Structure of 900503-08-4
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CAS No. : | 900503-08-4 |
Formula : | C18H30BNO4 |
M.W : | 335.25 |
SMILES Code : | CC1(C)C(C)(C)OB(C2=CC(N3C(OC(C)(C)C)=O)CCC3C2)O1 |
MDL No. : | MFCD22380007 |
InChI Key : | JNHGCLCLMOCPCQ-UHFFFAOYSA-N |
Pubchem ID : | 53393373 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 24 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.83 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 99.4 |
TPSA ? Topological Polar Surface Area: Calculated from |
48.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.93 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.34 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.02 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.27 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.5 |
Solubility | 0.106 mg/ml ; 0.000316 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.6 |
Solubility | 0.0843 mg/ml ; 0.000251 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.91 |
Solubility | 0.409 mg/ml ; 0.00122 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.26 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
5.74 |
* 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 |
---|---|---|
90% | With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere; | A mixture of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3- ene-8-carboxylate (Int-le) (10.1 g, 28.4 mmol), bis(pinacolato)diboron (8.7 g, 34.1 mmol), KOAc (8.4 g, 85.3 mmol), PdCl2(dppf)2.CH2Cl2 (1.4g, 1.7mmol), and dppf (1 g, 1.8 mmol) in dioxane (170 ml) was flushed with argon and stirred at 80C for 16 h. On cooling, the solvent was rotoevaporated, and the crude residue was redissolved in EtOAc (500 ml), washed with water (1 x 125 ml), brine (1 x 125 ml), and dried over gS0 . The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-40%) gave the desired product, tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2~ene-8-carboxylate (8.6 g, 90%). |
89% | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 3h; | tert-Butyl 3-[(trifluoromethane)sulfonyloxy]-8-azabicyclo[3.2. l]oct-2-ene-8- carboxylate (100 mg, 0.28 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (85 mg, 0.36 mmol), 1 , -bis(diphenyl- phosphanyl)ferrocene (5 mg, 0.01 mmol) and potassium acetate (82 mg, 0.84 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed for 5 minutes. Bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (7 mg, 0.01 mmol) was added and the mixture was heated at 80C for a total of 3 h. The reaction mixture was cooled and filtered over celite. The solid was washed with EtOAc (2 x 10 mL) and the combined filtrate was concentrated under vacuum. The crude product was purified using FCC, eluting with a gradient of 0-50% EtOAc in heptanes, to afford the title compound (86.8 mg, 89%) as a colourless oil. deltaH (500 MHz, CDCl3) 6.76 (s, 1H), 4.33 (d, J29.8 Hz, 2H), 2.79 (d, J 17.5 Hz, 1H), 2.12 (dd, J 13.3, 7.3 Hz, 1H), 1.92 (m, 2H), 1.65 (m, 2H), 1.46 (d, J 7.1 Hz, 9H), 1.26 (d, J 6.3 Hz, 12H). |
89% | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 3h;Ionic liquid; | tert-Butyl 3-[(trifluoromethane)sulfonyloxy]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (100 mg, 0.28 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (85 mg, 0.36 mmol), 1,1?-bis(diphenyl-phosphanyl)ferrocene (5 mg, 0.01 mmol) and potassium acetate (82 mg, 0.84 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed for 5 minutes. Bis[3-(diphenyl-phosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (7 mg, 0.01 mmol) was added and the mixture was heated at 80 C. for a total of 3 h. The reaction mixture was cooled and filtered over celite. The solid was washed with EtOAc (2×10 mL) and the combined filtrate was concentrated under vacuum. The crude product was purified using FCC, eluting with a gradient of 0-50% EtOAc in heptanes, to afford the title compound (86.8 mg, 89%) as a colourless oil. deltaH (500 MHz, CDCl3) 6.76 (s, 1H), 4.33 (d, J 29.8 Hz, 2H), 2.79 (d, J 17.5 Hz, 1H), 2.12 (dd, J 13.3, 7.3 Hz, 1H), 1.92 (m, 2H), 1.65 (m, 2H), 1.46 (d, J7.1 Hz, 9H), 1.26 (d, J6.3 Hz, 12H). |
79% | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere; | (0521) Tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]octan-2-en-8-carboxylate (9.8 g, 27.4 mmol), bis(pinacolato)diboron (10.4 g, 40.9 mmol), potassium acetate (5.4 g, 55 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (1.15 g, 1.4 mmol) and 1,1?-bis(diphenyphosphino)ferrocene (776 mg, 1.4 mmol) were dissolved in 1,4-dioxane (100 mL). Under the protection of nitrogen gas, the reaction was carried out at 80 C. under stirring for 16 h. After the reaction, the mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried with anhydrous sodium sulfate, filtrated, and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to get the title compound (7.3 g, yield: 79%). |
