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CAS No. : | 150691-04-6 | MDL No. : | MFCD01318943 |
Formula : | C10H16BNO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TUEIURIZJQRMQE-UHFFFAOYSA-N |
M.W : | 257.11 | Pubchem ID : | 4997616 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 66.62 |
TPSA : | 95.01 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.31 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.78 |
Log Po/w (WLOGP) : | 0.52 |
Log Po/w (MLOGP) : | -0.09 |
Log Po/w (SILICOS-IT) : | -1.45 |
Consensus Log Po/w : | -0.05 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.92 |
Solubility : | 3.07 mg/ml ; 0.0119 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.36 |
Solubility : | 1.13 mg/ml ; 0.00441 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.48 |
Solubility : | 0.851 mg/ml ; 0.00331 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.72 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
60% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5 h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at 20℃; for 3.5 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane at 20℃; |
To a solution of the compound of example 3 (15.92 g, 74.7 mmol) in tetrahydrofuran (200 ml) in an ice bath was added 1.6M n-butyllithium in hexane (100 ml, 164 mmol) dropwise over 30 minutes. The mixture remained a clear solution. In an ice bath it was added triisopropylborate (24.1 ml, 104 mmol) dropwise. The mixture was stirred at room temperature for 3.5 hrs, solution becoming cloudy. After it was cooled in an ice bath, 1N hydrochloride (200 ml) was added. The mixture was stirred at room temperature overnight. It was extracted with ether (2.x.50 ml). The organic extract was washed with 1N sodium hydroxide (2.x.60 ml). The aqueous solution was acidified to pH=1 with 6N hydrochloride, and then extracted with ether (2.x.100 ml). The ether extract was dried over magnesium sulfate, and concentrated in vacuo. The crude product was recrystallized by ether and hexane to give the title compound as a while solid (11.5 g, 60percent). ES-MS (M+H)+=258. |
60% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0 - 2℃; for 0.583333 h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at 35℃; for 1 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water for 0.5 h; |
Part A. Preparation of 2-(t-butylamino)sulfonylphenylboronic acid To a solution of 34.0 g (0.16 mol) of benzene-N-(t-butylsulfonamide in 500 ML of THF under N2 was added 160 ML (0.36 mol) of 2.25M n-butyllithium in hexane over 35 min, keeping the temperature between 0°-2°C. The reaction mixture was allowed to warm to room temperature over 1.5h, during which time a thick precipitate formed.. triisopropylborate (46 ML, 0.20 mol) was added, keeping the temperature below 35°C. After 1h, the reaction mixture was cooled, 1N HCl (260 ML) was added, and the mixture was stirred for 30 min.. After diluted with 520 ML of water, the mixture was extracted with 3x400 ML of ether.. The combined organic extracts were extracted with 3x250 ML of 1N NaOH. The aqueous extracts were acidified to PH 1 with 6N HCl, and then extracted with 3x250 ML of ether.. The ether extracts were washed with 250 ML of brine, dried over MgSO4, and the solvents were removed in vacuo to yield 45 g of a thick oil.. After addition of toluene (45 ML), the mixture was agitated for 1h on the rotary evaporator.. A small quantity of solid formed, which was used to induce partial solidification of the remaining crude product.. Addition toluene (150 ML) was added, and the mixture was reduced to 1/2 volume in vacuo, keeping the temperature from 0°-10°C. The resulting precipitate was collected and washed with hexane, then dried under vacuum to give 24.6 g (60percent) of the title compound as white crystals. m.p. 118°-119°C.1HNMR (CDCl3): d 1.18 (s, 9H); 5.13 (s, 1H); 6.29 (br s, 2H); 7.53 (m, 2H); 7.82 (d, 1H); 8.00 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -5 - 22℃; for 1 h; Inert atmosphere Stage #2: at -5 - 22℃; for 3 h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water |
Step 2: 2-Borono-N-tert-butylbenzenesulfonamide; 27 ml of n-butyllithium (15percent solution in n-hexane) are added dropwise at -5° C. to a solution of 4.29 g of N-tert-butylbenzenesulfonamide in 25 ml of THF under argon. The mixture is stirred at 22° C. for 1 h, re-cooled to -5° C., and 2.8 g of trimethyl borate are slowly added dropwise. The mixture is stirred at 22° C. for 3 h, before 100 ml of aqueous ammonium chloride solution is added dropwise. The phases are separated, and the aqueous phase is extracted a further twice with MTB ether. The combined organic phases are dried over magnesium sulfate. Filtered and evaporated to dryness in vacuo.Yield: 42percent of 2-borono-N-tert-butylbenzenesulfonamide;HPLC retention time: 2.42 min (method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36 mg (71%) | With sodium hydroxide; In ethanol; dichloromethane; ethyl acetate; toluene; | Step F 5-n-Butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of 41 mg (0.076 mmol) of 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step E) in 1 mL of toluene was treated with 39.2 mg (0.153 mmol) of 2-(N-t-butylsulfamoyl)phenylboronic acid (prepared from benzenesulfonyl chloride according to the procedures of Example 20, Steps A and B) in 157 mL of ethanol, followed by an additional 0.5 mL of ethanol, 0.24 mL (0.305 mmol) of 1.25N sodium hydroxide (aqueous), and 4.4 mg 0.0038 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was stirred at 90 C. for 6 hours and then concentrated. The residue was taken up in ethyl acetate and washed with H2 O and then brine. The organic phase was dried over Na2 SO4, filtered, and concentrated. The crude product was purified by flash chromatography on 15 cc of silica gel (gradient elution with 0.5-2% MeOH in CH2 Cl2), yielding 36 mg (71%) of white solid, mp 84-86 C.; TLC in 95:5 CH2 Cl2 --MeOH; mass spectrum (FAB) m/e 676 (M+Li)+. 400 MHz 1 H NMR (CD3 OD) delta0.9-1.0 (m, 6H), 1.04 (s, 9H), 1.35-1.46 (m, 4H), 1.59 (m, 2H), 1.61 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 3.37 (t, J=7.2 Hz, 2H), 5.10 (s, 2H), 7.25-7.66 (m, 6H), 7.67 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.4, 2.2 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H), 8.11 (d, J=8 Hz, 1H). |
36 mg (71%) | With sodium hydroxide; In ethanol; dichloromethane; ethyl acetate; toluene; | Step F 5-n-Butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of 41 mg (0.076 mmole) of 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step E) in 1 mL of toluene was treated with 39.2 mg (0.153 mmole) of 2-(N-t-butylsulfamoyl)phenylboronic acid (prepared from benzenesulfonyl chloride according to the procedures of Example 68, Steps A and B) in 157 muL of ethanol, followed by an additional 0.5 mL of ethanol, 0.24 mL (0.305 mmole) of 1.25 N sodium hydroxide (aqueous), and 4.4 mg 0.0038 mmole) of tetrakis(triphenylphosphine)-palladium(0). The mixture was stirred at 90 C. for 6 hours and then concentrated. The residue was taken up in ethyl acetate and washed with H2 O and then brine. The organic phase was dried over Na2 SO4, filtered, and concentrated. The crude product was purified by flash chromatography on 15 cc of silica gel (gradient elution with 0.5-2% MeOH in CH2 Cl2), yielding 36 mg (71%) of white solid, mp 84-86 C.; TLC in 95:5 CH2 Cl2 --MeOH; mass spectrum (FAB) m/e 676 (M+Li)+. 400 MHz 1 H NMR (CD3 OD) delta0.9-1.0 (m, 6H), 1.04 (s, 9H), 1.35-1.46 (m, 4H), 1.59 (m, 2H), 1.61 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 3.37 (t, J=7.2 Hz, 2H), 5.10 (s, 2H), 7.25-7.66 (m, 6H), 7.67 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.4, 2.2 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H), 8.11 (d, J=8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; toluene; for 6h;Heating / reflux; | To a solution of the compound of example 4 (6.4 g, 25 mmol) in toluene (120 ml) was added water (15 ml), 5N sodium hydroxide (40 ml), isopropanol (60 ml), 4-bromoaniline (8.57 g, 50 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.44 g, 1.25 mmol). The mixture was refluxed for 6 hrs, cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with water (50 ml), and dried over magnesium sulfate. After the evaporation of the solvent in vacuo, the crude reside was purified by silica gel chromatography using solvent system 30% ethyl acetate in hexane as eluent to give the title compound as a light yellowish solid (5 g, 66%). ES-MS (M+H)+=305. |
With sodium hydroxide; In water; ethyl acetate; isopropyl alcohol; toluene; | C. Preparation of [2-(4-aminophenyl)phenyl]sulfonyl}(tert-butyl)amine To a solution of 2-[(tert-butyl amino)sulfonyl]phenyl boronic acid (6.00 g, 23.35 mmol) in 120 ml toluene was added water (16 ml), isopropanol (60 ml), and NaOH (40 ml, 5M aqueous solution). To this were added 4-bromoaniline and Pd(Ph3P)4. This heterogeneous mixture is then refluxed for 6 hr, then stirred at room temperature over night before refluxing for another 1.5 hr. The reaction mixture is then extracted with water and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate. The organic layers are then dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel flash chromatography. The desired product can be eluded with 30% ethyl acetate in hexanes and concentrated to an orange solid (5.06 g, 16.65, 71%). ES-MS(M+H)+=305. | |
