4-chlorobenzenecarbothioamide

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

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

Procedure: In analogy to the procedure described in example 4 d], [rac]-3-(3,5-difluoro-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester [example 70 a]] was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-chloro-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-difluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-difluoro-phenyl)-2-ethoxy-propionic acid as light yellow amporphous solid. described in example 4 d

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

Procedure: In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(5-ethoxy-2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester [example 68 a]] was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-chloro-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-5-ethoxy-2-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-5-ethoxy-2-fluoro-phenyl)-2-ethoxy-propionic acid as light yellow solid. described in example 4 d

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

Procedure: In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-methanol (prepared from 4-chloro-thiobenzamide and ethyl 2-chloro-acetoacetate in analogy to the procedures described in examples 33 a] and 33 b]) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless oil.

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

Procedure: In analogy to the procedure described in example 4 a], 4-chlorothiobenzamide was reacted with 1,3-dichloroacetone followed by treatment with concentrated sulfuric acid to obtain 4-chloromethyl-2-(4-chloro-phenyl)-thiazole as colorless crystals.

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chlorothiobenzamide (0.519 g, 3.02 mmol) in acetone (5 mL) was added pyridine (0.367 mL, 4.53 mmol) and phenylacetyl chloride (0.480 mL, 3.63 mmol). The bright orange reaction mixture was heated to 55° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added. The precipitate was removed by filtration, washed with water, and dried to provide 0.721 g (82%) of the product as a red solid: 1H NMR (CDCl3) δ 9.34 (br s, 1H), 7.50-7.22 (m, 9H), 3.96 (s, 2H) ppm. to cool to room temperature The precipitate was removed by filtration washed with water dried

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

Procedure: Add a 1.0 M solution of sufuryl chloride in dichloromethane (20.0 mL, 20.0 mmol) dropwise to a solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (3.0 g, 18.8 mmol) in dichloromethane (20.0 mL) at 0° C. and stir under nitrogen at 0° C. for 2 h. Concentrate the reaction mixture on a rotavap (rotary evaporator), keeping the bath temperature at RT. Add 4-chlorothiobenz-amide (3.67 g, 21.5 mmol) to the residue, followed by methanol (30.0 mL) and heat to 60° C. for 18 h. Quench the reaction with water and extract with EtOAc (2×). Combine the organic portions, wash with brine, dry over MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on silica gel, using a gradient of EtOAc/Hexane (0-60%) to give the title compound (3.3 g, 57%). Exact mass=311.0, MS (ES+) 312.0 (M+1). 1H NMR (CDCl3): δ 7.89 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.88 (s, 3H), 3.82 (t, 2H, J=6.8 Hz), 3.47 (t, 2H, J=6.8 Hz), 3.38 (s, 3H). Concentrate the reaction mixture on a rotavap (rotary evaporator) at RT heat to 60° C. for 18 h Quench the reaction with water extract with EtOAc (2×) Combine the organic portions, wash with brine dry over MgSO4 filter concentrate under vacuum Purify by flash chromatography on silica gel

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

Procedure: Add a 1.0 M solution of sufuryl chloride in dichloromethane (20.0 mL, 20.0 mmol) dropwise to a solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (3.0 g, 18.8 mmol) in dichloromethane (20.0 mL) at 0° C. and stir under nitrogen at 0° C. for 2 h. Concentrate the reaction mixture on a rotavap (rotary evaporator), keeping the bath temperature at RT. Add 4-chlorothiobenz-amide (3.67 g, 21.5 mmol) to the residue, followed by methanol (30.0 mL) and heat to 60° C. for 18 h. Quench the reaction with water and extract with EtOAc (2×). Combine the organic portions, wash with brine, dry over MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on silica gel, using a gradient of EtOAc/Hexane (0-60%) to give the title compound (3.3 g, 57%). Exact mass=311.0, MS (ES+) 312.0 (M+1). 1H NMR (CDCl3): δ 7.89 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.88 (s, 3H), 3.82 (t, 2H, J=6.8 Hz), 3.47 (t, 2H, J=6.8 Hz), 3.38 (s, 3H). Concentrate the reaction mixture on a rotavap (rotary evaporator) at RT heat to 60° C. for 18 h Quench the reaction with water extract with EtOAc (2×) Combine the organic portions, wash with brine dry over MgSO4 filter concentrate under vacuum Purify by flash chromatography on silica gel

