methyl 2-amino-2-dimethoxyphosphorylacetate

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

Procedure: A stirred solution of methyl amino(dimethoxyphosphoryl)acetate (6 g) in dichloromethane (50 mL) is treated with benzoyl chloride (5 g) and the mixture allowed to stand at room temperature for 4 hours. The reaction mixture is washed twice with saturated aqueous sodium bicarbonate solution (75 mL), brine (50 mL), dried over magnesium sulphate and evaporated. The residual pale yellow oil is dissolved in ether (5 mL) and pentane added to give methyl benzoylamino(dimethoxyphosphoryl)acetate (4.25 g) as a white solid. The reaction mixture is washed twice with saturated aqueous sodium bicarbonate solution (75 mL), brine (50 mL) dried over magnesium sulphate evaporated The residual pale yellow oil is dissolved in ether (5 mL) pentane added

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

Procedure: Triphenylphosphine (1.31 g, 5 mmol) is added to a suspension of give 2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoic acid (Example 329; 1.81 g, 5 mmol) in dichloromethane (25 mL) at 25° C. The mixture is cooled to 0° C. and N-chlorosuccinimide (0.668 g, 5 mmol) is added. After stirring 15 min at 0° C., the mixture is stirred for an additional 15 min at 25° C. and then a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (3.01 g, 10 mmol) in dichloromethane (5 mL) is added in one portion. The reaction is stirred for 5 h, then the precipitated amine hydrochloride is filtered off, washed with dichloromethane and discarded. The filtrate is washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then is dried (MgSO4) and concentrated under reduced pressure. The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) and the appropriate fractions are combined and evaporated to yield rac.-N-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester. the mixture is stirred for an additional 15 min at 25° C. is added in one portion The reaction is stirred for 5 h the precipitated amine hydrochloride is filtered off washed with dichloromethane The filtrate is washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL) is dried (MgSO4) concentrated under reduced pressure The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) evaporated

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

Procedure: Triphenylphosphine (1.31 g, 5 mmol) is added to a suspension of give 2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoic acid (Example 329; 1.81 g, 5 mmol) in dichloromethane (25 mL) at 25° C. The mixture is cooled to 0° C. and N-chlorosuccinimide (0.668 g, 5 mmol) is added. After stirring 15 min at 0° C., the mixture is stirred for an additional 15 min at 25° C. and then a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (3.01 g, 10 mmol) in dichloromethane (5 mL) is added in one portion. The reaction is stirred for 5 h, then the precipitated amine hydrochloride is filtered off, washed with dichloromethane and discarded. The filtrate is washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then is dried (MgSO4) and concentrated under reduced pressure. The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) and the appropriate fractions are combined and evaporated to yield rac.-N-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester. the mixture is stirred for an additional 15 min at 25° C. is added in one portion The reaction is stirred for 5 h the precipitated amine hydrochloride is filtered off washed with dichloromethane The filtrate is washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL) is dried (MgSO4) concentrated under reduced pressure The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) evaporated

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

Procedure: N,N-dicyclohexylcarbodiimide (0.216 g, 1.05 mmol) and 1-hydroxybenzotriazole (0.027 g, 0.2 mol) were added to a solution of 2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoic acid (Example 124; 0.34 g, 1.0 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 197 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred for 12 h, then was filtered and diluted with ethyl acetate. The resulting solution was washed with water, dried (Na2SO4), evaporated and the residual material was chromatographed (50-80% ethyl acetate/hexanes) to give rac.-N-[2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (0.24 g, 45% yield). was filtered diluted with ethyl acetate The resulting solution was washed with water dried (Na2SO4) evaporated the residual material was chromatographed (50-80% ethyl acetate/hexanes)

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

Procedure: N,N-dicyclohexylcarbodiimide (0.216 g, 1.05 mmol) and 1-hydroxybenzotriazole (0.027 g, 0.2 mol) were added to a solution of 2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoic acid (Example 124; 0.34 g, 1.0 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 197 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred for 12 h, then was filtered and diluted with ethyl acetate. The resulting solution was washed with water, dried (Na2SO4), evaporated and the residual material was chromatographed (50-80% ethyl acetate/hexanes) to give rac.-N-[2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (0.24 g, 45% yield). was filtered diluted with ethyl acetate The resulting solution was washed with water dried (Na2SO4) evaporated the residual material was chromatographed (50-80% ethyl acetate/hexanes)

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

Procedure: O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.50 g, 9.2 mmol) was added to a solution of 4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoic acid (Example 90; 2.40 g, 8.4 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 1.80 g, 9.1 mmol) and diisopropylethylamine (1.50 g, 11.6 mmol) in N,N-dimethylformamide (50 mL). The solution was stirred overnight at room temperature. Ethyl acetate (200 mL) was added and the solution was washed with 1N hydrochloric acid solution, water and brine (200 mL each), dried (MgSO4), filtered and evaporated to give crude rac.-2-(dimethoxyphosphinyl)-N-[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]glycine methyl ester (2.47 g, 63% yield). This material was used in subsequent reactions without flrther purification. the solution was washed with 1N hydrochloric acid solution, water and brine (200 mL each) dried (MgSO4) filtered evaporated

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

Procedure: O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.4 g, 6.4 mmol) was added to a solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (Example 117; 1.9 g, 5.8 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 2.10 g, 10.6 mmol) in N,N-dimethylformamide (20 mL). 1-hydroxybenzotriazole (861 mg, 6.4 mmol) was then added, followed by diisopropylethylamine (2 mL, 11.6 mmol). The solution was stirred overnight at room temperature and then it was concentrated under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between water and ethyl acetate and the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine, then was dried (MgSO4), filtered and evaporated in vacuo. The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane) to give rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (2.1 g, 72% yield) which was used in subsequent reactions without further purification. it was concentrated under high vacuum to remove N,N-dimethylformamide The residue was partitioned between water and ethyl acetate the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine was dried (MgSO4) filtered evaporated in vacuo The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane)

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

Procedure: O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.4 g, 6.4 mmol) was added to a solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (Example 117; 1.9 g, 5.8 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 2.10 g, 10.6 mmol) in N,N-dimethylformamide (20 mL). 1-hydroxybenzotriazole (861 mg, 6.4 mmol) was then added, followed by diisopropylethylamine (2 mL, 11.6 mmol). The solution was stirred overnight at room temperature and then it was concentrated under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between water and ethyl acetate and the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine, then was dried (MgSO4), filtered and evaporated in vacuo. The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane) to give rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (2.1 g, 72% yield) which was used in subsequent reactions without further purification. it was concentrated under high vacuum to remove N,N-dimethylformamide The residue was partitioned between water and ethyl acetate the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine was dried (MgSO4) filtered evaporated in vacuo The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane)

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

Procedure: Diisopropylethylamine (0.48 mL, 2.8 mmol) was added to a solution of rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid (Example 93; 225 mg, 0.69 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (331 mg, 1 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol) and 1-hydroxybenzotriazole (102 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 17 h and then it was concentrated under high vacuum to remove N,N-dimethylformamide. Ethyl acetate (25 mL) was added and the resulting solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). Each of the aqueous layers was back-extracted in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to furnish rac.-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (240 mg, 72% yield) as an oil. it was concentrated under high vacuum to remove N,N-dimethylformamide Ethyl acetate (25 mL) was added the resulting solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL) Each of the aqueous layers was back-extracted in turn with ethyl acetate (10 mL) The combined organic layers were dried (MgSO4) filtered evaporated chromatographed over silica gel (50-100% ethyl acetate/hexanes

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

Procedure: Diisopropylethylamine (0.61 mL, 3.5 mmol) was added to a solution of rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoic acid (Example 96; 270 mg, 0.88 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (397 mg, 1.2 mmol) ), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (350 mg, 0.97 mmol) and 1-hydroxybenzotriazole (131 mg, 0.97 mmol) in N,N-dimethylformamide (7 mL). The solution was stirred at room temperature for 17 h and then it was concentrated under high vacuum to remove N,N-dimethylformamide. Ethyl acetate (25 mL) was added and the solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine. Each of the aqueous layers was back-washed in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and the resulting residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to flirnish N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (260 mg, 61% yield) as a colorless oil. it was concentrated under high vacuum to remove N,N-dimethylformamide Ethyl acetate (25 mL) was added the solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine Each of the aqueous layers was back-washed in turn with ethyl acetate (10 mL) The combined organic layers were dried (MgSO4) filtered evaporated the resulting residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes

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

Procedure: Diisopropylethylamine (1.05 mL, 6 mmol) was added to a solution of 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid (Example 94; 457 mg, 1.5 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (662.5 mg, 2.0 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (597 mg, 1.6 mmol) and 1-hydroxybenzotriazole (223 mg, 1.65 mmol) in N,N-dimethylformamide (12 mL). The solution was stirred at room temperature for 17 h and then it was evaporated in vacuo to remove N,N-dimethylformamide. A solution of the residue in ethyl acetate (40 mL) was washed in turn with 0.5N hydrochloric acid solution (20 mL), brine (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL). Each of the aqueous layers was extracted with ethyl acetate (20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting oil was chromatographed over silica gel (75% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to give rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (450 mg, 62% yield) as an oil. it was evaporated in vacuo to remove N,N-dimethylformamide A solution of the residue in ethyl acetate (40 mL) was washed in turn with 0.5N hydrochloric acid solution (20 mL), brine (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL) Each of the aqueous layers was extracted with ethyl acetate (20 mL) The combined organic layers were dried (Na2SO4) filtered evaporated under reduced pressure The resulting oil was chromatographed over silica gel (75% ethyl acetate/hexanes

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

Procedure: O-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (645 mg, 1.7 mmol) was added to a solution of 2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoic acid (Example 112; 520 mg, 1.6 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (370 mg, 1.9 mmol). 1-hydroxybenzotriazole (255 mg, 1.9 mmol) was then added, followed by diisopropylethylamine (1.25 mL, 7.2 mmol). The solution was stirred at room temperature for 65 h and then it was evaporated to dryness under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The ethyl acetate layer was washed with brine, 0.5N hydrochloric acid solution and brine. Each of the aqueous layers was extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, evaporated and the residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5-25% methanol/ethyl acetate) to give rac.-N-[2-chloro4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (120 mg, 15% yield). it was evaporated to dryness under high vacuum to remove N,N-dimethylformamide The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL) The ethyl acetate layer was washed with brine, 0.5N hydrochloric acid solution and brine Each of the aqueous layers was extracted with ethyl acetate The combined organic extracts were dried (Na2SO4) filtered evaporated the residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes