4-(difluoromethoxy)-3-methoxybenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chlorodifluoromethane is introduced into a mixture of 200 g of vanillin, 6.7 g of benzyltrimethylammonium chloride, 314 g of 50% strength sodium hydroxide solution and 2 liters of dioxane with vigorous stirring for about 2 h. The mixture is then partitioned between ice water and ethyl acetate, the organic phase is separated off, the aqueous phase is extracted twice by stirring with ethyl acetate, and the combined organic phases are dried over magnesium sulphate and concentrated in vacuo. To remove unreacted vanillin, the oil is chromatographed on neutral silica gel using toluene. After evaporating the eluate, 249 g of 4-difluoromethoxy-3-methoxybenzaldehyde are obtained as an oil. The mixture is then partitioned between ice water and ethyl acetate the organic phase is separated off the aqueous phase is extracted twice by stirring with ethyl acetate the combined organic phases are dried over magnesium sulphate concentrated in vacuo To remove unreacted vanillin the oil is chromatographed on neutral silica gel After evaporating the eluate, 249 g of 4-difluoromethoxy-3-methoxybenzaldehyde are obtained as an oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chlorodifluoromethane is introduced into a mixture of 200 g of vanillin, 6.7 g of benzyltrimethylammonium chloride, 314 g of 50% strength sodium hydroxide solution and 2 liters of dioxane with vigorous stirring for about 2 h. The mixture is then partitioned between ice water and ethyl acetate, the organic phase is separated off, the aqueous phase is extracted twice by stirring with ethyl acetate, and the combined organic phases are dried over magnesium sulphate and concentrated in vacuo. To remove unreacted vanillin, the oil is chromatographed on neutral silica gel using toluene. After evaporating the eluate, 249 g of 4-difluoromethoxy-3-methoxybenzaldehyde are obtained as an oil. The mixture is then partitioned between ice water and ethyl acetate the organic phase is separated off the aqueous phase is extracted twice by stirring with ethyl acetate the combined organic phases are dried over magnesium sulphate concentrated in vacuo To remove unreacted vanillin the oil is chromatographed on neutral silica gel After evaporating the eluate, 249 g of 4-difluoromethoxy-3-methoxybenzaldehyde are obtained as an oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 7.3 g of 80% strength sodium chlorite in 15 ml of water is added dropwise with continuous stirring to a mixture of 10.0 g of 4-difluoromethoxy-3-methoxybenzaldehyde, 6.5 g of sulphamic acid and 50 ml of glacial acetic acid. The internal temperature is kept between 30° and 35° C. by cooling with ice water. After dropwise addition is complete, the mixture is stirred for a further 1 h and then diluted with water. The precipitated 4-difluoromethoxy-3-methoxybenzoic acid is filtered off with suction, washed with water, dried in vacuo and crystallized from acetonitrile/petroleum ether (b.p. 40°) 2/8. Yield 7.1 g; m.p. 170° C. is kept between 30° and 35° C. After dropwise addition The precipitated 4-difluoromethoxy-3-methoxybenzoic acid is filtered off with suction washed with water dried in vacuo crystallized from acetonitrile/petroleum ether (b.p. 40°) 2/8

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)-3-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 422.01 g/mol. Prepared Subsequent purification by preparative HPLC afforded the target compound

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Repeating Example 3, except that 4-difluoromethoxy-3-methoxybenzaldehyde was replaced with 70 grams (0.3 mol) of 4-trifluoroethoxy-3-methoxybenzaldehyde to give 4-trifluoroethoxy-3-hydroxybenzaldehyde (m.p. 133˜135° C.) in a yield of 81%. 1H-NMR (ppm) δ: 9.81 (1H, s; —CHO); 7.26 (1H, m; 6-ArH); 7.17 (1H, m; 2-ArH); 6.79 (1H, m; 5-ArH); 4.88 (1H, s; —OH); 4.45 (2H, q; J3H-F=7.2 Hz; —CH2CF3). 13C-NMR (ppm)) δ: 191.0 (CHO), 157.2 (4-ArC), 146.2 (3-ArC), 130.6 (1-ArC), 126 (q, CF3), 123.5 (6-ArC), 116.7 (2-ArC), 116.2 (5-ArC), 87 (m, CH2).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Repeating Example 3, except that 4-difluoromethoxy-3-methoxybenzaldehyde was replaced with 70 grams (0.3 mol) of 4-trifluoroethoxy-3-methoxybenzaldehyde to give 4-trifluoroethoxy-3-hydroxybenzaldehyde (m.p. 133˜135° C.) in a yield of 81%. 1H-NMR (ppm) δ: 9.81 (1H, s; —CHO); 7.26 (1H, m; 6-ArH); 7.17 (1H, m; 2-ArH); 6.79 (1H, m; 5-ArH); 4.88 (1H, s; —OH); 4.45 (2H, q; J3H-F=7.2 Hz; —CH2CF3). 13C-NMR (ppm)) δ: 191.0 (CHO), 157.2 (4-ArC), 146.2 (3-ArC), 130.6 (1-ArC), 126 (q, CF3), 123.5 (6-ArC), 116.7 (2-ArC), 116.2 (5-ArC), 87 (m, CH2).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Piperidine (0.25 mL, 2.6 mmol) was added to a suspension of 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.52 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 mg, 2.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water, filtered and washed with water to afford (E)-2-[[3-methoxy-4-(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 172-174° C.; δH (500 MHz, DMSO-d6) 3.90 (s, 3H, OCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (t, J=75 Hz, 1H, OCHF2), 7.17 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.32 (dd, J5′,6′=8.0, J2′,6′=2.0 Hz, 1H, H6′), 7.56 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (dt, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.33 (s, 1H, NH), 13.60 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 56.1, 112.3, 114.5, 116.5 (t, J=256 Hz), 116.8, 120.4, 120.8, 121.4, 122.7, 122.9, 131.1, 132.9, 134.0, 140.6, 140.8, 150.7, 163.7, 169.4; HRMS (ESI−) calculated for C18H15F2NO5 [M-H ]− 362.0835, found 362.0839; νmax 1032, 1260, 1586, 1604, 1661, 2988, 3509 cm−1. The reaction flask was fitted with a Dean-Stark apparatus heated to reflux for 30 min the resulting suspension was filtered washed with toluene The piperidinium salt was dissolved in MeOH (5 mL) The crude product was collected by filtration recrystallised from EtOH/water filtered washed with water

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl chlorodifluoroacetate (1.4 mL, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 mL). The suspension was heated to 65-70° C. for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41%) as a colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J=74 Hz, 1H, OCHF2), 7.30 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.50 (d, J2,6=2.0 Hz, 1H, H2), 9.93 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.2, 110.9, 115.5 (t, J=256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8. The aqueous phase was extracted with EtOAc the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine dried concentrated The residue was purified by column chromatography eluting with 10% EtOAc/petrol

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl chlorodifluoroacetate (1.4 mL, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 mL). The suspension was heated to 65-70° C. for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41%) as a colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J=74 Hz, 1H, OCHF2), 7.30 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.50 (d, J2,6=2.0 Hz, 1H, H2), 9.93 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.2, 110.9, 115.5 (t, J=256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8. The aqueous phase was extracted with EtOAc the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine dried concentrated The residue was purified by column chromatography eluting with 10% EtOAc/petrol

Conditions: temp:0.00; pressure:0.00; stir: