[ CAS No. 28987-44-2 ] {[proInfo.proName]}

Name: 28987-44-2|2-Ethoxy-4-fluoro-1-nitrobenzene|98%
Brand: Ambeed
SKU: A323395
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Quality Control of [ 28987-44-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 28987-44-2 ]

Product Details of [ 28987-44-2 ]

CAS No. :	28987-44-2	MDL No. :	MFCD04115630
Formula :	C₈H₈FNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LEMJFSSYFHTFFP-UHFFFAOYSA-N
M.W :	185.15	Pubchem ID :	12918153
Synonyms :

Calculated chemistry of [ 28987-44-2 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.52
TPSA :	55.05 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.85
Log Po/w (XLOGP3) :	2.05
Log Po/w (WLOGP) :	2.55
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	0.43
Consensus Log Po/w :	1.81

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.42
Solubility :	0.699 mg/ml ; 0.00378 mol/l
Class :	Soluble
Log S (Ali) :	-2.83
Solubility :	0.271 mg/ml ; 0.00146 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.59
Solubility :	0.475 mg/ml ; 0.00256 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.11

Safety of [ 28987-44-2 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 28987-44-2 ]

* 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 [ 28987-44-2 ]

[ 28987-44-2 ] Synthesis Path-Downstream 1~71

1
[ 446-35-5 ]
[ 917-58-8 ]
[ 28987-48-6 ]
[ 28987-44-2 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1985,vol. 21,p. 2173 - 2178
Zhurnal Organicheskoi Khimii,1985,vol. 21,p. 2376 - 2382

2
[ 446-35-5 ]
[ 141-52-6 ]
[ 28987-48-6 ]
[ 28987-44-2 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1985,vol. 21,p. 2173 - 2178
Zhurnal Organicheskoi Khimii,1985,vol. 21,p. 2376 - 2382

Yield	Reaction Conditions	Operation in experiment
		Example 40-41 Compound 40 (m.p.=133-135 C.) and compound 41(m.p.=151-153 C.) were obtain from 4-fluoro-2-ethoxy-nitrobenzene by proceeding in a similar manner described in Experimental 39 step (a).

4
[ 75-89-8 ]
[ 446-35-5 ]
[ 28987-44-2 ]
[ 186386-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tert-butoxide; In tetrahydrofuran; at 0℃; for 0.5h;	To a solution of trifluoroethanol in 4 mL dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0 C. The resulting mixture was added dropwise to the solution of 2, 4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 mL dry THF at 0C. The mixture was stirred at 0C for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-fluoro-l-nitro-2- (2, 2,2- trifluoro-ethoxy)-benzene.

Reference： [1]Patent: WO2005/35520,2005,A1 .Location in patent: Page/Page column 72-74

5
[ 446-36-6 ]
[ 1972-28-7 ]
[ 28987-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; In tetrahydrofuran; ethanol; di-isopropyl ether; ethyl acetate;	(1) Synthesis of 2-Ethoxy-4-fluoronitrobenzene To a solution of ethanol (4.2 ml) in tetrahydrofuran (65 ml) was added a solution of triphenylphosphine (13 g) and 5-fluoro-2-nitrophenol (10 g) in tetrahydrofuran (65 ml). To this solution was added diethyl azodicarboxylate (10 ml) under ice-cooling and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure and diisopropyl ether was added. The precipitated crystals were collected by filtration and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give a yellow oil. To this oil was added ethyl acetate, washed with an aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (9.6 g) as a yellow oil. 1H-NMR(CDCl3)δ: 1.50(3H, t, J=7.3 Hz), 4.17(2H, q, J=7.3 Hz), 6.67-6.79(2H, m), 7.92(1H, dt, J=3.3, 2.6 Hz). MS(EI): 185(M+).

