54117-37-2|9-Benzyl-9H-carbazole-3-carbaldehyde| Ambeed

CAS No. :	54117-37-2
Formula :	C₂₀H₁₅NO
M.W :	285.34
SMILES Code :	O=CC1=CC2=C(C=C1)N(CC3=CC=CC=C3)C4=C2C=CC=C4
MDL No. :	MFCD00403522
InChI Key :	GSNXZYWQXATWRX-UHFFFAOYSA-N
Pubchem ID :	3091534

Safety of [ 54117-37-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319
Precautionary Statements:	P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313

Computational Chemistry of [ 54117-37-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	19
Fraction Csp3	0.05
Num. rotatable bonds	3
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	90.58
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	22.0 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.66
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	5.25
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.66
Log P_o/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.	3.59
Log P_o/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	4.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	4.15

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-5.36
Solubility	0.00125 mg/ml ; 0.00000439 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-5.46
Solubility	0.000987 mg/ml ; 0.00000346 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-7.0
Solubility	0.0000286 mg/ml ; 0.0000001 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly 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	No
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	Yes
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	Yes
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	Yes
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.	-4.31 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	1.0
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<1.0
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)	1.71

Application In Synthesis of [ 54117-37-2 ]

* 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 [ 54117-37-2 ]

[ 54117-37-2 ] Synthesis Path-Downstream 1~52

1
[ 19402-87-0 ]
[ 68-12-2 ]
[ 54117-37-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With trichlorophosphate; In chloroform; at 0 - 90℃; for 8h;	General procedure: DMF (0.4 ml)was added into a dried round-bottom flask and thesystem was cooled to 0 C. A solution of CHCl3 (3 ml) containing1ae1i (5 mmol) was then added following the addition of redistilled POCl3 (0.45 mL). Then, the solution mixture was heated to 90 C for 8 h. After most of the CHCl3 was removed the residue waspoured into ice water and the pH was then adjusted to 7-8 using NaHCO3, the water layer was extracted with CH2Cl2 and organiclayer was washed with water several times before being dried with Mg2SO4, after CH2Cl2 was removed, the crude product was purifiedby column chromatography using ethyl acetate/petroleum ether(1:10, V/V) as an eluent, and finally a primrose solid was obtainedfor 2a-2i in 62e81% yields.
80%	With trichlorophosphate; at 0 - 90℃; for 8h;	General procedure: DMF (0.4 ml) was added into a dried round-bottom flask and the system was cooled to 0 C. A solution of CHCl3 (3 ml) containing 1a-1m(5 mmol) was then added following the addition of redistilled POCl3 (0.45 mL).Then, the solution mixture was heated to 90 C for 8 h. After most of the CHCl3 was removed the residue was poured into ice water and the pH was then adjusted to 7-8 using NaHCO3, the water layer was extracted with CH2Cl2 and organic layer was washed with water several times before being dried with Mg2SO4, after CH2Cl2 was removed, the crude product was purified by column chromatography using ethyl acetate/petroleum ether (1:10, V/V) as an eluent, and finally a primrose solid was obtained for 2a-2m in 62-81% yields.
36.1%		Step 2. 9-Benzyl-9H-carbazole-3-carbaldehyde; A 50-mL 3-necked round-bottomed flask was charged with N,N-dimethylformamide (400 mg, 5.42 mmol, 2.80 equiv, 99%). To this, POCl3 (700 mg, 4.56 mmol, 2.40 equiv, 99%) was added drop wise with stirring at 0 C. and allowed to stir at room temperature for 1 hour. To this mixture was added 9-benzyl-9H-carbazole (500 mg, 1.93 mmol, 1.00 equiv, 99%) in small portions at 45 C. over 5 minutes. Then, the temperature was raised to 95 C. in an oil bath and allowed to stir for 18 hours. The progress was monitored by TLC (EtOAc:PE=1:4). Upon completion, the reaction mixture was cooled down to room temperature and quenched with water (20 mL). The resulting mixture was allowed to stir for an additional 4 hours at room temperature. The solids were collected by filtration and dried to afford 9-benzyl-9H-carbazole-3-carbaldehyde as green solid (200 mg, 36.1%). LCMS: [M+H]+: 286

2.64 g	With trichlorophosphate; at 80℃; for 3h;Cooling with ice;	In a 100mL three-necked flask equipped with a magnetic stirrer, 3g (12mmol) of the prepared N-benzylcarbazole dissolved in 10mL DMF was added. The mixture was subjected to an ice bath. 4mL POCl3 was slowly added dropwise. After addition of POCl3, the solution was cooled at room temperature giving a pale yellow solution. The solution was heated at 50C for 20min then temperature was raised to 80C. The solution turned dark red. the reaction was continued 3h forming a precipitate. The reaction was stopped. The mixture was filtered and dried to give 2.64g of N-benzylcarbazol-3-aldehyde as a pale yellow solid.
5.41 g	With trichlorophosphate; at 0 - 20℃; for 17h;Reflux;	A solution of CHCl3 (25 mL) containing 9-benzyl-9H-carbazole (6.43 g, 25 mmol) and DMF(1.86 mL) was cooled to 0C. POC13 (2.3 mL) was slowly added at 0C and the solution was allowedto stir to room temperature for one hour. Then, the solution mixture was refluxed for 16 h. Duringreaction, a yellow precipitate formed. After cooling, the solution was poured into ice water. Theyellow solid was filtered off, washed with ether and pentane, and dried under vacuum. The crudeproduct was recrystallized in ethanol, and cooled at -30C to end the precipitation (5.41 g, 76%yield).

