盐酸替罗非班

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 100-mL round-bottomed flask was added 2-amino-3-bromobenzoic acid (0.8 g, 3.70 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (0.709 g, 4.44 mmol, ChemBridge Inc.) in EtOAc (15 mL) followed by DIEA (1.61 mL, 9.26 mmol) and T3P (2.59 mL, 4.07 mmol, Sigma Aldrich). The mixture was stirred at RT for 2 h, then quenched with sat. NaHCO3. EtOAc (100 mL) was added and the layers were separated. The organic layer was washed with sat. NaHCO3 (20 mL), brine (15 mL), then dried (MgSO4), filtered and concentrated to give the crude product 485 mg. MS (ESI, pos. ion) m/z: 321 (M+1). quenched with sat. NaHCO3 EtOAc (100 mL) was added the layers were separated The organic layer was washed with sat. NaHCO3 (20 mL), brine (15 mL) dried (MgSO4) filtered concentrated

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of the compound of formula (IX) (5 g, 21 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (4.1 g, 33 mmol) in THF (150 mL) was added acetic acid (5 g, 83 mmol) followed by DIPEA (10.5 g, 83 mmol). The mixture was stirred at 35° C. (internal temperature) for 2.5 h and was then cooled to 20° C. (internal temperature). Sodium tri-acetoxyborohydride (8.8 g, 42 mmol) was added and the mixture was stirred at ambient temperature the reaction was complete (TLC analysis). 25% Aqueous sodium hydroxide (10 mL) and water (50 mL) were added and the mixture was stirred for 30 min The liquid phases were separated and the aqueous layer was extracted with THF (50 mL). The extract was combined with the former organic layer and the mixture was washed with saturated aqueous NH4Cl (50 mL). The organic layer was concentrated under vacuum. The crude product was purified by column chromatography, eluting with 5% MeOH in DCM providing the compound of formula (XI) (3.1 g) after evaporation of the product containing fractions. The compound of formula (XI): 1H NMR (300 MHz, d6-DMSO): δ 2.94 (dt, J=13.8 Hz, J=7.05 Hz, 1H), 3.00 (s, 1H), 3.24 (t, J=6.75 Hz, 1H), 3.77 (s, 1H), 6.42 (d, J=3.3 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.06 (s, 1H), 8.09 (dd, J=8.55 Hz, J=2.25 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H). was then cooled to 20° C. (internal temperature) the mixture was stirred at ambient temperature the reaction the mixture was stirred for 30 min The liquid phases were separated the aqueous layer was extracted with THF (50 mL) the mixture was washed with saturated aqueous NH4Cl (50 mL) The organic layer was concentrated under vacuum The crude product was purified by column chromatography eluting with 5% MeOH in DCM providing the compound of formula (XI) (3.1 g) after evaporation of the product containing fractions

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of the compound of formula (IX) (5 g, 21 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (4.1 g, 33 mmol) in THF (150 mL) was added acetic acid (5 g, 83 mmol) followed by DIPEA (10.5 g, 83 mmol). The mixture was stirred at 35° C. (internal temperature) for 2.5 h and was then cooled to 20° C. (internal temperature). Sodium tri-acetoxyborohydride (8.8 g, 42 mmol) was added and the mixture was stirred at ambient temperature the reaction was complete (TLC analysis). 25% Aqueous sodium hydroxide (10 mL) and water (50 mL) were added and the mixture was stirred for 30 min The liquid phases were separated and the aqueous layer was extracted with THF (50 mL). The extract was combined with the former organic layer and the mixture was washed with saturated aqueous NH4Cl (50 mL). The organic layer was concentrated under vacuum. The crude product was purified by column chromatography, eluting with 5% MeOH in DCM providing the compound of formula (XI) (3.1 g) after evaporation of the product containing fractions. The compound of formula (XI): 1H NMR (300 MHz, d6-DMSO): δ 2.94 (dt, J=13.8 Hz, J=7.05 Hz, 1H), 3.00 (s, 1H), 3.24 (t, J=6.75 Hz, 1H), 3.77 (s, 1H), 6.42 (d, J=3.3 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 8.06 (s, 1H), 8.09 (dd, J=8.55 Hz, J=2.25 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H). was then cooled to 20° C. (internal temperature) the mixture was stirred at ambient temperature the reaction the mixture was stirred for 30 min The liquid phases were separated the aqueous layer was extracted with THF (50 mL) the mixture was washed with saturated aqueous NH4Cl (50 mL) The organic layer was concentrated under vacuum The crude product was purified by column chromatography eluting with 5% MeOH in DCM providing the compound of formula (XI) (3.1 g) after evaporation of the product containing fractions

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 2-(methylsulfonyl)ethaneamine hydrochloride (90 mg), and triethylamine (120 μL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) to give the title compound (111 mg, yield 62%) as a pale-yellow amorphous solid. the mixture was extracted with ethyl acetate The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate filtered concentrated under reduced pressure The obtained crude product

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Into a round bottom flask was combined 5-nitro-isochromen-1-one (1.5 g, 0.0071 mol), 2-(methylsulfonyl)ethanamine hydrochloride (2.2 g, 0.014 mol) and methanol (45 mL, 1.1 mol). The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and was concentrated to yield a yellow solid. The solid was taken onto the next step without further purification. Into a round bottom flask was combined The mixture was heated at reflux for 1.5 hours was concentrated to yield a yellow solid The solid was taken onto the next step without further purification

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 8-bromo-N-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (400 mg, 0.73 mmol), Pd(OAc)2 (8 mg, 0.037 mmol), Xantphos (42 mg, 0.073 mmol), MeSO2(CH2)2NH2.HCl (175 mg, 1.095 mmol) and Na2CO3 (232 mg, 2.19 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon overnight. Then it was filtrated and concentrated, the crude product was purified by pre-TLC (eluted by DCM:MeOH=10:1) to give 438 (191.9 mg, yield 42%). 1H NMR (DMSO-d6, 400 MHz): δ8.74 (t, J=5.2 Hz, 1H, NH), 8.62 (t, J=5.2 Hz, 1H, NH), 8.12-7.44 (m, 6H, ArH), 6.61 (s, 1H, ═CH), 4.77 (d, J=4.8 Hz, 1H, OH), 4.20 (br s, 2H, CH2), 3.80-3.75 (m, 1H, CH), 3.67-2.98 (m, 14H, CH3, CH2), 1.05 (t, J=6.0 Hz, 3H, CH3). LC-MS: (ESI, m/z)=620 [M+H]+ Then it was filtrated concentrated the crude product was purified by pre-TLC (eluted by DCM:MeOH=10:1)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (400 mg, 0.70 mmol), Pd(OAc)2 (8 mg, 0.035 mmol), Xantphos (41 mg, 0.070 mmol), MeSO2(CH2)2NH2.HCl (169 mg, 1.06 mmol) and Na2CO3 (224 mg, 2.11 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon for 3 h. Then it was filtrated and concentrated, the crude product was purified by flash column chromatography on silica gel (petroleum ether:EtOAc=2:1˜1:5 as eluted solvent) to give a white solid which was washed with DCM and dried to give 432 (121.3 mg, yield: 27%). 1H NMR (DMSO-d6, 400 MHz): δ 8.73-6.60 (m, 8H, NH, ArH), 4.75-3.02 (m, 18H). LC-MS: (ESI, m/z)=638 [M+H]+ Then it was filtrated concentrated the crude product was purified by flash column chromatography on silica gel (petroleum ether:EtOAc=2:1˜1:5 as eluted solvent) to give a white solid which was washed with DCM dried

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (400 mg, 0.70 mmol), Pd(OAc)2 (8 mg, 0.035 mmol), Xantphos (41 mg, 0.070 mmol), MeSO2(CH2)2NH2.HCl (169 mg, 1.06 mmol) and Na2CO3 (224 mg, 2.11 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon for 3 h. Then it was filtrated and concentrated, the crude product was purified by flash column chromatography on silica gel (petroleum ether:EtOAc=2:1˜1:5 as eluted solvent) to give a white solid which was washed with DCM and dried to give 432 (121.3 mg, yield: 27%). 1H NMR (DMSO-d6, 400 MHz): δ 8.73-6.60 (m, 8H, NH, ArH), 4.75-3.02 (m, 18H). LC-MS: (ESI, m/z)=638 [M+H]+ Then it was filtrated concentrated the crude product was purified by flash column chromatography on silica gel (petroleum ether:EtOAc=2:1˜1:5 as eluted solvent) to give a white solid which was washed with DCM dried