Reference： [1]Patent: US6455528,2002,B1

6
[ 28987-44-2 ]
[ 178993-28-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	After the 5-fluoro-2-nitro-ethyl ether (6.8g) was dissolved in 150ml of methanol was added 10% Pd / C (680mg), purged with hydrogen, hydrogenated at room temperature with stirring. After completion of the reaction by TLC, filtered and the filtrate reduced the solvent was evaporated press 4-fluoro-2-ethoxy-aniline (5.2g, 92% yield).
92%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃;	5-fluoro-2-nitrophenylethyl ether (6.8 g) was dissolved in 150 ml of methanol,After addition of palladium on carbon (680 mg)Hydrogen replacement,Room temperature stirring hydrogenation,After TLC detection reaction was completed,filter,The filtrate was evaporated under reduced pressure to give 4-fluoro-2-ethoxyaniline (5.2 g, yield 92%).
		(2) Synthesis of 2-Ethoxy-4-fluoroaniline By similar reaction and treatment to that in Example 40(2) using 2-ethoxy-4-fluoronitrobenzene instead of 4-fluoro-2-methoxynitrobenzene, the title compound was obtained as a black oil. 1H-NMR(CDCl3)δ: 1.44(3H, t, J=7.3 Hz), 3.50(2H, br.s), 4.00(2H, q, J=7.3 Hz), 6.27-6.64(3H, m). IR(KBr): 3548, 3369, 2981, 1618, 1512 cm-1; MS(EI): 155(M+).

56 g	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 4h;	5-fluoro-2-nitrophenylethyl ether (68 g) was dissolved in 1 L of methanol, After the addition of palladium on carbon (5 g), the hydrogen was replaced twice and stirred at room temperature for about 4 hours. After the reaction was complete, the reaction was filtered and the filtrate was evaporated under reduced pressure to give 4-fluoro-2-ethoxyaniline 56g).
	With palladium 10% on activated carbon; hydrogen; In methanol; for 3h;	Intermediate 3: 2-Ethoxy-4-fluorobenzenamine To a 250 mL round-bottomed flask were added <strong>[28987-44-2]2-ethoxy-4-fluoro-1-nitrobenzene</strong> (3.70 g, 20.0 mmol) and 10% Pd/C (370 mg) in MeOH (80.0 mL). The mixture was stirred at rt for 3 h under a H2 atmosphere. The mixture was filtered and the filtrate was concentrated to dryness to give the title product (2.8 g, crude, 90%) as a dark oil. MS (ESI): mass calcd. for C8H10FNO 155.07, m/z found 156.2 [M+H]+.
3.8 g	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	10% 42 Pd/C (400 mg) was added into the solution of 345 <strong>[28987-44-2]2-ethoxy-4-fluoro-1-nitrobenzene</strong> (4.8 g, 26.0 mmol) in 43 methanol (40 mL), and reacted under hydrogen gas (balloon) at room temperature overnight, filtered on Celite, the filtrate was concentrated under reduced pressure, and the filtrate was separated on column chromatography (eluant:petroleum ether/ethyl acetate (v/v)=50:1), and afforded product 3.8 g of a pale yellow oil, LC-MS(APCI): m/z=156.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 6.63 (dd, J=8.5, 5.8 Hz, 1H), 6.56 (dd, J=10.4, 2.7 Hz, 1H), 6.50 (td, J=8.5, 2.7 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H), 3.42 (br, 2H), 1.45 (t, J=7.0 Hz, 3H).

Reference： [1]Patent: CN105461695,2016,A .Location in patent: Paragraph 0157; 0159
[2]Patent: CN107043368,2017,A .Location in patent: Paragraph 0118; 0120
[3]Patent: US6455528,2002,B1
[4]Patent: CN106995437,2017,A .Location in patent: Paragraph 0114; 0116; 0117; 0119
[5]Patent: US2018/289706,2018,A1 .Location in patent: Paragraph 0382
[6]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0446; 0448

7
[ 446-35-5 ]
[ 28987-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; In ethanol;	EXAMPLE 26A 2-Ethoxy-4-fluoronitrobenzene To a solution of anhydrous sodium ethoxide (0.55 mole) [prepared by dissolving sodium metal (12.6 g, 0.55 mole) in anhydrous ethanol (300 ml)] at 0 C. is added 2,4-difluoronitrobenzene (79.5 g, 0.50 mole) dropwise over an 8 hour period. Upon completion of addition the reaction mixture is allowed to warm to room temperature and stirred overnight. The solid is removed by filtration, and triturated with toluene and water. The toluene extract is combined with the original filtrate, dried with anhydrous sodium sulfate and the solvent is removed under vacuum to afford 218 g of a yellow oil which was distilled at 0.3 mm, b.p. 95-98 C. to afford substantially pure 2-ethoxy-4-fluoronitrobenzene. STR20

