1-chloro-2-fluoro-4-iodobenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In analogy to the procedure described in example 24E], 1-chloro-2-fluoro-4-iodobenzene and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by purification described in example 26A] yielded the title compound as off-white powder, mp. 106-107° C., dec. followed by purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In analogy to the procedure described in example 24E], 1-chloro-2-fluoro-4-iodobenzene and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by purification described in example 26A] yielded the title compound as off-white powder, mp. 106-107° C., dec. followed by purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 1-chloro-2-fluoro-4-iodobenzene (584 mg, 2.279 mmol), and the reaction mixture was stirred at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using four aqueous washes. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate, 0.220 g; purity, 93% by LCMS analysis. Analysis LCMS condition F: rt=2.59 min; ESI-MS(+) m/z 332.2 (M+H). To an oven dried 8 mL vial with teflon cap purged with N2 DMF was removed The organic phase was dried over anhydrous sodium sulfate filtered concentrated the crude product was purified by silica gel chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 1-chloro-2-fluoro-4-iodobenzene (584 mg, 2.279 mmol), and the reaction mixture was stirred at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using four aqueous washes. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate, 0.220 g; purity, 93% by LCMS analysis. Analysis LCMS condition F: rt=2.59 min; ESI-MS(+) m/z 332.2 (M+H). To an oven dried 8 mL vial with teflon cap purged with N2 DMF was removed The organic phase was dried over anhydrous sodium sulfate filtered concentrated the crude product was purified by silica gel chromatography

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 4-chloro-3-fluoroiodobenzene (74.27 g, 284 mmol) and cesium carbonate (185.0 g, 568 mmol) in tetrahydrofuran (730 mL) was added under an argon atmosphere cuprous iodide (2.16 g, 11.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (3.98 g, 5.7 mmol). Ethyl propiolate (57.0 g, 575 mmol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 38 h at 35° C., then filtrated over Hyflo® and the residue was washed with tetrahydrofuran (285 ml). The filtrate was evaporated and purification of the residue by chromatography (SiO2, heptane: ethyl acetate=90:10) afforded the title compound (57.1 g, 89%) as a yellow liquid. MS m/e: 226.0 [M]+. filtrated over Hyflo® the residue was washed with tetrahydrofuran (285 ml) The filtrate was evaporated purification of the residue by chromatography (SiO2, heptane: ethyl acetate=90:10)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon atmosphere, a four neck flask was charged with 1-chloro-2-fluoro-4-iodo-benzene (50.5 g, 0.20 mol), bis(triphenylphosphine) palladium(II) chloride (2.76 g, 3.94 mmol, 2 mol %), copper(I) iodide (1.50 g, 7.80 mol, 4 mol %) and dry THF (600 ml). At r.t., cesium carbonate (128.3 g, 0.39 mol, 2 eq.) was added over 5 min. Finally, propynoic acid ethyl ester (38.6 g, 0.39 mol, 2 eq.) was added, and the reaction was stirred for 48 h at 35° C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (50 ml) and heptane (100 ml). The resulting suspension was stirred at 40° C. for 1 h and filtered afterward over celite. The filtrate was concentrated, and the product was purified by silica gel filtration (toluene/heptane 1:2) to yield 38.8 g (87%) of the Vd as a light yellow solid. The reaction mixture was evaporated to dryness The resulting suspension was stirred at 40° C. for 1 h filtered afterward over celite The filtrate was concentrated the product was purified by silica gel filtration (toluene/heptane 1:2) to yield 38.8 g (87%) of the Vd as a light yellow solid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.2 mmol of Pd(PPh3)2Cl2 and 0.1 mmol of CuI are added to a mixture of 0.01 mol of 4-pentylphenylacetylene, 0.01 mol of 3-fluoro-4-chloro-iodobenzene and 40 ml of diethylamine at room temperature and stirred for 12 hours. After completion of the reaction, the suspension is filtered, and the filtrate is concentrated by evaporation. Purification by chromatography and/or crystallization gives 4-pentyl-3'-fluoro-4'-chloro tolan having C 49.6° I. After completion of the reaction the suspension is filtered the filtrate is concentrated by evaporation Purification by chromatography and/or crystallization

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In analogy to the procedure described in example 24E], 1-chloro-2-fluoro-4-iodobenzene and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by purification described in example 26A] yielded the title compound as off-white powder, mp. 106-107° C., dec. followed by purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 1-chloro-2-fluoro-4-iodobenzene (584 mg, 2.279 mmol), and the reaction mixture was stirred at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using four aqueous washes. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate, 0.220 g; purity, 93% by LCMS analysis. Analysis LCMS condition F: rt=2.59 min; ESI-MS(+) m/z 332.2 (M+H). To an oven dried 8 mL vial with teflon cap purged with N2 DMF was removed The organic phase was dried over anhydrous sodium sulfate filtered concentrated the crude product was purified by silica gel chromatography

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 4-chloro-3-fluoroiodobenzene (74.27 g, 284 mmol) and cesium carbonate (185.0 g, 568 mmol) in tetrahydrofuran (730 mL) was added under an argon atmosphere cuprous iodide (2.16 g, 11.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (3.98 g, 5.7 mmol). Ethyl propiolate (57.0 g, 575 mmol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 38 h at 35° C., then filtrated over Hyflo® and the residue was washed with tetrahydrofuran (285 ml). The filtrate was evaporated and purification of the residue by chromatography (SiO2, heptane: ethyl acetate=90:10) afforded the title compound (57.1 g, 89%) as a yellow liquid. MS m/e: 226.0 [M]+. filtrated over Hyflo® the residue was washed with tetrahydrofuran (285 ml) The filtrate was evaporated purification of the residue by chromatography (SiO2, heptane: ethyl acetate=90:10)