20191-74-6|2-Ethyl-5-nitroaniline| Ambeed

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Quality Control of [ 20191-74-6 ] Purity: 97% SDS Specification

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Product Details of [ 20191-74-6 ]

CAS No. :	20191-74-6
Formula :	C₈H₁₀N₂O₂
M.W :	166.18
SMILES Code :	NC1=CC([N+]([O-])=O)=CC=C1CC
MDL No. :	MFCD00034056
InChI Key :	MMZWMCKTKJKIMC-UHFFFAOYSA-N
Pubchem ID :	4155478

Safety of [ 20191-74-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302+H312+H332
Precautionary Statements:	P280

Computational Chemistry of [ 20191-74-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	49.44
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.	1.41
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	2.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.75
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.	0.94
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	-0.27
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.23

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.56
Solubility	0.461 mg/ml ; 0.00277 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.	-3.45
Solubility	0.0594 mg/ml ; 0.000358 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	-2.2
Solubility	1.04 mg/ml ; 0.00627 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	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.	-5.68 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)	1.86

Application In Synthesis of [ 20191-74-6 ]

* 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 [ 20191-74-6 ]

[ 20191-74-6 ] Synthesis Path-Downstream 1~35

1
[ 1204-29-1 ]
[ 20191-74-6 ]
[ 51529-96-5 ]

References: [1]Tetrahedron Letters,1994,vol. 35,p. 7867 - 7870.
[2]Journal of the American Chemical Society,1927,vol. 49,p. 3155.

2
[ 20191-74-6 ]
[ 90005-90-6 ]

Yield	Reaction Conditions	Operation in experiment
52%		Step3. A solution of sulfuric acid (98percent, 39 g, 390.00 mmol) in water (160 mL) was added to <strong>[20191-74-6]2-ethyl-5-nitrobenzenamine</strong> (12.9 g, 69.94 mmol, prepared as described in Step 2 above). The mixture was cooled to 0-5 0C, and a solution of sodium nitrite (5.63 g, 81.59 mmol) in water (20 mL) was then added. The resulting solution was maintained for 30 min at 0-5 0C. Sulfuric acid (65percent, 600 g, 3.98 mol) was then added, and the temperature was maintained at reflux for 1 hr. The reaction mixture was cooled in a bath of iced water, and the product was extracted with ethyl acetate. The organic layers were combined and washed with aqueous saturated sodium bicarbonate and brine (200 mL). The solution was dried (anhydrous MgSO-i), filtered, and concentrated. The residue was purified by eluting through a column with a 1 :10 (v/v) ethyl acetate/petroleum ether solvent system to afford 7.65 g (52 percent yield) of 2-ethyl-5-nitrophenol as a red solid.
	With sulfuric acid; water; sodium nitrite; at 0 - 5℃; for 1.5h;Heating / reflux;	Step 3; A solution of sulfuric acid (98percent, 39 g, 390.00 mmol) in water (160 mL) was added to <strong>[20191-74-6]2-ethyl-5-nitrobenzenamine</strong> (12.9 g, 69.94 mmol, prepared as described in Step 2 <n="55"/>above). The mixture was cooled to 0-5 0C5 and a solution of sodium nitrite (5.63 g, 81.59 mmol) in water (20 mL) was then added. The resulting solution was maintained for 30 minutes at 0-5 0C. Sulfuric acid (65percent, 600 g, 3.98 mol) was then added, and the temperature was maintained at reflux for 1 hr. The reaction mixture was cooled in a bath of iced water, and the product was extracted with ethyl acetate. The organic layers were combined and washed with aqueous saturated sodium bicarbonate and brine. The solution was dried (MgSO-j), filtered and concentrated. The residue was purified by eluting through a column with a 1 : 10 ethyl acetate/petroleum ether solvent system to afford 7.65 g of 2-ethyl-5-nitrophenol as a red solid.

References: [1]Patent: WO2007/103260,2007,A1 .Location in patent: Page/Page column 57.
[2]Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1048.
[3]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 668 - 671.
[4]Patent: WO2007/100880,2007,A1 .Location in patent: Page/Page column 53-54.

