1221398-11-3|6-Chloro-5-iodopyridin-2-amine| Ambeed

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Quality Control of [ 1221398-11-3 ] Purity: 96% SDS Specification

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Product Details of [ 1221398-11-3 ]

CAS No. :	1221398-11-3
Formula :	C₅H₄ClIN₂
M.W :	254.46
SMILES Code :	NC1=NC(Cl)=C(I)C=C1
MDL No. :	MFCD20486991
InChI Key :	LTQCXIAUNZHCCC-UHFFFAOYSA-N
Pubchem ID :	70700961

Safety of [ 1221398-11-3 ]

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

Computational Chemistry of [ 1221398-11-3 ] 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	1.0
Num. H-bond donors	1.0
Molar Refractivity	46.37
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.58
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	2.12
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.93
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.	1.76
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	2.32
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.94

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.25
Solubility	0.144 mg/ml ; 0.000567 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.	-2.57
Solubility	0.688 mg/ml ; 0.0027 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	-3.24
Solubility	0.148 mg/ml ; 0.000581 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.	-6.35 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	0.0
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)	2.28

Application In Synthesis of [ 1221398-11-3 ]

* 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 [ 1221398-11-3 ]

[ 1221398-11-3 ] Synthesis Path-Downstream 1~28

1
[ 557-21-1 ]
[ 1221398-11-3 ]
[ 53554-20-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Inert atmosphere;	24.2 6-Amino-2-chloro-nicotinonitrile 6-Chloro-5-iodo-pyridin-2-ylamine 24.1 (4.00 g, 15.7 mmol) is dissolved in 15 mL N,N-dimethylformamide, zinc cyanide (0.997 g, 8.50 mmol) is added and the mixture is vigorously stirred while purging the mixture with an argon stream for 5 min. (Tris(dibenzylideneacetone)-dipalladium(0) (0.642 g, 0.701 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0.784 g, 1.42 mmol) are added and stirred for 10 minutes at 120 C. The mixture is extracted with ethyl acetate and a half saturated aqueous solution of sodium bicarbonate. The organic phase is filtered over silica gel and concentrated. The mixture is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 100/0->50/50). Yield: 1.60 g (66% of theory) Mass spectrometry (ESI+): m/z=154 [M+H]+
62 mg	With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In water; N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation;	A mixture of 30 (500mg, 2.67mmol), Zn(CN)2 (188mg, 1.60mmol), Pd2(dba)3 (122mg, 0.13mmol), and dppf (148mg, 0.27mmol) was added degassed DMF/ H2O (99:1, 3.1mL). The reaction mixture was heated using conventional heating at 120C for 24h. The resulting mixture was cooled to rt, and sat. aq. NH4Cl/ conc. NH3/H2O (4:1:4, 10mL) was added resulting in precipitation. The mixture was cooled to 0C and filtered. The precipitate was washed with sat. aq. NH4Cl/conc. NH3/H2O (4:1:4, 10mL) and H2O at 5C and dried under vacuum affording the product as dark orange solid (279mg, 78%). mp. 162-164C. IR 2211cm-1. 1H NMR (CDCl3) delta 7.54 (d, J=8.4Hz, 1H), 6.33 (d, J=8.4Hz, 1H), 5.06 (b s, 2H), 2.55 (s, 3H). 13C NMR (CDCl3) delta 162.8, 159.9, 141.5, 118.9, 105.8, 97.6, 23.8.

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1697 - 1700.
[2]Patent: US2018/37594,2018,A1 .Location in patent: Paragraph 0344-0347.
[3]European Journal of Medicinal Chemistry,2014,vol. 84,p. 404 - 416.

2
[ 45644-21-1 ]
[ 1221398-11-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of 6-chloropyridin-2-amine (50.0 g, 389 mmol) in DMF (700 mL) was added N-iodosuccinimide (105 g, 467 mmol). The brown solution was stirred at rt for 12 h. The mixture was poured into water (2.1 L) and filtered. The filter cake was washed with water (2*500 mL) and then dried under vacuum. Purification (FCC, SiO2; 5-20% EtOAc/petroleum ether) afforded the title compound (83 g, 75%) as a pink solid. MS (ESI): mass calcd. for C5H4ClIN2, 253.9; m/z found, 254.7 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 7.74 (d, J=8.0 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 4.69 (br s, 2H).
73%	With N-iodo-succinimide; In N,N-dimethyl-formamide; for 43h;	36 (1.00g, 7.78mmol) was dissolved in DMF (40mL), the reaction flask was covered with aluminium foil, and NIS (970mg, 4.28mmol) was added. The reaction mixture was stirred for 19h before additional NIS (970mg, 4.28mmol) was added, and the reaction mixture was stirred for another 24h. H2O (200mL) was added, and the mixture was extracted with EtOAc (2×250mL). The combined organic layer was washed with H2O (2×200mL) and brine (200mL), dried over Na2SO4, and evaporated under vacuum. Recrystallization from EtOH followed by recrystallization of the mother liquor afforded the product as orange, needle-shaped crystals (1.45g, 73%). mp 154.3-155.9. 1H NMR (CDCl3) delta 7.75 (d, J=8.2Hz, 1H), 6.22 (d, J=8.2Hz, 1H). 13C NMR (CDCl3) delta 157.6, 151.6, 149.4, 108.8.
71%	With Iodine monochloride; acetic acid;	60 g of 6-chloro-2-aminopyridine was dissolved in 400 mL of glacial acetic acid, and 75.5 g of iodine chloride was added.The reaction mixture was stirred until the reaction was completed. Filtration, concentration to obtain fine products, the crude product was crystallized from ethanol to obtain 126.7 g of a product, the yield was 71%, and the purity of the product was determined by HPLC to be 99.5%.

