2,4-dihydroxybenzonitrile

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

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 19.2 g of sodium hydride in 400 ml of dimethyl sulphoxide is added dropwise a solution of 54.0 g of 2,4-dihydroxybenzonitrile in 200 ml of dimethyl sulphoxide. After formation of the sodium salt 86.0 g of 3,4-dichloro-α,α,α-trifluorotoluene and 0.1 g of copper powder are added and the reaction mixture is stirred at 115° C. for 68 hours. Then the mixture is poured onto 2 kg of ice and the aqueous mixture acidified with concentrated hydrochloric acid and extracted severl times with 500 ml portions of ethyl acetate. The combined organic phases are neutralized and dried over anhydrous sodium sulphate, and the solvent is evaporated off under reduced pressure. Finally, the residue is prified by column chromatographyon silica gel using ethyl acetate / n-hexane (7:3) as the eluent and crystallized from methylene chloride. There is obtained the intermediate 4-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-salicylonitrile, m.p. 155°-156° C.; mass spectrum; m/e 313, 294, 278, 250,223, 209, 90, 63; infrared spectrum: main peak at 2230 cm-1. extracted severl times with 500 ml portions of ethyl acetate dried over anhydrous sodium sulphate the solvent is evaporated off under reduced pressure crystallized from methylene chloride

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: D-cysteine hydrochloride monohydrate (6.8 g, 38.7 mmol) was added to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol) prepared in Example 1, in a mixture of degassed methanol (105 ml) and 0.1 M phosphate buffer, pH 5.95 (70 ml). NaHCO3 (3.25 g, 38.7 mmol) was carefully added and the mixture was stirred at 70° C. under Ar for 54 hours. Volatile components were removed under reduced pressure and the solution was acidified with 1 N HCl to pH 2. The resulting brown precipitate was vacuum filtered and the solid was washed with water (40 ml) and ethanol (20 ml). The crude product was dissolved in saturated NaHCO3 (700 ml) and the aqueous solution washed with ethyl acetate (2×200 ml). The aqueous layer was filtered through a fine frit and acidified with 1 N HCl to pH 2. The precipitated product was vacuum filtered. The aqueous layer was extracted with ethyl acetate (4×400 ml), the combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The remaining solid was combined with the precipitated product and dried under high vacuum at 40° C. for 12 hours to give 4,5-dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4(S)-carboxylic acid (4.08 g, 66%), mp 266-268° C. (dec) [Ind. J. Chem., Vol. 15B, Kishore et al, pages 255-257 (1977) for (L)-isomer: 261-262 C.]. 1H NMR (300 MHz, DMSO-d6) δ3.61 (m, 2 H), 5.38 (dd, 1 H, J=7.2/9.4 Hz), 6.31 (d, 1 H, J=2.3 Hz), 6.38 (dd, 1 H, J=2.3/8.6 Hz), 7.25 (d, 1 H, J=8.6 Hz), 10.25 (br s, 1 H), 12.60 (br s, 1 H), 13.15 (br s, 1 H). Anal. calc. for C10H9NO4S: C 50.20, H 3.79, N 5.85. Found: C 50.13, H 3.82, N 5.85. Volatile components were removed under reduced pressure filtered the solid was washed with water (40 ml) and ethanol (20 ml) The crude product was dissolved in saturated NaHCO3 (700 ml) the aqueous solution washed with ethyl acetate (2×200 ml) The aqueous layer was filtered through a fine frit filtered The aqueous layer was extracted with ethyl acetate (4×400 ml) the combined organic extracts were dried (Na2SO4) the solvent was removed in vacuo dried under high vacuum at 40° C. for 12 hours

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

Procedure: A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated NaHCO3 until the pK of the aqueous layer remained at 8, dried (Na2SO4) and the solvent removed in vacuo. Flash chromatography (SiO2, cyclohexane: ethyl acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ6.33 (d, 1 H, J=8.6 Hz), 6.43 (s, 1 H), 7.37 (d, 1 H, J=8.6 Hz), 10.35 (s, 1 H), 10.78 (s, 1 H). IR (KBr) 2200 cm−1. was refluxed for 6 hours After cooling the mixture was poured onto ice (100 g) extracted with ethyl acetate (4×50 ml) The combined organic layers were washed with saturated NaHCO3 until the pK of the aqueous layer dried (Na2SO4) the solvent removed in vacuo

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

Procedure: In a mixed solvent including methanol (30 mL) and phosphate buffer solution (20 mL), NaHCO3 (466 mg, 5.55 mmol) was carefully added to a solution including the obtained Compound 101a (0.5 g, 3.70 mmol) and L-cysteine hydrochloride monohydrate (974 mg, 5.55 mmol), and the reaction mixture was refluxed for 10 hours. After methanol was evaporated, the reaction mixture was acidified by using 1 N HCl to increase a pH to 2. The resultant precipitate was filtered, and washed with water to obtain Compound 101b (613 mg, 69%). was carefully added to a solution the reaction mixture was refluxed for 10 hours After methanol was evaporated to increase a pH to 2 The resultant precipitate was filtered washed with water

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

Procedure: In an acetic acid (10 mL) solvent, a solution including 2,3-dihydroxybenzaldehyde (3.0 g, 21.7 mmol), sodium acetate (NaOAc) (3.54 g, 43.4 mmol), and nitroethane (3.24 g, 43.4 mmol) was refluxed for 8 hours. After cooling, the reaction mixture was distributed between ethyl acetate and water. Until a pH of the residual aqueous layer reached 8, an organic layer was washed with a saturated NaHCO3 solution. The organic layer was evaporated, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (2:1) as a developer to obtain Compound 101a (1.88 g, 59%). was refluxed for 8 hours After cooling an organic layer was washed with a saturated NaHCO3 solution The organic layer was evaporated the residual was purified by silica gel column chromatography

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

Procedure: 4.00 g (S)-2-methylcysteine hydrochloride (23.3 mmol, 1.0 meq) and 3.14 g 2,4-dihydroxy benzonitrile (23.3 mmol, 1.0 meq) were suspended in 40 mL ethanol. After degassing this mixture with nitrogen (30 min) 4.95 g triethylamine (6.8 mL, 48.9 mmol, 2.05 meq) were added. The obtained suspension was heated under reflux in an atmosphere of nitrogen for 20 hours and then cooled to room temperature. From this suspension ethanol was evaporated under reduced pressure until an oil (20% of the initial volume) was obtained. This oil was dissolved in 50 mL water. The solution was adjusted to pH 7.5 with 1.20 ml 20% KOH and was extracted two times each with 20 mL methyl t-butyl ether (MTBE). The aqueous layer was separated, adjusted with 20% KOH to pH 11 and again extracted two times each with 20 mL MTBE. After separating the aqueous layer the pH was set with concentrated HCl to 7.5 and traces of MTBE were distilled off. Then the aqueous solution was acidified with 1.50 ml concentrated HCl to pH 1.5. The product precipitated. This suspension was stirred at 4° C. for 1 hour. Then the precipitate was filtered, washed two times each with 10 mL water (5° C.) and dried at 45° C. under vacuum. The reaction yielded 5.17 g (87.6%) of crude 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid product. 1H-NMR showed no significant impurity. were added The obtained suspension was heated under reflux in an atmosphere of nitrogen for 20 hours From this suspension ethanol was evaporated under reduced pressure until an oil (20% of the initial volume) was obtained was extracted two times each with 20 mL methyl t-butyl ether (MTBE) The aqueous layer was separated again extracted two times each with 20 mL MTBE After separating the aqueous layer the pH were distilled off The product precipitated Then the precipitate was filtered washed two times each with 10 mL water (5° C.) dried at 45° C. under vacuum

