858629-06-8|5-Fluoro-3-iodo-1H-indazole| Ambeed

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Quality Control of [ 858629-06-8 ] Purity: 97% SDS Specification

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Product Details of [ 858629-06-8 ]

CAS No. :	858629-06-8
Formula :	C₇H₄FIN₂
M.W :	262.02
SMILES Code :	FC2=CC=C1[NH]N=C(C1=C2)I
MDL No. :	MFCD06739145
InChI Key :	CZUPBTJBMHZBTJ-UHFFFAOYSA-N
Pubchem ID :	24728241

Safety of [ 858629-06-8 ]

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

Computational Chemistry of [ 858629-06-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	48.77
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	28.68 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.38
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	2.34
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.73
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.	2.73
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	3.42
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.52

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.54
Solubility	0.0748 mg/ml ; 0.000286 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.	-2.58
Solubility	0.687 mg/ml ; 0.00262 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	-4.14
Solubility	0.0189 mg/ml ; 0.0000719 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.	-6.24 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)	2.16

Application In Synthesis of [ 858629-06-8 ]

* 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 [ 858629-06-8 ]

[ 858629-06-8 ] Synthesis Path-Downstream 1~37

1
[ 24424-99-5 ]
[ 858629-06-8 ]
[ 944904-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine; at 20℃;	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]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434.
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6998 - 7003.
[3]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1501 - 1507.

2
[ 348-26-5 ]
[ 858629-06-8 ]

Yield	Reaction Conditions	Operation in experiment
96.1%	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	To a solution of 5-fluoro-1H-indazole (2.0 g, 14.0 mmol) in DIVIF (50 mL) was added ‘2 (7.46 g, 28.0 mmol) and KOH (2.4 g, 42 mmol), the mixture was stirred at room temperature for 0.5 hr. The reaction was monitored by TLC. After completion, the mixture was filtered, the filtrate was concentrated in vacuum to give a residue, which was purified by a silica gel column (PE/EA = 3/1) to afford 5-fluoro-3-iodo-1H-indazole (3.7 g, yield: 96.1%) as a white solid. ‘H NIVIR (400 IVIHz, DMSO-d6): ö = 13.64 (s, 1H), 7.63 (dd, J= 4.8, 4.4 Hz, 1H), 7.38-7.30 (m, 1H), 7.20 (dd, J=6.4,2.4Hz, 1H).
95.1%	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 1h;	5-Fluoro-1H-indazole (10.00 g, 73.46 mmol) was added into N,N-dimethylformamide(80 mL), then Iodine (28.0 g, 110 mmol) and potassium hydroxide (6.20 g, 110 mmol) wereadded. After addition, the mixture was reacted for 1 hour at room temperature. The reactionmixture was poured into aqueous sodium thiosulfate solution (300 mL, 5%). The resultingmixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers werewashed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated on a rotary evaporator to give a light yellow solid(18.3 g, 95.1 %)
87%	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole (3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol)in DMF (7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 × 30 mL). The solid was left to dry at 30 C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100%; m.p.: 136-138 C (lit.:[36] 134-136 C); IR (KBr) ν (cm-1): 3086 (NH); 424 (C-I). 1H-NMR δ (ppm): 13.50 (1H, s, H-1); 7.55(1H, d, J = 8.6 Hz, H-7); 7.45-7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). 13C-NMR δ(ppm): 140.41; 127.22; 126.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C7H5IN2: 243.9497,Found: 243.9499.3-Iodo-1H-indazole (1a). 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole(3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol) in DMF(7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 30 mL). The solid was left to dry at 30 C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100%; m.p.: 136-138 C (lit.: [36] 134-136 C)

References: [1]Patent: WO2018/132372,2018,A1 .Location in patent: Paragraph 01229.
[2]Patent: WO2018/188590,2018,A1 .Location in patent: Paragraph 00437.
[3]Synthesis,2011,p. 3089 - 3098.
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434.
[5]Molecules,2018,vol. 23.
[6]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6998 - 7003.

3
[ 67-56-1 ]
[ 201230-82-2 ]
[ 858629-06-8 ]
[ 78155-73-4 ]

References: [1]Synthesis,2011,p. 3089 - 3098.