Reference： [1]Patent: US4259510,1981,A

8
[ 446-36-6 ]
[ 75-03-6 ]
[ 28987-44-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetone; for 15h;Reflux;	Intermediate 2: 2-Ethoxy-4-fluoro-1-nitrobenzene To a 100 mL round-bottomed flask were added a mixture of 5-fluoro-2-nitrophenol (3.14 g, 20.0 mmol), iodoethane (3.43 g, 22.0 mmol), K2CO3 (5.52 g, 40.0 mmol), and acetone (30.0 mL). The mixture was heated at reflux for 15 h, and then concentrated under vacuum to dryness. Water (30 mL) was added to the residue and the resulting mixture was extracted with EtOAc (3*20 mL). The combined organic phases were washed with saturated NaCl(aq) (30 mL), dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound (3.7 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.92 (dd, J=9.0, 6.0 Hz, 1H), 6.80-6.65 (m, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;sealed tube;	To 5-fluoro-2-nitrophenol (8.3 g, 52.83 mmol) in 50 mL of DMF was added K2CO3 (14.6 g, 105.7 mmol), and ethyl iodide (8.53 mL, 105.7 mmol). The mixture was stirred at 60 C. for 24 h in a sealed tube. The mixture was poured into 500 mL of H2O and extracted with diethyl ether, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (9.69 g, 52.33 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.94 (m, 1H), 6.71-6.77 (m, 1H), 6.66-6.71 (m, 1H), 4.11-4.19 (m, 2H), 1.45-1.51 (m, 3H).
85%	With potassium carbonate; In butanone; at 80℃; for 18h;Inert atmosphere;	Dissolved the commercially available 5-fluoro-2-nitrophenol (250 mg, 1.59 mmol) in 2-butanone (10 ml) under Nitrogen. Added K2CO3 (659 mg, 4.77 mmol) and iodo-ethane (260 mg, 1.67 mmol). Stirred at 80 C. for 18 hours. Cooled, filtered off and washed with 2-butanone. The filtrate was concentrated in vacuo. Redissolved in EtOAc and washed with 0.5N NaOH (2×25 ml) and aq. sat. NaCl (25 ml). Dried over Na2SO4, filtered off and concentrated in vacuo. Gave 251 mg (85%) yellow liquid.GC: >95%MS: [M]+=185

83.1%	With potassium carbonate; In N,N-dimethyl-formamide; at 37℃;	5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), 56 potassium carbonate (13.17 g, 95.4 mmol) were suspended in 150 mL 40 DMF, 346 ethyl iodide (5.00 mL, 63.6 mmol) was added dropwise, and the reaction was heated to 37 C. with stirring. After TLC detected the reaction was complete, the system was poured in 252 ice-water, extracted with ethyl acetate (200 mL×3), the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the filtrate was separated on column chromatography (eluant:petroleum ether/ethyl acetate (v/v)=20:1), to afford 4.8 g of a yellow oil. Yield was 83.1%.
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;	5-fluoro-2-nitrophenol (300 mg), ethyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50 C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;	Step 1: Preparation of 4-fluoro-2-ethoxy-1-nitrobenzene 5-fluoro-2-nitrophenol (300 mg), ethyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50C overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.

Reference： [1]Patent: US2018/289706,2018,A1 .Location in patent: Paragraph 0379; 0380
[2]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 125
[3]ChemMedChem,2016,vol. 11,p. 488 - 496
[4]Patent: US2010/280268,2010,A1 .Location in patent: Page/Page column 49
[5]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0446; 0447
[6]ACS Infectious Diseases,2021,vol. 7,p. 1901 - 1922
[7]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6192 - 6196
[8]Patent: US2015/152069,2015,A1 .Location in patent: Paragraph 0187; 0188
[9]Patent: EP2883875,2015,A1 .Location in patent: Paragraph 0068

9
[ 110-85-0 ]
[ 28987-44-2 ]
[ 1089280-28-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	In 1,4-dioxane; at 120℃; for 72h;	To 2-(ethyloxy)-4-fluoro-1-nitrobenzene (Example 116, step A) (3.0 g, 16.2 mmol) in 60 mL of dioxane was added, piperazine (4.19 g, 48.61 mmol). The mixture was heated to 120 C. 72 h. The mixture was purified by flash chromatography to give the title compound of step A (3.6 g, 14.33 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=9.34 Hz, 1H), 6.40 (dd, J=9.34, 2.56 Hz, 1H), 6.30 (d, J=2.56 Hz, 1H), 4.13 (q, J=6.96 Hz, 2H), 3.30-3.33 (m, 4H), 2.95-3.02 (m, 4H), 1.48 (t, J=6.96 Hz, 3H).

