3-Iodo-6-(trifluoromethyl)-1H-indazole - Products - Pharmaceutical CDMO Supplier, Development & Manufacturing-EOS Med Chem

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3-Iodo-6-(trifluoromethyl)-1H-indazole
(World's Largest Pharmaceutical Supplier)

CAS Number: 1000341-27-4
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Assay: 95%

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CAS Number：1000341-27-4
Catalog Number: A181257
Chemcial Name:
MW(Molecular Weight)：
MF(Molecular Formula):
SMILES：

Product Details of [ 1000341-27-4 ]

CAS No. :	1000341-27-4
Formula :	C₈H₄F₃IN₂
M.W :	312.03
SMILES Code :	FC(C1=CC2=C(C=C1)C(I)=NN2)(F)F
MDL No. :	MFCD09263230
InChI Key :	ARPPCBLAYCXFHA-UHFFFAOYSA-N
Pubchem ID :	24729344

Safety of [ 1000341-27-4 ]

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

Computational Chemistry of [ 1000341-27-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	9
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	53.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	28.68 ??

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.52
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	3.12
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.34
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.	3.31
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	3.94
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.25

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.15
Solubility	0.0221 mg/ml ; 0.0000708 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.	-3.39
Solubility	0.127 mg/ml ; 0.000406 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	-4.73
Solubility	0.0058 mg/ml ; 0.0000186 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.	-5.99 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	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)	2.01

Application In Synthesis of [ 1000341-27-4 ]

* 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 [ 1000341-27-4 ]

[ 1000341-27-4 ] Synthesis Path-Downstream 1~12

1
[ 954239-22-6 ]
[ 1000341-27-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20.0??; for 3.0h;	I2 (330 mg, 1.30 mmol, 2.0 eq.) was added to a stirred solution of 14 (121 mg, 0.65 mmol, 1.0 eq.) and KOH (73 mg, 1.30 mmol, 2.0 eq.) in DMF (6.5 mL) at rt. After stirring at rt for 3 h, the reaction mixture was quenched with sat Na2S2O3(aq) and extracted with EtOAc, dried over MgSO4, and evaporated in reduced pressure, to give the crude product. Purification with Yamazen automated chromatography with Hex:EtOAc = 9:1 as eluent to give 15 (169 mg, 83%) as a colourless solid, 1H NMR (300 MHz, CDCl3) delta 10.65 (1H, br s), 7.82 (1H, d, J = 3.0 Hz), 7.65 (1H, d, J = 9.0 Hz), 7.47 (1H, dd, J = 9.0, 0.5 Hz); MS (ESI) m/z 313 [(M + H)+], RT 4.46 min (condition B).
	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20.0??; for 3.0h;	Reference Example 17; 6-Trifluoromethyl-3-iodo-1H-indazolePotassium hydroxide (73 mg, manufactured by Wako Pure Chemical Industries, Ltd.) and iodine (330 mg, manufactured by Kanto Chemical Co., Inc.) were added to a solution of 6-(trifluoromethyl)-1H-indazole (121 mg) synthesized according to the literature (Shoji, et al., Tetrahedron Lett., 2004, 45, 1769-1772) in N,N-dimethylformamide (6.5 mL, manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred for 3 hours at room temperature. An aqueous solution of sodium thiosulfate (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3??20 mL), washed with brine (40 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 169 mg of the title compound. LC-MS: HPLC retention time 4.46 minutes, m/z 313 (M+H), condition B-1.

References: [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2408 - 2412.
[2]Patent: US2010/29733,2010,A1 .Location in patent: Page/Page column 39-40.
[3]European Journal of Medicinal Chemistry,2020,vol. 187.

