823221-95-0|5-Chloro-4-iodo-2-(trifluoromethyl)pyridine| Ambeed

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Quality Control of [ 823221-95-0 ] Purity: 95% SDS Specification

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Product Details of [ 823221-95-0 ]

CAS No. :	823221-95-0
Formula :	C₆H₂ClF₃IN
M.W :	307.44
SMILES Code :	FC(C1=NC=C(Cl)C(I)=C1)(F)F
MDL No. :	MFCD18255894
InChI Key :	FOHPNORRPVAVJB-UHFFFAOYSA-N
Pubchem ID :	67478869

Safety of [ 823221-95-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 823221-95-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	46.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.11
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	3.05
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.51
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.	3.05
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	4.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.35

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.97
Solubility	0.0328 mg/ml ; 0.000107 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.	-2.99
Solubility	0.317 mg/ml ; 0.00103 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	-4.46
Solubility	0.0106 mg/ml ; 0.0000344 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.01 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<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)	1.89

Application In Synthesis of [ 823221-95-0 ]

* 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 [ 823221-95-0 ]

[ 823221-95-0 ] Synthesis Path-Downstream 1~26

1
[ 349-94-0 ]
[ 823221-95-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step C 5-chloro-4-iodo-2-(trifluoromethyl)pyridine Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-chloro-2-(trifluoromethyl)pyridine (as prepared in the previous step, 5 g, 27.62 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). LDA (3 g, 28.04 mmol, 1.05 equiv, as a THF solution) was added dropwise with stirring at -78 C. The resulting solution was stirred for 30 min at -78 C. A solution of I2 (7.4 g, 29.13 mmol, 1.05 equiv) in tetrahydrofuran (10 mL) was added dropwise with stirring at -78 C. The reaction mixture was stirred for an additional 2 h at -78 C., quenched with 15 mL of Na2S2O3(1M) and diluted with 100 mL of water. The resulting mixture was extracted with 3*50 mL of ether. The combined organic layers were washed with 50 ml brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (0:1), yielding 5-chloro-4-iodo-2-(trifluoromethyl)pyridine as a white solid.
	With n-butyllithium; iodine; diisopropylamine; In tetrahydrofuran; hexane; at -78℃; for 1h;	Step 1: LDA (lithium diisopropyl amide) preparation: To a solution of diisopropylamine (5.8 mL, 41.3 mmol) in THF (40 mL), at -78 C in a 250 mL 3 neck RBF, was added n-butyl lithium (1.6 M in hexane, 25.8 mL, 6.49 mmol) and the resulting solution was stirred at that temperature for 0.5 h. To a solution of iodine (8.37 g, 33.0 mmol) and 5-chloro-2-(trifluoromethyl) pyridine (10 g, 55.08 mmol) in THF (100 mL) at -78 C in a 500 mL 3 neck RBF, was added the above prepared LDA solution through a canula and the resulting solution was stirred at that temperature for 1 h.The reaction was stopped by the addition of saturated NH4C1 solution (50 mL) and extracted with MTBE (2 x 100 mL).The organic layer was washed with water (2 x 50 mL), dried over anhydrous Na2S04 and concentrated. The crude product was purified by column chromatography (2% EtOAc in petroleum ether) to yield 5-chloro-4-iodo-2- (trifiuoromethyl)pyridine. 1H NMR (300 MHz, DMSO-d6): 8.81(s, 1 H), 8.49 (s, 1H); GC-MS calc'd. for C6H2C1F3IN [M+H]+ 307.89, found 307.0.

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.
[2]Patent: US2011/306592,2011,A1 .Location in patent: Page/Page column 92.
[3]Patent: WO2015/17302,2015,A2 .Location in patent: Page/Page column 36; 37.

2
[ 823221-95-0 ]
[ 823221-96-1 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 2h;Inert atmosphere;	Step D 3-chloro-2-iodo-6-(trifluoromethyl)pyridine Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of <strong>[823221-95-0]5-chloro-4-iodo-2-(trifluoromethyl)pyridine</strong> (as prepared in the previous step, 2 g, 6.51 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of LDA (730 mg, 6.82 mmol, 1.05 equiv, as a THF solution) dropwise with stirring at -78 C. The resulting solution was stirred for 2 h at -78 C. The reaction was then quenched by the addition of 5 mL of water and diluted with 100 mL DCM. The resulting solution was washed with 50 mL brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1:10) eluent, yielding 3-chloro-2-iodo-6-(trifluoromethyl)pyridine as a yellow solid.

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.
[2]Patent: US2011/306592,2011,A1 .Location in patent: Page/Page column 92.

3
[ 40473-01-6 ]
[ 823221-95-0 ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.
[2]Patent: US2011/306592,2011,A1 .

4
[ 244221-57-6 ]
[ 823221-95-0 ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.
[2]Patent: US2011/306592,2011,A1 .

5
[ 823221-95-0 ]
3-chloro-6-(trifluoromethyl)pyridine-2-carboxylic acid [ No CAS ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.

6
[ 823221-95-0 ]
[ 1214333-69-3 ]

References: [1]Patent: US2011/306592,2011,A1 .

7
[ 823221-95-0 ]
ethyl (S)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

8
[ 823221-95-0 ]
ethyl (2S,5S)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-2-carboxylate [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

9
[ 823221-95-0 ]
1-(tert-butyl) 2-ethyl (2S,5S)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-1,2-dicarboxylate [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

10
[ 823221-95-0 ]
tert-butyl (2S,5S)-2-(3,5-bis(trifluoromethyl)benzoyl)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

11
[ 823221-95-0 ]
tert-butyl (2S,5S)-2-((E)-(3,5-bis(trifluoromethyl)phenyl)((tert-butylsulfinyl)imino)methyl)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

12
[ 823221-95-0 ]
tert-butyl (2S,5S)-2-((1R)-(3,5-bis(trifluoromethyl)phenyl)((tert-butylsulfinyl)amino)methyl)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)pyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

13
[ 823221-95-0 ]
(R)-(3,5-bis(trifluoromethyl)phenyl)((2S,5S)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-2-yl)methanamine [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

14
[ 823221-95-0 ]
(1R,5S,7aS)-1-(3,5-bis(trifluoromethyl)phenyl)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one [ No CAS ]

References: [1]Patent: WO2015/17302,2015,A2 .

15
[ 144978-35-8 ]
[ 823221-95-0 ]
ethyl (S)-2-((tert-butoxycarbonyl)amino)-5-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)-5-oxopentanoate [ No CAS ]