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CAS No. : | 227305-69-3 | MDL No. : | MFCD02681979 |
Formula : | C8H9BO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZIXLJHSFAMVHPC-UHFFFAOYSA-N |
M.W : | 163.97 | Pubchem ID : | 2773380 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 45.61 |
TPSA : | 49.69 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) : | -6.71 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.83 |
Log Po/w (WLOGP) : | -0.7 |
Log Po/w (MLOGP) : | -0.06 |
Log Po/w (SILICOS-IT) : | -0.14 |
Consensus Log Po/w : | -0.01 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.68 |
Solubility : | 3.4 mg/ml ; 0.0207 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.46 |
Solubility : | 5.74 mg/ml ; 0.035 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.57 |
Solubility : | 4.41 mg/ml ; 0.0269 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.02 |
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 |
---|---|---|
59% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 80℃; | Synthesis of 3-(2,3-dihydrobenzofuran-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA95); A solution of 2,3-dihydro-1-benzofaran-5-ylboronic acid (38 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of <strong>[862730-04-9]3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine</strong> (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80 C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA95 (15.7 mg, 59% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate; lithium chloride;bis-triphenylphosphine-palladium(II) chloride; In ethanol; water; toluene; for 1.66667h;Heating / reflux; | A mixture of 47 (200 mg, 0.308 MMOL), EtOH (1.5 ML), toluene (1.5 mL), 2,3- dihydrobenzofuran-5-boronic acid (50 mg, 0.308 mmol), 1M aq. NA2C03 (0. 48 ML, 0.48 mmol), LiCl (25 mg, 0.619 mmol) and PDCL2 (PPH3) 2 (15 mg, 0.021 mmol) was refluxed for 1 h 40 min. The reaction mixture was concentrated to afford a pale yellow solid, which was purified by silicagel chromatography using 30% ethyl acetate in hexane as eluent (gradient elution) to give the product 48 (187 mg, 86%) as a pale yellow solid ; 1H NMR (400 MHz, CDC13) S 3.27 (t, J = 17.2, 8.6 Hz, 2H), 4.61 (t, J = 17.4, 8.7 Hz, 2H), 6.86 (d, J = 8.2 Hz, 1H), 7.19-7. 23 (m, 7H), 7.33-7. 36 (m, 10H), 7.45 (t, J= 15.3, 7.26 Hz, 2H), 7.54-7. 58 (m, 1H), 7.65 (s, 1H), 7.74 (s, 1H), 7. 89 (d, J= 2.1 Hz, 1H), 7.97 (s, 1H), 8. 19-8.21 (m, 2H), 8.60 (d, J = 2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 108 2,3-Dihydrobenzofuran-5-ylboronic Acid Obtained as a colourless solid (38%), m.p. >240 C.(decomp.), from <strong>[66826-78-6]5-bromo-2,3-dihydrobenzofuran</strong> (Synthesis, 1988, 952) and trimethyl borate, using the procedure of Preparation 101. delta(DMSOd6): 3.33 (t,2H), 4.48 (t,2H), 6.68 (d,1H), 7.56 (d,1H), 7.63 (s,1H), 7.70 (brs,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With hydrogenchloride; In methanol; 1,2-dimethoxyethane; dichloromethane; water; | A. 3-(2,3-Dihydrobenzo[b]Furan-5-Yl)-1H-Indazole-5-Carbonitrile The title compound was prepared as described in Example 411, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.750 g, 2.45 mmol), in ethylene glycol dimethyl ether (50 mL), 2,3-dihydrobenzo[b]furan-5-boronic acid (0.480 g, 2.9 mmol), [1,l'-bis(diphenylphosphino-ferrocene] complex with dichloromethane (1:1) (0.200 g, 0.20 mmol) and potassium phosphate (5.2 g, 24 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45 C. for 5 h. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven to afford the title compound (0.350 g, 64 % yield over 2 steps): ES-MS (m/z) 262 [M+1]+. |
64% | With hydrogenchloride; In methanol; 1,2-dimethoxyethane; dichloromethane; water; | A. 3-(2.3-Dihydrobenzo[b]furan-5-yl)-1H-indazole-5-carbonitrile The title compound was prepared as described in Example 411, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.750 g, 2.45 mmol), in ethylene glycol dimethyl ether (50 mL), 2,3-dihydrobenzo[b]furan-5-boronic acid (0.480 g, 2.9 mmol), [1,1'-bis(diphenylphosphino-ferrocene] complex with dichloromethane (1:1) (0.200 g, 0.20 mmol) and potassium phosphate (5.2 g, 24 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45 C. for 5 h. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven to afford the title compound (0.350 g, 64% yield over 2 steps): ES-MS (m/z) 262 [M+1]+. |
64% | With hydrogenchloride; In methanol; 1,2-dimethoxyethane; dichloromethane; water; | A. 3-(2,3-Dihydrobenzo[b]furan-5-yl)-1H-indazole-5-carbonitrile The title compound was prepared as described in Example 411, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.750 g, 2.45 mmol), in ethylene glycol dimethyl ether (50 mL), 2,3-dihydrobenzo[b]furan-5-boronic acid (0.480 g, 2.9 mmol), [1,1'-bis(diphenylphosphino-ferrocene] complex with dichloromethane (1:1) (0.200 g, 0.20 mmol) and potassium phosphate (5.2 g, 24 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45 C. for 5 h. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven to afford the title compound (0.350 g, 64% yield over 2 steps): ES-MS (m/z) 262 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 12h; | To a solution of 4' - [ (5-bromo-2-butyl-4-methyl-6- oxopyrimidin-1 (6H) -yl) methyl]biphenyl-2-carbonitrile (0.96 g) and 2, 3-dihydro-l-benzofuran-5-ylboronic acid (0.54 g) in 1,4- dioxane were added 2 M aqueous cesium carbonate solution (4 bis (diphenylphosphino) ferrocene] dichloropalladium (0.09 g) , and the mixture was stirred at 900C for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.75 g, 72%) as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 0.93 (3H, t, J = 7.2), 1.33-1.51 (2H, m) , 1.65-1.81 (2H, m) , 2.24 (3H, s) , 2.74 (2H, t, J = 7.8), 3.24 (2H, t, J = 8.4), 4.59 (2H, t, J = 8.4), 5.38 (2H, s) , 6.83 (IH, d, J = 8.1), 7.05 (IH, d, J = 8.1), 7.19 (IH, s) , 7.34 (2H, d, J = 8.1), 7.40-7.57 (4H, m) , 7.59-7.69 (IH, m) , 7.76 (IH, d, J = 7.8) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 12h; | To a solution of 4' - [ (5-bromo-4-ethyl-6-oxo-2- propylpyrimidin-1 (6H) -yl) methyl]biphenyl-2-carbonitrile (1.0 g) and 2, 3-dihydro-l-benzofuran-5-ylboronic acid (0.56 g) in 1,4-dioxane (20 iriL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (0.09 g) , and the mixture was stirred at 9O0C for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M <n="206"/>hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.95 g, 87%) as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 1.02 (3H, t, J = 7.2), 1.18 (3H, t, J = 7.2), 1.71-1.91 (2H, m) , 2.49 (2H, q, J = 7.2), 2.73 (2H, t, J = 8.1), 3.24 (2H, t, J = 8.4), 4.58 (2H, t, J = 8.4), 5.37 (2H, s), 6.83 (IH, d, J = 8.4), 6.98-7.06 (IH, m) , 7.16 (IH, br), 7.35 (2H, d, J = 8.1), 7.41-7.57 (4H, m) , 7.60-7.68 (IH, m) , 7.76 (IH, d, J = 6.9) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 12h; | To a solution of 4' - [ (5-bromo-2-butyl-4-methyl-6- oxopyrimidin-1 (6H) -yl) methyl] -3' -fluorobiphenyl-2-carbonitrile 25 (0.5 g) and 2, 3-dihydro-l-benzofuran-5-ylboronic acid (0.27 g) in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (0.05 g) , and the mixture was stirred at 900C for 12 hr under an argon 30 atmosphere. The reaction mixture was diluted with ethyl <n="213"/>acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.43 g, 79%) as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 0.94 (3H, t, J = 7.2), 1.35-1.51 (2H, m) , 1.66-1.82 (2H, m) , 2.25 (3H, s) , 2.73 (2H, t, J = 8.1), 3.25 (2H, t, J = 8.7), 4.59 (2H, t, J = 8.7), 5.41 (2H, s) , 6.83 (IH, d, J = 8.1), 7.05 (IH, d, J = &.4), 7.19 (IH, s) , 7.24-7.36 (3H, m) , 7.43-7.53 (2H, m) , 7.61-7.71 (IH, m) , 7.77 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | In acetonitrile; at 20 - 120℃; for 0.333333h; | Intermediate 20: (+/-)-2,3-dihydro-1-benzofuran-5-yl(4-methylpiperazin-1-yl)acetic acid; <n="64"/>To a suspension of 502 mg of <strong>[227305-69-3]2,3-dihydro-1-benzofuran-5-ylboronic acid</strong> (3.06 mmole, ABCR) in 3 ml. of anhydrous MeCN, at RT, under N2, were added 282 mg of glyoxylic acid hydrate (3.06 mmole) and 340 mul_ of 1-methylpiperazine (3.06 mmole). The mixture was subjected to microwave irradiation (12O0C, 20 minutes) and was cooled down to RT. The solvent was evaporated and the dark residue triturated with Et2O until a light brown solid formed. The solid was filtered, rinsed with Et2O and dried under high vacuum. The title compound was obtained as a brown solid (434 mg, 51%); 1H-NMR (DMSO-d6): delta 2.13 (3H, s), 2.20-2.60 (8H, m), 3.18 (2H, t), 3.80 (1 H, s), 4.50 (2H, t), 6.67 (1 H, d), 7.10 (1 H, d), 7.25 (1 H, s); m/z (ES): 277.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | A mixture of N-(7-chloro-2-methylpyrazolo[l,5-a]pyrimidin-5-yl)-4-(2- hydroxypropan-2-yl)benzamide (2F, 0.05 g, 1.0 equivalent), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (2.0 equivalents), and PdCl2(dppf)/DCM (0.10 equivalent) in 2N Na2CO3 (0.3 M), dioxane (0.1M) and DMF (0.5M) was heated at 120 0C for 10 minutes in the microwave. After cooling to room temperature, the mixture was added water and EtOAc; and extracted with EtOAc twice and the combined organic layers were dried over Na2SO4. The solvent was removed in vacuo and the crude mixture was purified by preparatory HPLC (40-55% ACN/water, TFA mode) to afford the TFA salt of the titled compound 224 (35%) as a yellow solid. 1H NMR (400 MHz, DMSO-J6) delta ppm 1.46 (s, 6 H) 2.41 (s, 3 H) 3.29 - 3.33 (m, 2 H) 4.67 (t, J=8.72 Hz, 2 H) 5.19 (s, 1 H) 6.36 (s, 1 H) 7.00 (d, J=8.59 Hz, 1 H) 7.61 (d, J=8.59 Hz, 2 H) 7.91 - 7.97 (m, 2 H) 7.97 - 8.05 (m, 3 H) 11.13 (s, 1 H); ESI-MS: m/z 429.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.333333h;Microwave irradiation; | A suspension of N-(7-chloropyrazolo[l,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2- yl)benzamide (2D, 50 mg, 151 mmol), ,3-dihydrobenzofuran-5-ylboronic acid (50 mg, 305 mmol), and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 mumol) in 2:1 1 ,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1 ,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110 0C for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 45-70% (MeCNZH2O gradient + 0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (16.8 mg, 27%). Melting point (174.2.0-184.3 0C). 1HNMR (400 MHz, DMSO-J6) delta ppm 1.46 (s, 6 H) 3.32 (t, J=8.59 Hz, 2 H) 4.67 (t, J=8.72 Hz, 2 H) 6.56 (d, J=2.27 Hz, 1 H) 7.01 (d, J=8.59 Hz, 1 H) 7.62 (d, J=8.34 Hz, 2 H) 7.95 (dd, J=8.46, 1.64 Hz, 1 H) 8.00 - 8.08 (m, 4 H) 8.19 (d, J=2.02 Hz, 1 H) 11.20 (s, 1 H). ESI-MS: m/z 415.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; at 80℃; for 12.5h;Inert atmosphere; | Intermediate 107 3-(2,3-dihydrobenzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.70 g, 2.68 mmoles) in DMF (10 ml), ethanol (6 ml) and water (6 ml), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (0.527 g, 3.21 mmoles) and sodium carbonate (0.852 g, 8.04 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.610 g, 0.528 mmoles) was added under nitrogen atmosphere and heated to 80 C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.198 g, 29% yield 1H-NMR (delta ppm, DMSO-d6, 400 MHz): delta 13.42 (s, 1H), 8.18 (s, 1H), 7.48 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 4.61 (d, J=8.7 Hz, 2H), 3.27 (d, J=8.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux; Inert atmosphere; | 6-bromo-l -ethyl-9H-pyrido[3,4-b]indole (Intermediate 12; 0.38 mmol, 105 mg), 2,3- dihydrobenzofuran-5-ylboronic acid (191 mg, 1.16 mmol), potassium carbonate (257 mg, 1.88 mmol) and tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) were stirred in a mixture of dioxane (25 mL) and water (1 mL) for two hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C 18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a CI 8-column eluting with a gradient of water and acetonitrile (with 0.1% formic acid). Pure fractions were combined and adjusted to pH>9 with ammonia. The resulting precipitate was filtered, washed with water and dried to give 25 mg of E37. | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux; Inert atmosphere; | 6-bromo-1-ethyl-9H-pyrido[3,4-b]indole (Intermediate I2; 0.38 mmol, 105 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (191 mg, 1.16 mmol), potassium carbonate (257 mg, 1.88 mmol) and tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) were stirred in a mixture of dioxane (25 mL) and water (1 mL) for two hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a C 18-column eluting with a gradient of water and acetonitrile (with 0.1% formic acid). Pure fractions were combined and adjusted to pH>9 with ammonia. The resulting precipitate was filtered, washed with water and dried to give 25 mg of E37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 17h;Reflux; Inert atmosphere; | 6-bromo-l -trifluoromethyl-9H-pyrido[3,4-b] indole (Intermediate 13; 0.25 mmol, 80 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (104 mg, 0.48 mmol), potassium carbonate (176 mg, 0.80 mmol) and tetrakis(triphenylphosphine)palladium (12 mg, 0.006 mmol) were stirred in a mixture of dioxane (10 mL) and water (0.3 mL) for 17 hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C I S- cartridge (1 g). The filtrate was purified further by preparative HPLC on a C I S- column eluting with a gradient of water and acetonitrile (with 0.1 % formic acid) followed by open column chromatography on silica gel (conditioned with 5 % (w/w) of concentrated aq. ammonia solution)eluting with dichloromethane/n-heptane (2: 1). Pure fractions were combined and dried to give 48.0 mg of E36. | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 17h;Inert atmosphere; Reflux; | 6-bromo-1-trifluoromethyl-9H-pyrido[3,4-b]indole (Intermediate I3; 0.25 mmol, 80 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (104 mg, 0.48 mmol), potassium carbonate (176 mg, 0.80 mmol) and tetrakis(triphenylphosphine)palladium (12 mg, 0.006 mmol) were stirred in a mixture of dioxane (10 mL) and water (0.3 mL) for 17 hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C 18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a C18-column eluting with a gradient of water and acetonitrile (with 0.1% formic acid) followed by open column chromatography on silica gel (conditioned with 5 % (w/w) of concentrated aq. ammonia solution)eluting with dichloromethane/n-heptane (2:1). Pure fractions were combined and dried to give 48.0 mg of E36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux; Inert atmosphere; | 6-bromo-l -propyl-9H-pyrido[3,4-b]indole (Intermediate 14; 0.69 mmol, 200 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (346 mg, 2.08 mmol), potassium carbonate (484 mg, 3.46 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.028 mmol) were stirred in a mixture of dioxane (40 mL) and water (1 mL) for two hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C 18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a C 18-column eluting with a gradient of water and acetonitrile (with 0.1% formic acid). Pure fractions were combined and dried to give 93.7 mg of E38. | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux; Inert atmosphere; | 6-bromo-1-propyl-9H-pyrido[3,4-b]indole (Intermediate I4; 0.69 mmol, 200 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (346 mg, 2.08 mmol), potassium carbonate (484 mg, 3.46 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.028 mmol) were stirred in a mixture of dioxane (40 mL) and water (1 mL) for two hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a C18-column eluting with a gradient of water and acetonitrile (with 0.1% formic acid). Pure fractions were combined and dried to give 93.7 mg of E38. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere; | Benzyl 3-(3-(2,3-dihydrobenzofuran-5-yl)-l-trityl-lH-indazole-5- car boxam ido)p ip eridine-l -carboxy late Benzyl 3-(3-bromo-l-trityl-lH-indazole-5-carboxamido)piperidine-l-carboxylate (0.050 g, 0.0716 mmol), [l, -Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.0052 gf 0.00716 mmol), Potassium phosphate tribasic (0.046 g, 0.215 mmol) and <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (0.0129 g, 0.0788 mmol) was added into a flask. After purging the reaction vessel with nitrogen gas, dioxane (0.215 mL) and water (0.043mL) was added. The reaction was allowed to stir at 80 C for 16hrs. The reaction was quenched with water (ImL) and extracted with dichloromethane (3 chi 1 mL). The extracts were combined, dried using sodium sulfate, filtered through celite, and concentrated under vacuo. The crude product was progressed to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃;Inert atmosphere; | Synthesis of (R)-tert-butyl 3-(3-(2,3-dihydrobenzofuran-5-yI)-l-trityl-lH-indazole- 5-carboxamido)piperidine-l-carboxy.ate ( )-tert-butyl 3-(3 -bromo- 1 -trityl- 1 H-indazole-5-carboxamido)piperidine- 1 - carboxylate (650 mg, 1 mmol) was added to a vial containing 2,3-dihydrobenzofuran-5- ylboronic acid (180 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). After purging the vial with nitrogen gas, dioxane (3 mL) and 2M sodium carbonate (1.5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80 C for overnight. Upon completion, the mixture was concentrated under vacuo. Water (10 mL) was added and was extracted using dichloromethane (3 chi 25 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was purified using flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 1h;Reflux; Inert atmosphere; | 6-bromo-l-isopropyl-9H-pyrido[3,4-b]indole (Intermediate 15; 0.17 mmol, 50 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (62 mg, 0.345 mmol), potassium carbonate (120 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol) were stirred in dioxane (10 mL) for one hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C 18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a C 18-column eluting with a gradient of water and acetonitrile (with 0.1 % formic acid). Pure fractions were combined and dried to give 10 mg of E39. | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 1h;Reflux; Inert atmosphere; | 6-bromo-1-isopropyl-9H-pyrido[3,4-b]indole (Intermediate I5; 0.17 mmol, 50 mg), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-ylboronic acid</strong> (62 mg, 0.345 mmol), potassium carbonate (120 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol) were stirred in dioxane (10 mL) for one hours at reflux conditions under nitrogen atmosphere. After evaporating the solvent, the reaction mixture was redissolved in methanol and filtered through a C18-cartridge (1 g). The filtrate was purified further by preparative HPLC on a C 18-column eluting with a gradient of water and acetonitrile (with 0.1% formic acid). Pure fractions were combined and dried to give 10 mg of E39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere; | Acetyl chloride (3.32 mL, 46.7 mmol) was slowly added to a stirred solution of o-toluidine (5 g, 46.7 mmol) and pyridine (9.8 mL, 121.4 mmol) in DCM (50 mL) at 0C. The mixture was stirred for 1 hour at 0C and then allowed to warm to room temperature. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure to give N- acetyl-o-toluidine (6 g, 86% yield). N-acetyl-o-toluidine (4.8 g, 0.032 mol), 1 ,4- dibromobenzene (9.1 1 g, 0.039 mol), 2C03 (4.42 g, 0.032 mol), Cu powder (2.03 g, 0.032 mol) and iodine (812 mg, 0.032 mol) combined in NMP (70 mL) were heated at 180C overnight under an argon atmosphere. The reaction was then allowed to cool to room temperature and diluted with ethyl acetate (300 mL). This mixture was filtered through celite and washed with additional ethyl acetate. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure. The residue was purified over silica (100% heptane to 100 % ethyl acetate) to give N-(4-bromophenyl)-N-o-tolylacetamide (3.2 g, 33% yield). N-(4-bromophenyl)-N-o-toIylacetamide (1.13 g, 3.72 mmol) was dissolved in toluene. Sodium methoxide (4.5 mL, 26 mmol of a 30% solution in methanol) was added and the reaction heated at 100C. After 3 hours, TLC analysis indicated that all starting material had been consumed and the reaction was allowed to cool to room temperature. Water (1 mL) was added to quench the reaction before dilution with ethyl acetate (200 mL). The organics were washed with water and twice with brine, dried over MgS(¾ and filtered and the solvent removed under reduced pressure to give N-(4-bromophenyl)-2-methylaniline (76 mg, 100% yield). N-(4-bromophenyl)-2-methylaniline (l g, 3.82 mmol) and 2,3-dihydrobenzofuran-5- boronic acid (688.0 mg, 4.19 mmol) were combined in deoxygenated dioxane (30 mL). A potassium phosphate solution (2.43 g, 1 1.46 mmol, 6 mL deoxygenated water) was added to the reaction mixture. The reaction mixture was stirred rapidly under argon. PdCl2dppf (279.5 mg, 0.38 mmol) was added and the reaction mixture transferred to a pre-heated oil bath and stirred rapidly under argon at 90C. After 1 hour, TLC analysis indicated that all starting material had been consumed. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (100 mL). This mixture was filtered through celite and washed with additional ethyl acetate. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure. The residue was purified over silica (100% heptane to 9: 1 heptane/ethyl acetate) to give N-(4- (2,3-dihydrobenzofuran-5-yl)phenyl)-2-methylaniline (312 mg, 27% yield). N-(4- (2,3-dihydrobenzofuran-5-yl)phenyl)-2-methylaniline (100 mg, 0.033 mmol) was dissolved in a mixture of toluene (0.2 mL) and acetic acid (0.8 mL). Pd(OAc)2 (7.5 mg, 0.33 mmol) and Cs2C03 (1 1.7 mg, 0.036 mmol) were added and the reaction was heated at 100C for two hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (50 mL). This mixture was filtered through celite and washed with additional ethyl acetate. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure. The residue was purified over silica (100% heptane to 7:3 heptane/ethyl acetate) to give crude product. This residue was recrystalised from heptane (15 mL) which on cooling gave product 20.5 mg (19%) of E58 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,4-dioxane; water; at 120℃; for 0.5h;Microwave irradiation; | General procedure: 3'-(Trifluoromethanesulfonyl)fluorescein,3 (186 mg, 0.40 mmol), boronic acid, 4a-v (0.48 mmol), palladium acetate (4.5 mg, 0.02 mmol) and triphenylphosphine (21mg, 0.08 mmol) were stirred in degassed dioxane (10 mL). Potassium carbonate(83 mg, 0.60 mmol) in water (1 mL) was added and the resulting mixture was microwave irradiated at 120 C for 30 minutes. The reaction mixture was partitioned between EtOAc (50 mL) and 1 M HCl (40 mL), the aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification of the residue via chromatography on silica gel (4:1 Hex:EtOAc) or (1:9 MeOH:DCM) for compounds 5u and 5v. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.0833333h;Inert atmosphere; Microwave irradiation; | Example 69:5-(2,3-Dihydro-1 -benzofuran-5-yl)-3-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H- indole-7-carboxamide.A mixture of 5-bromo-3-(1 ,1-dioxidotetrahydro-2/-/-thiopyran-4-yl)-1/-/-indole-7- carboxamide (30 mg, 0.081 mmol), <strong>[227305-69-3]2,3-dihydro-1-benzofuran-5-ylboronic acid</strong> (26.5 mg, 0.162 mmol), and K2CO3 (33.7 mg, 0.242 mmol) in 1 ,4-dioxane (0.36 ml.) and water (0.180 ml.) was degassed in a Biotage microwave vial for 10 min. PdCl2(dppf) (5.91 mg, 8.08 mumol) was added, the vial was sealed, and the reaction was heated at 100 0C (bath temp) for 5 min in a Biotage microwave oven at high absorption. EtOAc (3 ml.) and water (1 ml.) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4 x 2 ml_). The combined organic layers were washed with saturated NaCI (1 x 2 ml_), dried (Na2SO4), and concentrated under a stream of nitrogen at 50 0C. The crude product was dissolved in DMSO (1.2 ml_), filtered through a 0.2 mm acrodisc, and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19 x 100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1 % NH4OH) to 70% CH3CN/H2O (0.1 % NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50 0C, giving 6.8 mg (20%) of the title compound. LC/MS: m/z 410.9 (M+H), Rt 1.71 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In ethanol; water; toluene; at 130℃; for 1h;Inert atmosphere; Sealed tube; | To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (65.0 mg, 0.39 mmol) in EtOH (0.5 mL) and toluene (0.5 mL) was added 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol). The reaction mixture was degassed with N2 for 5 minutes, treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol) and degassed with N2 for another 5 minutes. The suspension was sealed in a pressure tube and heated to 130 C. for 1 hour. As the reaction progressed, the suspension became clear, turned to orange and then dark brown. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL), and filtered through a syringe filter. The aqueous layer was acidified to pH 5 by 1 N HCl solution, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19*100 mm, 5 mum; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 8.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 9.0 to 10.0 min. Flow: 25 mL/min) to provide the title compound (24.8 mg, 22% yield). MS (ES+) 315.1 (M+H)+. Retention time=2.68 minutes (Column: Waters Atlantis dC18 4.6*50 mm, 5 mum; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 20h; | Compound 29 (0.1 g, 0.2486 mmol) and <strong>[227305-69-3](2,3-dihydrobenzofuran-5-yl)boronic acid</strong> (0.612 g, 1.5 eq) were suspended in DME (1,2-dimethoxyethane). Tetrakis(triphenylphosphine)- palladium(O) (0.03 g, 0.2 eq) and an aqueous 2M Na2CO3 solution (0.5 ml, 4 eq.) were added. The reaction mixture was stirred 20 h at 100C, subsequently dissolved in ethyl acetate and washed twice with water. The organic layer was concentrated in vacuo, the residue dissolved in methanol and purified by preparative HPLC to obtain the pure product (4 mg, 4% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 6h; | <strong>[460081-18-9]2-Chloro-oxazole-4-carboxylic acid ethyl ester</strong> (1.5 g, 8.5 mmol, 1 eq.) and 2,3-Dihydro-l- benzofuran-5-ylboronic acid (2.1 g, 12.8 mmol, 1.5 eq.) were suspended in DME (170 ml). Tetrakis(triphenylphosphine)palladium(0) (987 mg, 0.85 mmol, 0.1 eq.) and an aqueous 2M sodium carbonate solution (17.1 ml, 34.2 mmol, 4 eq.) were added. The reaction mixture was stirred at 90C for 6 h. DME was then removed under reduced pressure. The obtained residue was dissolved inEtOAc and was washed three times with water. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The obtained crude product was purified by - - flash column chromatography on silica gel (PE/EtOAc 9:1 to 8:2). The fractions containing the product were collected and concentrated in vacuo. The product was obtained as a yellow oil (472 mg, Purity: ca. 50%). LC/MS [M+H]+: 259.10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | The product was synthesized from methyl 4-([3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}amino)-2-hydroxybenzoate (Intermediate 5) (23 mg, 0.050 mmol) and <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (10 mg, 0.06 mmol) according to the General Procedure 9, described in Example 82, but without purification. The ester intermediate was treated with 1 M NaOH (300 muL) at 60 C. overnight. The crude product was purified by preparative HPLC (acidic system) and 4-([3-(2,3-dihydro-1-benzofuran-5-yl)-5-(trifluoromethyl)phenyl]sulfonyl}amino)-2-hydroxybenzoic acid was obtained in 83% yield (19.8 mg) over two steps. 1H NMR (500 MHz, CD3OD) delta ppm 3.27 (t, J=8.76 Hz, 2H) 4.61 (t, J=8.76 Hz, 2H) 6.68 (dd, J=8.67, 2.20 Hz, 1H) 6.74 (d, J=2.20 Hz, 1H) 6.84 (d, J=8.30 Hz, 1H) 7.35 (ddt, J=8.30, 2.14, 0.70 Hz, 1H) 7.42 (dt, J=2.14, 1.20 Hz, 1H) 7.74 (d, J=8.67 Hz, 1H) 7.98 (dq, J=1.68, 0.74 Hz, 1H) 8.03 (dq, J=1.68, 0.74 Hz, 1H) 8.14 (t, J=1.68 Hz, 1H). MS (ESI+) m/z 480 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | Intermediate 2 4-([5-Chloro-4-(2,3-dihydro-1-benzofuran-5-yl)thiophen-2-yl]sulfonyl}amino)-2-hydroxybenzoic acid A mixture of 4-[(4-bromo-5-chlorothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (150 mg, 0.36 mmol), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (65 mg, 0.40 mmol), DIPEA (140 mg, 1.1 mmol) and Pd(dppf)Cl2.CH2Cl2 (15 mg, 0.018 mmol) in aqueous dioxane (5 mL dioxane, 1 mL water) was heated at 80 C. under N2 atmosphere overnight. CH2Cl2 (50 mL) followed by 1 M Na2CO3 (10 mL) were added to the reaction mixture. The aqueous phase was washed with CH2Cl2 (2*50 mL) and then acidified with conc. H3PO4. EtOAc (100 mL) was added. The organic phase was washed with 1 M HCl (2*50 mL), water and brine, and dried with MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC (acidic system). The title compound was obtained as a white solid (50 mg, 31%). 1H NMR (500 MHz, CD3OD) delta ppm 3.24 (t, J=8.67 Hz, 2H) 4.58 (t, J=8.67 Hz, 2H) 6.72 (dd, J=8.55, 2.20 Hz, 1H) 6.76-6.81 (m, 2H) 7.22 (dd, J=8.18, 2.08 Hz, 1H) 7.33 (d, J=1.46 Hz, 1H) 7.54 (s, 1H) 7.78 (d, J=8.79 Hz, 1H). MS (ESI+) m/z 452 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 20 4-([3-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]sulfonyl}amino)-2-hydroxybenzoic acid A mixture of methyl 4-[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoate (Intermediate 4) (0.74 g, 2.0 mmol), <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (0.36 g, 2.2 mmol), DIPEA (1.1 g, 8.8 mmol) and Pd(dppf)Cl2.CH2Cl2 (66 mg, 81 mumol) in aqueous dioxane (20 mL dioxane, 3 mL water) was heated at 80 C. under N2 atmosphere overnight. Water and EtOAc were added. The organic phase was washed with 1 M H3PO4, sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated. To the residue was added 1 M NaOH (20 mL). The reaction was stirred at room temperature for 3 h. A spoonful of charcoal was added. The mixture was stirred for 1 h and filtered through a pad of celite. The mother liquid was washed twice with CH2Cl2 and acidified with conc. H3PO4. EtOAc was added. The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from water/MeOH. The title compound was obtained as a white solid. 1H NMR (600 MHz, CD3OD) delta ppm 3.26 (t, J=8.70 Hz, 2H) 4.59 (t, J=8.54 Hz, 2H) 6.66 (d, J=8.54 Hz, 1H) 6.73 (s, 1H) 6.80 (d, J=8.24 Hz, 1H) 7.31 (d, J=8.24 Hz, 1H) 7.39 (s, 1H) 7.54 (t, J=7.93 Hz, 1H) 7.70 (d, J=8.85 Hz, 1H) 7.73-7.80 (m, 2H) 7.95 (s, 1H). MS (ESI+) m/z 412 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 18h;Inert atmosphere; | Example 31. Preparation of Compound No. 82 [0178] N-(4-(2-Bromothiazol-4-yl)-3-chlorophenyl)-l, 1, 1-trifluoromethane sulfonamide (100 mg, 0.2380 mmol) and <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (58.5 mg, 0.3571 mmol), potassium carbonate (65 mg, 0.476 mmol), dimethyl formamide (5 mL), water (0.5 mL) were charged in a 2 neck round bottom flask and aerated with nitrogen gas for 5 min. After adding Pd(PPh3)4 (27.4 mg, 0.0238 mmol), the mixture was heated to 100 C for 18 h. The reaction was monitored by LCMS. The reaction mixture was allowed to cool to RT; water (10 mL) was added and the mixture extracted with EtOAc (3x25 mL). The combined organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC to afford N-{3-chloro-4-[2- (2,3-dihydro- 1 -benzofuran-5-yl)-l ,3-thiazol-4-yl]phenyl} -1,1,1 -trifluoromethanesulfonamide (15 mg) as a white solid. 1H NMR (400 MHz, Methanol-d4) delta (ppm): 7.97 (d, J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.63 (t, J = 8.7 Hz, 2H), 2.17 (t, J = 9.3 Hz, 2H). LCMS (M+l): 460.6. |
15 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 18h;Inert atmosphere; | N-(4-(2-Bromothiazol-4-yl)-3-chlorophenyl)-1,1,1-trifluoromethane sulfonamide (100 mg, 0.2380 mmol) and <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (58.5 mg, 0.3571 mmol), potassium carbonate (65 mg, 0.476 mmol), dimethyl formamide (5 mL), water (0.5 mL) were charged in a 2 neck round bottom flask and aerated with nitrogen gas for 5 min. After adding Pd(PPh3)4 (27.4 mg, 0.0238 mmol), the mixture was heated to 100 C. for 18 h. The reaction was monitored by LCMS. The reaction mixture was allowed to cool to RT; water (10 mL) was added and the mixture extracted with EtOAc (3*25 mL). The combined organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC to afford N-{3-chloro-4-[2-(2,3-dihydro-1-benzofuran-5-yl)-1,3-thiazol-4-yl]phenyl}-1,1,1-trifluoromethanesulfonamide (15 mg) as a white solid. 1H NMR (400 MHz, Methanol-d4) delta (ppm): 7.97 (d, J=8.5 Hz, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 4.63 (t, J=8.7 Hz, 2H), 2.17 (t, J=9.3 Hz, 2H). LCMS (M+1): 460.6. |
