446-18-4|4-Fluoro-2-methyl-5-nitroaniline| Ambeed

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Quality Control of [ 446-18-4 ] Purity: 97% SDS Specification

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Product Details of [ 446-18-4 ]

CAS No. :	446-18-4
Formula :	C₇H₇FN₂O₂
M.W :	170.14
SMILES Code :	NC1=CC([N+]([O-])=O)=C(F)C=C1C
MDL No. :	MFCD18824947

Safety of [ 446-18-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 446-18-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	44.59
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	71.84 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.2
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	1.53
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.05
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.	1.05
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	-0.16
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.13

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.16
Solubility	1.17 mg/ml ; 0.00687 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.	-2.65
Solubility	0.383 mg/ml ; 0.00225 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	-2.08
Solubility	1.42 mg/ml ; 0.00832 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.	-6.25 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.	0.55

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	3.0 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)	1.91

Application In Synthesis of [ 446-18-4 ]

* 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 [ 446-18-4 ]

[ 446-18-4 ] Synthesis Path-Downstream 1~35

1
[ 452-71-1 ]
[ 446-18-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sulfuric acid; nitric acid; at -5 - 0℃; for 2h;	Preparation of 1-fluoro-4-isothiocyanato-5-methyl-2-nitro-benzene IV-a Fuming nitric acid (3.35 mL, 84 mmol) in concentrated sulfuric acid (10 mL) was added dropwise to a -5C cooled solution of 4-fluoro-2-methyl-phenylamine (10.5 g, 84 mmol) in 90 mL of concentrated sulfuric acid. The reaction mixture was stirred at 0C for 2h and cold water added (300 mL). Then, a cold solution of NaOH (10 N) was slowly added until pH=10 and the resultant precipitate was filtered off to give intermediate IV-e as yellow solid (12.7 g, 89%). H NMR (400 MHz, DMSO-d6) delta 7.30 (d, J = 6.8 Hz, 1 H), 7.17 (d, J = 12.3 Hz, 1 H), 5.39 (s, 2H), 2.14 (s, 3H).
81.9%	With sulfuric acid; potassium nitrate; In sulfuric acid; at 0 - 20℃; for 1h;	Step-1: Preparation of 4-fluoro-2-methyl-5-nitroaniline A solution of 4-fluoro-2-methylaniline (12g, 96mmol) in Con.H2S04 (110ml) was cooled to 0C and added KNO3 (10.6g, 105.6mmol) and stirred at room temperature for lh. The reaction mass was diluted by water and basified with 20% NaOH. The compound was extracted with ethyl acetate, dried over Na2S04 and concentrated to obtain the title compound (15g, 81.9 %.) 1HNMR (CDCI3, 300MHz): delta 7.61 (d, 1H), 7.34 (d, 1H), 2.24 (s, 3H).
74%	With nitric acid; In sulfuric acid; at -10℃; for 0.166667h;	Concentrated nitric acid (17 g, 0.18 mol) was added dropwise to a stirred solution of 4-fluoro-2-methylanilme (20 g, 0.16 mol) in cone H2SO4 (300 mL) at -10 0C. The mixture was stirred at -10 0C for 10 min., and the reaction mixture was poured into ice water. The <n="93"/>resultant solid was collected by Filtration and partitioned between EtOAc and aq Na2COs solution (pH 8). The organic solution was washed with brine, dried (MgSO4) and concentrated to give 4-fluoro-2-methyl-5-nitroaniline (20 g, 74 % yield). 1H NMR (400 MHz, DMSO-J5): delta 121 (d, J= 6.8 Hz, 1 H), 7.14 (d, J= 12.4 Hz, 1 H), 5.37 (s, 2 H), 2.10 (s, 3 H).