2
[ 24424-99-5 ]
[ 1000341-27-4 ]
[ 1204772-93-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; triethylamine; In dichloromethane; at 20.0??; for 1.0h;	DMAP (33 mg, 0.271 mmol, 0.5 eq.) was added to a stirred solution of 15 (169 mg, 0.542 mmol, 1.0 eq.), Boc2O (237 mg, 1.08 mmol, 2.0 eq.) and Et3N (110 mg, 1.08 mmol, 2.0 eq.) in CH2Cl2 (5.4 mL) at rt. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with EtOAc, dried over MgSO4, and evaporated in reduced pressure, to give the crude product. Purification with Yamazen automated chromatography with Hex:EtOAc = 9:1 as eluent to give ethyl ester product 16 (231 mg, quant) as a colourless solid, 1H NMR (300 MHz, CDCl3) delta 8.50 (1H, s), 7.63 (1H, d, J = 1.5 Hz), 7.62 (1H, d, J = 1.5 Hz), 1.74 (9H, s); MS (ESI) m/z 413 [(M + H)+], RT 5.00 min (condition B).
	With dmap; triethylamine; In dichloromethane; at 20.0??; for 1.0h;	Reference Example 18; t-butyl 6-trifluoromethyl-3-iodo-1H-indazole-1-carboxylateTo a solution of the compound of Reference Example 17 (169 mg) in dichloromethane (5.4 mL, manufactured by Kanto Chemical Co., Inc.), dicarboxylic acid di-t-butyl ester (237 mg, manufactured by Wako Pure Chemical Industries, Ltd.), triethylamine (0.11 mL, manufactured by Wako Pure Chemical Industries, Ltd.) and dimethylaminopyridine (33 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) were added, and the mixture was stirred for one hour at room temperature. Water (20 mL) was added to the reaction solution, and the mixture was extracted with chloroform (3??20 mL), washed with brine (40 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3), to give 231 mg of the title compound. LC-MS: HPLC retention time 5.00 minutes, m/z 413 (M+H), condition B-1.
	With dmap; triethylamine; at 20.0??;	General procedure: 3-Iodo-1H-indazole (S1, 5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 mL). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-tert-butyl dicarbonate (5.4 mL, 24 mmol, 1.2 equiv). Triethylamine (5.4 mL, 39 mmol, 2.0 equiv) was slowly added to the clear, brown solution by syringe. The resulting solution was stirred at room temperature until it was complete as determined by TLC. The reaction was then diluted with water (75 mL) and ethyl acetate (50 mL). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 ?? 50 mL). The combined organic layers were washed with brine (100 mL), then shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. This material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2408 - 2412.
[2]Patent: US2010/29733,2010,A1 .Location in patent: Page/Page column 40.
[3]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1501 - 1507.
[4]European Journal of Medicinal Chemistry,2020,vol. 187.

3
[ 1000341-27-4 ]
C₁₇H₁₃F₃N₂O₂ [ No CAS ]

References: [1]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1501 - 1507.

4
[ 1000341-27-4 ]
[ 1204773-05-6 ]

References: [1]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1501 - 1507.

5
[ 1000341-27-4 ]
[ 151169-75-4 ]
(3-(3,4-dichlorophenyl)-6-(trifluoromethyl)-1H-indazole) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; In 1,4-dioxane; water; at 100.0??; for 16.0h;Inert atmosphere;	(1207) To the iodo compound 389 (30 mg, 0.16 mmol), in dioxanewater (31 ml), 3,4-dichloro phenyl boronic acid (37 mg, 0.19 mmol), sodium acetate (62 mg, 0.76 mmol) and PdCl2(dppf) (23 mg, 0.03 mmol) were added. Then the reaction mixture was heated to 100 C. for 16 h. Then reaction mixture was cooled and diluted with ethyl acetate. Organic layer was separated and washed with water, brine and dried. Crude residue was column chromatographed to yield 390 (3-(3,4-dichlorophenyl)-6-(trifluoromethyl)-1H-indazole) in 65% yield. 1H NMR (CDCl3): 10.41 (br s, 1H), 8.1 (m, 2H), 7.68-7.72 (m, 2H), 7.60 (m, 1H), 7.53 (d, 1H). Mass spectrum (ESI+): m/z=331 [M+1].

References: [1]Patent: US2016/168140,2016,A1 .Location in patent: Paragraph 1207.