甲基(2R)-3-碘-2-[(2-甲基丙烷-2-基)氧羰基氨基]丙酸酯

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

实验步骤: To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in N,N-dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1.48 mol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane) to provide the title compound as a mixture of diastereomers. MS: m/z=392.1 (M+Na). the mixture was then added to a stirring solution of pH 7 buffer The aqueous layer was extracted with EtOAc the combined organics were washed with pH 7 buffer dried over sodium sulfate filtered concentrated The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane)

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

实验步骤: To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in dry N,N-dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1483 mmol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqeuous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane) to provide the title compound as a mixture of diastereomers (150 g). MS 392.1 (M+Na). the mixture was then added to a stirring solution of pH 7 buffer The aqeuous layer was extracted with EtOAc the combined organics were washed with pH 7 buffer dried over sodium sulfate filtered concentrated The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred suspension of zinc (68 mg, 1.03 mmol) in DMF (2 mL) was treated with I2 (12 mg, 0.05 mmol). After the color disappeared, ((R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (110 mg, 0.34 mmol) and further I2 (12 mg, 0.05 mmol) were added. After 30 min, the mixture was de-gassed then 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (170 mg, 0.31 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (7 mg, 0.02 mmol) and Pd2(dba)3 (8 mg, 7.8 μmol) were added. After further de-gassing, DMF (2 mL) was added and the reaction mixture was heated at 50° C. overnight. The reaction mixture purified by column chromatography (EA/hexane) to provide 55 mg (25%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate as a colorless oil. LCMS-ESI (m/z) calculated for C37H55N3O6Si: 665.9. found 666.4 [M+H]+, tR=3.10 min (Method 8). the mixture was de-gassed After further de-gassing DMF (2 mL) was added The reaction mixture purified by column chromatography (EA/hexane)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred suspension of zinc (68 mg, 1.03 mmol) in DMF (2 mL) was treated with I2 (12 mg, 0.05 mmol). After the color disappeared, ((R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (110 mg, 0.34 mmol) and further I2 (12 mg, 0.05 mmol) were added. After 30 min, the mixture was de-gassed then 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (170 mg, 0.31 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (7 mg, 0.02 mmol) and Pd2(dba)3 (8 mg, 7.8 μmol) were added. After further de-gassing, DMF (2 mL) was added and the reaction mixture was heated at 50° C. overnight. The reaction mixture purified by column chromatography (EA/hexane) to provide 55 mg (25%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate as a colorless oil. LCMS-ESI (m/z) calculated for C37H55N3O6Si: 665.9. found 666.4 [M+H]+, tR=3.10 min (Method 8). the mixture was de-gassed After further de-gassing DMF (2 mL) was added The reaction mixture purified by column chromatography (EA/hexane)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was added diiodine (35.4 mg, 0.14 mmol). When the color was discharged, further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol) were added. After 30 min, DMF (1 mL) was added and the mixture de-gassed by bubbling through N2. To the reaction mixture were added 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol), Pd2dba3 (21 mg, 0.02 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (19 mg, 0.05 mmol), the mixture was further de-gassed then heated to 50° C. for 3 h. The reaction mixture was cooled and purified by column chromatography (10-80% EA in iso-hexanes). The product obtained was taken into DCM (4 mL) and washed with water (20 mL) and dried through a hydrophobic frit. The organics were suspended in ACN (4 mL) and concentrated to afford 432 mg (83%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate as a yellow foam. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.7; no ion observed, tR=3.36 min. (Method 4). the mixture de-gassed by bubbling through N2 the mixture was further de-gassed The reaction mixture was cooled purified by column chromatography (10-80% EA in iso-hexanes) The product obtained washed with water (20 mL) dried through a hydrophobic frit concentrated

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

实验步骤: To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) was added diiodine (44 mg, 0.17 mmol). When the color was discharged, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16 mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. After stirring at RT for 30 min, the reaction mixture was de-gassed by bubbling through N2 then 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (23.8 mg, 0.06 mmol), Pd2dba3 (26 mg, 0.03 mmol) and DMF (2 mL) were added. The reaction mixture was heated to 50° C. for 3 h, cooled and purified by column chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl) thiazol-2-yl)phenyl propanoate. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.3; no ion observed, tR=3.37 min. (Method 4). the reaction mixture was de-gassed by bubbling through N2 The reaction mixture was heated to 50° C. for 3 h cooled purified by column chromatography (10-80% EA in iso-hexanes)