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

Procedure: 4.00 g (S)-2-methylcysteine hydrochloride (23.3 mmol, 1.0 meq) and 3.14 g 2,4-dihydroxy benzonitrile (23.3 mmol, 1.0 meq) were suspended in 40 mL ethanol. After degassing this mixture with nitrogen (30 min) 4.95 g triethylamine (6.8 mL, 48.9 mmol, 2.05 meq) were added. The obtained suspension was heated under reflux in an atmosphere of nitrogen for 20 hours and then cooled to room temperature. From this suspension ethanol was evaporated under reduced pressure until an oil (20% of the initial volume) was obtained. This oil was dissolved in 50 mL water. The solution was adjusted to pH 7.5 with 1.20 ml 20% KOH and was extracted two times each with 20 mL methyl t-butyl ether (MTBE). The aqueous layer was separated, adjusted with 20% KOH to pH 11 and again extracted two times each with 20 mL MTBE. After separating the aqueous layer the pH was set with concentrated HCl to 7.5 and traces of MTBE were distilled off. Then the aqueous solution was acidified with 1.50 ml concentrated HCl to pH 1.5. The product precipitated. This suspension was stirred at 4° C. for 1 hour. Then the precipitate was filtered, washed two times each with 10 mL water (5° C.) and dried at 45° C. under vacuum. The reaction yielded 5.17 g (87.6%) of crude 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid product. 1H-NMR showed no significant impurity. were added The obtained suspension was heated under reflux in an atmosphere of nitrogen for 20 hours From this suspension ethanol was evaporated under reduced pressure until an oil (20% of the initial volume) was obtained was extracted two times each with 20 mL methyl t-butyl ether (MTBE) The aqueous layer was separated again extracted two times each with 20 mL MTBE After separating the aqueous layer the pH were distilled off The product precipitated Then the precipitate was filtered washed two times each with 10 mL water (5° C.) dried at 45° C. under vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: D-cysteine hydrochloride monohydrate (6.8 g, 38.3 mmol) was added to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol) prepared in Example 1, in a mixture of degassed methanol (105 ml) and 0.1 M phosphate buffer, pH 5.95 (70 ml). NaHCO3 (3.25 g, 38.7 mmol) was carefully added and the mixture was stirred at 70° C. under Ar for 54 hours. Volatile components were removed under reduced pressure and the solution was acidified with 1 N HCl to pH 2. The resulting brown precipitate was vacuum filtered and the solid was washed with water (40 ml) and ethanol (20 ml). The crude product was dissolved in saturated NaHCO3 (700 ml) and the aqueous solution washed with ethyl acetate (2×200 ml). The aqueous layer was filtered through a fine frit and acidified with 1 N HCl to pH 2. The precipitated product was vacuum filtered. The aqueous layer was extracted with ethyl acetate (4×400 ml), the combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The remaining solid was combined with the precipitated product and dried under high vacuum at 40° C. for 12 hours to give 4,5-dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4(S)-carboxylic acid (4.08 g, 66%), mp 266-268° C. (dec) [Ind. J. Chem., Vol. 15B, Kishore et al, pages 255-257 (1977) for (L)-isomer: 261-262° C.]. 1H NMR (300 MHz, DMSO-d6) δ 3.61 (m, 2H), 5.38 (dd, 1H, J=7.2/9.4 Hz), 6.31 (d, 1H, J=2.3 Hz), 6.38 (dd, 1H, J=2.3/8.6 Hz), 5 7.25 (d, 1H, J 8.6 Hz), 10.25 (br s, 1H), 12.60 (br s, 1H), 13.15 (br s, 1H). Anal. calc. for C10H9NO4S: C; 50.20, H; 3.79, N; 5.85. Found: C; 50.13, H; 3.82, N; 5.85. Volatile components were removed under reduced pressure filtered the solid was washed with water (40 ml) and ethanol (20 ml) The crude product was dissolved in saturated NaHCO3 (700 ml) the aqueous solution washed with ethyl acetate (2×200 ml) The aqueous layer was filtered through a fine frit filtered The aqueous layer was extracted with ethyl acetate (4×400 ml) the combined organic extracts were dried (Na2SO4) the solvent was removed in vacuo dried under high vacuum at 40° C. for 12 hours

