Structure of 376584-63-3
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CAS No. : | 376584-63-3 |
Formula : | C3H5BN2O2 |
M.W : | 111.90 |
SMILES Code : | OB(C1=NNC=C1)O |
MDL No. : | MFCD02020768 |
InChI Key : | NEUWPDLMDVINSN-UHFFFAOYSA-N |
Pubchem ID : | 11251979 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from |
69.14 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.84 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-2.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-1.27 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-1.25 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.4 |
Solubility | 44.4 mg/ml ; 0.397 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.13 |
Solubility | 82.7 mg/ml ; 0.739 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.07 |
Solubility | 96.1 mg/ml ; 0.859 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.58 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.1 |
* 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 5h; | 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 |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 12h;Product distribution / selectivity; | [00276] Using the same or analogous synthetic techniques and substituting with appropriate reagents, the following intermediates were prepared: |
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 |
---|---|---|
82% | An argon purged mixture of 7-iodotubericidine 1 (392 mg, 1 mmol), pyrazole-5- boronic acid (224 mg, 2 mmol), Na2CO3 (318 mg, 3 mmol), Pd(OAc)2 (11 mg, 0.05 mmol) and TPPTS (71 mg, 0.125 mmol) in water/MeCN (2:1, 5 ml) was stirred at 100 °C for 18 h. After cooling the mixture was neutralized by the addition of aq HCl (IM) and desalted by reverse phase chromatography (0-100percent MeOH in water) and re-purified by column chromatography on silica (8percent MeOH in CHCl3) affording title compound 2n as white glassy solid (273 mg, 82percent). White solid after recrystallization from boiling water. Mp 135 °C. 1H NMR (500 MHz, DMSO-^6): 3.55 (ddd, IH, Jgem = 12.1, J5-b,oH = 6.4, J5-M.bul. = 4.1, H-5'b); 3.66 (ddd, lH, Jgem= 12.1, J5 a,oH = 5.0, J5 a,4 = 3.9, H-5'a); 3.90 (ddd, lH, J4-,5- = 4.1, 3.9, J4-,3- = 3.2, H-4'); 4.11 (ddd, lH, J3-,2- = 5.2, J3-,2-= 4.8, J3-,4- = 3.2, H-3'); 4.44 (ddd, 1H, J2-,OH = 6.4, J2-J- = 6.3, J2-,3 = 5.2, H-2'); 6.04 (d, IH, J1 -;2- = 6.1, H-I '); 6.66 (dd, IH, J4,5 = 2.4, J4jNH = 1.9, H-4-pyrazole); 7.25 (bs, IH, NHaHb); 7.81 (dd, IH, J5,4 = 2.4, J5>;NH = 1.5, H-5-pyrazole); 7.86 (s, IH, H-6); 8.04 (s, IH, H-2); 9.24 (bs, IH, NHaHb); 12.88 (bs, IH, NH).13C NMR (125.7 MHz, DMSO-^6): 61.98 (CH2-5'); 70.76 (CH-3'); 73.75 (CH-2'); 85.27 (CH-4'); 87.32 (CH-I'); 100.36 (C-4a); 101.91 (CH-4-pyrazole); 109.76 (C-5); 120.64 (CH-6); 130.20 (CH-5-pyrazole); 146.26 (C-3-pyrazole); 151.02 (C-7a); 152.44 (CH-2); 158.47 (C-4). IR(KBr): 3411, 3290, 3136, 2665, 1633, 1597, 1576, 1550, 1474, 1301, 1138, 1109, 1082, 1050, 1019, 934, 798, 765, 651. MS (ESI): m/z 333 (M+H), 355 (M+Na). HRMS (ESI) for C14HnN6O4 [M+H] calcd: 333.1306; found: 333.1306. Anal. Calcd for Ci4Hi6N6O4-1.85H2O: C, 45.99; H, 5.43; N, 22.98. Found: C, 46.22; H, 5.44; N, 22.68. |
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 |
---|---|---|
19% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2h;Inert atmosphere; Reflux; Sealed vessel; | 2-Bromo-3-fluorobenzonitrile (1 .0 g, 5.0 mmol) and (1 H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml_) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3) (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. Cooled to 23 °C filtered and solid rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure.Chromatography (0-30percent ethyl acatate / hexanes) afforded 3-fluoro-2-(1 H- pyrazol-5-yl)benzonitrile (178 mg,19percent). |
19% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2h;Inert atmosphere; Reflux; | Intermediate 83: 3-Fluoro-2-(1 H-pyrazol-5-yl)benzoic acid.Method A:Step A: 2-Bromo-3-fluorobenzonitrile (1 .0 g, 5.0 mmol) and (1 H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHC03 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction was then cooled to 23 °C filtered and the solids were rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30percent ethyl acatate / hexanes) afforded 3-fluoro-2-(1 H-pyrazol-5-yl)benzonitrile (178 mg,19percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2h;Inert atmosphere; Reflux; Sealed vessel; | Methyl 2-bromo-5-fluorobenzoate (1 .0 gram, 4.2 mmol) and (1 H- pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHCO3 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3) (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23 °C, filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acatate/hexanes, 0-30percent) afforded methyl 5-fluoro-2-(1 H-pyrazol-5-yl)benzoate (415 mg, 44percent). |
44% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2.16667h;Inert atmosphere; Reflux; | Methyl 2-bromo-5-fluorobenzoate (1 .0 g, 4.2 mmol) and (1 H- pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHCO3 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23 oC, filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acatate/hexanes, 0-30percent) afforded methyl 5-fluoro-2-(1 H-pyrazol-5-yl)benzoate (415 mg, 44percent). |
44% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; for 2h;Inert atmosphere; Reflux; | Step A: Methyl 2-bromo-5-fluorobenzoate (1 .0 g, 4.2 mmol) and (1 H- pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHCO3 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3) (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23 C, filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acatate/hexanes, 0-30percent) afforded methyl 5-fluoro-2-(1 H-pyrazol-5-yl)benzoate (415 mg, 44percent). |
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2h;Inert atmosphere; Reflux; | Intermediate 51 : 5-Fluoro-2-(1 H-pyrazol-5-yl)benzoic acid. Step A: Methyl 2-bromo-5-fluorobenzoate (1 .0 g, 4.2 mmol) and (1 H- pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHC03 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23 °C, filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acatate/hexanes, 0-30percent) afforded methyl 5-fluoro-2-(1 H-pyrazol-5-yl)benzoate (415 mg, 44percent). |
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 |
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