potassium;ditert-butyl phosphate

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

Procedure: 35.5 Grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 30.7 g of potassium di(t-butyl) phosphate, 0.6 g of potassium carbonate, and 0.15 g of potassium iodide were slurried into 200 mL acetonitrile. The reaction mixture was heated at reflux for 2.5 hours. The solution was filtered to remove potassium chloride precipitate. The filtrate was cooled to 0° C. and filtered to give 22.3 g of the title compound (38.6% yield); mp 108.5° C. (d). 1H NMR (DMSO-d6): 1.3 ppm (s, 18H), 5.2 (d, 2H), 7.3-7.5 (m, 10H), 9.9 (s, 1H); doublet from long range phosphorus coupling. The reaction mixture was heated at reflux for 2.5 hours The solution was filtered to remove potassium chloride precipitate filtered

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

Procedure: Di-tert-butyl phospohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time, The reaction as then allowed to continue at room temperature for an additional half hour, Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C., a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the elude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield): 1HNMR (CD3OD, 300 MHz) δ 1.51 (s, 12H, 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) δ −11.3 (s, 1 P). The addition of acid the precipitation of potassium chloride The solid is then filtered washed with methanol cooled by a salt/ice bath with efficient stirring to give the elude product stirred for 1-2 hours The reaction is then filtered to concentrate the solution in DME The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield)

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of potassium ditert-butyl phosphate (261 kg, 1.00 mol eq), tetra-n-butylammonium hydrogensulphate (18.5 kg, 0.05 mol eq) and sodium hydrogencarbonate (400 kg, 4.50 mol eq) in water (1150 kg) is added isopropyl acetate (1275 kg). The mixture is warmed to about 35° C. and then to this is added chloromethylchlorosulphate (313 kg, 1.80 mol eq) over about 4 hours. The mixture is further stirred for about 45 minutes, cooled to about 25° C. and then the layers separated. The organic phase is cooled to about 10° C. and washed twice with 2% w/v aqueous potassium hydrogencarbonate solution (2×800 kg) and then with a mixed 2% w/v potassium hydrogencarbonate and 20% w/v potassium hydrogencarbonate aqueous solution (640 kg). The resulting organic solution is then distilled at <100 mbar to half volume, maintaining the temperature below 45° C. The resulting mixture is filtered, washing the filter with isopropyl acetate (115 kg), to give the title compound as a solution, with typical solution strength of about 25% w/v and yield of about 90%. This solution is then used directly in Example 1, Step C. cooled to about 25° C. the layers separated The organic phase is cooled to about 10° C. washed twice with 2% w/v aqueous potassium hydrogencarbonate solution (2×800 kg) The resulting organic solution is then distilled at <100 mbar to half volume maintaining the temperature below 45° C The resulting mixture is filtered washing the filter with isopropyl acetate (115 kg)

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

Procedure: 2,6-Dichloro-N-[4-(1-chloromethyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide from the previous step was dissolved in 50 mL DMF. Potassium carbonate (1 g) was added followed by potassium di(t-butyl)phosphate (2 g) and tetrabutylammonium iodide (50 mg). The mixture was stirred at 70° C. for four hours after which it was poured into 300 mL ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was further purified by silica gel chromatography (eluent: ethyl acetate), giving phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl ester as a colorless oil which slowly crystallized. The organic phase was washed with water and brine dried with magnesium sulfate evaporated under vacuum The crude product was further purified by silica gel chromatography (eluent: ethyl acetate)

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

Procedure: 2,6-Dichloro-N-[4-(1-chloromethyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide from the previous step was dissolved in 50 mL DMF. Potassium carbonate (1 g) was added followed by potassium di(t-butyl)phosphate (2 g) and tetrabutylammonium iodide (50 mg). The mixture was stirred at 70° C. for four hours after which it was poured into 300 mL ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was further purified by silica gel chromatography (eluent: ethyl acetate), giving phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl ester as a colorless oil which slowly crystallized. The organic phase was washed with water and brine dried with magnesium sulfate evaporated under vacuum The crude product was further purified by silica gel chromatography (eluent: ethyl acetate)

