methyl 2,3-dihydroxy-4-methoxybenzoate

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

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

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 121 (16.12 g, 0.081 mol) was dissolved in 500 mL of DMF. Then 100 mL of methylene chloride and 26 g (0.464 mol) of potassium carbonate were added. The mixture was heated to 105° C. with vigorous stirring for 6 hours. The potassium carbonate was filtered and the DMF was removed in vacuo. The residue was poured into ice-water and let stand overnight. The precipitated product 122 was filtered and washed with water until neutral. The dried gray white solid weighed 15.60 g (yield 91%) and was recrystallized from methanol as brilliant long needles, m.p. 122°-124° C. IR cm-1 1710 (ester C=O); 1H NMR δ ppm 3.90 (s, 3H, OCH3), 3.95 (s, 3H, ArOCH3), 6.11 (s, 2H, OCH2O), 6.57 and 7.45 (each d, J=9 Hz, 1H, ArH). Anal. (C10H10O5)C, H. The potassium carbonate was filtered the DMF was removed in vacuo The residue was poured into ice-water let stand overnight The precipitated product 122 was filtered washed with water until neutral was recrystallized from methanol as brilliant long needles, m.p. 122°-124° C

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 121 (16.12 g, 0.081 mol) was dissolved in 500 mL of DMF. Then 100 mL of methylene chloride and 26 g (0.464 mol) of potassium carbonate were added. The mixture was heated to 105° C. with vigorous stirring for 6 hours. The potassium carbonate was filtered and the DMF was removed in vacuo. The residue was poured into ice-water and let stand overnight. The precipitated product 122 was filtered and washed with water until neutral. The dried gray white solid weighed 15.60 g (yield 91%) and was recrystallized from methanol as brilliant long needles, m.p. 122°-124° C. IR cm-1 1710 (ester C=O); 1H NMR δ ppm 3.90 (s, 3H, OCH3), 3.95 (s, 3H, ArOCH3), 6.11 (s, 2H, OCH2O), 6.57 and 7.45 (each d, J=9 Hz, 1H, ArH). Anal. (C10H10O5)C, H. The potassium carbonate was filtered the DMF was removed in vacuo The residue was poured into ice-water let stand overnight The precipitated product 122 was filtered washed with water until neutral was recrystallized from methanol as brilliant long needles, m.p. 122°-124° C

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

Procedure: A mixture of 2,3-dihydroxy-4-methoxy benzoic acid methyl ester (0.45 mol), 1,3-dibromopropane (0.72 mol), K2CO3 (155 g) and CuO (3.6 g) in DMF (2500 ml) was stirred at 120° C. to 130° C. for 7 hours, cooled and filtered. The solvent was evaporated. HCl (aqueous solution of 0.5 N, 1000 ml)) was added. The mixture was extracted twice with DCM (750 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate/DCM 70/30/15). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding methyl 3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-carboxylate (intermediate 7). cooled filtered The solvent was evaporated HCl (aqueous solution of 0.5 N, 1000 ml)) was added The mixture was extracted twice with DCM (750 ml) The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate/DCM 70/30/15) The pure fractions were collected the solvent was evaporated The residue was crystallized from DIPE

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 2,3-dihydroxy-4-methoxy benzoic acid methyl ester (0.45 mol), 1,3-dibromopropane (0.72 mol), K2CO3 (155 g) and CuO (3.6 g) in DMF (2500 ml) was stirred at 120° C. to 130° C. for 7 hours, cooled and filtered. The solvent was evaporated. HCl (aqueous solution of 0.5 N, 1000 ml)) was added. The mixture was extracted twice with DCM (750 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate/DCM 70/30/15). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding methyl 3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-carboxylate (intermediate 7). cooled filtered The solvent was evaporated HCl (aqueous solution of 0.5 N, 1000 ml)) was added The mixture was extracted twice with DCM (750 ml) The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate/DCM 70/30/15) The pure fractions were collected the solvent was evaporated The residue was crystallized from DIPE

