205444-22-0|2-Chloro-4-iodo-6-(trifluoromethyl)pyridine| Ambeed

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Quality Control of [ 205444-22-0 ] Purity: 98% SDS Specification

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Product Details of [ 205444-22-0 ]

CAS No. :	205444-22-0
Formula :	C₆H₂ClF₃IN
M.W :	307.44
SMILES Code :	FC(F)(F)C1=CC(I)=CC(Cl)=N1
MDL No. :	MFCD10699394
InChI Key :	JHKQSKCFLAXPKK-UHFFFAOYSA-N
Pubchem ID :	10859785

Safety of [ 205444-22-0 ]

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

Computational Chemistry of [ 205444-22-0 ] 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.	2.19
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	3.38
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	3.43

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.18
Solubility	0.0203 mg/ml ; 0.0000661 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.	-3.33
Solubility	0.144 mg/ml ; 0.000468 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.	-5.78 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	2.0 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)	1.94

Application In Synthesis of [ 205444-22-0 ]

* 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 [ 205444-22-0 ]

[ 205444-22-0 ] Synthesis Path-Downstream 1~35

1
[ 75-77-4 ]
[ 205444-22-0 ]
2-Chloro-4-iodo-6-trifluoromethyl-3-trimethylsilanyl-pyridine [ No CAS ]

References: [1]Tetrahedron Letters,1998,vol. 39,p. 1749 - 1752.

2
[ 39890-95-4 ]
[ 205444-22-0 ]

Yield	Reaction Conditions	Operation in experiment
42%		To a cooled (-100C) solution of diisopropylamine (14.5 mL, 104 mmol) in 80 mL of THF under inert atmosphere was added dropwise n-butyllithium (65 mL of a 1.6 M solution in hexanes, 104 mmol) followed by a lOmL of THF solution of 2-chloro-6- (trifluoromethyl) pyridine (9.5 g, 52 mmol). After two hours, the temperature was raised to -78C and a 10 mL solution of iodine in THF (13 g, 52 mmol) was added. After 1 hour, the reaction was poured into water and extracted with DCM. The combined DCM layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 14.9 g of a mixture of 6-chloro-3-iodo-2-(trifluoromethyl)pyridine and 2-chloro-4-iodo-6- (trifluoromethyl)pyridine. This crude material was resubjected to LDA as follows. To a cooled (-78C) solution of diisopropylamine (14.5 mL, 104 mmol) in 80 mL of THF under inert atmosphere was added dropwise n-butyllithium (65 mL of a 1.6 M solution in hexanes, 104 mmol) followed by a 30 mL solution of the preceding crude mixture in THF. After three hours, the reaction mixture was poured in water and extracted with DCM. The DCM layers were washed with brine, dried (MgSC^), concentrated in vacuo, and purified via silica gel chromatography (0-20% EtOAc/hexanes) to afford Intermediate 9A as a white solid (6.9 g, 42%). l NMR (CDC13): delta 7.96 (s, 1H), 7.95 (s, 1H).

References: [1]Tetrahedron Letters,1998,vol. 39,p. 1749 - 1752.
[2]Patent: WO2018/5794,2018,A2 .Location in patent: Page/Page column 82.
[3]Patent: WO2016/44792,2016,A1 .

3
[ 205444-22-0 ]
2-Chloro-3,4-diiodo-6-trifluoromethyl-pyridine [ No CAS ]

References: [1]Tetrahedron Letters,1998,vol. 39,p. 1749 - 1752.

4
[ 124-38-9 ]
[ 205444-22-0 ]
2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		To a stirred solution of 1.1 g of <strong>[205444-22-0]2-chloro-4-iodo-6-trifluoromethyl-pyridine</strong> (3.58 mmol) in 15 ml THF under argon at -75 C., were added 2.2 ml of n-BuLi (1.6 M in hexane) within 15 min (temperature kept between -72 C. and -75 C.). After 5 additional min stirring at -75 C., the reaction mixture was poured on an excess of freshly crushed dry ice and stirred until RT was reached. The reaction mixture was then concentrated in vacuo, the remaining residue treated with 2M aqueous HCl and the resulting mixture was extrated with diethylether. The combined organic phases were washed with water, and then extracted with saturated NaHCO3 solution. The aqueous phase was then acidified with concentrated HCl, extracted twice with diethylether and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The remaining residue was recrystallized from 12 ml hot n-hexane, leading to 0.459 g (56%) of 2-chloro-6-trifluoromethyl-isonicotinic acid as an off-white solid. MS: 224.0 (M-H)-.

