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CAS No. : | 376584-63-3 | MDL No. : | MFCD02020768 |
Formula : | C3H5BN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NEUWPDLMDVINSN-UHFFFAOYSA-N |
M.W : | 111.90 | Pubchem ID : | 11251979 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 28.41 |
TPSA : | 69.14 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.58 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -0.84 |
Log Po/w (WLOGP) : | -1.91 |
Log Po/w (MLOGP) : | -2.25 |
Log Po/w (SILICOS-IT) : | -1.27 |
Consensus Log Po/w : | -1.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.4 |
Solubility : | 44.4 mg/ml ; 0.397 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.13 |
Solubility : | 82.7 mg/ml ; 0.739 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.07 |
Solubility : | 96.1 mg/ml ; 0.859 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.1 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With n-butyllithium; triisopropylborane In tetrahydrofuran; hexane at -78 - 20℃; for 5 h; | To a cooled solution (-780C) of l-(tetrahydro-pyran-2-yl)-lH-pyrazole (7.6g,52mmol) in THF (5OmL), "BuLi (33mL, 2.5M in hexane, 82.5mmol) and triisopropyl borane (12.7mL, 55mmol) are added dropwise maintaining the temperature at -7O0C. The reaction mixture is stirred at -7O0C for one hour and then allowed to reach room temperature over 4 hours. After quenching the reaction with 2M HCl, the solvent is removed in vacuo and the pH is adjusted to pH 6 using IM NaOH. A precipitate is formed, collected by filtration and washed with toluene and petroleum ether. Trituration with ethyl acetate affords the target compound as a white solid (2.7g, 48percent), which is used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 16h; | Example 32 Synthesis of 4-methy--2-(2iy-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide (2.0 g, 6.43 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added IH- pyrazole-5-boronic acid (1.44 g, 12.9 mmol), Pd(PPh3)4 (0.74 g, 0.643 mmol), and potassium carbonate (2.67 g, 19.3 mmol). The resulting mixture was degassed three times and heated to 100 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (ethyl acetate :hexane, 1 :1) to provide 4-methyl-2- (2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (1.25 g, 66percent yield) as a white solid. 1H NMR (400 MHz, DMSCW6) delta 8.76 (t, J = 4.0 Hz, IH), 7.89 (d, J = 4.0 Hz, 1 H), 7.31-7.36 (m, 4H)5 1. IA-1.21 (m, 1 H), 6.78 (d, J = 4.0 Hz, IH), 4.44 (d, J = 4.0 Hz, 2H), 2.60 (s, 3H); MS (M+H)+ = 299.1 ; R1 = 1.06 min; HRMS (M+H)+= 299.10.; Example 90 Part B. Synthesis of 4-methyl-2-(2H-pyrazoI-3-yI)-thiazole-5-carboxylic acid benzylamideA solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide (2.0 g, 6.43 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1 H-pyrazole-5- boronic acid (1.44 g, 12.86 mmol), Pd(PPh3)4 (0.74 g, 0.643 mmol), and potassium carbonate (2.67 g, 19.29 mmol). The resulting mixture was degassed three times and heated to 100 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1 :1 ethyl acetate:hexane to provide 4-methyl- 2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (1 .25 g, 66percent yield) as a white solid. MS (M+eta)+ = 299; R, = 1.06 min; HRMS (M + H) + = 299. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 16h; | To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (2.0 g, 7.99 mmol) in toluene (60 mL), water (20 mL) and ethanol (20 mL) was added IH- pyrazole-5-boronic acid (1.79 g, 15.99 mmol), Pd(PPh3^ (0.92 g, 0.80 mmol), and <n="82"/>50352potassium carbonate (3.30 g, 23.98 mmol). The resulting mixture was degassed three times and heated to 100 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes:ethyl acetate, 1 : 1) to provide 4-methyl-2-(2H-pyrazol- 3-yl)-thiazole-5-carboxylic acid ethyl ester (1.5 g, 83percent yield) as a yellow solid. MS (M+eta)+ = 238; R, = 1.2 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 16h; | To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (pyridine-3- ylmethyl)-amide (5.0 g, 16.0 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added lH-pyrazole-5-boronic acid (2.15 g, 19.2 mmol), Pd(PPh3)4 (1.85 g, 1.60 mmol), and potassium carbonate (6.64 g, 48.1 mmol). The resulting mixture was degassed three times and heated to 1000C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was recrystallized from ethyl acetate to provide 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5- carboxylic acid (pyridine-3-ylmethyl)amide as a white solid (4.20 g, 85percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); at 100℃; for 16h; | To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (5.0 g, 15.0 mmol) in toluene (3OmL), water (10 mL) and ethanol (10 mL) was added IH- pyrazole-5-boronic acid (1.70 g, 15.0 mmol), Pd(PPh3)4 (1.75 g, 1.52 mmol), and potassium carbonate (6.3 g, 45.6 mmol). The resulting mixture was degassed three times and heated to 100 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (ethyl acetate:hexane, 50:50) to provide 4-methyl-2-(2H-pyrazol-S-yO-thiazole-S-carboxylic acid 4-fluoro-benzylamide as yellow solid (3.25 g 68 percent) MS (M+H)+= 317; R1 = 1.13 min; HRMS (M+H)+= 317. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); | Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.27 mmol) was reacted with <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (0.060 g, 0.54 mmol), sodium carbonate (0.085 g, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g) to give 0.085 g (62percent yield) of the title material as a white solid after chromatography on silica gel. 1HNMR 400 MHz (CDCl3) ? (ppm): 1.63 (6H, s, 2xCH3), 4.03 (4H, m, 2xCH2), 4.65 (2H, d, J=6.5 Hz, NCH2), 5.25 (2H, s, OCH2), 6.54 (1H, d, J=2.5 Hz, CH), 7.03 (1H, m, aromatic), 7.25 (1H, dd, J=2.5 Hz and J=9.8 Hz, aromatic), 7.35 (3H, m, aromatics), 7.53 (2H, m, aromatics), 7.56 (1H, d, J=2.5 Hz, CH), 7.60 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.96 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN5O4 [M+H+]: 504.2047: found: 504.2068. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 20℃; for 4h;Heating / reflux; | [00207] To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one (0.765 g, 2.43 mmol) in DME-H2O (10:1 11 mL) was added lH-pyrazol-5- ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (Pd(dpprhof),0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the organic layer was dried with Na2SO4, and the product 8-ethyl-4-methyl- 2-(methylthio)-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77percent yield) was obtained by silica gel column chromatography. 1H NMR (400 MHz, CDCl3): delta 13.3 (bs, IH), 8.54 (s, IH), 7.82-7.07 (m, 2H), 4.45 (q, J= 7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J= 7.2Hz, 3H). EPO <DP n="66"/> |
77% | With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 20℃; for 4h;Heating / reflux; | To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one (0.765 g, 2.43 mmol) in DME-H2O (10: 1 1 1 mL) was added l H-pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (Pd(dpppf),0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the organic layer was dried with Na2SO4, and the product 8-ethyl-4-methyl-2-(methylthio)-6-(lH-pyrazol- 5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77percent yield) was obtained by silica gel column chromatography. 1H NMR (400 MHz, CDCl3): delta 13.3 (bs, IH), 8.54 (s, IH), 7.82-7.07 (m, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J = 7.2Hz, 3H). |
77% | With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 20℃; for 4h;Heating / reflux; | [00242] To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one (0.765 g, 2.43 mmol) in DME-H2O (10:1 11 mL) was added lH-pyrazol-5- ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (Pd(dpppf),0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the organic layer was dried with Na2SO4, and the product 8-ethyl-4-methyl- <n="74"/>2-(methylthio)-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77percent yield) was obtained by silica gel column chromatography. 1H NMR (400 MHz, CDCl3): delta 13.3 (bs, IH), 8.54 (s, IH), 7.82-7.07 (m, 2H), 4.45 (q, J= 7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J= 7.2Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.7% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; | Intermediate 6; [00234] In a 350 mL pressure tube 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3- d]rhoyrimidin-7(8H)-one (1.50 g, 5.05 mmol), l/f-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol), K2CO3 (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium (0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H2O. The tube was sealed, heated to 100 0C and allowed to react overnight. A color change was observed. LCMS indicated no presence of starting material. Sample was filtered through a syringe filter and evaporated to dryness. Compound was dissolved in ethyl acetate and triturated in hexane. Light yellow powder of 2-ammo-8-isopropyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- EPO <DP n="76"/>d]pyrimidin-7(8H)-one (195 mg, 13.7percent yield) was found to be 98percent pure by etaPLC. 1H NMR (400MHz, CDCl3) delta 12.97 (br s, IH), 8.35 (s, IH), 7.60 (br s, IH), 7.21 (s, 2H), 6.94 (s, IH)5 5.86 (br s, IH), 2.50 (m, 6H), 1.54 (s, 3H), MS (EI) for C14H16N6O: 285.0 (MH+). |
13.7% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; | In a 350 mL pressure tube 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one (1.50 g, 5.05 mmol), leta-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol), K2CO3 (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium (0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H2O. The tube was sealed, heated to 100 0C and allowed to react overnight. A color change was observed. LCMS indicated no presence of starting material. Sample was filtered through a syringe filter and evaporated to dryness. Compound was dissolved in ethyl acetate and triturated in hexane. Light yellow powder of 2-amino-8-isopropyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)- one (195 mg, 13.7percent yield) was found to be 98percent pure by etaPLC. 1H NMR (400MHz, CDCl3) delta 12.97 (br s, I H), 8.35 (s, IH), 7.60 (br s, IH), 7.21 (s, 2H), 6.94 (s, IH), 5.86 (br s, IH), 2.50 (m, 6H), 1.54 (s, 3H), MS (EI) for C14H16N6O: 285.0 (MH+). |