With sodium hydroxide; In water; ethyl acetate; isopropyl alcohol; toluene; | C. Preparation of [2-(4-aminophenyl)phenyl]sulfonyl}(tert-butyl)amine To a solution of 2-[(tert-butyl amino)sulfonyl]phenyl boronic acid (6.00 g, 23.35 mmol) in 120 ml toluene was added water (16 ml), isopropanol (60 ml), and NaOH (40 ml, 5M aqueous solution). To this were added 4-bromoaniline and Pd(Ph3P)4. This heterogeneous mixture is then refluxed for 6 hr, then stirred at room temperature over night before refluxing for another 1.5 hr. The reaction mixture is then extracted with water and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate. The organic layers are then dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel flash chromatography. The desired product can be eluded with 30% ethyl acetate in hexanes and concentrated to an orange solid (5.06 g, 16.65, 71%). ES-MS(M+H)+=305. |
With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; toluene; for 6h;Heating / reflux; | A. Preparation of 4- [(2-tert-butylaminosulfonyl)phenyl] -aniline; [0175] To a solution of tert-butylamine (5.73 g, 78.4 mmol) and triethylamine (16.6 mL, 119 mmol) in CH2Cl2 (200 mL) in an ice bath, benzenesulfonyl chloride (13.85g, 78.4mmol) was added dropwise. The mixture was stirred at room temperature overnight. It was washed with saturated Na2CO3 (60 mL) and brine (60 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2x50 mL). The combined organic extracts were dried over MgSO4. The solvent was evaporated in vacuo to give the titled compound as a light yellowish solid (15.9 g). MS 214 (M+H).[0176] To a solution of the solid (15.9 g, 74.7 mmol) in THF (200 mL) in an ice bath, n- butyllithium in hexane (1.6 M, 100 mL, 164 mmol) was added dropwise, followed by addition of triisopropylborate (24.1 mL, 104 mmol) dropwise. The mixture was stirred at room temperature for 4 h. While being cooled in an ice bath, IN hydrochloride (200 mL) was added. The mixture was stirred at room temperature overnight. It was extracted with ether (2x50 mL). The organic extract was washed with IN sodium hydroxide (2x60 mL). The aqueous solution was acidified to pH=l with 6N hydrochloride, and then extracted with ether (2xl00ml). The ether extract was dried over MgSO4, and concentrated in vacuo to give the titled compound as a white solid (11.5g). MS 258 (M+H).[0177] A mixture of the white solid (6.00 g, 23.4 mmol), 4-bromoaniline (4.01 g, 23.3 mmol) and Pd(Ph3P)4 (1.35 g, 1.17 mmol) in toluene (120 mL), water (16 mL), isopropanol (60 mL), and aq. NaOH (5M, 40 mL) was heated to reflux for 6 h. After being cooled down, the reaction mixture is partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by a silica gel flash column using 30% ethyl acetate in hexanes as eluents to give a solid (5.06g). MS 305 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; In water; benzene; for 5.5h;Heating / reflux; | Part B. Preparation of 2'-t-butylaminosulfonyl-4-nitro-[1,1']-biphenyl A mixture of 4.4 g (0.020 mol) of 1-bromo-4-nitrobenzene and 5.14 g (0.020 mol) of 2-(t-butylamino)sulfonylphenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (0.001 mol), 0.32 g of tetrabutylammonium bromide (0.001 mol), and 20 ML of 2M aqueous sodium carbonate were refluxed with 180 ML of benzene under N2 for 5.5h.. After cooling the mixture was diluted with methylene chloride and water. the two phases were separated and organic phase was washed with water and brine, dried over MgSO4 and concentrated.. The resulting solid was recrystallized from EtOAc/hexane to afford 3.25 g of the desired biphenyl.(49%).. 1HNMR (CDCl3): d 1.07(s, 9H); 3.60 (br s, 2H); 7.29 (d, 1H); 7.59 (m, 2H); 7.69 (d, 2H); 8.20 (d, 2H); 8.30 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To a solution of the compound of example 3 (15.92 g, 74.7 mmol) in tetrahydrofuran (200 ml) in an ice bath was added 1.6M n-butyllithium in hexane (100 ml, 164 mmol) dropwise over 30 minutes. The mixture remained a clear solution. In an ice bath it was added triisopropylborate (24.1 ml, 104 mmol) dropwise. The mixture was stirred at room temperature for 3.5 hrs, solution becoming cloudy. After it was cooled in an ice bath, 1N hydrochloride (200 ml) was added. The mixture was stirred at room temperature overnight. It was extracted with ether (2×50 ml). The organic extract was washed with 1N sodium hydroxide (2×60 ml). The aqueous solution was acidified to pH=1 with 6N hydrochloride, and then extracted with ether (2×100 ml). The ether extract was dried over magnesium sulfate, and concentrated in vacuo. The crude product was recrystallized by ether and hexane to give the title compound as a while solid (11.5 g, 60%). ES-MS (M+H)+=258. | |
60% | Part A. Preparation of 2-(t-butylamino)sulfonylphenylboronic acid To a solution of 34.0 g (0.16 mol) of benzene-N-(t-butylsulfonamide in 500 ML of THF under N2 was added 160 ML (0.36 mol) of 2.25M n-butyllithium in hexane over 35 min, keeping the temperature between 0-2C. The reaction mixture was allowed to warm to room temperature over 1.5h, during which time a thick precipitate formed.. triisopropylborate (46 ML, 0.20 mol) was added, keeping the temperature below 35C. After 1h, the reaction mixture was cooled, 1N HCl (260 ML) was added, and the mixture was stirred for 30 min.. After diluted with 520 ML of water, the mixture was extracted with 3x400 ML of ether.. The combined organic extracts were extracted with 3x250 ML of 1N NaOH. The aqueous extracts were acidified to PH 1 with 6N HCl, and then extracted with 3x250 ML of ether.. The ether extracts were washed with 250 ML of brine, dried over MgSO4, and the solvents were removed in vacuo to yield 45 g of a thick oil.. After addition of toluene (45 ML), the mixture was agitated for 1h on the rotary evaporator.. A small quantity of solid formed, which was used to induce partial solidification of the remaining crude product.. Addition toluene (150 ML) was added, and the mixture was reduced to 1/2 volume in vacuo, keeping the temperature from 0-10C. The resulting precipitate was collected and washed with hexane, then dried under vacuum to give 24.6 g (60%) of the title compound as white crystals. m.p. 118-119C.1HNMR (CDCl3): d 1.18 (s, 9H); 5.13 (s, 1H); 6.29 (br s, 2H); 7.53 (m, 2H); 7.82 (d, 1H); 8.00 (d, 1H). | |
A. Preparation of 4- [(2-tert-butylaminosulfonyl)phenyl] -aniline; [0175] To a solution of tert-butylamine (5.73 g, 78.4 mmol) and triethylamine (16.6 mL, 119 mmol) in CH2Cl2 (200 mL) in an ice bath, benzenesulfonyl chloride (13.85g, 78.4mmol) was added dropwise. The mixture was stirred at room temperature overnight. It was washed with saturated Na2CO3 (60 mL) and brine (60 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2x50 mL). The combined organic extracts were dried over MgSO4. The solvent was evaporated in vacuo to give the titled compound as a light yellowish solid (15.9 g). MS 214 (M+H).[0176] To a solution of the solid (15.9 g, 74.7 mmol) in THF (200 mL) in an ice bath, n- butyllithium in hexane (1.6 M, 100 mL, 164 mmol) was added dropwise, followed by addition of triisopropylborate (24.1 mL, 104 mmol) dropwise. The mixture was stirred at room temperature for 4 h. While being cooled in an ice bath, IN hydrochloride (200 mL) was added. The mixture was stirred at room temperature overnight. It was extracted with ether (2x50 mL). The organic extract was washed with IN sodium hydroxide (2x60 mL). The aqueous solution was acidified to pH=l with 6N hydrochloride, and then extracted with ether (2xl00ml). The ether extract was dried over MgSO4, and concentrated in vacuo to give the titled compound as a white solid (11.5g). MS 258 (M+H).[0177] A mixture of the white solid (6.00 g, 23.4 mmol), 4-bromoaniline (4.01 g, 23.3 mmol) and Pd(Ph3P)4 (1.35 g, 1.17 mmol) in toluene (120 mL), water (16 mL), isopropanol (60 mL), and aq. NaOH (5M, 40 mL) was heated to reflux for 6 h. After being cooled down, the reaction mixture is partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by a silica gel flash column using 30% ethyl acetate in hexanes as eluents to give a solid (5.06g). MS 305 (M+H). |
N-tert-Butylbenzenesulfonamide (2.00 g, 12.7 mmol) was dissolved in anhydrous THF (10 mL). After being cooled to -78 C., n-BuLi (2.5 M, 6.0 mL) was injected slowly to the above solution. After being stirred at this temperature for another 1 h, triisopropyl borate (11.9 g, 63.5 mmol) was added at -78 C. The resulting mixture was then allowed to warm to room temperature slowly for 8 h. 1N HCl (10 mL) was added to hydrolyze the borate. The organic layer was dried over Na2SO4. After removal of the solvent, the residue was used for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethanolamine;PdCl2[dppf]; In 1,2-dimethoxyethane; ethyl acetate; | Step 1: A solution of methyl 4-bromo-2-methyl benzoate (370 mg, 1.24 mmol, 1.0 equiv), 2-t-butylaminosulfonyl phenyl boronic acid (319 mg, 1.0 equiv), PdCl2(dppf) (101 mg, 0.1 equiv), TEA (860 muL, 5.0 equiv) in 10 mL of DME was degassed with Ar for 15 min, then heated to reflux overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, dried over MgSO4, evaporated. Flash chromatography on silica gel with 1:1 EtOAc/hexanes gave methyl 4-(2'-tert-butylaminosulfonyl)phenyl-2-methyl benzoate in 86% yield. LRMS found for C19H24NO4S (M+H)+: 362.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 12h; | A mixture of 2-(t-butylamino)sulfonylphenyl boronic acid (12.4 g, 0.048 mol), Compound 10c (13.6 g, 0.037 mol), Pd(dppf)Cl2CH2Cl2 (3.00 g, 3.70 mmol), TBAB (11.9 g, 0.037 mmol), and Na2CO3 (31.4, 0.296 mol) in 750 mL of mixed solvent (DME:water, 4:1) was heated at 90 C. for 12 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, hexanes:EtOAc, 1:1) to provide the title Compound 309 as a yellow oil. 1H-NMR (400 MHz, CD3OD) delta (ppm): 8.14 (dd, 1H, J=1.6 and 7.6 Hz) 7.84 (d, 2H, J=8.4 Hz) 7.73 (d, 2H, J=8.4 Hz) 7.70-7.62 (m, 4H) 7.54 (dt,1H, J=1.6 and 8.6 Hz) 7.41 (dd, 1H, J=1.2 and 7.6 Hz) 7.37-7.31 (m, 2H) 1.00 (s, 9H) MS (ESI, pos. ion) m/z: 490.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃; for 12h; | B. 2-tert-butoxycarbonylamino-5-(2-tert-butylaminosulfonyl-phenyl)-phenyl carbamic acid tert-butyl ester A solution of (5-bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester (4.0 g, 10.3 mmol), 2-(tert-butylaminosulfonyl)-phenyl boronic acid (5.3 g; 20.6 mmol), PdCl2 dppf (1.7 g, 0.20 mmol) and 1M Na2CO3 solution (83 mL, 82.7 mmol) in 1,2-dimethoxyethane was heated to 90 C. for 12 h under inert atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica, EtOAc: hexanes, 3:7) to afford the title compound as a yellow viscous oil (5.4 g, quantitative yield). 1H NMR (400 MHz, CDCl3) delta (ppm): 8.14 (m, 1H), 7.88 (m, 1H), 7.43-7.69 (m, 6H), 7.19 (m, 1H), 7.28 (m, 1H), 1.52 (s, 9H), 1.48 (s, 9H), 1.06 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H37N3O6S: 520.65 (M+H), Found 520.1. |
With tetrabutylammomium bromide; sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 12h; | A mixture of 2-(t-butylamino)sulfonylphenyl boronic acid (4.7 g, 0.018 mmol), Compound 16a (4.7 g, 0.012 mmol), Pd(dppf)Cl2.CH2Cl2 (0.99 g, 0.0012 mmol), TBAB (3.90 g, 0.012 mmol), and 20 mL of 1 M Na2CO3 (aq) in 100 mL of DME was heated at 100 C. for 12 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, hexanes:EtOAc, 2:1) to provide the title Compound 16b as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 150℃; for 1h;Microwave synthesizer; | A mixture of Compound 30a (25 mg, 0.075 mmol), 2-(tert-butylamino)sulfonylphenyl boronic acid (29 mg, 0.113 mmol), and Pd(dppf)Cl2.CH2Cl2 (12 mg, 0.015 mmol) in 3 mL of DME and sodium carbonate solution (1.0 M, 0.6 mL) was heated at 150 C. for 1 h in a Biotage Initiator microwave synthesizer. The mixture was filtered through a pad silica gel. The residue was purified by preative TLC (silica gel, 20×20 cm, 2000 microns, EtOAc:hexanes 3:7) to provide the title Compound 31a (12.8 mg). Mass Spectrum (LCMS, APCl pos.) Calcd. For C25H23N3O2S: 430.2 (M+H), Found 430.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; In water; toluene; for 4.5h;Heating / reflux; | A mixture of 15a (0.525 g, 1.09 mmol), 2-tert-butylsulfamoylphenyl boronic acid (0.339 [G,] [1.] 31 mmol), tetrabutylammonium bromide (0.018 mg, 0.055 mmol), sodium carbonate (0.232 g, 2.19 [MMOL),] and water (1 mL) in toluene [(I L] mL) was degassed with a stream of argon. Tetrakis (triphenylphosphine) Pd [(0)] (0.127 g, 0.109 mmol) was then added, and the mixture heated at reflux under an argon atmosphere for 4.5 h. The resulting solution was allowed to cool to RT and concentrated to a solid which was partitioned between EtOAc and water. The organic layer was separated and washed with brine and dried over [MGS04. CONCENTRATION] of the organic layer, and purification of the resulting residue by MPLC resulted in the product 15b (0.345 g, 52%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 110℃; for 17h; | Bromide 17a (0.172 g, 0.397 mmol) was combined with 2-tert-butylphenylsulfamoyl boronic acid (0.153 g, 0.595 mmol), [K3PO4] (0.126 g, 0.595 mmol), and anhydrous DMF [(5ML).] The mixture was degassed with argon before and after the addition of tetrakis (triphenylphosphine) palladium [(0)] (0.046 g, 0.040 mmol). The mixture was stirred at [110C] for 17 h before cooling and partitioning between EtOAc and [H20.] The organic layer was washed with brine and then dried over [MGS04.] Concentration of the solution under reduced pressure and purification of the crude product by flash chromatography revealed 17b [(0. 050] g, [22%)] as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; benzene; at 90℃; for 12h; | A suspension of 0.50 g of 2-(tert-butylsulfamoyl)phenyl(dihydroxy)borane, 0.802 g of 3-[N-[2-(4-bromophenyl)ethyl]sulfamoyl]-4-methoxybenzamide, 0.224 g of tetrakis(triphenylphosphine)palladium(0), 62 mg of tetrabutylammonium bromide, and 0.441 g of sodium carbonate in water (1.9 mL)-benzene (12 mL) was stirred at 90 ºC for 8 hours. To the mixture was added 0.205 g of sodium carbonate, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added 1 mol/L hydrochloric acid and a small amount of methanol, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate - hexane) to give 0.641 g of 3-[N-[2-(2'-tert-butylsulfamoylbiphenyl-4-yl)ethyl]sulfamoyl]-4-methoxybenzamide.1H-NMR (CDCl3) delta ppm: 1.01 (9H, s), 2.87 (2H, t, J=6.6Hz), 3.23 (2H, q, J=6.6Hz), 3.68 (1H, br s), 3.95 (3H, s), 4.96 (1H, t, J=6.6Hz), 5.30-6.50 (2H, br), 7.10 (1H, d, J=8.5Hz), 7.20 (2H, d, J=8.2Hz), 7.25-7.29 (1H, m), 7.44 (2H, d, J=8.2Hz), 7.49 (1H, td, J=7.6, 1.3Hz). 7.56 (1H, td, J=7.6, 1.3Hz), 8.17 (1H, dd, J=7.6, 1.3Hz), 8.19 (1H, dd, J=8.5, 2.2Hz), 8.27 (1H, d, J=2.2Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; toluene; for 3 - 4h;Heating / reflux; | To a solution of the compound of example 4 (2.06 g, 8 mmol) in toluene (60 ml) was added water (4 ml), 8N sodium hydroxide (8 ml), isopropanol (16 ml), 2-fluoro-4-iodoaniline (3.8 g, 16 mmol) and tetrakis(triphenylphosphine)palladium (0) (464 mg, 0.4 mmol). The mixture was refluxed for 3-4 hrs, cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with water (25 ml), and dried over magnesium sulfate. After the evaporation of the solvent in vacuo, the crude reside was purified by silica gel column chromatography using solvent system 20-30% ethyl acetate in hexane as eluent to give the title compound as a white solid (1.49 g, 58%). ES-MS (M+H)+=323. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 12h; | 2-(t-Butylaminosulfonyl)phenylboronic acid (1.0 g, 3.98 mmol), 3-bromobenzaldehyde (0.46 mL, 3.98 mmol), K3PO4 (1.27 g, 5.97 mmol), and Pd[PPh3]4 (0.46 g, 10%) were dissolved together in 30 mL of dioxane. The mixture was de-gassed and heated at 110 C. under N2 for 12 h. The reaction mixture was cooled, poured into water, and extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. It was concentrated and purified by chromatography (silica gel, 25% EtOAc in hexane) to give 1.15 g of the biarylaldehyde. MS: 339.3 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; toluene; for 3 - 4h;Heating / reflux; | To a solution of the compound of example 4 (2.06 g, 8 mmol) in toluene (60 ml) was added water (4 ml), 8N sodium hydroxide (8 ml), isopropanol (16 ml), 2-chloro-4-iodoaniline (4.06 g, 16 mmol) and tetrakis(triphenylphosphine)palladium(0) (464 mg, 0.4 mmol). The mixture was refluxed for 3-4 hrs, cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with water (25 ml), and dried over magnesium sulfate. After the evaporation of the solvent in vacuo, the crude reside was purified by silica gel column chromatography using solvent system 20-30% ethyl acetate in hexane as eluent to give the title compound as a white solid (1.43 g, 53%). ES-MS (M+H)+=339. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; In water; toluene; for 6h;Heating / reflux; | Method B A mixture of 12.8 g (0.047 mol) of <strong>[131818-17-2]1-Bromo-4-t-butoxycarbonylaminobenzene</strong> and 12.3 g (0.048 mol) of 2-(t-butylamino)sulfonylphenylboronic acid, 3.0 g of tetrakis(triphenylphosphine) palladium(0) (0.0026 mol), 0.80 g of tetrabutylammonium bromide (0.0024 mol), and 13.8 g (0.10 mol, in 30 ml of water) potassium carbonate were refluxed with 300 ML of toluene under N2 for 6h.. The toluene was removed in vacuo and the residue was dissolved in methylene chloride and water.. The two phases were separated and organic phase was washed with water and brine, dried over MgSO4 and concentrated. the crude product was purified by chromatography on silica gel eluted with EtOAc/hexane (1:3) to afford 12.66 g of the desired biphenyl.(67%). The protected aminobiphenyl compound (2.80 g, 6.9 mmol) was stirred with 10 ML of triflouroacetic acid and 20 ML of methylene chloride at room temperature for 2h.. The solvents were removed in vacuo.. The residue was dissolved in methylene chloride and precipitated with hexane to give 1.20 g of the desired product as the TFA salt. 1HNMR (DMSO-d6): d 1.01(s, 9H); 6.80 (s, 1H); 7.20-7.68 (m, 8H);8.03 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 2-methyl-propan-1-ol; water; toluene; at 80℃; for 5h; | Example 10 Synthesis of N-tert-Butyl-2-[6-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylamino)-pyridin-3-yl]-benzenesulfonamide (11) A mixture of (5-bromo-pyridin-2-yl)-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-amine (10) (564 mg, 1.55 mmol), tetrakis(triphenylphosphine) palladium(0) (174 mg, 0.15 mmol), cesium carbonate (1.56 g, 4.8 mmol), 2-tert-butylsulfamoyl-phenylboronic acid (438 mg, 1.7 mmol) in a solution of toluene (20 mL), iso-butyl alcohol (15 mL) and water (5 mL) was stirred at 80 C. under nitrogen for 5 h. The reaction was diluted with water and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel to give N-tert-butyl-2-[6-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylamino)-pyridin-3-yl]-benzenesulfonamide (11) as a colorless solid (554 mg, 74% yield). 