1077-96-9|5-Fluoro-1H-indazole-3-carboxylic acid| Ambeed

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Quality Control of [ 1077-96-9 ] Purity: 98% SDS Specification

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Product Details of [ 1077-96-9 ]

CAS No. :	1077-96-9
Formula :	C₈H₅FN₂O₂
M.W :	180.14
SMILES Code :	FC2=CC=C1[NH]N=C(C1=C2)C(=O)O
MDL No. :	MFCD03840628
InChI Key :	XFHIMKNXBUKQNS-UHFFFAOYSA-N
Pubchem ID :	14999052

Safety of [ 1077-96-9 ]

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

Computational Chemistry of [ 1077-96-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	43.01
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	65.98 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.6
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	1.51
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.82
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.	1.15
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	1.78
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.37

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.35
Solubility	0.796 mg/ml ; 0.00442 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.	-2.5
Solubility	0.565 mg/ml ; 0.00314 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	-2.56
Solubility	0.493 mg/ml ; 0.00274 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	No
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.	-6.33 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.	0.56

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	0.0 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)	1.6

Application In Synthesis of [ 1077-96-9 ]

* 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 [ 1077-96-9 ]

[ 1077-96-9 ] Synthesis Path-Downstream 1~27

1
[ 1077-96-9 ]
[ 129295-49-4 ]
5-Fluoro-1H-indazole-3-carboxylic acid (1-benzyl-4-methyl-[1,4]diazepan-6-yl)-amide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 1912 - 1930.

3
[ 67-56-1 ]
[ 1077-96-9 ]
[ 78155-73-4 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sulfuric acid; for 3h;Reflux;	A solution of the above solid (1.62 g) in methanol (30 mL) was added with concentrated sulfuric acid (4 mL), and the mixture was refluxed for 3 hours by heating. The reaction mixture was cooled to room temperature, and then poured into water (90 mL), and the precipitated solid was collected by filtration and washed with water to obtain methyl 5-fluoro-1H-indazole-3-carboxylate (1.35 g, 57%). 1H NMR (300 MHz, DMSO-d6) delta 3.92 (s, 3H), 7.37 (ddd, J = 2.2, 8.8, 9.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 14.08 (br s, 1H).

References: [1]European Journal of Organic Chemistry,2007,p. 4909 - 4916.
[2]Patent: EP2565192,2013,A1 .Location in patent: Paragraph 0350.
[3]Physical Chemistry Chemical Physics,2009,vol. 11,p. 341 - 348.

4
[ 443-69-6 ]
[ 1077-96-9 ]

Yield	Reaction Conditions	Operation in experiment
51%		To a solution of NaOH (1.24 g, 0.031 mol, 1.03 equiv.) in water (19 mL) heated at 50CC was added 5-Fluoroisatin (5 g, 0.03 mol, 1 equiv.). After 5 minutes, the dark- red solution was cooled to 0C and a cooled solution of sodium nitrite (2.07 g, 0.03 mol, I equiv.) in water (10 mL) was added slowly, followed by a cooled solution of (95%) (3.12 mL, 0.06 mol , 1.95 equiv.) in water (48 mL). The rate of addition was rapid such that the temperature never rose above 4C. To reduce the foaming which occurred throughout the period of stirring, a few millilitres of ether were added when necessary. After the end of addition, the cooled solution was stirred for one hour, maintaining the temperature below 4 C at all times. Then a cooled solution of SnC 1 (16.24 g, 0.072 mol, 2.4 equiv.) in HCl (35%) (24 mL) was added and the mixture was stirred for 16 h. The brown solution was filtrated and the resultion brown solid was washed with water to give a light brown solid (2.73 g, 51%); deltaEta (MeOH-£/6) 7.25 (1H, td, J 9.10 Hz and J2.14 Hz, ArH), 7.60 (1H, dd J 9.10 Hz and 4.28 Hz, ArH), 7.74 (1H, dd J 9.10 Hz and 2.10 Hz, ArH); LC-MS-EI 183.1 (MH+, 100)
		A solution of the substituted aniline (565 mL) in 6N hydrochloric acid (106 mL) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol (678 mL) and sodium sulfate (3.15 mol) in water (1.4 L) and the reaction mixture was stirred vigorously for 1 h. A solution of hydroxylamine hydrochloride (2.08 mol) in water (650 mL) was added in one portion and the reaction mixture was heated at 80 C. for 1.5 h. The reaction mixture was cooled to 10 C. and the precipitated solids were collected by filtration, washed with water, and dried to provide the amide in 91% yield. The amide was added to sulfuric acid (1.9L) and the reaction mixture was heated at 60 C. for 6 h. The reaction mixture was allowed to cool to room temperature and was cautiously poured onto ice (7 kg). The precipitated solids were collected by filtration, washed with water, and dried to provide the isatin in 61% yield. The conversion of the substituted isatins to the corresponding indazole-3-carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H. R., et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 C. for 30 min. The burgundy solution was allowed to cool to rt and was maintained for 1 h. The reaction mixture was cooled to 0 C. and was treated with a 0 C. solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0 C.) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the reaction mixture was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. This material was of sufficient purity (1H NMR and LC/MS) to use in the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to provide pure material.
		Example 66; 5-Ethyl-2-(5-fluoro-1H-indazol-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one; In an analogous manner as described for example 3, 5-ethyl-2-(5-fluoro-1H-indazol-3-yl)-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one was prepared from 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (see part A, starting materials) and 5-fluoro-1H-indazole-3-carboxylic acid (prepared from 5-fluoroisatin according to WO03/035065, reference example 26 and J. Am. Chem. Soc. 1952 (74), 2009-2012). MS: M=364.3 (ESI+) 1H-NMR (400 MHz, DMSO): delta (ppm)=1.21 (t, 3H), 1.33(s, 6H), 3.78 (bq, 2H), 7.03 and 7.39 (s, 1H), 7.39 (m, 1H), 7.44 and 7.74 (s, 1H), 7.70 (m, 1H), 8.13 (m, 1H), 12.97 and 13.03 (s, 1H), 13.69 (s, 1H)

