7.23 (1H, s), 6.39 (1H, s), 3.95 (3H, s), 2.49 (1H, m), 1.81-1.58 (4H, m), 1.06 (6H, t). LC-MS: MH+ 377. UV-Vis in ethyl acetate 340 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.2% | With potassium fluoride; potassium phosphate; In m-xylene; at 120℃; for 3h;Microwave irradiation; Inert atmosphere; Sealed tube; | Tert-butyl 3-((4-chlorophthalazin-1-yl)amino)pyrrolidine-1-carboxylate (900mg, 2.3mmol), <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (973mg, 4.7mmol), potassium fluoride (273mg, 4.7mmol), Potassium phosphate(1.25g, 4.7mmol) and m-xylene(5mL) were added to a microwave vial (20mL) equipped with a stir bar. The reation mixture was purged with nitrogen for 5min. Tetrakis(triphenylphosphine)platinum (266mg, 0.23mmol) was added. The vial was sealed and irradiated in the microwave at 120°C (high absorption setting) for 3h. The reaction mixture was concentrated under reduced pressure and washed with water and extracted with EtOAc, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography(hexane:ethyl acetate) to give tert-butyl 3-((4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)amino)pyrrolidine-1-carboxylate (700mg, 77.2percent). 1H NMR (400MHz, CDCl3) delta (ppm): 8.04 (s, 1H), 7.94 (d, J=7.0Hz, 1H), 7.86?7.72 (m, 2H), 7.60 (s, 1H), 6.51 (s, 1H), 5.94 (br, 1H), 5.07?4.93 (m, 1H), 3.97 (s, 3H), 3.93?3.74 (m, 1H), 3.66?3.35 (m, 3H), 2.38 (br, 1H), 2.11 (br, 1H), 1.43 (s, 9H). MS (ESI+): [M+H]+: 395.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; water; toluene; at 74℃; for 12h;Inert atmosphere; | Compound D-6 (0.20 g, 0.45 mmol, 1.0 eq.) Was dissolved in 18 mL of toluene, 6 mL of ethanol, 6 mL of waterTo the solution was added 0.10 g (0.90 mmol, 2.0 eq.) Of sodium carbonate and 0.10 g (0.49 mmol, 1.1 eq.) Of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester, After degassing with nitrogen for 20 min, 60 mg of tetrakis (triphenylphosphine) palladium was added followed by nitrogenDegassing gas for 10 min, stirring evenly after the reaction at 74 ° C for 12h; after the end of the reaction to cool to room temperature, adding methylene chloride diluteThe organic phase was washed three times with concentrated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (eluent: dichloromethane / methanol, 30: 1 by volume) to give a pink transparent solid 4 (0.20 g, yield 89percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 74℃; for 12h;Inert atmosphere; | Compound D-7 (0.20 g, 0.43 mmol, 1.0 eq.) Was dissolved in 18 mL of toluene, 6 mL of ethanol, 6 mL of waterTo a solution was added 0.09 g (0.86 mmol, 2.0 eq.) Of sodium carbonate and 0.10 g (0.47 mmol, 1.1 eq.) Of 1-methyl-1H-pyrazole-5-boronic acid dicarboxylate, After degreasing for 20 min, 60 mg of tetrakis (triphenylphosphine) palladium was added followed by nitrogenDegassing for 10 min, stirring evenly after the reaction at 74 ° C for 12h; after the end of the reaction to cool to room temperature, adding methylene chloride diluteThe organic phase was washed three times with concentrated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by column chromatography (eluentDichloromethane / methanol in a volume ratio of 30: 1) to give the title compound 6 (0.19 g, 87percent yield) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | To a round bottom flask equipped with septum contained IN-3-O1 (24.70 g, 60.21 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1H-pyrazole (25.06 g, 120.43 mmol), K2C03 (461.86 g, 361.29 mmol), PdC12(PPh3)2 (6.34 mg, 9.03 mmol) was added 361 mL 1 ,4-dioxane and 180 mL of water. After the addition, a vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100 °C and stirred at this temperature