13.7% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; | Synthesis 6; [00268] In a 350 mL pressure tube 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one (1.50 g, 5.05 mmol), lH-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol), K2CO3 (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium (0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H2O. The tube was sealed, heated to 100 0C and allowed to react overnight. A color change was observed. LCMS indicated no presence of starting material. The sample was filtered through a syringe filter and evaporated to dryness. The compound was dissolved in ethyl acetate and triturated in hexane. Light yellow powder of 2-amino-8-isopropyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 13.7percent yield) was found to be 98percent pure by etaPLC. 1H NMR (400MHz, CDCl3) delta 12.97 (br s, IH), 8.35 (s, IH), 7.60 (br s, IH), 7.21 (s, 2H), 6.94 (s, 1eta), 5.86 (br s, 1eta), 2.50 (m, 6eta), 1.54 (s, 3H), MS (EI) for Ci4Hi6N6O: 285.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 0.25h;Microwave irradiation; | Example 4.4; (RS)-N-(ethoxycarbonyl)-S-(4-[4-[(R)-2-(hydroxy-1-methylethyl]amino}-5-(5- pyrazol)pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide; <n="226"/>(RSJ-N-CethoxycarbonyO-S-C^K-^R^^hydroxy-i-methylethyllamino^delta-iodo- pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide (80 mg, 0.15 mmol), 1 H-pyrazol-5-yl-boronic acid (24.5 mg, 0.22 mmol), toluene (1.6 ml), ethanol (1.6 ml), palladium tetrakistriphenylphosphine (10.7 mg, 0.01 mmol) and sodium carbonate (0.3 ml, 1 M). are filled into a microwave tube and reacted under nitrogen for 15 mins at 120 0C. For the work-up, the reaction mixture is poured into dilute sodium carbonate solution and extracted with ethyl acetate (3x). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated under vacuum. After chromatographic purification, 30 mg (42percent) of the desired product are obtained.1H-NMR (DMSO): 12.99 (s, 1 H), 9.76 (s, 1 H), 8,78 (d, 1 H), 8,47 (s, 1 H), 8.05 (d, 2H), 7.78 (m, 3H), 6.79 (m, 1 H), 4.89 (t, 1 H), 4.31 (m, 1 H), 3.89 (m, 2H), 3.52 (m, 2H), 3.38 (s, 3H), 1.24 (2s, 3H), 1.07 (t, 3H). MS: 460 (MH+). |
42% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 120℃; for 0.25h;Microwave irradiation; | (RS)-N-(ethoxycarbonyl)-S-(4-[4-[(R)-2-(hydroxy-1-methylethyl]amino}-5-iodo-pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide (80 mg, 0.15 mmol), <strong>[376584-63-3]1H-pyrazol-5-yl-boronic acid</strong> (24.5 mg, 0.22 mmol), toluene (1.6 ml), ethanol (1.6 ml), palladium tetrakistriphenylphosphine (10.7 mg, 0.01 mmol) and sodium carbonate (0.3 ml, 1 M). are filled into a microwave tube and reacted under nitrogen for 15 mins at 120° C. For the work-up, the reaction mixture is poured into dilute sodium carbonate solution and extracted with ethyl acetate (3.x.). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated under vacuum. After chromatographic purification, 30 mg (42percent) of the desired product are obtained. 1H-NMR (DMSO): 12.99 (s, 1H), 9.76 (s, 1H), 8,78 (d, 1H), 8,47 (s, 1H), 8.05 (d, 2H), 7.78 (m, 3H), 6.79 (m, 1H), 4.89 (t, 1H), 4.31 (m, 1H), 3.89 (m, 2H), 3.52 (m, 2H), 3.38 (s, 3H), 1.24 (2s, 3H), 1.07 (t, 3H). MS: 460 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 170℃; for 0.333333h;Microwave irradiation; | A mixture of compound 129 (90 mg), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (60 mg), tetrakis(triphenylphosphine)palladium(0) (42 mg), 2M Na2CO3 (0.1 mL), ethanol (0.2 mL) and toluene (0.8 mL) was irradiated with microwaves (170° C., 20 min). Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with HPLC to give the title compound (10 mg) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) delta 0.99 (d, J=6.57 Hz, 6H), 2.16-2.40 (m, 1H), 4.01 (dd, J=7.20, 5.94 Hz, 2H), 6.73 (br. s., 1H), 7.29-7.48 (m, 3H), 7.70 (d, J=7.33 Hz, 1H), 7.79-7.93 (m, 2H). [M+H] calc'd for C14H16N4 241; found, 241. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 2.5h;microwave irradiation; | Example 31: l-[l-AUyl-6-(2H-pyrazol-3-yl)-lH-indol-3-yl]-2,2,2-tripiuoro-l-[l-(4- fluorophenyl)-lH-indazol-5-yl]ethanol; In a 10 mL microwave tube charged with 100.0 mg (0.18 mmol) of l-(l-allyl-6-bromo-lH- indol-3-yl)-2,2,2-trifluoro-l -[I -(4-fluorophenyl)- lH-indazol-5-yl]ethanol, 40.3 mg (0.36 mmol) of lH-pyrazole-5-boronic acid, 57.0 mg (0.53 mmol) of sodium carbonate, 23.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium, and 4 mL DMF was stirred in the microwave at 1200C for 2.5 hours. The mixture was then cooled to room temperature, quenched with saturated ammonia chloride solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes (30-80percent gradient). The major fractions were combined and concentrated in vacuo to afford 35.0 mg (36percent) of the title compound. MS m/z 532.5 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 130℃; for 1h;Microwave; | To a solution of 9-bromo-6-[(lR)-2-methyl-l-(trifluoromethyl)propyl]amino}benzo[c]-l,6-naphthyridin-l(2H)-one (33 mg, 0.08 mmol) in DMF (1 mL) and sodium carbonate (0.5 mL, 2.0 M), were added lithium chloride (19.7 mg, 0.464 mg), lH-pyrazol-5-ylboronic acid (17 mg, 0.16 mmol), and palladium tetrakis triphenylphosphine (27 mg). The mixture was degassed with nitrogen and heated in the microwave at 130°C for lhr. The resulting black solution was filtered and purifed by reverse phase HPLC to afford 6-[(lR)-2-methyl-l-(trifluoromethyl)propyl]amino}-9-(lH-pyrazol-5- yl)benzo[c]-l,6-naphthyridin-l(2H)-one. 1H NMR (OOO MHz, CD3OD) delta 10.3 (s, IH), 8.53 (d, IH), 8.16 (d, IH), 7.77 (s, IH), 7.50 (d, IH), 6.95 (s, IH), 6.74 (d, IH), 5.34 (m, IH), 2.43 (m, IH), 1.19 (d, 3H), 1.11 (d, 3H) . LRMS (ESI) calc'd for (C20Hi9F3N5O) [M+H]+, 402.2; found 402.1 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; | To a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (1.0 g, 2.8 mmol) and Hunig's base (600 muL, 3.4 mmol) in tetrahydrofuran (25 mL) was added 5-bromo- 2-methylaniline (600 mg, 3.2 mmol), and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give iV-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2- yl)amino]benzamide (1.0 g, 70percent) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 10.34 (s, IH), 9.77 (s, IH), 8.18 (d, 2), 7.98 (d, 2H), 7.82 (m, 6H), 7.65 (m, 4H), 7.41 (dt, IH), 7.35 (dd, IH), 7.25 (d, IH), 2.24 (s, 3H). MS (EI) for C28H21BrN4O: 511.2 (MH+). [00587] N-[2-methyl-5-(lH-pyrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2- yl)amino]benzamide. A mixture of 7V-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2- yl)amino]benzamide (116 mg, 0.228 mmol), pyrazole-2-boronic acid (218 mg, 1.9 mmol), potassium carbonate (1.4 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 <n="203"/>mmol) in dioxane (2 mL) was heated to 110 °C overnight. The reaction was cooled, concentrated on a rotary evaporator and purified by preparative reverse phase HPLC to give iV-[2-methyl-5-(lH-pyrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (78 mg, 69percent) as a yellow solid. 1H NMR (400 MHz, DMSOd6): delta 10.33 (s, IH), 9.79 (s, IH), 8.18 (d, 2H), 8.02 (d, 2H), 7.86 (m, 3H), 7.80 (m, 3H), 7.70 (s, IH), 7.64 (m, 3H), 7.60 (dd, IH), 7.42 (dt, IH), 7.31 (d, IH), 6.69 (d, IH), 2.50 (s, 3H). MS (EI) for C31H24N6O: 497.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; dimethyl sulfoxide; acetonitrile; at 150℃; for 0.416667h;Microwave irradiation; | Step c - 5-(4-methoxyphenyl)-2-(1 H-pyrazol-5-yl)oxazole-4-carboxamide; <n="141"/>To a mixture of 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxamide (0.025g, 0.07mmol), 1 H-pyrazole-5-boronic acid (0.02Og, 0.18mmol) and [1 ,1'- 6/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.003g, 0.004mmol) in acetonitrile (2ml_) and DMSO (0.5mL) was added a 1M sodium carbonate solution (0.1 ml_, O.immol) and the reaction heated in the microwave at 1500C for 15 minutes. A further portion of [1 ,1'-/?/s(diphenylphosphino)ferrocene]dichloro-palladium(ll) (0.003g, 0.004mmol) was added and the mixture heated at 15O0C for a further 10 minutes in the microwave. The reaction was diluted with EtOAc and washed 1 M sodium carbonate solution. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over MgSO4 and passed through a MP-SH resin cartridge (500mg). The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-(1 H-pyrazol-5-yl)oxazole-4- carboxamide (0.008g, 0.03mmol, 38percent) as a white solid. 1H NMR (DMSO) delta 3.84 (3H, s), 6.90 (1H, br. d), 7.09 (2H, d), 7.62 (1H, br. s), 7.67 (1H, br. s), 7.97 (1H, br. s), 8.27 (2H, br. d), 13.50 (1 H, br. s). LCMS (2) Rt: 1.98min; m/z (ES+) 285. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 12h; | [00274] A 10:1 solution of dioxane and water (11 mL) was added to a flask charged with 2-amino-6-bromo-4-methyl-(8-phenylmethyl)pyrido[2,3-<^pyrimidin-7(8H)-one (0.435 g, <n="86"/>1.27 mmol), lH-pyrazole-5-boronic acid (0.284 g, 2.54 mmol), Pd(PPh3)4 (0.073 mg, 0.063 mmol), and K2CO3 (0.527 g, 3.81 mmol). The flask was flushed with nitrogen and fitted with a reflux condenser and heated to 110 °C. After 12 h the reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with water. The aqueous phase was acidified to pH 1.0 and washed with ethyl acetate (100 mL). The organic phases were combined and washed with brine, separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was precipitated with ethyl acetate to give 2-Amino-4- methyl-8-(phenylmethyl)-6-(lH-pyrazol-3-yl)pyrido[2,3-<^pyrimidin-7(8H)-one (0.062 g, 15 percent yield) as a yellow solid: 1H NMR (400 MHz, DMSO-J6): 5 13.10 (bs, IH), 12.93 (bs, IH), 8.47 (s, IH), 7.76 (bs, IH), 7.51 (bs, IH), 7.28 (m, 5H), 6.97 (s, IH), 5.55 (s, 2H), 2.55 (bs, 3H); MS (EI) for C18W16N6O: 333.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 95℃; for 3h; | Example 12-Amino-4-methyl-6-(lH-pyrazol-5-yl)-8-(tetrahydrofuran-3-yl)pyrido[2,3-.pound./]pyrimidin-7(8H)-one[00272] A mixture of 2-amino-6-bromo-4-methyl-8-(tetrahydrofuran-3-yl)pyrido[2,3-(f]pyrimidin-7(SH)-one hydrobromide (100 mg, 0.247 mmol) prepared as described for Intermediate 6(a), lH-pyrazole-5-yl boronic acid (41.4 mg, 0.371 mmol), Pd(dpppf)2 (20.1 mg, 0.0247 mmol), TEA (100 mg, 0.99 mmol), dioxane (0.8mL), and water (0.2 mL) was heated to 95 0C for 3 hours (monitored by LC/MS). Cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the organic layer was dried with Na2SO4. The product 2-amino-4-methyl-6-(lH-pyrazol-5-yl)-8- (tetrahydrofuran-3-yl)pyrido[2,3-^pyrimidin-7(8H)-one {21.1percent, 36percent) was obtained by silica gel column chromatography. 1H NMR (300 MHz, DMSO-d6): delta 13.0 (bs, IH), 8.61 (s, IH), 7.72(s, IH), 7.25 (bd, 2H), 6.92 (S, IH), 6.25 (m, IH), 4.35~4.20(m, IH), 4.05~3.75(m,3H), 2.6(s, 3H), 2.48-2.40 (m,lH), 2.13-2.0 (m, IH). MS (EI) for C15H16N6O2: 313.2 (M+l+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
