* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 25℃; for 4 h;
EXAMPLE 2 Preparation of tert-butyl 4-((lR,2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2. l]octane-2- carboxamido)piperidine- 1 -carboxylate Compound 1 prepared according to Example 1 was used in the subsequent hydro- debenzylation reaction shown below. Compound 1 prepared using triphosgene was used as a comparator. Into a dried and cleaned autoclave was charged urea 1 (3.0g) and THF (72 mL). Then Pd/C (10 wtpercent loading) was charged into the reaction mixture, followed by charging to 50 psig (total inside pressure). The mixture was aged at 25 °C, 50 psig for 4 hours to achieve a full conversion. The reaction mixture was vented with gas and filtered to remove Pd/C and washed with THF (5X vol., 15 mL). The organic solution was concentrated down to 1/10 volume and the solvent switched to IP Ac (45 ml) to afford a slurry of the product. The slurry was agitated for an additional 4 hr. The reaction mixture was filtered to collect the solid and washed with IP Ac (9 mL) to afford a white solid. The solid was dried under vacuum and N2 sweep to afford the title compound (-95percent yield, >98 LCAP). Spectral data matched that of the previously reported compound. See Mangion et ah, 201 1, Org. Lett. 13:5480. Table 1 shows the comparison of urea 1 prepared using the process of the invention (i.e., with a silicon- containing compound and CDI) or a previously published process (i.e., with triphosgene) in the subsequent hydroxyl-debenzylation reaction.
90%
With [10%-Pd/Al2O3]; hydrogen In tetrahydrofuran at 25℃; for 22 h;
tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxamido)piperidine-l -carboxylate (9.2 g, 20.1 mmol) was charged to a glass bottle, and the solids were dissolved in THF (150 mL). The solution was then charged to a hydrogenation reactor along with Pd/Al203 (10 wtpercent, 1.5 g). The reaction was purged three times with hydrogen and then set to a hydrogen pressure of 50 psi. The reaction temperature was adjusted to 25°C and the reaction was allowed to agitate for 22 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through SOLKA-FLOC® (Interational Fiber Corporation, North Tonawanda, NY) to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to iPrOAc to a final volume of 40 mL. The resulting iPrOAc slurry was aged at room temperature for 1 hour. The solids were then filtered and washed with iPrOAc (20 mL) and dried under vacuum and N2 at 40°C to afford the title product (6.62 g., 17.97 mmol, 90percent isolated yield). Spectral data matched the reference compound.
8.45 g
With palladium 10% on activated carbon; hydrogen In methanol at 35℃; for 2 h;
To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S,5R)-tert-butyl{(6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2- yl-carbonyl)amino)piperidine-1-carboxylate (9 g, 19.5 mmol) in methanol (90 ml) followed by 10percent palladium on carbon (2.7 g) at 35°C. The reaction mixture was stirred under 1 atm hydrogen pressure at 35°C for 2 hours. The catalyst was removed by filtering the reaction mixture under suction over a celite bed. The celite bed was washed with dichloromethane (50 ml). The combined filtrate was evaporated under vacuum below 35°C to provide (2S,5R)-tert-butyl{(6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.11 oct-2-yl-carbonyl)amino}piperidine-1-carboxylate in 8.45 g quantity; it was used as such for the next reaction. Analysis NMR: (CDCl3,) = 6.60 (d, 1H), 3.88-4.10 (m, 4H), 3.78 (s, 1H), 3.20 (d, 1H), 3.90 (t, 2H), 2.80 (d, 1H), 2.46 (dd, 1H), 2.1-2.2 (m, 1H), 2.85-2.20 (m, 4H), 1.70-1.80 (m, 1H), 2.47 (s, 9H), 1.30-1.41 (m, 3H). MS (ES+) C17H28N4O5 = 369.4 (M+1).
