N-[bis[(2-methylpropan-2-yl)oxy]phosphanyl]-N-propan-2-ylpropan-2-amine

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

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

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

Procedure: A solution of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (4.0 g) and 1-H-tetrazole (0.45 M in acetonitrile, 70 mL) in THF (160 mL) was treated with di-tert-butyl diisopropylphosphoramidite (16.4 mL) at rt for 2 h. The solution was cooled to 0° C. and treated with 30% aqueous H2O2 (11 mL) for 30 min. Work-up (EtOAc, aq. NaHCO3) and reverse-phase preparative HPLC gave the title compound, as a solid. HPLC Rt=6.13 min.

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

Procedure: To a solution of (S)-1-(1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (6.1 g, 14.66 mmol) in THF (20 mL) was added tetrazole (0.34 M in acetonitrile, 172.0 mL, 58.64 mmol) followed by addition of di-tert-butyl diisopropylphosphoramidite (9.3 mL, 29.32 mmol) at RT The resulting solution was stirred at RT for 2 h. To this mixture was added MCPBA (70%, 7.3 g, 29.32 mmol) at RT. The reaction mixture was stirred at RT overnight and quenched with Na2SO3. The mixture was filtered and the filtrate was concentrated and dissolved in EtOAc. The organic mixture was washed with NaOH (1N×2), NaHCO3 (sat.), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-di-tert-butyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentyl phosphate (4.1 g, 54%). LRMS (M+H+−2 tBu) m/z 491.2. The reaction mixture was stirred at RT overnight quenched with Na2SO3 The mixture was filtered the filtrate was concentrated dissolved in EtOAc The organic mixture was washed with NaOH (1N×2), NaHCO3 (sat.), and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-1-(1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (6.1 g, 14.66 mmol) in THF (20 mL) was added tetrazole (0.34 M in acetonitrile, 172.0 mL, 58.64 mmol) followed by addition of di-tert-butyl diisopropylphosphoramidite (9.3 mL, 29.32 mmol) at RT The resulting solution was stirred at RT for 2 h. To this mixture was added MCPBA (70%, 7.3 g, 29.32 mmol) at RT. The reaction mixture was stirred at RT overnight and quenched with Na2SO3. The mixture was filtered and the filtrate was concentrated and dissolved in EtOAc. The organic mixture was washed with NaOH (1 N×2), NaHCO3 (sat.), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-di-tert-butyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentyl phosphate (4.1 g, 54%). LRMS (M+H+ −2 tBu) m/z 491.2. The reaction mixture was stirred at RT overnight quenched with Na2SO3 The mixture was filtered the filtrate was concentrated dissolved in EtOAc The organic mixture was washed with NaOH (1 N×2), NaHCO3 (sat.), and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-1-(1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (6.1 g, 14.66 mmol) in THF (20 mL) was added tetrazole (0.34 M in acetonitrile, 172.0 mL, 58.64 mmol) followed by addition of di-tert-butyl diisopropylphosphoramidite (9.3 mL, 29.32 mmol) at RT The resulting solution was stirred at RT for 2 h. To this mixture was added MCPBA (70%, 7.3 g, 29.32 mmol) at RT. The reaction mixture was stirred at RT overnight and quenched with Na2SO3. The mixture was filtered and the filtrate was concentrated and dissolved in EtOAc. The organic mixture was washed with NaOH (1 N×2), NaHCO3 (sat.), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-di-tert-butyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentyl phosphate (4.1 g, 54%). LRMS (M+H+−2 tBu) m/z 491.2. The reaction mixture was stirred at RT overnight quenched with Na2SO3 The mixture was filtered the filtrate was concentrated dissolved in EtOAc The organic mixture was washed with NaOH (1 N×2), NaHCO3 (sat.), and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethanol (0.74 g; 1.94 mmol) in a mixture of THF (10 mL) and CH2Cl2 (10 mL) was added a tetrazole solution in CH3CN ((8.60 ml; 0.45 mol/1; 3.87 mmol) at RT. The resulting mixture was stirred for 30 minutes and subsequently di-tert-butyl N,N-diisopropylphosphoramidite (0.98 ml; 3.10 mmol) was added and stirred overnight at RT. Subsequently, the mixture was cooled to 4° C., and a solution of tert-butyl hydroperoxide in nonane (0.31 ml; ˜5.5 mol/L, 2.90 mmol) was added. Thereafter the mixture was stirred at RT for another 30 min. The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc) to afford phosphoric acid di-tert-butyl ester 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethyl ester (0.66 g). stirred overnight at RT Thereafter the mixture was stirred at RT for another 30 min The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution extracted with EtOAc The organic layer was dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, EtOAc)