0.49 g	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 16h;	To an N,N-dimethylformamide (30 mL) solution of 2-amino-6-chloropyridine (1.0 g) was added N-iodosuccinimide (1.75 g) and the mixture stirred at room temperature for 16 hours. To the reaction mixture, water (200 mL) was added followed by extraction into ethyl acetate. The combined organic layers were dried, filtered and concentrated. The residue was triturated with dichloromethane and the resultant precipitate collected by filtration to give the title compound having the following physical properties (0.49 g). LC/MS tR 1.72 minutes; MS (ES+) m/z 254 (M+H) a.
	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 25℃; for 18h;Inert atmosphere;	Step 1 : 6-chloro-5-iodopyridin-2-amine To a solution of 6-chloropyridin-2-amine (10 g, 78 mmol) in DMF (100 mL) was added l-iodopyrrolidine-2,5-dione (17.50 g, 78 mmol). The reaction mixture was allowed to stir under N2 balloon at 25C for 18 h. LCMS showed some of the desired product. The reaction was then diluted with EtOAc (100 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over Na2S04, and concentrated in vacuo. The residue was then washed with DCM (30 mL) and then dried to give the title compound. MS (ESI) m/z 254.8 (M+H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1697 - 1700.
[2]Patent: US2018/111933,2018,A1 .Location in patent: Paragraph 0243.
[3]European Journal of Medicinal Chemistry,2014,vol. 84,p. 404 - 416.
[4]Patent: CN109776401,2019,A .Location in patent: Paragraph 0007-0008.
[5]Patent: WO2013/93484,2013,A1 .Location in patent: Page/Page column 243.
[6]Patent: WO2016/168098,2016,A1 .Location in patent: Page/Page column 50.

3
[ 1221398-11-3 ]
[ 4023-34-1 ]
[ 1221398-13-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1697 - 1700.

4
potassium phosphate [ No CAS ]
[ 1221398-11-3 ]
[ 5720-06-9 ]
[ 603-35-0 ]
2-chlorobenzofuro[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	palladium diacetate; In water; acetonitrile;	Potassium phosphate (12.72 g, 60 mmol), triphenyl phosphine (0.682 g, 2.40 mmol), <strong>[1221398-11-3]6-chloro-5-iodo-2-aminopyridine</strong> (6.1 g, 24 mmol), 2-methoxybenzeneboronic acid (5.10 g, 33.5 mmol) and palladium acetate (0.27 g, 1.20 mmol) were sequentially added to degassed acetonitrile (200 mL) and water (60 mL) under nitrogen. The reaction mixture was heated at 75 C. for overnight, then cooled to room temperature. The organic layer was separated and aqueous layer and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified by silica column using hexanes and ethyl acetate as eluent furnishing 4.05 g of title compound. Synthesis of 2-chlorobenzofuro[2,3-b]pyridine:

References: [1]Patent: US2012/61654,2012,A1 .

5
[ 657408-07-6 ]
potassium phosphate [ No CAS ]
Pd₂(bda)3 [ No CAS ]
[ 98-80-6 ]
2-chlorobenzofuro[2,3-b]pyridine [ No CAS ]
[ 1221398-11-3 ]

Yield	Reaction Conditions	Operation in experiment
	With nitrogen; In water; toluene;	2-chlorobenzofuro[2,3-b]pyridine (1.33 g, 6.53 mmol), phenylboronic acid (1.19 g, 9.80 mmol), potassium phosphate (4.51 g, 19.59 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.214 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.13 mmol) were to toluene (40 mL) and water (4 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 1.45 g of title compound. Synthesis of Compound 8: Iridium intermediate (1.15 g, 1.55 mmol) and 2-phenylbenzofuro[2,3-b]pyridine (1.14 g, 4.66 mmol) was mixed in 30 mL of anhydrous ethanol.

References: [1]Patent: US2012/61654,2012,A1 .

6
[ 124-38-9 ]
[ 1221398-11-3 ]
[ 1060811-66-6 ]