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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 350-46-9 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1935 - 1946
[3] Patent: WO2016/73652, 2016, A1,
[4] Patent: CN105418590, 2016, A,
[5] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 545 - 557
[6] Patent: WO2017/139274, 2017, A1,
2
[ 350-46-9 ]
[ 52768-17-9 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 96, p. 369 - 380
3
[ 350-46-9 ]
[ 2632-65-7 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[2] Patent: CN105503775, 2016, A,
4
[ 350-46-9 ]
[ 2359-60-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[3] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1803 - 1806
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[5] Journal of Chemistry, 2014, vol. 2014,
[6] Patent: CN105503775, 2016, A,
[7] Patent: US2013/45977, 2013, A1,
[8] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
5
[ 350-46-9 ]
[ 2524-67-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4377 - 4385
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10685 - 10699
[6] Journal of Chemistry, 2014, vol. 2014,
[7] RSC Advances, 2015, vol. 5, # 113, p. 93433 - 93437
[8] Patent: US2015/336982, 2015, A1,
[9] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 9, p. 1289 - 1298
[10] Patent: CN106432239, 2017, A,
[11] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
[12] Patent: CN104583195, 2018, B,
[13] Patent: US2013/45977, 2013, A1,
[14] European Journal of Medicinal Chemistry, 2019, p. 161 - 175
[15] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
6
[ 109-97-7 ]
[ 350-46-9 ]
[ 4533-42-0 ]
Yield
Reaction Conditions
Operation in experiment
95.6%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5 h;
General procedure: A well-stirred mixture of pyrrole/indole (0.128mol) and K2CO3 (35.4g, 0.257mol) in DMF (150mL) was heated at 100°C for 30min. Then, p-fluoronitrobenzene (21.6g, 0.153mol) was added and the mixture was stirred for another 5h. Upon cooling to room temperature, the mixture was poured into water (300mL) to stir for 30min and filtered. The residue was washed with water, dried to give crude product and then treated with diethyl ether to afford 1a–1b.
38%
With potassium hydroxide In dimethyl sulfoxide at 80℃; for 16 h;
General procedure: A mixture of 2-fluorobenzamide (1a, 69.5 mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16 h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture was extracted with ethyl acetate three times (3 * 10 mL). The combined organic phases were dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05 in volume) to afford 2aa as a white solid in 80percent yield (60.7 mg).
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 96, p. 369 - 380
[2] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[3] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[4] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[5] Russian Journal of Organic Chemistry, 2008, vol. 44, # 10, p. 1517 - 1521
[6] Tetrahedron, 2018, vol. 74, # 2, p. 303 - 307
With potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide
33.1 1-(4-nitrophenyl)-1H-imidazole: 9 g (64.5 mmoles) of potassium carbonate and 5 g (3.75 ml; 35.2 mmol) of 1-fluoro-4-nitrobenzene are added to a solution of 2 g of imidazole (29.4 mmol) in 14 ml of DMF. The reaction mixture is agitated for 1.5 hours at 110° C. Ethyl acetate (50 ml) is added to the medium which is washed 3 times with 50 ml of water. The organic phases are dried over magnesium sulphate and concentrated under vacuum. 4.4 g of product are thus obtained (yield=80percent) in the form of a clear oil and used without further purification in the following stages. NMR 1H (CDCl3, 100 MHz, δ): 6.92 (t, 1H, Arom. H imidazole), 7.16 (s, 1H, Arom. H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, Arom. H), 7.59 (s, 1H, Arom. H imidazole).
80%
With potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide
33.1 1-(4-nitrophenyl)-1H-imidazole 9 g (64.5 mmoles) of potassium carbonate and 5 g (3.75 ml; 35.2 mmol) of 1-fluoro-4-nitrobenzene are added to a solution of 2 g of imidazole (29.4 mmol) in 14 ml of DMF. The reaction mixture is agitated for 1.5 hours at 110° C. Ethyl acetate (50 ml) is added to the medium which is washed 3 times with 50 ml of water. The organic phases are dried over magnesium sulphate and concentrated under vacuum. 4.4 g of product are thus obtained (yield=80percent) in the form of a clear oil and used without further purification in the following stages. NMR 1H (CDCl3, 100 MHz, δ): 6.92 (t, 1H, Arom. H imidazole), 7.16 (s, 1H, Arom. H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, Arom. H), 7.59 (s, 1H, Arom. H imidazole).
95%
With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether
a 4-(Imidazol-1-yl)nitrobenzene To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.19 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
95%
With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether
a 4-(Imidazol-1-yl)nitrobenzene To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.19 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
95%
With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether
1. 4-(Imidazol-1-yl)nitrobenzene. To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum dessicator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 9 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
95%
With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether
Step 4 4-(Imidazol-1-yl)nitrobenzene To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.59 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1935 - 1946
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 24, p. 4981 - 5001
[3] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[4] Australian Journal of Chemistry, 1993, vol. 46, # 4, p. 417 - 425
[5] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[6] Green Chemistry, 2016, vol. 18, # 20, p. 5580 - 5585
[7] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[8] Inorganic Chemistry, 2011, vol. 50, # 5, p. 1889 - 1897
[9] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[10] Patent: US2003/78420, 2003, A1,
[11] Patent: US6809088, 2004, B2,
[12] Patent: US6335445, 2002, B1, . Location in patent: Page column 84
[13] Synthetic Communications, 1993, vol. 23, # 14, p. 1947 - 1952
[14] Tetrahedron, 2007, vol. 63, # 37, p. 9163 - 9171
[15] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 11, p. 1437 - 1444
[16] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[17] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[18] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5263 - 5267
[19] Patent: EP698024, 1997, B1,
[20] Patent: US5889008, 1999, A,
[21] Patent: US5981529, 1999, A,
[22] Patent: US5854268, 1998, A,
[23] Bulletin of the Chemical Society of Japan, 2011, vol. 84, # 2, p. 205 - 210
[24] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[25] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5505 - 5512
[26] Patent: US5532236, 1996, A,
[27] Patent: US6150391, 2000, A,
13
[ 18156-74-6 ]
[ 350-46-9 ]
[ 2301-25-9 ]
[ 420-56-4 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154
14
[ 5587-42-8 ]
[ 350-46-9 ]
[ 2301-25-9 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3286 - 3295
15
[ 350-46-9 ]
[ 358789-72-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 2173 - 2185
16
[ 106-52-5 ]
[ 350-46-9 ]
[ 358789-72-7 ]
Reference：
[1] Patent: WO2016/196776, 2016, A2,
17
[ 110-91-8 ]
[ 350-46-9 ]
[ 10389-51-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate In dimethyl sulfoxide
To A mixture of 4-fluoro nitro benzene 19b (425mg, 3.01 MMOL) and K2CO3 (623 mg, 4. 52 MMOL) in dimethyl sulfoxide (3 mL) was added morpholine (0.52 mL, 6.02 MMOL) and the reaction continued as described above to afford amine 595 mg of 22b in 95percent YIELDS. H- NMR (500 MHz, CDCI3) : 6 3.37 (4Hs, t, J =4.88 Hz), 3.86 (4Hs, t, J = 5.12 Hz), 6.83 (2Hs, d, J = 9.52 Hz), 8.14 (2Hs, d, J =9. 52 Hz); ESI-MASS : 231. 0 (M+23).
95.8%
for 5 h; Reflux
The p-fluoronitrobenzene (5.00 g, 35.4 mmol) and morpholine (9.25 g, 106 mmol) were dissolved in a toluene solution.The reaction system was refluxed for 5 h.Spin dry to give a yellow solid 7.06g.The yield was 95.8percent.
88%
With potassium carbonate In dimethyl sulfoxide at 90℃;
4-Fluoronitrobenzene (382 mg, 2.7 mmol) was dissolved in DMSO (7 ml), potassium carbonate (561 mg, 4.0 mmol) and morpholine (472 mg, 5.4 mmol) were added, and the mixture was stirred at 90° C. overnight. Then, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated aqueous NaCl. The organic layer was dried over Na2CO3, the solvent was evaporated, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (2:1)) to give compound Y180 (yield; 493 mg, 88percent). Compound Y180 (483 mg, 2.3 mmol) was dissolved in methanol (25 ml), Pd/C (205 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. Then, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate (1:2)) to give compound Y183 (yield; 358 mg, 87percent). Compound Y491 (mentioned later) (134 mg, 0.3 mmol) was dissolved in dichloromethane (4 ml), compound Y183 (158 mg, 0.9 mmol) and triethylamine (123 μl, 0.9 mmol) were added, and the mixture was stirred at room temperature for 45 min. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (22:1)) to give the title compound (yield; 120 mg, 69percent). 1H NMR (500 MHz, CDCl3) δ8.43 (s, 1H), 8.00 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=8.0 Hz), 7.53 (t, 1H, J=8.0 Hz), 7.43 (bs, 1H), 6.98 (dd, 2H, J=9.0, 3.5 Hz), 6.76 (dd, 2H, J=9.0, 3.5 Hz), 5.55 (dd, 1H, J=6.5, 6.0 Hz), 4.05 (bs, 2H), 3.83-3.81 (m, 4H), 3.10-3.08 (m, 4H), 2.80-2.63 (m, 4H), 1.64-1.54 (m, 3H), 1.42 (s, 9H), 1.86-1.01 (m, 2H) 13C NMR (125 MHz, CDCl3) δ155.0, 150.1, 141.6, 140.8, 131.3, 131.0, 129.8, 127.4, 125.8, 125.6, 116.2, 79.7, 66.9, 58.6, 50.9, 49.2, 48.7, 36.5, 29.6, 28.6, 18.5 HRMS (FAB-) m/z: [M-H]- calcd for C27H37N4O7S2, 593.2104. found, 593.2197
82%
With potassium carbonate In dimethyl sulfoxide at 80℃; for 18 h;
1-Flouro-4-nitrobenzene (2.9 g, 20.56 mmol) and morpholine (3.6 g, 41.13 mmol) were dissolved in DMSO (15 mL), potassium carbonate was added and the mixture was stirred at 80° C. for 18 hours. After cooled to room temperature, the mixture was poured into water (100 mL), there was yellow solid precipitated. After filtration, the filter cake was washed with water. The filter cake was then dried in vacuum for 24 hours to give compound 7-b (3.5 g, yield: 82percent), which was used directly for the next step without purification.