1H-NMR (CDCl3): delta 8.15 (d, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.68 (d, 1H), 7.55 (t, 1H), 7.46 (t, 1H), 7.27 (d, 1H), 6.47 (d, 1H), 4.91 (s, 2H), 4.84 (t, 1H), 4.44 (d, 2H), 3.76 (s, 1H), 2.40 (s, 3H), 1.55 (s, 6H), 1.03 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 85℃; for 1.5h; | 2.1 1.0 g of <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong>, 8.0 ml of 2M sodium carbonate solution and 75 mg of PdCl2(dppf) are added successively to a solution of 0.7 g of "AD" in 40 ml of ethylene glycol dimethyl ether, and the mixture is stirred at 85 for 1.5 hours. Conventional work-up gives 0.65 g of 2'-tert-butylaminosulfonylbiphenyl-4-yl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propylcarbamate ("AE"), m.p. 122-123, EI 562. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;Pd(Ph3P)4; In 1,2-dimethoxyethane; | Synthesis of methyl 4-(2-t-butylaminosulfonylphenyl)-benzoate A solution of 2-t-butylaminosulfonyl-benzeneboronic acid (250 mg, 0.965 mmol) and methyl 4-bromobenzoate (172 mg, 0.8 mmol) in degassed DME (5 mL) and 2M Na2CO3 (1.5 mL) under N2 was treated with Pd(Ph3P)4 (46 mg, 5 mol %), and heated to reflux for 1.5 h. Conventional workup followed by flash chromatography gave the title compound in a quantitative yield. 1H-NMR (500 MHz, CDCl3) delta8.18 (d, J=7.8 Hz, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.59-7.50 (m, 4H), 7.29 (d, J=7.3 Hz, 1H), 3.95 (s, 3H), 3.48 (s, 1H), 1.02 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethanolamine;PdCl2[dppf]; In 1,2-dimethoxyethane; | Step 2: A solution of 3-[2-(5-bromo-1,3-dioxoisoindolin-2-yl)ethoxy]benzonitrile (124 mg, 0.3 mmol, 1.0 equiv), 2-tert-butylaminosulfonyl phenyl boronic acid (86 mg, 1.0 equiv), PdCl2(dppf) (27 mg, 0.1 equiv), TEA (230 muL, 5.0 equiv) in 5 mL of DME was degassed with Ar for 15 min, refluxed overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, dried over MgSO4, and evaporated. Flash chromatography on silica gel gave 3-{2-[5-(2'-tert-butylaminosulfonyl)phenyl-1,3-dioxoisoindolin-2-yl]ethoxy}benzonitrile in 75% yield. LRMS found for C27H26N3O5S (M+H)+: 504.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
480 mg (52%) | With n-Bu4NBr;Pd(Ph3P)4; In benzene; | Ethyl 4-[4-(2-t-butylaminosulfonylphenyl)-phenyl]-1-(3-cyanobenzyl)-pyrrole-3-carboxylate A solution of ethyl 4-(4-bromophenyl)-1-(3-cyanobenzyl)-pyrrole-3-carboxylate (1.39 g, 3.4 mmol), 2-t-butylaminosulfonyl-benzeneboronic acid (874 mg, 3.40 mmol), Pd(Ph3P)4 (196 mg, 5 mol %), n-Bu4NBr (55 mg, 5 mol %) and 2M NaCO3(3.4 mL) in benzene (30 mL) was refluxed for 5 h. The reaction was diluted with ethyl acetate, washed with water, dried and concentrated. The oily residue was flash-chromatographed to give 480 mg (52%) of the title compound. 1H-NMR (500 MHz, CDCl3) delta8.17 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.55-7.48 (m, 5H), 7.47-7.41 (m, 3H), 7.35 (d, J=7.3 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 5.14 (s, 2H), 4.23 (q, J=6.9 Hz, 2H), 3.66 (s, 1H), 1.28 (t, J=6.9 Hz, 3H), 1.00 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethanolamine;PdCl2[dppf]; In 1,2-dimethoxyethane; ethyl acetate; | Step 2: A solution of methyl 2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenyl acetate (540 mg, 1.5 mmol, 1.0 equiv), 2-t-butylaminosulfonyl phenyl boronic acid (385 mg, 1.0 equiv), PdCl2(dppf) (122 mg, 0.1 equiv), TEA (1.1 mL, 5.0 equiv) in 10 mL of DME was degassed with Ar for 15 min, then heated to reflux overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, dried over MgSO4, evaporated. Flash chromatography on silica gel with 1:1 EtOAc/hexanes gave methyl 2-[5-(2'-tert-butylaminosulfonyl)phenyl-oxoisoindolin-2-yl]-2-phenylacetate in 92% yield. LRMS found for C27H29N2O5S (M+H)+: 493.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; n-butyllithium; In tetrahydrofuran; | EXAMPLE 8 Preparation of Boronic Acids Synthesis of 2-t-butylaminosulfonyl-benzeneboronic acid (J. Med. Chem. 1999, 42, 2752-2759) To a solution of t-butylaminosulfonylbenzene (30 g, 0.14 mol) in dry THF (350 mL) at 0 C. was added n-BuLi (2.2 M in Hex, 130 mL) in 30 minutes, then the reaction was stirred for 30 minutes at 10 C. Triisopropylborate (36 g) was added while keeping the inner temperature below 35 C. After stirring for 1 h, the reaction was cooled with ice bath, treated with 1 N HCl (228 mL), then stirred for 1 day. The reaction was extracted with ether (200 mL*3), then the organic layer was reextacted with 1N NaOH (200 mL*3). Acidification of the aqueous exact with 6N HCl to pH 1, reextraction with ether (200 mL*3), drying with MgSO4 followed by concentration gave 18 g (50%) of the title compound as white solid. The following boronic acids were prepared similarly. | |
With n-butyllithium; In tetrahydrofuran; | B. Preparation of 2-[(tert-butyl amino)sulfonyl]phenyl boronic acid To (tert-butyl)(phenylsulfonyl)amine (17.43 g, 81.83 mmol) in 180 ml dry THF in an ice bath was added nBuLi (66 ml, 2.5M in hexanes) via addition funnel. Then triisopropyl borate (33 ml, 143.06 mmol) was added via addition funnel. The mixture was warmed to room temperature and allowed to stir for 4 hr. The reaction mixture was then cooled in an ice bath before HCL (82 ml, 3M) was added dropwise. This was allowed to stir at room temperature for 3 hr. The mixture was then put in the freezer over the weekend. The reaction was then warmed to room temperature and extracted with ether. The aqueous layers were washed twice more with ether. The combined organic layers were washed three times with 5M NaOH aqueous solution. The combined basic layers were acidified to pH=1 with 6M HCL solution. These acidified layers were then extracted three times with ether. These ether layers were then dried over MgSO4, filtered, then concentrated in vacuo to about 50 ml solution. To this solution was added hexanes and a minimal amount of ethyl acetate. A white precipitate is observed and the mixture in stored in the freezer to allow for crystallization. The white solid is then filtered and collected (14.65 g, 57mml, 70%) ES-MS(M+H)+=258. | |
With n-butyllithium; In tetrahydrofuran; | B. Preparation of 2-[(tert-butyl amino)sulfonyl]phenyl boronic acid To (tert-butyl)(phenylsulfonyl)amine (17.43 g, 81.83 mmol) in 180 ml dry THF in an ice bath was added nBuLi (66 ml, 2.5M in hexanes) via addition funnel. Then triisopropyl borate (33 ml, 143.06 mmol) was added via addition funnel. The mixture was warmed to room temperature and allowed to stir for 4 hr. The reaction mixture was then cooled in an ice bath before HCL (82 ml, 3M) was added dropwise. This was allowed to stir at room temperature for 3 hr. The mixture was then put in the freezer over the weekend. The reaction was then warmed to room temperature and extracted with ether. The aqueous layers were washed twice more with ether. The combined organic layers were washed three times with 5M NaOH aqueous solution. The combined basic layers were acidified to pH=1 with 6M HCL solution. These acidified layers were then extracted three times with ether. These ether layers were then dried over MgSO4, filtered, then concentrated in vacuo to about 50 ml solution. To this solution was added hexanes and a minimal amount of ethyl acetate. A white precipitate is observed and the mixture in stored in the freezer to allow for crystallization. The white solid is then filtered and collected (14.65 g, 57 mml, 70%) ES-MS(M+H)+=258. |
With hydrogenchloride; n-butyllithium; | Step D 2-(N-t-Butylsulfamoyl)phenylboronic acid To a solution of 11.2 mmol of N-t-butylbenzenesulfonamide (from Step C) in anhydrous THF (20 mL) cooled to -40 C. under N2 was addeel 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. To the mixture, containng the dianion at 0 C., was added triisopropyl borate (3.9 mL, 1.5 equiv). The next day, 2 N HCl (3 mL) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with EtOAc. The organic solution was washed with 2N HCl, H2 O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. The material was used in the next step without further purification. | |