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

实验步骤: To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) was added diiodine (44 mg, 0.17 mmol). When the color was discharged, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16 mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. After stirring at RT for 30 min, the reaction mixture was de-gassed by bubbling through N2 then 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (23.8 mg, 0.06 mmol), Pd2dba3 (26 mg, 0.03 mmol) and DMF (2 mL) were added. The reaction mixture was heated to 50° C. for 3 h, cooled and purified by column chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl) thiazol-2-yl)phenyl propanoate. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.3; no ion observed, tR=3.37 min. (Method 4). the reaction mixture was de-gassed by bubbling through N2 The reaction mixture was heated to 50° C. for 3 h cooled purified by column chromatography (10-80% EA in iso-hexanes)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine (20.2 mg, 0.08 mmol). After the color disappeared, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (175 mg, 0.53 mmol) and further iodine (20.2 mg, 0.08 mmol) were added. After 30 min, the mixture was de-gassed by bubbling through N2 then treated with 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol), Pd2dba3 (12.2 mg, 0.01 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (10.9 mg, 0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to 50° C. for 2 h, cooled to RT and purified by column chromatography (gradient of 15-95% EA in iso-hexanes) to afford 188 mg (65%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate. the mixture was de-gassed by bubbling through N2 cooled to RT purified by column chromatography (gradient of 15-95% EA in iso-hexanes)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine (20.2 mg, 0.08 mmol). After the color disappeared, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (175 mg, 0.53 mmol) and further iodine (20.2 mg, 0.08 mmol) were added. After 30 min, the mixture was de-gassed by bubbling through N2 then treated with 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol), Pd2dba3 (12.2 mg, 0.01 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (10.9 mg, 0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to 50° C. for 2 h, cooled to RT and purified by column chromatography (gradient of 15-95% EA in iso-hexanes) to afford 188 mg (65%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate. the mixture was de-gassed by bubbling through N2 cooled to RT purified by column chromatography (gradient of 15-95% EA in iso-hexanes)

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

实验步骤: A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet, a mechanical stirred, an addition funnel and a thermocouple was charged with 4-bromo-3,5-dimethyl-benzonitrile (210 g, 1.0 mol) and DMAc (750 ml). The resulting suspension was stirred and heated to 35° C. to dissolve the solids. To the resulting mixture was then added P(o-tol)3 (6.0 g, 0.02 mol), Pd2(dba)3 (9.2 g, 0.01 mol) and the resulting mixture heated to about 75-80° C. The cooled mixture prepared in STEP A above was added by cannula to the reaction mixture at a rate which maintained the temperature at about 75-80° C. (about 2 hours). The resulting suspension was cooled to ambient temperature, then aged overnight with moderate agitation. The resulting suspension was then heated to about 35-40° C., filtered with silica (540 g). The silica bed was washed with DMAc (400 mL×2), the combined DMAc solutions cooled to about 0-5° C. and then added slowly to a mixture of ice and deionized water. The resulting mixture was maintained cold for 2 hours, over which time a white solid was observed to precipitate. The resulting mixture was then warmed to ambient temperature and aged overnight. The solid precipitate was cooled by vacuum filtration using a Buchner funnel. The filter cake was rinsed with deionized water (1 L×3), air dried overnight, then dried in a vacuum oven overnight. MeOH (1 L) was added to the solid and the resulting slurry was cooled to about 0-5° C., then aged at this temperature for 1 hour, with stirring. The solid was collected by filtration, washed with cold methanol (400 mL) and dried in a vacuum oven at 45° C. to yield the title compound as an off-white solid. A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet to dissolve the solids maintained the temperature at about 75-80° C. (about 2 hours) The resulting suspension was cooled to ambient temperature The resulting suspension was then heated to about 35-40° C. filtered with silica (540 g) The silica bed was washed with DMAc (400 mL×2) the combined DMAc solutions cooled to about 0-5° C. added slowly to a mixture of ice The resulting mixture was maintained cold for 2 hours, over which time a white solid to precipitate The resulting mixture was then warmed to ambient temperature and aged overnight The solid precipitate was cooled by vacuum filtration The filter cake was rinsed with deionized water (1 L×3), air dried overnight dried in a vacuum oven overnight MeOH (1 L) was added to the solid the resulting slurry was cooled to about 0-5° C. aged at this temperature for 1 hour with stirring The solid was collected by filtration washed with cold methanol (400 mL) dried in a vacuum oven at 45° C.

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 50 mL three-necked round bottom flask equipped with an addition funnel, magnetic stirrer, heating mantel, and thermocouple was charged under nitrogen dry DMAc (2 mL), I2 (38.1 mg, 0.15 mmol) and zinc powder activated (washed with 10% HCl, rinsed with H2O and acetone) (393 mg, 6 mmol). The resulting mixture was stirred at 23° C. until the red color of I2 disappeared (2 minutes). A solution of Boc-β-iodo-L-alanine methyl ester (1 g, 3 mmol) in DMAc (2 mL) was added slowly, (temperature change from 21° C. to 29° C.) and the resulting mixture was stirred at 80° C. for 0.5-1 hour, then co cooled to 35° C. To the resulting mixture were added, successively, 4-bromo-3,5-dimethyl-benzonitrile (315 mg, 1.5 mmol) in DMAc (6 mL), P(o-tol)3 (36.5 mg, 0.12 mmol) and Pd2(dba)3 (55 mg, 0.06 mmol). The resulting mixture was heated to 70° C., with stirring for 1 hour, then cooled to ambient temperature. The resulting mixture was diluted with EtOAc (15 mL) and filtered with STAND SUPER-CEL 815520. The EtOAc solution was quenched with 1 N HCl (40 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with H2O (2×50 mL) and then with 50% brine, dried over Na2SO4, filtered and evaporated to dryness in vacuo to yield a brown solid. The title compound was crystallized from EtOAc (5 mL) and heptane (40 mL) to yield a white solid. A 50 mL three-necked round bottom flask equipped with an addition funnel, magnetic stirrer heating mantel thermocouple was charged under nitrogen dry DMAc (2 mL) (washed with 10% HCl, rinsed with H2O and acetone) (393 mg, 6 mmol) (2 minutes) (temperature change from 21° C. to 29° C.) and the resulting mixture was stirred at 80° C. for 0.5-1 hour co cooled to 35° C To the resulting mixture were added The resulting mixture was heated to 70° C. with stirring for 1 hour cooled to ambient temperature filtered with STAND SUPER-CEL 815520 The EtOAc solution was quenched with 1 N HCl (40 mL) extracted with ethyl acetate (20 mL) The combined organic phases were washed with H2O (2×50 mL) with 50% brine, dried over Na2SO4 filtered evaporated to dryness in vacuo to yield a brown solid The title compound was crystallized from EtOAc (5 mL) and heptane (40 mL) to yield a white solid

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 50 mL three-necked round bottom flask equipped with an addition funnel, magnetic stirrer, heating mantel, and thermocouple was charged under nitrogen dry DMAc (2 mL), I2 (38.1 mg, 0.15 mmol) and zinc powder activated (washed with 10% HCl, rinsed with H2O and acetone) (393 mg, 6 mmol). The resulting mixture was stirred at 23° C. until the red color of I2 disappeared (2 minutes). A solution of Boc-β-iodo-L-alanine methyl ester (1 g, 3 mmol) in DMAc (2 mL) was added slowly, (temperature change from 21° C. to 29° C.) and the resulting mixture was stirred at 80° C. for 0.5-1 hour, then co cooled to 35° C. To the resulting mixture were added, successively, 4-bromo-3,5-dimethyl-benzonitrile (315 mg, 1.5 mmol) in DMAc (6 mL), P(o-tol)3 (36.5 mg, 0.12 mmol) and Pd2(dba)3 (55 mg, 0.06 mmol). The resulting mixture was heated to 70° C., with stirring for 1 hour, then cooled to ambient temperature. The resulting mixture was diluted with EtOAc (15 mL) and filtered with STAND SUPER-CEL 815520. The EtOAc solution was quenched with 1 N HCl (40 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with H2O (2×50 mL) and then with 50% brine, dried over Na2SO4, filtered and evaporated to dryness in vacuo to yield a brown solid. The title compound was crystallized from EtOAc (5 mL) and heptane (40 mL) to yield a white solid. A 50 mL three-necked round bottom flask equipped with an addition funnel, magnetic stirrer heating mantel thermocouple was charged under nitrogen dry DMAc (2 mL) (washed with 10% HCl, rinsed with H2O and acetone) (393 mg, 6 mmol) (2 minutes) (temperature change from 21° C. to 29° C.) and the resulting mixture was stirred at 80° C. for 0.5-1 hour co cooled to 35° C To the resulting mixture were added The resulting mixture was heated to 70° C. with stirring for 1 hour cooled to ambient temperature filtered with STAND SUPER-CEL 815520 The EtOAc solution was quenched with 1 N HCl (40 mL) extracted with ethyl acetate (20 mL) The combined organic phases were washed with H2O (2×50 mL) with 50% brine, dried over Na2SO4 filtered evaporated to dryness in vacuo to yield a brown solid The title compound was crystallized from EtOAc (5 mL) and heptane (40 mL) to yield a white solid