Reference： [1]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 147

10
[ 50533-97-6 ]
[ 28987-44-2 ]
[ 1124330-03-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 100℃; for 4h;	4-(Dimethylamino)piperidine (2.89 g) was added to a stirred solution of 2-ethoxy-4-fluoro- 1 -nitrobenzene (3.79 g) and DIPEA (7.1 mL) in DMA (17.5 mL). The mixture was then heated to 1000C for 4h. The mixture was then concentrated in vacuo and purified by SCX, eluting with 7M NH3/ MeOH to afford the title compound (6.10 g, 102 %) as a yellow solid; 1H NMR: 1.39 (5H, m), 1.82 (2H, d), 2.19 (6H, s), 2.36 (IH, m), 2.96 (2H, t), 4.00 (2H, d), 4.19 (2H, q), 6.50 (IH, dd), 6.58 (IH, d), 7.86 (IH, d); m/z: MH+ 294.

Reference： [1]Patent: WO2009/24824,2009,A1 .Location in patent: Page/Page column 88

11
[ 108-01-0 ]
[ 28987-44-2 ]
[ 1124330-06-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; at 80℃; for 16h;	7V,7V-Dimethylethanolamine (5.02 mL) was added a mixture of 2-ethoxy-4-fluoro-l- nitrobenzene (4.63 g) and tetra-n-butylammonium bromide (1.61 g) in toluene (20 mL) and 25% w/v aq. KOH (20 mL). The mixture was heated to 800C for 16h and was then poured onto ice water (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic portions were washed with water (2 x 50 mL) and brine (2 x 50 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC using 5-10% (2M NH3 /MeOH) in DCM afforded the title compound (3.50 g, 55%) as a yellow gum; 1H NMR: 1.35 (3H, t), 2.23 (6H, s), 2.65 (2H, t), 4.20 (4H, m), 6.66 (IH, dd), 6.79 (IH, d), 7.92 (IH, ); m/z: MH+ 255.

Reference： [1]Patent: WO2009/24824,2009,A1 .Location in patent: Page/Page column 89

12
[ 4318-37-0 ]
[ 28987-44-2 ]
[ 1124330-01-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 100℃; for 4h;	<strong>[4318-37-0]1-Methylhomopiperazine</strong> (2.82 mL) was added to a stirred solution of 2-ethoxy-4-fiuoro-l- nitrobenzene (3.5 g) and DIPEA (6.54 mL) in DMA (17.5 mL). The mixture was heated at 1000C for 4h then diluted with water (75 mL) and extracted with DCM (3 x 150 mL). The combined organic portions were washed with brine (3 x 75 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound (5.0 g, 95%) as a gum; 1H NMR: 1.37 (3H, t), 1.94-1.87 (2H, m), 1.96 (3H, s), 2.67 (2H, t), 3.57 (2H, t), 3.66-3.63 (2H, m), 4.18 (2H, q), 6.27 (IH, d), 6.42 (IH, dd), 7.87 (IH, d); m/z: MH+ 280.

Reference： [1]Patent: WO2009/24824,2009,A1 .Location in patent: Page/Page column 87

13
[ 109-01-3 ]
[ 28987-44-2 ]
1-(3-ethoxy-4-nitro-phenyl)-4-methyl-piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	at 20℃; for 18h;	(b)1-(3-ethoxy-4-nitro-phenyl)-4-methyl-piperazineN-Methylpiperazine (603 pL, 5.44 mmol) was added to 2-ethoxy-4-fluoro-1-nitro-benzene (500 mg, 2.7 mmol) and the resulting mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and subsequently extracted with ethyl acetate.The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacua. The crude product was purified by column chromatography on silica (DCM/MeOH = 10/0 to 9/1 vlv%) to yield the title compound (646 mg, 90%).