To a stirred solution of 0.30 g of N-(tert-butyl)-benzenesulfonamide in 5.0 mL of tetrahydrofuran was added dropwise 2.21 mL of 1.5 mol/L n-butyl lithium-hexane solution over 4 minutes under ice-cooling and argon atmosphere. The temperature of the reaction mixture was turned to room temperature gradually, and stirred for 1. 5 hours. To the stirred reaction mixture were added 0.40 mL of triisopropyl borate and 2.0 mL of tetrahydrofuran, and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture was added 2.3 mL of 1 mol/L hydrochloric acid, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was extracted with 1 mol/L sodium hydroxide solution, and the aqueous layer was acidified by addition of 6 mol/L hydrochloric acid. After the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 0.180 g of 2-(tert-butylsulfamoyl)phenyl(dihydroxy)borane.1H-NMR (CDCl3) delta ppm: 1.19 (9H, s), 5.01 (1H, br s), 6.03 (2H, br s), 7.52 (1H, td, J=7.3, 1.3Hz), 7.56 (1H, td, J=7.3, 1.3Hz), 7.85 (1H, dd, J=7.3, 1.3Hz), 8.02 (1H, dd, J=7.3, 1.3Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; | Example 37 To a solution of 7-[(6-bromo-2-oxohydroquinolyl)methyl]naphthalene-2-carbonitrile (30 mg, 0.077 mmol), 2-[(tert-butyl)amino]sulfonyl}phenylboronic acid (20 mg, 0.077 mmol), Pd2(dba)3 (1 mg, 1.5 mol %), and cesium carbonate (25 mg, 0.093 mmol) in dry dioxane (300 muL) was added tri-t-butylphosphine (0.7 uL, 3.6 mol %). The reaction was heated to 75 C. for 11 h, cooled to room temperature, and diluted with CH2Cl2 (2 mL). The solution was then filtered through celite, washed with 1N HCl and sat. NaCl, dried over MgSO4, and concentrated in vacuo to afford 7-[6-(2-[(tert-butyl)amino]sulfonyl}phenyl)-2-oxohydroquinolyl]methyl}naphthalene-2-carbonitrile (34 mg, 85%). ES-MS (M+H)+=522.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;Pd(Ph3P)4; In 1,2-dimethoxyethane; water; ethyl acetate; | Example 15 N-(2,6-Dichlorobenzoyl)-4-[2-[N-(tert-butyl)sulfamoyl]phenyl]-L-phenylalanine methyl ester 2-[N-(tert-Butyl)sulfamoyl]benzeneboronic acid (0.4 g) was dissolved in DME (10 mL). To this solution was added K2CO3 (0.1 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester (0.1 g), Pd(Ph3P)4 (0.1 g) and water (0.2 mL). The mixture was heated at 80 C. overnight. After cooling, EtOAc and water were added to the mixture. The EtOAc phase was dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give 100 mg of the title compound. ESMS: m/z 585 ([M+Na]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine;PdCl2[dppf]; In 1,2-dimethoxyethane; hexane; ethyl acetate; | Example 2 Preparation of (tert-Butoxy)-N-[2-([4-(2-[(tert-butyl)amino]sulfonyl}phenyl)phenyl]sulfonyl}amino)ethyl]carboxamide A mixture of the compound in example 1 (380 mg, 1.0 mmol), 2-[(tert-butyl)amino]sulfonyl}phenyl boronic acid (308 mg, 1.2 mmol), triethyl amine (0.7 mL, 5.0 mmol), and PdCl2(dppf) (40 mg, 0.05 mmol) in DME (15 mL), was heated at 90 C. overnight. Upon completion of reaction, the mixture was filtered through a short plug of silica gel. The silica gel was washed with a mixture of EtOAc:Hexane (1:1), and the combined filtrate was evaporated to give 500 mg of the titled compound as a brown solid in 98% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.34 g (49%) | With tetrabutylammomium bromide; In dichloromethane; water; benzene; | Part B. Preparation of 2-amino-5-(2-t-butylaminosulfonyl)phenylpyridine. A mixture of 1.55 g (9.0 mmol) of 2-amino-5-bromopyridine and 2.3 g (9.0 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 0.52 g of tetrakis(triphenylphosphine) palladium(O) (0.45 mmol), 0.15 g of tetrabutylammonium bromide (0.45 mmol) and 9 mL of 2M aqueous sodium carbonate were refluxed with 80 mL of benzene under Ar for 5 hours. After cooling, the mixture was diluted with 25 mL of methylene chloride and 25 mL of water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 50% EtOAc/hexane to afford 1.34 g (49%) of the aniline. 1 H NMR (CDCl3): delta 8.18 (d, 1H); 8.07 (m, 1H); 7.70 (dd, 1H); 7.58 (dt, 1H); 7.48 (dt, 1H); 7.28 (d, 1H); 6.56 (d, 1H); 4.62 (br s, 2H); 3.88 (br s, 1H); 1.06 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.65 g (49%) | With nitrogen; tetrabutylammomium bromide; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In benzene; | Part D. Preparation of trans-1-[(2'-tert-butylaminosulfonyl-[1,1']-biphenyl-4-yl)methyl]-3-carbomethoxy-4-(3-cyanophenyl)pyrrolidine. To a solution of trans-1-(4-bromobenzyl)-3-carbomethoxy-4-(3-cyanophenyl)pyrrolidine (1.0 g, 2.5 mmol) in 50 mL of benzene was added <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong> (0.90 g, 3.5 mmol), tetrabutylammonium bromide (0.04 g, 0.12 mmol), sodium carbonate (0.79 g, 7.5 mmol) and 8.2 mL of H2 O. This mixture was degassed with a stream of nitrogen and then tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) was added and the reaction mixture was stirred at 80 C. for 6 h. The mixture was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with H2 O and brine, dried over MgSO4 and was concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexanes/ethyl acetate) to afford 0.65 g (49%) of the title compound. MS (ESI) 532.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.52 g (85%) | With nitrogen; tetrabutylammomium bromide; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In benzene; | Part D. Preparation of trans-2-[(2'-tert-butylaminosulfonyl-[1,1']-biphenyl-4-yl)methyl]-4-carbomethoxy-5-(3-cyanophenyl)isoxazolidine. To a solution of trans-2-(4-bromobenzyl)-4-carbomethoxy-5-(3-cyanophenyl)isoxazolidine (0.46 g, 1.15 mmol) in 20 mL of benzene was added <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong> (0.45 g, 1.72 mmol), tetrabutylammonium bromide (0.04 g, 0.12 mmol), sodium carbonate (0.36 g, 3.4 mmol) and 2 mL of H2 O. This mixture was degassed with a stream of nitrogen and then tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) was added and the reaction mixture was stirred at 80 C. for 6 h. The mixture was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with H2 O and brine, dried over MgSO4 and was concentrated in vacuo. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford 0.52 g (85%) of the title compound. MS (ESI) 534.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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0.22 g (69%) | With nitrogen; tetrabutylammomium bromide;tetrakis(triphenylphosphine) palladium(0); In benzene; | Part G. Preparation of trans-1-(methylsulfonyl)-3-([2'-tert-butylaminosulfonyl-[1,1']-biphenyl-4-yl)methylcarbonyl)-4-(3-cyanophenyl)pyrrolidine. To a solution of trans-1-(methylsulfonyl)-3-[(4-bromophenyl)methylcarbonyl]-4-(3-cyanophenyl)pyrrolidine (0.25 g, 0.56 mmol) in 10 mL of benzene was added <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong> (0.29 g, 1.12 mmol), tetrabutylammonium bromide (0.04 g, 0.11 mmol) and aqueous sodium carbonate (1.12 mL of a 2.0M aq solution, 2.24 mmol). This mixture was degassed with a stream of nitrogen and then tetrakis(triphenylphosphine)palladium (0.07 g, 0.06 mmol) was added and the reaction mixture was stirred at 80 C. for 6 h. The mixture was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with H2 O and brine, dried over MgSO4 and was concentrated in vacuo. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.22 g (69%) of the title compound. MS (ESI) 580.4 (M+H)+. |
0.22 g (69%) | With nitrogen; tetrabutylammomium bromide;tetrakis(triphenylphosphine) palladium(0); In benzene; | Part G. Preparation of trans-1-(methylsulfonyl)-3-([2'-tert-butylaminosulfonyl-[1,1']-biphenyl-4-yl)methylcarbonyl)-4-(3-cyanophenyl)pyrrolidine. To a solution of trans-1-(methylsulfonyl)-3-[(4-bromophenyl)methylcarbonyl]-4-(3-cyanophenyl)pyrrolidine (0.25 g, 0.56 mmol) in 10 mL of benzene was added <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong> (0.29 g, 1.12 mmol), tetrabutylammonium bromide (0.04 g, 0.11 mmol) and aqueous sodium carbonate (1.12 mL of a 2.0 M aq solution, 2.24 mmol). This mixture was degassed with a stream of nitrogen and then tetrakis(triphenylphosphine)palladium (0.07 g, 0.06 mmol) was added and the reaction mixture was stirred at 80 C for 6 h. The mixture was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with H2O and brine, dried over MgSO4 and was concentrated in vacuo. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.22 g (69%) of the title compound. MS (ESI) 580.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In chloroform; | 2-Amino-4-(4-methoxyphenyl)-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]thiazole 2-amino-4-(4-methoxyphenyl)-5-(4-bromophenyl)thiazole (1.68 g, 4.15 mmol), sodium carbonate (0.88 g, 8.31 mmol), tetrabutylammoniumbromide (0.134 g, 0.415 mmol) and <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenyl boronic acid</strong> (1.50 g, 5.82 mmol) were combined in a solution containing 1:1:4 of benzene:acetonitrile:water and degassed with N2 for 15 min. After the N2 purge, tetrakistriphenylphosphine palladium (0) was added and the reaction mixture heated to reflux overnight. The solution was diluted with EtOAc, placed in a separatory funnel and washed with three, 150 mL portions of brine. The organics were dried over MgSO4, filtered through a plug of silica gel and the volatiles removed in vacuum. The residue was dissolved in a minimal amount of hot CHCl3, the product triturated with Et2 O and isolated (1.59 g, 71.3%) by vacuum filtration. MS (NH3 -DCI) 537.