15 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 18h;Inert atmosphere; | N-(4-(2-Bromothiazol-4-yl)-3-chlorophenyl)-1,1,1-trifluoromethane sulfonamide (100 mg, 0.2380 mmol) and <strong>[227305-69-3]2,3-dihydrobenzofuran-5-boronic acid</strong> (58.5 mg, 0.3571 mmol), potassium carbonate (65 mg, 0.476 mmol), dimethyl formamide (5 mL), water (0.5 mL) were charged in a 2 neck round bottom flask and aerated with nitrogen gas for 5 min. After adding Pd(PPh3)4 (27.4 mg, 0.0238 mmol), the mixture was heated to 100 C. for 18 h. The reaction was monitored by LCMS. The reaction mixture was allowed to cool to RT; water (10 mL) was added and the mixture extracted with EtOAc (3*25 mL). The combined organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC to afford N-{3-chloro-4-[2-(2,3-dihydro-1-benzofuran-5-yl)-1,3-thiazol-4-yl]phenyl}-1,1,1-trifluoromethanesulfonamide (15 mg) as a white solid. 1H NMR (400 MHz, Methanol-d4) delta (ppm): 7.97 (d, J=8.5 Hz, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 4.63 (t, J=8.7 Hz, 2H), 2.17 (t, J=9.3 Hz, 2H). LCMS (M+1): 460.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With tetrakis(actonitrile)copper(I) hexafluorophosphate; In methanol; for 12h; | Example 11 Synthesis of 3-(2,3-dihydro-benzofuran-5-yl)-6-hydroxymethyl-6-methyl-6,7-dihydro-3H-pyrano[3,4-d]imidazol-4-one (42 Enantiomers A and B) A mixture of 0.15 g (0.82 mmol) of I-26, 0.15 g (0.91 mmol) of <strong>[227305-69-3]2,3-dihydro-1-benzofuran-5-ylboronic acid</strong> 92 mg (0.25 mmol) of Cu(MeCN)4PF6 in 6 mL of MeOH is vigorously stirred for 12 h. The mixture is filtered through diatomaceous earth, concentrated and purified via column chromatography (0-7% MeOH in CH2Cl2) to provide 60 mg (0.20 mmol) of 42. Chiral chromatography (LUX 5u Cellulose 3 Prep, 10% (1:1 MeOH/EtOH):CO2, 88 g/min, 120 bar, 40 C.) delivers 30 mg (0.10 mmol) each of 42 enantiomer A and 42 enantiomer B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); triethylamine; In 1,2-dimethoxyethane; at 85℃; for 2h; | General procedure: Ethyl 4-{1-[3-(3,5-dichlorophenyl)-5-[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl]ethyl}benzoate (1.0 g, 1.9 mmol), 4-(tert-butyl)phenyl boronic acid (430.9 mg, 2.4 mmol), and TEA (1.0 g, 10.2 mmol) were dissolved in dimethoxyethane. The catalyst Pd(PPh3)4 (129.2 mg, 0.1 mmol) was added, and the mixture was deoxygenated before refluxed in 85 C for 2 h. The mixture was extracted with EtOAc, washed with saturated brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography to afford ethyl 4-{1-[3-(3,5-dichlorophenyl)-5-[4-(tert-butyl)phenyl]-1H-pyrazol-1-yl]ethyl}benzoate as a colorless oil (632.8 mg, 65.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In acetonitrile; at 60℃; | (Step 1) A solution of <strong>[227305-69-3](2,3-dihydrobenzofuran-5-yl)boronic acid</strong> (680 mg, 4.15 mmol), glyoxylic acid monohydrate (382 mg, 4.15 mmol) and diallylamine (0.510 mL, 4.15 mmol) in acetonitrile (15 mL) was stirred overnight at 60C. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Diol, solvent gradient; 0?10% MeOH/ethyl acetate) to give 2-(diallylamino)-2-(2,3-dihydrobenzofuran-5-yl)acetic acid (1.02 g, 3.73 mmol, 90%) as a colorless oil. 1H NMR(300 MHz,DMSO-d6):delta3.06-3.25(6H,m),4.33(1H,s),4.44-4.60(2H,m),5.05-5.24(4H,m),5.79(2H,ddt,J=16.8,10.4,6.2 Hz),6.72(1H,d,J=7.9 Hz),7.00-7.13(1H,m),7.22(1H,s),12.37(1H,brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 111℃; for 0.166667h;Microwave irradiation; Inert atmosphere; | To a degassed solution of methyl 4-(4-(2-(2-bromo-5-fluorophenyl)-l,l- difluoroethyl)phenyl)butanoate (80 mg, 0.193 mmol), (2,3-dihydrobenzofuran-5- yl)boronic acid (63.2 mg, 0.385 mmol), sodium bicarbonate (32.4 mg, 0.385 mmol) in dioxane (4 mL) :water (1 mL), tetrakis(triphenylphosphine)palladium(0) (5.57 mg, 0.019 mmol) was added and the reaction mixture was heated in microwave at 111 C for 10 minutes. Reaction mixture was concentrated and purified by column chromatography to provide methyl 4-(4-(2-(2-(2,3-dihydrobenzofuran-5-yl)-5-fluorophenyl)-l,l- difluoroethyl)phenyl)butandate (58 mg, 0.128 mmol, 66.2 % yield). *H NMR (300 MHz, CDCI3) : delta 7.42-6.96 (m, 7H), 6.74-6.65 (m, 3H), 4.65 (t, J = 8.7 Hz, 2H), 3.68 (s, 3H), 3.44 (t, J = 15.9 Hz, 2H), 3.23 (t, J = 8.7Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.37 9 (t, J =7.5 Hz, 2H), 2.01-1.91 (m, 2H); MS (m/z): 477 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 2h; | First step((1- (benzofuran-2-yl) -5- (2,3-dihydrobenzofuran-5-yl) lH-pyrrol-3-yl) methyl)(methyl) amino tert-butyl. The ((1- (benzofuran-2-yl) -5-bromo--1H- pyrrol-3-yl) methyl) (methyl) carbamate2b (150mg, 0.32mmol), 2 , 3-dihydro-1-benzofuran-5-yl boronic acid 7a (58mg, 0.35mmol)and sodium carbonate (51mg, 0.48mmol) were added sequentially to 6mL of 1,4-dioxane andwater (V / V = 5:1) mixed solvent, the addition was completed, stir, then add [1,1'-bis(diphenylphosphino) ferrocene] palladium dichloride (23mg, 0.03mmol), was heated to 100, stirring for 2 hours. To the reaction mixture was added 50mL of ethyl acetate, andthen washed with saturated sodium chloride solution (10mL × 2), dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated, purified by thin layerchromatography with a developing solvent system, the resulting residue was purified byC, to give the title product ((1- (benzofuran-2-yl) -5- (2,3-dihydrobenzofuran-5-yl) lH-pyrrol-3-yl) methyl) (methyl yl) carbamate 7b (83mg, pale yellow oil) yield: 51.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium carbonate; bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine; In water; N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Inert atmosphere; | 3-Iodo-6-(4-pyridinyl)imidazo[l,2-a]pyridine (0.156 mmol, 50.0 mg), (2,3-dihydrobenzofuran- 5-yl) boronic acid (1.0 eq., 0.156 mmol, 25.5 mg), Na2C03 (4.0 eq., 0.623 mmol, 66.0 mg), and a mixture of 4: 1 DMF/water (2 mL) were added to a microwave vial. The vial was purged with Ar(g) then tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.01 eq., 1.6 muetaiotaomicron, 1.5 mg) and tricyclohexylphosphine (0.03 eq., 4.7 muetaiotaomicron, 1.4 mg) was added. The reaction was microwave irradiated under Ar (g) at 130 C for 30 min. then filtered through celite washing down with CH2CI2 and MeOH. The filtrate was evaporated in vacuo and DMF was removed by azeotroping with toluene. The crude material was purified via reverse phase preparative LCMS eluting with a water/acetonitrile gradient to obtain 77 (0.050 mmol, 15.8 mg). Yield: 32%, pale yellow solid. lH NMR (400 MHz, DMSO-d6) delta 8.72 (s, 1H), 8.64 (s, 2H), 7.81 - 7.74 (m, 3H), 7.71 (s, 1H), 7.69 (dd, J = 9.4, 1.7 Hz, 1H), 7.59 (s, 1H), 7.46 (dd, J = 8.2, 1.9 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 4.61 (t, J = 8.7 Hz, 2H), 3.28 (t, J= 8.7 Hz, 2H). 1 C NMR (100 MHz, DMSO-d6) delta 159.91, 150.24, 144.17, 132.75, 128.71, 128.16, 125.18, 123.37, 122.94, 122.08, 121.35, 120.47, 117.87, 109.68, 71.33, 29.09; [M+H]+ = 314.