851386-34-0|2,3-Difluoro-4-iodopyridine| Ambeed

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Quality Control of [ 851386-34-0 ] Purity: 98% SDS Specification

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Product Details of [ 851386-34-0 ]

CAS No. :	851386-34-0
Formula :	C₅H₂F₂IN
M.W :	240.98
SMILES Code :	IC1=C(F)C(F)=NC=C1
MDL No. :	MFCD09909609
InChI Key :	AIXBVJWFQNYGJA-UHFFFAOYSA-N
Pubchem ID :	11447837

Safety of [ 851386-34-0 ]

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

Computational Chemistry of [ 851386-34-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	36.87
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.	1.71
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	2.04
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.8
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.	2.28
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	3.24
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.41

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.11
Solubility	0.186 mg/ml ; 0.000772 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.	-1.94
Solubility	2.77 mg/ml ; 0.0115 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-3.54
Solubility	0.0695 mg/ml ; 0.000288 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	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.	-6.32 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<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)	2.21

Application In Synthesis of [ 851386-34-0 ]

* 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 [ 851386-34-0 ]

[ 851386-34-0 ] Synthesis Path-Downstream 1~35

1
[ 851386-34-0 ]
copper(l) cyanide [ No CAS ]
[ 1210041-67-0 ]

References: [1]Synthesis,2010,p. 63 - 66.

2
[ 1513-66-2 ]
[ 851386-34-0 ]

Yield	Reaction Conditions	Operation in experiment
63%		To a flask containing THF (35 mL) was added LDA (1.0 M solution in hexane) (26.1 mL, 26.1 mmol) at -78 °C, then a solution of 2,3-difluoropyridine (2.5 g, 21.72 mmol) in THF (6 mL) was added dropwise at -78 °C. The reaction mixture turned into bright yellow suspension after addtion of pyridine. The resulting mixture was stirred at -78 °C for 1 h, then iodine (6.62 g, 26.1 mmol) was added in several batches at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. To the reaction mixture was added NH4CI solution and the reaction mixture was stirred for 10 min. The resulting mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated NaHCCb solution, dried over MgSCk The filtrate was concentrated in vacuo. The extract was purified via silica gel flash column chromatography, eluting with 0-15percent ethyl acetate in hexane to give Intermediate 21A (yellow solid, 3.3 g, 13.69 mmol, 63percent yield). LC-MS Anal. Calc'd for C5H2F2IN 240.92, found [M+H] 242.1. Tr = 0.82 min (Method A). NMR (499MHz, chloroform-d) delta 7.68 (dd, J=5.2, 0.9 Hz, 1H), 7.57 (dd, J=5.2, 3.5 Hz, 1H).

References: [1]Patent: WO2018/209049,2018,A1 .Location in patent: Paragraph 00226.
[2]Synthesis,2010,p. 63 - 66.

3
[ 851386-34-0 ]
[ 1227580-21-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	With water; acetic acid;Reflux;	A mixture of 2,3-difiuoro-4-iodopyridine (from Ark Pharm, 3.0 g, 12 mmol) in acetic acid (30 mL) and water (15 mL) was heated to reflux overnight. Most of the solvent was removed by vacuum and the remaining was neutralized with aq. NaHCCb and extracted by EtOAc. The organic layers were combined, dried and concentrated. The white solid crude product obtained (2.5 g, 84%) was used directly in the next step without further purifications. LCMS calc. for C5H4FINO (M+H)+ m/z = 239.9; found, 240.0
71.4%	With acetic acid; In water;Reflux;	2,3-Difluoro-4-iodopyridine (300 mg, 1 .24 mmol) was suspended in acetic acid: water (2:1 , 15 mL). The mixture was heated to reflux and stirred at this temperature overnight. Reaction was concentrated to dryness, and triturated in water (10 mL) for 30 min. The solid was collected via filtration, washed with water (2x10 mL), and pentane (2x20 mL) and dried under vacuum to afford the title compound as a white solid (354 mg, 71.4%). LC-MS m/z 342.0 (M+1 ). 1H NMR (400 MHz, METHANOL-^) delta ppm 6.56 - 6.82 (m, 1 H) 6.83 - 7.18 (m, 1 H).
65.3%	With water; potassium hydroxide; In 1,4-dioxane; at 100℃;	[00495] To a solution of 2,3-Difluoro-4-iodopyridine (0.250 g, 1.04 mmol) in a mixture of water (1.04 mL, 1.04 mmol) and dioxane (0.10 mL) was added powdered KOH (0.116 g, 2.07 mmol) and heated to 100 °C overnight. The mixture was cooled to room temperature, at which time a white solid crashed out. Water (15 mL) and 3 mL glacial acetic acid were added and the reaction mixture was stirred for 30 min. The aqueous layer was extracted with 4:1 DCM:IPA (3 x10 mL), dried over Na2SO4, filtered and concentrated to afford 3-fluoro-4-iodopyridin-2(1H)-one (0.162 g, 0.678 mmol, 65.3 percent yield) as a white solid.