3
[ 33098-65-6 ]
[ 20191-74-6 ]

References: [1]Bulletin de la Societe Chimique de France,1958,p. 152,156.

4
[ 578-54-1 ]
[ 20191-74-6 ]

Yield	Reaction Conditions	Operation in experiment
80.1%	With sulfuric acid; nitric acid; at 0 - 20℃; for 0.5h;	2-ethylaniline (24.2 g, 0.2 mol) was added to concentrated sulfuric acid (100 ml).Cooled to below 0 ° C,Fuming nitric acid (18.6 g, 0.3 mol) was slowly added dropwise,The mixture was stirred at room temperature for 30 min.The reaction solution was poured into ice water (1000 ml)Slowly add 50percent sodium hydroxide solution to adjust the pH to about 8.filter,The cake was recrystallized from petroleum ether,Yielding yellow needle-shaped solid 2 (26.6 g, 80.1percent),
75.3%	With sulfuric acid; nitric acid; at 0 - 5℃; for 0.5h;	2- Ethyl aniline (12.1g, 0.1mol) was dissolved in concentrated sulfuricacid (50mL), cooled to 0-5 ° C, and slowly added dropwise fuming nitric acid (9.3g,0.15mol), Bi drops, heat stirring 30min. The reaction solution was poured intoice-water (a 500 mL), and solid sodium hydroxide was added slowly under cooling was adjusted to pH7 -, a solidprecipitated. After filtration cake was dried and recrystallized fromcyclohexane to give yellow crystals 12.5g, yield 75.3percent
17%		2-ethylaniline (12. Ig, 99.8mmol, 1 equiv) was dissolved in concentrated sulphuric acid (50ml) and cooled down to O0C. Fuming nitric acid (9.3g, 147.6mmol, 1.5 equiv) was then added slowly keeping the temperature below 5°C. The reaction was left warm up to room temperature and stirred overnight. The reaction mixture was poured onto ice- water (250ml) and neutralised with sodium hydroxide 6M. The solid was filtered off and dried in an oven to remove as much water as possible. The red solid was then taken up in petrol (250ml x 4) and decanted over filter paper to crystallise out the desired compound as yellow solid. (2.7g, 17percent). IH NMR spectra were recorded at ambient temperature using a Bruker Advance DRX (400MHz) spectrometer, both with a triple resonance 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane.1H NMR (CDCl3, 400MHz) delta= 7.51 (d, J = 8Hz, IH), 7.43 (s, IH), 7.10 (d, J = 8Hz, IH), 3.7 (br s, 2H), 2.5 (q, J = 7Hz, 2H), 1.21 (t, J = 7Hz, 3H).

		Example 2 1-(4-(4-(4-(3-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone and N4-(3-methyl-1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine To a solution of 2-ethylaniline (12.1 g, 0.1 mol) in conc. H2SO4 (50 mL) at 0° C. was added fuming HNO3 (9.3 g) drop wise. After stirring at ambient temperature for 30 min, the mixture was poured into ice-water, and 2 N NaOH was added to neutralize the excess acid. The resulting reddish-brown solid was collected by filtration and washed with petroleum ether to give 2-ethyl-5-nitroaniline as crude product (9 g).
	With sulfuric acid; potassium nitrate;	5-Amino-2-chlorophenol1 2d was synthesized from 2-amino-5-nitrophenol 5 in two steps: 1) formation of the diazonium salt with NaNO2 and reaction with CuCl to give the corresponding 2-chloro-5-nitrophenol 6 in 68percent yield and 2) careful reduction of the nitro group with H2 (1 atm) in presence of Adam's catalyst to give the final amine derivative in 57percent yield (Scheme 2).5-Amino-2-ethyl/n-prorhoyl/z-propylphenol 2e-g was synthesized in four steps from the corresponding 2-emyl/rc-propyl/z-propylamline 7e-g. The first step was nitration with potassium nitrate in presence of sulfuric acid to give exclusively the corresponding 5-nitro-2- alkylaniline2 8e-g; reaction with NaNO2, followed by reaction with H2O at 8O0C for 2h gave the corresponding 5-nitro-2-alkylphenol derivatives3 9e-g and finally, hydrogenation of the nitro group gave the corresponding amine derivatives 2e-g (Scheme X). 2-Amine-4-hydroxybenzonitrile4 2h was obtained from 2-methoxy-4-nitrobenzonitrile 10 by hydrolisis of the methyl ether with LiCl and posterior, reduction of the nitro group with SnCl2.2H2O in presence of 6N HCl (Scheme 2).