With di-<i>tert</i>-butyl dicarbonate; hydrogen In tetrahydrofuran at 23℃; for 5 h;
Benzyl 4-([(2Rs5S)-6-(benzyloxy)-7-oxo-l,6-diazabicycio[3.2.1]oct-2- yl]carbonyl}amino)piperidine-l-carboxylate starting material (1.9 kg (at) 97 wt percent) and Boc2ψ(0.776 kg) were charged to a glass bottle, and the solids were dissolved in THF (15 L). The solution was then charged to a hydrogenation reactor along with Pd(OH)2 (184.3 g) and another portion of THF (10.8 L). The reaction was carried out at 45 psig H2, 23 0C for 5 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through solka flok to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to EtOAc to a volume of 10 L. Approximately 30 L EtOAc was used during the solvent switch and the THF level after a constant volume distillation (10 L at a maximum temperature of 200C) was determined by proton NMR to be ~ 4 mol percent THF; EtOAc. The resulting EtOAc slurry was aged at room temperature for 1 hour, after which hexanes (4 L) was added over 1 hour at room temperature. The slurry was aged for an additional 1 hour after which the supernatant concentration was measured (target: ~ 6 mg/g). The solids were then filtered and washed with 60 percent EtOAc/hexanes solution (3 x 3 L) and dried under vacuum and N2 at room temperature to afford the title product (80percent isolated yield). 1H NMR (400 MHz, CDCl3 ): 8.60 (br s, IH), 6.67 (d, J= 8.2 Hz, IH), 4.12 - 4.00 (m, 2H), 4.00 - 3.91 ( m, IH), 3.89 (d, J= 7.8 Hz, IH), 3.81 - 3.76 (m, IH), 3.19 (dt, J= 11.2, 2.9 Hz, 1 H), 2.90(t, J= 11.9 Hz, 2H) 2.82 (d, J= 11.3 Hz, IH), 2.45 (dd, J= 15.0, 6.7 Hz, IH), 2.21-2.11 (m, IH)5 2.02-1.85 ( m, 3H), 1.80-1.69 (m, IH), 1.48 (s, 9H), 1.44-1.30 (m, 2H)
To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (25,5R)-tert-butyl{(6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-1-carboxylate (6.40 g, 7.6 mmol) in dichioromethane (90 ml), triethyl amine (9.3 ml), followed by pyridine - sulfur trioxide complex (5.4 g, 34.2 mmol) at 35C under stirring. The reaction mixture was stirred for additional 4 hours at 35 C. The solvent was evaporated under vacuum below 40 C to provide a residue. The residue was stirred with 0.5 N aqueous potassium dihydrogen phosphate solution (90 ml) for 1 hour. The resulting solution was extracted with dichloromethane (2 x 100 ml) to remove impurities. To the aqueous layer was added tetrabutyl ammonium hydrogen sulfate (6.9 g, 20.52 mmol) and the reaction mixture was stirred for 14 hours at 35 C. It was extracted with dichloromethane (3 x 30 ml). Combined organic layer was dried over sodium sulfate and evaporated under vacuum to provide tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino}piperidine-1-carboxylate in 8.0 g quantity in 62% yield. Analysis NMR: (CDCl3,) = 6.64 (d, 1H), 4.36 (br s, 1H), 4.05(br s, 2H), 3.90-4.00 (m, 1H), 3.87 (d, 1H), 2.28-3.34 (m, 1OH), 3.80-3.95 (m, 2H), 3.74 (d, 1H), 2.42 (dd, 1H), 2.15-2.24 (m, 1H), 1.82-1.97 (m, 4H), 1.61-1.74 (m, 14 H), 1.41-1.52 (m, 10 H), 1.02 (t, 12H). MS (ES-) C17H27N4O8S. N(C4H9)4 = 447.4 (M-1) as a free sulfonic acid.
To a solution of tert-butyl 4-([(2S,5R)-6-hydroxy-7-oxo-l,- diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperidine-l-carboxylate (36 mg, 0.098 mmol) in pyridine (0.5 mL) was added sulfur trioxide pyridine complex (70 mg, 0.440 mmol). The mixture was stirred at room temperature under nitrogen overnight LC/MS analysis showed incomplete reaction. The reaction was filtered and the solids were washed with dry pyridine and dichloromethane. The filtrate was collected and concentrated under vacuum. The residue was redissolved in dry pyridine (0.75 mL) and sulfur trioxide pyridine complex (31 mg) was added followed by activated 4A molecular sieves. The reaction was stirred for 4 hours but there was little change by LC/MS. The reaction was filtered and the sieves were washed with dichloromethane. The filtrate was concentrated in vacuo and suspended in saturated aqueous potassium dihydrogen phosphate solution. The resulting mixture was washed with ethyl acetate. The aqueous layer was collected and tetrabutylammoniurn hydrogen sulfate (0.034 mg, 0.098 mmol) was added. The mixture was stirred for 10 minutes then extracted with EtOAc (4X). The <n="63"/>organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a yellow oil.
tert-Butyl 4-([(2S,5R)-6-hydroxy-7-oxo-l,6-diazabicycIo[3.2.1]oct-2- yl]carbonyl}amino)piperidine-l-carboxylate , (3.0 kg), THF (30 L), 2-picoline (1.61 L) and pyridine- SO3 complex (4.54 kg) were charged to a flask under nitrogen. No exotherm was observed. The heterogeneous mixture was allowed to stir overnight (~15 h). DCM (8 L) was <n="73"/>then added and the mixture was concentrated by vacuum distillation, removing ~30 L of THF/DCM. Additional DCM (28 L) was added, followed by the addition of water (20 L). The flask was placed in an ice bath and K2HPO4 (2.20 kg) was added over 4 minutes, followed by a water rinse (1 L). BU4NHSO4 (2.90 kg) was then added over 10 minutes followed by additional water (4 L). The biphasic mixture was stirred for 30 minutes, after which the bottom organic layer was transferred to a 100-L extractor via an in-line filter. The aqueous layer remaining in the flask was rinsed with additional DCM (2 x 4 L), and then also transferred to the extractor. A small amount of aqueous layer (~2 L) had also been transferred, and the two layers were separated. The organic layer was returned to the extractor and washed with water (1 x 6 L); pH was 4.5. The organic layer was separated and charged to a new flask via an in-line filter. The mixture was solvent-switched to 2,2,2-trifluoroethanol by vacuum distillation (34 L final volume) and used as is in the next step. Water content by Karl-Fisher titration was 1900 ppm.In a smaller-scale experiment using the same procedure, evaporation of the solvent gave a solid from which lH NMR data were collected. 1H NMR (400 MHz, CDCl3 ): 6.65 (d, J = 8.4 Hz, IH), 4.37-4.32 (m, IH), 4.18-4.00 (m, 2H), 4.00-3.89 (m,lH), 3.87(d, J= 7.7 Hz, IH), 3.36-3.27 (m, 9H), 2.95-2.79 (m, 2H), 2.75(d, J= 11.4 Hz, IH), 2.42(dd, J= 15.0, 6.9 Hz, IH) 2.24-2.11(m, 2H), 1.96-1.81 (m, 3H), 1.74-1.60 (m, 8H), 1.47(s, 9H), 1.46 (m, 8H), 1.39 (m, 2H),1.01 (t, J=7.3, 12H)
tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxamido)piperidine-l-carboxylate (20 g, 54.3 mmol), THF (200 mL), 2-picoline (10.9 mL, 309 mmol) and pyridine-S03 complex (30.2 g, 190 mmol) were charged to a flask under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 h). The reaction mixture was cooled to -10C then DCM (200 mL) was added. 0.5 M K2HP04 (168 mL, 84 mmol) was added over 10 minutes. Bu4NHS04 (19.4 g, 57 mmol) was then added over 10 minutes. The biphasic mixture was stirred for 30 minutes, phase cut and the water layer was back extracted with 40 ml of DCM. The combined DCM solution was washed with water (120 ml), phase cut and the organic solution was solvent-switched to MeCN (320 ml) by vacuum distillation with 3 bed volumes of MeCN (total 1.0 L) and used as is in the next step.