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 6h;Inert atmosphere; | Under nitrogen protection,To 3-((((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid tert-butyl ester (714 mg, 2.0 mmol),Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added to a 20 mL 1,4-dioxane solution of boranoic acid pinacol ester (508 mg, 2.0 mmol) and KOAc (392 mg, 4.0 mmol).The reaction mixture was stirred at 90 C for 6 h under nitrogen.TLC showed the reaction was completed.The reaction system is poured into 100 mL of water.Extract with EA (50 mL x 3).The organic phase is washed once with saturated brine.The anhydrous Na2SO4 was sufficiently dried and concentrated under reduced pressure.Column chromatography with residue (PE: EA = 20:1)Purification afforded 520 mg (yield: 78%) of title compound.It is a pale yellow solid. |
76% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 20h; | B. A 200 mL round bottom flask was charged with Compound 6b (1.4 g, 3.92 mmol), Pd(dppf)2CI2 (0.09 g, 0.12 mmol), K2CO3 (1.15 g, 11.7 mmol), and <n="188"/>dioxane (23.0 ml_). Bis(pinacolato)diboron (1.1 g, 4.33 mmol) was added and the mixture was heated to 80 0C for 20 h. The mixture was concentrated in-vacuo and purified via flash chromatography (230-400 mesh silica gel 60, DCM) to give 1.0 g (76%) of Compound 6c as a white solid. 1H NMR (300 MHz, CDCI3) delta 6.76 (d, J = 5.3 Hz, 1 H), 4.27-4.35 (m, 2 H), 2.80-2.90 (m, 1 H), 2.03-2.12 (m, 1 H), 1.88-1.94 (m, 4 H), 1.44 (s, 9 H), and 1.26 (s, 12 H). |
42% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere; | To a solution of the product from the previous step (2.20 g, 4.00 mmol) in dioxane (13.3 mL) under N2were added KOAc (1.257 g, 12.81 mmol) , PdCl2(dppf) (0.293 g, 0.400 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.34 g, 9.20 mmol) and the resulting mixture was stirred at 100 C for 4 h. The reaction was cooled to RT, water (10 mL) was added and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 50 %) EtOAc in hexanes to afford the title compound (1.12 g, 42 % yield) as a colorless liquid.MS (ES+) C18H30BNO4 requires: 335, found 336 [M+H]+ |
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; | The product of Preparation 3 (7.65 g, 0.0214 mol) was dissolved in 1,4-dioxane (75 mL, 0.96 mol). To the reaction mixture was added bis(pinacolato)diboron (5.71 g, 0.0225 mol), and potassium acetate (6.30 g, 0.0642 mol), 1,1'-bis(diphenylphosphino)-ferrocene (0.5 g, 0.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (0.5 g, 0.6 mmol). The reaction mixture was purged with nitrogen, stirred at 80 C. overnight, and cooled to room temperature. The solution was filtered through Celite and concentrated. The crude product was purified by flash column chromatography eluting with (5-10%) ethyl acetate in hexanes to give the title compound (4.2 g) as an oil. | |
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 16h; | A mixture of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1 ]oct-3- ene-8-carboxylate (10.1 g, 28.4 mmol), bis(pinacolato)diboron (8.7 g, 34.1 mmol), KOAc (8.4 g, 85.3 mmol), PdCl2(dppf)2.CH2Cl2 (1.4g, Ummol), and dppf (1 g, 1.8 mmol) in dioxane (170 ml) was flushed with argon and stirred at 80C for 16 h. On cooling, the solvent was evaporated, and the crude residue was redissolved in EtOAc (500 ml), washed with water (1 x 125 ml), brine (1 x 125 ml), and dried over MgS04. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0- 40%) gave the desired product, tert-butyl 3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-8- azabicyc3o[3.2.1]oct-2-ene-8-carboxylate. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere; | A mixture of Example 223A (10 g, 28.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (7.82 g, 30.8 mmol), potassium acetate (7.42 g, 76 mmol), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (1.024 g, 1.399 mmol) in 1,4-dioxane (500 mL) was degassed with argon and the mixture was stirred at 80C under argon overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using an ISCO Companion eluting with ethyl acetate/petroleum ether (1 :50 to 1 :20) to provide the title compound. MS (DCI+) m/z 336.2 (M+H)+. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | The intermediate obtained in the above step was dissolved in anhydrous 1,4-dioxane (200 mL).Add boranoic acid pinacol ester (8.1 g, 31.96 mmol, 1.2 eq)And potassium acetate (9.1 g, 93.22 mmol, 3.5 eq),1,1'-bis(triphenylphosphine)ferrocene (737.8 mg, 1.33 mmol, 0.05 eq) was added under nitrogen.And 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane (974.3 mg, 1.33 mmol, 0.05 eq),The temperature was raised to 100 C for 3 h under nitrogen protection.After being cooled to room temperature, saturated brine (100 mL) was added, and extracted with ethyl acetate (100 mL×3), and the organic phase was combined, dried and filtered.The filtrate was concentrated under reduced pressure to give a product. |
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