iV-(2-chloro-6-methylphenyl)-2-(2-methyl-6-(lH-pyrazol-5-yl)pyrimidin-4- ylamino)thiazole-5-carboxamideA mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (38 mg, 0.074 mmol), l//-rhoyrazol-5-ylboronic acid (11 mg, 0.098 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), sodium carbonate (26 mg, 0.25 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 0C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50percent TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 percent TFA in water) and lyophilized to yield the title compound as a slightly yellow fluffy solid.1H-NMR (400 MHz, d6-DMSO) delta 12.22 (br s, IH), 10.00 (s, IH), 8.32 (s, IH), 7.88 (d, J = 2.0 Hz, IH), 7.46 (s, IH), 7.41 (dd, J = 1.6, 7.6 Hz, IH), 7.31-7.25 (m, 2H), 6.91 (d, J= 2.0 Hz, IH), 2.67 (s, 3H), 2.25 (s, 3H); MS (m/z): 426.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100℃; for 0.75h; | Step 3: 9-Bromo-N-r2,6-dichloro-4-('lH-pyrazol-5-vpiphenyl]-l-methoxybenzo|'c1-2,6- naphthyridin-5-amine; To a solution of 9-bromo-N-(2,6-dichloro-4-iodophenyl)-l-methoxybenzo[c]-2,6- naphthyridin-5-amine (500 mg, 0.87 mmol) in DMF (20 mL), was added lH-pyrazol-5-ylboronic acid (107 mg, 0.96 mmol), PdCl2(dppf)-Ceta2Cl2 adduct (142 mg, 0.17 mmol) and sodium carbonate (0.87 mL, 1.74 mmol, 2M in water). The solution was heated to 1000C in the microwave in a sealed tube for 45 min. The reaction was diluted with ethyl acetate:THF (2:1) and extracted with water followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with THF in hexanes( 10-50percent) to afford the title compound. <n="76"/>LRMS (ESI) calc'd for C22H15BrCl2N5O [M+H]+, 513.9; found 514.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; at 80℃; for 4h; | Step 2: 6-{|"2,6-Dichloro-4-(lH-pyrazol-5-yl)phenyllaminolpyridor4,3-cl-l,6- naphthyridin- 10(9HVone To a solution of N-(2,6-dichloro-4-iodophenyl)-10-ethoxypyrido[4,3-c]-l,6- naphthyridin-6-amine (200 mg, 0.40 mmol) were added lH-pyrazol-5-ylboronic acid (48 mg, 0.43 mmol) 2.0 M solution OfNaHCO3 (1 mL) and tetrakis(triphenylphosphine)palladium (0) (90 mg, 0.78 mmol) and the mixture was heated to 8O0C for 4 hr. After cooling to room temperature, the reaction mixture was extracted with EtOAc and water. Column chromatography (100percent Hex to 100percent EtOAc) afforded the cross-coupled product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate;palladium diacetate; In water; acetonitrile; at 100℃; for 5h; | To an argon purged mixture of free riboside 4 (100 mg, 0.35 mM), IH- pyrazole-5-boronic acid (47 mg, 0.42 mM), Na2(COs)2 (111 mg, 1.06 mM) is added a pre-prepared solution of Pd(OAc)2 (4 mg, 0.018 mM) and TPPTS (25 <n="82"/>mg, 0.044 niM) in water/CH3CN (2:1, 3 mL). The reaction mixture is stirred at 100°C for 5 h. After cooling the mixture is neutralized by the addition of aqueous HCl (3M sol.) and purified by reverse phase chromatography affording product 3q (71 mg, 64percent) as amorphous glassy solid. Compound is lyophylized. 1H NMR (600 MHz, DMSO-J6): 3.56 (ddd, IH, Jgem= 11.9, J5-b,oH= 5.7, J5-M'= 4.0, H-5'b); 3.63 (ddd, IH, Jgem= 11.9, J5-a,oH= 5.1, J5-^4-= 4.0, H-5'a); 3.93 (td, IH, J4<,5.= 4.0, J4-,3-= 3.4, H-4'); 4.13 (ddd, IH, J3-,2-= 5.1, J3,0H= 4.9, J3- A-= 3.4, H-3'); 4.45 (td, IK, Jtau,v= JT1OH= 6.2, J2-,3- = 5.1, H-2'); 5.11 (dd, lH, J0H,5- = 5.7, 5.1, OH-5'); 5.19 (d, IH, Joty- 4.9, OH-3') 5.39 (d, IH, JOu,r= 6.2, OHT); 6.24 (d, IH, Jva>= 6.2, H-I '); 7.07 (s, IH, H-4-pyrazolyl); 7.21 (d, IH, J5>6 = 3.5, H-5); 7.86 (d, IH, J6,5 = 3.5, H-6); 7.93 (s, IH, H-3-pyrazolyl); 8.79 (s, IH, H-2); 13.40 (s, IH5 NH). 13C NMR (151 MHz, DMSO-J6): 61.83 (CH2-5'); 70.84 (CH-3'); 74.23 (CH-2'); 85.35 (CH-4'); 86.87 (CH-I '); 102.79 (CH-5); 105.17 (CH-4-pyrazolyl); 114.28 (C-4a); 127.58 (CH-6); 130.02 (CH-3- pyrazolyl); 150.70 (C-5-pyrazolyl); 150.92 (C-4); 151.15 (CH-2); 152.10 (C- 7a);. MS FAB, mlz (rel. percent): 318 (100)[M+H]. HR MS (FAB): calcd for C14H16N5O4 [M+H] 318.1202, found 318.1200. Anal. Calcd for C14H15N5O4-H2O: C, 50.15; H, 5.11; N, 20.89. Found: C, 50.04; H, 4.92; N, 20.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium phosphate tribasic trihydrate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 120℃; for 0.5h;Microwave irradiation; | 6) Synthesis of 4-fluoro-N-[2-oxo-6-(1H-pyrazol-5-yl)- 4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}benzamide N-[6-bromo-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.112 mmol), 1H-pyrazol-5-boronic acid (29 mg, 0.23 mmol), a palladium chloride-1,1-bis (diphenylphosphino)ferrocene complex (18.3 mg, 0.022 mmol) and potassium phosphate trihydrate (60 mg, 0.23 mmol) were suspended in DMF (0.5 mL) and water (0.05 mL), and the mixed solution was stirred at 120°C for 30 minutes under microwave irradiation. After the reaction solution was left to cool, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC, whereby the objective compound (10 mg, 21percent) was obtained as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) delta: 3.97 (1H, d, J = 13.7 Hz), 4.36 (1H, dd, J = 13.7, 6.3 Hz), 6.60 (1H, d, J = 2.4 Hz), 6.88 (1H, d, J = 8.3 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.76-7.62 (6H, m), 8.58-8.60 (1H, br m), 9.71 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.416667h;Inert atmosphere; microwave reactor; | {1-[4-(7-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]- cyclobutylj-carbamic acid te/t-butyl ester (81 mg, 0.15 mmol), 1 H-pyrazole-5-boronic acid (22 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol) and sodium carbonate (32 mg, 0.30 mmol) were suspended in DME (2 mL) and water (1 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150°C for 25 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was subjected to flashchromatography (Si02, 40percent ethyl acetate in cyclohexane) to give the title compound as a pale brown oil (36 mg, 45percent). LCMS (Method B): RT = 4.82 min, [M+Hf = 534. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 928h;Inert atmosphere; Reflux; | Example 311 -methylethyl [(cis)-1 -acetyl-2-methyl-6-(1 H-pyrazol-5-yl)-1 ,2,3,4-tetrahydro-4- quinolinyljcarbamate1 -Methylethyl ((cis)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61 )(100 mg, 0.271 mmol) was dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 1 H-pyrazol- 5-ylboronic acid (36.4 mg, 0.325 mmol, available from Frontier Scientific) followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90°C. After 21 hours a sample of tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was added to the reaction which was left to stir under nitrogen at the same temperature. Another sample of 1 H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol) was added after 171 hours total reaction time and heating and stirring continued. Another sample of 1 H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol) was added to the mixture after 345 hours. After 391 hours total reaction time the reaction was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter was extracted twice more using EtOAc (2 x 40 mL). Organic fractions were combined, washed (brine (80 mL), dried (sodium sulfate), filtered and evaporated to dryness to give a clear, colourless solid (1 10 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 100percent EtOAc in cyclohexane. Product- containing fractions were evaporated to dryness to give a clear, colourless solid (6 mg). LCMS (Method C): Rt = 0.76, MH+ = 357 | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 391h;Inert atmosphere; | 1-Methylethyl ((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) was dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (36.4 mg, 0.325 mmol, available from Frontier Scientific) followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. After 21 hours a sample of tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was added to the reaction which was left to stir under nitrogen at the same temperature. Another sample of <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (36.4 mg, 0.325 mmol) was added after 171 hours total reaction time and heating and stirring continued. Another sample of <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (36.4 mg, 0.325 mmol) was added to the mixture after 345 hours. After 391 hours total reaction time the reaction was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter was extracted twice more using EtOAc (2.x.40 mL). Organic fractions were combined, washed (brine (80 mL), dried (sodium sulfate), filtered and evaporated to dryness to give a clear, colourless solid (110 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 100percent EtOAc in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (6 mg).LCMS (Method C): Rt=0.76, MH+=357 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.138889h;microwave irradiation; | Example 5; Entry 5, Table 1; 7-(2-C-methyl-beta-D-ribofuranosyl)-5-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; Pd(PPh3)4 (0.1 eq) was added to a 0.1 M solution of 5-iodo-7-(2-C-methyl-beta-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, <strong>[376584-63-3]1H-pyrazole-5-boronic acid</strong> (1.5 eq) and Na2CO3 (2M aq. solution, 15 eq) in dioxane. The reaction mixture was heated at 120° C. for 500 seconds under microwave irradiation and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by preparative RP-HPLC eluting with MeCN/water containing 0.1percent TFA to give the title compound as a solid (65percent). 1H NMR (300 MHz, DMSO-d6) delta 13.14 (s, 1H), 10.65 (bs, 1H), 8.60 (bs, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 7.93 (bs, 1H), 6.63 (bs, 1H), 6.20 (s, 1H), 4.04 (d, J=9.1 Hz, 1H), 3.99-3.87 (m, 2H), 3.75 (m, 1H), 0.78 (s, 3H); MS (ES+) C15H18N6O4 requires: 346, found: 347 [M+H]+. |
65% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.138889h;Microwave irradiation; | General procedure: Pd(PPh3)4 (0.1 equiv) was added to a 0.1 M solution in dioxane of hetroaryl-boronic acid (1.5 equiv), Na2CO3 (2 M aq solution, 15 equiv) and iodide 620 or iodide 19 (vide infra). The reaction mixture was heated at 120 °C for 500 s under microwave irradiation and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by preparative RP-HPLC eluting with MeCN/water containing 0.1percent TFA to give the title compound as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Example 23; Entry 25, Table 1; 1-(2-C-methyl-beta-D-ribofuranosyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(2-C-methyl-beta-D-ribofuranosyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared according to the procedure described in J. Med. Chem. 1993, 36 (22), 3424-3430) was dissolved in a 1:1:1 v/v/v mixture of dioxane/CH3CN/H2O to give a 0.07 M solution. 1H-Pyrazol-5-ylboronic acid (2.0 eq), K2CO3 (2.6 eq), and Pd(PPh3)4 (0.06 eq) were added under argon and the resulting reaction mixture was stirred at reflux for 10 hrs. The mixture was then cooled to RT, diluted with water and extracted several times with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in MeOH to give a 0.07 M solution and 2M aq. NaOH (1.2 eq) was added. After stirring 30 min at RT, the reaction mixture was neutralized by addition of 2M aq. HCl until pH 7 was reached. The title compound was obtained in 28percent yield over 2 steps after HPLC purification; 1H NMR (400 MHz, DMSO-d6): 13.34 (1H, br s), 9.28 (1H, br s), 8.22 (1H, s), 8.05 (1H, br s), 7.96 (1H, d, J=2.4 Hz), 6.75 (1H, d, J=2.4 Hz), 6.18 (1H, s), 5.17 (1H, s), 5.08 (1H, d, J=7.3 Hz), 4.76-4.79 (1H, m), 4.26 (1H, t, J=8.2 Hz), 3.97-4.01 (1H, m), 3.68-3.81 (2H, m), 0.80 (3H, s). MS (ES+) C14H17N7O4 requires: 347, found: 348 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Microwave irradiation; | Sodium carbonate (43.0 mg), 1 H-pyrazole-5-boronic acid (24.8 mg) and bis(triphenylphosphine)palladium(ll) chloride (13.0 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added. The reaction mixture was heated at 120°C for 30 min (microwave). Ethyl acetate (2 ml) was added and the water layer was separated. The organic phase was dried and the solvent evaporated. The residue was chromatographed (0-5percent methanokDCM) and the product further purified by MDAP (formate modifier). The resulting gum was loaded on a 1 g SCX-2 column and washed with ammonia in methanol (2M) to give 2-[(4S)-6-(4-chlorophenyl)-1 -methyl-8-(1 H-pyrazol-5-yl)- 4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-N-ethylacetamide as a brown oil (15.6 mg). LCMS (formate): MH+ 460 / 462, RT 0.80 min Example 5: 2-[(4S)-6-(4-Chlorophenyl)-1 -methyl-8-(1 H-pyrazol-4-yl)-4H- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; toluene; at 80℃; for 2h;Inert atmosphere; | Synthesis of SI 0-5-1. ; S1°-5_1 To a pressure vial was charged with compound S10-4 (20 mg, 0.024 mmol), lH-pyrazole-5-boronic acid (26 mg, 0.12 mmol, 5 eq), dichloro[l,l '- bis(diphenylphosphino)ferrrocene] palladium(II) dichloromethane adduct (1.0 mg, 0.0012 mmol, 0.05 eq), and sodium carbonate (13 mg, 0.12 mmol, 5 eq). The vial was briefly evacuated and filled with N2. Toluene (1 mL), 1,4-dioxane (1 mL), and H2O (0.2 mL) were added. The reaction mixture was heated with an 80°C oil bath for 2 h, cooled to rt, diluted with EtOAc, washed with aqueous phosphate buffer (pH = 7) and brine, dried over Na2S04, and concentrated. Purification of the residue by Biotage flash chromatography gave compound S10-5-1 as a light yellow solid (7.40 g, 31percent): 1H NMR (400 MHz, CDC13) .pound.7.62 (s, 1 H), 7.25-7.52 (m, 11 H), 6.78 (d, J = 1.8 Hz, 1 H ), 5.36 (s, 2 H), 5.21 (d, J= 11.4 Hz, 1 H), 5.16 (d, J= 11.4 Hz, 1 H), 3.99 (d, J= 10.4 Hz, 1 H), 3.51 (dd, J= 4.9, 15.9 Hz, 1 H), 2.98-3.06 (m, 1 H), 2.45- 2.58 (m, 9 H), 2.15 (d, J= 14.6 Hz, 1 H), 0.84 (s, 9 H), 0.28 (s, 3 H), 0.15 (s, 3 H); MS (electrospray) m/ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 2h;microwave irradiation; Inert atmosphere; | Example 195; N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(1 H-pyrazol-5-yl) imidazo 1 ,2-b]pyridazin-3-yl}benzamide; To a mixture of 125 mg (314 mol)4-[6-chloro-8-(isobutylamino)imidazo[1 ,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylb enzamide, which was prepared according to example 194a, 1 1 1 mg (942 muiotatauiotaomicron) 1 H-pyrazol-5-yl boronic acid, 44 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.63 mL of an aqueous 10percent sodiumbicarbonate solution and the mixture was stirred at 120° C for 2 hours under microwave irradiation. Then the mixture was filtered and concentrated and purified by chromatography to give 41 mg of the title compound.1 H-NMR (DMSO-d6): delta= 0.48-0.69 (4H), 0.91 (6H), 2.02 (1 H), 2.39 (3H), 2.82 (1 H), 3.17 (2H), 6.72 (1 H), 6.78 (1 H), 7.39 (1 H), 7.85 (1 H), 8.00 (1 H), 8.10 8.17 (2H), 8.29 (1 H), ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; sodium carbonate;di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium; In water; acetonitrile; at 150℃; for 1.5h;Inert atmosphere; Microwave irradiation; | Example 99Step 13-(1 H-Pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl- 1 H-pyrazolo[4, 3-c]pyridineTo a microwave vial was charged 3-iodo-4-(tetrahydro-2/-/-pyran-4-yloxy)-1 -trityl-1 H- pyrazolo[4,3-c]pyridine (0.100 g, 0.170 mmol) , <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (0.0310 g, 0.238 mmol), potassium acetate (0.0234 g, 0.238 mmol), sodium carbonate (0.0252 g, 0.238 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll) (0.0120 g, 0.017 mmol). Acetonitrile (1.3 mL, 25 mmol) and degassed water (0.4 mL, 20 mmol) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 150 °C under microwave irradiation for 90 minutes. Upon reaction completion, the reaction mixture was filtered through Celite.(R)., washing with EtOAc and concentrated in vacuo dryness to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; hexane; water; at 100℃; for 18h;Inert atmosphere; | A mixture of 4-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole (200 mg, 0.46 mmol), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (100 mg, 0.92 mmol), Pd(dba)2 (40 mg, 0.046 mmol), Cs2CO3 (300 mg, 0.92 mmol) and P(t-Bu)3 (10 wt percent in hexane, 20 mg, 0.092 mmol) in dioxane (20 mL) and water (10 mL), was stirred at 100° C. for 18 h under a nitrogen atmosphere.The reaction mixture was cooled and then concentrated.The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (140 mg 72percent), as a white solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/3) 1H NMR of the major tautomer (300 MHz, DMSO-d6) delta ppm 2.45 (s, 3H), 3.08 (s, 4H), 3.71 (s, 4H), 6.00 (s, 2H), 6.37 (d, 1H, J=7.2 Hz), 6.96 (s, 1H), 7.24-7.72 (m, 6H), 7.83-7.87 (m, 1H), 8.01 (d, 1H, J=7.2 Hz), 8.25 (d, 1H, J=4.2 Hz), 13.24 (br s, 1H); LC-MS: m/e=424 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; hexane; water; at 80℃; for 3h;Inert atmosphere; | A mixture of 4-bromo-1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole (prepared following the same procedure as for Example 21, 250 mg, 0.55 mmol), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (64 mg, 0.57 mmol), Pd(dba)2 (32 mg, 0.055 mmol), Cs2CO3 (358 mg, 1.1 mmol) and P(t-Bu)3 (10 wt percent in hexane, 110 mg, 0.055 mmol) in dioxane (16 mL) and water (8 mL), was stirred at at 80° C. for 3 h under a nitrogen atmosphere.The reaction mixture was cooled and then concentrated.The resulting residue was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the crude product (122 mg).The crude product was purified by Prep-HPLC to the pure product (72 mg, 30percent), as a white solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/3) 1H NMR of the major tautomer (300 MHz, DMSO-d6) delta ppm 2.46 (s, 3H,), 3.12-3.14 (m, 4H), 3.73-3.76 (m, 4H), 5.57 (s, 2H), 6.36 (d, 1H, J=7.8 Hz), 6.97 (s, 1H), 7.20-7.28 (m, 2H), 7.37 (s, 1H), 7.53-7.61 (m, 2H), 13.17 (s, 1H); LC-MS: m/e=442 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; | To 5(24.8 mg, 0.053 mmol) was added <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (14.81 mg, 0.132 mmol), and 1,1'-bis(diphenylphosphino) ferrocene-palladium dichloride (7.75 mg, 10.59 mumol). Then 1,4dioxane was added (1 mL) and lastly aqueous sodium carbonate (2M, 58.3 uL). The reaction mixture was heated at 90 °C overnight. The reaction was cooled to ambient temperature, and the mixture was diluted with DCM and filtered through celite. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (0-5percent MeOH in DCM) to give 6 (NEU-0000260) as a white solid . 1H NMR (500 MHz, d6-DMSO) delta 11.10 (br, 1H), 7.90 (s, 1H), 7.62-7.50 (m, 3H), 7.33 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.63 -6.61 (m, 2H), 6.0 (d, J = 6.5 Hz, 2H), 4.24 (d, J = 18.5 Hz, 1H), 4.08 (dd, J= 11. 5 Hz, J = 4.25Hz, 1H), 4.04 (d, J = 17.5 Hz, 1H), 3.29 (d, J = 4.5 Hz, 1H), 2.98 (dd, J= 15 Hz, J = 11Hz, 1H), 2.85 ( s, 3H). LCMS found 456.01, [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | l-(4,8-Dichloroquinolin-3-yl)ethanone (0.1 g, 0.417 mmol), potassium carbonate (0.173 g, 1.250 mmol), lH-pyrazol-5-ylboronic acid (0.070 g, 0.625 mmol), and PdCi2(dppf)2CH2Cl2 (0.034 g, 0.042 mmol) were combined in 3 mL of anhydrous DMF under an atmosphere of N2. The solution was heated to 80 °C overnight and then cooled to rt and diluted with ethyl acetate. The organic phase was washed with, brine, H20, then with brine again. The organic phase was dried over Na2S04, filtered, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using a gradient of 10percent ethyl acetate/hexane to 60percent ethyl acetate/hexane. The fractions containing the product were combined and concentrated under vacuum to give l-(8-chloro-4-(lH-pyrazol-5-yl)quinolin- 3-yl)ethanone as a clear film. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 9.24 (1 H, s), 8.00 (1 H, dd, J=7.3, 1.2 Hz), 7.96 (1 H, d, J=2.0 Hz), 7.81 (1 H, d, J=2.4 Hz), 7.70 (1 H, dd, J=8.6, 1.2 Hz), 7.57 (1 H, dd, J=8.6, 7.6 Hz), 6.71 (1 H, t, J=2.2 Hz), 1.97 (3 H, s). Mass Spectrum (ESI) m/e = 272.0 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.138889h;Microwave irradiation; | General procedure: Pd(PPh3)4 (0.1 equiv) was added to a 0.1 M solution in dioxane of hetroaryl-boronic acid (1.5 equiv), Na2CO3 (2 M aq solution, 15 equiv) and iodide 620 or iodide 19 (vide infra). The reaction mixture was heated at 120 °C for 500 s under microwave irradiation and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by preparative RP-HPLC eluting with MeCN/water containing 0.1percent TFA to give the title compound as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 2.5h;Microwave irradiation; | Step 2: (7aS,9R,11aS)-11a-Benzyl-9-ethyl-9-hydroxy-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid [2-methyl-6-(2H-pyrazol-3-yl)-pyridin-3-yl]-amide (87, R4=Phenyl, R5=Methyl, R7=(2H-pyrazol-3-yl)(7aS,9R,11aS)-11a-Benzyl-9-ethyl-9-hydroxy-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (6-bromo-2-methyl-pyridin-3-yl)-amide (86, R4=Phenyl, R5=Methyl) (50 mg, 0.091 mmol), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> [Frontier] (20 mg, 0.18 mmol), Na2CO3 (39 mg, 0.37 mmol) and PdCl2(PPh3)2 (13 mg, 0.018 mmol) in a mixture of DME (2 mL), EtOH (0.6 mL) and water (0.8 mL) was added to a microwave vial. The mixture was heated in a CEM microwave at about 150° C. for about 2.5 h (250 psi maximum pressure, 5 min ramp, 300 max watts). The mixture was partitioned between EtOAc (20 mL) and water (15 mL). The organic layer was washed with saturated aqueous NaCl (10 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified on silica gel (4 g) eluting with a gradient of 0-7.5percent MeOH in DCM. The fractions with the desired material were concentrated under reduced pressure to give a glass. The material was dissolved in MeOH (2 mL) then water (12 mL) was added. The mixture was concentrated under reduced pressure to remove MeOH. The mixture was allowed to stand at rt overnight then the solids were collected by filtration to give (7aS,9R,11aS)-11a-benzyl-9-ethyl-9-hydroxy-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid [2-methyl-6-(2H-pyrazol-3-yl)-pyridin-3-yl]-amide (87, R4=Phenyl, R5=Methyl, R7=2H-pyrazol-3-yl (25.1 mg, 51percent); LC/MS, method 2, Rt=2.36 min; MS m/z: 535 (M+H)+; 1H NMR (400 MHz, DMSO-d6) delta 13.35 (s, 0.2H), 12.98 (s, 0.6H), 9.94 (bs, 1H), 7.83-7.77 (m, 4H), 7.57 (dd, J=8.2, 2.2 Hz, 1H), 7.08-7.04 (m, 3H), 6.84-6.80 (m, 2H), 6.61-6.58 (m, 2H), 3.89 (s, 1H), 3.58 (d, J=12.8 Hz, 1H), 3.30-3.27 (m, 1H), 3.01-3.08 (m, 1H), 2.61 (d, J=12.8 Hz, 1H), 2.48 (s, 3H), 2.46-2.40 (m, 1H), 1.94-1.86 (m, 1H), 1.85-1.73 (m, 2H), 1.50-1.66 (m, 2H), 1.41-1.44 (m, 1H), 1.29-1.37 (m, 1H), 1.05-1.28 (m, 5H), 0.71 (t, J=7.4 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 7h;Reflux; | Step b) 4-[5-(2H-Pyrazol-3-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester; 0.2 g of compound of step a), 0.069 g of 1 H-pyrazole-5-boronic acid, 0.03 g of palladium tetrakis(triphenylphosphine), 0.087 g of sodium bicarbonate, 15 ml of DME and 2 ml of water are charged. The mixture is refluxed for 7 hours. The resulting product is filtered through celite and the solvent is evaporated off. 0.23 g of crude product is isolated. The residue is purified by flash chromatography on a Biotage.