Reference： [1]Patent: WO2015/155042,2015,A1 .Location in patent: Page/Page column 30
[2]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 30 - 38

14
[ 28987-44-2 ]
[ 760968-77-2 ]
[ 951667-63-3 ]

Yield	Reaction Conditions	Operation in experiment
50%		5-Hydroxy-2-(toluene-4-sulfonylamino)-benzoic acid methyl ester (200 mg, 0.622 mmol) was dissolved in dry DMF (5 ml) under Nitrogen. Added K2CO3 (215 mg, 1.56 mmol) and 2-Ethoxy-4-fluoro-1-nitro-benzene (121 mg, 0.653 mmol). Heated to 80 C. for 3 hours. Cooled to room temperature. Added EtOAc, washed with 0.5 M KHSO4 (2×25 ml), aq. sat. NH4Cl (25 ml), 0.5 M NaOH (2×25 ml) and aq. sat. NaCl (25 ml). Dried over Na2SO4, filtered off and concentrated in vacuo. Stripped with CH2Cl2. Stirred up in EtOH. Gave crystal formation. Filtered off and washed with EtOH, dried on filter and on vacuo line. Gave an off white solid 150 mg (y:50%).LC: >95%MS: [M+H]+=487

Reference： [1]Patent: US2010/280268,2010,A1 .Location in patent: Page/Page column 49

15
[ 110-91-8 ]
[ 28987-44-2 ]
[ 415686-74-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4377 - 4385

16
[ 28987-44-2 ]
[ 1246529-73-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4377 - 4385

17
[ 28987-44-2 ]
[ 761441-14-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4377 - 4385

18
[ 28987-44-2 ]
[ 1395171-63-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4377 - 4385

19
[ 28987-44-2 ]
1-(4-(4-((4-((4-(4-acetylpiperazin-1-yl)-2-ethoxyphenyl)amino)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6192 - 6196

20
[ 28987-44-2 ]
1-(4-(4-amino-3-ethoxyphenyl)piperazin-1-yl)ethanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6192 - 6196
[2]Patent: US2015/152069,2015,A1
[3]Patent: EP2883875,2015,A1

21
[ 28987-44-2 ]
1-(4-(4-(2,5-dichloropyrimidin-4-ylamino)-3-ethoxyphenyl)piperazin-1-yl)ethanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6192 - 6196

22
[ 13889-98-0 ]
[ 28987-44-2 ]
1-(4-(3-ethoxy-4-nitrophenyl)piperazin-1-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	Step 2: Preparation of 1-(4-(3-ethoxy-4-nitrophenyl)piperazin-1-yl)ethanone The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80C overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid. 1H-NMR(300 MHz, CDCl3) δ 7. 97 (d, J = 9.3 Hz, 1H), 6.40(dd, J = 2.5, 9.3 Hz, 1H), 6.32(d, J = 2.5 Hz, 1H), 4.15(q, J = 7.0 Hz, 2H), 3.79(m, 2H), 3.66(m, 2H), 3.40(m, 4H), 2.15(s, 3H), 1.50(t, J = 7.0 Hz, 3H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80 C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid. [0190]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6192 - 6196
[2]Patent: EP2883875,2015,A1 .Location in patent: Paragraph 0069
[3]Patent: US2015/152069,2015,A1 .Location in patent: Paragraph 0189; 0190

23
[ 64-17-5 ]
[ 446-35-5 ]
[ 28987-44-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate;Heating;	To ethanol (70 mL) was added compound 68 2,4-difluoro-1-nitrobenzene (5.0 g, 31.44 mmol), and cesium carbonate (30.66 g, 94.34 mmol). The mixture was heated and stirred overnight. After TLC indicated the reaction was completed, the mixture was evaporated to dryness, diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent, thus obtaining a crude product. The crude product was further isolated and purified by column chromatography to obtain a white solid (5.5g, yield 95%).
92%		(aox-4-fluoro-1-nitro-benzeneTo a cold (0 C) mixture of ethanol (0.735 mL, 12.6 mmol) in THE (15 mL)was added sodium hydride (60% dispersion in mineral oil, 553 mg, 13.83 mmol). The reaction mixture wasstirred at 0C for 15 mm, after which a solution of 2,4-difluoro-1-nitrobenzene (1.38 mL, 12.6 mmol) in THE (25 mL) was added dropwise. After stirring for an additional 90 mm at room temperature the reaction was quenched with water the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacua. The residue was purified by column chromatography (heptane/ethylacetate = 100/0 to 85/15 v/v%) to afford 2-ethoxy-4-fluoro-1-nitro-benzene (2.15 g, 92 %).
		Ethanol (83mg, 1.82mmol) Soluble in toluene (8ml), Cool to 0 - 5 C in an ice bath, Slowly add potassium tert-butoxide (205mg, 1.82mmol), Keep the temperature at 0 - 5 C, Stir for 15 minutes, Slowly add 2,4-difluoronitrobenzene (290mg, 1.82mmol), React in ice bath for 2 hours, Diluted with water and extracted with ethyl acetate, Dry over anhydrous sodium sulfate and filter, Concentrate under reduced pressure to give a light yellow solid.