69%
at 100℃; for 10 h;
8 (7G, 49.65 mmol) and 9 (8.65 g, 99.29 mmol) were dissolved in 20 ml of dioxane and heated at 100 ° C for 10 hours. The reaction was quenched at room temperature and 300 ml of water was added to precipitate a yellow solid. Filtration to give the product 7.13 g (yield:69percent)
66%
With potassium carbonate In dimethyl sulfoxide for 0.00833333 h; Microwave irradiation
Synthesis of 4-(4-Nitro-phenyl)-morpholine A mixture of 1-fluoro-4-nitro-benzene (500 mg, 3.54 mmol), morpholine (620 mg, 7.08 mmol) and K2CO3 (733 mg, 5.3 mmol) in DMSO (5 mL) was irradiated in a microwave (160 W) for 30 seconds (3*10 seconds). The reaction mixture was cooled to room temperature and poured onto ice. The resulting precipitated was filtered to afford 490 mg (66percent) of 4-(4-nitro-phenyl)-morpholine. 1H NMR: (DMSO-d6): δ 8.1 (m, 2H), 7.1 (m, 2H), 3.42 (t, 4H), 3.4 (t, 4H).
Reference：
[1] Patent: US6379400, 2002, B1,
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 9, p. 1289 - 1298
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[4] Patent: WO2005/7625, 2005, A2, . Location in patent: Page 60
[5] Green Chemistry, 2016, vol. 18, # 20, p. 5580 - 5585
[6] Patent: CN104583195, 2018, B, . Location in patent: Paragraph 0486; 0487; 0488; 0489; 0490
[7] Journal of Organic Chemistry, 1981, vol. 46, # 18, p. 3634 - 3638
[8] Patent: US2013/45977, 2013, A1, . Location in patent: Paragraph 0215; 0216; 0217; 0218
[9] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10685 - 10699
[10] Green Chemistry, 2018, vol. 20, # 8, p. 1748 - 1753
[11] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0144; 0145
[12] RSC Advances, 2015, vol. 5, # 113, p. 93433 - 93437
[13] Journal of Chemistry, 2014, vol. 2014,
[14] Patent: CN106432239, 2017, A, . Location in patent: Paragraph 0066; 0075; 0076
[15] Patent: US2009/239848, 2009, A1, . Location in patent: Page/Page column 30
[16] Organic Magnetic Resonance, 1982, vol. 18, # 2, p. 104 - 108
[17] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[18] Chemical Communications, 2005, # 22, p. 2857 - 2859
[19] Patent: EP1479675, 2004, A1, . Location in patent: Page 65
[20] Patent: EP1571154, 2005, A1,
[21] Patent: US2005/222408, 2005, A1,
[22] Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3507 - 3525
[23] Patent: EP1479676, 2004, A1, . Location in patent: Page 56
[24] Journal of Medicinal Chemistry, 2010, vol. 53, # 11, p. 4367 - 4378
[25] Patent: WO2007/64818, 2007, A1, . Location in patent: Page/Page column 11
[26] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3286 - 3295
[27] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[28] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4377 - 4385
[29] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
[30] European Journal of Medicinal Chemistry, 2019, p. 161 - 175
[31] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
18
[ 110-91-8 ]
[ 350-46-9 ]
[ 67-63-0 ]
[ 10389-51-2 ]
Reference：
[1] Patent: US2003/162787, 2003, A1,
19
[ 110-85-0 ]
[ 350-46-9 ]
[ 6269-89-2 ]
Yield
Reaction Conditions
Operation in experiment
85.1%
Reflux
A mixture of 4-nitrofluorobenzene (70.7 g), piperazine (49.8 g) and acetonitrile (400 mL) was stirred at refluxing overnight. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was allowed to cool down to room temperature, basified with saturated K2CO3 solution (500 mL), and then extracted with ethyl acetate. The combined organic layers was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afforded 1 -(4-nitrophenyl)piperazme 2 (88.4 g, 85.1percent, M+.H+= 208.5) as a yellow solid.
Reference：
[1] RSC Advances, 2015, vol. 5, # 113, p. 93433 - 93437
[2] Patent: WO2015/6754, 2015, A2, . Location in patent: Paragraph 00285
[3] Patent: US5008267, 1991, A,
[4] Patent: WO2007/53095, 2007, A1, . Location in patent: Page/Page column 52
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 12, p. 3513 - 3516
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1935 - 1946
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[3] Patent: US2015/336982, 2015, A1,
[4] Patent: WO2016/57834, 2016, A1,
[5] Patent: WO2016/73652, 2016, A1,
26
[ 350-46-9 ]
[ 2221-00-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5263 - 5267
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[3] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1935 - 1946
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[5] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5505 - 5512
[6] Patent: US5532236, 1996, A,
27
[ 103-76-4 ]
[ 350-46-9 ]
[ 5521-38-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate In dimethyl sulfoxide at 80℃; for 16 h;
To a stirred suspension of 1—fluoro—4—nitrobenzene (2 g,14.17 mmol) and potassium carbonate (3.92 g, 28.3 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added 2— (piperazin—1—yl)ethanol (2.089 mL, 17.01 mmol) and the mixture was heated at 80 °C for 16 hours. After coolingthe mixture was partitioned between water (100 mL) and ethyl acetate (30 mL) . The aqueous layer was separated and extracted with ethyl acetate (2 x 30 mL) . The combined organic fractions were reduced in vacuo. The residue was triturated in water (100 mL) . The solid wascollected by filtration under vacuum and dried for 16 hours under vacuum and flowing nitrogen to give the title compound (3.45 g, 97 percent) . ‘H NMR (400 MHz, CDC13) : 3 8.11 (d, 2H), 6.82 (d, 2H), 3.68 (t, 2H), 3.44 (t, 4H), 2.67 (t, 4H), 2.62 (t, 2H), 2.55 (br s, 1H) . LCMS (Method C):RT = 0.45 mi m/z = 252 [M+H].
95.6%
With triethylamine In dimethyl sulfoxide at 90℃;
To a solution of l-fluoro-4-nitrobenzene (4.23 g, 30 mmol, 1.0 eq.) in DMSO (40 mL) was added TEA (9.1 g, 90 mmol, 3.0 eq.) followed by 2-(piperazin-l-yl)ethanol (3.9 g, 30 mmol, 1.0 eq.) and the mixture was stirred at 90 °C overnight. The mixture was poured into ice-water (400 mL), filtered and dried in vacum to afford 2-(4-(4-nitrophenyl)piperazin- l-yl)ethanol as a yellow solid (7.2 g, 95.6percent).
86%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5 h;
Step: 3A-lSynthesis of 2-[4-(4-Nitro-phenyI)-piperazin-l-yl]-ethanol. Procedure:K2C03 (3.912g, 0.02834mol) followed by 1 -Fluoro-4-nitro-benzene (2g, 0.01417mol) was added to a solution of 2-Piperazin-l-yl-ethanol (5.21ml, 0.0425 lmol) in DMF (10ml) and the reaction flask was maintained at 80°C for 5hrs. The reaction was monitored by the TLC (10percent MeOH: CHC13). The resultant was quenched with ice to afford 3g (86percent yield) of 2-[4-(4-Nitro-phenyl)-piperazin-l-yl]-ethanol as a yellow solid.
72%
With N-ethyl-N,N-diisopropylamine In acetonitrile for 15 h; Reflux; Sealed tube; Inert atmosphere
[00212] Step 1 : To a solution of 4-fluoronitrobenzene (2.0g, 14.16 mmol) in AcN (15 mL), 2-(piperazin-l-yl)ethanol (1.85 g, 14.17mmol) and DIEA (2.97 mL, 17.01 mmol) were added. The mixture was refluxed for 15 h (in a sealed tube). After cooling, the resulting mixture was poured to water (300 ml). The mixture was stirred at room temperature for 30 min. The solids were collected by filtration and washed with water to afford the the desired product as off white solids (2.74g, 72percent yield). ESI-MS calcd for (C12H17N303) 251, found 252 [M+H]+.
To a mixture of 4-FLUORO nitro benzene 19b (425 mg, 3.01 MMOL) and K2CO3 (623 mg, 4.52 MMOL) in dimethyl sulfoxjde (3 mL) was added 1-benzyl piperazine (1.04 mL, 6.02 MMOL) and the reaction continued as described above to afford amine 805 mg of 24b in 90percent YIELDS. 1H-NMR (500 MHz, CDC13) : D 2. 59 (4Hs, t, J = 4.88 Hz), 3.42 (4Hs, t, J = 5.12 Hz), 3.57 (2Hs, s), 6. 81 (2Hs, d, J = 7.32 Hz), 7.29 (1H, sextet, J = 1.22 Hz), 7.34 (4Hs, d, J = 7.39 Hz), 8. 12 (2Hs, d; J = 7.32 Hz); ESI-MASS : 298. 2 (M+1).
65%
at 20℃;
General procedure: Synthesisof compounds (1-18) has been carriedout according to the procedure previously standardized in our laboratory with severalmodifications.1 Briefly, an equimolar mixture (0.01 mol) of 1-fluoro-4-nitrobenzeneand respective alkyl /heteroaryl/ aryl substituted piperazinein 30 ml of dried dimethylformamide (DMF)/ dried dimethylsulfoxide (DMSO) was stirredat room temperature for 4-8 h. Reaction completion was monitored by TLC andreaction mixture diluted with water (40 ml). Product has been extracted withchloroform and dried over anhydrous sodium sulphate. The chloroform was thenevaporated under reduced pressure to give pure 1-(4-nitro phenyl)-4-substituedpiperazine derivatives (1-18).
57%
With potassium carbonate In ethanol for 18 h; Heating / reflux
EXAMPLE 1 Preparation of 1-Benzyl-4-(4-nitrophenyl)piperazine A stirred solution of 1-benzylpiperazine (8.81 g, 50.0 mmol), 4-fluoronitrobenzene (5.31 ML, 50.0 mmol), and K2CO3 (6.90 g, 50.0 mmol) in ethanol is heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water, and extracted with CH2Cl2.The combined extracts are dried over MgSO4 and concentrated in vacuo to give a solid residue.The solid is triturated with 20:80 ethyl acetate:hexanes and filtered.The filtercake is air-dried to afford the title compound as orange crystals, 8.45 g (57percent yield), mp 218-219° C., characterized by NMR and mass spectral analyses.
