4-methoxy-3-propan-2-yloxybenzaldehyde

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

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

Procedure: A mixture of 3-hydroxy-4-methoxybenzaldehyde (20.0 g), anhydrous potassium carbonate (26.2 g) and 2-bromopropane (18.3 mL) in dry dimethylformamide (300 mL) is stirred and heated at 55°-65° C. for 24 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo at 40° C., to give 4-methoxy-3-prop-2-yloxybenzaldehyde, in the form of an oil (24.2 g). heated at 55°-65° C. for 24 hours extracted with ethyl acetate The extract is dried over magnesium sulfate concentrated in vacuo at 40° C.

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

Procedure: Under reflux, 20 ml of methanol solution containing 4.27 g of 3-isopropoxy-4 -methoxybenzaldehyde and 10.81 g of ferric chloride hexahydrate was added dropwise to 35 ml of methanol solution containing 3.50 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2. The resulting mixture was refluxed for 1 hour and then cooled, and the insoluble matter was collected by filtration. This was suspended in ethyl acetate/water and alkalified with liquid ammonia, and then the insoluble matter was removed by Celite filtration. The ethyl acetate layer was collected and dried over magnesium sulfate, and then the solvent was evaporated. By crystallizing the resulting residue with ethyl acetate/hexane, 4.92 g (70%) of the title compound was obtained. Its physical property values coincided with the data obtained in the above step (1). Under reflux obtained in Reference Example 2 The resulting mixture was refluxed for 1 hour cooled the insoluble matter was collected by filtration the insoluble matter was removed by Celite filtration The ethyl acetate layer was collected dried over magnesium sulfate the solvent was evaporated By crystallizing the resulting residue with ethyl acetate/hexane

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5.98 g portion of a known compound 3-isopropoxy-4-methoxybenzaldehyde was added to 4.49 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2, and the mixture was stirred for 18 hours in 37 ml of nitrobenzene while heating at 150° C. After cooling, nitrobenzene was evaporated under a reduced pressure. By crystallizing the resulting residue with ethyl acetate/hexane, 4.90 g (55%) of the title compound was obtained. Its physical property values are shown as the Compound No. 1 in Table 1. obtained in Reference Example 2 After cooling nitrobenzene was evaporated under a reduced pressure By crystallizing the resulting residue with ethyl acetate/hexane

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5.98 g portion of a known compound 3-isopropoxy-4-methoxybenzaldehyde was added to 4.49 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2, and the mixture was stirred for 18 hours in 37 ml of nitrobenzene while heating at 150° C. After cooling, nitrobenzene was evaporated under a reduced pressure. By crystallizing the resulting residue with ethyl acetate/hexane, 4.90 g (55%) of the title compound was obtained. Its physical property values are shown as the Compound No. 1 in Table 1. obtained in Reference Example 2 After cooling nitrobenzene was evaporated under a reduced pressure By crystallizing the resulting residue with ethyl acetate/hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PP3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429,1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm1. 1H n.m.r. δ7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ150.5 (C), 146.7(C), 136.4 (CH), 127.7(C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0(C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22)(M+•), 310 (50) 308 (100) 306 (50) [(M−C3H6)+•], 295 (30), 293 (61) 291 (33) [(M−C3H6−CH3+•)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%. to warm to room temperature After this time the reaction mixture was re-cooled to 0° C. to stir at room temperature for 1 h filtered through a No The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PP3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429,1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm1. 1H n.m.r. δ7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ150.5 (C), 146.7(C), 136.4 (CH), 127.7(C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0(C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22)(M+•), 310 (50) 308 (100) 306 (50) [(M−C3H6)+•], 295 (30), 293 (61) 291 (33) [(M−C3H6−CH3+•)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%. to warm to room temperature After this time the reaction mixture was re-cooled to 0° C. to stir at room temperature for 1 h filtered through a No The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1

