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With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In methanol; at 35℃;Inert atmosphere; |
Example 10: Preparation of (S )-2-((( I R,2R)-2-(5 -(6-methoxy-3 -((3R,5 S)-5- (rnethoxvcarbonyflpylTolidin-3 -yloxy)guinoxalin-2-yl)pent-4-ynyl)cyclopropoxy)carbonylarnino)-3 ,3 -dirnethylbutanoic acid (16) :To a three-neck flask were added copper(I) iodide (0.219 g, 1 .152 mmol),chloroquinoxaline MsOH salt 14 (50 g, 115 mmol), alkyne acid TBA salt 15 (49.3 g, 121 mmol),and bis(triphenylphosphine)palladium(I1) dichioride (0.404 g, 0.573 mmol). The flask was vacuumed degassed with N2. MeOH (500 ml) was added and the reaction mixture was vacuum degassed again with N2. Triethylamine (32.1 ml, 230 mmol) was added. The reaction solution was aged at 35 C for 3-5 hours. The batch was then concentrated to a volume of100 mL invacuum. THF (250 mL) and EtOAc (250 mL) were added. The reaction mixture was cooled to below 5C. HC1 solution (1 N, 180 mL) was added slowly at below 5 C until the reaction solution was pH adjusted to 2. NaCl aq. solution (10%, 350 mL) was added. The separated aqueous phase was back-extracted with a solution of THE (250 mL) and EtOAc (250 mE). The combined organic phase was washed with 10% NaC1 aq. solution (500 mL). The organic phasewas azeotropically concentrated in vacuum with THF at below 20C until the KF of the solution was less than 500 ppm. Then, the reaction solvent was switched to DMAc (650 mL) in vacuum at below 20 C. |
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With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In methanol; at 35℃;Inert atmosphere; |
To a three-neck flask were added copper(I) iodide (0.219 g, 1.152 mmol), chloroquinoxaline MsOH salt 14 (50 g, 115 mmol), alkyne acid TBA salt 15 (49.3 g, 121 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.404 g, 0.573 mmol). The flask was vacuumed degassed with N2. MeOH (500 ml) was added and the reaction mixture was vacuum degassed again with N2. Triethylamine (32.1 ml, 230 mmol) was added. The reaction solution was aged at 35 C for 3-5 hours. The batch was then concentrated to a volume of-100 mL in vacuum. THF (250 mL) and EtOAc (250 mL) were added. The reaction mixture was cooled to below 5 C. HCl solution (1 N, -180 mL) was added slowly at below 5 C until the reaction solution was pH adjusted to -2. NaCl aq. solution (10%, 350 mL) was added. The separated aqueous phase was back-extracted with a solution of THF (250 mL) and EtOAc (250 mL). The combined organic phase was washed with 10% NaCl aq. solution (500 mL). The organic phase was azeotropically concentrated in vacuum with THF at below 20 C until the KF of the solution was less than 500 ppm. Then, the reaction solvent was switched to DMAc (650 mL) in vacuum at below 20 C. A solution of HATU (55.1 g, 145 mmol) in DMAc (650 mL) at ambient temperature was vacuumed degassed with N2. The solution was then cooled to 0 C and DIPEA (58.5 mL, 335 mmol) was added dropwise at below 0-5 C. Then, the above solution of alkyne quinoxaline acid 16 (65 g assay, 1 12 mmol) in DMAc was added dropwsie over 10 hours, while maintaining