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethanol (0.74 g; 1.94 mmol) in a mixture of THF (10 mL) and CH2Cl2 (10 mL) was added a tetrazole solution in CH3CN ((8.60 ml; 0.45 mol/1; 3.87 mmol) at RT. The resulting mixture was stirred for 30 minutes and subsequently di-tert-butyl N,N-diisopropylphosphoramidite (0.98 ml; 3.10 mmol) was added and stirred overnight at RT. Subsequently, the mixture was cooled to 4° C., and a solution of tert-butyl hydroperoxide in nonane (0.31 ml; ˜5.5 mol/L, 2.90 mmol) was added. Thereafter the mixture was stirred at RT for another 30 min. The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc) to afford phosphoric acid di-tert-butyl ester 2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethyl ester (0.66 g). stirred overnight at RT Thereafter the mixture was stirred at RT for another 30 min The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution extracted with EtOAc The organic layer was dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, EtOAc)

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

Procedure: To a solution of 2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethanol (1.33 g; 4.0 mmol) in a mixture of THF (15 mL) and CH2Cl2 (15 mL) was added a tetrazole solution in CH3CN (17.6 mL; 0.45 mol/L; 7.9 mmol) at RT. The resulting mixture was stirred for 30 minutes and subsequently di-tert-butyl N,N-diisopropylphosphoramidite (2.00 ml; 6.3 mmol) was added and stirred overnight at RT. Subsequently, an aqueous hydrogen peroxide solution (1.80 ml; 300 g/1; 15.9 mmol) was added and the mixture stirred at RT for another 15 min. The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford phosphoric acid di-tert-butyl ester 2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl ester (0.71 g). stirred overnight at RT the mixture stirred at RT for another 15 min The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution extracted with EtOAc The organic layer was dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, Et2O)

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

Procedure: To (S)-(9H-fluoren-9-yl)methyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate (5260 mg, 10.45 mmol) was added imidazole (818 mg, 12.02 mmol), imidazole HCl (1857 mg, 17.77 mmol), and DMF (Volume: 50 mL). The reaction was stirred to dissolve under argon for 2-3 minutes. Then di-tert-butyl diisopropylphosphoramidite (4928 mg, 17.77 mmol) was added drop wise over 2-3 minutes and stirred at room temperature for 2 hours. The reaction was followed by neutral LCMS and by TLC eluting with 1:1 ethyl acetate/heptane. The crude reaction was placed in a water bath, hydrogen peroxide 30% (5.34 mL, 52.3 mmol) was added slowly, and the mixture was stirred at room temperature for 30 minutes, followed by LCMS. The crude reaction was placed in an ice bath and excess saturated sodium thiosulphate was added (carefully) drop wise over 5-10 minutes. To the crude reaction mixture was added 800 ml of ethyl acetate washed with water (3×), saturated salt solution, dried sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 300 g column eluting from 0-55% ethyl acetate in heptane. The desired peak was concentrated to constant mass to give 6560 mg of the desired product as free base used as is, (86% yield). LCMS (m/z): 696.3 (MH+) weak, 1.25 min. Note: −112 fragment at 584.2 is major ion in LCMS as expected from loss of two t-butyl protecting groups. 1H NMR (<cd3od>) d: 7.79 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.3 Hz, 2H), 7.58 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.34-7.42 (m, 2H), 7.22-7.32 (m, 2H), 7.12 (d, J=9.1 Hz, 1H), 4.90 (t, J=6.0 Hz, 1H), 4.41-4.48 (m, 1H), 4.31-4.40 (m, 1H), 4.21 (t, J=6.6 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 1.42 (s, 9H), 1.40 (s, 9H). to dissolve under argon for 2-3 minutes stirred at room temperature for 2 hours eluting with 1:1 ethyl acetate/heptane The crude reaction was placed in a water bath the mixture was stirred at room temperature for 30 minutes The crude reaction was placed in an ice bath To the crude reaction mixture washed with water (3×), saturated salt solution, dried sodium sulfate filtered concentrated to residue The crude was purified by silica gel chromatography eluting from 0-55% ethyl acetate in heptane The desired peak was concentrated to constant mass