References: [1]Patent: CN103373989,2016,B .Location in patent: Paragraph 0031; 0032.
[2]Patent: CN103739550,2016,B .Location in patent: Paragraph 0125-0129.
[3]Tetrahedron,1990,vol. 46,p. 6085 - 6112.
[4]Journal of Medicinal Chemistry,2008,vol. 51,p. 4632 - 4640.
[5]Patent: WO2009/62658,2009,A1 .Location in patent: Page/Page column 33; 1/10.
[6]Chemische Berichte,1964,vol. 97,p. 1896 - 1901.
[7]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 668 - 671.
[8]Journal of Organic Chemistry,1955,vol. 20,p. 1026,1027.
[9]Patent: US2009/54425,2009,A1 .Location in patent: Page/Page column 22.
[10]Patent: WO2007/38387,2007,A2 .Location in patent: Page/Page column 24; 25.
[11]Chinese Chemical Letters,2014,vol. 25,p. 989 - 994.

5
[ 20191-74-6 ]
[ 42782-54-7 ]

References: [1]Journal of Medicinal Chemistry,1973,vol. 16,p. 765 - 770.

6
[ 20191-74-6 ]
[ 133053-77-7 ]

References: [1]Tetrahedron,1990,vol. 46,p. 6085 - 6112.

7
[ 20191-74-6 ]
[ 149-73-5 ]
[ 133053-75-5 ]

References: [1]Tetrahedron,1990,vol. 46,p. 6085 - 6112.

8
[ 20191-74-6 ]
[ 52121-34-3 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

9
[ 1204-29-1 ]
aqueous ammonium sulfide solution [ No CAS ]
[ 20191-74-6 ]
[ 51529-96-5 ]

References: [1]Chemische Berichte,1909,vol. 42,p. 2634.

11
[ 20191-74-6 ]
[ 933045-59-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 668 - 671.

12
[ 20191-74-6 ]
N-(4-ethyl-3-(3-methylbut-2-enyloxy)phenylthiazol)-2-amine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 668 - 671.

13
[ 20191-74-6 ]
[ 207923-07-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 668 - 671.

14
[ 20191-74-6 ]
[ 52121-36-5 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

15
[ 20191-74-6 ]
[ 52121-38-7 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

16
[ 20191-74-6 ]
[ 186666-76-2 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

17
[ 20191-74-6 ]
[ 1028308-26-0 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

18
[ 20191-74-6 ]
[ 186666-73-9 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

19
[ 20191-74-6 ]
[ 186666-72-8 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

20
[ 20191-74-6 ]
6-Bromo-7-ethyl-5-nitro-1,4-dihydro-quinoxaline-2,3-dione [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 730 - 738.

21
[ 20191-74-6 ]
[ 133053-76-6 ]

References: [1]Tetrahedron,1990,vol. 46,p. 6085 - 6112.

22
[ 20191-74-6 ]
[ 133053-79-9 ]

References: [1]Tetrahedron,1990,vol. 46,p. 6085 - 6112.

23
[ 20191-74-6 ]
[ 133053-78-8 ]

References: [1]Tetrahedron,1990,vol. 46,p. 6085 - 6112.

24
[ 20191-74-6 ]
[ 1834-91-9 ]

References: [1]Huaxue Xuebao/Acta Chimica Sinica,1958,vol. 24,p. 240,249.
Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1056, 1057.

25
[ 20191-74-6 ]
[ 5230-72-8 ]

References: [1]Huaxue Xuebao/Acta Chimica Sinica,1958,vol. 24,p. 240,249.
Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1056, 1057.