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With tetrabutylammomium bromide; potassium carbonate; In water; toluene; | PART E: Preparation of 5-Methoxycarbonyl-1-[2'-((t-butylamino)sulfonyl)biphen-4-yl]methyl-2-propyl-4-([4-(2-pyridyl)-piperazin-1-yl]methyl)imidazole A mixture of 0.92 g (1.80 mmole) of the bromobenzylimidazole prepared in Example 114, Part C, 0.46 g (1.80 mmole) 2-((t-butylamino)sulfonyl)phenyl boronic acid (Example 114, Part D), 0.06 g (0.019 mmole) tetrabutylammonium bromide, and 0.50 g (3.62 mmole) potassium carbonate in 1 mL of water and 9 mL of toluene was degassed and placed under a nitrogen atmosphere. To this mixture was added 0.10 g (0.087 mmole) of tetrakis(triphenylphosphine)-palladium and the degassing procedure repeated. The reaction mixture was refluxed overnight, cooled, diluted to 25 mL with toluene and washed with 50 mL water. The aqueous layer was washed an additional two times with 25 mL of toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide;tetrakis(triphenylphosphine)palladium (0); In ethanol; ethyl acetate; toluene; | Step J 3-n-Butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile A reaction flask was charged with 155 mg (0.299 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile (from Step H), 3.5 mL of toluene, 2.4 mL of ethanol, 615 muL (0.598 mmol) of a 250 mg/mL solution of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step I) in ethanol, 950 muL (1.20 mmol) of 1.25N NaOH, and 17 mg of tetrakis(triphenylphosphine)palladium(0). The mixture was stirred under N2 at 90 C. for 5 hours, then cooled and concentrated. The residue was partitioned between 30 mL of ethyl acetate and 25 mL of H2 O. The organic layer was washed with brine, dried (Na2 SO4), filtered, and evaporated in vacuo. The yellow residual oil was flash chromatographed on silica gel (elution with 3:1 and then 1:1 hexane-EtOAc) to give a 77% yield of the title compound as a slightly yellow, stiff foam; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 650 (M+1)+. 400 MHz 1 H NMR (CDCl3) delta0.92 (t, J=7.3 Hz, 3H), 100 (s, 9H), 1.21 (t, J=7.5 Hz, 3H), 1.38 (m, 2H), 1.65 (m, 2H), 2.39 (q, J=7.5 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 3.98 (s, 1H), 4.02 (s, 2H), 7.2-7.6 (m, 8H), 7.82 (d, J=2.5 Hz, 1H), 8.15 (dd, J=7.9, 1.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide;tetrakis(triphenylphosphine)palladium (0); In water; toluene; | STR106 Part E. Preparation of 1-((2'-(t-butylaminosulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole From 0.16 g (0.29 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole, using 0.12 g (0.47 mmol) of 2-(t-butylamino)sulfonylphenyl boronic acid, 0.12 g (0.86 mmol)potassium carbonate, 0.016 g (0.05 mmol) tetrabutylammonium bromide, 0.02 g (0.02 mmol) tetrakis(triphenylphosphine)palladium(0), with 1 mL of water and 2 mL of toluene as solvent, 0.08 g (40%) of the title compound was obtained following the procedure of Example 3, Part F, after purification by preparative TLC (silica gel; 20% acetone, 30% ethyl acetate, 50% hexane). 1 H NMR (300 MHz, CDCl3): delta0.97 (m, 12H, overlapping t-butyl singlet and methyl triplet); 1.32 (t, 3H, J=7.3 Hz); 1.72 (m, 2H); 2.63 (t, 2H, J=7.3 Hz); 2.83 (q, 2H, J=7.3 Hz); 3.57 (s, 1H); 5.06 (s 2H); 5.58 (s,2H); 6.61 (t, 1H, J=8.1 Hz); 6.87-7.09 (m, 7H); 7.12 (d, 1H, J=8.1 Hz); 7.23-7.29 (m,5H); 7.51 (m, 2H); 8.15 (d, 1H, J=7.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.96 g (92%) | With sodium hydroxide; In ethanol; toluene; | Step E N-t-Butyl-3'-fluoro-4'-methyl-2-biphenylsulfonamide To a vigorously stirred solution of 4.27 g (16.6 mmol) of 2-(N-t-butylsulfamoyl)phenylboronic acid (from Step D), 32 mmol (26 mL of a 1.25N aqueous solution) of NaOH in 40 mL of ethanol was added 1.89 g (10 mmol, 1.27 mL) of 4-bromo-2-fluorotoluene, 60 mL of toluene, and 289 mg (0.25 mmol) of tetrakis(tfiphenylphosphine)palladium. The mixture was stirred at 90 C. for 4.5 h, cooled to room temperature, and the volatiles were removed in vacuo. The residue was extracted with ethyl acetate (3*) and the combined organic layers were washed with water, brine, and dried (Na2 SO4). The crude product obtained after filtration and removal of solvents was flash chromatographed over silica gel (elution with hexane-EtOAc) to afford 2.96 g (92%) of the desired product cleanly (TLC in 4:1 hexane-EtOAc) as an off-white foam; mass spectrum (FAB) m/e 322 (M+1)+. 400 MHz 1 H NMR (CDCl3)delta1.01 (s, 9H), 2,32 (s, 3H), 3.59(br s, 1H), 7.13-7.28 (m, 4H), 7.44-7.56 (m, 2H), 8.14 (dd, J=7.8, 1.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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0.65 g (49%) | With nitrogen; tetrabutylammomium bromide; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; benzene; | Part D. Preparation of trans-1-[(2'-tert-butylaminosulfonyl-[1,1']-biphenyl-4-yl)methyl]-3-carbomethoxy-4-(3-cyanophenyl)pyrrolidine. To a solution of trans-1-(4-bromobenzyl)-3-carbomethoxy-4-(3-cyanophenyl)pyrrolidine (1.0 g, 2.5 mmol) in 50 mL of benzene was added <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong> (0.90 g, 3.5 mmol), tetrabutylammonium bromide (0.04 g, 0.12 mmol), sodium carbonate (0.79 g, 7.5 mmol) and 8.2 mL of H2O. This mixture was degassed with a stream of nitrogen and then tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) was added and the reaction mixture was stirred at 80 C for 6 h. The mixture was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with H2O and brine, dried over MgSO4 and was concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexanes/ethyl acetate) to afford 0.65 g (49%) of the title compound. MS (ESI) 532.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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0.52 g (85%) | With nitrogen; tetrabutylammomium bromide; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; benzene; | Part D. Preparation of trans-2-[(2'-tert-butylaminosulfonyl-[1,1']-biphenyl-4-yl)methyl]-4-carbomethoxy-5-(3-cyanophenyl)isoxazolidine. To a solution of trans-2-(4-bromobenzyl)-4-carbomethoxy-5-(3-cyanophenyl)isoxazolidine (0.46 g, 1.15 mmol) in 20 mL of benzene was added <strong>[150691-04-6]2-(tert-butylaminosulfonyl)phenylboronic acid</strong> (0.45 g, 1.72 mmol), tetrabutylammonium bromide (0.04 g, 0.12 mmol), sodium carbonate (0.36 g, 3.4 mmol) and 2 mL of H2O. This mixture was degassed with a stream of nitrogen and then tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) was added and the reaction mixture was stirred at 80 C for 6 h. The mixture was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with H2O and brine, dried over MgSO4 and was concentrated in vacuo. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford 0.52 g (85%) of the title compound. MS (ESI) 534.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 120h; | Example 15; A mixture of 6- [2- (2, 4-difluorophenyl) -6- (dimethylaminomethyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidin-3-yl]pyridazin-3 (2H) -one (73 mg) , 2-[(tert- butylamino) sulfonyl]phenylboronic acid (147 mg) , cupric acetate monohydrate (8 mg) and pyridine (77 muL) in DMF (1.5 mL) was stirred at room temperature for 5 days. To the EPO <DP n="73"/>mixture was added water (40 mL) , and the mixture was extracted with EtOAc (40 mL) . The extract was washed with brine (40 mL) and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution: methanol/chloroform = 0% to 5%) to give N- (tert-butyl) -2- [3-{2- (2, 4-difluorophenyl) -6- t (dimethylamino) methyl] -4, 5, 6, 7-tetrahydropyrazolo [1,5- a]pyrimidin-3-yl}-6-oxo-l (6H) - pyridazinyl] benzenesulfonamide (74 mg) as pale brown amorphous.Mass ESI (+) 598 (M+1)1H-NMR (500 MHz, CDCl3) delta 1.28 (9H, s) , 2.22 (6H, s) , 2.28-2.39 (3H, m) , 3.04 (IH, brs) , 3.44 (IH, d, J=Il.0 Hz),3.77 (IH, brs), 4.24 (IH, d, J=Il.0 Hz), 5.36 (IH, s) , 6.07 (IH, brs), 6.81 (IH, d, J=IO.2 Hz), 6.92 (IH, t, J=IO.0 Hz), 6.97-7.01 (2H, m) , 7.50 (IH, d, J=7.9 Hz), 7.55 (IH, dd, J=7.8, 14.7 Hz), 7.61 (IH, t, J=7.9 Hz), 7.70 (IH, t, J=7.1 Hz), 8.17 (IH, d, J=7.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | A 12-L 4-neck round bottom flask equipped with a thermocouple, heating mantle, mechanical stirrer, reflux condenser with argon outlet to a bubbler, and an argon inlet adapter was purged with argon for 1 h. Solid Na2CO3 (336.8 g, 3.18 mol) and water (975 mL) were added and the contents stirred until completely dissolved. There was no attempt to control the rise in temperature to 38 C. To the solution were added 2-(tert-butylamino) sulfonylphenylboronic acid (163.4 g, 0.637 mol), 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (196.6 g, 0.53 mol) and DME (2 L). The argon inlet was removed and the heterogeneous mixture was sparged as vigorously as possible with two pipette-tip argon lines for 1 h. 1,1'-Di(tbpf)-palladium dichloride (34.5 g, 0.053 mol) was added, the argon inlet replaced, and the reaction was warmed to 61 C., where it was held for 30 min. Two additional liters of sparged DME was added, and the heating resumed to 78 C. and maintained for 12 h. The heating was turned off (automatically) and the reaction was allowed to cool to room temperature overnight.The reaction was diluted with water (1.5 L), transferred to a 22-L separatory funnel, and the layers were separated. The top layer (O1) was diluted with EtOAc (1 L), and additional separation of an aqueous bottom layer (A1) that resulted was drained with the initial bottom layer (thick with salts). The EtOAc diluted top layer (O1) was put aside. The aqueous fraction (A1) was diluted with water (1 L, to dissolve all the salts), returned to the separatory funnel, and extracted with EtOAc (1.5 L). The resulting aqueous layer (A2) was removed and saved for later. The remaining organic layer (O2) was combined with the first EtOAc diluted top layer (O1) and the combined fraction was washed with water (1.5 L). The resulting aqueous layer (A3) was drained into