overnight. The solvent was evaporated and the residue was diluted with EtOAc (600 mL) and water (500 mL). The organic layers was evaporated and dried over Na2SO4, filtered and evaporated onto 50 g of silica gel and purified by flash chromatography (0-100percent Solvent B/hexanes, while Solvent B is a solvent mixture of 1percent MeOH in EtOAc) to afford a brownish solid. This solid was redissolved in EtOAc and evaporated onto 50 g of silica gel and repeated the flash chromatography for two times to afford a white solid (25.1 g, 91percent yield). LC/MS (Rt = 1.68 mm, +ESI m/z: MH+ = 456.3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With palladium diacetate; sodium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; at 105℃; for 16h;Sealed tube; Inert atmosphere; Sonication; | In a sealed tube a mixture of N-tert-butyl-3-(4-chlorophenyl)-5-iodobenzamide (intermediate 1)(103 mg, 0.25 mmol), commercially available 1 -methyl-5- (4,4,5 ,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67.6 mg, 325 j.imol), 1,2-dimethoxyethane (1.67 ml) and 2Msodium carbonate solution (416 jil, 833 imol) was purged with argon in an ultrasonic bath for 5mi triphenylphosphine (13.1 mg, 50 imol) and palladium(II)acetate (5.61 mg, 25 imol) were added and the reaction mixture was allowed to stir for 16h at 105°C. The crude reaction mixture was purified by flash chromatography on silica gel [heptane/ethyl acetate (10-60percent)] to yield the title compound (73 mg, 79percent) as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; tert-butyl XPhos; In 1,4-dioxane; water; at 90.0℃; for 6.0h;Inert atmosphere; | Compound 1-h (210 mg, 0.84 mmol), 1-methyl-pyrazole-5-boronicacidpinacolester (175 mg, 0.84 mmol),bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.05 mmol), 2-di-tert-butylphosphino-2?,4?,6?-triisopropylbiphenyl(33 mg, 0.08 mmol) and 2 M aqueous sodium carbonate solution (3.4 mL, 6.72 mmol) were dissolved in 1,4-dioxane (7mL). The reaction mixture was replaced with nitrogen three times to remove the oxygen inside the system and thenheated at 90C for 6 hours. The reaction was cooled to room temperature, diluted with ice water (100 mL) and extractedwith dichloromethane (100 mL 3 3). The combined organic phases were washed successively with water (50 mL 3 3)and brine (50 mL),dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.The residue was purified bypreparativehigh performance liquid chromatography to deliver a yellow solid 4-b (100 mg,yield: 48%).LC-MS (ESI): m/z = 251 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 6h; | Pd(pph3)4 (30 mg, 0.026 mmol), (1-methyl-1H-pyrazole-3)-boronic acid (108.2 mg, 0.52 mmol),NaCO3 (82.6 mg, 0.78 mmol) and compound g (100 mg, 0.26 mmol) were added to the reaction tube.Then, H2O (0.39 ml) and 1,4-dioxane (0.65 ml, 0.4 M) were added to remove nitrogen three times, and the mixture was heated to 90C and stirred for 6 hours.Cool to room temperature, dilute with water, extract twice with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate.Purification by silica gel column (PE:EA=2:1) gave 77 mg of pale yellowish-green solid, ie SKLB-C4596, yield: 77.5%. |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 6h; | General procedure: Under N2 atmosphere, a mixture of 6 (100.0 mg, 0.26 mmol),Pd(pph3)4 (30.0 mg, 0.026 mmol), 2.0M aq Na2CO3 (0.29 ml,0.78 mmol) and 1-Methyl-1H-pyrazole-5-boronic acid pinacolester (108.2 mg, 0.52 mmol) in 1,4-Dioxane (0.65 ml) was heated to90 C and stirred for 6 h. The reaction mixture was cooled, dilutedwith ethyl acetate, washed with water, dried over anhydrousNa2SO4, filtered and concentrated under vacuum. Purification onsilica using a solvent