1079991-68-6|4-Fluoro-2-methyl-3-nitrobenzoic acid| Ambeed

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Quality Control of [ 1079991-68-6 ] Purity: 98% SDS Specification

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Product Details of [ 1079991-68-6 ]

CAS No. :	1079991-68-6
Formula :	C₈H₆FNO₄
M.W :	199.14
SMILES Code :	O=C(O)C1=CC=C(F)C([N+]([O-])=O)=C1C
MDL No. :	MFCD28797610
InChI Key :	MLCPINGKKONVKT-UHFFFAOYSA-N
Pubchem ID :	53430695

Safety of [ 1079991-68-6 ]

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

Computational Chemistry of [ 1079991-68-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	47.15
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	83.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.96
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	1.74
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.16
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.	1.27
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	-0.02
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.36
Solubility	0.877 mg/ml ; 0.00441 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.	-3.1
Solubility	0.157 mg/ml ; 0.00079 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	-1.82
Solubility	2.99 mg/ml ; 0.015 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	No
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.	-6.28 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	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)	1.92

Application In Synthesis of [ 1079991-68-6 ]

* 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 [ 1079991-68-6 ]

[ 1079991-68-6 ] Synthesis Path-Downstream 1~11

1
[ 321-21-1 ]
[ 1079991-68-6 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; at 0 - 10℃;	Reference Example 75 methyl 3-amino-4-fluoro-2-methylbenzoate To fuming nitric acid (20.3 mL, 409 mmol) was slowly added dropwise 4-fluoro-2-methylbenzoic acid (4.50 g, 29.2 mmol) while maintaining the temperature of the reaction mixture at 5-10C. The reaction solution was stirred at 0-5C for 1 hr, and poured into ice. The precipitated solid was recovered, washed with water, and dried under reduced pressure to give 4-fluoro-2-methyl-3-nitrobenzoic acid (5.70 g, purity 25%) as a crudely purified product. 1H-NMR (CDCl3) delta: 2.63 (3H, s), 7.22 (1H, m), 8.23 (1H, dd, J = 8.8, 5.2 Hz), hidden (1H).
	With nitric acid; at 10℃;	Compound 301-A1 (4-fluoro-2-methylbenzoic acid, CAS number 321-21-1, 100 g, 649 mmol) was added to660 mL of fuming HNO3, dropwise to keep the temperature below 10C. The mixture was stirred for 1?2 hours. Themixture was poured into ice-water (2.4L) and stirred for 30 minutes. The result solid was filtered and washed with coldwater and then dissolved in 1.5 L of EtOAc. The EtOAc phase was washed with water and brine, dried over Na2SO4,and then filtered. The Na2SO4 solid was washed with EtOAc (200mL3). The combined EtOAc phase was concentratedto give crude product 301-A2 which was directly used in next step without purification.

References: [1]Patent: EP2141150,2010,A1 .Location in patent: Page/Page column 84.
[2]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0159; 0165-0166.

2
[ 67-56-1 ]
[ 1079991-68-6 ]
[ 1079991-69-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; for 12.0h;Reflux;	A solution of the obtained crudely purified product (5.70 g, purity 25%) of <strong>[1079991-68-6]4-fluoro-2-methyl-3-nitrobenzoic acid</strong> and sulfuric acid (1.00 mL, 18.8 mmol) in methanol (100 mL) was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous sodium hydroxide solution (10%), water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 4-fluoro-2-methyl-3-nitrobenzoate (6.01 g, purity 25%) as a crudely purified product. Recrystallization from ether gave methyl 4-fluoro-2-methyl-3-nitrobenzoate (3.01 g, purity 50%) as a crudely purified product. 1H-NMR (CDCl3) delta: 2.57 (3H, s), 3.88 (3H, s) 7.04 (1H, d, J = 8.0 Hz), 8.06 (1H, dd, J = 8.4, 3.2 Hz).
20 g	With sulfuric acid; under 760.051 Torr;Reflux;	To a solution of 301-A2 (110 g, 502 mmol) in 1.5 L of methanol was added 20 mL of conc. H2SO4. The mixturewas heated to reflux for overnight. The mixture was cooled to room temperature, then concentrated to about 100 mLand then diluted with 500 mL of cold water. The mixture was extracted with EtOAc (500 mL3). The combined organicphase was washed with sat.NaHCO3, water and brine, dried over Na2SO4, filtered and washed with EtOAc, the EtOAcphase was concentrated to dry to give crude product. The crude was recrystallized from PE/EtOAc (10:1, 400 mL) toremoved most major by-products, the residue was purified by column chromatography on slica gel (PE/ EtOAc: 100:1)to give product 301-A (methyl 4-fluoro-2-methyl-3-nitrobenzoate, 20 g, two steps yield: 19%).1H NMR (DMSO-d6, 300 MHz): 8.08 (dd, J = 5.7, 9.0 Hz, 1H), 7.58 (t, J = 9.0 Hz, 1H), , 3.85 (s, 3H), delta 2.45 (s, 3H)

References: [1]Patent: EP2141150,2010,A1 .Location in patent: Page/Page column 84.
[2]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0103; 0159; 0165; 0167.

3
[ 321-21-1 ]
[ 64695-92-7 ]
[ 1079991-68-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sulfuric acid; potassium nitrate; at 0 - 20℃; for 6.0h;Inert atmosphere;	[000146] To a stirred solution of 4-fluoro-2-methylbenzoic acid 83 (500 mg, 3.24 mmol) in concentrated sulfuric acid (2.5 mL) under inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol) at 0 C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), filtered the precipitated solid and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 84 (300 mg, 60%) as brown syrup. TLC: 10% MeOH/ CH2C12 (R 0.3); 1H-NMR (DMSO-d6, 500 MHz): oe 13.56 (br s, 1H), 8.52 (d, J= 8.0 Hz, 1H), 7.61 (d, J 12.5 Hz, 1H), 2.63 (s, 3H).
	With nitric acid; acetic acid; at 80℃; for 6.0h;Inert atmosphere;	To a stirred solution of 4-fluoro-2-methylbenzoic acid 16 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered anddried in vacuo to afford mixture of compounds 17 and 18 (5.3 g, 40%) as white solid. TLC: 70%EtOAc/ hexanes(R 0.4); ?H NMR (DMSO-d6, 400 MHz): oe 13.30 (br s, 2H), 8.52 (d, J = 8.0Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J= 9.3 Hz, 1H), 2.63(s, 6H), 2.48 (s, 3H); (?H NMR showed mixture of compounds 17 & 18 in the ratio of 2: 1).

References: [1]Patent: WO2015/138895,2015,A1 .Location in patent: Paragraph 000146.
[2]Patent: WO2018/53157,2018,A1 .Location in patent: Page/Page column 146.

4
[ 1079991-69-7 ]
[ 1079991-68-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; sodium hydroxide; In methanol; at 25℃;	A solution of compound 301-A (methyl 4-fluoro-2-methyl-3-nitrobenzoate, 3.0 g, 14.1 mmol), NaOH (1.6 g, 42.3mmol) in H2O/MeOH (30 mL/30 mL) was stirred at 25 C for overnight. Then the mixture was adjusted pH = 5, extractedby EtOAc (100 mL x 3), washed by brine (100 mL x 2), dried, filtered and concentrated to give compound 301-C (4-fluoro-2-methyl-3-nitrobenzoic acid, 2.8 g, yield: 100%) as a white solid.1H NMR (300 MHz, DMSO-d6) delta 8.06-8.11 (m, 1H), 8.18 (t, J = 9.0 Hz, 1H), 2.47 (s, 3H).

References: [1]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0159-0160.

5
[ 1079991-68-6 ]
4-fluoro-3-nitrophthalic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium permanganate; sodium hydroxide; In water; at 85℃; for 3.0h;	To a solution of 301-C (2.8 g, 14.1 mmol), NaOH (1.6 g, 42 mmol) in H2O (30 mL) was added KMnO4 (17.7 g,112 mmol) portion-wise during 3 hours at 85 C and then the mixture was stirred for 3 hours at 85 C. Then the mixturewas filtered and the cake was washed with H2O (50 mL x 3). The filtrate was adjusted pH = 1, extracted by EtOAc (100mL x 3), washed by brine (100 mL x 2), dried, filtered and concentrated to give 301-E (4-fluoro-3-nitrophthalic acid, 900mg, yield: 28%) as a white solid.1H NMR (300 MHz, DMSO-d6) delta 8.12-8.17 (m, 1H), 7.75-7.81 (m, 1H).

References: [1]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0159; 0161.

6
[ 1079991-68-6 ]
3-amino-4-fluorophthalic acid [ No CAS ]