methyl 4-amino-5-chloro-2-hydroxybenzoate

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

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

Procedure: To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2. the reaction was quenched by adding MeOH at 0° C. the resulting mixture was stirred at room temperature for about 15 min concentrated in vacuo DCM and water were added to the residue this mixture was mixed thoroughly The layers were separated the aqueous layer was extracted with DCM dried (Na2SO4) filtered the solvent was removed in vacuo

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

Procedure: To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2. the reaction was quenched by adding MeOH at 0° C. the resulting mixture was stirred at room temperature for about 15 min concentrated in vacuo DCM and water were added to the residue this mixture was mixed thoroughly The layers were separated the aqueous layer was extracted with DCM dried (Na2SO4) filtered the solvent was removed in vacuo

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

Procedure: 4-Amino-5-chlorosalicylic acid (24 g) is added to a stirred solution of thionyl chloride (30 ml) in methanol (300 ml) cooled to 0° C., and the mixture is stirred under reflux for 18 hours. The reaction mixture is evaporated and the residue is recrystallized from EtOH-H2O to give methyl 4-amino-5-chlorosalicylate which is used directly in the next step. under reflux for 18 hours The reaction mixture is evaporated the residue is recrystallized from EtOH-H2O

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

Procedure: 4-Amino-5-chlorosalicylic acid (24 g) is added to a stirred solution of thionyl chloride (30 ml) in methanol (300 ml) cooled to 0° C., and the mixture is stirred under reflux for 18 hours. The reaction mixture is evaporated and the residue is recrystallized from EtOH-H2O to give methyl 4-amino-5-chlorosalicylate which is used directly in the next step. under reflux for 18 hours The reaction mixture is evaporated the residue is recrystallized from EtOH-H2O

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

Procedure: A cooled (0° C.) suspension of 60% sodium hydride/oil dispersion (1.40 g, 0.035 mole) in anhydrous dimethylformamide (60 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole) and stirred for 30 minutes at room temperature. 2-Chloro-N,N-diethylacetamide (5.40 g, 0.036 mole) was added, and the mixture was stirred at 100°-110° C. for 3 hours until gas chromatography indicated absence of 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester. The solution was cooled and added to ice water (350 ml), then extracted with ether (3×200 ml). The combined organic solution was dried (magnesium sulfate) and concentrated in vacuo. Filtration through alumina (eluted with 3% methanol/methylene chloride) and trituration from petroleum ethers (30°-60°) afforded 8.66 g (92%) of 4-amino-5-chloro-2-[2-(diethylamino)-2-oxoethoxy]benzoic acid methyl ester as a colorless solid; mp 97.5° -99.5° C. (ethyl acetate/hexane). A cooled the mixture was stirred at 100°-110° C. for 3 hours until gas chromatography The solution was cooled extracted with ether (3×200 ml) The combined organic solution was dried (magnesium sulfate) concentrated in vacuo Filtration through alumina (eluted with 3% methanol/methylene chloride) and trituration from petroleum ethers (30°-60°)

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

Procedure: A suspension of 60% sodium hydride/oil dispersion (1.52 g, 0.038 mole) in anhydrous dimethylformamide (50 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 g, 0.038 mole). The mixture was stirred at 95°±5° C. for one hour, cooled to room temperature, and added to water (250 ml). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 ml). The concentrated ethereal extracts were combined with the filtered solid, taken up in 20% aqueous ethanol (100 ml), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 ml) and petroleum ether (30°-60°, 50 ml), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 ml). The suspension was filtered and solid was air dried, dissolved in methylene chloride (150 ml) containing a little methanol, dried (sodium sulfate), and concentrated in vacuo. Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops) afforded 4.25 g (62.2%) of the title compound as a pale tan solid; mp 136°-137° C. The mixture was stirred at 95°±5° C. for one hour cooled to room temperature The solid was removed by filtration the filtrate was extracted with ether (2×100 ml) treated with potassium hydroxide (10 g) refluxed for 45 minutes The ethanol was removed in vacuo the aqueous solution was extracted with ether (50 ml) and petroleum ether (30°-60°, 50 ml) cooled (0° C.) The suspension was filtered dried dissolved in methylene chloride (150 ml) containing a little methanol dried (sodium sulfate) concentrated in vacuo Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops)