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 2-chloro-3-oxo-pentanedioic acid diethyl ester (1370 g, 5.50 mol) in EtOH (8.5 L) and add 4-chloro-thiobenzamide (885 g, 5.00 mol). Heat the mixture to 75° C. and stir mechanically for 5.5 h. Cool the mixture to 45° C., then slowly add water (3.5 L) and stir overnight. Collect the yellow precipitate and wash the solids with 50% EtOH/water (4 L). Dry in an oven to obtain 1505 g (81%) of the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.90 (d, 2H, J=7.4), 7.41 (d, 2H, J=7.4), 4.34 (q, 2H, J=6.8), 4.24 (s, 2H), 4.19 (q, 2H, J=7.4), 1.36 (t, 3H, J=6.8), 1.27 (t, 3H, J=6.8). Cool the mixture to 45° C. Collect the yellow precipitate wash the solids with 50% EtOH/water (4 L) Dry in an oven

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 2-chloro-3-oxo-pentanedioic acid diethyl ester (1370 g, 5.50 mol) in EtOH (8.5 L) and add 4-chloro-thiobenzamide (885 g, 5.00 mol). Heat the mixture to 75° C. and stir mechanically for 5.5 h. Cool the mixture to 45° C., then slowly add water (3.5 L) and stir overnight. Collect the yellow precipitate and wash the solids with 50% EtOH/water (4 L). Dry in an oven to obtain 1505 g (81%) of the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.90 (d, 2H, J=7.4), 7.41 (d, 2H, J=7.4), 4.34 (q, 2H, J=6.8), 4.24 (s, 2H), 4.19 (q, 2H, J=7.4), 1.36 (t, 3H, J=6.8), 1.27 (t, 3H, J=6.8). Cool the mixture to 45° C. Collect the yellow precipitate wash the solids with 50% EtOH/water (4 L) Dry in an oven

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

Procedure: Dissolve 4-chlorothiobenzamide (74.0 g, 431.1 mmol) in EtOH (470 mL) and treat with ethyl-4-chloroacetoacetate (58.0 mL, 70.1 g, 426.0 mmol). Stir the resulting solution mechanically at reflux for 2 h. Cool to room temperature, add water (1000 mL), and extract with Et2O (2000 mL, then 2×500 mL). Combine the organic solutions and wash with brine (950 mL). Concentrate in vacuo to give an oil that solidifies upon standing (121.8 g). Recrystallize the crude material from isopropanol/water to give the title compound (107.3 g, 89% yield). ES/MS m/z (35Cl) 282.1 [M+1]+. at reflux for 2 h extract with Et2O (2000 mL Combine the organic solutions and wash with brine (950 mL) Concentrate in vacuo to give an oil that Recrystallize the crude material from isopropanol/water

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

Procedure: Dissolve 4-chlorothiobenzamide (74.0 g, 431.1 mmol) in EtOH (470 mL) and treat with ethyl-4-chloroacetoacetate (58.0 mL, 70.1 g, 426.0 mmol). Stir the resulting solution mechanically at reflux for 2 h. Cool to room temperature, add water (1000 mL), and extract with Et2O (2000 mL, then 2×500 mL). Combine the organic solutions and wash with brine (950 mL). Concentrate in vacuo to give an oil that solidifies upon standing (121.8 g). Recrystallize the crude material from isopropanol/water to give the title compound (107.3 g, 89% yield). ES/MS m/z (35Cl) 282.1 [M+1]+. at reflux for 2 h extract with Et2O (2000 mL Combine the organic solutions and wash with brine (950 mL) Concentrate in vacuo to give an oil that Recrystallize the crude material from isopropanol/water