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Product Details of [ 900503-08-4 ]

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

Safety of [ 900503-08-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 900503-08-4 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

48.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.93
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.34
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.02
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.27
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.91

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.5
Solubility 0.106 mg/ml ; 0.000316 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.6
Solubility 0.0843 mg/ml ; 0.000251 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.91
Solubility 0.409 mg/ml ; 0.00122 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.26 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

5.74

Application In Synthesis of [ 900503-08-4 ]

* 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.

  • Downstream synthetic route of [ 900503-08-4 ]

[ 900503-08-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 73183-34-3 ]
  • [ 185099-68-7 ]
  • [ 900503-08-4 ]
YieldReaction ConditionsOperation 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.

  • 2
  • [ 25602-68-0 ]
  • [ 900503-08-4 ]
 

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Technical Information

Categories

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