D-苏氨醇

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

实验步骤: 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.75 g, 3.91 mmol) synthesized in Example (106c) was dissolved in methanol (30 mL), and D-threoninol (1.00 g, 9.51 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.85 g, 10.30 mmol) were added, followed by stirring at room temperature for 5 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.76 g, yield 84%) as a white solid. After the solvent was distilled off under reduced pressure a saturated aqueous ammonium chloride solution (50 mL) was added extraction The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The resulting residue was purified silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%)

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

实验步骤: 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.75 g, 3.91 mmol) synthesized in Example (106c) was dissolved in methanol (30 mL), and D-threoninol (1.00 g, 9.51 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.85 g, 10.30 mmol) were added, followed by stirring at room temperature for 5 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.76 g, yield 84%) as a white solid. After the solvent was distilled off under reduced pressure a saturated aqueous ammonium chloride solution (50 mL) was added extraction The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The resulting residue was purified silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%)

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

实验步骤: 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k), commercially available D-threoninol (0.34 g, 3.23 mmol), HOBT•H2O (0.40 g, 3.23 mmol) and N-methylmorpholine (0.59 mL, 5.38 mmol) were dissolved in N,N-dimethylformamide (20 mL), and WSCI•HCl (0.62 g, 3.23 mmol) was added at room temperature, followed by stirring for 20 hours under nitrogen atmosphere. To the reaction solution, saturated brine (30 mL) was added, and extraction was carried out with ethyl acetate (60 mL). After washing with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-7%) to afford the desired compound (1.24 g, 86%) as a white solid. extraction After washing with 1N hydrochloric acid a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-7%)

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

实验步骤: 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k), commercially available D-threoninol (0.34 g, 3.23 mmol), HOBT•H2O (0.40 g, 3.23 mmol) and N-methylmorpholine (0.59 mL, 5.38 mmol) were dissolved in N,N-dimethylformamide (20 mL), and WSCI•HCl (0.62 g, 3.23 mmol) was added at room temperature, followed by stirring for 20 hours under nitrogen atmosphere. To the reaction solution, saturated brine (30 mL) was added, and extraction was carried out with ethyl acetate (60 mL). After washing with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-7%) to afford the desired compound (1.24 g, 86%) as a white solid. extraction After washing with 1N hydrochloric acid a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-7%)

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

实验步骤: D-threoninol (2 g, 19.02 mmol) was dissolved in DMF (15 ml), treated with imidazole (3.89 g, 57.1 mmol) and stirred at RT for 5 min. Then, TBDPS-Cl (5.13 ml, 19.97 mmol) was added dropwise to the reaction solution under argon. The reaction solution was stirred for 16H at RT. Then it was diluted in EtOAc and washed twice with saturated NaHCO3 solution and once with brine. Organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc: 100%→0% heptane.) to give the title compound (3.21 g, 47%). tR: 0.98 min (LC-MS 1); ESI-MS: 344.3 [M+H]+ (LC-MS 1). The reaction solution was stirred for 16H at RT washed twice with saturated NaHCO3 solution and once with brine Organic layer was dried over Na2SO4 filtered concentrated The residue was purified by flash chromatography (heptane/EtOAc: 100%→0% heptane.)

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

实验步骤: D-threoninol (2 g, 19.02 mmol) was dissolved in DMF (15 ml), treated with imidazole (3.89 g, 57.1 mmol) and stirred at RT for 5 min. Then, TBDPS-Cl (5.13 ml, 19.97 mmol) was added dropwise to the reaction solution under argon. The reaction solution was stirred for 16H at RT. Then it was diluted in EtOAc and washed twice with saturated NaHCO3 solution and once with brine. Organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (heptane/EtOAc: 100%→0% heptane.) to give the title compound (3.21 g, 47%). tR: 0.98 min (LC-MS 1); ESI-MS: 344.3 [M+H]+ (LC-MS 1). The reaction solution was stirred for 16H at RT washed twice with saturated NaHCO3 solution and once with brine Organic layer was dried over Na2SO4 filtered concentrated The residue was purified by flash chromatography (heptane/EtOAc: 100%→0% heptane.)

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

实验步骤: 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.75 g, 3.91 mmol) synthesized in Example (106c) was dissolved in methanol (30 mL), and D-threoninol (1.00 g, 9.51 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.85 g, 10.30 mmol) were added, followed by stirring at room temperature for 5 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.76 g, yield 84%) as a white solid. After the solvent was distilled off under reduced pressure a saturated aqueous ammonium chloride solution (50 mL) was added extraction The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The resulting residue was purified silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%)

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

实验步骤: N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) 7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+. the precipitated 1,3-dicyclohexylurea filtered off the reaction mixture stirred at RT overnight extracted with about x ml of 5% NaHCO3 by washing with brine The organic layer was dried (Na2SO4) evaporated to a syrup chromatographed by silica gel column chromatography Fractions containing the product evaporated to a white solid (9.94 g, 80%)

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

实验步骤: N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) 7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+. the precipitated 1,3-dicyclohexylurea filtered off the reaction mixture stirred at RT overnight extracted with about x ml of 5% NaHCO3 by washing with brine The organic layer was dried (Na2SO4) evaporated to a syrup chromatographed by silica gel column chromatography Fractions containing the product evaporated to a white solid (9.94 g, 80%)

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

实验步骤: N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) δ7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+. the precipitated 1,3-dicyclohexylurea filtered off the reaction mixture stirred at RT overnight extracted with about x ml of 5% NaHCO3 by washing with brine The organic layer was dried (Na2SO4) evaporated to a syrup chromatographed by silica gel column chromatography Fractions containing the product evaporated to a white solid (9.94 g, 80%)

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

实验步骤: N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) 7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+. the precipitated 1,3-dicyclohexylurea filtered off the reaction mixture stirred at RT overnight extracted with about x ml of 5% NaHCO3 by washing with brine The organic layer was dried (Na2SO4) evaporated to a syrup chromatographed by silica gel column chromatography Fractions containing the product evaporated to a white solid (9.94 g, 80%)

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

实验步骤: According to the same conditions resulting in the preparation of the compound 2, the compound 12 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of D-threoninol. Yield=42%, Oil. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.7 Hz, Harom), 7.97 (d, 2H, J=8.3 Hz, Harom), 7.78-7.69 (m, 2H, Harom) 7.63 (s, 1H, 1H, Harom), 7.45 (d, 2H, J=8.3 Hz, Harom), 7.26-7.21 (m, 1H, Harom), 6.71 (bs, 1H, NH), 5.62 (d, 1H, J=6.6 Hz, NH), 4.77 (d, 2H, J=6.0 Hz, CH2), 4.22-4.15 (m, 1H, CH), 3.97-3.84 (m, 3H, CH 4-CH2), 3.01 (hept, 1H, J=7.0 Hz, CH), 1.29 (d, 3H, J=6.2 Hz, CH3), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (EST): m/z 448 (MH+).