References: [1]European Journal of Organic Chemistry,2004,p. 3793 - 3798.
[2]Patent: US2007/185058,2007,A1 .Location in patent: Page/Page column 17.

5
[ 205240-59-1 ]
[ 205444-22-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere;	To a mixture of 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (3.07 g, 10.0 mmol) in THF (35 mL) was added dropwise LDA (5.5 mL, 2M) at -78 oC via syringe under N2 atmosphere. The reaction mixture was stirred at that temperature for 1 h. The reaction mixture was quenched with aqueous HCl (15mL, 1 M) at -78 oC and stirred for 0.5 h. The mixture was warmed to r.t., stirred for another 0.5 hr, and then concentrated under reduced pressure. The aqueous layer was separated and extracted with EA (2 x 100 mL). Combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography (eluted with PE) to give the 2-chloro-4-iodo-6- (trifluoromethyl)pyridine (2.5 g, 81% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6) delta 8.39 (s, 1H), 8.34 (s, 1H).

References: [1]European Journal of Organic Chemistry,2004,p. 3793 - 3798.
[2]Patent: WO2016/44792,2016,A1 .Location in patent: Page/Page column 174; 175.

6
[ 945717-57-7 ]
[ 205444-22-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -75 - -72℃; for 1.83333h;	To a stirred solution of 3.05 ml of n-BuLi (1.6 M in hexane, 4.88 mmol) under argon at -75 C. was added 0.69 ml of diisopropylamine (4.88 mmol) in 2.5 ml THF over 5 min (temperature between -72 and -75 C.). After 10 min at -75 C. a solution of 1.5 g of 6-chloro-3-iodo-2-trifluoromethyl-pyridine (4.88 mmol) in 3.5 ml THF was added dropwise over 20 min at the same temperature. After 1.5 hours stirring at -75 C., 6 ml 2M aqueous HCl were added (temperature was allowed to raise to RT). The mixture was then diluted with water, extracted with diethylether and the combined organic phases were successively washed with saturated NaHCO3 solution and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by silicagel chromatography (eluent:heptane/AcOEt 95:5) leading to 1.145 g (69%) of 2-chloro-4-iodo-6-trifluoromethyl-pyridine as a white powder. MS: 307.0

References: [1]Patent: US2007/185058,2007,A1 .Location in patent: Page/Page column 17.

7
[ 205444-22-0 ]
2-chloro-6-(trifluoromethyl)isonicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With copper(l) cyanide; In 1-methyl-pyrrolidin-2-one; at 120℃; for 0.166667h;sealed vessel;	Step A. 2-Chloro-6-(trifluoromethyl)isonicotinonitrile2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (0.50 g, 1.5 mmol, prepared according to the method described in European Journal of Organic Chemistry, (18) 3793-3798; 2004) and copper cyanide (0.52 g, 5.8 mmol) were mixed in N- methylpyrrolidinone (2 mL). The reaction vial was sealed and heated in the microwave to 120 C for 10 minutes. The mixture was diluted with water and EtOAc and was filtered. The organic layer was washed with water (3x), followed by brine, dried over sodium sulfate and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (0.24 g, 64%).

References: [1]Patent: WO2012/68450,2012,A1 .Location in patent: Page/Page column 266.

8
[ 205444-22-0 ]
[ 1379376-03-0 ]

References: [1]Patent: WO2012/68450,2012,A1 .

9
[ 205444-22-0 ]
[ 1379376-04-1 ]

References: [1]Patent: WO2012/68450,2012,A1 .

10
[ 205444-22-0 ]
2-[(1-{cis-3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinamide [ No CAS ]
2-[(1-{trans-3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinamide [ No CAS ]

References: [1]Patent: WO2012/68450,2012,A1 .

11
[ 205444-22-0 ]
2-[(1-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinonitrile [ No CAS ]

References: [1]Patent: WO2012/68450,2012,A1 .

12
[ 205444-22-0 ]
{cis-3-(4-[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile [ No CAS ]