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

Procedure: A solution of 1H-tetrazole (2.37 g, 33.9 mmol, 3.0 equiv), di-tert-butyl-N,N-diisopropylphosphoramidite (7.42 mL, 22.6 mmol, 2.0 equiv), and ethyl(2R)-4-(4′-hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate (4.25 g, 11.3 mmol, 1.0 equiv) in tetrahydrofuran (113 mL) was allowed to stir overnight at room temperature. A solution of saturated sodium sulfite (330 mL) was added, and the mixture was extracted with dichloromethane (3×440 mL). The combined organic layers were washed with water (3×330 mL), brine (3×330 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (50% ethyl acetate in heptane) to provide a colorless oil (5.84 g, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3H) 1.50-1.52 (m, 18H) 1.71 (s, 3H) 2.17-2.30 (m, 1H) 2.46-2.61 (m, 2H) 2.72-2.85 (m, 1H) 3.04 (s, 3H) 4.26 (qd, J=7.13, 1.27 Hz, 2H) 7.21-7.28 (m, 4H) 7.45-7.53 (m, 4H). the mixture was extracted with dichloromethane (3×440 mL) The combined organic layers were washed with water (3×330 mL), brine (3×330 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography on silica gel (50% ethyl acetate in heptane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)-amide (33a) (100 mg, 0.234 mmol), tetrazole (23 mg, 0.327 mmol) and di-tert-butyl diisopropylphosphoramidite (0.096 mL, 0.304 mmol) were dissolved/suspended in 30 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was stirred for about 3 hours, after which time the reaction was cooled to −78° C. and tert-butyl hydrogen peroxide (0.100 mL of 70% solution in water) was added. The cooling bath was then taken away and the reaction was slowly warmed up to room temperature and reacted over night. The reaction mixture was then partitioned between a solution of ethyl ether/ethyl acetate (5:1) and saturated aqueous NaHCO3. The organic layer was saved and successively washed with 10% aqueous sodium sulfite, 3 times with water and finally with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in 3 mL of a solution of TFA/DCM (2:1) under an atmosphere of dry N2. The reaction was stirred at room temperature for about 2 hours after which time it was concentrated under vacuum and the resulting residue was stirred in methanol for about 1 hour. The off-white solid was collected via suction filtration, washed with methanol followed by ethyl ether and then air-dried to give the desired compound (74). the reaction was slowly warmed up to room temperature reacted over night The reaction mixture was then partitioned between a solution of ethyl ether/ethyl acetate (5:1) and saturated aqueous NaHCO3 successively washed with 10% aqueous sodium sulfite, 3 times with water and finally with brine The resulting organic layer was dried over MgSO4 filtered concentrated under vacuum The residue was dissolved in 3 mL of a solution of TFA/DCM (2:1) under an atmosphere of dry N2 The reaction was stirred at room temperature for about 2 hours after which time it was concentrated under vacuum the resulting residue was stirred in methanol for about 1 hour The off-white solid was collected via suction filtration washed with methanol air-dried