65300-53-0|4-(2-(4-Nitrophenoxy)ethyl)morpholine| Ambeed

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Quality Control of [ 65300-53-0 ] Purity: 98% SDS Specification

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Product Details of [ 65300-53-0 ]

CAS No. :	65300-53-0
Formula :	C₁₂H₁₆N₂O₄
M.W :	252.27
SMILES Code :	O=[N+](C1=CC=C(OCCN2CCOCC2)C=C1)[O-]
MDL No. :	MFCD00434241
InChI Key :	BERKHGFFGHNCSO-UHFFFAOYSA-N
Pubchem ID :	800881

Safety of [ 65300-53-0 ]

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

Application In Synthesis of [ 65300-53-0 ]

* 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 [ 65300-53-0 ]

[ 65300-53-0 ] Synthesis Path-Downstream 1~35

1
[ 3240-94-6 ]
[ 100-02-7 ]
[ 65300-53-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In acetonitrile; for 2.5h;Reflux;	A mixture of 18a (3.04g, 22mmol), 18b (3.72g, 20mmol) and K2CO3 (2.07g, 60mmol) in CH3CN (8OmL) was heated under reflux for 2.5h. The solid was filtered off and the filtrate was evaporated under vacuum. The residue was purified by column chromatography (EA:PE=1 :2) to provide 18c (4.58g, 91%).

References: [1]Patent: WO2009/154769,2009,A1 .Location in patent: Page/Page column 46.
[2]Bulletin de la Societe Chimique de France,1955,p. 1353,1358.
[3]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5738 - 5748.

2
[ 65300-53-0 ]
[ 52481-41-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 5%-palladium/activated carbon; hydrogen; In tetrahydrofuran; methanol; under 2068.65 Torr; for 17h;	A solution of 22 (33.3 g, 132 mmol) in MeOH (170 mL) and THF (50 mL) with Pd/C (5%, ca. 3 g) was hydrogenated at 40 psi overnight (17 h). The mixture was filtered through Celite and the Celite plug was washed with CH2Cl2:MeOH (5:1) several times. The combined filtrates were evaporated to give 23 as a pink solid (29.0 g, 99%); δH (CDCl3) 6.77-6.72 (m, 2H), 6.65-6.60 (m, 2H), 4.04 (t, J = 5.8 Hz, 2H), 3.76-3.70 (m, 4H), 3.41 (br s, 2H), 2.76 (t, J = 5.8 Hz, 2H), 2.60-2.54 (m, 4H); consistent with that reported [11]. [Found: C, 64.94; H, 8.08; N, 12.66. C12H18N2O2 requires C, 64.84; H, 8.16; N, 12.60].
96%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 25℃; under 760.051 Torr; for 18h;	Under hydrogen (1 atm), to a solution of compound 8-b (900 mg, 3.57 mmol) in ethanol (50 mL) was added 10% Pd-C (0.5 g). The mixture was stirred at 25 C. for 18 hours, and then filtrated. The filtrate was concentrated under reduced pressure to give light yellow oil 8-a (760 mg, yield: 96%), which was used directly for the next step without purification.
95%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃;	the compound 4-[2-(4-Nitrophenoxy) ethyl] morpholine (5) 1.12g (5mmol) dissolved in 60mL of Methanol, added the 0.20g of Palladium on carbon, then passes through the hydrogen at room temperature for reduction reaction, TLC monitors the reaction process, then obtained the compound 4-[2-(4-aminophenoxy) ethyl] morpholine (6) 0.92g, yield 95%.