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

Procedure: Following the general procedure, dialkylation of compound 513 (198 mg, 1 mmol) with compound 523 (301 mg, 1.1 mmol) in DMSO (5 mL) in the presence of K2CO3 (345 mg, 2.5 mmol) afforded compound 524 as a white solid material after purification by column chromatography (50-65% EtOAc in light petroleum). LC-MS: RT=2.65 min.; m/z 311.23 (M+H)+. 1H NMR (DMSO-d6): 7.37 (1H, d, J 8.8), 6.81 (1H, d, J 8.8), 4.80 (1H, d, J 6.4), 4.78 (1H, d, J 6.4), 4.07 (2H, s), 4.01 (2H, s), 3.81 (7H, s), 3.76 (3H, s).

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

Procedure: Following the general procedure, dialkylation of compound 513 (1.19 g, 6 mmol) with compound 521 (2.0 g, 6.62 mmol) in DMSO (30 mL) in the presence of K2CO3 (2.07 g, 15 mmol) afforded compound 522 as a white solid material after purification by column chromatography (30-40% EtOAc in light petroleum). LC-MS: RT=2.99 min.; m/z 339.31 (M+H)+, 361.25 (M+Na)+. 1H NMR (CDCl3): δ 7.45 (1H, d, J 8.8), 6.59 (1H, d, J 8.8), 4.22 (2H, s), 4.18 (2H, s), 3.89 (3H, s), 3.86 (7H, s), 1.43 (6H, s).

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

Procedure: Following the general procedure, dialkylation of compound 513 (95 mg, 0.48 mmol) with compound 519 (240 mg, 0.53 mmol) in DMSO (3 mL) in the presence of K2CO3 (166 mg, 1.2 mmol) afforded compound 520 as a white solid material after purification by column chromatography (45-65% EtOAc in light petroleum). LC-MS: RT=2.40 min.; 1H NMR (DMSO-d6): δ 7.34 (1H, d, J 8.8), 6.78 (1H, d, J 8.8), 3.99 (4H, s), 3.80 (3H, s), 3.76 (3H, s), 3.61 (4H, t, J 5.5), 1.54 (4H, t, J 5.5).

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

Procedure: A solution of commercially available 2,3-dihydroxy-4-methoxybenzoic acid (11.6 g, 63 mmol) in anhydrous MeOH (150 mL) was cooled in an ice-bath and conc. H2SO4 (8 mL) added dropwise. The reaction mixture was refluxed for 12 h, then cooled to rt and the solvent was removed under reduced pressure. H2O (100 mL) and sat aq NaHCO3 (50 mL) were added and extracted with EtOAc (3×100 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford compound 513 as a pale yellow solid, which was used in the next step without further purification. LC-MS: RT=2.31 min.; m/z 197.3 (M−H)−. 1H NMR (CDCl3): δ 10.83 (1H, s), 7.41 (1H, d, J 9.0), 6.50 (1H, d, J 8.9), 5.45 (1H, s), 3.94 (3H, s), 3.93 (3H, s). The reaction mixture was refluxed for 12 h the solvent was removed under reduced pressure were added extracted with EtOAc (3×100 mL) The combined organic phase was dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: A mixture of 2,3-dihydroxy-4-methoxy benzoic acid methyl ester (0.45 mol), 1,3-dibromopropane (0.72 mol), K2CO3 (155 g) and CuO (3.6 g) in DMF (2500 ml) was stirred at 120° C. to 130° C. for 7 hours, cooled and filtered. The solvent was evaporated. HCl (aqueous solution of 0.5 N, 1000 ml)) was added. The mixture was extracted twice with DCM (750 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate/DCM 70/30/15). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding methyl 3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-carboxylate (intermediate 7). cooled filtered The solvent was evaporated HCl (aqueous solution of 0.5 N, 1000 ml)) was added The mixture was extracted twice with DCM (750 ml) The organic layer was separated dried filtered the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate/DCM 70/30/15) The pure fractions were collected the solvent was evaporated The residue was crystallized from DIPE