26
[ 20191-74-6 ]
[ 90610-19-8 ]

References: [1]Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1048.

27
[ 20191-74-6 ]
[ 90564-14-0 ]

References: [1]Huaxue Xuebao/Acta Chimica Sinica,1958,vol. 24,p. 240,249.
Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1056, 1057.

28
[ 20191-74-6 ]
[ 100961-78-2 ]

References: [1]Huaxue Xuebao/Acta Chimica Sinica,1958,vol. 24,p. 240,249.
Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1056, 1057.

29
[ 20191-74-6 ]
[ 100965-09-1 ]

References: [1]Huaxue Xuebao/Acta Chimica Sinica,1958,vol. 24,p. 240,249.
Scientia Sinica (English Edition),1958,vol. 7,p. 1043,1056, 1057.

30
[ 20191-74-6 ]
[ 50775-72-9 ]

References: [1]Journal of Medicinal Chemistry,1973,vol. 16,p. 765 - 770.

31
[ 63024-77-1 ]
[ 20191-74-6 ]
[ 263270-83-3 ]
[ 263270-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	The N-(5-amino-2-ethylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide used as a starting material was prepared as follows: 3-Chloromethylbenzoyl chloride (11.93 g) was added to a stirred mixture of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> (10 g), triethylamine (17.3 ml) and methylene chloride (283 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated. Methylene chloride was added to the residue and the resultant precipitate was isolated and washed in turn with 1N aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and diethyl ether. There was thus obtained 3-chloromethyl-N-(2-ethyl-5-nitrophenyl)benzamide (11.14 g); NMR Spectrum: (DMSOd6) 2.77 (m, 2H), 4.05 (s, 2H), 7.5-7.6 (m, 2H), 7.65-7.7 (m, 1H), 7.95-8.0 (m, 1H), 8.05-8.1 (m, 2H), 8.25 (s, 1H), 10.26 (s, 1H).

References: [1]Patent: US6455520,2002,B1 .

32
[ 20191-74-6 ]
[ 91880-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	In N-(2-ethyl-5-nitrophenyl)acetamide;	Step 1 Preparation of 2-ethyl-5-nitroacetanilide The procedure is carried out in a manner identical to that in step 1 of Example 3, using 2-ethyl-5- nitroaniline as the starting material. Analysis of the product recrystallized from ethanol gives the following results: m.p.=158° C.

References: [1]Patent: US5254135,1993,A .

33
[ 20191-74-6 ]
C₈H₈N₃O₂⁽¹⁺⁾*HO^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite;	5-Amino-2-chlorophenol1 2d was synthesized from 2-amino-5-nitrophenol 5 in two steps: 1) formation of the diazonium salt with NaNO2 and reaction with CuCl to give the corresponding 2-chloro-5-nitrophenol 6 in 68percent yield and 2) careful reduction of the nitro group with H2 (1 atm) in presence of Adam's catalyst to give the final amine derivative in 57percent yield (Scheme 2).5-Amino-2-ethyl/n-prorhoyl/z-propylphenol 2e-g was synthesized in four steps from the corresponding 2-emyl/rc-propyl/z-propylamline 7e-g. The first step was nitration with potassium nitrate in presence of sulfuric acid to give exclusively the corresponding 5-nitro-2- alkylaniline2 8e-g; reaction with NaNO2, followed by reaction with H2O at 8O0C for 2h gave the corresponding 5-nitro-2-alkylphenol derivatives3 9e-g and finally, hydrogenation of the nitro group gave the corresponding amine derivatives 2e-g (Scheme X). 2-Amine-4-hydroxybenzonitrile4 2h was obtained from 2-methoxy-4-nitrobenzonitrile 10 by hydrolisis of the methyl ether with LiCl and posterior, reduction of the nitro group with SnCl2.2H2O in presence of 6N HCl (Scheme 2).

References: [1]Patent: WO2007/38387,2007,A2 .Location in patent: Page/Page column 24; 25.