A solution phenyl chlorothionocarbonate (1.25 eq.) in ciichloromethane is added to a solution of pyridine (1.25 eq.), 4-dimethylaminopyridme (0.1 eq.) and tert-butyl A- ([(2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperidine-l- carboxylate (see Example 1, Step 2) in dichloromethane. The resulting mixture is stirred at room temperature overnight then cooled in an ice bath and quenched by addition of water. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography to afford the title compound.
With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 1h;
To a solution of tert-butyl 4-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (75b) (0.6 g, 1.31 mmol) in MeOH (6 mL) was added 10% palladium on carbon (0.2 g). The reaction mixture was stirred under 1 atm hydrogen pressure for 1 h. After the mixture was filtered through a pad of Celite, the filtrate was concentrated under vacuum to give a crude product (75c) (0.48 g, yield 100%) that was used directly for the next step. 1H NMR (300 MHz, CDCl3): delta 6.62 (d, 1H, J=7.8 Hz), 3.86-4.01 (m, 4H), 3.75 (s, 1H), 3.17 (d, 1H), 2.91 (t, 2H), 2.81 (d, 1H), 2.42 (m, 1H), 2.13 (m, 1H), 1.88 (m, 4H), 1.74 (m, 1H), 1.45 s, 9H), 1.31 (m, 2H).
Ca. 95%
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; at 25℃; under 3345.86 Torr; for 4h;
EXAMPLE 2 Preparation of tert-butyl 4-((lR,2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2. l]octane-2- carboxamido)piperidine- 1 -carboxylate Compound 1 prepared according to Example 1 was used in the subsequent hydro- debenzylation reaction shown below. Compound 1 prepared using triphosgene was used as a comparator. Into a dried and cleaned autoclave was charged urea 1 (3.0g) and THF (72 mL). Then Pd/C (10 wt% loading) was charged into the reaction mixture, followed by charging to 50 psig (total inside pressure). The mixture was aged at 25 C, 50 psig for 4 hours to achieve a full conversion. The reaction mixture was vented with gas and filtered to remove Pd/C and washed with THF (5X vol., 15 mL). The organic solution was concentrated down to 1/10 volume and the solvent switched to IP Ac (45 ml) to afford a slurry of the product. The slurry was agitated for an additional 4 hr. The reaction mixture was filtered to collect the solid and washed with IP Ac (9 mL) to afford a white solid. The solid was dried under vacuum and N2 sweep to afford the title compound (-95% yield, >98 LCAP). Spectral data matched that of the previously reported compound. See Mangion et ah, 201 1, Org. Lett. 13:5480. Table 1 shows the comparison of urea 1 prepared using the process of the invention (i.e., with a silicon- containing compound and CDI) or a previously published process (i.e., with triphosgene) in the subsequent hydroxyl-debenzylation reaction.
90%
With [10%-Pd/Al2O3]; hydrogen; In tetrahydrofuran; at 25℃; under 2585.81 Torr; for 22h;
tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2- carboxamido)piperidine-l -carboxylate (9.2 g, 20.1 mmol) was charged to a glass bottle, and the solids were dissolved in THF (150 mL). The solution was then charged to a hydrogenation reactor along with Pd/Al203 (10 wt%, 1.5 g). The reaction was purged three times with hydrogen and then set to a hydrogen pressure of 50 psi. The reaction temperature was adjusted to 25C and the reaction was allowed to agitate for 22 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through SOLKA-FLOC (Interational Fiber Corporation, North Tonawanda, NY) to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to iPrOAc to a final volume of 40 mL. The resulting iPrOAc slurry was aged at room temperature for 1 hour. The solids were then filtered and washed with iPrOAc (20 mL) and dried under vacuum and N2 at 40C to afford the title product (6.62 g., 17.97 mmol, 90% isolated yield). Spectral data matched the reference compound.
With hydrogen;palladium 10% on activated carbon; In methanol; for 3h;Product distribution / selectivity;
Palladium on carbon (30.5 mg; 10% Pd/C) was added to a solution of tert-butyl 4- ([(2S,5R)-6-(benzyloxy)-7-oxo-l6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperidine-l- carboxylate (151 mg, 0.33 mmol) in methanol (3 mL), and the resulting mixture was stirred under hydrogen (balloon) for 3 hours. TLC analysis showed the reaction was complete. The reaction mixture was filtered through a microfilter and the filtrate was concentrated under vacuum to afford the title compound as a yellow oil.
Palladium on carbon (394 mg; 10% Pd/C) was added to a solution of the product of step 1 (1.81 g, 3.95 mmol) in methanol (50.6 mL) and the resulting mixture was stirred under hydrogen (balloon) overnight. LC/MS analysis indicated the reaction was not complete. Acetic acid (6 drops) and additional catalyst (159 mg of 10% Pd/C) were added to the reaction and the resulting mixture was stirred under hydrogen (balloon) for an additional 90 minutes. Additional catalyst (0.2085 g of 10% Pd/C) was added to the reaction and stirring under hydrogen was continued for an additional 2.5 hours at which time the reaction was judged complete by LC-MS analysis. The reaction was filtered through a celite pad and the collected solid was washed well wtih MeOH. The filtrate was concentrated under vacuum to afford the title compound as a colorless oil which was used without purification in the next step.
8.45 g
With palladium 10% on activated carbon; hydrogen; In methanol; at 35℃; under 760.051 Torr; for 2h;
To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S,5R)-tert-butyl{(6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2- yl-carbonyl)amino)piperidine-1-carboxylate (9 g, 19.5 mmol) in methanol (90 ml) followed by 10% palladium on carbon (2.7 g) at 35C. The reaction mixture was stirred under 1 atm hydrogen pressure at 35C for 2 hours. The catalyst was removed by filtering the reaction mixture under suction over a celite bed. The celite bed was washed with dichloromethane (50 ml). The combined filtrate was evaporated under vacuum below 35C to provide (2S,5R)-tert-butyl{(6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.11 oct-2-yl-carbonyl)amino}piperidine-1-carboxylate in 8.45 g quantity; it was used as such for the next reaction. Analysis NMR: (CDCl3,) = 6.60 (d, 1H), 3.88-4.10 (m, 4H), 3.78 (s, 1H), 3.20 (d, 1H), 3.90 (t, 2H), 2.80 (d, 1H), 2.46 (dd, 1H), 2.1-2.2 (m, 1H), 2.85-2.20 (m, 4H), 1.70-1.80 (m, 1H), 2.47 (s, 9H), 1.30-1.41 (m, 3H). MS (ES+) C17H28N4O5 = 369.4 (M+1).
With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 1h;
To a solution of tert-butyl 4-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20b) (0.6 g, 1.31 mmol) in MeOH (6 mL) was added 10% palladium on carbon (0.2 g). The reaction mixture was stirred under 1 atm hydrogen pressure for 1 h. After the mixture was filtered through a pad of Celite, the filtrate was concentrated under vacuum to give a crude product (20c) (0.48 g, yield 100%) that was used directly for the next step. 1H NMR (300 MHz, CDCl3): delta 6.62 (d, 1H, J=7.8 Hz), 3.86-4.01 (m, 4H), 3.75 (s, 1H), 3.17 (d, 1H), 2.91 (t, 2H), 2.81 (d, 1H), 2.42 (m, 1H), 2.13 (m, 1H), 1.88 (m, 4H), 1.74 (m, 1H), 1.45 s, 9H), 1.31 (m, 2H).
With pyridine; sulfur trioxide pyridine complex; at 20℃;
To a solution of the product of step 2 (1.455 g, 3.95 mmol; theoretical yield of step 2) in dry pyridine (30 mL) was added sulfur trioxide pyridine complex (3.2 g, 20.11 mmol) at room temperature under nitrogen. The resulting thick mixture was stirred over the weekend.The reaction was filtered and the white insoluble solids were washed well with dichloromethane. The filtrate was concentrated in vacuo. The residue was further azeotroped with toluene to remove excess pyridine to afford the title compound which was used without purification in the next step.