(R). column, elution being carried out with 7 hexane/3 ethyl acetate. 0.11 g of the title compound is isolated in the form of a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1.5h;Inert atmosphere; | Preparation of compound 39a: 2-(3-(6-Cyclopropylpyrazin-2-yl)-l-tosyl-l/7-indol-5- yl)-5-(l/7-pyrazol-5-yl)-l,3,4-oxadiazoleA brown mixture of 2-bromo-5-(3-(6-cyclopropylpyrazin-2-yl)-l -tosyl-li7-indol-5-yl)- 1,3,4-oxadiazole (48.4 mg, 0.090 mmol), l//-pyrazol-3-ylboronic acid (JW Pharmlab, LLC, Levittown, PA; 30.3 mg, 0.271 mmol), Pd(PPh3)4 (20.85 mg, 0.018 mmol), and potassium carbonate (37.4 mg, 0.271 mmol) in a mixture of dioxane (1.0 mL) and H20 (0.250 mL) was stirred under argon at 100 °C for 1.5 h. The mixture was cooled to RT, concentrated onto silica gel, and purified chromatographically (silica gel, 0-100percent (10percent MeOH-EtOAc)/Hex) to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-l -tosyl-l//-indol-5-yl)- 5-(l//-pyrazol-5-yl)-l ,3,4-oxadiazole (19.6 mg, 0.037 mmol, 42 percent ) as a light-yellow solid: MS (ESI, pos. ion) m/z: 524.2 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With sodium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 100℃; under 103432.0 Torr; for 0.25h;Microwave irradiation; | 1,1 l-Difluoro-13-methyl-2-(trifluoromethylsulfonyloxy)chromeno[4,3,2- gA]phenanthridin-13-ium trifluoromethanesulfonate (53 mg, 0.086 mmol, Example 18), sodium acetate (15 mg, 0.18 mmol, 2.2 equ), lH-pyrazole-5-boronic acid (14 mg, 0.129 mmol, 1.5 equ), tetrakis triphenylphosphine palladium(O) (10 mg, 10 molpercent), 1,2-dimethoxyethane (3.75 mL), and water (1.25 mL) were heated under MW irradiation at 100°C for 15 min. (300W, 2000psi.). The reaction mixture was then evaporated to dryness, and purified by flash chromatography (gradient elution DCM:MeOH 90percent-85percent) to give the title compound as an orange solid (7 mg, 15percent yield).<1/4 (DMSO-i3/4: 13.46 (1H, s), 8.74-8.79 (2H, m), 8.62-8.65 (1H, dd, J=9.9, 2.5), 8.45-8.51 (2H, m), 8.02-8.09 (4H, m), 6.94 (1H, m), 4.70 (3H, d, J=9.7).m/z (ES+): 386.0 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With sodium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; under 10343.2 Torr; for 0.25h;Microwave irradiation; | A mixture of 4,1 l-difluoro-l 3-methyl-2-(trifluoromethylsulfonyloxy)chromeno [4,3,2- g/z]phenanfhridin-13-ium triflate (100 mg, 0.162 mmol, Example 70), lH-pyrazol-5-ylboronic acid (36 mg, 0.32 mmol, 2 equ), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.0213 mmol, 0.13 equ) and sodium acetate (38 mg, 0.469 mmol, 2.9 equ) in 2:1 DME:H20 (1.5 mL) was heated under microwave radiation for 15 min. at 100°C (300W, 200psi, run time 30s, cooling system on). The mixture was concentrated to dryness in vacuo and the crude product was dissolved in DCM:MeOH, absorbed on silica and purified by flash chromatography (gradient elution DCM:MeOH 98percent-96percent-94percent-92percent-90percent) to give the title compound as an orange solid (25 mg, 29percent yield). (DMSO-i3/4: 13.4 (1H, s), 8.73-8.75 (1H, d, J=8.8), 8.51 (1H, s (br)), 8.45-8.49 (1H, dd, J=8.1), 8.40-8.43 (1H, d, J=9.0), 8.28-8.32 (1H, d, J=13.4), 8.05-8.10 (3H, m), 7.99 (1H, m), 7.22 (1H, s (br)), 4.71 (3H).m/z (ES+): 386.0 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; under 5171.62 Torr; for 0.333333h;Microwave irradiation; | l l-Fluoro-13-methyl-2-(trifluoromethylsulfonyloxy)chromeno[4,3,2-g/i]phenanthridin- 13-ium trifluoromethanesulfonate (65 mg, 0.10 mmol, Example 84), sodium acetate (20 mg, 0.24 mmol, 2.2 equ), lH-pyrazol-5-ylboronic acid (18 mg, 0.16 mmol, 1.5 equ), tetrakis triphenylphosphine palladium(O) (11 mg, 10 molpercent), 1,2-dimethoxyethane (3 mL), and water (1 mL) were heated under MW irradiation at 100°C for 20 min. (200W, lOOpsi.). The reaction mixture was then evaporated to dryness, and purified by flash chromatography (gradient elution DCM:MeOH 95percent-90percent) to give the title compound as a red solid (37 mg, 66percent yield).<1/4 (DMSO-d6): 13.31 (1H, s), 8.96-8.98 (1H, d, J= 8.6), 8.77-8.79 (1H, d, J=8.1), 8.65-8.66 (1H, d, J=1.2), 8.41-8.45 (3H, m), 7.98-8.08 (4H, m), 7.19-7.20 (1H, d, J=2.3), 4.74 (3H, s).m/z (ES+): 368.0 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; at 150℃; for 0.25h;Microwave irradiation; | Synthesis of (S)-N* 1 *-[6-methyl-7-(2H-pyrazol-3-yl)-2-pyridin-4-yl-thieno[3,2- d] rimidin-4-yl]-3-phenyl-propane-l,2-diamine [388] A microwave vial was charged with (S)-N* l *-(7-bromo-6-methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl)-3-phenyl-propane-l,2-diamine [300] (50mg, 0.100 mmol), lH-pyrazole-5-boronic acid (13mg, 0.115 mmol), tetrakis (triphenyl phosphine) palladium (11 mg, 0.009 mmol), Na2C03 (2M in water, IotaOmicronOmicronmuIota, 0.2 mmol) and EtOH (2 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then filtered through a plug of silica, washed with methanol and the filtrate was concentrated under reduced pressure. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was purified by preparative HPLC (method B) to yield to the title compound. LCMS method: 4, RT: 3.71 min, MI: 442 [M+l]. 1H NMR (DMSO,300MHz): 8.67 (d,2H), 8.06 (d,2H), 8.30 (d,lH), 7.88 (d,lH), 7.33 (m,5H), 3.88 (m,lH), 3.41 (m,2H), 2.93 (m,2H), 2.83 (s,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A microwave vial was charged with (R)-3-(6-Bromo-7-methyl-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester [BB-35] (lOOmg, 0.200 mmol), lH-pyrazole-5-boronic acid (26mg, 0.23 mmol), tetrakis (triphenyl phosphine) palladium (31 mg, 0.02 mmol), Na2C03 (2M in water, 200mu1, 0.4 mmol) and EtOH (2 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then filtered through a plug of silica, washed with methanol and the filtrate was concentrated under reduced pressure. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was purified by preparative HPLC (method B) to yield to the title compound. LCMS method: 2, RT: 2.43min, MI: 378. 1H NMR (DMSO, 300MHz): 8.28 (dd,lH), 8.73 (dd,2H), 8.35 (dd,2H), 7.95 (d,lH), 4.93 (m,lH), 3.48(m,lH), 3.25 (etaiota,IotaEta), 3.17m,lH), 3.14(m,lH), 2.61 (s,3H), 2.28 (M,1H), 2.05 (m,lH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.333333h;Inert atmosphere; Sealed tube; Microwave irradiation; | Into a microwave vial, 2-bromo-4-(4-methoxybenzylamino)thieno[3,2-c]pyridine-7-carboxamide (0.10 g, 0.25 mmol), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (0.057 g, 0.51 mmol) and sodium carbonate (0.054 g, 0.51 mmol) were added. 1,4-dioxane (2.0 ml) and water (0.5 ml) were added and the vial was purged with N2. Finally, Pd(Ph3P)4 (0.015 g, 0.01 mmol) was added and the vial was sealed. The reaction was allowed to run in the microwave at 150 °C for 20 minutes. After this time, the reaction mixture was diluted with EtOAc and then filtered through celite. The solution was dried over MgSO4, filtered and concentrated. 127 mg of thecrude desired product was isolated for >98percent yield (impurities present) and carried on to the next step with no further purification.LC-MS: [M+1]+ 380 | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 150℃; for 0.333333h;Inert atmosphere; Sealed tube; | Into a microwave vial, 2-bromo-4-(4-methoxybenzylamino)thieno[3,2-c]pyridine-7-carboxamide (0.10 g,0.25 mmol), <strong>[376584-63-3]1H-pyrazol-5-ylboronic acid</strong> (0.057 g, 0.51 mmol) and sodium carbonate (0.054 g, 0.51 mmol) were added. 1,4-dioxane (2.0 ml) and water (0.5 ml) were added and the vial was purged with N2. Finally, Pd(Ph3P)4(0.015 g, 0.01 mmol) was added and the vial was sealed. The reaction was allowed to run in the microwave at 150 °C for 20 minutes. After this time, the reaction mixture was diluted with EtOAc and then filteredt hrough celite. The solution was dried over MgSO4, filtered and concentrated. 127 mg of the crude desired product was isolated for >98percent yield (impurities present) and carried on to the next stepwith no further purification. LC-MS: [M+1]+ 380 Mass: Calculated for C19H17N5O2S, 379.44 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 150℃;Microwave irradiation; Sealed tube; | To a microwave vial containing3-bromo-4-(4-methoxybenzylamino)thieno[3,2-c]pyridine-7-carbonitrile (0.19 g, 0.49 mmol) was added 1H-Pyrazole-5-boronic acid (0.11 g, 0.99 mmol), sodium carbonate (0.11 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.02 mmol) and 4:1 dioxane(1.0 mL): water (0.25 mL) (degassed). The vial was sealed and heated in the microwave at 150 °C for 1 h. After this time, additional 29 mg of tetrakispalladium was added and the reaction was heated in the microwave at 150 °C for 30 minutes. After this time, added 0.11 g of boronic acid (2eq) and heated for 2 h at 120 °C in the microwave reactor. Added 68 mg of tetrakis pd(0) and 11 mg of <strong>[376584-63-3]1H-pyrazole-5-boronic acid</strong> to light green solution and heated in microwave at 150 °C for 20 min. The reaction mixture was filtered through celite and washed with ethyl acetate. The resulting filtrate was diluted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was taken on with no purification. 1H NMR(300 MHz, DMSO-d6) d: ppm 3.72 (s, 2 H); 4.75 (d, 1 H); 6.25 (t, 2 H);6.89 (d2 H); 7.17 - 7.32 (m, 4 H); 7.93 (d, 1 H); 8.16 (s, 1 H); 8.41 (s, 1 H);11.19 (s, 1 H); 13.24 (br. s., 1 H).LC-MS: [M+1]+ 362 | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 150℃; for 0.5h;Sealed tube; | To a microwave vial containing 3-bromo-4-(4-methoxybenzylamino)thieno[3,2-c]pyridine-7-carbonitrile (0.19 g,0.49 mmol) was added 1H-Pyrazole-5-boronic acid (0.11 g,0.99 mmol), sodium carbonate (0.11 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.02 mmol) and 4:1 dioxane (1.0 mL): water (0.25 mL) (degassed). The vial was sealed and heated in the microwave at 150 °C for 1 h. After this time, additional 29 mg of tetrakispalladium was added and the reaction was heated in the microwave at 150 °C for30 minutes. After this time, added 0.11g of boronic acid (2 eq) and heated for 2 h at 120 °C in the microwave reactor. Added 68 mg of tetrakispd(0) and 11 mg of <strong>[376584-63-3]1H-pyrazole-5-boronic acid</strong> to light green solution and heated in microwave at 150 °C for 20 min. The reaction mixture was filtered through celite and washed with ethyl acetate. The resulting filtrate was diluted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was taken on with nopurification. 1HNMR (300 MHz, DMSO-d6) d: ppm 3.72 (s, 2 H); 4.75 (d, 1 H); 6.25 (t, 2 H); 6.89 (d2 H); 7.17 - 7.32 (m, 4 H); 7.93 (d, 1 H); 8.16 (s, 1 H); 8.41 (s, 1 H);11.19 (s, 1 H); 13.24 (br. s., 1 H). LC-MS: [M+1]+ 362 Mass: Calculated for C19H15N5OS, 361.42 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; water; at 150℃; for 0.5h;Microwave irradiation; | 4- [5 -Chloro-8-( 1 H-pyrazol-3 -yl)-2-pyridin-4-yl-pyrido [3 ,4-d]pyrimidin-4-yl] -piperazine- 1-carboxylic acid tert-butyl ester [A076] A mixture of 4-(5,8-Dichloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-l- carboxylic acid tert-butyl ester [A075] (0.07 g, 0.15 mmol), potassium phosphate tribasic [K3PO4 212.27g/mol 21.2g in 100 mL deionised water] (0.3 mL, 0.3 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol), lH-Pyrazole-5-boronic acid (24 mg, 0.21 mmol) and DMA (1 mL) were heated in muwave at 150°C for 30min. Acetic acid (0.52 mL) was added and the mixture was left to stir at rt for 20mins and then the crude product was loaded onto an SCX cartridge and the cartridge was washed with methanol then the product was eleuted with 2M ammonia / methanol. The eluent was concentrated under reduced pressure and the crude reaction mixture was purified by normal phase chromatography (S1O2, ethyl acetate: cyclohexane elution) to give the title compound [A076]: LCMS method: 1, RT:5.62 min, MI 493 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120 - 165℃; for 1h;Inert atmosphere; Sealed tube; Microwave irradiation; | Step 2: 5-(2-Methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine To a stirred suspension of <strong>[376584-63-3](1H-pyrazol-5-yl)boronic acid</strong> (14 mg, 0.139 mmol) and 5-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.127 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (40 mg, 0.380 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 30 minutes, then again at 145° C. Additional catalyst and boronate were added and the mixture was heated for an additional 30 minutes under microwave irradiation at an increased temperature of 160° C. The reaction mixture was diluted with DCM (20 mL), washed with saturated NaHCO3(aq) (10 mL) and the organic phase was separated and concentrated in vacuo to afford the crude product as an oily residue. The crude material was purified by mass directed preparative HPLC under basic conditions (NH4OH midified) to afford the title compound as a white solid (12.5 mg, 23percent yield). LC-MS: Rt 0.81 min; MS m/z 427.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) delta ppm 12.99 (br. s., 1H), 8.12 (d, J=8.08 Hz, 1H), 7.82 (br. s., 1H), 7.60 (s, 1H), 7.54 (d, J=6.06 Hz, 1H), 6.84 (d, J=2.02 Hz, 1H), 4.31-4.41 (m, 1H), 4.01 (s, 3H), 2.99 (s, 3H), 1.61 (dd, J=12.13, 3.54 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in 1 ,4-dioxane: water (4: 1) (15 mL) was added (iH-pyrazol-5-yl)boronic acid (0.188 g, 1.687 mmol), followed by potassium carbonate (0.537 g, 3.894 mmol) and 1 ,1 ' -Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (methanol/dichloromethane = 3/97) to give the titled compound (0.340 g, 70 percent) as a sticky solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; tetrabutylammomium bromide; potassium carbonate; In 1,4-dioxane; water; at 130℃; for 0.75h;Microwave irradiation; | General procedure: General Procedure F: To a stirred suspension of 2-(4-(benzyloxy)-3-bromophenyl)-5-(4-(ethylsulfonyl)piperazin-1- yl)-3H-imidazo[4,5-b]pyridine A131 (51 mg, 0.090 mmol), the desired boronic acid (0.1 1 mmol, 1.1 equiv), PdCI2(PPh3)2 (7 mg, 0.009 mmol, 0.1 equiv) and TBAB (6 mg, 0.009 mmol, 0.1 equiv) in 1 ,4-dioxane:water (3: 1 , 1 mL) was added K2C03 (38 mg, 0.27 mmol, 3 equiv). The reaction mixture was irradiated in the microwave at 130 °C for 45 minutes. Water (3 mL) and EtOAc (10 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (10 mL). The organic layers were combined and dried (Na2S04), filtered and concentrated in vacuo. The crude material was purified by column chromatography (12 g Si02 cartridge, 0-10percent MeOH in DCM) and the fractions containing product were combined and concentrated in vacuo to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; for 16h;Reflux; Inert atmosphere; | A mixture of Example 1 (20 mg, 0.044 mmol), lH-pyrazole-3-boronic acid (30 mg, 0.26 mmol), Pd(dppf)Ci2 (2 mg, 0.003 mmol) and potassium phosphate (126 mg, 0.53 mmol) in dioxane was heated to reflux under nitrogen atmosphere and stirred for 16 hrs. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried, concentrated and the residue purified by Biotage column chromatography to give Example 12 (7.3 mg, 37percent). MS (ESI Found M+l : 448); XH NMR (CD3OD, 300Hz): delta 7.89- 7.86 (m, 2H), 7.79-7.77(d, 1H, J= 6.0 Hz ), 7.75 (s, 1H), 7.65 (s, 1H), 7.52-7.49 (m, 2H), 7.32- 7.30 (d, 1H, J= 6.0 Hz), 6.92 (s, 1H), 6.64-6.63 (d, 1H, J= 1.8 Hz), 1.99 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.5% | With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In ethanol; water; at 85℃; for 1h; | General procedure: Aryl halide, palladium(II) bis(triphenylphosphine) dichloride or (triphenylphosphine) palladium (0.05eq), boronic acid or pinacol ester (1.1 eq) and cesium fluoride (2 eq) were weighed out into a microwave vessel or sealed tube. Ethanol (3 mL/mmol) and water (0.6 mL/mmol) were added. The vessel was capped and heated thermally or in a microwave vessel at 70-100° C. for 1 hour. The reaction mixture wasconcentrated under vacuum and the residue was purified by silica gel columnchromatography to afford the Suzuki coupling product. |
65.5% | With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In ethanol; water; at 85℃;Microwave irradiation; | General procedure: Similar to as described in General Procedure X, <strong>[376584-63-3](1H-pyrazol-5-yl)boronic acid</strong> was reacted with ethyl6-chloro-2- (3- [2- [(3R)-3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl] ethynyl]phenyl)pyrimidine-4-carboxylate to give the title compound (123 mg, 65.5 percent) as orange oil. LC-MS (ES, m/z): 432 [M+H] . Aryl halide, palladium (II) bis(triphenylphosphine) dichloride or tetrakis (triphenylphosphine) palladium (0.OSeq), boronic acid or pinacol ester (1. leq) and cesium fluoride (2eq) were weighed out into a microwave vessel or sealed tube. Ethanol (3 mL/mmol) and water (0.6 mL/mmol) were added. The vessel was capped and heated thermally or in a microwave vessel at 70-400 °C for 1 hour. The reaction mixture was concentrated under vacuum and the residue was purified by silicagel column chromatography to afford the Suzuki coupling product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 90℃; for 18h; | To a solution of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-hi]indole-2(lH)- carboxylate (50 mg, 0.142 mmol) in Dioxane (1 ml) was added (lH-pyrazol-5-yl)boronic acid (23.76 mg, 0.212 mmol), potassium phosphate (90.13 mg, 0.425 mmol), and Pd(dppf)2, DCM (11.64 mg, 14.15 muiotaetaomicron). Mixture was heated to 90 °C for 18h. Solid was filtered and washed with CH3CN.Residue was purified by HPLC to give tert-butyl 8-(lH-pyrazol-5-yl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate. Tert-butyl 8-(lH-pyrazol-5-yl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate was dissolved in DCM with 4M HC1 in dioxane (0.708 ml, 2.831 mmol) added. Reaction was stirred under room temperature for 2h. Solid was filtered and washed with MTBE to give the title compound (9.85 mg). LCMS m/z = 241.0 [M+H]+; NMR (400 MHz, D20) delta 3.29 (t, J = 8.4 Hz, 2H), 3.35-3.38 (m, 2H), 3.60 (t, J = 8.4 Hz, 2H), 3.62-3.65 (m, 2H), 4.38 (s, 2H), 6.78 (d, J = 2.3 Hz, 1H), 7.25-7.31 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.5% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | To a solution of (4S)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (300 mg, 0.947 mmol), <strong>[376584-63-3](1H-pyrazol-5-yl)boronic acid</strong> (127 mg, 1.137 mmol) and K3PO4 (402 mg, 1.894 mmol) in 1,4-dioxane (9 mL), water (3 mL) degassed with argon for 20 min was added X-phos (45.2 mg, 0.095 mmol), tris(dibenzylideneacetone)dipalladium(0) (43.4 mg, 0.047 mmol) again degassed with argon for 10 min. The reaction mixture was stirred at 100 C. for 4 h and cooled to room temperature. The reaction mixture was filtered through celite then the filtrate was diluted with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with water, brine solution, dried over sodium sulfate and evaporated to give crude compound (TLC eluent: 5% MeOH in DCM: Rf-0.3; UV active). The crude compound was purified by column chromatography using 100-200 silica gel mesh and eluted with 2-3% MeOH/DCM to afford pure (4S)-N-(pyrazin-2-yl)-7-(1H-pyrazol-5-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (100 mg, 0.280 mmol, 29.5% yield) as pale yellow solid, LCMS (m/z): 349.2 [M+H]+. 1H NMR (400 MHz, CDCl3): delta 14.58 (s, 1H), 12.8-11.0 (br, 1H), 9.50 (d, J=1.5 Hz, 1H), 8.41 (dd, J=2.6, 1.5 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.97 (d, J=17.7 Hz, 1H), 5.63 (dd, J=6.0, 3.2 Hz, 1H), 3.33-3.14 (m, 3H), 3.03 (dd, J=12.1, 3.3 Hz, 1H), 2.35 (dddd, J=14.0, 9.9, 6.1, 4.1 Hz, 1H), 2.17-2.02 (m, 1H). |