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

Procedure: A suspension of 60% sodium hydride/oil dispersion (1.52 g, 0.038 mole) in anhydrous dimethylformamide (50 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 g, 0.038 mole). The mixture was stirred at 95°±5° C. for one hour, cooled to room temperature, and added to water (250 ml). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 ml). The concentrated ethereal extracts were combined with the filtered solid, taken up in 20% aqueous ethanol (100 ml), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 ml) and petroleum ether (30°-60°, 50 ml), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 ml). The suspension was filtered and solid was air dried, dissolved in methylene chloride (150 ml) containing a little methanol, dried (sodium sulfate), and concentrated in vacuo. Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops) afforded 4.25 g (62.2%) of the title compound as a pale tan solid; mp 136°-137° C. The mixture was stirred at 95°±5° C. for one hour cooled to room temperature The solid was removed by filtration the filtrate was extracted with ether (2×100 ml) treated with potassium hydroxide (10 g) refluxed for 45 minutes The ethanol was removed in vacuo the aqueous solution was extracted with ether (50 ml) and petroleum ether (30°-60°, 50 ml) cooled (0° C.) The suspension was filtered dried dissolved in methylene chloride (150 ml) containing a little methanol dried (sodium sulfate) concentrated in vacuo Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops)

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

Procedure: A suspension of 50% sodium hydride/oil dispersion (1.00 g, 0.025 mole) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (4.03 g, 0.020 mole), stirred for 30 minutes, then treated with 2-(bromomethy)tetrahydro-2H-pyran (4.66 g, 0.026 mole). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (250 ml). The aqueous mixture was extracted with ether (2×200 ml), and the combined ethereal solution was dried (magnesium sulfate), concentrated in vacuo, an taken up in 95% ethanol (40 ml), water (20 ml) and 50% sodium hydroxide (20 ml) were added, and the mixture was refluxed for one hour, cooled on an ice bath, and concentrated in vacuo in order to remove most of the ethanol. Water was added to a total volume of 200 ml, and the aqueous solution was extracted with ether (2×100 ml), cooled on an ice bath, and adjusted to pH~4 with concentrated hydrochloric acid (32 ml). A solid soon precipitated, and this was filtered, washed with water, air dried, and recrystallized from ethyl acetate to afford 3.45 g (60%) of the title compound as colorless crystals; mp 146.5°-147.5° C. The mixture was heated to 95°±5° C. for 1.5 hours cooled The aqueous mixture was extracted with ether (2×200 ml) the combined ethereal solution was dried (magnesium sulfate) concentrated in vacuo water (20 ml) and 50% sodium hydroxide (20 ml) were added the mixture was refluxed for one hour cooled on an ice bath concentrated in vacuo in order to remove most of the ethanol Water was added to a total volume of 200 ml the aqueous solution was extracted with ether (2×100 ml) cooled on an ice bath A solid soon precipitated this was filtered washed with water, air dried recrystallized from ethyl acetate

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

Procedure: A suspension of 60% sodium hydride/oil dispersion (1.00 g, 0.025 mole) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (4.03 g, 0.020 mole), stirred for 30 minutes, then treated with 2-bromoethyl methyl ether (3.48 g, 0.025 mole). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (250 ml). The aqueous suspension was filtered, and the solid was washed with water, air dried, collected, and recrystallized from ether/hexane to afford 2.75 g (53%) of 4-amino-5-chloro-2-(2-methoxyethoxy)benzoic acid methyl ester; mp 121.0°-122.5° C. The mixture was heated to 95°±5° C. for 1.5 hours cooled The aqueous suspension was filtered the solid was washed with water, air dried collected recrystallized from ether/hexane

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

Procedure: A solution of 4-amino-5-chloro-2-hydroxybenzoic acid (1.88 g, 0.010 mole) in absolute methanol (20 ml) was treated with 25% sodium methoxide/methanol (2.16 g, 0.010 mole), stirred for 30 minutes, and concentrated in vacuo. The solid residue was taken up in anhydrous acetone (30 ml), treated with dimethyl sulfate (1.64 g, 0.013 mole) and refluxed for 2 hours. The resultant solution was diluted with water (100 ml), and the precipitate was filtered, washed with water, and dried exhaustively in vacuo to afford 1.75 g (87%) of the title compound as fine colorless needles. The material was recrystallized from ethyl acetate/hexane; mp 138°-139° C. concentrated in vacuo refluxed for 2 hours the precipitate was filtered washed with water dried exhaustively in vacuo

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

Procedure: To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2. the reaction was quenched by adding MeOH at 0° C. the resulting mixture was stirred at room temperature for about 15 min concentrated in vacuo DCM and water were added to the residue this mixture was mixed thoroughly The layers were separated the aqueous layer was extracted with DCM dried (Na2SO4) filtered the solvent was removed in vacuo