4
[ 110-68-9 ]
[ 201230-82-2 ]
[ 858629-06-8 ]
[ 1352415-07-6 ]

References: [1]Synthesis,2011,p. 3089 - 3098.

Yield	Reaction Conditions	Operation in experiment
	With iodine; sodium hydroxide; In methanol; at 20℃; for 48h;	General procedure: 3-lodo-1H-indazole Iodine (5.8 g, 22.9 mmol) was added in portions over approximately 20 min to a solution of indazole (2.5 g, 21.7 mmol) in methanol (63 ml) and 2N sodium hydroxide solution (65 ml). The mixture remained colourless and a white precipitate slowly formed. The mixture was stirred at room temperature 48 h. The mixture was cooled in an ice-bath and 7.5 ml of concentrated hydrochloric acid was slowly added. The mixture was further acidified with 2N hydrochloric acid. 20% w/v Sodium thiosulfate pentahydrate solution was added until the iodine colour disappeared. The precipitate was filtered, washed with water and dried in the oven at 50 ºC to constant weight. The solid was taken up in methanol, filtered and the filtrated was evaporated under reduced pressure to give 5.0 g (20.6 mmol, 95%) of the title compound as a white solid. Purity 100%.1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.43-7.59 (m, 3H), 7.21-7.26 (m, 1H).UPLC/MS (3 min) retention time 1.56 min.LRMS: m/z 245 (M+1).
	With iodine; sodium hydroxide; In methanol; at 20℃; for 48h;	General procedure: Iodine (5.8 g, 22.9 mmol) was added in portions over approximately 20 min to a solution of indazole (2.5 g, 21 .7 mmol) in methanol (63 ml) and 2N sodium hydroxide solution (65 ml). The mixture remained colourless and a white precipitate slowly formed. The mixture was stirred at room temperature 48 h. The mixture was cooled in an ice-bath and 7.5 ml of concentrated hydrochloric acid was slowly added. The mixture was further acidified with 2N hydrochloric acid. 20% w/v Sodium thiosulfate pentahydrate solution was added until the iodine colour disappeared. The precipitate was filtered, washed with water and dried in the oven at 50 C to constant weight. The solid was taken up in methanol, filtered and the filtrated was evaporated under reduced pressure to give 5.0 g (20.6 mmol, 95%) of the title compound as a white solid. Purity 100%. 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.43-7.59 (m, 3H), 7.21 -7.26 (m, 1 H). UPLC/MS (3 min) retention time 1 .56 min. LRMS: m/z 245 (M+1 ).

6
[ 858629-06-8 ]
C₁₆H₁₃FN₂O₂ [ No CAS ]

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

7
[ 858629-06-8 ]
[ 57614-63-8 ]

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

8
[ 353-83-3 ]
[ 858629-06-8 ]
[ 1613515-95-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate; In acetonitrile;Reflux;	General procedure: Potassium carbonate (791 mg, 5.7 mmol) was added to a solution of 3-iodoindazole (700 mg, 2.9 mmol) and 2-chloroethyl methyl ether (406 mg, 4.3 mmol) in ACN (20 mL) at rt. The reaction was heated to reflux overnight, and then was filtered and concentrated. The residue was purified by silica gel chromatography (15%-50% EtOAc/hexanes) to give 530 mg (63%) of the title compound as a light yellow oil. The title compound was prepared in 46% yield from 5-fluoro-3-iodo-indazole and 1,1,1-trifluoro-2-iodoethane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 4.91-4.97 (2H, m), 7.17 (1H, dd, J=2.0, 8.0 Hz), 7.30 (1H, td, J=2.0, 8.4 Hz), 7.38 (1H, dd, J=3.6, 9.2 Hz).

References: [1]Patent: US2014/171432,2014,A1 .Location in patent: Paragraph 0234; 0323; 0324.

