182438-98-8|9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide| Ambeed

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Quality Control of [ 182438-98-8 ] Purity: 95% SDS Specification

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Product Details of [ 182438-98-8 ]

CAS No. :	182438-98-8
Formula :	C₂₀H₁₉BrF₃NO
M.W :	426.27
SMILES Code :	O=C(C1(CCCCBr)C2=C(C3=C1C=CC=C3)C=CC=C2)NCC(F)(F)F
MDL No. :	MFCD27978674
InChI Key :	HAZOEBWGAVOBLO-UHFFFAOYSA-N
Pubchem ID :	10526437

Safety of [ 182438-98-8 ]

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

Computational Chemistry of [ 182438-98-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	26
Num. arom. heavy atoms	12
Fraction Csp3	0.35
Num. rotatable bonds	8
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	99.48
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.1 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.58
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	5.37
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	6.46
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.	4.45
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	6.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	5.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-5.68
Solubility	0.000892 mg/ml ; 0.00000209 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.	-5.73
Solubility	0.000785 mg/ml ; 0.00000184 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	-8.84
Solubility	0.000000622 mg/ml ; 0.0000000015 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	No
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	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	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	Yes
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.	-5.09 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	1.0
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	1.0
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<3.0
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)	3.39

Application In Synthesis of [ 182438-98-8 ]

* 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 [ 182438-98-8 ]

[ 182438-98-8 ] Synthesis Path-Downstream 1~35

1
[ 76320-88-2 ]
[ 182438-98-8 ]
[ 194219-92-6 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.

2
[ 32046-84-7 ]
[ 182438-98-8 ]
[ 194220-00-3 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.

3
[ 373-88-6 ]
[ 331767-53-4 ]
[ 182438-98-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylamine; In dichloromethane;	c. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic Acid-(2,2,2-trifluoro-ethyl)-amide 23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane at 0 C. under nitrogen and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice each with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1). Yield: 15.8 g (58.6% of theory), Melting point: 172 C.
	With triethylamine; In dichloromethane;	EXAMPLE III 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide 23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane at 0 C. under nitrogen and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1). Yield: 15.8 g (58.6% of theory), melting point: 172 C.
	With triethylamine; In dichloromethane;	c. 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide 23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise at 0 C. under nitrogen to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1). Yield: 15.8 g (58.6% of theoretical), Melting point: 172 C.

With triethylamine; In dichloromethane; at 0℃; for 1h;Inert atmosphere;

To a solution of above obtained acid (60 g, 173 mmol) and DIVIF (100 1iL) inCH2C12 (600 mL) under argon at 00 C. was added oxalyl chloride (104 mL, 2.OM inCH2C12, 208 mmol) drop wise. The reaction was stined at 0C. for 10 mm, then warmed to RT and stined for 1.5 h. The reaction was concentrated to give the crude acid chloride as yellow oil. To a suspension of 2,2,2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) in CH2C12 (500 mL) at 0C. under argon was added triethylamine (73 mL, 521 mmol) followed by drop wise addition of a solution of the crude acid chloride in CH2C12(15 mL). The reaction was stined at 0 C. for 1 h, diluted with CH2C12 (500 mL), and washed with water (2x300 mL), iN HC1 (2x300 mL) to give 80 g of an oil whichwas purified by flash chromatography on silica gel (2.5 kg). The crude product was loaded in a mixture of CH2C12 and hexane, and eluted with a step gradient of 10% EtOAc/hexane (4L) to 15% EtOAc/hexane (2L) to 20% EtOAc/hexane (4L). Pure fractions were combined and evaporated to give 9-(4-bromobutyl)-N-(2,2,2- trifluoroethyl-9H-fluorene-9-carboxamide of formula II as a white solid.Yield: 52.5 gm.Chromatographic purity (by HPLC): E 90%.Dimer impurity A: 12.11%.

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5067 - 5070.
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.
[3]Patent: US2003/166637,2003,A1 .
[4]Patent: US2003/114442,2003,A1 .
[5]Patent: US6818644,2004,B1 .
[6]Patent: WO2016/71849,2016,A1 .Location in patent: Page/Page column 15; 16.

4
[ 90349-14-7 ]
[ 182438-98-8 ]
[ 194219-96-0 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.

5
[ 10597-52-1 ]
[ 182438-98-8 ]
[ 335065-63-9 ]

Yield	Reaction Conditions	Operation in experiment
42%		To a stirred solution of 2.50 g (15.0 mmol) of Part A compound in 30 mL of DMF at room temperature under argon was added 3.0 g (22 mmol) of potassium carbonate and, after 30 min, 6.80 g (16.0 mmol) of [297.2] (prepared in Example 273 part A (2)). After 24h, the reaction mixture was quenched with 200 mL of water. The gummy solid that formed was collected, washed with water and dissolved in dichloromethane. This solution was washed twice with water, once with brine, dried (MgSO4) and evaporated. The resulting semi-solid was triturated with cold ether and collected. Without characterization, a stirred slurry of this material and 200 mg of 10% palladium-on-charcoal in 50 mL of ethanol was purged with argon and evacuated three times. Hydrogen was introduced to the partially evacuated solution via a bladder. After 20 h, the reaction mixture was purged with argon, passed through a 0.45 µ nylon filter, washing with dichloromethane and evaporated. The oily product was purified by flash chromatography on silica gel (5x25 cm columm, 3:97 methanol/ethyl acetate) to give title compound as a white amorphous solid, 3.02 g, 42% overall yield from Part A compound.

References: [1]Patent: EP904262,2004,B1 .Location in patent: Page 211.
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.

6
[ 208773-27-7 ]
[ 182438-98-8 ]
[ 335065-64-0 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.

7
[ 208773-26-6 ]
[ 182438-98-8 ]
[ 335065-65-1 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 851 - 856.

8
[ 182438-98-8 ]
[ 122-52-1 ]
[ 194212-36-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5067 - 5070.

9
[ 92-54-6 ]
[ 182438-98-8 ]
[ 331767-10-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N-methyl-acetamide; water;	d. 9-[4-(4-phenyl-piperazin-1-yl)-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide A suspension of 0.4 g (0.93 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide, 0.153 ml (1 mmol) of 1-phenylpiperazine, 0.8 g of potassium carbonate and 1 ml water in 30 ml dimethylformamide is stirred for 10 hours at 80 C. The reaction mixture is then poured onto water, extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/methanol=15:1). Yield: 0.1 g (19.7% of theoretical), Melting point: 127-128 C.