References: [1]European Journal of Medicinal Chemistry,2018,vol. 145,p. 498 - 510.
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1320 - 1323.
[3]Journal of Polymer Science, Part A: Polymer Chemistry,2017,vol. 55,p. 1189 - 1199.
[4]Patent: US8080566,2011,B1 .Location in patent: Page/Page column 41.
[5]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.
[6]Patent: CN105348277,2016,A .Location in patent: Paragraph 0012.
[7]Molecules,2017,vol. 22.

2
[ 19402-87-0 ]
[ 93-61-8 ]
[ 54117-37-2 ]

References: [1]Heterocycles,1988,vol. 27,p. 2341 - 2344.
[2]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 230 - 232.

3
[ 54117-37-2 ]
[ 51761-07-0 ]

Yield	Reaction Conditions	Operation in experiment
40%		Step 3. 9H-Carbazole-3-carbaldehyde; A 250-mL round-bottomed flask was charged with a solution of AlCl3 (9.26 g, 69.45 mmol, 20.00 equiv, 99%) in 1,2-dichloroethane (150 mL). To this was added <strong>[54117-37-2]9-benzyl-9H-carbazole-3-carbaldehyde</strong> (1 g, 3.47 mmol, 1.00 equiv, 99%) in several batches at room temperature over 5 minutes. The resulting mixture was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of H2O/ice (100 mL). The solids were filtered out. The resulting solution was extracted with DCM (3×100 mL) and the combined organic layers were concentrated on a rotary evaporator to give a residue that was purified by silica gel column chromatography eluted with PE:EtOAc (10:1) to afford 9H-carbazole-3-carbaldehyde as green solid (270 mg, 40%). LCMS: [M+H]+: 196

References: [1]Patent: US8080566,2011,B1 .Location in patent: Page/Page column 42.
[2]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 230 - 232.

4
[ 54117-37-2 ]
[ 105-53-3 ]
[ 129356-37-2 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

6
[ 86-74-8 ]
KOH [ No CAS ]
[ 54117-37-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 230 - 232.

7
[ 54117-37-2 ]
[ 142750-20-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 230 - 232.

8
[ 100-44-7 ]
disodium-compound of 1,1,2,2-tetraphenyl-ethane [ No CAS ]
[ 54117-37-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 230 - 232.

9
[ 54117-37-2 ]
[ 129356-40-7 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

10
[ 54117-37-2 ]
[ 129356-41-8 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

11
[ 54117-37-2 ]
[ 129356-44-1 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

12
[ 54117-37-2 ]
[ 129356-39-4 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

13
[ 54117-37-2 ]
5-(N-β-hydroxyethyloxyethyl-3-carbazolylmethyl)-2,2-dimethyl-1,3-dioxane [ No CAS ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

14
[ 54117-37-2 ]
[ 129356-38-3 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

15
[ 54117-37-2 ]
[ 129073-14-9 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

16
[ 54117-37-2 ]
3-(2,2-Dimethyl-[1,3]dioxan-5-ylmethyl)-9-[3-(9-methyl-2,7-dinitro-9H-fluoren-9-yl)-propyl]-9H-carbazole [ No CAS ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

17
[ 54117-37-2 ]
[ 129045-65-4 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

18
[ 54117-37-2 ]
[ 129242-32-6 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 908 - 925.

19
[ 86-74-8 ]
[ 54117-37-2 ]

References: [1]Patent: US8080566,2011,B1 .
[2]Patent: CN105348277,2016,A .
[3]Australian Journal of Chemistry,2016,vol. 69,p. 1268 - 1276.
[4]European Journal of Medicinal Chemistry,2018,vol. 145,p. 498 - 510.
[5]Molecules,2017,vol. 22.
[6]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1320 - 1323.

20
[ 54117-37-2 ]
[ 1352654-67-1 ]

References: [1]Patent: US8080566,2011,B1 .

21
[ 100-39-0 ]
[ 54117-37-2 ]

22
[ 1134-35-6 ]
[ 54117-37-2 ]
[ 1428875-52-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With chloro-trimethyl-silane; In N,N-dimethyl-formamide; at 100℃; for 48h;	The antenna ligand for NC-11 was synthesized in a pressure tube containing 4,4'- dimethyl-2,2'-bipyridine (2g, 0.0108 mol) and 9-benzyl- H-carbazole-3-carbaldehyde (6.19g, 0.0217mol) and 0.065mol of trimethylchlorosilane, and magnetic stirrer bar in 70ml DMF. The reaction temperature was raised to 100C and allowed to run for 48 hours with continuous stirring. During the course of the reaction, the color of the reaction mixture changed to yellow and turned orange on cooling and release of pressure from the tube. The solvent was removed using rotary evaporator, and the orange product was recovered by addition of water and filtration under vacuum to furnish the ancillary ligand in 84% yield. Scheme 3 shows a schematic of the synthesis of the antenna ligand for NC-11.

References: [1]Patent: WO2013/49019,2013,A1 .Location in patent: Page/Page column 17.

23
[ 54117-37-2 ]
[ 98-80-6 ]
9-benzylcarbazol-3-yl(phenyl)methanone [ No CAS ]