Reference：
[1] British Journal of Pharmacology, 2018, vol. 175, # 12, p. 2399 - 2413
[2] European Journal of Organic Chemistry, 2001, # 16, p. 3105 - 3118
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[4] Patent: WO2005/7625, 2005, A2, . Location in patent: Page 61
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[6] Patent: US2004/167122, 2004, A1, . Location in patent: Page/Page column 12
[7] Patent: US4906634, 1990, A,
[8] Patent: US5051423, 1991, A,
[9] Patent: US2005/222408, 2005, A1,
[10] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
29
[ 2759-28-6 ]
[ 350-46-9 ]
[ 16155-08-1 ]
Reference：
[1] Patent: US5086055, 1992, A,
30
[ 350-46-9 ]
[ 101-79-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 16, p. 4477 - 4492
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 1, p. 219 - 232
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 11, p. 4811 - 4815
[4] MedChemComm, 2015, vol. 6, # 4, p. 671 - 676
[5] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 273 - 292
[6] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1588 - 1592
Stage #1: With potassium carbonate; triethylamine In acetonitrile at 20℃; for 0.333333 h; Stage #2: for 12 h; Heating / reflux
To 4-piperidone hydrochloride (2.17g, lβ.Ommol) in acetonitrile (20ml) was added triethylamine (3.9ml) and potassium carbonate (2.9g, 21.0mmol). After stirring for 20 min at room temperature, l-fluoro-4-nitrobenzene (Ig, 7.09mmol) was added and the reaction mixture was heated to reflux for 12 hr. The reaction mixture was then cooled and filtered and the filtrate concentrated under reduced pressure to give a residue. The EPO <DP n="56"/>residue was dissolved in water, extracted with ethyl acetate, dried and evaporated to give l-(4-nitro-phenyl)-piperidin-4-one (0.6g, 38percent).
Reference：
[1] Patent: WO2006/123145, 2006, A1, . Location in patent: Page/Page column 54-55
[2] Synthesis, 1981, # 8, p. 606 - 608
[3] Synthesis, 1981, # 8, p. 606 - 608
[4] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 32 - 45
[5] Patent: CN106905245, 2017, A,
42
[ 41979-39-9 ]
[ 350-46-9 ]
[ 23499-01-6 ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: for 2 h; Reflux Stage #2: With potassium carbonate In acetonitrileReflux
Reference Example 43; 1-(4-Nitro-phenyl)-piperidin-4-one; Piperidin-4-one hydrochloride was added to a methanolic solution of sodium methoxide (prepared from anhydrous methanol (50 mL) and sodium metal (0.85 g, 37 mmol)) and heated at reflux for 2 h then concentrated to dryness in vacuo. The residue was dissolved in acetonitrile (100 mL), then potassium carbonate (10.22 g, 74 mmol) and 1-fluoro-4-nitro-benzene (3.92 mL, 37 mmol) were added and the mixture was heated at reflux overnight. The solvent was evaporated in vacuo, the residue being washed with water then 50percent diethyl ether/petroleum ether and dried in vacuo to afford 1-(4-nitro-phenyl)-piperidin-4-one (3.01 g, 37percent) as a yellow solid.
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 10 h;
A stirred mixture of 4-fluoronitrobenzene (1.5 g, 1.0 eq), piperidin-4-one (1.5 eq) K2C03 (3 eq), and DMF (12 mL) in a vial was heated at 90°C for 10 h. After completion of starting material, the mixture was poured in ice water (200 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was dried over anhydrous Na2S04> filtered and concentrated. The resulting residue was purified by column chromatography by using 100-200 silica gel and eluted with 17percent EtOAc in hexane to obtain l-(4-nitrophenyl) piperidin-4-one (1.35 g, 49.2percent) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.088 (d, 2H), 7.045 (d, 2H), 3.835 (t, 4H), 2.527 (t, 4H).
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 7, p. 2282 - 2284
45
[ 675-20-7 ]
[ 350-46-9 ]
[ 38560-30-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5339 - 5356
46
[ 350-46-9 ]
[ 190728-25-7 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 1, p. 11 - 17
47
[ 350-46-9 ]
[ 367-21-5 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
[2] Journal of the American Chemical Society, 1971, vol. 93, # 5, p. 1190 - 1198
48
[ 350-46-9 ]
[ 120-83-2 ]
[ 1836-75-5 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h; Stage #2: at 20 - 50℃; for 13 h;
General procedure: 0.69 g (17.3 mmol) of 60percent NaH dispersion in mineral oil was washed with hexane and suspended in 20 ml DMF. The solution of corresponding phenol (12.9 mmol) in DMF (20 ml) was then added dropwise. After stirring for 1h at room temperature the solution of 4-nitrobenzene (1.5g, 10.3 mmol) in DMF (4 ml) was added. After further stirring for 1h at room temperature the mixture was heated for 12h at 50 °C. After reaction was complete the reaction mixture was saturated by the solution of NH4Cl. The mixture was extracted with diethyl ether. The organic layer was washed with 0.2 M solution of NaOH until bleaching of the water layer and then washed by 1 M solution of HCl and brine.The organic layer was dried over anhydrous MgSO4. The resulting solution was concentrated in vacuo and purified using column chromatography with hexane-ethyl acetate (5:1) as the eluent to give compounds 2a-d with the following characteristics:
Reference：
[1] Canadian Journal of Chemistry, 2015, vol. 94, # 1, p. 95 - 104
[2] European Journal of Organic Chemistry, 2011, # 8, p. 1587 - 1592
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1588 - 1592
[4] New Journal of Chemistry, 2015, vol. 39, # 9, p. 7281 - 7292
[5] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 273 - 292
49
[ 350-46-9 ]
[ 350-30-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 20℃; for 2 h;
35 mmol (5 g) of p-fluoronitrobenzene was suspended in 15 mL of a 20percent solution of nitric acid and sulfuric acid (1: 1) by volume,In the presence of iodine (0.5 g) catalysis, 42 mmol (5.6 g) of N-chlorosuccinimide,The reaction was completed at room temperature for 2 hours. The reaction was completed, diluted with 30 mL of water, extracted with ethyl acetate (3 × 30 mL), washed with 20percent sodium thiosulfate (2 × 20 mL) and 20 mL of brine, dried over anhydrous sodium sulfate, After evaporation to give the crude 3-chloro-4-fluoronitrobenzene, the crude product was recrystallized from methanol to give pure 3-chloro-4-fluoronitrobenzene 4.6g, a yield of 75percent.
Reference：
[1] Patent: CN106631811, 2017, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015; 0016; 0017; 0018
[2] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
[3] Journal of the American Chemical Society, 1971, vol. 93, # 5, p. 1190 - 1198
50
[ 7782-50-5 ]
[ 7705-08-0 ]
[ 350-46-9 ]
[ 350-30-1 ]
Reference：
[1] Chem. Zentralbl., 1914, vol. 85, # II, p. 1432
51
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
[2] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
[3] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
52
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 446-35-5 ]
[ 2265-94-3 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
53
[ 350-46-9 ]
[ 33543-55-4 ]
Reference：
[1] Journal of Physical Organic Chemistry, 1999, vol. 12, # 5, p. 357 - 363
[2] Journal of the American Chemical Society, 1982, vol. 104, # 23, p. 6393 - 6397
[3] Tetrahedron, 1972, vol. 28, p. 3833 - 3843
[4] Organic Letters, 2013, vol. 15, # 13, p. 3366 - 3369
[5] Organic Process Research and Development, 2002, vol. 6, # 3, p. 230 - 233
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 47, p. 14017 - 14021[7] Angew. Chem., 2015, vol. 127, # 47, p. 14223 - 14227,5
54
[ 98-95-3 ]
[ 402-67-5 ]
[ 446-35-5 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
55
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 446-35-5 ]
[ 2265-94-3 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
56
[ 109-73-9 ]
[ 350-46-9 ]
[ 58259-34-0 ]
Reference：
[1] Journal of Materials Chemistry, 1999, vol. 9, # 8, p. 1699 - 1705
[2] Bulletin de la Societe Chimique de France, 1956, p. 311,315
[3] New Journal of Chemistry, 2012, vol. 36, # 7, p. 1519 - 1526
57
[ 109-86-4 ]
[ 350-46-9 ]
[ 22483-40-5 ]
Yield
Reaction Conditions
Operation in experiment
53.7%
With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 60℃; for 16 h;
Synthesis of compound 130.2. To a solution of 130.1 (2.0g, 14.1 8mmol, l .Oeq) in DMF (25 mL) were added 2-methoxyethan-l-ol (7.0g, 92.13mmol, 6.5eq) and potassium tert- butoxide (1.43, 12.8 mmol, 0.95eq). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, mixture was poured into water and product was extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 130.2 (1.5 g, 53.7 percent). MS (ES): m/z 197.1 [M+H]+.
Reference：
[1] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00768; 00769
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5177 - 5181
[3] Patent: WO2017/102014, 2017, A1, . Location in patent: Page/Page column 24
58
[ 33311-29-4 ]
[ 350-46-9 ]
[ 22483-40-5 ]
Reference：
[1] Patent: US5880130, 1999, A,
59
[ 350-46-9 ]
[ 2657-87-6 ]
Reference：
[1] Journal of the American Chemical Society, 1934, vol. 56, p. 117,118
60
[ 456-22-4 ]
[ 7697-37-2 ]
[ 453-71-4 ]
[ 350-46-9 ]
Reference：
[1] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1921, vol. <5> 7, p. 536[2] Chem. Zentralbl., 1922, vol. 93, # I, p. 22
General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).
Reference：
[1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8
63
[ 106-53-6 ]
[ 350-46-9 ]
[ 21969-12-0 ]
Reference：
[1] Green Chemistry, 2016, vol. 18, # 20, p. 5580 - 5585
[2] Patent: WO2012/31196, 2012, A1, . Location in patent: Page/Page column 237
64
[ 350-46-9 ]
[ 156150-67-3 ]
Reference：
[1] Journal of the American Chemical Society, 1971, vol. 93, # 5, p. 1190 - 1198
65
[ 350-46-9 ]
[ 1435-48-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
66
[ 350-46-9 ]
[ 75-05-8 ]
[ 405-67-4 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 2, p. 293 - 304
67
[ 350-46-9 ]
[ 57478-19-0 ]
Reference：
[1] MedChemComm, 2015, vol. 6, # 4, p. 671 - 676
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 3046 - 3059
68
[ 446-35-5 ]
[ 367-25-9 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 11, p. 3203 - 3207[2] Angew. Chem., 2013, vol. 125, # 11, p. 3285 - 3289,5
Reference：
[1] Journal of the Korean Chemical Society, 2010, vol. 54, # 5, p. 659 - 664
[2] Molecular Crystals and Liquid Crystals, 2017, vol. 650, # 1, p. 1 - 6
71
[ 350-46-9 ]
[ 39905-48-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 10, p. 3580 - 3600
[2] Journal of the Chemical Society, 1954, p. 1795,1797
72
[ 350-46-9 ]
[ 115619-01-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[2] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[3] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
73
[ 350-46-9 ]
[ 57260-71-6 ]
[ 182618-86-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
To a solution of terf-butyl-piperazine (1 eq) and 4-fluoro-nitrobenzene (1.1 eq) in DMF (0.43 M), K2CO3 (1.1 eq) was added. The mixture was heated to 50 °C with stirring overnight. At this time the reaction was allowed to cool to RT and partitioned between EtOAc and IN aqueous HCl. The aqueous fraction was extracted with EtOAc and the combined organics washed with brine, before being dried over Na2SO4, filtered and evaporated in vacuo to afford the title compound as yellow solid (97 percent); MS (ES+) m/z 308 (M+H)+.