50%	With nitric acid; In sulfuric acid;	Step 1 2-amino-5-fluoro-4-nitrotoluene 1.3 g (10 mmol) of 4-fluoro-2-methylaniline were introduced into 10 ml of concentrated sulfuric acid and cooled to -10 C. A cold solution of 0.4 ml (10 mmol) of fuming nitric acid in 2 ml of concentrated sulfuric acid was added slowly dropwise. The resulting mixture was stirred for 3 hours at 0 C. and subsequently poured into ice. The precipitated product was filtered with suction and washed. 0.85 g (50% of the theoretical yield) of product was obtained. The yellow crystalline product had a melting point of 178 C. 1 H-NMR(D6 -DMSO): delta=2.24 (s; 3H, --CH3) 5.78 (br. s; 2H, --NH2 exchange with D2 O) 7.28 (d, J=12 Hz; 1H, 6-H) 7.57 (d, J=6.8 Hz; 1H, 3-H) MS (70ev): m/e=170(M+.)
	With sulfuric acid; guanidine nitrate; at 0 - 20℃; for 0.5h;	[445] 4-fluoro-2-methylaniline (1 g, 8 mmol) was added to concentrated sulfuric acid (15 mL) at 00 C, followed by the addition of guanidine nitrate (1 g, 8 mmol). The mixture was then warmed to rt and stirred for 30 mm. Subsequently, the mixture was poured onto ice and neutralized with aqueous sodium hydroxide (4N) until the pH was 9. The mixture was then diluted with EtOAc and water, the organic phase was isolated, and the aqueous phase was extracted with additional EtOAc (2x). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give 4- fluoro-2-methyl-5-nitroaniline (Al) as an orange solid.

References: [1]Patent: WO2014/202763,2014,A1 .Location in patent: Page/Page column 51.
[2]Patent: WO2015/193846,A1 .Location in patent: Page/Page column 57; 58.
Patent: ,2015, .Location in patent: Page/Page column 57; 58.
[3]Patent: WO2008/33999,2008,A2 .Location in patent: Page/Page column 91-92.
[4]Patent: US5645610,1997,A .
[5],1952,vol. <3> 3,p. 6.
Chem.Abstr.,1955,p. 203.
[6]Patent: WO2015/175632,2015,A1 .Location in patent: Paragraph 445.

2
[ 446-18-4 ]
[ 108-24-7 ]
[ 13429-10-2 ]

References: [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356.

3
4-Fluoro-2-methyl-phenylamine; compound with sulfuric acid [ No CAS ]
[ 446-18-4 ]

References: [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356.

5
[ 686759-47-7 ]
[ 446-18-4 ]
[ 1011463-88-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	With N-ethyl-N,N-diisopropylamine; sodium iodide; In acetonitrile; at 60℃;	To a solution of 5-(chloromethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (11.5 g) and Example Dl (9.6 g, 56 mmol) in anhydrous CH3CN (160 mL) was added NaI (1.7 g, 11 mmol) and diisopropylethylamine (14.6 g, 112 mmol), then the mixture was stirred at 60 0C overnight. After removing the solvent, the residue was purified by column chromatography to give 5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methyl -2-(methylthio)pyrimidin-4- amine (7 g, 37 % yield). .H NMR (400 MHz, DMSO-J6): USD 7.83 (s, 1 H), 7.22 (d, J = 12 Hz, 1 H), 7.08 (m, 1 H), 6.98 (d, J = 8 Hz, 1 H), 5.79 (s, 1 H), 4.09 (d, J= 8 Hz, 2 H), 2.85 (d, J = 4 Hz, 3 H), 2.37 (s, 3 H), 2.17 (s, 3 H); MS (ESI) m/z: 337.9 [M + H]+.

References: [1]Patent: WO2008/33999,2008,A2 .Location in patent: Page/Page column 68.