A2. The remaining organic layer (O3) was washed with water (1 L), and the resulting aqueous layer (A4) was drained into A2. The remaining organic layer (O4) was washed with aqueous trithiocyanuric acid, trisodium salt (5%, 1 L), and this aqueous layer (A5) was discarded. The remaining organic layer (O5) was washed with brine (2×1 L), and the resulting aqueous layer (A6) was saved in A2. The remaining washed organic layer (O6) was drained into two 4-L Erlenmeyer flasks and dried (Na2SO4). The combined aqueous A2 layer was returned to the separatory funnel, extracted with EtOAc (1 L) and the resulting organic layer (O7) was saved for washing the drying agent and celite later. The dried organic layer (O6) was decanted from the drying agent and transferred to a 20-L round bottom flask with Si-thiol functionalized silica gel (Silicycle, 510 g). The drying agent was filtered with Celite, and washed with the EtOAc washing (O7) and combined. The organics were swirled on the 20-L rotary evaporator at a bath temperature of 45 C. for 1 h. The silica gel was removed by filtration (sintered glass funnel-golden brown), washed ad lib with EtOAc, and treated again with Si-thiol functionalized silica gel (Silicycle, 510 g) in a 20-L round bottom flask, with swirling at 45 C. for 1 h. The silica gel was removed by filtration (sintered glass funnel-sandy brown), washed ad lib with EtOAc, and the organics were concentrated in vacuo on a large rotary evaporator. The resulting thick oil crystallized in the flask; a minimum amount of EtOAc (1.5 L) was used to redissolve the oil at room temperature. Heptane (1.5 L) was carefully added and the dark solution was transferred to a BIOTAGE column (5 kg, pre-wetted with 8 L 2:1 heptane/EtOAc). The column was eluted with 16 L 1:1 heptane/EtOAc (2-L fractions collected), 16 L 1:1 heptane/EtOAc (3-L fractions collected), and 16 L 70% EtOAc (2-L fractions collected) in heptane. After evaporation, the product fractions (B1) (147 g, HPLC: 94.2% purity at 6.853 min, 8.96 min impurity at 3.39%) and (B2) (145 g, 97.9% purity at 6.725 min, with only impurity at 5.95 min, 0.58) were treated separately for recyrstallization.The B1 product fraction sample (previously transferred to a 3-L round bottom flask) was dissolved in boiling toluene (210 mL) and pre-warmed heptane (180 mL) was added until just cloudy. A stir bar was added, the mixture was stirred at room temperature; and within 4-5 min, a thick solid precipitated that was not stirrable. Immediately, a portion of toluene (250 mL) was added using it to transfer the suspension to a 12-L 4-neck round bottom flask equipped with a thermocouple, heating mantle, mechanical stirrer, and reflux condenser. Additional toluene (1100 mL) was added with warming to near reflux (100 C.), enough to completely dissolve the solid. Pre-warmed heptane (1700 mL) was added, followed by the careful addition of more heptane (room temperature, 1200 mL) until the solution was permanently cloudy. The heating mantle was removed, and notice was taken of the oily black film on the bottom of the flask, and the solution was quickly decanted to a clean 12-... |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,2-dimethoxyethane; water; at 80℃; for 12h; | B. 2-[2-(4-trifluoromethyl-benzylamino)-1H-benzoimidazol-5-yl]-benzenesulfonamide A mixture of (5-bromo-1H-benzoimidazol-2-yl)-(4-trifluoromethyl-benzyl)-amine (0.142 g, 0.384 mmol), <strong>[150691-04-6]2-(tert-butylamino)sulfonylphenylboronic acid</strong> (0.146 g, 0.576 mmol), sodium carbonate (0.241 g, 2.30 mmol), and 1,1'-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.025 g, 0.0384 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80 C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product as an off-white solid. The resulting product was dissolved in trifluoroacetic acid (3 mL) and heated to 60 C. for 2 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as an off-white solid (0.043 g, 73%). 1H NMR (400 MHz, CD3OD) delta (ppm): 8.12 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.71 (d, 2H, J=8.0 Hz), 7.64-7.60 (m, 3H), 7.55 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.47 (d, 1H, J=1.2 Hz), 7.41 (d, 1H, 8.8 Hz), 7.36 (dd, 1H, J=8.8 Hz, J=1.6 Hz), 7.31 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 5.00 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H21F3N5O2S: 488.5 (M+MeCN+H), Found 488.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,2-dimethoxyethane; water; at 80℃; for 12h; | D. 2-[2-{difluoro-(4-trifluoromethyl-phenoxy)-methyl]-1H-benzoimidazol-5-yl}-benzenesulfonamide A mixture of 5-bromo-2-[difluoro-(4-trifluoromethyl-phenoxy)-methyl]-1H-benzoimidazole (0.050 g, 0.123 mmol), <strong>[150691-04-6]2-(tert-butylamino)sulfonylphenylboronic acid</strong> (0.047 g, 0.185 mmol), sodium carbonate (0.078 g, 0.738 mmol), and 1,1'-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.008 g, 0.0123 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80 C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product as a off-white solid. The resulting product was dissolved in trifluoroacetic acid (1 mL) and heated to 60 C. for 2 hours. Concentration of the reaction mixture provided the crude material, which was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as an off-white solid (0.043 g, 73%). 1H NMR (400 MHz, CD3OD) delta (ppm): 8.14 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.79-7.76 (m, 3H), 7.72 (d, 1H, J=9.2 Hz), 7.64 (td, 1H, J=8.2 Hz, J=1.2 Hz), 7.58-7.54 (m, 3H), 7.44-7.40 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H18F5N4O3S: 525.4 (M+MeCN+H), Found 525.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,2-dimethoxyethane; water; at 90℃; for 12h; | F. 2-[2-(4-cyclopropyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzenesulfonamide A mixture of 5-bromo-2-(4-cyclopropyl-phenoxymethyl)-1H-benzoimidazole (0.030 g, 0.0874 mmol), <strong>[150691-04-6]2-(tert-butylamino)sulfonylphenylboronic acid</strong> (0.029 g, 0.114 mmol), sodium carbonate (0.079 g, 0.524 mmol), and 1,1'-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.006 g, 0.00874 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90 C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product. It was then dissolved in trifluoroacetic acid (3 mL) and heated to 60 C. for 2 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a light brown solid. 1H NMR (400 MHz, CD3OD) delta (ppm): 8.14 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.77 (s, 1H), 7.73 (d, 1H, J=9.2 Hz), 7.65 (td, 1H, J=8.2 Hz, J=1.6 Hz), 7.50 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.51 (dd, 1H, J=8.8 Hz, J=1.2 Hz), 7.41 (dd, 1H, J=6.0 Hz, J=1.2 Hz), 7.08-6.99 (m, 4H), 5.50 (s, 2H), 1.90-1.84 (m, 1H), 0.92-0.90 (m, 2H), 0.62-0.58 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H22N3O3S: 420.5 (M+H), Found 420.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 18h;Reflux; | Part B. Preparation of 1-(3-cyanophenyl)-5-[2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)methylcarbonyl]-3-methylpyrazole. A mixture of the bromide above (0.14 g, 0.37 mmol), 2M Na2CO3 (1 mL), 2-t-butylsulfonimide boronic acid (0.13 g, 0.50 mmol) and 1:1 ethanol/toluene (15 mL) was degassed with nitrogen for 15 minutes. Tetrakis(triphenylphoshine) palladium (2 mg) was added and the reaction was heated to reflux for 18h. The reaction was concentrated and the residue was taken up in ethyl acetate, washed with water and dried (MgSO4). The product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 0.19 g (100%) of a clear viscous oil.: 1H-NMR(CDCl3)delta: 8.18 (dd, J=1.46,7.69Hz, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.52 (d, J=8.40Hz, 2H), 7.51 (m, 2H), 7.34 (d, J=8.05Hz, 2H), 7.33 (m, 1H), 6.95 (s, 1H), 4.21 (s, 2H), 3.48 (s, 1H), 2.40 (s, 3H), 0.97 (s, 9H); MS (ESI) m/z 535.19 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene;Reflux; | A mixture of the above part B amide (0.4 g, 1 mmol), 2-(t-butylsulfonamide)-phenylboronic acid (0.38 g, 1.5 mmol), 2M Na2CO3 (1.3 mL),toluene (10 mL) and ethanol(10 mL) was degassed with nitrogen and then tetrakistriphenylphosphine palladium (10mg) was added. The reaction was heated to reflux overnight then cooled, filtered and concentrated. The residue was diluted with water and then extracted with ethyl acetate and dried (MgSO4). The crude product was purified by flash chromatography on silica gel using hexanes/ ethyl acetate (2:1) as eluent to afford 0.46 g (86%) of a foam; 1H-NMR(CDCl3) delta: 7.94 (m,5H), 7.63 (m,7H), 7.32 (d,J=7.7Hz, 1H), 6.55 (s,1H), 4.13 (s,1H), 2.39 (s,3H), 0.99 (s,9H); MS m/z 514.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 15h; | To a nitrogen purged solution of 1-(3-cyanophenyl)-3-ethyl-5-((4-bromo-2-fluorophenyl))aminocarbonyl)pyrazole(0.23 g, 0.56 mmol), 2-tert-butylaminosulfonylphenylboronic acid(0.17 g, 0.67 mmol) and sodium carbonate(0.12 g,1.12 mmol) in 10 mL ethanol and 20 mL toluene was added catalytic tetrakistriphenylphosphine palladium. The reaction mixture was heated to 80C for 15h, concentrated under reduced pressure and purified by flash chromatography to afford 0.13 g of 1-(3-aminomethylphenyl)-3-ethyl-5-[(2'-fluoro-2-tertbutylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole. 1H-NMR(DMSO-d6) delta: 8.36 (t, 1H, J = 8.0Hz), 8.16 (m,1H), 7.97 (bd, 1H, J = 3.0Hz), 7.85 (s,1H), 7.77 (d, 1H, J = 8.1Hz), 7.70 (d, 1H, J = 7.8Hz), 7.54 (m,3H), 7.41 (dd, 1H, J1 = 1.8Hz, J2 = 11.7Hz), 7.25 (m,2H) 6.76 (s,1H), 3.67 (s,1H), 2.79 (q, 2H, J = 8.0Hz), 1.36 (t, 3H, J = 8.0Hz), 1.06 (s,9H). Ammonia CI mass spectrum analysis m/z(relative intensity) 546 (M+H, 100). 