4-((2-甲氧基乙氧基)甲氧基)苯甲醛

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

实验步骤: A mixture of 4-((2-methoxyethoxy)methoxy)benzaldehyde (Intermediate I, 1.86 g, 8.85 mmol) and NH4OAc (0.75 g, 9.73 mmol) in dry THF (15 mL) and CH3NO2 (15 mL) was refluxed for 20 h and allowed to reach room temperature. The volume of the reaction was reduced to approx. ⅓, by rotatory evaporation; the resulting solution was poured into water (15 mL) and extracted with AcOEt (2×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes) affording 1.77 g of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene [Rf=0.7 (50% AcOEt/Hexanes), yellow solid, 79% yield]. was refluxed for 20 h to reach room temperature The volume of the reaction was reduced to approx. ⅓, by rotatory evaporation the resulting solution was poured into water (15 mL) extracted with AcOEt (2×15 mL) The organic layers were washed with brine (20 mL) dried over anhydrous Na2SO4 filtered After removal of the solvent the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyethoxymethyl chloride (5.10 mL, 45.0 mmol) was slowly added to a mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and K2CO3 (6.20 g, 45.0 mmol) in acetone (70 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 40 h. After removal of the solvent, the crude residue was dissolved in EtOAc (50 mL) and consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 6.85 g of 4-((2-methoxyethoxy)methoxy)benzaldehyde were obtained [Rf=0.6 (50% AcOEt/Hexanes), colorless oil, 80% yield], that were used without further purification. to reach room temperature After removal of the solvent the crude residue was dissolved in EtOAc (50 mL) consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL) The organic layer was dried over anhydrous Na2SO4 filtered After removal of the solvent

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyethoxymethyl chloride (5.10 mL, 45.0 mmol) was slowly added to a mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and K2CO3 (6.20 g, 45.0 mmol) in acetone (70 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 40 h. After removal of the solvent, the crude residue was dissolved in EtOAc (50 mL) and consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 6.85 g of 4-((2-methoxyethoxy)methoxy)benzaldehyde were obtained [Rf=0.6 (50% AcOEt/Hexanes), colorless oil, 80% yield], that were used without further purification. to reach room temperature After removal of the solvent the crude residue was dissolved in EtOAc (50 mL) consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL) The organic layer was dried over anhydrous Na2SO4 filtered After removal of the solvent

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

实验步骤: 0.16 mol of 4-hydroxybenzaldehyde and 0.32 mol of ethyldiisopropylamine are dissolved in 250 ml of CH2Cl2 (anhydrous), and 0.24 mol of 2-methoxyethoxymethyl chloride are then added dropwise at room temperature. The mixture is stirred at this temperature for 2 hours, then the solvent is removed in vacuo. The residue is taken up using 200 ml of EA and the solution is washed once each with 200 ml of Na2CO3 solution and 200 ml of NaH2PO4 solution, dried over Na2 SO4 and the solvent removed in vacuo. 34 g of a light brown oil are obtained, which is reacted further without purification. the solvent is removed in vacuo the solution is washed once each with 200 ml of Na2CO3 solution and 200 ml of NaH2PO4 solution dried over Na2 SO4 the solvent removed in vacuo

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

实验步骤: 0.16 mol of 4-hydroxybenzaldehyde and 0.32 mol of ethyldiisopropylamine are dissolved in 250 ml of CH2Cl2 (anhydrous), and 0.24 mol of 2-methoxyethoxymethyl chloride are then added dropwise at room temperature. The mixture is stirred at this temperature for 2 hours, then the solvent is removed in vacuo. The residue is taken up using 200 ml of EA and the solution is washed once each with 200 ml of Na2CO3 solution and 200 ml of NaH2PO4 solution, dried over Na2 SO4 and the solvent removed in vacuo. 34 g of a light brown oil are obtained, which is reacted further without purification. the solvent is removed in vacuo the solution is washed once each with 200 ml of Na2CO3 solution and 200 ml of NaH2PO4 solution dried over Na2 SO4 the solvent removed in vacuo

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

实验步骤: A mixture of 4-((2-methoxyethoxy)methoxy)benzaldehyde (Intermediate I, 1.86 g, 8.85 mmol) and NH4OAc (0.75 g, 9.73 mmol) in dry THF (15 mL) and CH3NO2 (15 mL) was refluxed for 20 h and allowed to reach room temperature. The volume of the reaction was reduced to aprox. ⅓, by rotatory evaporation; the resulting solution was poured into water (15 mL) and extracted with AcOEt (2×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes) affording 1.77 g of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene [Rf=0.7 (50% AcOEt/Hexanes), yellow solid, 79% yield]. was refluxed for 20 h to reach room temperature ⅓, by rotatory evaporation the resulting solution was poured into water (15 mL) extracted with AcOEt (2×15 mL) The organic layers were washed with brine (20 mL) dried over anhydrous Na2SO4 filtered After removal of the solvent the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyethoxymethyl chloride (5.10 mL, 45.0 mmol) was slowly added to a mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and K2CO3 (6.20 g, 45.0 mmol) in acetone (70 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 40 h. After removal of the solvent, the crude residue was dissolved in EtOAc (50 mL) and consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 6.85 g of 4-((2-methoxyethoxy)methoxy)benzaldehyde were obtained [Rf=0.6 (50% AcOEt/Hexanes), colorless oil, 80% yield], that were used without further purification. to reach room temperature After removal of the solvent the crude residue was dissolved in EtOAc (50 mL) consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL) The organic layer was dried over anhydrous Na2SO4 filtered After removal of the solvent