Reference： [1]Patent: EP3372594,2018,A1 .Location in patent: Paragraph 0175; 0176
[2]Patent: WO2015/155042,2015,A1 .Location in patent: Page/Page column 30
[3]Organic Process Research and Development,2014,vol. 18,p. 912 - 918
[4]Patent: CN111217816,2020,A .Location in patent: Paragraph 0275; 0278-0281
[5]Bioorganic and Medicinal Chemistry,2021,vol. 48

24
[ 28987-44-2 ]
[ 1124330-34-2 ]

Reference： [1]Patent: WO2015/155042,2015,A1
[2]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 30 - 38

25
[ 28987-44-2 ]
3-ethoxy-N₁-hexylbenzene-1,4-diamine [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 488 - 496

26
[ 28987-44-2 ]
[ 1415301-95-9 ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 488 - 496

27
[ 111-26-2 ]
[ 28987-44-2 ]
3-ethoxy-N-hexyl-4-nitroaniline [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 488 - 496

28
[ 74-96-4 ]
[ 446-36-6 ]
[ 28987-44-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl-formamide; at 37℃;	5-fluoro-2-nitrophenol (120 g, 1 eq), potassium carbonate (316 g, 3 eq) was suspended in 2 L DMF, and bromoethane (166 g, 2 eq) The temperature was raised to 37 C, After the TLC test reaction was completed, the system was poured into ice water and the product precipitated and washed with water to give 5-fluoro-2-nitrophenylethyl ether (138.6 g, yield 98%).
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 37℃;	The 5-fluoro-2-nitrophenol (6g, 1eq), potassium carbonate (15.8g, 3eq) was suspended in 150mlN, N, N-Dimethylformamide, was added dropwise bromoethane (8.3g, 2eq), the reaction temperature was raised to 37 [deg.] C with stirring, TLC detection reactionAfter completion, the system was poured into ice water, the precipitated product was filtered washed with diethyl ether to give 5-fluoro-2-nitrobenzene (6.8g, yield97%).
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 35 - 40℃;	5-fluoro-2-nitrophenol (6 g, 1 eq),Potassium carbonate (15.8 g, 3 eq)Was added to 150 ml of N, N-dimethylformamide,Bromoethane (8.3 g, 2 eq) was added dropwise with stirring,Raising the temperature to 35-40 C stirring reaction,After TLC detection reaction was completed,The reaction solution was poured into ice water,Product precipitation, filtration, washing,5-fluoro-2-nitrophenylethyl ether (6.8 g, yield 97%).

Reference： [1]Patent: CN106995437,2017,A .Location in patent: Paragraph 0114; 0116-0118
[2]Patent: CN105461695,2016,A .Location in patent: Paragraph 0157; 0158
[3]Patent: CN107043368,2017,A .Location in patent: Paragraph 0118; 0119

29
[ 28987-44-2 ]
2-ethoxy-4-fluoro-5-nitroaniline [ No CAS ]

Reference： [1]Patent: CN105461695,2016,A
[2]Patent: CN106995437,2017,A
[3]Patent: CN107043368,2017,A
[4]Patent: US2019/152954,2019,A1

30
[ 28987-44-2 ]
N-(2-ethoxy-4-fluoro-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: CN106995437,2017,A

31
[ 28987-44-2 ]
N-(4-fluoro-2-ethoxy-5-nitrophenyl)-4-(1-methyl-1H-indole-3-yl)-pyrimidin-2-amine [ No CAS ]