94%	With palladium 10% on activated carbon; hydrogen; for 3.5h;Reflux;	A mixture of compound 10 (10.10 g, 40 mmol) and Pd/C (1.01 g, 10% (w/w)) were added in ethanol (50 mL). The reaction mixture was stirred reflux for 3.5 h under the action of H2. The mixture was filtered under the action of diatomaceous earth and the filtrate was concentrated at 50 C to obtain compound 11. Red solid. Yield: 94.0%; 1H NMR (400 MHz, DMSO-d6) δ: 6.63, (d, J =8.8 Hz, 2H), 6.48, (d, J =8.8 Hz, 2H), 4.57, (s, 2H), 3.92, (t, J =6.0 Hz, 2H), 3.57, (t, J =4.8 Hz, 4H), 2.61, (t, J =5.6 Hz, 2H), 2.44, (t, J =4.4 Hz, 4H). MS [ESI]: m/z, 223.2 [M+H]+.
92%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃;	Into a Round bottom flask, [A] 4-[2-(4-Nitro-phenoxy)-ethyl]-morpholine (3.70 g,0.0147 mol), 10 % Pd/C(10:90, Palladium: carbon black, 1.6 g, 0.0015 mol), and Ethanol (100 niL, 2 mol) were added. The mixture was evacuated under house vacuum and charged with ahydrogen balloon (3X). The reaction was stired at room temperature under an atmosphere of Hydrogen via a balloon. The solid was filtered. The solvent was removed under vacuum to give 4-(2-Morpholin-4-yl-ethoxy)-phenylamine a white solid (3.0Og, 92%). NMR 1H (DSMO-d6)- 6.63 (dd, IH, J= 1.92, 4.76 Hz), 6.49 (dd, 2H, J= 1.97, 4.72 Hz), 4.52 (bs, 2H), 3.91 (t, 2H, J= 5.84 Hz), 3.56 (t, 4H, J= 4.60 Hz), 2.60 (t, 2H, J= 4.580 Hz), 2.47 (t, 4H, J= 4.48 Hz)
63%	With hydrogen;palladium dihydroxide; In ethanol; under 3750.38 Torr; for 2h;	Step 1 4-(2-Morpholιn-4-yl-ethoxy)-phenylamιne[00307] To a solution of 4-[2-(4-nitro-phenoxy)-ethyl]-morpholme (2 25g, 8 93mmol) m ethanol(4OmL) is added palladium hydroxide (0 313g, 0 45mmol) and the mixture is stirred in a Parr-apparatus under hydrogen pressure (5 bars) for 2 hours Filtration over Celite 521 and evaporation gave a red oil puϖfed by silica gel column chromatography Elution with DCM and a mixture 90 10 DCM MeOH affords the title compound as a white solid (1 256g, 63%) 1H-NMR (400MHz, CDCl3) δ (ppm) 2 52 2 63 (4H, m), 2 71-2 80 (2H, t), 3 46 (2H, br s), 3 70-3 78 (4H, m), 4 00-4 10 (2H, m), 6 65 (2H, d), 6 77 (2H, d)
	With hydrogen;palladium 10% on activated carbon; In ethanol; water; at 20℃; under 2999.54 Torr; for 1h;	Example 6 4-(2-(Morpholin-4-yl)ethoxy)phenylamine (11): A solution of 10 (6.00 g, 23.8 mmol) in 95% EtOH (40 mL) was hydrogenated over Pd/C (10%, 350 mg) at 58 psi H2 for 1 h at room temperature. The formed solid was removed by filtration through Celite, which was washed thoroughly with EtOH (100 mL) and MeOH (50 mL); the filtrate was concentrated in vacuo to give 11 (5.29 g, quant.) as a reddish brown oil, which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 2.57 (mc, 4H, 3"-H2, 5"-H2), 2.76 (t, J=5.8 Hz, 2H, 2'-H2), 3.40 (sbr, 2H, NH2), 3.73 (mc, 4H, 2"-H2, 6"-H2), 4.03 (t, J=5.8 Hz, 2H, 1'-H2), 6.59-6.66 (m 2H, 2-H, 6-H), 6.71-6.78 (m, 2H, 3-H, 5-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ=54.0 (C-3", C-5"), 57.7 (C-2'), 66.3 (C-1'), 66.8 (C-2", C-6"), 115.7 (C-3, C-5), 116.2 (C-2, C-6), 140.2 (C-1), 151.7 (C-4) ppm; MS (70 eV, EI): i/z (%) 222 (17) [M]+, 100 (100) [M-CH2OC6H4-NH2]+.
	With hydrogen;palladium 10% on activated carbon; In methanol; under 22801.5 Torr;	b. EPO <DP n="66"/>The nitro compound (prepared as in step a, 80 g, 0.32 mole) was dissolved in MeOH (1.5 L) and added to a 4 L autoclave. To this was added 10% Pd/C (5 g) and the autoclave charged with hydrogen (30 atmospheres). The reaction was stirred overnight, then filtered to remove the catalyst. The filtrate was concentrated and distilled under vacuum to give an oil. The oil was taken up in hot cylohexane. The excess solvent was decanted off, and the solution cooled, and filtered. The solids were washed with hexanes to give the product (23.7 g)IH NMR (300 MHz, DMSO-d6) δ ppm 6.67 (d, 2H, J = 8.7), 6.53 (d, 2H, J = 8.7), 4.62 (s, 2H), 3.95 (t, 2H, J = 5.9), 3.6 (m, 4H), 2.64 (t, 2H, J = 5.7), 2.47 (m, 4H)
	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2999.54 Torr; for 24h;	A solution of 10 (6.00 g, 23.8 mmol) in 95% EtOH (40 mL) was hydrogenated over Pd/C (10%, 350 mg) at 58 psi H2 for 1 h at room temperature. The formed solid was removed by filtration through Celite, which was washed thoroughly with EtOH (100 mL) and MeOH (50 mL); the filtrate was concentrated in vacuo to give 11 (5.29 g, quant.) as a reddish brown oil, which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): 5 = 2.57 (m, 4 H, 3"-H2, 5"-H2), 2.76 (t, J= 5.8 Hz, 2 H, 2'-H2), 3.40 (sbr, 2 H, NH2), 3.73 (In0, 4 H, 2"-H2, 6"-H2), 4.03 (t, J= 5.8 Hz, 2 H, 1'-H2), <n="88"/>6.59-6.66 (m, 2 H, 2-H, 6-H), 6.71-6.78 (m, 2 H, 3-H, 5-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ = 54.0 (C-3", C-5"), 57.7 (C-21), 66.3 (C-I1), 66.8 (C-2", C-6"), 115.7 (C-3, C-5), 116.2 (C-2, C-6), 140.2 (C-I), 151.7 (C-4) ppm; MS (7O eV, EI): m/z (%) = 222 (17) [M]+, 100 (100) [M-CH2OC6H4-NH2]+.