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

Procedure: A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer remained at 8, dried (Na2SO4) and the solvent removed in vacuo. Flash chromatography (SiO2, cyclohexane:ethyl acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.33 (d, 1 H, J=8.6 Hz), 6.43 (s, 1H), 7.3, (d, 1H, J=8.6 Hz), 10.35 (s, 1H), 10.78 (s, 1H). IR (KBr) 2200 cm−1. was refluxed for 6 hours After cooling the mixture was poured onto ice (100 g) extracted with ethyl acetate (4×50 ml) The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer dried (Na2SO4) the solvent removed in vacuo

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

Procedure: A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer remained at 8, dried (Na2SO4) and the solvent removed in vacuo. Flash chromatography (SiO2, cyclohexane:ethyl acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.33 (d, 1 H, J=8.6 Hz), 6.43 (s, 1H), 7.3, (d, 1H, J=8.6 Hz), 10.35 (s, 1H), 10.78 (s, 1H). IR (KBr) 2200 cm−1. was refluxed for 6 hours After cooling the mixture was poured onto ice (100 g) extracted with ethyl acetate (4×50 ml) The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer dried (Na2SO4) the solvent removed in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: D-cysteine hydrochloride monohydrate (6.8 g, 38.7 mmol) was added to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol) prepared in Example 1, in a mixture of degassed methanol (105 ml) and 0.1 M phosphate buffer, pH 5.95 (70 ml). NaHCO3 (3.25 g, 38.7 mmol) was carefully added and the mixture was stirred at 70° C. under Ar for 54 hours. Volatile components were removed under reduced pressure and the solution was acidified with 1 N HCl to pH 2. The resulting brown precipitate was vacuum filtered and the solid was washed with water (40 ml) and ethanol (20 ml). The crude product was dissolved in saturated NaHCO3 (700 ml) and the aqueous solution washed with ethyl acetate (2×200 ml). The aqueous layer was filtered through a fine frit and acidified with 1 M HCl to pH 2. The precipitated product was vacuum filtered. The aqueous layer was extracted with ethyl acetate (4×400 ml), the combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The remaining solid was combined with the precipitated product and dried under high vacuum at 40° C. for 12 hours to give 4,5-dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4(S)-carboxylic acid (4.08 g, 66%), mp 266-268° C. (dec) [Ind. J. Chem., Vol. 15B, Kishore et al, pages 255-257 (1977) for (L)-isomer: 261-262° C.]. 1H NMR (300 MHz, DMSO-d6) δ 3.61 (m, 2H), 5.38 (dd, 1H, J=7.2/9.4 Hz), 6.31 (d, 1H, J=2.3 Hz), 6.38 (dd, 1H, J=2.3/8.6 Hz), 7.25 (d, 1H, J=8.6 Hz), 10.25 (br s, 1H), 12.60 (br s, 1H), 13.15 (br s, 1H). Anal. calc. for C10H9NO4S: C 50.20, N 3.79; N 5.85. Found: C 50.13, H 3.82, N 5.85. Volatile components were removed under reduced pressure filtered the solid was washed with water (40 ml) and ethanol (20 ml) The crude product was dissolved in saturated NaHCO3 (700 ml) the aqueous solution washed with ethyl acetate (2×200 ml) The aqueous layer was filtered through a fine frit filtered The aqueous layer was extracted with ethyl acetate (4×400 ml) the combined organic extracts were dried (Na2SO4) the solvent was removed in vacuo dried under high vacuum at 40° C. for 12 hours