95%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 18 h;
To a solution of 1-fluoro-4-nitrobenzene (5 g, 35.43 mmol) and tert-butyl piperazine-1- carboxylate (6.6 g, 35,43 mmol) in DMF (100 mL) was added potassium carbonate (14.7g, 106.36 mmol) and the mixture was stirred at 50 °C for 18 h, then allowed to cool to room temperature and concentrated under reduced pressure. The oily residue was washed with diethyl ether (3x) to give tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate as a yellow solid (8.2 g, 95percent). ‘HNMR(400 MFIz, Chloroform-d) ppm 1.48 (s, 9 H) 3.38- 3.45(m,4H)3.56-3.63 (m,4H)6.75 -6.86(m,2H)8.07-8.20(m,2H). C15H21N304MS m/z 308.1 (M+H)
85.3%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
Compound 18 (10.0 g, 70.87 mmol) was added to the reaction flask, respectively,Compound 36 (15.84 g, 85.05 mmol)Dissolved in DMF,K2CO3 (15.67 g, 113.39 mmol) was added,80 ° C under the conditions of reaction,TLC tracking, to be completely complete,The reaction system is poured into ice water,There is a yellow solid precipitation,Filter the solid, beat with ether,18.58 g of compound 40 was dried,Yield: 85.3percent.
77%
With N-ethyl-N,N-diisopropylamine In ethyl acetate
4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77percent).
77%
With N-ethyl-N,N-diisopropylamine In ethyl acetate
4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77percent).
77%
With N-ethyl-N,N-diisopropylamine In ethyl acetate
4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid Tert-butyl Ester 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77percent).
48%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
Step: 5aSynthesis of 4-(4-Nitro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester.Procedure:K2C03 (2.7g, 0.0194mol) was added to 1 -Fluoro-4-nitro-benzene (2.5g, 0.0177mol) and Piperazine-1 -carboxylic acid tert-butyl ester (3.2g, 0.0177mol) in DMF (10ml) at 80°C. The reaction was monitored by the TLC (30percent EtOAc: hexane). The resultant was cooled to RT and precipitated by the addition of ice. The precipitate was collected and dried at reduced pressure to afford 2.6g (48percent yield) of 4-(4-Nitro-phenyl)-piperazine-l- carboxylic acid tert- buyl ester.
Reference：
[1] Patent: WO2006/38039, 2006, A1, . Location in patent: Page/Page column 17; 30
[2] Patent: WO2017/123542, 2017, A1, . Location in patent: Page/Page column 398; 399
[3] Patent: CN106905245, 2017, A, . Location in patent: Paragraph 0314; 0315; 0316; 0317; 0318
[4] Patent: US2003/13708, 2003, A1,
[5] Patent: US2004/87575, 2004, A1,
[6] Patent: US2004/110745, 2004, A1,
[7] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2179 - 2191
[8] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 117
[9] Tetrahedron Letters, 1997, vol. 38, # 23, p. 4091 - 4094
[10] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[11] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2549 - 2552
[12] Patent: US5556969, 1996, A,
[13] Patent: WO2005/14599, 2005, A1, . Location in patent: Page/Page column 51
[14] Patent: US2007/60577, 2007, A1, . Location in patent: Page/Page column 49
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3086 - 3090
[16] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5552 - 5556
[17] Patent: CN107245073, 2017, A, . Location in patent: Paragraph 0133; 0134; 0135
[18] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
[19] Patent: WO2006/122806, 2006, A2, . Location in patent: Page/Page column 70
74
[ 56621-48-8 ]
[ 350-46-9 ]
[ 112559-81-6 ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium carbonate In N,N-dimethyl acetamide; water
(a) A mixture of 91.7 parts of 4-(1-piperazinyl)phenol, 71.0 parts of 1-fluoro-4-nitrobenzene, 60.0 parts of potassium carbonate and 450 parts of N,N-dimethylacetamide was stirred over weekend at room temperature. Water was added and after standing for 5 hours, the product was filtered off. It was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 114.4 parts (76percent) of 4-[4-(4-nitrophenyl)-1-piperazinyl]phenol; mp. 260.0° C. (intermediate 9).
Reference：
[1] Patent: US4791111, 1988, A,
75
[ 350-46-9 ]
[ 170911-92-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2179 - 2191
[3] Patent: WO2017/123542, 2017, A1,
[4] Patent: CN107245073, 2017, A,
[5] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
76
[ 350-46-9 ]
[ 57260-71-6 ]
[ 170911-92-9 ]
Reference：
[1] Patent: CN106905245, 2017, A,
77
[ 350-46-9 ]
[ 138227-63-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 561 - 566
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 1 - 7
[3] Patent: WO2008/141976, 2008, A1,
78
[ 350-46-9 ]
[ 109384-19-2 ]
[ 138227-63-1 ]
Reference：
[1] Patent: WO2015/92431, 2015, A1,
79
[ 350-46-9 ]
[ 13143-47-0 ]
Reference：
[1] Patent: WO2014/135471, 2014, A1,
80
[ 350-46-9 ]
[ 425378-68-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 4, p. 1235 - 1238
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 13, p. 2871 - 2876
83
[ 26690-80-2 ]
[ 350-46-9 ]
[ 159184-14-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 13, p. 2871 - 2876
84
[ 350-46-9 ]
[ 442549-42-0 ]
Reference：
[1] Patent: WO2012/59932, 2012, A1,
85
[ 5308-25-8 ]
[ 350-46-9 ]
[ 115619-00-6 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate In dimethyl sulfoxide at 20℃; Inert atmosphere; Schlenk technique
General procedure: A solution of 4-fluoronitrobenzene 6 (2 g, 14.2 mmol) and anhydrous K2CO3 (2.2 g, 15.6 mmol) in DMSO (5 mL) was stirred at room temperature for 10 min. The appropriate secondary amine (14.2 mmol) was added dropwise, and the resulting reaction mixture was stirred at room temperature for 10 h. The mixture was then poured into ice-water to form a precipitate collected by filtration then dried to give the nitrophenyl derivative 7a–7e.
80%
at 20℃;
General procedure: Synthesisof compounds (1-18) has been carriedout according to the procedure previously standardized in our laboratory with severalmodifications.1 Briefly, an equimolar mixture (0.01 mol) of 1-fluoro-4-nitrobenzeneand respective alkyl /heteroaryl/ aryl substituted piperazinein 30 ml of dried dimethylformamide (DMF)/ dried dimethylsulfoxide (DMSO) was stirredat room temperature for 4-8 h. Reaction completion was monitored by TLC andreaction mixture diluted with water (40 ml). Product has been extracted withchloroform and dried over anhydrous sodium sulphate. The chloroform was thenevaporated under reduced pressure to give pure 1-(4-nitro phenyl)-4-substituedpiperazine derivatives (1-18).
Reference：
[1] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[3] Patent: US2004/122237, 2004, A1, . Location in patent: Page 180
[4] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
[5] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
86
[ 4606-65-9 ]
[ 350-46-9 ]
[ 166438-83-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 100℃; for 12 h;
A stirred mixture of piperidin-3-ylmethanol (2.0 g, 1.0 eq), l-fluoro-4- nitrobenzene (2.94 g, 1.2 eq), in DMSO (20 mL) in a vial was closed and the contents heated at 100°C for 12 h while monitoring by TLC. After completion of starting material, the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2S04> filtered and concentrated to obtain (l-(4-nitrophenyl)piperidin-3- yl)methanol as yellow solid (3.0 g, 75percent). 1H NMR (400 MHz, DMSO-d6): δ 8.08 (d, IH), 6.805 (d, IH), 3.98 (m, IH), 3.81 (d,lH), 3.64 (m, IH), 3.53 (m, IH), 3.041 (m, IH), 2.878 (m, IH), 1.838 (m, 3H), 1.621 (m, 2H), 1.294 (d, IH).
With Aliquat 336; sodium hydroxide; In 1,2-dichloro-ethane; at 0 - 5℃; for 4h;
Dichloromethane of Example 1 was changed to 1,2-dichloroethane. Other operations were the same.Obtained 255 g of 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene, yield: 94.4%, HPLC purity: 99.3% Dissolve 150 g of 2-(5-ethyl-2-pyridyl)ethanol in 450 g of dichloromethane, add 150 g of solid sodium hydroxide (96%) and 7.5 g of 75% trioctylmethylammonium chloride,Temperature control 0-5 C, add 150g of fluoronitrobenzene / 150g dichloromethane solution, after adding the end of the reaction temperature 0-5 C reaction 4 hours, the end of the reaction, temperature control 0-5 C drops 300g of water,Stir for 5 minutes, stand for stratification, wash the organic layer with 200g*3 water three times, wash once with saturated saline 100g, add 10g of anhydrous magnesium sulfate, add 5g of activated carbon to decolorize, filter, and concentrate the filtrate under reduced pressure to dryness.Add 300g of petroleum ether and incubate at 0-5C for 2 hours, filter and blow at 30-40C.Obtained 254 g of 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene, yield: 94.0%, HPLC purity: 99.2%.
88.4%
With sodium hydroxide; In water; at 20 - 35℃; for 16h;Product distribution / selectivity;
Example-1: Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III).Process A : To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I), (100.0 g, 0.66 mol,) l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7 mol), in D.M. water (250 ml) at 20 to25C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 350C. The reaction mixture was stirred at30 to 35C for 16 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O0C) was added and the mixture was stirred for 1.5 hr, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O0C) and suck dried under vacuum for 25 to 30 minutes. The light green to yellow solid was dried at35 to 400C for 15 hr to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 55 to 6O0C) and filtered hot through cloth to remove un- dissolved particles. The solution was then cooled to 0 to 50C, stirred for 1 hr filtered, washed with cold diisopropyl ether (25 ml, 0 to 50C) and dried at 35 to 4O0C to obtain pure 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III ) as a light yellow solid.Yield =159.2g (88.40%); Purity (HPLC) >99.50%; Assay (HPLC) > 98.0% w/w.;Melting point =45 to 47C.Alternately, the wet crude product after filtration can also be dissolved in hot isopropyl ether and crystallized at 0 to 5C to obtain the pure product. EPO <DP n="19"/>IR(KBr, Cm .-"U1)= 2972.44, 2928.67, 1602.22, 1593.00, 1508.2, 1339.73, 1264.27, 1109.55, 853.89, 751.44, 657.50. 1H-NMR ( 300 MHz, CDCl3 ) delta = 1.24(t, 3H, CH2- CH3); 2.62 (q, 2H, CH2-CH3); 3.26 (t, 2H, CH2-CH2-O); 4.01(t, 2H, CH2-CH2-O); 6.93-8.40(m, 7H, aromatic H ).13C-NMR (75.47 MHz, CDCl3) delta =14.86 (CH2-CH3); 25.24 (CH2-CH3); 36.70 (CH2-CH2-O); 67.63(CH2-CH2-O); 114.05 122.84, 125.30,135.40, 136.80, 140.87,148.67, 154.42, 163.52 (aromatic C) APCIMS MH+ =273 (M+l) Elemental analysis for C15H16N2O3,
88.11%
With sodium hydroxide; In water; dimethyl sulfoxide; at 20 - 35℃; for 12h;Product distribution / selectivity;
Process B: To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I)(100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (H), (100 g, 0.7 mol), dimethyl sulfoxide (200 ml) and water (50 ml ) at 20 to 250C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 35C. The reaction mixture was stirred at 30 to 350C for 12 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O0C ) was added and the mixture was stirred for 1.5 hr, filtered washed with ice-cold water (2 x 250 ml, 5- 1O0C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35 to 400C for 15 hr to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O0C) and filtered through cloth to remove un- dissolved particles. The solution was then cooled to 0 to +50C, stirred for 1 hr, filtered, EPO <DP n="20"/>washed with cold diisopropyl ether (25 ml, 0 to +5C) and dried at 35 to 4O0C to obtain pure 4-[2-(5-EthyI-2-pyridyl)ethoxy]nitrobenzene (III ) as a light yellow solid. Yield = 158.6 g (88.11 %); Purity (HPLC) >99.50%, Assay > 98.0% w/w; Melting point = 45 to 470C Alternately, the wet crude product after filtration can also be dissolved in hot diisopropyl ether and crystallized at 0 to +50C to obtain the pure product.