19F NMR (dmso-d6,300MHz) delta:-130.963. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Step 2: 2-Borono-<strong>[2512-24-5]N-tert-butylbenzenesulfonamide</strong>; 27 ml of n-butyllithium (15% solution in n-hexane) are added dropwise at -5 C. to a solution of 4.29 g of <strong>[2512-24-5]N-tert-butylbenzenesulfonamide</strong> in 25 ml of THF under argon. The mixture is stirred at 22 C. for 1 h, re-cooled to -5 C., and 2.8 g of trimethyl borate are slowly added dropwise. The mixture is stirred at 22 C. for 3 h, before 100 ml of aqueous ammonium chloride solution is added dropwise. The phases are separated, and the aqueous phase is extracted a further twice with MTB ether. The combined organic phases are dried over magnesium sulfate. Filtered and evaporated to dryness in vacuo.Yield: 42% of 2-borono-<strong>[2512-24-5]N-tert-butylbenzenesulfonamide</strong>;HPLC retention time: 2.42 min (method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; at 120℃; for 16h;Inert atmosphere; | Step 3: 2-[2-Amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-N-tert-butylbenzenesulfonamide (?A1?); 1.6 g of 2-borono-N-tert-butylbenzenesulfonamide, 2.66 g of potassium carbonate, 86 mul of water and 196 mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 2 g of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline in 100 ml of ethanol under argon. The mixture is heated at 120 C. for 16 h, giving a clear solution. The hot solution is filtered through kieselguhr and rinsed with ethanol. The filtrate is evaporated to dryness in vacuo. Crystallisation of the residue from 5 ml of acetonitrile/water gives the product.Yield: 2.3 g (95%) of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-N-tert-butylbenzenesulfonamide (?A1?);LC-MS retention time: 2.04 min (method 1);1H NMR (500 MHz, DMSO-d6/TFA) delta [ppm] 8.082 (dd, 1H), 8.032 (d, 1H), 7.985 (dd, 1H), 7.828 (d, 1H), 7.698 (t, 1H), 7.645 (t, 1H), 7.443-7.419 (m, 2H), 7.353-7.295 (m, 2H), 7.255 (d, 1H), 5.002 (s, 2H), 4.853 (s, 2H), 0.867 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 4h;Reflux; Inert atmosphere; | Under argon atmosphere, aqueous (5 mL) solution of potassium phosphate (1.02 g, 4.81 mmol) and tetrakistriphenylphosphine palladium (64 mg, 0.0555 mmol) were added to 1,4-dioxane (10 mL) solution of 5-(4-bromobenzyl)-6-butyl-3-(5-methoxypyrimidin-2-yl)-2-met hylpyrimidin-4(3H)-one (410 mg, 0.925 mmol) and 2-(N-tert-butylsulfamoyl)phenylboronic acid (571 mg, 2.22 mmol), and refluxed for 4 hours under heating. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residues obtained were subjected to silica gel column chromatography (hexane/acetone=5:1) to obtain N-tert-butyl-4'-[4-butyl-1-(5-methoxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-sulfonamide (360 mg, 68%) as a pale yellow amorphous.1H-NMR (CDCl3) delta:8.54 (2H, s), 8.15 (1H, dd, J=7.9, 1.3 Hz),7.53 (1H, td, J=7.6, 1.5 Hz), 7.45 (1H, td, J=7.7, 1.5 Hz),7.43-7.35 (4H, m), 7.28 (1H, dd, J=7.7, 1.3 Hz),4.01 (3H, s), 3.96 (2H, s), 3.53 (1H, s),2.64 (2H, t, J=7.9 Hz), 2.16 (3H, s), 1.67-1.58 (2H, m),1.46-1.36 (2H, m), 0.95 (3H, t, J=7.3 Hz), 0.95 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 8h; | A mixture of 12-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (200 mg, 0.53 mmol), 2-(N-tert-butylsulfamoyl)phenylboronic acid (274 mg, 1.07 mmol), Pd(dppf)Cl2 (38.9 mg, 0.0530 mmol), and CS2CO3 (350 mg, 1.07 mmol) in 1,4-dioxane (5 mL) was heated to 100 C. for 8 h. After filtration, the filtrate was purified by reverse phase combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to afford N-tert-butyl-2-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}benzene-1-sulphonamide (250 mg, 93% yield) as white solid. LCMS (ESI) m/z: 507.2 [M+H+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In dimethyl sulfoxide; at 70℃; for 15h;Inert atmosphere; Sealed tube; | Step B: 4?-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl-2-sulfonamide (1860) To a 5 mL sealable vial equipped with a stir bar were added 5-(4-bromophenyl)pyrazin-2-amine (40 mg, 0.16 mmol), (2-(N-(tert-butyl)sulfamoyl)phenyl)-boronic acid (62 mg, 0.24 mmol), K2CO3 (66 mg, 0.48 mmol) and Pd(dppf)Cl2.CH2Cl2 (12 mg, 0.016 mmol). The vial was then sealed, evacuated, backfilled with argon and charged with argon sparged DMSO (0.64 mL). The vial was heated at 70 Celsius for 15 hours. The reaction mixture was cooled to rt diluted with ethyl acetate (2 mL) and water (2 mL), the layers separated and the aqueous layer further extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried with Na2SO4 and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C20H22N4O2S, 382.15; m/z found, 383.1 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 8.48-8.39 (d, J=1.5, 1H), 8.23-8.18 (dd, J=8.0, 1.4, 1 H), 8.18-8.15 (d, J=1.4, 1H), 7.99-7.95 (d, J=8.4, 1H), 7.65-7.61 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 1H), 7.38-7.31 (dd, J=7.5, 1.4, 1H), 3.70 (s, 1H), 1.25 (s, 1H), 1.03 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 15h;Sealed tube; Inert atmosphere; | Step A: 4?-Bromo-N-(tert-butyl)-3?-fluoro-[1,1?-biphenyl]-2-sulfonamide (1489) 1-Bromo-2-fluoro-4-iodobenzene (117 mg, 0.389 mmol) and (2-(N-(tert-butyl)sulfamoyl)phenyl) boronic acid (100 mg, 0.389 mmol) were added to a 5 mL sealable vial equipped with a stir bar. 1,4-Dioxane (1 mL) and 2 M Na2CO3 (1 mL) solution were added. Argon was bubbled through the solvent while it was rapidly stirred for 10 min then Pd(dppf)Cl2.CH2Cl2 (14 mg, 0.019 mmol) was added. The mixture was then stirred for 15 hours at 80 Celsius under an argon atmosphere. The reaction was diluted with 2 mL of ethyl acetate and 2 mL of water and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried with Na2SO4 and concentrated to dryness. The crude product was purified by FCC to give the title compound. 1H NMR (500 MHz, CDCl3) delta 8.20-8.15 (dd, J=7.9, 1.4, 1H), 7.64-7.59 (dd, J=8.2, 7.1, 1H), 7.60-7.55 (m, 1H), 7.54-7.49 (m, 1H), 7.31-7.27 (m, 2H), 7.21-7.16 (dd, J=8.5, 2.2, 1H), 3.65 (s, 1H), 1.07 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In tetrahydrofuran; water; at 20℃; for 15h;Inert atmosphere; | Step A: 4?-(5-Aminopyrazin-2-yl)-N-(tert-butyl)-3?-fluoro-[1,1?-biphenyl]-2-sulfonamide (0616) To a nitrogen flushed flask containing 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine (82.8 g, 370 mmol), <strong>[150691-04-6](2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid</strong> (100.0 g, 388.9 mmol), and chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) (5.83 g, 7.41 mmol) were added N2 sparged THF (926 mL) and sparged 0.5 M K3PO4(aq) (1.65 L, 825 mmol). The mixture was stirred for 15 hours at room temperature. The layers were separated and the organic layer was washed with 600 mL brine, dried over MgSO4, filtered, and concentrated to dryness to give a solid residue. The solid was dissolved in 900 mL DMA, stirred with 60 g activated charcoal at 80 Celsius for 2 hours, and then stirred at room temperature for an additional 16 hours. The charcoal was removed by filtration and then washed with 150 mL DMA. The combined filtrates were treated three times with fresh Silicycle brand SiliaMetS Thiol Pd Scavenger (30 g, 15 g, 7.5 g) in DMA at 80 Celsius for 8 hours to 16 hours. Upon cooling to rt the scavenger was filtered off and the filtrate was concentrated to dryness. The resulting solid was triturated in toluene (1.2 L) at 90 Celsius for 2 hours. Upon cooling to rt the solid was collected by filtration and washed twice with toluene (700 mL) and twice with hexanes (700 mL) yielding the title compound (120.0 g, 80.9%). MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) delta 8.42-8.37 (m, 1H), 8.10-8.02 (m, 2H), 7.95-7.86 (m, 1H), 7.70-7.63 (m, 1H), 7.63-7.58 (m, 1H), 7.41-7.35 (m, 1H), 7.35-7.26 (m, 2H), 7.00-6.92 (s, 1H), 6.79-6.66 (s, 2H), 1.10-0.95 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | . A solution of 58A Enantiomer 1 (100 mg, 0.222 mmol) in DMF (2 mL) was treated with 2-(tert-butyl amino)sulfonylphenylboronic acid (171 mg, 0.665 mmol) and K2C03 (122 mg, 0.886 mmol) in water (0.5 mL). This mixture was purged with nitrogen for 15 min, treated with tetrakis(triphenylphosphine)palladium(0) (25.6 mg, 0.022 mmol), and heated overnight at 90 C. The reaction was concentrated under reduced pressure, suspended in water (10 mL), and extracted with ethyl acetate(2xl5 mL). The combined organic layer was dried over sodium sulphate, concentrated under reduced pressure, and purified by flash chromatography to afford 58B (brown solid, 55 mg, 0.086 mmol, 38.7 % yield). LC-MS Anal. Calc'd for C34H37N304S 583.25, found [M+H] 584.2. Tr = 1.11 min (Method AA). |
Tags: 150691-04-6 synthesis path| 150691-04-6 SDS| 150691-04-6 COA| 150691-04-6 purity| 150691-04-6 application| 150691-04-6 NMR| 150691-04-6 COA| 150691-04-6 structure
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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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