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (500 mg, 0.91 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), Xantphos (53 mg, 0.091 mmol), MeSO2(CH2)2NH2.HCl (218 mg, 1.36 mmol) and Na2CO3 (289 mg, 2.73 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon overnight. Then it was filtrated and concentrated, the crude product was purified by pre-TLC (DCM:MeOH=10:1 as eluted solvent) to give 387 (101.5 mg, yield 18%). 1H NMR (DMSO-d6, 400 MHz): δ8.73 (s, 1H, NH), 8.60 (s, 1H, NH), 8.12-7.45 (m, 6H, ArH), 6.61 (s, 1H, ═CH), 4.76 (d, J=4.8 Hz, 1H, OH), 4.20 (br s, 2H, CH2), 3.80-3.77 (m, 1H, CH), 3.67-2.98 (m, 14H, CH3, CH2), 1.06 (t, J=5.2 Hz, 3H, CH3). LC-MS: (ESI, m/z)=542 [M+Na]+ Then it was filtrated concentrated the crude product was purified by pre-TLC (DCM:MeOH=10:1 as eluted solvent)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 8-bromo-N-(2-chloro-5-((R)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (500 mg, 0.91 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), Xantphos (53 mg, 0.091 mmol), MeSO2(CH2)2NH2.HCl (218 mg, 1.36 mmol) and Na2CO3 (289 mg, 2.73 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon overnight. Then it was filtrated and concentrated, the crude product was purified by pre-TLC (DCM:MeOH=10:1 as eluted solvent) to give 387 (101.5 mg, yield 18%). 1H NMR (DMSO-d6, 400 MHz): δ8.73 (s, 1H, NH), 8.60 (s, 1H, NH), 8.12-7.45 (m, 6H, ArH), 6.61 (s, 1H, ═CH), 4.76 (d, J=4.8 Hz, 1H, OH), 4.20 (br s, 2H, CH2), 3.80-3.77 (m, 1H, CH), 3.67-2.98 (m, 14H, CH3, CH2), 1.06 (t, J=5.2 Hz, 3H, CH3). LC-MS: (ESI, m/z)=542 [M+Na]+ Then it was filtrated concentrated the crude product was purified by pre-TLC (DCM:MeOH=10:1 as eluted solvent)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzamido)ethyl acetate (400 mg, 0.69 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), Xantphos (40 mg, 0.069 mmol), MeSO2CH2CH2NH2.HCl (165 mg, 1.04 mmol) and Na2CO3 (219 mg, 2.07 mmol) in toluene (5 mL) was heated at 80° C. under atmosphere of CO from balloon overnight. Then it was filtrated and concentrated, the crude product was purified by column (EtOAc:MeOH=10:1) to afford 385 (76.8 mg, yield: 18%). 1HNMR (DMSO-d6, 400 MHz): δ8.70 (t, J=5.6 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 8.07-7.41 (m, 6H), 6.57 (s, 1H), 4.72 (s, 1H), 4.71 (t, J=5.6 Hz, 1H), 3.63-2.95 (m, 16H). LC-MS: (ESI, m/z)=606 [M+H]+ Then it was filtrated concentrated the crude product was purified by column (EtOAc:MeOH=10:1)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 8-bromo-N-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (400 mg, 0.73 mmol), Pd(OAc)2 (8 mg, 0.037 mmol), Xantphos (42 mg, 0.073 mmol), MeSO2(CH2)2NH2.HCl (175 mg, 1.095 mmol) and Na2CO3 (232 mg, 2.19 mmol) in toluene (5 mL) and DMF (5 mL) was heated at 80° C. under atmosphere of CO from balloon for overnight. Then it was filtrated and concentrated, the crude product was purified by flash column chromatography on silica gel (DCM:MeOH=20:1 as eluted solvent) to give a white solid which was washed with MeOH and dried to give 384 (206.7 mg, yield 46%). 1H NMR (DMSO, 400 MHz): δ8.74 (t, J=5.6 Hz, 1H, NH), 7.87-6.61 (m, 7H, ArH), 5.75 (d, J=6.0 Hz, 1H, OH), 4.48-2.99 (m, 19H). LC-MS: (ESI, m/z)=618 [M+H]+ Then it was filtrated concentrated the crude product was purified by flash column chromatography on silica gel (DCM:MeOH=20:1 as eluted solvent) to give a white solid which was washed with MeOH dried