gradient of 10-30% ethyl acetate in hexanesyielded the desired compound 1j (77.0 mg, 77.5%). Compounds 1akwere prepared according to general procedure as described forcompound 1j using corresponding aryl bromide 2-4 and theappropriate boronic acid or boronic acid pinacol ester. The characterizationdata for compounds 1a-k were provided below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 140℃; for 0.5h;Inert atmosphere; Microwave irradiation; Sealed tube; | General procedure: A reaction vial was charged with a mixture of the bromide (1 equiv.), the organoboron reagent (1-3 equiv.), a Pd catalyst (0.05-0.1 equiv.) and an inorganic base (2-5 equiv.) in 1 ,4-dioxane/water or DME/water and the 02 was removed by evacuating and refilling with N2 three times before the reaction tube was sealed. The reaction was heated under the indicated conditions for the indicated time before being cooled to RT and saturated NH4CI(aq) was added. The mixture was then extracted with DCM (x3) using a Biotage phase separator. The combined organic phases were concentrated and the residue purified by flash chromatography (Biotage KP-Sil and KP-NH, 0-100percent EtOAc in cyclohexane or PE, then 0- 30percent MeOH in EtOAc) to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 140℃; for 1h;Inert atmosphere; Microwave irradiation; Sealed tube; | General procedure: A reaction vial was charged with a mixture of the bromide (1 equiv.), the organoboron reagent (1-3 equiv.), a Pd catalyst (0.05-0.1 equiv.) and an inorganic base (2-5 equiv.) in 1 ,4-dioxane/water or DME/water and the 02 was removed by evacuating and refilling with N2 three times before the reaction tube was sealed. The reaction was heated under the indicated conditions for the indicated time before being cooled to RT and saturated NH4CI(aq) was added. The mixture was then extracted with DCM (x3) using a Biotage phase separator. The combined organic phases were concentrated and the residue purified by flash chromatography (Biotage KP-Sil and KP-NH, 0-100percent EtOAc in cyclohexane or PE, then 0- 30percent MeOH in EtOAc) to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; at 110℃; for 3h;Inert atmosphere; | 2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl trifluoromethanesulfonate (90.0 g, 171 mmol) ("Intermediate- 10" as described in WO2016020320) was dissolved in 2250 mL cyclopentyl methyl ether. <strong>[847818-74-0]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (74.7 g, 341 mmol) was added followed by 260 mL aqueous potassium carbonate solution (2.0 M) and bis(triphenylphosphine)palladium(II)dichloride (12.0 g, 17.1 mmol). The reaction mixture was stirred under nitrogen at 110 °C for 3 hours (TLC control, ethyl acetate). After cooling the mixture was filtered over Celite®and the filter cake was washed with cyclopentyl methyl ether. The solvent was evaporated in vacuo. The residue was suspended in a mixture of n-hexane/ethyl acetate (1 : 1) and passed through a plug of silicagel (n-hexane/ethyl acetate 1 : 1 -> ethyl acetate). The solvent was evaporated in vacuo and the darkgreen oil (78.4 g, 171 mmol, 100 percent yield) was used without any further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In tetrahydrofuran; ethanol; water; at 50℃; for 12h;Inert atmosphere; | tert-Butyl (2-(4-chloro- 1 H-pyrrolo[2, 3-b]pyridin-2-yl)ethyl)carbamate (Intermediate 55, 295mg, 1.00 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (312 mg, 1.50 mmol),potassium phosphate (630 mg, 3.00 mmol) and X-Phos-Pd-G3 (34 mg, 0.04 mmol) were added to a flame dried flask under argon and purged with argon three times. Degassed THF/ethanol/water (3:1:1, 5 mL) was added, and the reaction mixture was heated at 50 o for 12 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate.The combined organic layers were washed with brine, and concentrated in vacuo. The residue was purified by FCC eluting with Petrol:EtOAc:MeOH (gradient elution, 10:10:1, to 0:10:1) to give the title compound (340 mg, 99%) as a white solid.LCMS (Method 4): Rt 2.46 mi mlz 342, [MH].1H NMR (400 MHz, CDCI3) 1.40 (9H, 5), 3.10 (2H, t, J = 6.5 Hz), 3.59 (2H, q, J=6.5Hz), 3.92 (3H, 5), 4.81 (1H, 5), 6.26 (1H, 5), 6.51 (1H, d, J=1.8 Hz), 7.06 (1H, d, J=5.0 Hz), 7.62 (1H, d, J=1.9 Hz), 8.36 (1H, d, J=4.9 Hz), 11.92 (1H, 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | 2-fluoro-4-methyl-bromobenzoate 1A (2.3 g, 10 mmol) tetrakis(triphenylphosphine)palladium (1.15g, 1 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester 2a (2.5 g, 12 mmol) and potassium phosphate trihydrate (4.0 g, 15 mmol) were added into a 100 ml three-necked bottle containing 50 mL of DMF in sequence under nitrogen protection and the reaction was placed at 90 C with fully stirring overnight. The reaction mixture was cooled to room temperature after the reaction completes, the reaction mixture was poured into 100 mL of water and was extracted three times with ethyl acetate, and combined the organic layers, after washing twice with saturated sodium chloride, anhydrous sodium sulphate was dried and concentrated under reduced pressure, and the obtained crude product was purified by silica gelcolumn chromatography to obtain a pale yellow solid 2.38 g of intermediate 3Aa with a yield 85%, 1H NMR 500 MHz,CDCl3) delta 8.09 -7.99(m, 1H), 7.55 (d, J= 1.9 Hz, 1H), 7.29 (dd, J= 8.1, 1.6 Hz, 1H), 7.23 (dd,J= 11.3, 1.6Hz, 1H), 6.40 (d, J= 1.9 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H). ESI(M+H)+=235. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 16h;Inert atmosphere; | To a mixture of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (0.800 g, 4.19 mmol) and l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.133 g, 5.45 mmol), K2C03 (1.736 g, 12.57 mmol) in DME (6.0 mL) / H20 (1.0 mL) was added pd(dppf)Cl2 (306.5 mg, 0.420 mmol). Then the mixture was stirred at 100 C for 16 hours under N2. The mixture was filtrated and the organic layer was concentrated. Water (40 mL) was added, and it was extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over Na2S04, filtered and concentrated. It was purified by chromatography on silica (0-30% EtOAc in petroleum ether, Rf = 0.5) to afford 3-fluoro-4-(l-methyl-lH-pyrazol-5-yl)phenol (557 mg, 69%) as yellow solid. XH NMR (400 MHz, DMSO-c) delta 10.25 (br s, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 7.27-7.23 (m, 1 H), 6.74-6.69 (m, 2 H), 6.28 (d, J= 2.0 Hz, 1 H), 3.68 (s, 3 H). LCMS (Method = CC): RT = 0.655 min, m/z = 192.8 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | under the protection of nitrogen, the compound 10 (2.53 g, 10 mmol), tetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester 2a (2.31 g, 12 Methyl) and potassium phosphate trihydrate (7.5 g, 15 mmol) were sequentially added to a 100 ml three-necked bottle containing 50 mL of DMF, and the reaction system was placed at 90 C and stirred thoroughly overnight. After the reaction completes and was cooled to room temperature, the reaction solution was poured into 100 mL of water, extracted three times with ethyl acetate, the organic layer was combined, washed twice with saturated sodium sulfate and dried over anhydrous sodium sulfate. anhydrous sodium sulphate was dried and concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography to obtain the 2.38g of intermediate 11 with a yield of 92%, ESI(M+H)+=257. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 0 - 100℃; for 10h;Inert atmosphere; | General procedure: Tetrakistriphenylphosphane Pd (0) (3.45g, 3mmol) was added to a stirred suspension of 4-halogen substituted aromatic ester or aldehyde (30mmol), 1-methyl-5-(4,4,5,5-tetramethyl- [1-3] dioxaborolan-2-yl)-1H-pyrazole (7.5g, 36mmol) and potassium phosphate (12g, 45mmol) in dimethylformamide (100mL) at 0C under nitrogen protection. The reaction mixture was heated at 100C for 10h, then poured into H2O (300mL) and extracted with ethyl acetate (100mL×3). The combined organic layers were washed with saturated brine (200mL×3), dried over Na2SO4, and concentrated under vacuum to afford the crude product, then purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 60℃; for 2h; | Methyl 2-bromo[l,2,4]triazolo[l,5-a]pyridine-6-carboxylate (0.15 g, 0.58 mmcl) obtained in(Example 13-c), 1-methyl-lH-pyrazole-5-bcrcnic acid pinacol ester (0.18 g, 0.87 mmcl), [1,1?-bis(diphenylphosphino)ferrocenelpalladium(II) dichioridedichloromethane adduct (24 mg, 0.029 mmol), and potassiumcarbonate (0.24 g, 1.7 mmol) were suspended in1,4-dioxane (3 mL) and water (1 mL) and then stirred at60C for 2 h. After cooling to room temperature, thereaction solution was poured into water (30 mL) , followed by partition operation using ethyl acetate. The organicphase was washed with brine, then dried over magnesium sulfate, and filtered. Then, the solvent was distilled off under reduced pressure to give the crude title compound. The crude product was purified by silica gel column chromatography (AcOEt:hexane = 15:85 to 55:45) to give the title compound (0.14 g, 94%) as a scud.?H NNR (400 MHz, CDC1,) oe (ppm) 4.01 (s, 3 H),4.37 - 4.39 (m, 3 H), 7.04 (d, J=2.2 Hz, 1 H), 7.58 (d, J=2.0 Hz, 1 H), 7.78 (dd, J=9.3, 0.9 Hz, 1 H), 8.13 (dd, J=9.3, 1.7 Hz, 1 H), 9.32 (dd, J=l.7, 0.9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 2h; | A mixture of 2,4-dichloropyrimidine (1.04 g, 7 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.46 g, 7 mmol), K2C03 (1.93 g, 14 mmol) and Pd(dppf)Cl2 (512 mg, 0.7 mmol) in Dioxane/H20 (20 mL/5 mL) was stirred at l20C for 2 hours. The mixture was concentrated in-vacuo and the residue was purified by flash chromatography on silica gel (Petroleum Ether/Ethyl Acetate = 2/1) to afford 2-chloro-4-(l-methyl-lH-pyrazol-5-yl)pyrimidine (1.3 g, 96%). 1H NMR (400 MHz, CDCI3): 5 4.33 (s, 3H), 6.82 (d, J= 2.0 Hz, 1H), 7.48 (d, J= 52 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 8.63 (d, J= 5.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water;Inert atmosphere; Reflux; | General procedure: To a solution of 2a (1.00 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 mmol) in 8 mL of 1,4-dioxane and 2 mL of water was added K3PO4 (2.00 mmol) followed by PdCl2(dppf)DCM (0.10 mmol) under argon with stirring. The mixture was refluxed overnight until the reaction was completed. The reaction mixture was cooled down to room temperature and filtered. Then, the filtrate was concentrated by rotary evaporation. The residue was poured into water and extracted with ethyl acetate. The product was isolated by flash chromatography on silica gel using 1:3 EtOAc-hexane as eluant. The product was a colorless oil (87% yield). |
Tags: 847818-74-0 synthesis path| 847818-74-0 SDS| 847818-74-0 COA| 847818-74-0 purity| 847818-74-0 application| 847818-74-0 NMR| 847818-74-0 COA| 847818-74-0 structure
[ 1047644-76-7 ]
1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
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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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