References: [1]Patent: WO2016/196244,2016,A1 .Location in patent: Page/Page column 234.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670.
[3]Patent: WO2011/73845,2011,A1 .Location in patent: Page/Page column 111.
[4]Patent: WO2019/113190,2019,A1 .Location in patent: Paragraph 00495.

4
[ 851386-34-0 ]
[ 1312479-44-9 ]

References: [1]Patent: WO2011/73845,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670.

5
[ 851386-34-0 ]
[ 1312479-45-0 ]

References: [1]Patent: WO2011/73845,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670.

6
[ 851386-34-0 ]
[ 1312479-46-1 ]

References: [1]Patent: WO2011/73845,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670.

7
[ 851386-34-0 ]
[ 1312479-47-2 ]

References: [1]Patent: WO2011/73845,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670.

8
[ 851386-34-0 ]
[ 1312473-96-3 ]

References: [1]Patent: WO2011/73845,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1662 - 1670.

9
[ 851386-34-0 ]
[ 1333331-85-3 ]
[ 1333331-90-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 85℃; for 48h;Sealed vial;	To a 20 mL microwave vial (Biotage) was added 0.70 g (3.03 mmol) 3-[(4- methoxybenzyl)oxy]pyridin-4(lH)-one, 1.26 g (9,08 mmol) potassium carbonate, 1.10 g (4.54 mmol) <strong>[851386-34-0]2,3-difluoro-4-iodopyridine</strong> and 15 mL DMSO, A yellow suspension formed and the vial was sealed and heated at 85 °C for 48 h on a heat block. The suspension was cooled, diluted with ethyl acetate, and washed twice with 10 mL brine. The organic layer was dried over sodium sulfate, filtered, and evaporated onto silica gel. Purification by flash chromatography (silica gel 0-100percent hexanes/EtOAc gradient, followed by 10percent MeOH in EtOAc) afforded 3'-fluoro-4'-iodo- 3-[(4-methoxybenzyl)oxy]-4H-l,2'-bipyridin-4-one as a yellow solid. LCMS (M+H)+ 453,3.

References: [1]Patent: WO2011/109254,2011,A1 .Location in patent: Page/Page column 135.

10
[ 851386-34-0 ]
N-{1-[3-Fluoro-4-(4-fluorophenyl)pyridin-2-yl]-1H-pyrazol-3-yl}-2-(trifluoromethyl)benzamide [ No CAS ]

References: [1]Patent: US2015/239847,2015,A1 .

11
[ 851386-34-0 ]
N-[1-(3-fluoro-4-iodopyridin-2-yl)-1H-pyrazol-3-yl]-2-(trifluoromethyl)benzamide [ No CAS ]

References: [1]Patent: US2015/239847,2015,A1 .