6
[ 1011464-04-2 ]
[ 446-18-4 ]
[ 1011464-05-3 ]

Yield	Reaction Conditions	Operation in experiment
71.6%	In pyridine; at 50℃; for 8h;	A mixture of 5-(chloromethyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4- diamine (2.7 g, 11.1 mmol) and Example Dl (1.9 g, 11.1 mol) in pyridine (60 mL) was stirred at 50 0C for 8 h. The pyridine was removed under reduced pressure and the residue was purified by slica gel chromatography to give 5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N4- isopropyl-N2-methoxy-N2-niethylpyridine-254-diamine (3.0 g, 71.6% yield). 1H NMR (400 MHz, DMSO-ffc): delta 7.84 (s, 1 H), 7.32 (d, J= 12.4 Hz, 1 H), 7.16 (d, J= 6.4 Hz, 1 H), 6.22 (s, 1 H), 6.00 (t, J= 5.2 Hz, 2 H), 4.28 (d, J- 5.2 Hz, 2 H), 3.82 (m, 1 H), 3.72 (s, 3 H), 3.17 (s, 3 H), 2.27 (s, 3 H), 1.27 (d, J= 6.4 Hz, 6 H).

References: [1]Patent: WO2008/33999,2008,A2 .Location in patent: Page/Page column 72.

7
[ 449811-29-4 ]
[ 446-18-4 ]
[ 1011464-19-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium tris(acetoxy)borohydride; In acetic acid; at 20℃;	To a solution of 6-chloro-4-(metlrylamino)nicotinaldehyde (1.00 g, 5.88 mmol) and Example Dl (1.00 g, 5.88 mmol) in glacial acetic acid (7.5 mL) was added sodium triacetoxy borohydride (2.49 g, 11.7 mmol). The mixture was stirred overnight at RT. Another portion of sodium triacetoxy borohydride (1.30 g, 6.11 mmol) was added and the mixture was stirred another 24 h. The reaction was diluted with ice water and basified (pH ~ 7-8) with NaOH. The yellow precipitate was collected by filtration, washed with H2O and dried under vacuum to give <n="78"/>crude 2-chloro-5-((4-fluoro-2-methyl-5"nitrophenylamino)methyl)-N-methylpyridin-4-amine (2.04 g, 107 % yield), which was used without further purification. MS (ESI) m/z: 325.0 [M+H]+.

References: [1]Patent: WO2008/33999,2008,A2 .Location in patent: Page/Page column 76-77.

8
[ 50893-53-3 ]
[ 446-18-4 ]
[ 173552-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	With calcium carbonate; In 1,4-dioxane; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	Step 2 2-chloroethyl-N-[(4-fluoro-2-methyl-5-nitro)phenyl]-carbamate 5 g (29 mmol) of <strong>[446-18-4]2-amino-5-fluoro-4-nitrotoluene</strong> was heated with 2.5 g calcium carbonate in 200 ml dioxan at 70 C., reacted with 3.1 ml of chloroformic acid chloroethyl ester and heated for 3 hours at 100 C. The resultant solution was filtered hot and the filtrate is introduced into 500 ml of ice water. The ocher colored precipitate was filtered with suction and recrystallized from an ethanol-water mixture. The resulting 6.6 g (81% of theoretical) of 2-chloroethyl-N-[(4-fluoro-2-methyl-5-nitro)phenyl]-carbamate had a melting point of 113 C. 1 H-NMR(D6 -DMSO): delta=2.33 (s; 3H, --CH3) 3.88 (t; 2H, --CH2 Cl) 4.38 (t; 2H, --CH2 CH2 Cl) 7.49 (d, J=12.3 Hz; 1H, 6-H) 8.22 (d, J=7.3 Hz; 1H, 3-H) 9.44 (br.s; 2H, --NH, exchange with D2 O) MS(70ev): m/e=276(M+.)

References: [1]Patent: US5645610,1997,A .

9
[ 446-18-4 ]
(4-fluoro-2-methyl-5-nitrophenyl)-(5-pyridin-4-yloxazol-2-yl)amine [ No CAS ]

References: [1]Patent: WO2014/202763,2014,A1 .

10
[ 446-18-4 ]
2-methyl-5-nitro-N₁-(5-pyridin-4-yloxazol-2-yl)benzene-1,4-diamine [ No CAS ]

References: [1]Patent: WO2014/202763,2014,A1 .