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

Procedure: To a solution of potassium di-tert-butylphosphate (2.45 g, 9.51 mmol), sodium bicarbonate (3.19 g, 38.0 mmol) and tetrabutylammonium hydrogen sulfate (340.2 mg, 0.972 mmol) in water (80 mL), was added methylene chloride (50 mL). The mixture was cooled to 0° C. and stirred vigorously under argon for 10 min. Chloromethyl chlorosulfate (1.92 g, 1.2 mL, 11.6 mmol) in methylene chloride (30 mL) was added slowly and the reaction was stirred at room temperature overnight. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate and concentrated to give di-tert-butyl chloromethyl phosphate as a colorless oil (1.46 g, 59% yield). the reaction was stirred at room temperature overnight The organic layer was separated washed with brine dried over anhydrous sodium sulfate concentrated

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

Procedure: To a solution of potassium di-tert-butylphosphate (2.45 g, 9.51 mmol), sodium bicarbonate (3.19 g, 38.0 mmol) and tetrabutylammonium hydrogen sulfate (340.2 mg, 0.972 mmol) in water (80 mL), was added methylene chloride (50 mL). The mixture was cooled to 0° C. and stirred vigorously under argon for 10 min. Chloromethyl chlorosulfate (1.92 g, 1.2 mL, 11.6 mmol) in methylene chloride (30 mL) was added slowly and the reaction was stirred at room temperature overnight. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate and concentrated to give di-tert-butyl chloromethyl phosphate as a colorless oil (1.46 g, 59% yield). the reaction was stirred at room temperature overnight The organic layer was separated washed with brine dried over anhydrous sodium sulfate concentrated

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

Procedure: Methyl 4-(bromomethyl)benzoate (1200 mg, 5.24 mmol), potassium di-tert-butyl phosphate (1431 mg, 5.76 mmol) and sodium iodide (785 mg, 5.24 mmol) were combined in DMF (3.00 mL) under nitrogen. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ether, washed with 10% LiCl solution and brine, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation 55A (571 mg, 1.593 mmol, 30%): 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.53-7.37 (m, 2H), 5.05 (d, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J=0.4 Hz, 18H). washed with 10% LiCl solution and brine dried (MgSO4) filtered concentrated in vacuo The residue was purified by silica gel chromatography (hexane/EtOAc) to provide

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

Procedure: 35.5 Grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 30.7 g of potassium di(t-butyl) phosphate, 0.6 g of potassium carbonate, and 0.15 g of potassium iodide were slurried into 200 mL acetonitrile. The reaction mixture was heated at reflux for 2.5 hours. The solution was filtered to remove potassium chloride precipitate. The filtrate was cooled to 0° C. and filtered to give 22.3 g of the title compound (38.6% yield); mp 108.5° C. (d). 1H NMR (DMSO-d6): 1.3 ppm (s, 18H), 5.2 (d, 2H), 7.3-7.5 (m, 10H), 9.9 (s, 1H); doublet from long range phosphorus coupling. The reaction mixture was heated at reflux for 2.5 hours The solution was filtered to remove potassium chloride precipitate filtered

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

Procedure: Di-tert-butyl phospohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time, The reaction as then allowed to continue at room temperature for an additional half hour, Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C., a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the elude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield): 1HNMR (CD3OD, 300 MHz) δ 1.51 (s, 12H, 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) δ −11.3 (s, 1 P). The addition of acid the precipitation of potassium chloride The solid is then filtered washed with methanol cooled by a salt/ice bath with efficient stirring to give the elude product stirred for 1-2 hours The reaction is then filtered to concentrate the solution in DME The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield)

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

Procedure: Di-tert-butyl phospohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time, The reaction as then allowed to continue at room temperature for an additional half hour, Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C., a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the elude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield): 1HNMR (CD3OD, 300 MHz) δ 1.51 (s, 12H, 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) δ −11.3 (s, 1 P). The addition of acid the precipitation of potassium chloride The solid is then filtered washed with methanol cooled by a salt/ice bath with efficient stirring to give the elude product stirred for 1-2 hours The reaction is then filtered to concentrate the solution in DME The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of chiral 2-iodoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 11, 20 mg, 0.026 mmol) in dimethyl formamide (2 mL) was added potassium di-tert-butylphosphate (Accela ChemBio, 21.8 mg, 0.088 mmol). The reaction mixture was heated at 60° C. for 6 h. The mixture was diluted with ethyl acetate, washed with water and then brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography to give chiral 2-(di-tert-butoxyphosphoryloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (12 mg, 54% yield). MS (ES+) m/z calcd. for C41H50Cl2F2N3O8PNa: [(M+Na)+]: 874. found: 874. washed with water brine, dried over anhydrous sodium sulfate concentrated The crude material was purified by flash chromatography