With di-tert-butyl dicarbonate; hydrogen;palladium dihydroxide; In tetrahydrofuran; at 23℃; under 2327.23 Torr; for 5h;Product distribution / selectivity;
Benzyl 4-([(2Rs5S)-6-(benzyloxy)-7-oxo-l,6-diazabicycio[3.2.1]oct-2- yl]carbonyl}amino)piperidine-l-carboxylate starting material (1.9 kg (at) 97 wt %) and Boc2theta(0.776 kg) were charged to a glass bottle, and the solids were dissolved in THF (15 L). The solution was then charged to a hydrogenation reactor along with Pd(OH)2 (184.3 g) and another portion of THF (10.8 L). The reaction was carried out at 45 psig H2, 23 0C for 5 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through solka flok to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to EtOAc to a volume of 10 L. Approximately 30 L EtOAc was used during the solvent switch and the THF level after a constant volume distillation (10 L at a maximum temperature of 200C) was determined by proton NMR to be ~ 4 mol % THF; EtOAc. The resulting EtOAc slurry was aged at room temperature for 1 hour, after which hexanes (4 L) was added over 1 hour at room temperature. The slurry was aged for an additional 1 hour after which the supernatant concentration was measured (target: ~ 6 mg/g). The solids were then filtered and washed with 60 % EtOAc/hexanes solution (3 x 3 L) and dried under vacuum and N2 at room temperature to afford the title product (80% isolated yield). 1H NMR (400 MHz, CDCl3 ): 8.60 (br s, IH), 6.67 (d, J= 8.2 Hz, IH), 4.12 - 4.00 (m, 2H), 4.00 - 3.91 ( m, IH), 3.89 (d, J= 7.8 Hz, IH), 3.81 - 3.76 (m, IH), 3.19 (dt, J= 11.2, 2.9 Hz, 1 H), 2.90(t, J= 11.9 Hz, 2H) 2.82 (d, J= 11.3 Hz, IH), 2.45 (dd, J= 15.0, 6.7 Hz, IH), 2.21-2.11 (m, IH)5 2.02-1.85 ( m, 3H), 1.80-1.69 (m, IH), 1.48 (s, 9H), 1.44-1.30 (m, 2H)
2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate[ No CAS ]
tert-butyl 4-((2S,5R)-6-(((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
tert-Butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (3.26 mmol) was dissolved in THF (14 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resulting solution was cooled to -78 C. under a nitrogen atmosphere. A solution of NaHMDS in THF (1M, 3.59 mL, 3.59 mmol) was added dropwise, and the mixture was stirred at -78 C. for 10 min. A solution of 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (21a) (878 mg, 3.59 mmol) in THF (2 mL) was then added to the reaction mixture via a syringe. After 10 min at -78 C., the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/ hexane (1:1) as eluent to give the product (21b) (0.96 g, yield 48%) as a white foam. MS (ESI) C25H42N4O11S=607.0 (M+1)+.
48%
tert-Butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (76b) (3.26 mmol) was dissolved in THF (14 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resulting solution was cooled to -78 C. under a nitrogen atmosphere. A solution of NaHMDS in THF (1M, 3.59 mL, 3.59 mmol) was added dropwise, and the mixture was stirred at -78 C. for 10 min. A solution of 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (21a) (878 mg, 3.59 mmol) in THF (2 mL) was then added to the reaction mixture via a syringe. After 10 min at -78 C., the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1) as eluent to give the product (76c) (0.96 g, yield 48%) as a white foam. MS (ESI) C25H42N4O11S=607.0 (M+1)+.