	With hydrogen;palladium over charcoal; In ethanol; at 20℃;	Step B: 8.1 g (32 [MMOL)] of [4- [2- (4-NITRO-PHENOXY)-ETHYL]-MORPHOLINE] is dissolved in 100 mL of ethanol and subjected to catalytic hydration at rt using 681 mg of [PD/C.] After filtration trough HYFLO and removal of the solvent under reduced pressure, the crude product is purified by bulb-to-bulb distillation (0.13 mbar; [200C)] to obtain 4- (2-morpholin-4-yl-ethoxy)- phenylamine. Title compound: ES-MS: 223 [M+H] [+] ; single peak at [TR=] 3 min (System 2).
	With 5%-palladium/activated carbon; hydrogen; In methanol; at 20℃; for 4h;	General procedure: N,N-Dimethyl-3-(4-nitrophenoxy) propan-1-amine (d14) (3.92 mmol) was dissolved in 30 mL anhydrous methanol, and then 0.1 g Pd/C (5%) was added to this solution. After that, the mixture was reacted at room temperature under N2 for 4 h. The mixture was filtered, and Pd/C was washed with methanol for 3-4 times. The organic phases were combined and methanol was removed by reduced pressure distillation to give the crude product. The residue was reserved for the next step.
	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 4h;	General procedure: In 100 mL flask, 4-nitrophenol (1.39 g, 10 mmol) was dissolved in 20 mL anhydrous DMF. Then 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (1.57 g, 10 mmol) and Cs2CO3 (5.29 g, 15 mmol) were added to the solution. Under nitrogen, the mixture was heated to 100 C, and reacted for 2.5 h. The mixture was filtered, and the filtrate was poured to ice water (200 mL). The aqueous phase was extracted by EtOAc. The combined organic phase was washed by Na2CO3, water, saturated sodium chloride. The organic layer was dried over Na2SO4 to afford (8). N,N-dimethyl-3-(4-nitrophenoxy) propan-1-amine (8) (3.92 mmol) was dissolved in 30 mL anhydrous methanol, then 0.10 g Pd/C (5%) was added to this solution. After that, the mixture was reacted at room temperature under H2 for 4 h. The mixture was filtered, and Pd/C was washed with methanol for 3-4 times. The organic phases were combined and methanol was removed by reduced pressure distillation to yield (9a) for next step without purification.
	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 1h;	Compound 4a was synthesized in the same manner as in Reaction Scheme 1 above.Compound 3a and 10% palladium were added to methanol, stirred at room temperature under hydrogen for 1 hour, and filtered. The filtrate was concentrated in vacuo and the crude product was used in the next reaction without further purification.
	With palladium on activated charcoal; hydrogen; In methanol; at 20℃;	To a solution of 10a-f (0.1 mmol) in dry methanol (10 mL) was added catalytic amount ofPd-C, and then the mixture was stirred under hydrogen atmosphere at room temperature for 12hours. The Pd-C was filtered and the filtrate was evaporated to dryness under reduced pressure toafford final basic chains 11a-f, which were used without further purification.
	With hydrogen;palladium 10% on activated carbon; In methanol;	To a solution of 18c (160mg, 0.63mmola) in methanol (1OmL) was added 10% Pd/C (140mg). The mixture was hydrogenated under H2 atmosphere overnight. Pd/C was filtered off and the filtrate was evaporated to provide crude 18d (135mg, 96%) which was used for next step without purification.
2 g	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 12h;	General procedure: PdeC (0.27 g, 10% m/m) wasadded to a solution of 8a (2.7 g, 13.0 mmol) in ethanol (20 ml) andhydrogenated for 12 h at room temperature. The resultant wasfiltered, washed with ethanol and concentrated. 2.2 g of 9a aspurple solid was obtained; yield: 94%.
	With ammonium chloride; zinc; In water; at 20 - 70℃; for 1h;Inert atmosphere;	General procedure: 11a-b (50 mmol), 2,4,5-trichloropyrimidine (50 mmol) andDIPEA (100 mmol) in acetonitrile, it was gradually heated to 80 Cand stirred for 10 h. The precipitate was filtrated and washed withwater, and the acquired production could directly be used withoutfurther purification. 13a-k was prepared according to the reportedprocess [20e22,24]. Ar atmosphere, a mixture of 13a-k (15 mmol),ammonium chloride (20 mmol) and zinc powder (120 mmol) inethanol/water (100/20 mL) was reacted at 70 C for 1 h. After thereaction, the solvent was distilled off and the residuewas dispersedin dichloromethane. The zinc powder was removed by filtration,and the organic layer was washed with dilute ammonia and driedover anhydrous sodium sulfate. The organicwas vacuum distilled to give the crude which was purified by silica-gel column separationto get the 14a-k. A mixture of 12a-b (5.0 mmol), 14a-k (5.0 mmol), and p-TsOH(7.5 mmol) in ethyl alcohol was gradually heated to 70 C andstirred for 3 h. After reaction, the solvent was vacuum distilled andthe residuum was dispersed with saturated sodium bicarbonate/ethyl acetate. The crude product was purified using flash chromatographywith dichloromethane/methanol as eluents.Ar atmosphere,15a-k (2.0 mmol) and hydroxylamine (40 mmol)in anhydrous methanol, sodium methoxide (25 mmol) in methanolsolution was slowly added to the mixture. After the addition, thereaction was allowed to warm room temperature and stirred for2 h. Adjusted pH to 6 with dilute hydrochloric acid, the inorganicsalt was removed by filtration and the rest of organic phase wasvacuum distilled to produce the 9~a k.