29.5% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | To a solution of (4S)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-l,4-methanopyrido[2,3- £][l,4]diazepine-5(2H)-carboxamide (300 mg, 0.947 mmol), (lH-pyrazol-5-yl)boronic acid (127 mg, 1.137 mmol) and K3P04 (402 mg, 1.894 mmol) in 1,4-dioxane (9 mL), water (3 mL) degassed with argon for 20 min was added X-phos (45.2 mg, 0.095 mmol), tris(dibenzylideneacetone)dipalladium(0) (43.4 mg, 0.047 mmol) again degassed with argon for 10 min. The reaction mixture was stirred at 100 C for 4 h and cooled to room temperature. The reaction mixture was filtered through celite then the filtrate was diluted with water and extracted with EtOAc (3 X 10 mL). The combined organic layers were washed with water, brine solution, dried over sodium sulfate and evaporated to give crude compound (TLC eluent: 5% MeOH in DCM: R/-0.3; UV active). The crude compound was purified by column chromatography using 100-200 silica gel mesh and eluted with 2- 3% MeOH/DCM to afford pure (45)-N-(pyrazin-2-yl)-7-(lH-pyrazol-5-yl)-3,4-dihydro- l,4-methanopyrido[2,3-6][l,4]diazepine-5(2H)-carboxamide (100 mg, 0.280 mmol, 29.5 % yield) as pale yellow solid, LCMS (m/z): 349.2 [M+H]+.1H NMR (400 MHz, CDC13): delta 14.58 (s, 1H), 12.8 - 11.0 (br, 1H), 9.50 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 2.6, 1.5 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 17.7 Hz, 1H), 5.63 (dd, J = 6.0, 3.2 Hz, 1H), 3.33 - 3.14 (m, 3H), 3.03 (dd, J = 12.1, 3.3 Hz, 1H), 2.35 (dddd, J = 14.0, 9.9, 6.1, 4.1 Hz, 1H), 2.17 - 2.02 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In water; acetonitrile; at 130℃; for 0.25h; | General procedure: 7-iodo-2-(pyridin-4-yl)-5-tosyl-5H-pyrrolo[3,2-b]pyrazine (40, 0.08 g, 0.17 mmol), 3-Pyridylboronic acid (0.03 g, 0.24 mmol), 0.01 g of trans-dichlorobis(triphenylphosphine)palladium(II)(0.01 g,0.014 mmol), acetonitrile (0.6 mL) and 1M potassium acetate (0.6 mL) wereplaced in a 10 mL CEM microwave vial. The vial was capped and irradiated in a CEMmicrowave reactor for 15 minutes at 130 °C. Water (2 mL) andethyl acetate (4 mL) were added and the layers were partitioned. The aqueouslayer was extracted with ethyl acetate (2 x 2 mL). The combined organic extractswere washed with saturated sodium chloride (5 mL), dried over MgSO4and concentrated under reduced pressure. The residue was dissolvedin a mixture of tetrahydrofuran (2 mL), methanol (0.5 mL) and 1N NaOH (0.5 mL)and stirred for 2 hours at room temperature. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC toafford 7-(pyridin-3-yl)-2-(pyridin-4-yl)-5H-pyrrolo[3,2-b]pyrazine(22, 7.3 mg, 16percent) as a whitesolid: 1H NMR (400 MHz, DMSO-d6) delta 12.61 (s, 1H), 9.51 (d, J= 1.7 Hz, 1H), 9.10 (s, 1H), 8.75 (d, J = 6.1 Hz, 2H), 8.69 ? 8.65 (m,2H), 8.47 (dd, J = 4.7, 1.5 Hz, 1H), 8.22 (d, J = 6.1 Hz, 2H),7.50 (dd, J = 7.9, 4.7 Hz, 1H); ESMS m/z274.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 18h; | 3-Bromo-5-morpholino-4-oxa-1thia-7indenone (Compound 126) (48 mg, 0.15 mmol), <strong>[376584-63-3]1H-pyrazole-5-boronic acid</strong> (21 mg, 0.18 mmol), Pd[PPh3]4 (20 mg., 0.015 mmol) were taken into a mixture of toluene (0.8 mL), H2O/EtOH 1:1 (0.9 mL) under stirring and heated to 80° C. for 18 hours. Then the reaction mixture was cooled and diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with water, dried (Na2SO4), filtered and concentrated to yield a eluting solid product (40 mg). The crude was perused by preparative TLC plate on silica gel, eluting with 30:70 v/v ethyl acetate: CH2Cl2 yielding (8 mg, 0.026 mmol. 18percent) of the final compound 129. HPLC (254 nm)-Rt 0.65 min. MS (ESI) mo/z 304.1 [M+H]+Purity=>95percent by UV (254 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate monohydrate; In 1,4-dioxane; water; at 85℃; for 5.5h;Inert atmosphere; | To flask containing 7 (250 mg, 0.369 mmol) was added <strong>[376584-63-3]1H-pyrazole-5-boronic acid</strong> (49.6 mg, 0.443 mmol), Na2CO3·H2O (137.0 mg, 1.11 mmol) and Pd(PPh3)4 (12.8 mg, 0.011 mmol). The mixture was diluted with 1,4-dioxane (4.0 mL) and H2O (1.0 mL), then was flushed with N2 and was heated to 85 °C for 5.5 h. The mixture was cooled to rt and stirred overnight. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-20percent EtOAc/hexanes with 0.1percent NH4OH added to the mobile phase. The fractions containing the product were combined and concentrated under reduced pressure to give 10 as a white foam (134.0 mg, 61percent). LCMS: m/e 595.2 (M + H)+, 2.60 min (method 10). 1H NMR (500 MHz, CDCl3) delta 7.50 (d, J = 1.8 Hz, 1H), 7.40-7.29 (m, 5H), 6.20 (d, J = 1.8 Hz, 1H), 5.74-5.70 (m, 1H), 5.17 (d, J = 12.5 Hz, 1H), 5.10 (d, J = 12.5 Hz, 1H), 4.74 (d, J = 1.5 Hz, 1H), 4.61 (s, 1H), 3.04 (td, J = 10.8, 4.6 Hz, 1H), 2.32-2.19 (m, 2H), 2.14 (dd, J = 17.5, 6.6 Hz, 1H), 1.95-1.81 (m, 2H), 1.76-0.86 (m, 17H), 1.70 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.91 (s, 3H), 0.82 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Example 185 2-('7-Hvdroxy-5-oxo-9-('lH-pyrazol-5-yl -3-('4-('trifluoromethyl phenyl -3,5-dihvdro-2H- [1.41oxazino[2.3.4-ij1quinoline-6-carboxamido)acetic acid A microwave vial was charged with Intermediate 2 (50 mg, 0.086 mmol), (lH-pyrazol-5- yl)boronic acid (14.39 mg, 0.129 mmol) and a2C03 (0.129 mL, 0.257 mmol). This mixture was evacuated and backfilled with 2 (3 times). DMF (1 mL) was added and the mixture was heated via microave at 100 °C for 30 min. The mixture was cooled, diluted with ethyl acetate (5 mL), and washed with satuated aqueous ammonium chloride and brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane (10-50percent) to give tert-butyl 2-(7- hydroxy-5-oxo-9-(lH-pyrazol-5-yl)-3-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H- [l,4]oxazino[2,3,4-ij]quinoline-6-carboxamido)acetate. To this lBu ester in 1 ml DCM was added 1 ml TFA. The reaction was stirred at rt for overnight. The reaction mixture was concentrated and the TFA azeotroped off with acetonitrile (x 3). The resulting solid was triturated with hexanes (x 2) to afford the title compound as a solid. LC/MS (m/z): 515 (M+H)+. Human HIF-PHD2 IC50: 12 nM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 15h; | Example 27: aR,2R)- V-r5-(Dimethylsulfamoyl)-l-methyl-lH-pyrazol-4-yll-2-r4-qH- Pyrazol-5-yl)benzoyllcvclohexanecarboxamide Pd(dppf)Cl2*DCM (43 mg, 0.06 mmol), K2C03 (108 mg, 0.78 mmol, 3.00 equiv) and water (1 mL) was added to a solution of (li?,2i?)-2-(4-bromobenzoyl)-N-[5- (dimethylsulfamoyl)-l-methyl-lH-pyrazol-4-yl]cyclohexanecarboxamide (Intermediate 61, 130 mg, 0.26 mmol) and lH-pyrazol-5-ylboronic acid (59 mg, 0.53 mmol) in 1,4- dioxane (10 mL) and the reaction mixture was stirred at 85°C for 15 h. The mixture was diluted with EtOAc and the organic layer was concentrated in vacuum. The residue was purified by preparative TLC (50percent MeOH in DCM) followed by CI 8 column chromatography (20percent MeCN in water) to give the title compound (18.7 mg, 15percent) as a white solid. 1 H NMR (400 MHz, CD3OD) delta 1.72-1.28 (m, 4H), 1.90 (t, 2H), 2.11 (t, 2H), 2.84 (s, 6H), 2.96 (t, 1H), 3.79 (t, 1H), 4.01 (s, 3H), 6.80 (s, 1H), 7.72 (s, 1H), 7.99-7.89 (m, 3H), 8.06 (d, 2H) MS m/z 485 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 1.5h;Inert atmosphere; | Intermediate 74: 4-[({(lR,6R and lS,65)-6-[2-Chloro-4-(lH-pyrazol-5-yl)benzoyl]- cyclohex-3-en-l-yl}carbonyl)amino -l-methyl-lH-pyrazole-5-carboxamide (±)-trans 4-([(lR,6R and l£6S)-6-(4-Bromo-2-chlorobenzoyl)cyclohex-3-en-l- yl]carbonyl}amino)-l-methyl-lH-pyrazole-5-carboxamide (Intermediate 73, 230 mg, 0.49 mmol), lH-pyrazol-5-ylboronic acid (1 12 mg, 1 mmol), K2CO3 (140 mg, 1.01 mmol) and Pd(dtbpf)Cb (20 mg, 0.03 mmol) were suspended in a mixture of dioxane (8 ml) and water (2 mL). The reaction vessel was evacuated and purged with nitrogen (g) and then heated at 90°C for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOH (50 mL). NaHC03 (sat., aq) was added until pH 8 and the reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC on a XBridge CI 8 column (IotaOmicronmuiotaeta, 250x19 ID mm) using a gradient of 5-95percent MeCN in a H20/MeCN/NH3 (95/5/0.2) buffer system as mobile phase to give the title compound (28 mg, 13percent). MS m/z 451.1 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 0.75h;Inert atmosphere; Microwave irradiation; | Intermediate 82: 4-[({(lR,6R or lS,6S)-6-[2-Fluoro-4-(lH-pyrazol-5-yl)benzoyl]- cyclohex-3-en-l-yl}carbonyl)amino]- -methyl-lH-pyrazole-5-carboxamide (-)-trans or (+)-trans Pd(dtbpf)Cl2 (20 mg, 0.03 mmol) was added to a mixture of 4-([(lR,6R or 15,6S)-6-(4- bromo-2-fluorobenzoyl)cyclohex-3-en- 1 -yljcarbonyl} amino)- 1 -methyl-lH-pyrazole-5- carboxamide (Intermediate 81, 140 mg, 0.31 mmol), lH-pyrazol-5-ylboronic acid (70 mg, 0.63 mmol), K2C03 (170 mg, 1.23 mmol) in dioxane (2.5 mL) and water (1.2 mL). The reaction mixture was purged with nitrogen (g) and then heated in a microwave reactor at 80°C for 45 min. NaHC03 (sat., aq) was added to the reaction mixture and the mixture was extracted with EtOAc. The organic phase was dried using a phase separator, concentrated in vacuo and the crude product was purified by preparative HPLC on a XBridge CI 8 column (IotaOmicronmualphaiota, 250x19 ID mm) using a gradient of 20-65percent MeCN in a H20/MeCN/NH3 (95/5/0.2) buffer system as mobile phase to give the title compound (52 mg, 38percent). MS m/z 435.2 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; Microwave irradiation; | Example 42: l-Ethyl-4-r({qR,2R and lS.2S)-2-r4-qH-pyrazol-5-yl)benzoyll- cvclohexyl}carbonyl)aminol-lH-pyrazole-3-carboxamide A solution of K2CO3 (147 mg, 1.06 mmol) in degassed water (1.5 mL) was added to a mixture of 4-([(lR,2R and 15',25)-2-(4-bromobenzoyl)cyclohexyl]carbonyl}amino)-l- ethyl-lH-pyrazole-3-carboxamide (Intermediate 98, 119 mg, 0.27 mmol), lH-pyrazol-5- ylboronic acid (45 mg, 0.40 mmol) and Pd(dppf)Cl2*DCM (22 mg, 0.03 mmol) in degassed dioxane (1.5 mL), and the reaction mixture was heated in a microwave reactor at 100°C for 1 h. The reaction mixture was partitioned between EtOAc and NaCl (sat., aq) and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC on a Xbridge Prep C18 column (5muiotaeta, 150x19 ID mm) using a gradient of 5-95percent MeCN in a H20/MeCN/NH3 (95/5/0.2) buffer system as mobil phase to give the title compound (39 mg, 34percent). 1H NMR (600 MHz, DMSO) delta 1.13 - 1.25 (m, 1H), 1.31 (t, 3H), 1.43 (t, 1H), 1.51 (t, 2H), 1.79 (dd, 2H), 2.00 (dd, 2H), 2.82 - 2.91 (m, 1H), 3.73 (t, 1H), 4.08 (q, 2H), 6.85 (d, 1H), 7.48 (s, 1H), 7.63 (s, 1H), 7.79 - 8.11 (m, 6H), 9.77 (s, 1H), 13.09 (s, 1H). MS m/z 433.2 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,2-dimethoxyethane; ethanol; water; at 140℃; for 0.25h; | Example 48: (1R,2R and lS,2S)- V-(3-Methyl-l,2-thiazol-5-yl)-2-r4-qH-pyrazol-5- vDbenzoyllcvclohexanecarboxamide (±)-trans A solution of K3PO4 (38 mg, 0.18 mmol) in water (0.2 mL) was added to a mixture of (IR,2R and lS,2S)-2-(4-bromobenzoyl)-N-(3 -methyl- l,2-thiazol-5- yl)cyclohexanecarboxamide (Intermediate 100, 24 mg, 0.06 mmol), lH-pyrazol-5- ylboronic acid (7 mg, 0.06 mmol), and Pd(dppf)Cl2 (5 mg, 5.89 muiotaetaomicron) in a mixture of DME (0.6 mL) and EtOH (0.2 mL) and the reaction mixture was heated at 140°C for 15 min. The reaction mixture was diluted with EtOAc and the organic phase was extracted with water, dried using a phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC on a Xbridge Prep CI 8 OBD column (5muiotaeta, 150x19 ID mm) using a gradient of 5-95percent MeCN in a H2O/NH3 (100/0.2, pHIO) buffer system as mobile phase to give the titel compound (8 mg, 35percent). ^ NMR ^OO MHz, DMSO) 5 1.1 - 1.3 (m, 1H), 1.3 - 1.44 (m, 1H), 1.44 - 1.64 (m, 2H), 1.78 (d, 1H), 1.86 (d, 1H), 1.97 - 2.12 (m, 2H), 2.29 (s, 3H), 2.84 - 3.04 (m, 1H), 3.81 (s, 1H), 6.69 (s, 1H), 6.86 (d, 1H), 7.73 - 8.15 (m, 5H), 11.96 (s, 1H), 13.10 (s, 1H). MS m/z 395.