the internal temperature at 0 C. After addition, the batch was agitated at 0 C for additional 2 hours. EtOAc (750 mL) was added at below 5 C. A solution of 10% NaCl aq. solution (400 mL), water (125 mL) and 1 N HCl solution (100 mL) was slowly added while maintaining the batch temperature at below 5 C. The solution was then adjusted to pH = 2 with 1 N HCl (?25 mL). The separated aqueous phase was backextracted with EtOAc (500 mL). The combined organic phase was washed with 10% NaCl aq. solution (500 mL). After 10% NaCl aq. solution (500 mL) was added to the combined organic phase, the mixed solution was cooled to 0-5 C. I N NaOH aq. solution (-25 mL) was added to adjust the pH = ?7. The separated organic phase was filtered through Celite and solvent switched to IP A at a final volume of 300 mL. Acetic acid (5.0 mL) was added, and the batch was then heated up to reflux for 30 min. The slurry was cooled to 60 C and water (250 mL) was added dropwise over 1 hour. After addition, the batch was aged for additional 30 min before slowly cooling to ambient temperature in about 2 hours. After aging at least 1 hour, the batch was filtered. The wet cake was displacement washed with 50% aq IPA (100 mL). Suction dry at ambient temperature afforded 56 g of macrocyclic alkyne ester 17.'H NMR (400 MHz, CDCl3) delta 7.80 (d, J = 9.2 Hz, I H), 7.17 (dd, J = 9.2, 2.8 Hz, 1 H), 7.04 (d, J = 2.8 Hz, 1 H), 5.82 (t, J = 4.2 Hz, 1 H), 5.26 (d, J = 9.9 Hz, 1 H), 4.62 (dd, J = 10.3, 7.3 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.40 (d, J = 9.9 Hz, 1 H), 4.03 (dd, J = 11.6, 4.4 Hz, 1 H), 3.91 (s, 3 H), 3.87 (m, 1 H), 3.73 (s, 3 H), 2.85 (dt, J = 12.1, 4.2 Hz, 1 H), 2.76 (d, J = 14.4, 7.3 Hz, 1 H), 2.49 (dt, J = 12.2, 5.4 Hz, 1 H), 2.30 (ddd, J = 14.6, 10.1, 4.2 Hz, 1 H), 1.99 (m, 1 H), 1.82 (m, 1 H), 1.74 (m, 1 H), 1.08 (s, 9 H), 0.92 (m, 2 H), 0.76 (m, 1 H), 0.47 (m, 1 H). 13C NMR (100 MHz, CDCl3) delta 172.3, 171.3, 161.2, 157.4, 156.3, 140.4, 134.3, 130.2, 129.5, 119.5, 105.7, 98.9, 75.5, 75.2, 59.4, 58.1, 55.7, 55.6, 54.1, 52.3, 35.3, 35.0, 29.9, 28.0, 26.3,18.7, 18.3, 10.3. IPC HPLC conditions: Ascentis Express CI 8 column, 100 x 4.6 mm, 2.7micron; Column temperature of 40 C; Flow rate of 1.8 mL/min; and Wavelength of 215 nm. |
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With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In methanol; at 35℃;Inert atmosphere; |
To a 3-neck flask were added Cul (0.219 g, 1.152 mmol), chloroquinoxaline MsOH salt from Example 12 (50 g, 115 mmol), alkyne acid TBA salt from Example 10 (49.3 g, 121 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.404 g, 0.573 mmol). The flask was vacuumed degassed with N2. MeOH (500 ml) was added, and the reaction mixture was vacuum degassed again with N2. TEA (32.1 ml, 230 mmol) was added. The reaction solution was aged at 35C for 3 h to 5 h. The batch was then concentrated to a volume of -100 mL in vacuum. THF (250 mL) and EtOAc (250 mL) were added. The reaction mixture was cooled to below 5C. HC1 solution (1 N, -180 mL) was added slowly at below 5C until the reaction solution was pH adjusted to -2. NaCl aq. solution (10%, 350 mL) was added. The