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 150℃; for 0.5h;Inert atmosphere; Microwave irradiation; | General procedure: Step 1: To a solution of <strong>[153463-65-1]3,5-dichloro-4-pyridinecarbonitrile</strong> in anhydrous dioxane (0.38 M) in a CEM microwave reaction vial, the desired arylboronic acid (1 equiv.), PCy3 ligand (0.025 eq) and K3PO4 (1.27 M aqueous solution, 1.7 equiv.) are added. The reaction mixture is first rigorously degassed with argon and then Pd2(dba)3 (0.01 equiv.) is added and the reaction mixture is further degassed with argon and then heated at 150 C. for 30 min using a CEM microwave. After cooling, the crude reaction mixture is diluted with ethyl acetate and filtered through silica gel and the residue is concentrated under reduced pressure. The residue is applied to a silica gel column and the desired arylpyridine intermediate (3) is eluted with either hexanes/ethyl acetate or methanol/methylene chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45 mg | With tetrakis(actonitrile)copper(I) hexafluorophosphate; In methanol; for 48h; | A mixture of 0.10 g (0.73 mmol) of C-AAK, 0.13 g (0.81 mmol) of 2,3-dihydro-l-benzofuran-5- ylboronic acid and the 82 mg (0.22 mmol) of Cu(CN)4PF6, 4 mL of MeOH is stirred for 2 days. The mixture is filtered through diatomaceous earth and the filtrate is concentrated and purified by flash chromatography first on silica (0-10% MeOH in CH2C12), then on a KPNH- silica column (0-100% EtO Ac/heptane) to provide 45 mg (0.18 mmol) of C-AAE. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 70℃; for 18h; | A solution of DBU (22 mu, 0.146 mmol) and Intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA (10 mg, 0.022 mmol) and <strong>[227305-69-3](2,3-dihydrobenzofuran-5-yl)boronic acid</strong> (25 mg, 0.152 mmol) before stirring for 18 h at 70C. The mixture was diluted with water then extracted with dichloromethane (3 x 8 mL). The organic phases were combined then filtered and concentrated under reduced pressure. The crude product was purified by chromatography on the (0635) Companion (4 g column, 2-5% MeOH/DCM) to afford (,S)-l-(2,3-dihydrobenzofuran-5- yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-l-(l, l-dioxidotetrahydro-2H-thiopyran-4-yl)-lH- benzo[ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 40℃; for 108h; | CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 mu, 0.133 mmol), (,S)-5-(5-(3,5-dimethylisoxazol-4-yl)-l-(4-hydroxycyclohexyl)-lH- benzo[<i]imidazol-2-yl) pyrrolidin-2-one (50 mg, 0.127 mmol) and (2,3- dihydrobenzofuran-5-yl)boronic acid (22.86 mg, 0.139 mmol) in acetonitrile (4 mL) with stirring for 108 h at 40C. The mixture was concentrated under reduced pressure then purified by chromatography on the Companion (12g column, 0-10% MeOH in DCM, gradient elution) to afford (,S)-l-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5- dimethylisoxazol-4-yl)-l-(4-hydroxycyclohexyl)-lH-benzo[<i]imidazol-2-yl)pynOlidin- 2-one (13 mg, 19%) as an off white solid; Rt 1.59 min; m/z 513 (M+H)+ (ES+); 1H MR (de-DMSO) delta: 7.77 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 2.2, 1.2 Hz, 1H), 7.12 (dd, J = 8.4, 1.7 Hz, 1H), 7.01 (dd, J = 8.6, 2.3 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.94 (dd, J = 8.3, 2.7 Hz, 1H), 4.72 (d, J = 4.2 Hz, 1H), 4.45 (m, 4H), 3.67 (m, 1H), 3.43 - 3.28 (m, 1H), 3.20 - 3.05 (m, 2H), 2.78 (dt, J = 16.0, 9.0 Hz, 1H), 2.66 - 2.51 (m, 1H), 2.38 (s, 3H), 2.31 - 2.15 (m, 5H), 2.01 - 1.91 (m, 1H), 1.88 (m, 1H), 1.75 (m, 1H), 1.48 - 1.30 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 40℃; for 18h; | CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 mu, 0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and (2,3-dihydrobenzofuran-5- yl)boronic acid (22.08 mg, 0.135 mmol) in acetonitrile (4ml) with stirring for 18 h at 40C. The mixture was concentrated under reduced pressure. The residue was taken up in the minimum of DCM, passed through a syringe filter and the solution then purified by chromatography on the Companion (12 g column, 0-10% MeOH in DCM, gradient elution) to afford (,S)-l-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)- l-((lr,4,S)-4-methoxycyclohexyl)-7H-benzo[<i]imidazol-2-yl)pynOlidin-2-one (46 mg, 71%) as an off white solid; Rt 1.88 min (method 1), m/z 527 (M+H)+ (ES+); 1H MR (d6-DMSO) delta: 7.79 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.5, 1.7 Hz, 1H), 7.01 (dd, J = 8.5, 2.4 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.97 - 5.89 (m, 1H), 4.45 (m, 2H), 3.29 (d, J = 8.7 Hz, 1H), 3.29 (s, 3H), 3.20 - 3.04 (m, 2H), 2.77 (dd, J = 16.3, 8.9 Hz, 1H), 2.60 (m, 1H), 2.38 (s, 3H), 2.28 ( m, 1H), 2.21 (s, 3H), 2.16 (m, 1H), 2.12 (m, 4H), 1.81 (d, J = 12.4 Hz, 1H), 1.38 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 40℃; for 15h; | CuTMED A (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL, 0.123 mmol), Intermediate E9 (50 mg, 0.117 mmol) and (2,3-dihydrobenzofuran-5- yl)boronic acid (21.05 mg, 0.128 mmol) in acetonitrile (3.53 mL, 67.7 mmol) with stirring for 15 h at 40C. The mixture was concentrated under reduced pressure. The residue was taken up in the minimum of DCM, passed through a syringe filter and the solution then purified by chromatography on the Companion (12g column, 0-10% (0810) MeOH in DCM, gradient elution) to afford (55)-l-(2,3-dihydrobenzofuran-5-yl)-5-(5- (3 , 5 -dimethyli soxazol-4-yl)- 1 -( 1 , 1 -dioxido tetrahy dro-2H-thiopyran-3 -yl)- 1H- benzo[<i]imidazol-2-yl)pyrrolidin-2-one (28 mg, 42%) as a yellow solid; Rt 1.72 min (0811) (method 1), m/z 547 (M+H)+ (ES+); 1H MR (d6-DMSO) delta: 8.13 - 8.02 (m, 1H), 7.65 (dd, J = 8.2, 1.7 Hz, 1H), 7.38 (dd, J = 44.0, 2.2 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.06 (dd, J = 8.6, 2.3 Hz, 0.5H), 6.86 (d, J = 8.7 Hz, 0.5H), 6.63 (dd, J = 14.3, 8.5 Hz, 1H), 5.94 (dd, J = 8.2, 2.4 Hz, 0.5H), 5.87 - 5.79 (m, 0.5H), 4.90 - 4.72 (m, 1H), 4.49 - 4.42 (m, 2H), 4.11 - 3.97 (m, 1H), 3.65 - 3.45 (m, 1H), 3.23 - 3.05 (m, 3H), 2.86 - 2.54 (m, 2H), 2.50 (p, J = 1.8 Hz, 2 H), 2.39 (m+d, J = 4.1 Hz, 4H), 2.34 - 2.25 (m, 1H), 2.21 (d, J = 3.8 Hz, 3H), 2.11 (d. J = 18.1 Hz, 1H), 1.99 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; acetonitrile; at 40℃; for 15h; | CuTMED A (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 mu,, 0.115 mmol), Intermediate E10 (50 mg, 0.109 mmol) and (2,3-dihydrobenzofuran-5- yl)boronic acid (19.71 mg, 0.120 mmol) in acetonitrile (3310 mu^, 63.4 mmol) and DCM (1.5 mL) with stirring for 15 h at 40C. The mixture was concentrated under reduced pressure. The residue was taken up in the minimum of DCM, passed through a syringe filter and the solution then purified by flash chromatography on the Companion (12g column, 0-10% MeOH in DCM, gradient elution) to afford (5)-l-(2,3- dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-l-(l- (methylsulfonyl)piperidin-4-yl)-lH-benzo[<i]imidazol-2-yl)pynOlidin-2-one (32 mg, 50%) as a white solid; Rt 1.75 min (method 1), m/z 576 (M+H)+ (ES+); 1H NMR (d6- DMSO) delta: 7.70 