9
[ 858629-06-8 ]
[ 100-39-0 ]
[ 1613515-96-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In acetonitrile;Reflux;	General procedure: Potassium carbonate (791 mg, 5.7 mmol) was added to a solution of 3-iodoindazole (700 mg, 2.9 mmol) and 2-chloroethyl methyl ether (406 mg, 4.3 mmol) in ACN (20 mL) at rt. The reaction was heated to reflux overnight, and then was filtered and concentrated. The residue was purified by silica gel chromatography (15%-50% EtOAc/hexanes) to give 530 mg (63%) of the title compound as a light yellow oil. The title compound was prepared in 75% yield from 5-fluoro-3-iodo-indazole and benzyl bromide according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 5.59 (2H, s), 7.11-7.21 (5H, m), 7.23-7.31 (3H, m).

References: [1]Patent: US2014/171432,2014,A1 .Location in patent: Paragraph 0234; 0327; 0328.

10
[ 3814-30-0 ]
[ 858629-06-8 ]
[ 1613516-08-7 ]
[ 1613516-09-8 ]

Yield	Reaction Conditions	Operation in experiment
72%; 18%	With potassium carbonate; In acetonitrile;Reflux;	General procedure: Potassium carbonate (791 mg, 5.7 mmol) was added to a solution of 3-iodoindazole (700 mg, 2.9 mmol) and 2-chloroethyl methyl ether (406 mg, 4.3 mmol) in ACN (20 mL) at rt. The reaction was heated to reflux overnight, and then was filtered and concentrated. The residue was purified by silica gel chromatography (15%-50% EtOAc/hexanes) to give 530 mg (63%) of the title compound as a light yellow oil. The title compounds were prepared from 5-fluoro-3-iodo-indazole and (bromomethyl)cyclopentane according to the procedure for Preparation 10A. [0365] 1-(cyclopentylmethyl)-<strong>[858629-06-8]5-fluoro-3-iodo-1H-indazole</strong> (72%) was isolated as the major isomer eluting first. 1H NMR (400 MHz, CDCl3): δ 1.25-1.32 (2H, m), 1.50-1.65 (6H, m), 2.48-2.56 (1H, m), 4.27 (2H, d, J=7.5 Hz), 7.09 (1H, dd, J=8.3, 2.3 Hz), 7.18 (1H, td, J=8.9, 2.4 Hz), 7.32 (1H, dd, J=9.1, 4.0 Hz). [M+H] calc'd for C13H14FIN2, 345. found 345. [0366] 2-(cyclopentylmethyl)-5-fluoro-3-iodo-2H-indazole (18%) was isolated as the minor isomer eluting second. 1H NMR (400 MHz, CDCl3): δ 1.33-1.42 (2H, m), 1.56-1.73 (6H, m), 2.62-2.70 (1H, m), 4.41 (2H, d, J=7.6 Hz), 7.00 (1H, dd, J=8.8, 2.4 Hz), 7.09 (1H, td, J=9.2, 2.4 Hz), 7.65 (1H, dd, J=9.3, 4.5 Hz). [M+H] calc'd for C13H14FIN2, 345. found 345.

References: [1]Patent: US2014/171432,2014,A1 .Location in patent: Paragraph 0234; 0363; 0364; 0365; 0366.

11
[ 858629-06-8 ]
[ 107-06-2 ]
[ 1613516-88-3 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate; In acetonitrile;Reflux;	To a solution of 5-fluoro-3-iodo-indazole (3.0 g, 11.5 mmol) and 1,2-dichloroethane (5.7 g, 57.3 mmol) in ACN (50 mL) was added K2CO3 (3.2 g, 22.9 mmol) at rt. The reaction was stirred overnight at reflux. The reaction mixture was filtered and concentrated in vacuo. Purification by silica gel chromatography (30:1:5 hexanes/EtOAc/DCM) gave 2.5 g (67%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 3.97 (2H, t, J=6.0 Hz), 4.69 (2H, t, J=6.0 Hz), 7.13 (1H, dd, J=1.8, 7.8 Hz), 7.22-7.29 (1H, m), 7.42 (1H, dd, J=3.9, 9.3 Hz).

References: [1]Patent: US2014/171432,2014,A1 .Location in patent: Paragraph 0609; 0610.

12
[ 858629-06-8 ]
[ 1613515-93-7 ]