References: [1]European Journal of Organic Chemistry,2006,p. 2314 - 2321.
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5738 - 5748.
[3]Tetrahedron,2019,vol. 75,p. 3001 - 3007.
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 6179 - 6194.
[5]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0149; 0152.
[6]Patent: CN103980152,2016,B .Location in patent: Paragraph 0045; 0047.
[7]Bioorganic and Medicinal Chemistry Letters,2020,vol. 30.
[8]Patent: WO2010/71885,2010,A1 .Location in patent: Page/Page column 398-399.
[9]Patent: WO2007/131991,2007,A1 .Location in patent: Page/Page column 70.
[10]Bulletin de la Societe Chimique de France,1955,p. 1353,1358.
[11]Journal of the American Chemical Society,1938,vol. 60,p. 896,899.
[12]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 3580 - 3600.
[13]Patent: US2009/318668,2009,A1 .Location in patent: Page/Page column 48.
[14]Patent: WO2007/18941,2007,A2 .Location in patent: Page/Page column 65.
[15]Patent: WO2007/89149,2007,A2 .Location in patent: Page/Page column 86-87.
[16]Patent: WO2004/5282,2004,A1 .Location in patent: Page 41.
[17]Chemical Biology and Drug Design,2011,vol. 78,p. 695 - 699.
[18]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2527 - 2534.
[19]Chemical Biology and Drug Design,2014,vol. 83,p. 592 - 599.
[20]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2871 - 2876.
[21]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1044 - 1054.
[22]European Journal of Medicinal Chemistry,2017,vol. 133,p. 329 - 339.
[23]Patent: KR2016/147170,2016,A .Location in patent: Paragraph 0058; 0060; 0090; 0091; 0092.
[24]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2668 - 2673.
[25]Patent: WO2009/154769,2009,A1 .Location in patent: Page/Page column 46.
[26]European Journal of Medicinal Chemistry,2019,vol. 181.
[27]European Journal of Medicinal Chemistry,2021,vol. 223.