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.18 (dd, J = 8.4, 1.7 Hz, 1H), 7.05 (dd, J = 8.5, 2.4 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 5.94 (dd, J = 8.2, 2.7 Hz, 1H), 4.73 - 4.63 (m, 1H), 4.47 (t, J = 8.7 Hz, 2H), 3.77 (t, J = 14.9 Hz, 2H), 3.10 (t, J = 8.7 Hz, 2H), 3.02 (s, 3H), 3.00 - 2.90 (m, 2H), 2.78 (dt, 1H), 2.70 - 2.56 (m, 1H), 2.46 - 2.31 (m+s, 5H), 2.26 - 2.16 (m+s, 4H), 1.99 - 1.90 (m, 1H), 1.52 - 1.44 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 40℃; for 18h; | A solution of DBU (20 mu, 0.133 mmol) and Intermediate El (50 mg, 0.1 13 mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA (10 mg, 0.022 mmol) and <strong>[227305-69-3](2,3-dihydrobenzofuran-5-yl)boronic acid</strong> (20.33 mg, 0.124 mmol) before stirring for 18 h at 40C. The mixture was concentrated under reduced pressure then purified by chromatography on the Companion (12 g column, 0-50% MeAc/DCM) to afford (-S)-l- (2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-l-((R)-l- (methylsulfonyl)pyrrolidin-3-yl)-lH-benzo[<i]imidazol-2-yl)pynOlidin-2-one (24 mg, 37%) as an off white solid; Rt 1.72 min (method 1), m/z 562 (M+H)+ (ES+); IH MR (d6-DMSO) delta: 7.72 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 2.3, 1.2 Hz, 1H), 7.24 (dd, J = 8.5, 1.6 Hz, 1H), 7.05 (dd, J = 8.5, 2.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.93 (dd, J = 8.3, 2.8 Hz, 1H), 5.52 - 5.40 (m, 1H), 4.47 (t, J = 8.7 Hz, 2H), 3.80 - 3.71 (m, 1H), 3.71 - 3.64 (m, 1H), 3.63 - 3.55 (m, 1H), 3.33 - 3.29 (m, 1H), 3.14 - 3.09 (m, 2H), 3.08 (s, 3H), 2.84 - 2.70 (m, 1H), 2.68 - 2.57 (m, 1H), 2.49 - 2.41 (m, 2H), 2.39 (s, 3H), 2.26 (s, 1H), 2.22 (s, 3H), 2.21 - 2.09 (m, 1H); Chiral HPLC (Diacel Chiralpak IA, 5 mupiiota, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT = 1 1.67 min, >99% de 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In nitromethane; at 60℃; for 12h; | General procedure: A 10-mL screw-cap glass tube with PP-cap was charged with a magnetic stirring bar, 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (1a; 68.0 mg, 0.25 mmol, 1.0 equiv), glyoxylic acid monohydrate (2; 30.0 mg, 0.33 mmol, 1.3 equiv), boronic acid 3 (0.5 mmol, 2.0 equiv), and nitromethane (1.5 mL, 0.17 M wrt sulfonamide) and firmly closed. The resulting mixture was stirred at 60 C for 12 h. After cooling to r.t., the mixture was diluted with acetone and filtered through a Celite/silica gel mixture and the filtrate was concentrated under reduced pressure. Purification of the crude residueby flash column chromatography afforded the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | To a mixed solution of the compound 1 (171 mg), the compound 2 (164 mg), and dichlorobis(triphenylphosphine)palladium (18 mg) in dioxane (3 mL), a 2 mol/L aqueous solution of sodium carbonate (1 mL) was added thereto, and the reaction mixture was stirred for 15 minutes at 150C in a microwave reactor (Initiator, manufactured by Biotage Inc.) The reaction mixture was cooled to room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the reaction mixture was extracted twice with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent: chloroform-methanol = 100:5), and the resultant residue was converted to a dihydrochloride with hydrochloric acid (a 4 mol/L ethyl acetate solution) to give the compound 3 (200 mg) as a dark brown solid. MS(APCI): 381 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
128 mg | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwave irradiation; | To a mixed solution of the compound 1 (149 mg), the compound 2 (164 mg), and dichlorobis(triphenylphosphine)palladium (18 mg) in dioxane (3 mL) was added a 2 mol/L aqueous solution of sodium carbonate (1 mL). The reaction mixture was stirred for 15 minutes at 150C in a microwave reactor (Initiator, manufactured by Biotage Inc.) The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium hydrogen carbonate was added thereto. Then, the reaction mixture was extracted twice with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent: chloroform-methanol; gradient: 100:0-95:5). The resultant crystalline residue was recrystallized with ethyl acetate to give the compound 3 (128 mg) as a dark brownish red solid. MS (APCI) 382 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere; | (2,3-Dihydrobenzofuran-5-yl)boronic acid (85.1 mg, 0.519 mmol, 1.5 equiv), Na2C03 (109 mg, 1.04 mmol, 3 equiv), SPhos (14.2 mg, 0.034 mmol, 0.1 equiv) and Pd(OAc)2 (3.9 mg, 0.017 mmol, 0.05 equiv) were added to a stirred methyl 4-(l-((2-bromothiazol-4-yl) methyl)-4-methyl- lH-pyrrole-2-carboxamido) benzoate (48) (150 mg, 0.346 mmol, 1 equiv) in DMF (10 mL) and H20 (3 mL) at ambient temperature. The reaction mixture was degassed for 5 min. with N2 gas and heated to 90 C and stirred for 16 h. The reaction mixture was cooled to ambient temperature and then concentrated under vacuum. The residue was acidified with 1.5 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate (2X30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2S04, filtered through celite bed and concentrated under vacuum to provide compound 56 as a pale brown solid (150 mg, crude) without further purification. LC-MS (ESI+): m/z 474.0 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | Compound SM (300 mg, 1.83 mmol),5-bromo-4-phenylthiazol-2-amine (460 mg, 1.83 mmol),Pd(dppf)Cl2 dichloromethane complex (150 mg, 0.183 mmol),Potassium carbonate (630 mg, 4.58 mmol) was dissolved in a mixed solvent of 1,4-Diox/H2O (3:1), and N2 was substituted three times and then reacted at 90 C overnight.After complete reaction, the system was cooled to room temperature, filtered through celite, and the filtrate was diluted with water.Extract with ethyl acetate, combine the organic phases, wash with water, and wash with saturated brine.Dry over anhydrous sodium sulfate, then filter and the filtrate was dried.The thin layer chromatography plate is purified and then purified by high performance liquid chromatography to obtain 5-(2,3-dihydrobenzofuran-5-yl)-4-phenylthiazole-2-amine (33 mg, yield 6%,White solid). |
Tags: 227305-69-3 synthesis path| 227305-69-3 SDS| 227305-69-3 COA| 227305-69-3 purity| 227305-69-3 application| 227305-69-3 NMR| 227305-69-3 COA| 227305-69-3 structure
[ 763120-44-1 ]
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[ 445303-12-8 ]
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Precautionary Statements-General | |
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P103 | Read label before use |
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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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