ethyl 3-(3-hydroxyphenyl)propanoate

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:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled solution of 3-(3-hydroxyphenyl)propionic acid (20.0 g, 120 mmol) in ethanol was dropwise added thionyl chloride (8.8 ml, 120 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and submitted to flash chromatography (10% ethyl acetate in toluene eluent) to give 23.3 g of 3-(3-hydroxy-phenyl)propionic acid ethyl ester. concentrated in vacuo

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

Procedure: To an acetone solution (0.15 M, 170 mL) of 3-(3-Hydroxy-phenyl)-propionic acid ethyl ester (5.0 g, 25.77 mmol) was added K2CO3 (10.69 g, 77.32 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.68 g, 25.77 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (30% ethyl acetate/hexanes) gave the product as a white solid in 93% yield (6.0 g). LCMS (m/z) M+H: 187 the mixture was heated to reflux for 30 min the resulting mixture was heated to reflux overnight After cooling to room temperature the solids were removed by filtration washed well with ethyl acetate The filtrate was concentrated partitioned between ethyl acetate and 1N HCl The organic portion was washed successively with 5% NaHCO3 and brine dried (MgSO4) filtered concentrated to a solid Purification by FCC (30% ethyl acetate/hexanes)

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

Procedure: To a 0° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (1.0 g, 5.15 mmol) in diethyl ether (50 ml) was added sulfuryl chloride (0.493 mL, 6.18 mmol). After 2.5 h at 0° C., the reaction was quenched with sat. sodium carbonate (50 ml). The aqueous layer was extracted with ethyl acetate. The organic portions were combined and dried with magnesium sulfate. The solvent was removed in vacuo to afford crude product, which was purified by column chromatography (10% ethyl acetate/hexanes). The title compound was obtained as colorless oil (0.73 g, yield 62%): 1H NMR (CDCl3) δ 6.96 (d, J=10.1 Hz, 1H); 6.54 (d, J=2.97 Hz, 1H); 6.46 (dd, J=8.6, 3.0 Hz, 1H); 3.96 (dd, J=12.5 5.3 Hz, 2H); 2.82-2.78 (m, 2H); 1.08-1.00 (m, 3H). the reaction was quenched with sat. sodium carbonate (50 ml) The aqueous layer was extracted with ethyl acetate dried with magnesium sulfate The solvent was removed in vacuo to afford crude product, which was purified by column chromatography (10% ethyl acetate/hexanes)

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

Procedure: To a 0° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (1.0 g, 5.15 mmol) in diethyl ether (50 ml) was added sulfuryl chloride (0.493 mL, 6.18 mmol). After 2.5 h at 0° C., the reaction was quenched with sat. sodium carbonate (50 ml). The aqueous layer was extracted with ethyl acetate. The organic portions were combined and dried with magnesium sulfate. The solvent was removed in vacuo to afford crude product, which was purified by column chromatography (10% ethyl acetate/hexanes). The title compound was obtained as colorless oil (0.73 g, yield 62%): 1H NMR (CDCl3) δ 6.96 (d, J=10.1 Hz, 1H); 6.54 (d, J=2.97 Hz, 1H); 6.46 (dd, J=8.6, 3.0 Hz, 1H); 3.96 (dd, J=12.5 5.3 Hz, 2H); 2.82-2.78 (m, 2H); 1.08-1.00 (m, 3H). the reaction was quenched with sat. sodium carbonate (50 ml) The aqueous layer was extracted with ethyl acetate dried with magnesium sulfate The solvent was removed in vacuo to afford crude product, which was purified by column chromatography (10% ethyl acetate/hexanes)

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

Procedure: To a −10° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (2.0 g, 10.31 mmol) in chloroform (0.2 M, 51 mL) was added N-bromosuccinimide (1.93 g, 10.83 mmol). After stirring at RT overnight, the solution was concentrated in vacuo and purified by flash column chromatography (SiO2, 5% to 15% ethyl acetate/hexanes) to give the product as a colorless oil (0.45 g, 16%). the solution was concentrated in vacuo purified by flash column chromatography (SiO2, 5% to 15% ethyl acetate/hexanes)

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

Procedure: To a −10° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (2.0 g, 10.31 mmol) in chloroform (0.2 M, 51 mL) was added N-bromosuccinimide (1.93 g, 10.83 mmol). After stirring at RT overnight, the solution was concentrated in vacuo and purified by flash column chromatography (SiO2, 5% to 15% ethyl acetate/hexanes) to give the product as a colorless oil (0.45 g, 16%). the solution was concentrated in vacuo purified by flash column chromatography (SiO2, 5% to 15% ethyl acetate/hexanes)

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

Procedure: To a solution of commercially available 3-(3-hydroxy-phenyl)-propionic acid (25 g, 150.4 mmol) in ethanol (250 mL) was added concentrated sulfuric acid (3.0 mL). The solution was heated to reflux overnight. The solvent was removed in vacuo, and the resulting oil was diluted ethyl acetate and placed in a separatory funnel. The organic portion was extracted 2× with 5% NaHCO3 and once with brine. The solution was dried (MgSO4), filtered and concentrated to a dark tan oil (30 g). This material was carried on to the next step without further purification. The solution was heated to reflux overnight The solvent was removed in vacuo placed in a separatory funnel The organic portion was extracted 2× with 5% NaHCO3 The solution was dried (MgSO4) filtered concentrated to a dark tan oil (30 g) This material was carried on to the next step without further purification

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

Procedure: Treatment of ethyl 3-(3-hydroxyphenyl)propionate with dimethoxymethane and substitution of the product for ethyl 3-(3-chlorophenyl)propionate in the procedure of Example 4 leads to the production of 5-[3-(methoxymethoxy)benzyl]-2-methylthio-4-pyrimidone and 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-[3-(methoxymethoxy)benzyl]-4-pyrimidone. Treatment of this product with hydrochloric acid gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-hydroxybenzyl)-4-pyrimidone.