separated aqueous phase was back-extracted with a solution of THF (250 mL) and EtOAc (250 mL). The combined organic phase was washed with 10% NaCl aq. solution (500 mL). The organic phase was azeotropically concentrated in vacuum with THF at below 20C until the KF of the solution was less than 500 ppm. Then, the reaction solvent was switched to DMAc (650 mL) in vacuum at below 20C. A solution of HATU (55.1 g, 145 mmol) in DMAc (650 mL) at RT was vacuumed degassed with N2. The solution was then cooled to 0C, and DIPEA (58.5 mL, 335 mmol) was added dropwise at below 0C to 5C. Then, the above solution of alkyne quinoxaline acid (65 g assay, 112 mmol) in DMAc was added dropwise over 10 h, while maintaining the internal temperature at 0C. After addition, the batch was agitated at 0C for additional 2 h. EtOAc (750 mL) was added at below 5C. A solution of 10% NaCl aq. solution (400 mL), water (125 mL) and 1 N HC1 solution (100 mL) was slowly added while maintaining the batch temperature at below 5C. The solution was then adjusted to pH = 2 with 1 N HC1 (~25 mL). The separated aqueous phase was back-extracted with EtOAc (500 mL). The combined organic phase was washed with 10% NaCl aq. solution (500 mL). After 10% NaCl aq. solution (500 mL) was added to the combined organic phase, the mixed solution was cooled to 0C to 5C. 1 N NaOH aq. solution (~25 mL) was added to adjust the pH = ~7. The separated organic phase was filtered through CELITE (filter aid, Fisher Scientific, Fair Lawn, NJ) and solvent-switched to IPA at a final volume of 300 mL. AcOH (5.0 mL) was added, and the batch was then heated to reflux for 30 min. The slurry was cooled to 60C, and water (250 mL) was added dropwise over 1 h. After addition, the batch was aged for additional 30 min before slowly cooling to RT in about 2 h. After aging at least 1 h, the batch was filtered. The wet cake was displacement washed with 50% aq. IPA (100 mL). Suction-drying at RT afforded 56 g of macrocyclic alkyne ester. XH NMR (400 MHz, CDC13) delta 7.80 (d, J = 9.2 Hz, 1 H), 7.17 (dd, J = 9.2, 2.8 Hz, 1 H), 7.04 (d, J = 2.8 Hz, 1 H), 5.82 (t, J = 4.2 Hz, 1 H), 5.26 (d, J = 9.9 Hz, 1 H), 4.62 (dd, J = 10.3, 7.3 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.40 (d, J = 9.9 Hz, 1 H), 4.03 (dd, J = 11.6, 4.4 Hz, 1 H), 3.91 (s, 3 H), 3.87 (m, 1 H), 3.73 (s, 3 H), 2.85 (dt, J = 12.1, 4.2 Hz, 1 H), 2.76 (d, J = 14.4, 7.3 Hz, 1 H), 2.49 (dt, J = 12.2, 5.4 Hz, 1 H), 2.30 (ddd, J = 14.6, 10.1, 4.2 Hz, 1 H), 1.99 (m, 1 H), 1.82 (m, 1 H), 1.74 (m, 1 H), 1.08 (s, 9 H), 0.92 (m, 2 H), 0.76 (m, 1 H), 0.47 (m, 1 H). 1 C NMR (100 MHz, CDC13) delta 172.3, 171.3, 161.2, 157.4, 156.3, 140.4, 134.3, 130.2, 129.5, 119.5, 105.7, 98.9, 75.5, 75.2, 59.4, 58.1, 55.7, 55.6, 54.1, 52.3, 35.3, 35.0, 29.9, 28.0, 26.3, 18.7, 18.3, 10.3. IPC HPLC conditions: Ascentis Express C18 column, 100 x 4.6 mm, 2.7 mupiiota; Column temperature of 40C; Flow rate of 1.8 mL/min; and Wavelength of 215 nm. Gradiant: min 0.1% PO. 0 10 90 6 95 5 9 95 5 9.1 10 90 Retention times: min. De-BOC quinoxaline 2.3 Alkyne quinoxaline acid 3.3 Alkyne macrocyclic ester 5.7 |
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