3-chloro-4-hydroxy-5-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:

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

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

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

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

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

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

Procedure: 37.2 g of commercial 5-chloro vanillin and 800 ml of dichloromethane were mixed together under nitrogen and cooled to 0° C. 300 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for one night at ambient temperature. It was concentrated, cooled again to 0° C. and acidified. The crystallized product was separated, washed with water, dried and crystallized from an isopropanol-water mixture (1-2 by volume) to obtain 26.6 g of the expected product melting at >260° C. the mixture stood for one night at ambient temperature It was concentrated cooled again to 0° C. The crystallized product was separated washed with water dried crystallized from an isopropanol-water mixture (1-2 by volume)

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

Procedure: To a solution of 3-Chloro-4-hydroxy-5-methoxybenzaldehyde (1.0 g, 5.4 mmol) in dichloromethane (150 ml) stirred at −78° C. was added dropwise a solution of boron tribromide in dichloromethane (5.4 ml of 1M solution, 5.4 mmol). Upon completion of the addition, the resulting solution was stirred 18 h at room temperature. The reaction was quenched by addition of methanol then evaporated twice from methanol and the residue purified by reversed-phase preparative HPLC to afford the title compound (0.66 g, 72%). 1H NMR (400 MHz, CD3OD) δ 9.69 (s, 1H), 7.42 (s, 1H), 7.25 (s, 1H). M+1=173. b) 4-Butoxy-3-chloro-5-hydroxybenzaldehyde A solution consisting of 3-chloro-4,5-dihydroxybenzaldehyde (3.0 g, 17.4 mmol), n-butanol (1.42 g, 19.1 mmol), triphenylphosphine (5.02 g, 19.4 mmol), and diethylazodicarboxylate (3.32 g, 19.1 mmol) in THF (60 ml) was stirred at room temperature for 24 h. All volatiles were removed in-vacuo and the residue purified by preparative HPLC to afford the title compound (2.7 g, 68%). 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.46 (d, j=1.8 Hz, 1H), 7.38 (d, j=1.8 Hz, 1H), 5.91 (s, 1H), 4.18 (t, j=6.7 Hz, 2H), 1.83 (m, 2H), 1.51 (m, 2H), 1.00 (t, j=7.4). M+1=299. c) (2-Butoxy-3-chloro-5-formylphenoxy)acetic acid ethyl ester Sodium hydride (84 mg 60% in mineral oil, 2.09 mmol) was added in portions to a solution of 4-butoxy-3-chloro-5-hydroxybenzaldehyde (400 mg, 1.74 mmol) in DMF (5 ml). The resultant mixture was stirred at room temperature for 10 min then ethyl bromoacetate (583 mg, 3.5 mmol) was added slowly. After 1.5 h at room temperature, HPLC indicated complete reaction. The mixture was partitioned between ethyl acetate and water, the organic solution was washed with water then brine and dried with magnesium sulfate. Removal of all volatiles in-vacuo afforded the title compound (100% crude yield). 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.55 (d, j=1.8 Hz, 1H), 7.25 (d, j=1.8 Hz, 1H), 4.73 (s, 2H), 4.21-4.30 (m, 4H) 1.79-1.60 (m, 2H), 1.52-1.60 (m, 2H), 1.31 (t, j=7.1 Hz, 3H), 0.98 (t, j=7.1 Hz, 3H). M+1=315. d) 2-Butoxy-3-chloro-5-[(formylhydroxyamino)methyl]phenoxyacetic acid ethyl ester 2-Butoxy-3-chloro-5-formylphenoxyacetic acid ethyl ester was converted to the title compound using the methods described in example 2d. 1H NMR (400 MHz, CDCl3) δ 8.38* 8.00 (s, 1H), 7.01* 6.98 (s, 1H), 6.70 (s, 1H), 4.68 (s, 2H), 4.60* 4.54 (s, 2H), 4.25 (q, j=7.1 Hz, 2H), 4.07 (t, j=6.6 Hz, 2H) 1.75-1.82 (m, 2H), 1.50-1.56 (m, 2H), 1.29 (t, j=7.1 Hz, 3H), 0.97 (t, j=7.3 Hz, 3H). M+1=360. * signals due to minor rotamer e) 2-Butoxy-3-chloro-5-[(formylhydroxyamino)methyl]phenoxyacetic acid A solution of 2-butoxy-3-chloro-5-[(formylhydroxyamino)methyl]phenoxyacetic acid ethyl ester (0.45 mmol crude) in methanol (5 ml) with 10% aqueous NaOH solution (0.5 ml) was stirred for 1 h. To the resulting solution was added ethyl acetate (20 ml) and water (20 ml). The pH was brought to 6 with 3 N HCl and the layers separated. The organic extract was dried with magnesium sulfate and all volatiles removed. The residue was purified by preparative HPLC to afford the title compound (29 mg, 20% for four steps). 1H NMR (400 MHz, CD3OD) δ 8.37* 8.18 (s, 1H), 7.04* 7.02 (s, 1H), 6.90* 6.88 (s, 1H), 4.75* 4.74 (s, 2H), 4.63* 4.10 (m, 2H), 1.76-1.79 (m, 2H), 1.53-1.59 (m, 2H), 0.98-1.02 (m, 3H). M+1=332. * signals due to rotamer f) 2-{2-Butoxy-3-chloro-5-[(formylhydroxyamino)methyl]-phenoxy}-N-hydroxyformamide To a solution of 2-butoxy-3-chloro-5-[(formylhydroxyamino)methyl]phenoxyacetic acid (crude 0.5 mmol) in THF (4 ml) with TEA (0.167 ml, 1.2 mmol) was added ethyl chloroformate (0.115 ml, 1.2 mmol). This was stirred 15 min then methyl amine (0.21 ml of 40% aqueous solution) was added and stirring continued for an additional 30 min. The mixture was partitioned between ethyl acetate and water aqueous layer adjusted to pH 5 with 1 N HCl). The organic extract was dried with magnesium sulfate and all volatiles removed in vacuo. Purification by preparative HPLC afforded the title compound (10 mg). 1H NMR (400 MHz, CD3OD) δ 8.38* 8.18 (s, 1H), 7.11* 7.08 (s, 1H), 6.98* 6.95 (s, 1H), 4.59-4.65 (m, 4H), 2.84 (s, 3H), 1.76-1.80 (m, 2H), 1.55-1.60 (m, 2H), 1.01 (t, j=7.4 Hz, 3H). M+1=345. * signals due to rotamer Upon completion of the addition The reaction was quenched by addition of methanol then evaporated twice from methanol the residue purified by reversed-phase preparative HPLC