3
[ 622-40-2 ]
[ 350-46-9 ]
[ 65300-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 20℃;	A solution of 4-fluoronitrobenzene (0.141 g, 0.106 ML, 0. 001MOL), aminoalcohol (1.1 equiv) in tetrahydrofuran (8-10 mL) was cooled to 0 C in a sealed tube. A solution of KHMDS (0.5 M in toluene) was added dropwise, and the reaction mixture was allowed to reach room temperature. The mixture was partitioned between sat. aq. K2CO3 and ethylacetate. The organic layer was separated, dried over anhydrous NA2S04, and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0 to 10% methanol-dichloromethane) to afford the alkoxynitrobenzene
		a. 4~[2-(4-nitro-phenoxy)-θthyl]-morpholine; Sodium hydride (60 %, 8.4 g) was suspended in THF (400 mL) and then treated with 4-(2-hydroxyethyl)morpholine (25 g, 0.191 mole) in portions (caution: foaming and gas evolution.). After the addition the mixture was stirred for 1 hour at room temperature, and then cooled to 0 0C. 1-fluoro-4-nitro-benzene (26.95 g, 0.191 mole) was dissolved in THF (50 mL) and added dropwise to the stirring alkoxide. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent volume was reduced by two thirds and diluted with water (1.5 L). This solution was extracted with DCM, dried (Na2SO4), filtered and concentrated to an oil. The oil was triturated with hexanes to give an orange-yellow solid which was filtered and washed with more hexanes (29 g).
	With triethylamine; In acetonitrile; for 3h;Reflux;	General procedure: To a stirred solution of 1-fluoro-4-nitrobenzene 7 (2.0 g, 14.2 mmol) in 20 mL acetonitrilewas added morpholine (1.9 g, 21.3 mmol) followed by triethylamine(4.3 g, 5.9 mL, 42.5 mmol). The mixture was stirred at reflux for 3 h.After the reaction was cooled to room temperature, it was pouredinto 80 mL water and extracted with ethyl acetate (2 x 80 mL). Thecombined organic layers were washed with brine (60 mL), driedover sodium sulfate, concentrated in vacuo, then dried under vacuumto obtain 2.7 g of 8a as yellow solid; yield: 92%; 8a was usedwithout further purification.

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 3580 - 3600.
[2]Patent: WO2005/9978,2005,A1 .Location in patent: Page 100; 103.
[3]Patent: WO2007/18941,2007,A2 .Location in patent: Page/Page column 64.
[4]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2871 - 2876.
[5]European Journal of Medicinal Chemistry,2019,vol. 181.

5
[ 3647-69-6 ]
sodium-<4-nitro-phenolate [ No CAS ]
[ 65300-53-0 ]

References: [1]Journal of Organic Chemistry,1951,vol. 16,p. 1421,1424.

6
[ 3240-94-6 ]
[ 1124-31-8 ]
[ 65300-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; for 24h;Reflux;	Example 5 4-[2-(4-Nitrophenoxy)ethyl]morpholine (10): A solution of KOH (3.3 g, 58 mmol) in EtOH (15 mL) was added dropwise to a solution of 4-nitrophenol (9) (7.0 g, 50 mmol) in EtOH (10 mL). After stirring for 30 min at room temperature the salt was collected by filtration, washed with cold EtOH and dried in vacuo to give the potassium salt of 9 as a yellow solid (7.1 g, 40 mmol). The salt (7.1 g, 40 mmol) was dissolved in toluene (100 mL), a solution of 4-(2-chloroethyl)-morpholine (6.5 g, 43 mmol) in toluene (100 mL) was added and the mixture was heated at reflux for 24 h. After cooling to room temperature the precipitate was separated by filtration, washed thoroughly with toluene, and the filtrate was concentrated in vacuo to give 10 as a pale yellow solid (7.2 g, 57% overall yield), which was used for the next step without further purification. 1H NMR (200 MHz, CDCl3): δ=2.54-2.64 (m, 4H, 3-H2, 5-H2), 2.84 (t, J=5.5 Hz, 2H, 1'-H2), 3.69-3.78 (m, 4H, 2-H2, 6-H2), 4.20 (t, J=5.5 Hz, 2H, 2'-H2), 6.92-7.01 (m, 2H, 2"-H, 6"-H), 8.16-8.25 (m, 2H, 3"-H, 5"-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ=54.1 (C-3, C-5), 57.3 (C-1'), 66.7 (C-2'), 66.9 (C-2, C-6), 114.5 (C-2", C-6"), 125.9 (C-3", C-5"), 141.6 (C-4"), 163.7 (C-1") ppm; MS (70 eV, EI): m/z (%)=252 (8) [M]+, 100 (100) [M-CH2OC6H4-NO2]+.
	In toluene; for 24h;Heating / reflux;	A solution of KOH (3.3 g, 58 mmol) in EtOH(15 mL) was added dropwise to a solution of 4-nitrophenol (9) (7.0 g, 50 mmol) in EtOH (10 mL). After stirring for 30 min at room temperature the salt was collected by filtration, washed with cold EtOH and dried in vacuo to give the potassium salt of 9 as a yellow solid (7.1 g, 40 mmol). The salt (7.1 g, 40 mmol) was dissolved in toluene (10O mL), a solution of 4-(2-chloroethyl)~ morpholine (6.5 g, 43 mmol) in toluene (100 mL) was added and the mixture was heated at reflux for 24 h. After cooling to room temperature the precipitate was separated by filtration, washed thoroughly with toluene, and the filtrate was concentrated in vacuo to give 10 as a pale yellow solid (7.2 g, 57% overall yield), which was used for the next step without further purification. 1H NMR (200 MHz, CDCl3): δ = 2.54-2.64 (m, 4 H, 3-H2, 5-H2), 2.84 (t, J= 5.5 Hz, 2 H, 1'-H2), 3.69-3.78 (m, 4 H, 2-H2, 6-H2), 4.20 (t, J= 5.5 Hz, 2 H, 2'-H2), 6.92-7.01 (m, 2 H, 2"-H, 6"-H), 8.16-8.25 (m, 2 H, 3"-H, 5"-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ = 54.1 (C-3, C-5), 57.3 (C-I'), 66.7 (C-21), 66.9 (C-2, C-6), 114.5 (C-2", C-6"), 125.9 (C-3", C-5"), 141.6 (C-4"), 163.7 (C-I") ppm; MS (70 eV, EI): m/z (%) = 252 (8) [M]+, 100 (100) [M-CH2OC6H4-NO2]*.

References: [1]European Journal of Organic Chemistry,2006,p. 2314 - 2321.
[2]Patent: US2009/318668,2009,A1 .Location in patent: Page/Page column 48.
[3]Patent: WO2007/89149,2007,A2 .Location in patent: Page/Page column 86.

7
[ 65300-53-0 ]
[ 902454-19-7 ]

References: [1]European Journal of Organic Chemistry,2006,p. 2314 - 2321.
[2]Tetrahedron,2019,vol. 75,p. 3001 - 3007.

8
[ 65300-53-0 ]
5-[(2-morpholin-4-yl)ethoxy]-1H-indole-2-carboxylic acid hydrochloride [ No CAS ]

References: [1]European Journal of Organic Chemistry,2006,p. 2314 - 2321.
[2]Tetrahedron,2019,vol. 75,p. 3001 - 3007.

9
[ 65300-53-0 ]
[ 74773-30-1 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 3580 - 3600.

10
[ 65300-53-0 ]
[ 74773-31-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 3580 - 3600.

11
[ 65300-53-0 ]
[ 74773-32-3 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 3580 - 3600.

12
[ 65300-53-0 ]
[ 109473-83-8 ]

References: [1]Bulletin de la Societe Chimique de France,1955,p. 1353,1358.

13
[ 65300-53-0 ]
[ 101956-11-0 ]

References: [1]Bulletin de la Societe Chimique de France,1955,p. 1353,1358.

14
[ 622-40-2 ]
[ 100-00-5 ]
[ 65300-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 3.5h;	[STEP A : TO THE SOLUTION OF 8.0 G (51 MMOL) OF 1-CHLORO-4-NITROBENZENE AND 6.7 G (6.3 ML; 51] mMol) of N-hydroxyethyl-morpholine in 50 mL of DMF at [0C] is added 2.7 g of NaH portionwise over 2.5 h. After stirring another hour at rt, the reaction mixture is poured onto 200 mL of water and stirred. The precipitated crystals are filtered and dried at [60C] under vacuum to obtain [4- [2- (4-NITRO-PHENOXY)-ETHYL]-MORPHOLINE. TITLE] compound: ES-MS: 253 [M+H] + ; single peak at tR= 4.8 min (System 2).

References: [1]Patent: WO2004/5282,2004,A1 .Location in patent: Page 40-41.

Yield	Reaction Conditions	Operation in experiment
		The following compounds were obtained in the same manner as Reference Example 2. 4-(3-Phthalimidopropoxy)nitrobenzene, mp. 186-188 C. 4-[2-(N-Morpholino)ethoxy]nitrobenzene, mp. 88-89 C.

16
[ 350-46-9 ]
[ 65300-53-0 ]

References: [1]European Journal of Medicinal Chemistry,2017,vol. 133,p. 329 - 339.

17
[ 110-91-8 ]
[ 13288-06-7 ]
[ 65300-53-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In acetonitrile; at 80℃; for 4h;	Into a 30 mL vial, [A] l-(2-Bromo-ethoxy)-4-nitro-benzene (5.00 g, 0.0203 mol), Morpholine (3.54 mL, 0.0406 mol) , Acetonitrile (15.0 mL, 0.287 mol) and Potassium carbonate (5.62 g, 0.0406 mol) were added. The reaction was heated at 80 0C for 4 hours. The reaction was partitioned with water (250 mL). The solid was filtered and washed with water. The resulting solid was dried under vacuum overnight to give 4-[2-(4- Nitrophenoxy)-ethyl] -morpholine as an off-white solid (4.3Og, 84%). NMR 1H (DSMO- d6)- 8.20 (d, IH, J= 9.34 Hz), 7.17 (d, 2H, J= 9.34 Hz), 4.24 (t, 2H, J= 5.65 Hz), 3.57 (t, 4H, J= 4.60 Hz), 2.72 (t, 2H, J= 4.68 Hz), 2.47 (t, 4H, J= 4.52 Hz),
900 mg	With potassium carbonate; In acetonitrile; for 3h;Reflux;	Compound 8-c (1.0 g, 4.08 mmol) and morpholine (702 mg, 8.16 mmol) were dissolved in acetonitrile (5 mL), potassium carbonate (1.2 g, 8.16 mmol) was added. The mixture was refluxed for 3 hours, and then cooled to room temperature, after filtration, the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure, the residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and washed with water (50 mL×3) and saturated brine (50 mL) in sequence. After dried over anhydrous sodium sulfate, the mixture was filtrated, and the filtrate was concentrated in vacuum to give light yellow solid 8-b (900 mg), which was used directly for the next step without further purification.

References: [1]Patent: WO2010/71885,2010,A1 .Location in patent: Page/Page column 398.
[2]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0149; 0151.