2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate[ No CAS ]
2-methoxyethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate trifluoroacetate[ No CAS ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate[ No CAS ]
tert-butyl 4-((2S,5R)-6-(((2,2-dimethyl-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
tert-Butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (2.18 mmol) was dissolved in THF (14 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resulting solution was cooled to -78 C. under nitrogen. A solution of NaHMDS in THF (1M, 2.62 mL, 2.62 mmol) was added dropwise, and the mixture was stirred at -78 C. for 10 min. A solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b) (106b) (0.86 g, 2.62 mmol) in THF (1 mL) was then added to the reaction mixture via a syringe. After stirring for 1 h at -78 C., the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/ hexane (1:3 to 1:1) as eluent to give the product (25c) as a yellow paste (0.44 g, yield 31%). 1H NMR (300 MHz, CDCl3): delta 6.73 (d, 1H, J=8.1 Hz), 4.78-4.98 (m, 3H), 4.47 (d, 1H, J=8.7 Hz), 3.93-4.15 (m, 5H), 3.27 (d, 1H), 2.83-2.92 (m, 3H), 2.41-2.45 (m, 1H), 2.18 (s, 3H), 2.15 (m, 1H), 1.78-1.92 (m, 4H), 1.45 (s, 9H), 1.23-1.58 (m, 8H). MS (ESI) C27H40N4O13S=661 (M+1)+.
31%
Step 3: Synthesis of tert-butyl 4-((2S,5R)-6-(((2,2-dimethyl-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (80c) tert-Butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (80b) (2.18 mmol) was dissolved in THF (14 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resulting solution was cooled to -78 C. under nitrogen. A solution of NaHMDS in THF (1M, 2.62 mL, 2.62 mmol) was added dropwise, and the mixture was stirred at -78 C. for 10 min. A solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b) (106b) (0.86 g, 2.62 mmol) in THF (1 mL) was then added to the reaction mixture via a syringe. After stirring for 1 h at -78 C., the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:3 to 1:1) as eluent to give the product (80c) as a yellow paste (0.44 g, yield 31%). 1H NMR (300 MHz, CDCl3): delta 6.73 (d, 1H, J=8.1 Hz), 4.78-4.98 (m, 3H), 4.47 (d, 1H, J=8.7 Hz), 3.93-4.15 (m, 5H), 3.27 (d, 1H), 2.83-2.92 (m, 3H), 2.41-2.45 (m, 1H), 2.18 (s, 3H), 2.15 (m, 1H), 1.78-1.92 (m, 4H), 1.45 (s, 9H), 1.23-1.58 (m, 8H). MS (ESI) C27H40N4O13S=661 (M+1)+.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate[ No CAS ]
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate trifluoroacetate[ No CAS ]
ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate[ No CAS ]
tert-butyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
A flask was charged with <strong>[1174020-64-4]<strong>[1174020-64-4]tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate</strong> hydrate</strong> (2) (3.7 g, 9.6 mmol) dissolved in THF (150 mL) and cooled to -78 C. A solution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (ca. 0.67 M, 29 mL, 19 mmol) in EtOAc was added dropwise to the reaction mixture at a rate such that the reaction temperature did not exceed -55 C., and this was stirred for 15 min. 1,8-Diazabicyclo[5.4.0]undec-7-ene (4.4 mL, 29 mmol) was added dropwise to the reaction mixture at such a rate that the reaction temperature did not exceed -58 C., and this was stirred for 10 min. The mixture was warmed to 0 C. at a rate not exceeding 20 C. per min. The reaction mixture was stirred at 0 C. (ice/water bath) until the starting material was consumed (within 1 h; reaction was followed by HPLC at 196 nm). The mixture was poured into ice cold H2O (300 mL), extracted with EtOAc (200 mL), and the organic layer was washed with brine (200 mL), dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (0:1 to 7:3) as eluent to give the title compound (4) (4.4 g, 80%) as a white foam. LC-MS: m/z=577.1 [M+H]+; 1H-NMR (300 MHz, CDCl3): delta 6.43 (d, J=8.7 Hz, 1H), 4.71 (d, J=9.3 Hz, 1H), 4.60 (d, J=8.7 Hz, 1H), 4.21-3.93 (m, 7H), 3.29-3.26 (m, 1H), 2.92-2.83 (m, 3H), 2.48-2.41 (m, 1H), 2.17-2.14 (m, 1H), 1.94-1.83 (m, 4H), 1.46 (s, 9H), 1.40-1.25 (m, 11H); 13C-NMR (75 MHz, CDCl3): delta 174.1, 167.9, 167.1, 154.7, 80.4, 79.9, 62.0, 61.3, 60.1, 47.1, 46.8, 42.8, 42.6, 32.1, 31.9, 28.5, 22.1, 21.7, 20.8, 17.6, 14.1.