Conditions: temp:61.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Silver trifluoroacetate (12.3 g, 56.7 mmol) was added to a solution of isovanillin isopropyl ether (10.0 g, 51.5 mmol) in dry chloroform (120 mL) under nitrogen and the resultant slurry stirred and heated to 61° C. Iodine (14.4 g, 56.7 mmol) was then added portionwise (6 portions) over 0.6 h and the reaction allowed to reflux for a further 6.5 h. The reaction mixture was then cooled and filtered, rinsing with chloroform (50 mL). The filtrate was washed with Na2S2O5 (10% solution in water, 150 mL), NaHCO3 (sat. in water, 150 mL) and water (150 mL) dried (MgSO4) and concentrated under vacuum. The solid residue was suspended in hexane (200 mL) and stirred vigoursly for 1 h, cooled in an ice bath for 1 h and filtered rinsing with ice cold hexane (200 mL) to give the title compound as a cream solid (15.3 g, 93%) mp 75-6° C. IR (KBr disc, cm−1) 3072, 2978, 2932, 1673, 1581, 1503, 1438, 1385, 1332, 1260, 1215, 1174, 1157, 1133, 1105, 1024, 939. 1H NMR 300 MHz, CDCl3) δ9.77 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 4.57 (septet, J=6.0 Hz, 1H), 3.86 (s,3H), 1.31 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MH, CDCl3) δ194.7(−), 155.5(+), 47.9 (+), 128.2 (+), 122.2 (−), 114.1 (−), 110.8 (+), 92.4 (+), 71.3 (−), 56.4 (−), 21.77 (−), MS (70eV) m/z (%): 320 (M+•, 43), 278 (100), 249 (17), 207 (12), 150 (40). Anal. Calcd for C11H13O3I: C, 41.27; H, 4.09; I, 39.64. Found: C, 41.06; H, 3.80; I, 39.59. to reflux for a further 6.5 h The reaction mixture was then cooled filtered rinsing with chloroform (50 mL) The filtrate was washed with Na2S2O5 (10% solution in water, 150 mL), NaHCO3 (sat. in water, 150 mL) and water (150 mL) dried (MgSO4) concentrated under vacuum stirred vigoursly for 1 h cooled in an ice bath for 1 h filtered rinsing with ice cold hexane (200 mL)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Isopropyl bromide (19.0 mL, 200 mmol) was added to a suspension of K2CO3 (42.0 g, 302 mmol) and isovanillin (23 g, 151.3 mmol) in DMF (100 gmL) and the stirring slurry heated to 80° C. for 13 h. The reaction mixture was then cooled to room temperature, diluted with ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (29.3 g, 100%) which required no further purification. The spectra of this material are identical with those previously reported (H. Ishii, I.-S. Chen and T. Ishikawa J. Chem. Soc., Perkin Trans. 1, 1987, 671.). The reaction mixture was then cooled to room temperature washed with H2O (4×200 mL) dried (MgSO4) concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Isopropyl bromide (19.0 mL, 200 mmol) was added to a suspension of K2CO3 (42.0 g, 302 mmol) and isovanillin (23 g, 151.3 mmol) in DMF (100 gmL) and the stirring slurry heated to 80° C. for 13 h. The reaction mixture was then cooled to room temperature, diluted with ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (29.3 g, 100%) which required no further purification. The spectra of this material are identical with those previously reported (H. Ishii, I.-S. Chen and T. Ishikawa J. Chem. Soc., Perkin Trans. 1, 1987, 671.). The reaction mixture was then cooled to room temperature washed with H2O (4×200 mL) dried (MgSO4) concentrated under reduced pressure

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

Procedure: A mixture of 3-isopropoxy4-methoxy-benzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (6.96 g. 20 mmol) in toluene (100 ml) is heated at reflux for 2 hours, cooled to ambient temperature and evaporated. The crude product is taken in to dichloromethane and eluted through a pad of silica to afford (E)-3-(3-isopropoxy-4-methoxy-phenyl)-acrylic acid ethyl ester, TLC Rf 0.70 (1:1 hexane-ethyl acetate). This intermediate is dissolved in nitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) is added and the reaction heated at 70° C. for 36 hours. The solvent is evaporated, the residue is taken into ethyl acetate and washed with 2N aqueous HCl, water and brine. After drying over sodium sulfate and evaporation, the crude product is purified by flash column chromatography (4:1 hexane-ethyl acetate elution) to afford 3-(3-isopropoxy-4-methoxy-phenyl)-4-nitro-butyric acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 1.20 (t J 7 3H), 1.38 (d J 7 6H), 2.75 (d J 6 2H), 3.90 (m 1H), 4.10 (m 2H), 4.48-4.78 (m 3H), 6.75-6.86 (m 3H). This intermediate is converted into [1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin4-yl]-acetic acid using the general procedure for Intermediate 20. Characterised as the ethyl ester, [MH]+ 496. is heated at reflux for 2 hours evaporated eluted through a pad of silica

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

Procedure: A mixture of 3-isopropoxy4-methoxy-benzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (6.96 g. 20 mmol) in toluene (100 ml) is heated at reflux for 2 hours, cooled to ambient temperature and evaporated. The crude product is taken in to dichloromethane and eluted through a pad of, silica to afford (E)-3-(3-isopropoxy-4-methoxy-phenyl)-acrylic acid ethyl ester, TLC Rf 0.70 (1:1 hexane-ethyl acetate). This intermediate is dissolved in nitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) is added and the reaction heated at 70° C. for 36 hours. The solvent is evaporated, the residue is taken into ethyl acetate and washed with 2N aqueous HCl, water and brine. After drying over sodium sulfate and evaporation, the crude product is purified by flash column chromatography (4:1 hexane-ethyl acetate elution) to afford 3-(3-isopropoxy-4-methoxy-phenyl)-4-nitro-butyric acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 1.20 (t J 7 3H), 1.38 (d J 7 6H), 2.75 (d J 6 2H), 3.90 (m 1H), 4.10 (m 2H), 4.48-4.78 (m 3H), 6.75-6.86 (m 3H). This intermediate is converted into [1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin-4-yl]-acetic acid using the general procedure for Intermediate 20. Characterised as the ethyl ester, [MH]+ 496. is heated at reflux for 2 hours evaporated eluted through a pad of, silica