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; water; at 140℃; for 0.25h; | Example 49: (1R,2R and lS,lS)- V-(4-Cvano-3-methyl-l,2-thiazol-5-yl)-2-r4-aH- pyrazol-S-vDbenzoyllcvclohexanecarboxamide (±)-trans A solution of K3PO4 (74 mg, 0.35 mmol) in water (0.3 mL) was added to a mixture of (1R,2R and 1 S, 15)-2-(4-bromobenzoyl)-N-(4-cyano-3 -methyl- l,2-thiazol-5- yl)cyclohexanecarboxamide (Intermediate 101, 51 mg, 0.12 mmol), lH-pyrazol-5- ylboronic acid (13 mg, 0.12 mmol), and Pd(dppf)C *DCM (10 mg, 0.01 mmol) in a mixture of DME (1 mL) and EtOH (0.3 mL) and the reaction mixture was heated at 140°C for 15 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with water, dried using a phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC on a Xbridge Prep CI 8 OBD column (5muiotaeta, 150x19 ID mm) using a gradient of 5-95percent MeCN in a H2O/NH3 (100/0.2, pHIO) buffer system as mobile phase to give the title compound (14 mg, 29percent). ^ NMR ^OO MHz, DMSO) delta 1.15 - 1.24 (m, 1H), 1.28 - 1.39 (m, 1H), 1.46 (d, 1H), 1.59 (d, 1H), 1.78 (s, 1H), 1.87 (d, 1H), 2.05 (s, 1H), 2.12 (d, 1H), 2.41 (s, 3H), 3.21 (s, 1H), 3.84 (s, 1H), 6.86 (d, 1H), 7.76 - 8.2 (m, 5H), 12.83 (s, 1H), 13.10 (s, 1H). MS m/z 420.1 [M+]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45 mg | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 140℃; for 0.25h;Microwave irradiation; | Step2: (\R2R and \S2S)-N-(5-Cyc\ovvom\-\ -methyl- \H-\, 2,3-triazol-4-viy2-r4-(lH- pyrazol-5-yl)benzovHcvclohexanecarboxamide lH-Pyrazol-5-ylboronic acid (35.8 mg, 0.32 mmol), and Pd(dppf)Cl2*DCM (25.9 mg, 0.03 mmol) were added to a mixture of (\R,2R and 15',2i?)-2-(4-bromobenzoyl)-N-(5- cyclopropyl-1 -methyl- lH-1, 2, 3-triazol-4-yl)cyclohexanecarboxamide (Example 33 Step 1, 138 mg, 0.32 mmol) in DME (2.4 mL) and water (0.8 mL). A solution of K3P04 (204 mg, 0.96 mmol) in water (0.90 mL) was added to the reaction mixture and it was heated in a microwave reactor at 140°C for 15 min. The reaction mixture was diluted with EtOAc and the organic phase was extracted with water, dried using a phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC on a Xbridge CI 8 column (5um, 150x19 ID mm) using a gradient of 5-95percent MeCN in a H20/MeCN/NH3 (95/5/0.2, pHIO) buffer system as mobile phase to give the title compound (45 mg, 33percent). NMR (600 MHz, DMSO) delta 0.56 (tt, 2H), 0.67 - 0.79 (m, 2H), 1.13 - 1.24 (m, 1H), 1.37 (t, 1H), 1.45 - 1.58 (m, 2H), 1.61 (tt, 1H), 1.78 (d, 1H), 1.87 (d, 1H), 1.96 (d, 1H), 2.17 (d, 1H), 2.88 - 2.96 (m, 1H), 3.74 (t, 1H), 3.92 (s, 3H), 6.84 (d, 1H), 7.84 (s, 1H), 7.96 (d, major rotamer),7.97 - 8.97 (m, minor rotamer), 8.03 (d, 2H), 9.70 (s, 1H), 13.08 (s, major rotamer), 13.5 (s, minor rotamer). Mixture of rotamers in ratio major:minor 1 :0.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; water; at 140℃; for 0.5h; | Step 2: (\R2R and l£25VN-(3-Methyl-l,2-oxazol-5-ylV2 4-qH-pyrazol-5- yl)benzoyl"|cyclohexanecarboxamide A solution of K3P04 (155 mg, 0.73 mmol) in water (0.6 mL) was added to a mixture of (\R,2R and 1 S, 25)-2-(4-bromobenzoyl)-N-(3 -methyl- l,2-oxazol-5- yl)cyclohexanecarboxamide (Example 44 Step 1, 95 mg, 0.24 mmol), lH-pyrazol-5- ylboronic acid (27 mg, 0.24 mmol) and Pd(dppf)Cl2*DCM (20 mg, 0.02 mmol) in a mixture of DME (1.8 mL) and EtOH (0.6 mL) and the reaction mixture was heated at 140°C for 15 min. lH-Pyrazol-5-ylboronic acid (27 mg, 0.24 mmol) and Pd(dppf)Cl2*DCM (20 mg, 0.02 mmol) were added and the reaction mixture was heated at 140°C for 15 min. The reaction mixture was diluted with EtOAc and the organic layer was washed with water, dried using a phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC on a XBridge CI 8 OBD column (5um, 150x19 ID mm) using a gradient of 10-60percent MeCN in a H2O/NH3 (100/0.2, pHIO) buffer system as mobile phase and then by preparative HPLC on a Sunfire Prep C18 column (5muiotaeta, 150x19 ID mm) using a gradient of 5-95percent MeCN in a HCO2H/H2O (0.1M) buffer system as mobile phase to give the title compound (10 mg, 1 1percent). ^ NMR ^OO MHz, DMSO) delta 1.11 - 1.21 (m, 1H), 1.32 (d, 1H), 1.39 - 1.5 (m, 1H), 1.55 (d, 1H), 1.77 (d, 1H), 1.85 (d, 1H), 2.01 (d, 1H), 2.11 (s, 4H), 2.82 - 2.97 (m, 1H), 3.66 - 3.85 (m, 1H), 5.97 (s, 1H), 6.86 (d, 1H), 8.04 (d, 5H), 11.64 (s, 1H), 13.10 (s, 1H). MS m/z 379.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2.5h;Inert atmosphere; | Step 2: (1R2R and l£25VN-(4-Methyl- -oxazol-2-ylV2 4-qH-pyrazol-5- yl)benzoyl1cyclohexanecarboxamide K2CO3 (113 mg, 0.82 mmol) dissolved in water (1 mL) was added to a mixture of (IR,2R and 15',25)-2-(4-bromobenzoyl)-N-(4-methyl-l,3-oxazol-2-yl)cyclohexanecarboxamide (Example 45 Step 1, 80 mg, 0.20 mmol), lH-pyrazol-5-ylboronic acid (46 mg, 0.41 mmol) and Pd(dppf)Cl2*DCM (13.2 mg, 0.02 mmol) in dioxane (2 mL). The reaction mixture was evacuated and purged with nitrogen (g), and then heated at 80°C for 2.5 h. The reaction mixture was partitioned between EtOAc and NaHCC^ (sat., aq). The organic phase was filtered using a phase separator, concentrated in vacuo, and the crude product was purified by flash chromatography (80percent EtOAc in heptane). The product containing fractions were collected, evaporated and triturated with Et20. The crude product was purified by flash chromatography (80percent EtOAc in heptane) and the product containing fractions were combined and evaporated to dryness and finally triturated with Et20 to give the title compound (21 mg, 28percent). NMR (500 MHz, CDCI3, 28°C) delta 1.15 - 1.38 (m, 2H), 1.38 - 1.57 (m, 1H), 1.77 - 1.94 (m, 3H), 2.07 (d, 5H), 2.92 (d, 1H), 3.69 - 3.87 (m, 1H), 6.69 (d, 1H), 7.09 (s, 1H), 7.65 (d, 1H), 7.86 (d, 2H), 8.02 (d, 2H). MS m/z 377.2 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; water; at 140℃; for 0.25h; | Step 2: (\R2R and ltS,2t^-N-(3-Cvclopropyl-l,2,4-thiadiazol-5-vn-2-r4-(lH-pyrazol-5- yl)benzoyl"|cyclohexanecarboxamide A solution of K3PO4 (204 mg, 0.96 mmol) in water (0.9 mL) was added to a mixture (\R,2R and 15*,25)-2-(4-bromobenzoyl)-N-(3-cyclopropyl- 1 ,2,4-thiadiazol-5- yl)cyclohexanecarboxamide (Example 47 Step 1, 139 mg, 0.32 mmol), lH-pyrazol-5- ylboronic acid (36 mg, 0.32 mmol), and Pd(dppf)C *DCM (26 mg, 0.03 mmol) in a mixture of DME (2.4 mL) and EtOH (0.8 mL) and the reaction mixture was heated at 140°C for 15 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with water, dried using a phase separator and concentrated in vacuo. The crude product was purfied by preparative HPLC on a Xbridge Prep OBD CI 8 column (5muiotaeta, 150x19 ID mm) using a gradient of 5-95percent MeCN in a H20/NH3 (100/0.2, pHIO) buffer system as mobile phase to give the title compound (35 mg, 26percent>). NMR (600 MHz, DMSO) delta 0.85 - 1.05 (m, 4H), 1.09 - 1.24 (m, 1H), 1.32 (d, 1H), 1.39 - 1.51 (m, 1H), 1.81 (dd, 2H), 1.96 - 2.21 (m, 3H), 2.95 - 3.09 (m, 1H), 3.72 - 3.87 (m, 1H), 6.86 (d, 1H), 7.85 (s, 1H), 7.89 - 8.14 (m, 4H), 13.10 (s, 2H). MS m/z 422.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.9% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate I-10 (0.020 g, 0.054 mmol) and <strong>[376584-63-3](1H-pyrazol-5-yl)boronic acid</strong> (6.01 mg, 0.054 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (2.63 mg, 3.22 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.100 mL, 0.300 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90 °C in the microwave for 30 minutes. The reaction mixture was diluted with EtOAc and filtered through a micron filter and concentrated in vacuo. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 30percent to 75percent B in 10 minutes) to yield Example 40 (0.005 g, 0.014 mmol, 25.9 percent yield): 1H NMR (500MHz, METHANOL-d4) delta 8.68 (s, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.18 (s, 1H), 7.86-7.52 (m, 4H), 6.66 (d, J=2.2 Hz, 1H), 2.66 (s, 3H). LC^MS: method H, RT = 1.04 min, MS (ESI) m/z: 360.1 (M+H)+. Analytical HPLC Method B: 100percent purity |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.6% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate I-13 (0.0125 g, 0.036 mmol) and <strong>[376584-63-3](1H-pyrazol-5-yl)boronic acid</strong> (3.99 mg, 0.036 mmol) were dissolved in DMF (1 mL). PdCl2(dppf)-CH2Cl2 adduct (1.749 mg, 2.141 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Na2CO3, 3 M aqueous solution (0.050 mL, 0.150 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90 °C in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 10percent to 45percent B in 10 minutes) to yield Example 48 (0.0032 g, 9.48 mumol, 26.6 percent yield): 1H NMR (500MHz, DMSO-d6) delta 9.11 (s, 1H), 8.70 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 6.80 (s, 1H), 4.82 (s, 2H), 3.48 (s, 3H), 2.67 (s, 3H). LC^MS: method H, RT = 1.10 min, MS (ESI) m/z: 338.3 (M+H)+. Analytical HPLC Method B: 100percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.7% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate I-18 (20.4 mg, 0.053 mmol) and <strong>[376584-63-3](1H-pyrazol-5-yl)boronic acid</strong> (8.87 mg, 0.079 mmol) were dissolved in DMF (528 muL). PdCl2(dppf)-CH2Cl2 (2.59 mg, 3.17 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (31.7 muL, 0.063 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 100 °C in the microwave for 30 minutes. The compound was diluted with DMF and purified by preparative HPLC (Method D, 35 to 75percent B in 10 minutes) to give Example 9 (10.6 mg, 0.028 mmol, 52.7percent): 1H NMR (500MHz, METHANOL-d4) delta 8.65 (s, 1H), 8.55 (s, 1H), 7.74 (s, 1H), 7.68 (br. s., 1H), 7.84-7.49 (m, 1H), 6.59 (br. s., 1H), 2.69 (br. s., 3H), 2.66 (s, 3H); LC^MS: Method H, RT = 1.07 min, MS (ESI) m/z: 374.0 (M+H)+; Analytical HPLC Method B: 98percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In toluene; at 90℃; for 5h;Inert atmosphere; | To a solution of Example 25h (164 mg, 0.43 mmol) in toluene (12 mL) was added Example 39a (73 mg, 0.65 mmol), K3P04 (273 mg, 1.29 mmol), Pd(OAc)2 (22 mg, 0.043 mmol) and Sphos (35 mg, 0.086 mmol). The degassed mixture was stirred at 90°C under N2 for 5 hours. The solvent was evaporated and the residue was purified by prep-TLC (Petroleum ether/EtOAc = 7/2) to give the desired product Example 39b (39.5 mg, yield 25percent) as a yellow solid. MS [M+1]= 370.1. |
Tags: 376584-63-3 synthesis path| 376584-63-3 SDS| 376584-63-3 COA| 376584-63-3 purity| 376584-63-3 application| 376584-63-3 NMR| 376584-63-3 COA| 376584-63-3 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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