methyl 2-hydroxy-5-iodobenzoate

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: Under argon atmosphere 240 mg of 2,5-dimethoxyphenylacetylene and 493 mg of methyl 5-iodosalicylate are dissolved in 20 ml of oxygen-free and dry benzene. The mixture is treated with 85 mg of tetrakis (triphenylphosphine)palladium, 20 mg of copper(I)iodide and 450 mg of triethylamine, stirred at room temperature overnight and then poured onto 100 ml of aqueous pH 7 buffer. After extraction with ethyl acetate and purification by chromatography on silicagel, 5-[2-(2,5-dimethoxyphenyl)ethinyl]-2-hydroxybenzoic acid methyl ester is obtained (colorless crystals of M.P. 105°-108°). poured onto 100 ml of aqueous pH 7 buffer After extraction with ethyl acetate and purification by chromatography on silicagel

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

Procedure: 5-Iodosalicylic acid (Aldrich Chemical Company, Milwaukee, Wis.) is converted to the methyl ester by reaction with methanol, trimethyl orthoformate and sulfuric acid. The 5-iodosalicylic acid methyl ester thus obtained is reacted with (trimethylsilyl)acetylene (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium. The trimethylsilyl group is removed and two equivalents of the resultant 5-acetylenylsalicylic acid methyl ester is reacted with 4,4'-dibromobiphenyl (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium as above. The resultant alkynyl analogue of Chrysamine G, 4,4'-bis(3-methoxycarbonyl-4-hydroxyphenylacetylenyl)-biphenyl is prepared by hydrolysis of the ester as described above.

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

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

Procedure: rac-5-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethynyl]-2-hydroxybenzoic acid methyl ester was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-hydroxy-5-iodobenzoic acid methyl ester [M. Covello, Chim. Ther. 2, 73 (1967)] as described in Example 4. The compound was isolated by chromatography over silica gel using methylene chloride and was crystallized from ethyl acetate/hexane to yield colorless crystals with m.p. 151°-153° C. The compound was isolated by chromatography over silica gel was crystallized from ethyl acetate/hexane to yield colorless crystals with m.p. 151°-153° C.

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

Procedure: rac-5-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethynyl]-2-hydroxybenzoic acid methyl ester was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-hydroxy-5-iodobenzoic acid methyl ester [M. Covello, Chim. Ther. 2, 73 (1967)] as described in Example 4. The compound was isolated by chromatography over silica gel using methylene chloride and was crystallized from ethyl acetate/hexane to yield colorless crystals with m.p. 151°-153° C. The compound was isolated by chromatography over silica gel was crystallized from ethyl acetate/hexane to yield colorless crystals with m.p. 151°-153° C.

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

Procedure: 2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (8.0 g) synthesized in Example 4 and 5-iodosalicylic acid methyl ester (7.3 g) were dissolved in tetrahydrofuran (130 mL), triphenylphosphine (9.0 g) and diethyl diazodicarboxylate (14.9 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (14.3 g) as a colorless oil. cooling The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1)

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

Procedure: 2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (8.0 g) synthesized in Example 4 and 5-iodosalicylic acid methyl ester (7.3 g) were dissolved in tetrahydrofuran (130 mL), triphenylphosphine (9.0 g) and diethyl diazodicarboxylate (14.9 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (14.3 g) as a colorless oil. cooling The reaction mixture was concentrated under reduced pressure the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1)

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

Procedure: Reflux a mixture of 2-hydroxy-5-iodo-benzoic acid methyl ester (TCI; 5.5 g, 20 mmol) and ethyl bromoacetate (Aldrich; 6.7 g, 40 mmol) in acetone (60 mL) in the presence of potassium (5.5 g, 40 mmol) for 3 h. Filter out the solid and evaporate acetone to give a white residue. Dissolve the residue in ethyl acetate and wash with brine. Evaporate the solvent in vacuum to give final product as a white solid (7 g, 96%). MS (electrospray, m/z) 365 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=2.0 Hz, 1H), 7.70 (dd, J=8.8, 2.8 Hz, 1H), 6.6 (d, J=8.8 Hz, 1H), 4.68 (s, 2H), 4.3 (q, J=6.8 Hz, 2H), 3.9 (s, 1H), 1.3 (t, J=6.8 Hz, 3H). Reflux Filter out the solid evaporate acetone to give a white residue wash with brine Evaporate the solvent in vacuum

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

Procedure: Reflux a mixture of 2-hydroxy-5-iodo-benzoic acid methyl ester (TCI; 5.5 g, 20 mmol) and ethyl bromoacetate (Aldrich; 6.7 g, 40 mmol) in acetone (60 mL) in the presence of potassium (5.5 g, 40 mmol) for 3 h. Filter out the solid and evaporate acetone to give a white residue. Dissolve the residue in ethyl acetate and wash with brine. Evaporate the solvent in vacuum to give final product as a white solid (7 g, 96%). MS (electrospray, m/z) 365 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=2.0 Hz, 1H), 7.70 (dd, J=8.8, 2.8 Hz, 1H), 6.6 (d, J=8.8 Hz, 1H), 4.68 (s, 2H), 4.3 (q, J=6.8 Hz, 2H), 3.9 (s, 1H), 1.3 (t, J=6.8 Hz, 3H). Reflux Filter out the solid evaporate acetone to give a white residue wash with brine Evaporate the solvent in vacuum

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

Procedure: A solution of methyl 5-iodosalicylate (2.00 g, 7.20 mmol) in DMF (20 mL) was treated with imidazole (1.22 g, 18.0 mmol) then chlorotriisopropylsilane (1.85 mL, 8.60 mmol). The mixture was stirred at RT for 18 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with a 10% aqueous citric acid solution, 1N aqueous NaOH solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% EtOAc in cyclohexane, to give the title compound as a colorless oil (2.88 g, 92%). LCMS (Method 3): Rt 5.72 min, m/z 435 [MH+]. The mixture was evaporated in vacuo the residue was partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (2×) The combined organic layers were washed with a 10% aqueous citric acid solution, 1N aqueous NaOH solution and brine dried (Na2SO4) filtered evaporated in vacuo The residue was purified by FCC