12
[ 1820-80-0 ]
[ 851386-34-0 ]
[ 67-68-5 ]
1-(3-fluoro-4-iodopyridin-2-yl)-1H-pyrazole-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In methanol; water; ethyl acetate;	Step 1: 1-(3-Fluoro-4-iodopyridin-2-yl)-1H-pyrazole-3-amine (via A-1) A mixture of 3-aminopyrazole (0.50 g), <strong>[851386-34-0]2,3-difluoro-4-iodopyridine</strong> (1.45 g), potassium carbonate (3.3 g) and 10 ml anhydrous dimethyl sulphoxide was stirred at 85° C. for 48 hours. For work-up, 100 ml of water were added at room temperature and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and then concentrated completely and chromatographed on silica gel using an ethyl acetate/methanol gradient. This gave 705 mg of the title compound. HPLC-MS: log P=1.38; mass (m/z): 304.9 (M+H)+; 1H-NMR (DMSO-D6) 5.91 (m, 1H), 7.62 (m, 1H), 7.85 (m, 1H), 8.08 (m, 1H).

References: [1]Patent: US2015/239847,2015,A1 .

13
[ 16066-84-5 ]
[ 851386-34-0 ]
C₁₁H₁₄F₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 100℃; for 13.5h;	Compound a70 (1.0g, 4.15mmol) was dissolved in dioxane (16 mL), tert-butyl methyl carbamate (653mg, 4.98mmol), 2- dicyclohexylphosphino-2 ', 4', 6'-triisopropyl biphenyl (297mg, 0.622mmol), potassium phosphate (2.20g, 10.73mmol)And tris (dibenzylideneacetone) palladium(190mg, 0.207mmol) was added, and the mixture was stirred for 5 hours at 100°C .Tertiary butyl methyl carbamate (218mg, 1.66mmol),2-dicyclohexyl phosphino-2 ', 4', 6'-triisopropyl biphenyl(99mg, 0.207mmol),Potassium phosphate (0.73g, 3.57mmol)And tris (dibenzylideneacetone) palladium (0)(63.3mg, 0.069mmol) was added and stirred for 3 hours and a half.Tertiary butyl methyl carbamate (435mg, 3.32mmol),2-dicyclohexyl phosphino-2 ', 4', 6'-triisopropyl-biphenyl (99 mg, 0.207 mmol) and tris (dibenzylideneacetone) palladium (0) (63.3 mg, 0.069 mmol) was added to 5 hours It was semi-stirring.Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography - (hexanes-ethyl acetate) to give compound a71 (0.75 g, 74percent yield).
74%	With potassium phosphate; XPhos; In 1,4-dioxane; at 100℃; for 13.5h;	Step 1 Preparation of Compound c71 (0551) Compound c70 (1.0g, 4.15mmol) was dissolved in dioxane (16mL), and tertiary butyl methyl carbamate (653mg, 4.98mmol), 2- dicyclohexylphosphino-2 ', 4' , 6'-triisopropyl-biphenyl (297mg, 0.622mmol), potassium phosphate (2.20g, 10.73mmol) and tris (dibenzylideneacetone) palladium (190mg, 0.207mmol) were added to the mixture at 100 °C for 5 hours. Tertiary butyl methyl carbamate (218mg, 1.66mmol), 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl biphenyl (99mg, 0.207mmol), potassium phosphate (0.73g, 3.57mmol) and tris (dibenzylideneacetone) palladium (0) (63.3mg, 0.069mmol) were added to the mixture and the mixture was stirred for 3 hours. Tertiary butyl methyl carbamate (435mg, 3.32mmol), 2- dicyclohexylphosphino-2 ', 4', 6'-triisopropyl biphenyl (99mg, 0.207mmol) and tris (dibenzylideneacetone) palladium (0) (63.3mg, 0.069mmol) was then added to the mixture and the mixture was stirred for 5.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound c71 (0.75g, 74percent yield). [M + H] = 244.95, Method Condition 3: retention time 2.08 min

References: [1]Patent: JP2016/79168,2016,A .Location in patent: Paragraph 0233.
[2]Patent: EP3059225,2016,A1 .Location in patent: Paragraph 0551.

14
[ 851386-34-0 ]
C₂₁H₂₉FN₄O₄ [ No CAS ]