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CAS No. : | 1174020-64-4 | MDL No. : | MFCD30609552 |
Formula : | C17H28N4O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SXKJDJFTBGADNS-OLZOCXBDSA-N |
M.W : | 368.43 | Pubchem ID : | 45258964 |
Synonyms : |
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.82 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 103.96 |
TPSA : | 102.42 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.27 cm/s |
Log Po/w (iLOGP) : | 2.65 |
Log Po/w (XLOGP3) : | 0.39 |
Log Po/w (WLOGP) : | 0.02 |
Log Po/w (MLOGP) : | 0.94 |
Log Po/w (SILICOS-IT) : | -1.27 |
Consensus Log Po/w : | 0.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.97 |
Solubility : | 3.91 mg/ml ; 0.0106 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.11 |
Solubility : | 2.88 mg/ml ; 0.00782 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.41 |
Solubility : | 144.0 mg/ml ; 0.391 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 5.01 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 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) |
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