11
[ 446-18-4 ]
5-methyl-N₄-(5-pyridin-4-yloxazol-2-yl)benzene-1,2,4-triamine [ No CAS ]

References: [1]Patent: WO2014/202763,2014,A1 .

12
[ 446-18-4 ]
4-[2-(4-fluoro-2-methyl-5-nitrophenylamino)thiazol-4-yl]benzonitrile [ No CAS ]

References: [1]Patent: WO2014/202763,2014,A1 .

13
[ 446-18-4 ]
(6-methyl-2-morpholin-4-ylmethyl-3H-benzoimidazol-5-yl)-(5-pyridin-4-yloxazol-2-yl)amine [ No CAS ]

References: [1]Patent: WO2014/202763,2014,A1 .

14
[ 446-18-4 ]
[ 102368-13-8 ]
1-fluoro-4-isothiocyanato-5-methyl-2-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In dichloromethane; for 4h;	To a solution of IV-e (600 mg, 3.53 mmol) in DCM (40 ml_) was added 1 ,1 '-Thiocarbonyldi- 2(1 H)-pyridone (232 mg, 3.88 mmol) and the reaction mixture was stirred for 4h. After evaporation of solvent the resulting crude product was purified by silica gel chromatography using 25% AcOEt in cyclohexane as eluent to give 1 -fluoro-4- isothiocyanato-5-methyl-2-nitro-benzene IV-a as a yellow syrup (740 mg, 99%).

References: [1]Patent: WO2014/202763,2014,A1 .Location in patent: Page/Page column 51-52.

15
[ 446-18-4 ]
[ 1147550-11-5 ]
[ 75-36-5 ]
1-acetyl-3-(4-fluoro-2-methyl-5-nitrophenyl)thiourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		Preparation of 1 -acetyl-3-(4-fluoro-2-methyl-5-nitro-phenyl)-thiourea V-a To a solution of ammonium thiocyanate (805 mg, 10.6 mmol) in acetone (15 mL) was added dropwise AcCI (0.76 mL, 10.6 mmol). The reaction mixture was heated at 60 ' for 1 h. After cooling a solution of compound IV-e (1 .5 g, 8.82 mmol) in acetone (5 mL) was added and the reaction mixture stirred for 2h at room temperature. Water (60 mL) was added and the mixture was stirred for 1 h. The precipitate filtered, washed with water and dried under vacuum to give the title compound V-a (2.05 g, 86%). H NMR (400 MHz, DMSO-d6) delta 12.20 (s, 1 H), 1 1 .67 (s, 1 H), 8.48 (d, J = 7.4 Hz, 1 H), 7.59 (d, J = 12.2 Hz, 1 H), 2.31 (s, 3H), 2.18 (s, 3H).

References: [1]Patent: WO2014/202763,2014,A1 .Location in patent: Page/Page column 54.

16
[ 446-18-4 ]
[ 100243-39-8 ]
(S)-1-(4-amino-5-methyl-2-nitrophenyl)pyrrolidin-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.3%	With potassium carbonate; In tetrahydrofuran; at 70℃; for 12h;	Step-2: Preparation of (S)-1-(4-amino-5-methyl-2-nitrophenyl)pyrrolidin-3-ol. A solution of <strong>[446-18-4]4-fluoro-2-methyl-5-nitroaniline</strong> (1 1g, 64.32mmol), potassium carbonate (35.5g, 257.30 mmol) and (S)-pyrrolidin-3-ol (8.7g, 70.76mmol) in THF was stirred at 70C for 12h. The reaction mixture was filtered and filtrate was purified by column chromatography elution with 50% ethyl acetate in hexane to obtain the title compound (11g, 72.3 %.). LCMS: 97.15% m/z = 238.3(M+1).

References: [1]Patent: WO2015/193846,A1 .Location in patent: Page/Page column 58.
Patent: ,2015, .Location in patent: Page/Page column 58.

17
[ 446-18-4 ]
(S)-1-(6-nitro-1H-indazol-5-yl)pyrrolidin-3-ol [ No CAS ]