1.62 g		(a) Step 1 The synthesis was performed with reference to the known literature (). Aqueous sodium hydroxide (0.500 g, 12.5 mmol, 11 mL) was heated to 50C, and added with 5-fluoroisatin (2.00 g, 12.1 mmol). The reaction mixture was stirred at 50C for 1 hour, and then cooled on ice. Aqueous sodium nitrite (0.835 g, 12.1 mmol, 4 mL) was cooled on ice, and then added dropwise to the reaction mixture. Then, the mixture was added dropwise with concentrated sulfuric acid (2.31 g, 23.6 mmol) in ice-cooled water (19 mL), and the mixture was stirred for 1 hour under ice cooling. Then, the reaction mixture was added dropwise with an ice-cooled solution of tin(II) chloride dihydrate (6.54 g, 29.0 mmol) in concentrated hydrochloric acid (9.7 mL). The reaction mixture was stirred overnight at room temperature, and then filtered, and the resulting solid was washed with water to obtain a pale brown solid (1.62 g).
		Example 33; 4-([1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoic acid; The title compound was prepared as illustrated in scheme 3 and 5.Step 1. A solution of 5-fluoro-isatin (10.0 g, 60.6 mmol) in 1N NaOH (61 mL) was stirred at 60 C. for 20 min. The solution was cooled to 3 C. and a solution of sodium nitrite (4.59 g, 66.6 mmol) in water (20 mL) was added, and the mixture stirred for 20 min. The resulting solution was added dropwise to a cooled solution of concentrated sulfuric acid (3.64 ml, 67.9 mmol) in water (130 mL) so that the temperature remained between 0 and 4 C. The mixture was stirred at 0-5 C. for 2 h, then added portionwise to a solution of SnCl2 (22.0 g, 116 mmol) in concentrated HCl (46 mL). The mixture was left for 5 hours, upon which crystallization took place. The crystals were filtered off, washing with water, to yield 5-fluoro-1H-indazole-3-carboxylic acid as a white solid (9.76 g). The raw material was then dissolved in tetrahydrofuran (100 mL) and treated with carbonyldiimidazole (CDI, 9.82 g, 60.6 mmol). The mixture was warmed to reflux and stirred for 2 hours. EtOH (100 mL) was then added, and the mixture stirred at reflux for further 5 hours. The volatiles were evaporated and the residue redissolved in warm ethyl acetate. The organic solution was washed with 1N HCl, and then with water, dried with sodium sulphate and evaporated. The raw material was purified by flash chromatography (heptane/ethyl acetate 1:1, followed by a second chromatography with dichloromethane/diethyl ether 9:1) to yield 5-fluoro-1H-indazole-3-carboxylic acid ethyl ester as an off-white solid, 6.22 g (49.3%).

References: [1]Patent: WO2011/61469,2011,A1 .Location in patent: Page/Page column 34-35.
[2]Patent: US2005/250808,2005,A1 .Location in patent: Page/Page column 39.
[3]Patent: US2006/142247,2006,A1 .Location in patent: Page/Page column 39.
[4]Patent: EP2565192,2013,A1 .Location in patent: Paragraph 0349.
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 6259 - 6272.
[6]Patent: US2008/103182,2008,A1 .Location in patent: Page/Page column 18.

5
[ 1903-91-9 ]
[ 1077-96-9 ]
C₁₁H₁₁FN₄O₂ [ No CAS ]

References: [1]Journal of Organic Chemistry,2011,vol. 76,p. 1177 - 1179.

6
[ 1077-96-9 ]
[ 1263816-14-3 ]

References: [1]Journal of Organic Chemistry,2011,vol. 76,p. 1177 - 1179.

7
[ 479079-15-7 ]
[ 1077-96-9 ]
[ 1309446-90-9 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a round bottomed flask was added 5-Fluoro-lH-indazole-3-carboxylic acid from Production Example 4 (2.73 g, 0.015 mol, 1 equiv.) in DMF (40 mL) under nitrogen. Carbodiimidazole (CDI) (2.98 g, 0.018 mol, 1.1 equiv.) was added to the resulting yellow solution and this was stirred at room temperature for 30 minutes. N-(tert- butoxycarbonyl)-2-aminoacetarnidoxime (3.46 g, 0.018 mol, 1.1 equiv.) in DMF (20 mL) was then added and the solution was stirred overnight at room temperature. The solvent was removed in vacuo on a high vacuum pump, and the crude solid was dissolved in dichloromethane. The resulting precipitate was filtered off and dried in in vacuo to give a light brown powder (4.04 g, 75%); LC-MS-EI 352.4(MH+, 100).

References: [1]Patent: WO2011/61469,2011,A1 .Location in patent: Page/Page column 35.

8
[ 1077-96-9 ]
[ 1309060-93-2 ]

References: [1]Patent: WO2011/61469,2011,A1 .

9
[ 1077-96-9 ]
[ 1309060-64-7 ]

References: [1]Patent: WO2011/61469,2011,A1 .

10
[ 1077-96-9 ]
[ 1309060-65-8 ]

References: [1]Patent: WO2011/61469,2011,A1 .

11
[ 1077-96-9 ]
[ 1309060-66-9 ]

References: [1]Patent: WO2011/61469,2011,A1 .

12
[ 1077-96-9 ]
C₂₁H₁₉FN₄O₃*(x)ClH [ No CAS ]