330 mg
tert-Butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (1.31 mmol) was dissolved in THF (7.0 mL) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (3 mL), and the resulting solution was cooled to -78 C. under a nitrogen atmosphere. A solution of NaHMDS in THF (1M, 1.31 mL, 1.31 mmol) was added dropwise, and the mixture was stirred at -78 C. for 10 min. A solution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (352 mg, 1.44 mmol) in THF (1 mL) was then added to the reaction mixture via syringe. After 10 min at -78 C., the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/ hexane (1:1) as eluent to give the product (20d) (330 mg, yield 44%) as a white foam. 1H NMR (300 MHz, CDCl3): delta 6.44 (d, 1H, J=8.1 Hz), 4.59-4.73 (dd, 2H, J=8.7 Hz), 3.89-4.23 (m, 7H), 3.28 (d, 1H), 2.83-2.92 (m, 3H), 2.42-2.49 (m, 1H), 2.14-2.17 (m, 1H), 1.80-1.97 (m, 4H), 1.46 (s, 9H), 1.58-1.23 (m, 11H). MS (ESI) C24H40N4O10S=577 (M+1)+.
ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate[ No CAS ]
ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate trifluoroacetate[ No CAS ]
(2S,5R)-2-((1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate trietylamine salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sulfur trioxide pyridine complex; In dichloromethane; at 35℃;
To a solution of <strong>[1174020-64-4]tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate</strong> (20c) (1.92 g, 5.21 mmol) in DCM (30 mL) was added triethylamine (3 mL) and pyridine-sulfur trioxide complex (3.34 g, 21.0 mmol). The reaction was stirred at 35 C. overnight. The mixture was concentrated under vacuum to give a crude residue. The residue was stirred with 0.5 N aqueous potassium dihydrogen phosphate solution (30 mL) for 1 h. The resulting solution was extracted three times with DCM. The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give triethylamine salt of (2S,5R)-2-((1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate (26a) (2.3 g, yield 80%). (1333) To a solution of above product (26a) (2.2 g, 4.0 mmol) in DCM (30 mL) was added 0.5 N aqueous dipotassium hydrogen phosphate (12.4 mL) at 0 C. After stirred at 0 C. for 10 min, tetrabutyl ammonium hydrogen sulfate (1.49 g, 4.4 mmol) was added. The resulting solution was stirred at room temperature for 30 min. After the organic layer was separated, the aqueous layer was extracted three times with DCM. The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography using 10% MeOH in DCM as eluent to give the product (26a) (1.35 g, yield 49%) as a white solid. 1H NMR (300 MHz, CDCl3): delta 6.55 (d, 1H, J=8.1 Hz), 4.33 (br s, 1H), 4.03 (m, 2H), 3.91-3.95 (m, 1H), 3.86 (d, 1H), 3.48 (m, 1H), 3.25-3.31 (m, 10H), 2.85 (m, 2H), 2.73 (d, 1H), 2.39 (dd, 1H), 2.13 (m, 1H), 1.81-1.92 (m, 4H), 1.60-1.71 (m, 11H), 1.29-1.50 (m, 14H), 1.00 (t, 12H). MS (ESI) C17H28N4O8S=446.9 (M-1)+.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
acetoxymethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
1-(isobutyryloxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
(pivaloyloxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
(isobutyloxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
1-acetoxyethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
1-(pivaloyloxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
(((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)oxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
1-(((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)oxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate[ No CAS ]
ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate trifluoroacetate[ No CAS ]
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