34
[ 1204-29-1 ]
[ 20191-74-6 ]

Yield	Reaction Conditions	Operation in experiment
51%	With iron; acetic acid; for 0.166667h;Heating / reflux;	Step 2. Iron (25.8 g, 460.71 mmol) was added in several portions to a solution of l-ethyl-2,4-dinitrobenzene (30 g, 137.76 mmol, prepared as described in Step 1 above) in acetic acid (350 mL), while maintaining the temperature at reflux. The resulting solution was maintained at reflux for a further 10 min. The product was precipitated by the addition of ice, and then extracted with ethyl acetate. The organic layers were combined, dried (anhydrous MgSO-j), filtered, and concentrated. The residue was purified by eluting through a column <n="58"/>with a 1 : 10 (v/v) ethyl acetate/petroleum ether solvent system to afford 12.9 g (51 percent yield) of 2-ethyl-5-nitro-benzenamine as a brown solid.
	With iron; acetic acid; for 0.166667h;Heating / reflux;	Step 2; Iron (25.8 g, 460.71 mmol) was added in several portions to a solution of l-ethyl-2,4-dinitrobenzene (30 g, 137.76 mmol, prepared as described in Step 1 above) in acetic acid (350 mL), while maintaining the temperature at reflux. The resulting solution was maintained at reflux for a further 10 min. The product was precipitated by the addition of ice, and the product was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered, and concentrated. The residue was purified by eluting through a column with a 1 : 10 ethyl acetate/petroleum ether solvent system to afford 12.9 g of 2-ethyl-5- nitrobenzenamine as a brown solid.

References: [1]Patent: WO2007/103260,2007,A1 .Location in patent: Page/Page column 56-57.
[2]Patent: WO2007/100880,2007,A1 .Location in patent: Page/Page column 53.

35
[ 20191-74-6 ]
[ 6494-19-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With tert.-butylnitrite; In acetic acid; at 20℃; for 0.75h;Inert atmosphere;	Intermediate Example 1 Preparation of 3-methyl-1H-indazol-6-amine To a solution of 10 g (.06 mol) of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> (prepared by nitration of 2-ethylaniline:) in 300 ml of glacial acetic acid, at room temperature, was added a solution of 8.98 ml (.06 mol) of tert-butyl nitrite in 40 ml of acetic acid dropwise over 15 min. After the addition was complete the solution was allowed to stir for 30 min. The acetic acid was removed in vacuo to afford an orange solid. The solid was dissolved in approximately 120 ml of ethyl acetate and washed with 3 x 100 ml sat. aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to afford 3-methyl-6-nitroindazole as a yellow solid (10.4 g, 98percent). To a stirred solution of 10 g (.06 mol) of 3-methyl-6-nitroindazole in 100 ml of 2-methoxyethyl ether, at 0 °C, was added a solution of 45 g (.24 mol) of tin(II) chloride in 86 ml of concentrated HCl dropwise over 15 min, in order to keep the reaction temperature below 100 °C. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 20 min. Approximately 70 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (10 g, 92 percent), the HCl salt of 3-methyl-1H-indazol-6-amine.
98%	With tert.-butylnitrite; acetic acid; for 0.5h;	A solution of tert-butyl nitrite (12.5ml, 0.075mol) in glacial aceticacid (50ml) was added dropwise to a 2-1 (12.5g, 0.075mol) in glacial aceticacid (375mL) solution. Continue stirring the reaction 30min. The reactionsolution was concentrated to dryness, the resulting orange solid was dissolvedin ethyl acetate (150 mL), and saturated aqueous sodium bicarbonate (125mL ×3), dried, filtered, and concentrated to give 13.0 g of a yellow solid, yield98percent,
40.5%	With acetic acid; sodium nitrite; at 0 - 25℃;	Step 1 3-Methyl-6-nitro-1H-indazole Following generally the procedure reported by Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73, <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 424 mg) in water (1 ml) was added all at once. Stirring was continued for 15 minutes at 25° C. After 3 hours, residual solids were filtered off and discarded, and the filtrate was allowed to stand for 3 days at room temperature. The solution was concentrate in vacuo, and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was filtered and washed thoroughly with cold water, dried and purified by flash chromatography (4:1 hexanes/ethyl acetate) to give 3-methyl-6-nitro-1H-indazole (436 mg, 40.5percent) as a solid.