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

Procedure: To a flask containing of dichloromethane (58 ml) was added powdered 4 A sieves (3.37 g, activated at 500° C. for 8 h), phenylboronic acid (3.53 g, 28.95 mmol), 3-chloro-4-hydroxy-5-methoxybenzaldehyde (1.08 g, 5.79 mmol), copper (II) acetate (1.05 g, 5.79 mmol), pyridine (2.33 ml, 28.95 mmol) and triethylamine (4.0 ml, 28.95 mmol). The reaction flask was fitted with a drying tube and stirred overnight at room temperature. Filtration through celite and removal of volatiles in vacuo followed by column chromatography (silica, 10% ethyl acetate in hexane) provided the title compound as a yellow solid (540 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.28 (t, j=8.0 Hz, 2H), 7.05 (t, j=7.2 Hz, 1H), 6.83 (d, j=8.4 Hz, 2H), 3.84 (s, 3H). M+1=263 was added The reaction flask was fitted with a drying tube Filtration through celite and removal of volatiles in vacuo

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

Procedure: To a flask containing of dichloromethane (58 ml) was added powdered 4 A sieves (3.37 g, activated at 500° C. for 8 h), phenylboronic acid (3.53 g, 28.95 mmol), 3-chloro-4-hydroxy-5-methoxybenzaldehyde (1.08 g, 5.79 mmol), copper (II) acetate (1.05 g, 5.79 mmol), pyridine (2.33 ml, 28.95 mmol) and triethylamine (4.0 ml, 28.95 mmol). The reaction flask was fitted with a drying tube and stirred overnight at room temperature. Filtration through celite and removal of volatiles in vacuo followed by column chromatography (silica, 10% ethyl acetate in hexane) provided the title compound as a yellow solid (540 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.28 (t, j=8.0 Hz, 2H), 7.05 (t, j=7.2 Hz, 1H), 6.83 (d, j=8.4 Hz, 2H), 3.84 (s, 3H). M+1=263 was added The reaction flask was fitted with a drying tube Filtration through celite and removal of volatiles in vacuo