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyethoxymethyl chloride (5.10 mL, 45.0 mmol) was slowly added to a mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and K2CO3 (6.20 g, 45.0 mmol) in acetone (70 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 40 h. After removal of the solvent, the crude residue was dissolved in EtOAc (50 mL) and consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 6.85 g of 4-((2-methoxyethoxy)methoxy)benzaldehyde were obtained [Rf=0.6 (50% AcOEt/Hexanes), colorless oil, 80% yield], that were used without further purification. to reach room temperature After removal of the solvent the crude residue was dissolved in EtOAc (50 mL) consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL) The organic layer was dried over anhydrous Na2SO4 filtered After removal of the solvent

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

实验步骤: To a solution of 4-hydroxy-benzaldehyde (3.7 g, 30 mmol) and diisopropylethylamine (7.6 mL) in CH2Cl2 (60 mL) was added MEMCl (5.0 mL) in CH2Cl2 (17 mL) dropwise at 0° C. The mixture was stirred at RT for 3 h, quenched with Hcl (60 mL, 0.5 N). The mixture was extracted with CH2Cl2. The organic phase was washed with NaOH solution (1 N) and water. The separated organic phase was dried under Na2SO4, filtered and concentrated to give 6.2 g of product (97%) which was pure enough to be used to the next reaction without further purification. 1HNMR (200 MHz, CDCl3): δ 3.36 (s, 3H), 3.54 (m, 2H), 3.83 (m, 2H), 5.41 (s, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 9.90 (s, 1H). quenched with Hcl (60 mL, 0.5 N) The mixture was extracted with CH2Cl2 The organic phase was washed with NaOH solution (1 N) and water The separated organic phase was dried under Na2SO4 filtered concentrated

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

实验步骤: To a solution of 4-hydroxy-benzaldehyde (3.7 g, 30 mmol) and diisopropylethylamine (7.6 mL) in CH2Cl2 (60 mL) was added MEMCl (5.0 mL) in CH2Cl2 (17 mL) dropwise at 0° C. The mixture was stirred at RT for 3 h, quenched with Hcl (60 mL, 0.5 N). The mixture was extracted with CH2Cl2. The organic phase was washed with NaOH solution (1 N) and water. The separated organic phase was dried under Na2SO4, filtered and concentrated to give 6.2 g of product (97%) which was pure enough to be used to the next reaction without further purification. 1HNMR (200 MHz, CDCl3): δ 3.36 (s, 3H), 3.54 (m, 2H), 3.83 (m, 2H), 5.41 (s, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 9.90 (s, 1H). quenched with Hcl (60 mL, 0.5 N) The mixture was extracted with CH2Cl2 The organic phase was washed with NaOH solution (1 N) and water The separated organic phase was dried under Na2SO4 filtered concentrated

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

实验步骤: To a solution of 4-hydroxy-benzaldehyde (3.7 g, 30 mmol) and diisopropylethylamine (7.6 mL) in CH2Cl2 (60 mL) was added MEMCl (5.0 mL) in CH2Cl2 (17 mL) dropwise at 0° C. The mixture was stirred at RT for 3 h, quenched with Hcl (60 mL, 0.5 N). The mixture was extracted with CH2Cl2. The organic phase was washed with NaOH solution (1 N) and water. The separated organic phase was dried under Na2SO4, filtered and concentrated to give 6.2 g of product (97%) which was pure enough to be used to the next reaction without further purification. 1HNMR (200 MHz, CDCl3): δ 3.36 (s, 3H), 3.54 (m, 2H), 3.83 (m, 2H), 5.41 (s, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 9.90 (s, 1H). quenched with Hcl (60 mL, 0.5 N) The mixture was extracted with CH2Cl2 The organic phase was washed with NaOH solution (1 N) and water The separated organic phase was dried under Na2SO4 filtered concentrated

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

实验步骤: 4-Methoxyethoxymethoxybenzaldehyde (420 mg) and 3,5-bis(trifluoromethyl)phenylacetonitrile (506 mg) were subjected to condensation in accordance with process A of (production process 2), and the resultant product was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (122 mg, yield: 17%).