	With tert.-butylnitrite; acetic acid; at 20℃; for 1h;	To a mixture of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> (2 g, 12 mmol) in acetic acid (AcOH) (60 mL) at ambient temperature was added a solution of tert-butyl nitrite (t-BuONO) (1.8 mL, 12 mmol) in AcOH (8 mL). After stirring at ambient temperature for 1 h, AcOH was removed in vacuo. The resulting residue was dissolved in ethyl acetate (EtOAc), washed with Sat. NaHCO3, dried over Na2SO4, and concentrated to afford 3-methyl-6-nitroindazole (1.2 g).
		First Step [Show Image] To a glacial acetic acid solution (300 mL) of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> (15.8 g, 95 mmol), a glacial acetic acid solution (40 mL) of tert-butyl nitrite (9.8 g, 95 mmol) was gradually added over 15 minutes, After stirring for 30 minutes, acetic acid was distilled off under reduced pressure to obtain an orange solid. The resulting solid was dissolved in ethyl acetate and then washed three times with 100 mL of a saturated sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure to obtain 11.7 g of 6-nitro-3-methylindazole. 1H-NMR (CDCl3) d (ppm): 2.65 (s, 3H), 7.79 (d, 1H, J = 8.4 Hz), 8.03 (d, 1H, J = 8.4 Hz), 8.40 (s, 1H), 10.30 (br, 1H).
	With acetic acid; sodium nitrite; In water; at 40℃; for 0.025h;	Step 1. Dissolve <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> in acetic acid to form a 22percent by mass solution and a 30percent by mass aqueous solution of sodium nitrite as the reaction material, and use a metering pump to pass the reaction material into the microchannel. Preheating in each straight channel module in the reactor, controlling the molar ratio of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> to sodium nitrite by flow rate = 1:1.2, controlling the acetic acid of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> Solution flow rate: 22mL / min, control the flow rate of sodium nitrite solution: 5.2mL / min,The <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> acetic acid solution is driven into the first microchannel module preheating module, and the temperature is controlled to 40 ° C;The acetic acid solution of <strong>[20191-74-6]2-ethyl-5-nitroaniline</strong> and the sodium nitrite solution are separately mixed into the second mixing module of the micromixer by respective metering pumps;Step 2: Continue through a series of enhanced mass transfer microchannel modules and DC type microchannel modules. After the reaction process is completed, the reaction temperature is 40 ° C and the reaction residence time is 90 s, and the product flows out from the outlet of the reactor;Step 3, the product is pre-cooled to 20 ° C, and then added to ice water under stirring, filtered, the filter cake is washed with ice water, added to toluene for 1 hour, washed twice with toluene, dried to obtain a bright yellow solid 3-methyl-6-nitro-1H-carbazole; total yield 80percent to 90percent.

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4632 - 4640.
[2]Patent: EP2311825,2015,B1 .Location in patent: Paragraph 0157 - 0159.
[3]Patent: CN103739550,2016,B .Location in patent: Paragraph 0125-0126; 0130-0132.
[4]Letters in Organic Chemistry,2012,vol. 9,p. 276 - 279.
[5]Patent: US2010/160388,2010,A1 .Location in patent: Page/Page column 54.
[6]Patent: US2009/54425,2009,A1 .Location in patent: Page/Page column 22.
[7]Patent: EP2226315,2010,A1 .Location in patent: Page/Page column 39-40.
[8]Chinese Chemical Letters,2014,vol. 25,p. 989 - 994.
[9]Patent: CN109384725,2019,A .Location in patent: Paragraph 0027; 0028; 0029; 0030; 0031-0034.

Historical Records

Technical Information

• Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Friedel-Crafts Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Leuckart-Wallach Reaction • Mannich Reaction • Petasis Reaction • Preparation of Alkylbenzene • Preparation of Amines • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Specialized Acylation Reagents-Vilsmeier Reagent • Ugi Reaction • Vilsmeier-Haack Reaction

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[ 20191-74-6 ]

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CAS No.: 20191-74-6

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