18
[ 100-02-7 ]
[ 3647-69-6 ]
[ 65300-53-0 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2.5h;	A mixture of 4-nitrophenol (11.13 g, 80 mmol), 4-(2-chloroethy)morpholine hydrochloride (15.64 g, 84 mmol) and Cs2CO3 (33.90 g, 104 mmol) were added in DMF (80 mL). The whole solution was stirred at 100 C for 2.5 h. The reaction mixture was allowed to cool at r.t and water (400 mL) was added. The mixture was stirred at 0 C for 30 minutes, filtered, dried to obtain compound 10. White solid. Yield: 91.1%; 1H NMR (400 MHz, CDCl3-d) δ: 8.19, (d, J =9.2 Hz, 2H), 6.96, (d, J =9.2 Hz, 2H), 4.20, (t, J =5.6 Hz, 2H), 3.74, (t, J =4.8 Hz, 4H), 2.84, (t, J =5.6 Hz, 2H), 2.59, (t, J =4.8 Hz, 4H). MS [ESI]: m/z, 253.2 [M+H]+.
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;Inert atmosphere;	To a stirred mixture of 4-nitrophenol (21) (42 g, 0.30 mol) and 4-(2-chloroethyl)morpholine hydrochloride (56 g, 0.30 mol) in anhydrous DMF (400 mL) was added dry K2CO3 (104 g, 0.75 mol). The mixture was stirred under nitrogen at 80-90 C (bath temperature) for 3 h, then at 20 C overnight (15 h). The mixture was poured into ice-water (1.5 L) and stirred at 0 C for 1 h. The precipitated solid was filtered off, washed with water (6 * 100 mL) until the washes were colourless, then dried to give 22 as a pale yellow solid (68.4 g, 90%); mp 79-81 C [lit. mp 82-83 C (EtOAc/hexane) [21]]; δH (CDCl3) 8.23-8.17 (m, 2H), 6.99-6.94 (m, 2H), 4.20 (t, J = 5.7 Hz, 2H), 3.76-3.71 (m, 4H), 2.84 (t, J = 5.7 Hz, 2H), 2.62-2.55 (m, 4H); consistent with that reported [11]. [Found: C, 57.36; H, 6.44; N, 11.25.C12H16N2O4 requires C, 57.13; H, 6.39; N, 11.10].
82%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;	p-nitrophenol (4) 1.39g (10mmol) dissolved in anhydrous DMF, and then added the 5.29g (15mmol) of Cs2O3, 2-chloroethyl morpholine hydrochloride (10mmol), allow to warm at 100 C for 4 hours under the Nitrogen protection, and TLC monitors the reaction process. After completion of the reaction, the reaction solution was added to 100 mL of ice water and extracted three times with ethyl acetate. The organic phases were combined and washed successively with saturated sodium carbonate solution, water and saturated sodium chloride solution, and the final organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure then obtained compound 4-[2-(4-Nitrophenoxy) ethyl] morpholine (5) 1.84g, yield 82%.

With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2.5h;Inert atmosphere;

General procedure: In 100 mL flask, 4-nitrophenol (1.39 g, 10 mmol) was dissolved in 20 mL anhydro-DMF. Then 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (1.57 g, 10 mmol) and Cs2CO3 (5.29 g, 15 mmol) were added to the solution. Under N2, the mixture was heated to 100 C, and was reacted for 2.5 h. The mixture was filtered, and the filtrate was poured to ice water (200 mL). The aqueous phase was extracted by EtOAc (30 mL × 3). The combined organic phase was washed by Na2CO3 (10 mL × 4), water (10 mL × 2), saturated sodium chloride (15 mL). The organic layer was dried over Na2SO4, filtered, and distilled under vacuum to give the crude product.

References: [1]Bioorganic and Medicinal Chemistry Letters,2020,vol. 30.
[2]Tetrahedron,2019,vol. 75,p. 3001 - 3007.
[3]Patent: CN103980152,2016,B .Location in patent: Paragraph 0045-0046.
[4]Chemical Biology and Drug Design,2011,vol. 78,p. 695 - 699.
[5]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2527 - 2534.
[6]Chemical Biology and Drug Design,2014,vol. 83,p. 592 - 599.

19
[ 65300-53-0 ]
4-(2-morpholinoethoxy)-N-(prop-2-ynyl)aniline [ No CAS ]