87.3%
With sodium hydroxide; tetrabutyl-ammonium chloride; In water; dimethyl sulfoxide; at 20 - 35℃; for 12h;Product distribution / selectivity;
Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III). Process D: To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I) (100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7mol), tetra butyl ammonium chloride (5.0 g, 70% solution in water), dimethylsulf oxide (200 ml) and water (50 ml) at 20 to 25C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 35C. The reaction mixture was stirred at 35C for 12 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O0C) was added and the mixture was stirred for 2 hrs, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O0C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35 to 4O0C for 15 hrs to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O0C) and filtered hot through cloth to remove un-dissolved particles. The solution was then cooled to 0 to +50C and stirred for 1 hr, filtered, washed with cold diisopropyl ether (25 ml, 0 to +50C) and dried at 35 to 4O0C to obtain pure 4-[2-(5- Ethyl-2-pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid.. Yield = 157.3 g (87.3%); Purity (HPLC) >99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 47C.Alternately, the wet crude product after filtration can also be dissolved in hot diisopropyl ether and crystallized at 0 to +5C to obtain the pure product. The reaction can also be performed in other common solvents like methylene dichloride, chloroform, 1, 2-dichloroethane, benzene, toluene, ortho and para xylenes, diethyl ether, diisopropyl ether, dibutyl ether, tertiary butylmethyl ether, 1, 4-dioxane, EPO <DP n="22"/>tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane and acetonitrile. However, since the compound was completely or partially soluble in these solvents, it does not crystallized out from the mixture as such and has to be extracted in hot solvent, the aqueous layer was separated, washed with water, dried on sodium sulphate and evaporated to give the crude product which was then re-crystallized from diisopropyl ether. The yield varies between 75 to 91%. When the reaction was carried out in methanol and ethanol, in addition to the product, large amounts of other impurities are also formed and the product can not be easily isolated or crystallized. However with n- propanol, iso-propanol, n-butanol, iso-butanol and other long chain alcohols, less amount of impurities where formed and the pure product can be was isolated in relatively lower yields (60 to 70 0Zo).
87.83%
With sodium hydroxide; tetrabutyl-ammonium chloride; In water; at 20 - 35℃; for 12h;Product distribution / selectivity;
Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III) Process C: To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I) (100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7 mol), tetra butyl ammonium chloride (5.0 g, 70% solution in water), and water (250 ml) at 20 to 250C, sodium hydroxide (70.0 g, 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 350C. The reaction mixture was stirred at 30 to 350C for 12 hrs and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O0C) was added and the mixture was stirred for 1.5 hrs, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O0C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 350C for 15 hrs to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O0C) and filtered hot through cloth to remove un-dissolved particles. The solution was then cooled to 0 to +50C, stirred for 1 hr, filtered, washed with cold diisopropyl ether (25 ml, 0 to +5C) and dried at 35 to 4O0C to obtain pure 4-[2-(5- Ethyl-2-pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid. Yield = 158.1 g (87.83 %); Purity (HPLC) >99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 47C Alternately, the wet crude product after filtration can also be dissolved in hot EPO <DP n="21"/>diisopropyl ether and crystallized at 0 to +5C to obtain the pure product.
64.50 - 73.66%
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate; In N,N-dimethyl-formamide; at 55 - 90℃; for 24 - 60h;Product distribution / selectivity;
Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III). Process E : A suspension of finely powdered anhydrous potassium carbonate (400.0 g, 4.37 mol) 2-(5-ethyl-2-pyridyl)ethanol (I) (100 g, 0.66 mol), l-fluoro-4-nitrobenzene (II) (100.0 g, 0.70 mol) and tetra n-butyl ammonium hydrogen sulfate (20.0 g) in dry dimethylformamide (200 ml) was heated at 55 to 60C over a period of 24 hrs, when the TLC of the mixture indicated it to be complete. The mixture was cooled to 450C, diisopropyl ether (800 ml), followed by water (1.0 It) was added and the mixture was vigorously stirred at 45 to 5O0C. The organic layer was separated, washed with water (3 x 200 ml), and evaporated to give crude residue which was then crystallized from diisopropyl ether (400 ml) at 0 to +50C to afford 4-[2-(5-Ethyl-2- pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid. Yield = 132.6 g (73.66%); Purity (HPLC) > 99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 470C. EPO <DP n="23"/>Alternatively, after the reaction was over, the hot mixture was filtered through cloth to remove the inorganic salts and the filtrate was diluted with excess of water and extracted with diisopropylether and worked up and crystallized as mentioned above.Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III). Process F : A suspension of finely powdered anhydrous potassium carbonate (400.0 g, 4.37 mol) 2-(5-ethyl-2-pyridyl)ethanol (T) (50.0 g, 0.33 mol), and l-fluoro-4- nitrobenzene (H) (50.0 g, 0.35 mol) and tetra n-butyl ammonium hydrogen sulfate (20.0 g) in dry dimethylformamide (100 ml) was heated at 85 to 9O0C over a period of 60 hrs, when the TLC of the mixture indicated it to be complete. The mixture was cooled to 450C, diisopropyl ether (400 ml), followed by water (500 ml) was added and the mixture was vigorously stirred at 45 to 500C. The organic layer was separated, washed with water (3 x 200 ml), and evaporated to give crude residue which was then crystallized from diisopropyl ether (200 ml) at 0 to +50C to afford 4-[2-(5-Ethyl-2- pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid. Yield = 58.10 g (64.50%); Purity (HPLC) > 99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 460C.
62.9%
In N,N-dimethyl-formamide;
(a) To a solution of 2-(5-ethyl-2-pyridyl)ethanol (53.0 g) and 4-fluoronitrobenzene (47.0 g) in DMF (500 ml) was added portionwise under ice-cooling 60% sodium hydride in oil (16.0 g). The mixture was stirred under ice-cooling for one hour, then at room temperature for 30 minutes, poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4). The solvent was evaporated off to give 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene as crystals (62.0 g, 62.9%). Recrystallization from ether-hexane gave colorless prisms, m.p. 53-54 C.
With potassium hydroxide; In acetone; at 15 - 20℃;Cooling; Industry scale;
Example 1Step a: Preparation of 4-[2-(5-ethyl-2-pyridyl)ethoxy1nitrobenzene 25.0 g of 2-(5-ethyl-2-pyridyl)ethanol and 100 g of acetone were loaded in a flask of appropriate capacity. The mixture was brought to 15-200C and 25.0 g of potassium hydrate were added while cooling was maintained. 1-fluoro-4- nitrobenzene (30.0 g) was then poured while maintaining the temperature at 15- 2O0C. The temperature of 15-200C was maintained for at least 4 hours. 20 g of 80% acetic acid, 125 g of distilled water, 75 g of toluol were added after monitoring by TLC, at the end of the reaction and maintaining the temperature in the range of 15-2O0C. The solution was subsequently stirred at 15-200C for at least 15 minutes, and the lower aqueous phase was then separated and discarded. Distilled water (25 g) was added to the organic phase. After stirring at 15-2O0C for at least 15 minutes, the lower aqueous phase was separated and discarded. 30.0 g of distilled water were then added to the organic phase. The solution was brought to the temperature of 25-350C, while maintaining in brine, <n="7"/>and 32% hydrochloric acid (22.5 g) was poured. The pH was then checked to be lower than 1.0 while maintaining at 30-35C for at least 5 minutes. The lower aqueous phase containing the product was separated and the top organic phase was discarded. 20.0 g of toluol were added to the aqueous phase loaded again in the reactor. After stirring at 30-350C for at least 5 minutes, the lower aqueous phase containing the product was separated and the top organic phase was discarded. 20.0 g of toluol were added to the aqueous phase loaded again in the reactor and the mixture was stirred at 30-350C for at least 5 minutes. The lower aqueous phase containing the product was separated, and the top organic phase was discarded. 60 g of methanol were added to the aqueous phase loaded again in the reactor and the mass was cooled to 10-150C. 30.0 g of 30% ammonia were poured while maintaining in brine. The mass was maintained at 10-150C for at least 30 minutes, then cooled to -10-0C for at least 30 minutes, then centrifuged by washing with 30.0 g of distilled water. The product was dried and 37.0 Kg of ? corresponding dry product were obtained.
With potassium carbonate; In acetonitrile; at 73℃; for 18h;
General procedure: Step 1, 10.0 mmol of p-fluoronitrobenzene and compound A2 were dissolved in acetonitrile.The molar ratio of p-fluoronitrobenzene to compound A2 is C2,And adding potassium carbonate to the above solution,The molar ratio of potassium carbonate to p-fluoronitrobenzene is C3,The mixture was stirred at the temperature indicated by C1 for 18 h. After cooling to room temperature, The reaction solution was diluted with 40 mL of water and extracted with 3×40 mL of ethyl acetate.The organic phase was combined, washed with 2×50 mL of brine and dried over anhydrous sodium sulfate.Concentrated in vacuo and the residue obtained was purified by silica gel column chromatography(Eluent: n-hexane / ethyl acetate = 10:1) gave Compound A3.
Step 1: Synthesis of 1-methyl-3-(4-nitrophenoxy)pyrrolidine To a solution of potassium tert-butoxide (1.43 g, 12.9 mmol) in THF (6 mL) was added 1-methylpyrrolidin-3-ol (645 mg, 6.39 mmol). The reaction mixture was stirred at room temperature for 1 h. Then 1-fluoro-4-nitrobenzene (900 mg, 6.39 mmol) was added to the above solution and stirred for another 2 h. After the removal of the volatile, the residual was dissolved in ethyl acetate (40 mL), and then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EA:PE=1:4) to give desired product as a yellow oil (626 mg, 44percent).
With sodium hydride; In 1-methyl-pyrrolidin-2-one;
Reference Example 33 4-Fluoronitrobenzene and 1-methylpyrrolidin-3-ol were allowed to undergo the reaction in 1-methylpyrrolidone in the presence of sodium hydride. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(1-methylpyrrolidin-3-yl)oxoaniline. F: 193.
4-hydroxy-1-(4-nitrophenyl)pyrrolidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In water; for 16h;Heating / reflux;
10 g (70.9 mmol) of 4-fluoronitrobenzene, 11.75 g (85 mmol) of potassium carbonate and 9.3 g (70.8 mmol) of <strong>[3398-22-9]trans-4-hydroxyproline</strong> were stirred in 100 ml of distilled water. The mixture was refluxed for 16 hours and was then cooled to room temperature. The product was extracted with ethyl acetate. The organic phases were washed with a saturated solution, dried over sodium sulphate and concentrated under reduced pressure. The oil obtained was crystallized from an ethyl acetate/heptane mixture. A yellow powder was obtained. 1H NMR (400 MHz-DMSO) ppm 1.99-2.30 (m, 2H); 3.68 (m,1H); 4.46 (m, 2H); 5.27 (m, 1H); 6.58 (d, 2H); 8.07 (d, 2H)
Syntheses of Exemplified Compounds (see Tables for Compound Characterization) Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, <strong>[5369-19-7]3-tert-butylaniline</strong> was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene.
Syntheses of Exemplified Compounds (See Tables for Compound Characterization) Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, <strong>[5369-19-7]3-tert-butylaniline</strong> was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene.
SYNTHESES OF EXEMPLIFIED COMPOUNDS (See Tables for Compound Characterization) Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, <strong>[5369-19-7]3-tert-butylaniline</strong> was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene.
With hydrogenchloride; ammonia; In methanol; N,N-dimethyl-formamide;
Method 19 4-[(1-Methylpiperidin-2-yl)methoxy]nitrobenzene Sodium hydride (60percent dispersion in oil; 400 mg, 10.0 mmol) was added to a solution of 2-hydroxymethyl-1-methylpiperidine (1.29 g, 10.0 mmol) in DMF (20 ml) and the mixture was stirred for 2 hours. 4-Fluoronitrobenzene (1.4 g, 10.0 mmol) was added and the mixture was heated at 80° C. for 17 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2*100 ml). The extracts were washed with water (2*100 ml) and then extracted with 2M hydrochloric acid (2*50 ml). The combined acidic extracts were washed with ether (2*100 ml) and then basified by addition of 0.88 ammonia solution. The basified solution was extracted with ether (2*100 ml) and the extracts were washed with water (2*100 ml) and saturated sodium chloride (100 ml) and dried. Volatile material was removed by evaporation and a saturated solution of hydrogen chloride in methanol was added to the residue. Evaporation gave the hydrochloride salt of the product as an oil (2.4 g). NMR (asterisk denotes conformeric form): 1.4-1.6 (m, 1H), 1.6-1.9 (m, 4H), 1.9-2.0 (m, 1H), 2.75 (s, 3H)*, 2.8 (s, 3H)*, 3.0-3.2 (m, 2H)*, 3.3-3.4 (m, 2H)*, 3.4-3.6 (m, 1H)*, 3.7-3.9 (m, 1H)*, 4.4 (m, 2H), 7.2 (d, 2H), 8.2 (d, 2H), 10.6-10.8 (br s, 1H)*. 11.0-11.1 (br s, 1H)*; MS (MH+): 251.2.
With potassium tert-butylate; In 2-methoxy-ethanol; N,N-dimethyl-formamide;
The <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> used as starting material was obtained as follows: Potassium tert-butoxide (2 g) was added portionwise to a stirred mixture of 4-fluoronitrobenzene (2.8 g), 2-methoxyethanol (10 ml) and DMF (20 ml). The mixture was stirred and heated to 60 C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4)- and evaporated. The residue was recrystallized from a mixture of hexane and ethyl acetate. There was thus obtained 4-(2-methoxyethoxy)nitrobenzene (1.06 g), m.p. 86 C. The product so obtained was dissolved in ethyl acetate and hydrogenated in the presence of a 10% Pd/C catalyst to give <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (0.7 g). NMR Spectrum: (CD3 SOCD3) 3.3 (s, 3H), 3.6 (t, 2H), 3.9 (t, 2H), 4.6 (s, 2H), 6.5 (d, 2H), 6.7 (d, 2H).
Example 1a Preparation of 4-fluoro-N-isopropylaniline 520 parts of toluene, 423 parts (3 mol) of 4-fluoronitrobenzene, 192 parts (3.3 mol) of acetone and 8 parts of catalyst (5percent Pt on charcoal, water-moist, water content 50percent) are placed in a hydrogenation autoclave. After the gas space has been flushed three times with each of nitrogen and hydrogen, the mixture is heated to from 80°=0 to 85° C. with stirring and reduced at a hydrogen pressure of from 0.2 to 1.0 MPa. When after about 2 hours the uptake of hydrogen falls sharply, the pressure is raised to 2.0 MPa and stirring is continued at 85° C for 30 minutes until there is no longer any drop in pressure. The batch is cooled to 60° C., the autoclave is let down and flushed with nitrogen, and the catalyst is filtered off on a pressure filter at from 50° to 60° C. The aqueous phase is separated off from the filtrate and toluene is distilled off until the water content of the solution is <0.02percent. The solution is processed further in accordance with Example 2. Alternatively, the solution can be worked up by distillation and the product isolated. Yield 97-98percent; purity by GC: >=99.2percent; boiling point: 91° to 92° C./10 torr.
platinum; In acetone;
a) Preparation of N-isopropyl-4-fluoroaniline 564.5 g (4 mol) of 4-fluoronitrobenzene, 255.6 g (4.4 mol) of acetone and 8 g of a platinum catalyst on activated charcoal (sulfited; 50percent moisture content) are placed in an autoclave (volume: 2 liters) fitted with a reciprocating stirrer, and are reacted at 80° to 90° C. under a hydrogen pressure of 6 to 10 bar, with stirring. When the uptake of hydrogen has ceased, the mixture is cooled, the autoclave is depressurized and the catalyst is filtered off. This gives 812 g of a reaction mixture composed of an aqueous phase and an organic phase.
a 1-(3-Fluorobenzyloxy)-4-nitro-benzene A mixture of 5.04 g (40 mmol) 3-fluorobenzyl alcohol and 1.29 g (4 mmol) tris-(dioxa-3,6-heptyl)amine is treated with 2.47 g (44 mmol) of potassium hydroxide. The mixture is stirred at room temperature for 10 min, then 5.55 g (44 mmol) of 4-fluoro-nitrobenzene is slowly added through a dropping funnel. The mixture is kept for 45 min at 80° C., cooled to room temperature and diluted with about 75 ml water. Extraction with ethyl acetate and washing with 2M aqueous hydrochloric acid yields a yellowish organic phase, which is dried and evaporated. The residue is recrystallized from methanol to give 6.07 g (61percent) of the title compound. Yellow crystals, mp=104-105° C.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Heating / reflux;
a) 4-(3-Hydroxypiperidin-1 -yl)nitrobenzeneTo a solution of 4-fluoronitrobenzene (1 g, 7.09 mmol) in AcN (16 ml_), 3- hydroxypipehdine hydrochloride (1.04 g, 7.57 mmol) and DIEA (1.32 ml_, 7.57 mmol) were added. The mixture was stirred and refluxed for 18 h. The resulting mixture was cooled until room temperature and evaporated. The crude product thus obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 1.15 g of the desired compound (51 % yield).
51%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;Heating / reflux;
To a 4-fluoronitrobenzene solution (1 g, 7.09 mmol) in AcN (16 mL), 3- hydroxypipehdine hydrochloride (1.04 g, 7.57 mmol) and DIEA (1.32 mL, 7.57 mmol) were added. The mixture was stirred and refluxed for 18 h. The resulting mixture was cooled until room temperature and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc <n="67"/>mixtures of increasing polarity as eluent, to afford 1.15 g of the desired compound (51 % yield).
A. 1-[2-(4-Nitro-phenoxy)ethyl]-1H-imidazole A stirred solution of 2-imidazol-1-yl-ethanol (J. Med. Chem., 39(10), 1991, (1996)) (3.9 g, 35 mmol) in dimethylformamide (75 mL) at 15 C. was treated portionwise with 60% sodium hydride (0.84 g, 35 mmol) and stirred at room temperature for 30 minutes. The mixture was rechilled and 4-fluoro-1-nitrobenzene (4.93 g, 35 mmol) added dropwise. The mixture was stirred cold for 30 minutes and heated at 35-40 C. for 30 minutes. A little water was added and the volatiles were removed on a pump. The residue was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and evaporated. Chromatography on silica gel and eluding with methanol/triethyl-amine/dichloromethane (2:2:96) and crystallization of the purified product from dichloromethane/ether gave 3.4 g (42%) of 1-[2-(4-nitro-phenoxy)ethyl]-1H-imidazole as a colorless solid, mp 55-57 C. Mass spectrum (LR-APCl) MH+=234
1-(Hydroxyethyl)imidazole (5.30 g; 47.3 mmol) was dissolved in anhydrous THF (50 mL) and cooled in an ice-bath. Sodium hydride (2.08 g of a 60 wt % dispersion in oil, 52.0 mmol) was added in portions over 10 min. The ice-bath was removed, and the mixture was stirred at room temperature for 20 min. A solution of 1-fluoro-4-nitrobenzene (5.0 mL, 47.2 mmol) in anhydrous THF (10 mL) was added over 5 min and the mixture stirred for a further 1.5 hr. Water (a few mL) was cautiously added and the mixture concentrated under reduced pressure. The residue was partitioned between EA (75 mL) and water (75 mL), and the phases separated. The aqueous phase was extracted twice with EA and the combined organic layers extracted three times with 1N hydrochloric acid. The pH of these acidic extracts was then adjusted to 7 with 5N aqueous sodium hydroxide and the resulting milky solution extracted three times with EA. The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 1-(2-(4-nitrophenoxy)-ethyl)-1H-imidazole (5.46 g) as a brown oil. A solution of 1-(2-(4-nitrophenoxy)ethyl)-1H-imidazole (5.46 g; 2.34 mmol) in ethanol (60 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.40 g) at room temperature for 20 hr. The mixture was filtered through diatomaceous earth and then concentrated under reduced pressure to give 4-[2-(1H-imidazol-1-yl)ethoxy]benzenamine (4.56 g) as a white solid.
A DMF solution (200 mL) of (3-hydroxypropyl)pyrrolidine (100 g) was dropwise added to a DMF (500 mL) suspension of sodium hydride (43.2 g, 60 % oil dispersion), at 0C. The reaction liquid was stirred at 0C for 10 minutes, then a DMF solution (200 mL) of 4-fluoronitrobenzene (109 g, 0.774 mol) was dropwise added to it, stirred at 0C for 1 hour and then at room temperature for 16 hours. The obtained reaction liquid was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfide, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate = 1/1 to chloroform/methanol = 9/1 to 5/1) to obtain a compound 3 (155 g, yield 83 %) as a yellow oily substance. 1HNMR (400 MHz, CDCl3, delta ppm): 1.77-1.82 (4H, m), 2.00-2.08 (2H, m), 2.50-2.54 (4H, m), 2.63 (2H, t, J=7.2 Hz), 4.12 (2H, t, J=6.4 Hz), 6.94 (2H, d, J=9.6 Hz), 8.17 (2H, d, J=9.6 z).
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.
With 1,4-diaza-bicyclo[2.2.2]octane; In acetonitrile; at 80℃; for 72.0h;
Step 3: 4-(4-Nitrophenoxy)H-pyrrolo[l,2-b]pyridazine; Pyrrolo[l,2-b]pyridazin-4(lH)-one (1 10 mg, 820 mumol), l-fluoro-4-nitrobenzene (174 mg, 1.23 mmol), and l,4-diaza-bicyclo[2.2.2]octane (184 mg, 1.64 mmol) were combined in acetonitrile (3 ml) and heated for 72 hours at 80 0C. The mixture was concentrated and purified using 100% CH2Cl2 to afford 4-(4-nitrophenoxy)H-pyrrolo[l,2-b]pyridazine.
(D) To a solution of t-butyl methyl malonate (1.91 g, 11 mmol) in DMF (10 mL) was added NaH (0.849 g, 21 mmol, 60percent dispersion in oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C., after which 4-fluoro-nitrobenzene (1.41 g, 10 mmol) was added. The reaction mixture was stirred for 12 h at RT, then poured into water (100 mL) and the product extracted with EtOAc (100 mL). The organic layer was washed with water (3*100 mL), dried over Na2SO4, and evaporated under vacuum. The crude product was purified by column chromatography (SiO2, hexanes:EtOAc 9:1) to provide 2-(4-nitrophenyl)-malonic acid t-butyl ester methyl ester (2 g, 68percent yield).
4-ethoxycarbonyl-1-(4-nitrophenyl)imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium carbonate; In acetonitrile; at 60℃; for 16h;
Intermediate 86Ethyl 1 -(4-nitrophenyl)-1 H-imidazole-4-carboxylateA mixture of ethyl 1 H-imidazole-4-carboxylate (8 g, 57.1 mmol), 4-fluoro-1 -nitrobenzene (8.05 g, 57.1 mmol) and potassium carbonate (8.68 g, 62.8 mmol) in acetonitrile (100 mL) was stirred at 60°C for 16 h then cooled to room temperature and most the solvent was removed in vacuo. The residue was partitioned between AcOEt (200 mL) and water (150 mL) and the layers were separated. The organic phase was dried over MgS04 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5percent MeOH in DCM) gave ethyl 1 -(4-nitrophenyl)-1 /-/-imidazole-4- carboxylate (12.53 g, 48.0 mmol, 84percent) as a yellow oil.LCMS (method G): Retention time 0.80 min, [M+H]+ = 262.0
84
With potassium carbonate; In acetonitrile; at 60℃; for 16h;
A mixture of <strong>[23785-21-9]ethyl 1H-imidazole-4-carboxylate</strong> (8 g, 57.1 mmol), 4-fluoro-1-nitrobenzene (8.05 g, 57.1 mmol) and potassium carbonate (8.68 g, 62.8 mmol) in acetonitrile (100 mL) was stirred at 60° C. for 16 h then cooled to room temperature and most the solvent was removed in vacuo. The residue was partitioned between AcOEt (200 mL) and water (150 mL) and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5percent MeOH in DCM) gave ethyl 1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (12.53 g, 48.0 mmol, 84percent) as a yellow oil.LCMS (method G): Retention time 0.80 min, [M+H]+=262.0
With potassium carbonate; In acetonitrile; for 4h;Reflux;
Intermediate 5To a solution of <strong>[202982-70-5]3-chloro-5-fluorophenol</strong> (1.46 g, 10 mmol) and 1-fluoro-4-nitrobenzene (1.41 g, 10 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.76 g, 20 mmol) and the reaction mixture was heated to reflux for 4 hours. After filtration, the solvent was removed. The residue obtained was washed with n-hexane (2 times 15 mL) and dried to afford the title compound (2.38 g) which was directly used in the next step.
Example 12; 1-Ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 12a) 1-(4-nitrophenyl)-<strong>[271-73-8]1H-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong></strong> To a stirred solution of <strong>[271-73-8]1H-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong></strong> (300 mg) in DMF (3.0 mL) was added sodium hydride (101 mg) (60percent in mineral oil) with ice-cooling. The mixture was stirred at room temperature for 30 min, and then 1-fluoro-4-nitrobenzene (355 mg) was added. After stirring at room temperature for 2 h, the mixture was warmed up to 50° C. The mixture was stirred at 50° C. for 12 h. Cesium carbonate (821 mg) was added and the mixture was stirred at 100° C. for 12 h, and treated with water and AcOEt. The insoluble material was filtered off. The organic layer was separated and the aqueous layer was extracted with AcOEt. The organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was used for the next reaction.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
Example 1 Synthesis of TNPE The following is an exemplary procedure for the synthesis of 1,1,1-tris[4-(4-nitrophenoxy)phenyl]ethane (TNPE, III) as depicted in . <strong>[27955-94-8]1,1,1-tris(4-hydroxyphenyl)ethane</strong> (THPE, I) (10.0 g, 33.0 mmol), 1-fluoro-4-nitrobenzene (II) (15.4 g, 109 mmol), potassium carbonate (15.1 g, 109 mmol), and DMF (100 mL) were placed into a 250 mL three-necked flask equipped with a magnetic stir bar and nitrogen inlet and outlet. The mixture was stirred at room temperature for 24 hours and filtered. The filtrate was diluted with ethyl acetate (400 mL), and the organic layer was separated. The organic layer was washed with water three times. It was then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to 75 mL on a rotary evaporator and stored in a refrigerator for several days to afford 11.2 g (51percent) of off-white crystals, m.p. 98-99° C. MS (m/e): 669 (M+). Anal. Calcd. for C38H27N3O9: C, 68.18percent; H, 4.06percent; N, 6.27percent; O, 21.50percent. Found: C, 67.69percent; H, 4.26percent; N, 6.21percent; O, 21.22percent. FT-IR (KBr, cm-1): 3076, 2979, 1586, 1513, 1486, 1344, 1248, 1165, 1107, 874, 846. 1H-NMR (DMSO-d6, delta in ppm): 2.26 (s, 3H, CH3), 7.17-7.27 (m, 18H, Ar-H), 8.28-8.31 (d, 6H, Ar-H).
1-chloro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 100℃;
D7 l-Chloro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzeneTo a mixture of <strong>[6294-93-5]4-chloro-3-(trifluoromethyl)phenol</strong> (1.00 g, 5.09 mmol), l-f uoro-4- nitrobenzene (0.718 g, 5.09 mmol) and potassium carbonate (2.1 1 g, 15.3 mmol) in dimethyl sulfoxide (DMSO) (25 mL) was heated at 100 °C overnight, then diluted with ethyl acetate (200 mL) and water (200 mL). The separated aqueous part was extracted with ethy acetate (100 mL) twice. Combined organic parts were washed with water then brine, dried over sodium sulfate and concentrated. Purification via ISCO system afforded the desired product (800 mg) as a white solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 6h;
Step 1. 4-[4-(4-Trifluoromethylphenyl)-lH-imidazol-l-yl]-nitrobenzene. 4-Trifluoromethylphenyl imidazole (1.43 g, 6.7 mmol), 4-fluoro nitrobenzene (1.2 g, 8.5 mmol) and potassium carbonate (1.5 g, 10.9 mmol) were combined in DMF (15 mL) and heated at 100 0C for 6 h. The cooled solution was then poured onto water (100 mL), and the resulting solid was filtered and air-dried to give the title imidazole (1.0 g) as a light yellow solid: mp 197 0C. Anal. Calcd. for Ci6Hi0F3N3O2: C, 57.66; H, 3.02; N, 12.61. Found: C, 57.69; H, 3.01; N, 12.48.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 90℃; for 3h;Inert atmosphere;
EXAMPLEHereinafter, the present invention is described further in detail with reference to the example. The present invention is not limited to the following example.<Reaction 1>100.0 g (471.3 mmol) of 2,7-dihydroxy-9-fluorenone, 146.3 g (1036.8 mmol) of 4-fluoronitrobenzene as the compound (A), 260.5 g (1885.0 mmol) of potassium carbonate as a catalyst, and 1000 mL of N-methylpyrrolidone (NMP) as a reaction solvent were put into a four-necked separable flask with an internal volume of 2 L. Under stirring, the mixture in the flask was subjected to the reaction represented by formula (12) below in a nitrogen atmosphere at 90° C. for 3 hours. After the completion of the reaction, the contents of the flask were cooled to room temperature. Thereafter, they were poured into 10 L of ice water and precipitated crystal was collected by filtration. The collected crystal was washed sequentially with water and ethanol, followed by drying under reduced pressure. Thus, 197.4 g (yield rate: 92.2percent) of the compound (B) shown on the right-hand side of formula (12) was obtained as an ocherous crystal. The compound (B) shown on the right-hand side of formula (12) is 2,7-bis(4-nitrophenoxy)-9-fluorenone.
92.2%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 90℃; for 3h;Inert atmosphere;
100.0 g (471.3 mmol) of 2,7-dihydroxy-9-fluorenone, 146.3 g (1036.8 mmol) of 4-fluoronitrobenzene as the compound , 260.5 g (1885.0 mmol) of potassium carbonate as a catalyst, and 1000 mL of N-methylpyrrolidone (NMP) as a reaction solvent were put in a four-necked separable flask with an internal volume of 2 L. Under stirring, the mixture in the flask was subjected to the reaction represented by formula (13) below in a nitrogen atmosphere at 90° C. for 3 hours. After the completion of the reaction, the contents in the flask were cooled to room temperature. Thereafter, they were poured into 10 L of ice water and precipitated crystal was collected by filtration. The collected crystal was washed sequentially with water and ethanol, followed by drying under reduced pressure. Thus, 197.4 g (yield rate: 92.2percent) of the compound shown on the right-hand side of formula (13) was obtained as an ocherous crystal. The compound shown on the right-hand side of formula (13) is 2,7-bis(4-nitrophenoxy)-9-fluorenone.
With potassium carbonate; In acetonitrile; for 4h;Reflux;
To a solution of <strong>[827-99-6]3-trifluoromethoxy phenol</strong> (1.78g, lOmmol) and 1-fluoro-4-nitrobezene (1.41g, lOmmol) in CH3CN (4OmL) K2C03 (2.76g, 2Ommol) was added and the reaction mixture was heated to reflux for 4hrs. After filtration, the solvent was removed and the residue was washed with n-hexane (2xl5mL) and dried to afford 2.83g of nitro intermediate. To a solutionof nitro intermediate in THE (4OmL) and water (iOmL) Iron (11.20g, 200mmol) and then NH4CI (10.70g. 200mmol) were added and the reaction mixture was heated to reflux for 4hrs. After filtration, the solvent was concentrated and the residue poured into 50mL of water. The mixture was extracted with ethyl acetate (3x5OmL) and the combined organic phases were dried over MgSO4. Removal of solvent afforded 2.58g of the aniline intermediate. 269mg ofthe obtained aniline intermediate were dissolved in DCM (2OmL), Triethylamine (202mg,2mmol) and then triphosgene (118.4mg, 0.4mmol) were added and the reaction mixture was stirred at room temperature for 4hrs. Triethylamine (202mg, 2mmol) and acetohydrazide (74mg, lmmol) were added to the above solution and the reaction mixture was stirred at room temperature overnight. Removal of solvent afforded crude material, which was purifiedby flash chromatography on silica gel using dichloromethane/methanol 200:1 as eluents to give 288mg of urea intermediate. It was dissolved in an aqueous 2M solution of NaOH (l5mL) and the reaction mixture was heated to reflux for l2hrs. The mixture was neutralized with aqueous 6N HCI and extracted with DCM (3x5OmL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude compound. which was purified byflash chromatography on silica gel using dichloromethane/methanol 100:1 as eluents to afford 35mg of title compound as white solid.MS_i (ESI) m/z calcd for Ci6Hi2F3N3O3 351.28, found 352.i(MH ).1HNMR (400 MHz, DMSO-d6): 5 ppm li.60 (1H, s), 7.58-7.45 (3H, m), 7.22-7.08 (5H, m), 2.06 (3H, s).
tert-butyl 3-fluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.6%
To a solution of tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate (10.07 g, 46 mmol, 1 eq.) in DMA (200 mL) cooled at 0 C was added NaH (3.7 g, 92 mmol, 2 eq.) in small portions and the resulting mixture was stirred at 0 C for 30 min.Then l-fluoro-4- nitrobenzene (4.9 mL, 46 mmol, 1 eq.) was added slowly and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (1000 mL), extracted with EA (3x200 mL) and the organic layers were combined, washed with brine (600 mL), dried over anhydrous Na2S04, concentrated and purified via column chromatography (PE/EA=2/1) to afford tert- butyl 3-fluoro-4-(4-nitrophenoxy)piperidine-l-carboxylate (8.7 g, 55.6%) as a yellow solid.
214 mg
With potassium tert-butylate; In tetrahydrofuran;Cooling with ice; Reflux;
Potassium tert-butoxide (202 mg) was added to a mixture containing 4-fluoronitrobenzene (141 mg), <strong>[373604-28-5]tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate</strong> (commercially available from Ark Pharm, Inc, 219 mg)and THF (10 mL) under ice cooling, and the mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, ethyl acetate was then added thereto, and washing with a saturated sodium bicarbonate aqueous solution was performed. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure, and thereby a yellow solid (214 mg) containing tert-butyl 3-fluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate was obtained.
1-(tert-butyl) 2-methyl 4-(4-nitrophenyl)piperazine-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a stirred solution of 1-tert-butyl 2-methyl piperazine-l,2-dicarboxylate (1.0 g) and K2C03 (1.12 g, 2 eq) in DMF (15 mL), l-fluoro-4-nitrobenzene (0.86 g, 1.5 eq) was added and the mixture stirred at 90 C for 12 h. After TLC showed completion of starting material, the mixture was poured into ice cold water and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with water (3 x 50 mL), dried over Na2S04 and concentrated to afford the final compound (1.3 g, 87%) as yellow solid. 1H NMR (400MHz, CDCI3): delta 8.22 (d, 2H), 6.98 (d, 2H), 4.38 (t, 2H), 3.67 (t, 2H). LCMS calculated for (M) 365.39 and found (M+H) 366.21, LCMS showed 86.8 % purity.
With 3 % platinum on carbon; hydrogen; toluene-4-sulfonic acid; In toluene; at 70 - 80℃; under 3750.38 - 15001.5 Torr; for 4h;Autoclave; Large scale;
4 - fluoronitrobenzene 10kg (70 52mol.), 2, 2 -. Dimethoxypropane 7 · 42kg (. 70 52mol), l 74kg p-toluenesulfonic acid, 871 g of platinum on carbon (content 3percent) and 18kg 50L toluene were charged into an autoclave, stirred, temperature to 70-80 ° C, the hydrogen pressure maintained at 5 -20bar, until the pressure is constant, about 4 hours of reaction, the reaction mixture was cooled and filtered to remove the catalyst. 3kg washing water was added, points to the water layer, the organic phase was stripped of toluene to give 10. 76 kg N - isopropyl-4 - fluoroaniline, yield 98percent.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 75℃;Sealed tube; Inert atmosphere;
[00357] Step 1 : To a solution of 4-fluoronitrobenzene (0.55ml, 5.13 mmol) in AcN (6 mL), Octahydro-lH-pyrido[l,2-a]pyrazine (600 mg, 4.28 mmol) and DIEA (1.1 mL, 6.42 mmol) were added. The mixture was stirred at 75 C for overnight (in a sealed tube). The resulting mixture was cooled to room temperature and then concentrated. The crude product was purified by column chromatography (0-5% MeOH in DCM) to afford the desired product as yellow oil (1.03g, 92% yield). ESI-MS: calcd for (C14H19N302) 261, found 262 (MH+).
1-[(4,4-difluorocyclohexyl)oxy]-4-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
To a solution of <strong>[22419-35-8]4,4-difluorocyclohexan-1-ol</strong> (368 mg, 2.70 mmol) in 14 mL of dry THF was added at room temperature NaH (116 mg, 2.84 mmol, 60percent dispersion in mineral oil). The mixture was stirred at room temperature for 5 minutes then 1-fluoro-4-nitrobenzene (0.301 mL, 2.84 mmol) was added and the reaction was stirred at room temperature for 4 hours. Then more NaH was added (95 mg, 60percent dispersion in mineral oil) and the mixture was stirred at room temperature for further 2 hours. Et2O was added to the reaction mixture. The organic phase was washed with water (twice), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica flash chromatography with 0percent to 15percent of ethyl acetate in cyclohexane to give 1-[(4,4-difluorocyclohexyl)oxy]-4-nitrobenzene (685 mg, 80percent yield) as a yellow solid. MS found for C12H13F2NO3 as (M+H)+ 258.0.
With hydrogen; at 60℃; under 5250.53 Torr;Autoclave;
4 mol of 4-fluoronitrobenzene, 2 mol of acetone, and Raney nickel catalyst were placed in an autoclave and the temperature was raised to 60 degrees. Into the hydrogen, the pressure is maintained at 0.7MPA until the pressure is constant, cooling to 30 degrees, filtering the catalyst, Take the organic phase to remove water to give N-isopropyl-4-fluoroaniline; (1H-NMR shows 4 hydrogens on delta 7.04 benzene ring, hydrogen chemical signal on delta 4.96 tertiary carbon CH-, delta 1.04 is 6 hydrogen signals on two methyl groups); yield (93percent, Purity 94percent).
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃;
General procedure: Substituted amine (1.2 equiv) was added to a mixture of 4-fluoronitrobenzene (1 equiv) and K2CO3 (2.0 equiv) in DMF (7mL/g). The reaction mixture was stirred at 40C and followed by TLC. After completion of the reaction, the mixture was poured into stirring ice-water. The resulting precipitate was filtered and dried to obtain compounds 11 as a yellow solid.
4-bromo-N,N-bis(4-nitrophenyl)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With cesium fluoride; In dimethyl sulfoxide; at 150℃; for 24h;Inert atmosphere;
2.291 g (0.01 mol) of <strong>[20358-02-5]2-amino-4-bromobenzothiazole</strong> and 5.305 mL (0.05 mol) of p-fluoronitrobenzene were added to a 250 mL three-necked flask.DMSO is a solvent, magnetically stirred and argon gas, heated to 150 C in an oil bath.Further, 3.038 g (0.02 mol) of cesium fluoride (CsF) was added, and the mixture was refluxed for 24 hours.The reaction solution was poured into ice water, extracted with dichloromethane, and the solvent was evaporated to -101.The product was purified by column chromatography using dichloromethane: n-hexane = 1:1 (volume ratio) as mobile phase and silica gel as stationary phase.The product was collected, dried and dried in vacuo at 80 C for 24 h.The product was obtained in 3.770 g in a yield of 80%.
tert-butyl 3-(hydroxymethyl)-4-(4-nitrophenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium carbonate; In N,N-dimethyl-formamide; for 12h;
To a stirred solution of 135 1-fluoro-4-nitro-benzene (500 mg, 3.54 mmol, 1.0 eq) and 136 <strong>[301673-16-5]tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate</strong> (560 mg, 3.54 mmol, 1.0 eq) in 47 DMF (10 mL) was added 64 K2CO3 (732 mg, 5.31 mmol, 1.5 eq). Reaction mixture was heated at 50° C. for 12 h. Progress of the reaction was monitored by LCMS. Upon the consumption of starting material, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL×2). Combined organic layer was washed with water (50 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude was purified by combi-flash (0-50percent EtOAc-hexane) to obtain 137 tert-butyl 3-(hydroxymethyl)-4-(4-nitrophenyl) piperazine-1-carboxylate (400 mg, 33percent). LCMS: 338.3 [M+1]+
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
A mixture containing 1-fluoro-4-nitrobenzene (282 mg), <strong>[7343-34-2]3,5-dimethyl-1H-1,2,4-triazole</strong> (194 mg), potassium carbonate (552 mg)and DMF (6 mL) was stirred at 80 C. overnight. The reaction mixture was cooled to room temperature and ethyl acetate was then added thereto, and washing with water was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and thereby 3,5-dimethyl-1-(4-nitrophenyl)-1H-1,2,4-triazole (330 mg) was obtained.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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