Home Cart 0 Sign in  
X

[ CAS No. 350-46-9 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
3d Animation Molecule Structure of 350-46-9
Chemical Structure| 350-46-9
Chemical Structure| 350-46-9
Structure of 350-46-9 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 350-46-9 ]

Related Doc. of [ 350-46-9 ]

Alternatived Products of [ 350-46-9 ]

Product Details of [ 350-46-9 ]

CAS No. :350-46-9 MDL No. :MFCD00007282
Formula : C6H4FNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :WFQDTOYDVUWQMS-UHFFFAOYSA-N
M.W : 141.10 Pubchem ID :9590
Synonyms :

Calculated chemistry of [ 350-46-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 35.22
TPSA : 45.82 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.39
Log Po/w (XLOGP3) : 1.8
Log Po/w (WLOGP) : 2.68
Log Po/w (MLOGP) : 1.2
Log Po/w (SILICOS-IT) : 0.51
Consensus Log Po/w : 1.52

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.23
Solubility : 0.837 mg/ml ; 0.00593 mol/l
Class : Soluble
Log S (Ali) : -2.38
Solubility : 0.586 mg/ml ; 0.00416 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.51
Solubility : 0.437 mg/ml ; 0.0031 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.27

Safety of [ 350-46-9 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P210-P260-P264-P270-P271-P273-P280-P301+P312+P330-P302+P352+P312-P304+P340+P311-P314-P370+P378-P403+P233-P403+P235-P405-P501 UN#:2811
Hazard Statements:H227-H302+H312-H331-H373-H402 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 350-46-9 ]

* 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.

  • Upstream synthesis route of [ 350-46-9 ]
  • Downstream synthetic route of [ 350-46-9 ]

[ 350-46-9 ] Synthesis Path-Upstream   1~111

  • 1
  • [ 350-46-9 ]
  • [ 17635-45-9 ]
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 ]
  • [ 80650-45-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5473 - 5476
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1253 - 1256
[3] Patent: WO2014/176258, 2014, A1,
[4] Chemical Communications, 2017, vol. 53, # 95, p. 12814 - 12817
  • 6
  • [ 109-00-2 ]
  • [ 350-46-9 ]
  • [ 80650-45-9 ]
Reference: [1] Patent: US9138427, 2015, B2,
  • 7
  • [ 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
  • 8
  • [ 350-46-9 ]
  • [ 67455-41-8 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 113, p. 93433 - 93437
  • 9
  • [ 109-97-7 ]
  • [ 350-46-9 ]
  • [ 4533-42-0 ]
YieldReaction ConditionsOperation 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
  • 10
  • [ 5382-16-1 ]
  • [ 350-46-9 ]
  • [ 142752-12-3 ]
Reference: [1] Patent: WO2012/59932, 2012, A1,
[2] Patent: WO2014/183300, 2014, A1,
  • 11
  • [ 350-46-9 ]
  • [ 142752-12-3 ]
Reference: [1] Patent: US2014/121200, 2014, A1,
[2] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
  • 12
  • [ 350-46-9 ]
  • [ 16153-81-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10685 - 10699
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 8, p. 2349 - 2352
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[7] Journal of Chemistry, 2014, vol. 2014,
[8] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[9] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1863 - 1873
[10] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 179 - 190
[11] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
[12] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 896 - 905
[13] Patent: CN103408540, 2016, B,
[14] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 510 - 527
[15] Patent: CN106905245, 2017, A,
[16] Patent: CN105017160, 2017, B,
[17] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 2173 - 2185
[18] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
[19] Patent: CN108690006, 2018, A,
  • 13
  • [ 109-01-3 ]
  • [ 350-46-9 ]
  • [ 16153-81-4 ]
Reference: [1] Patent: WO2011/120025, 2011, A1,
[2] Patent: WO2008/139161, 2008, A1,
  • 14
  • [ 350-46-9 ]
  • [ 50609-01-3 ]
Reference: [1] Patent: WO2016/34642, 2016, A1,
  • 15
  • [ 288-32-4 ]
  • [ 350-46-9 ]
  • [ 2301-25-9 ]
YieldReaction ConditionsOperation in experiment
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).
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,
  • 16
  • [ 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
  • 17
  • [ 5587-42-8 ]
  • [ 350-46-9 ]
  • [ 2301-25-9 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3286 - 3295
  • 18
  • [ 350-46-9 ]
  • [ 358789-72-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 2173 - 2185
  • 19
  • [ 106-52-5 ]
  • [ 350-46-9 ]
  • [ 358789-72-7 ]
Reference: [1] Patent: WO2016/196776, 2016, A2,
  • 20
  • [ 110-89-4 ]
  • [ 350-46-9 ]
  • [ 6574-15-8 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In dimethyl sulfoxide at 90℃; for 9 h; 4-Fluoronitrobenzene (323 mg, 2.3 mmol) was dissolved in DMSO (5 ml), potassium carbonate (475 mg, 3.5 mmol) and piperidine (460 μl, 4.6 mmol) were added, and the mixture was stirred at 90° C. for 9 hr.
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 to give compound Y197 (yield; 472 mg, 100percent).
Compound Y197 was dissolved in ethyl acetate (20 ml), Pd/C (186 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr.
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; chloroform:methanol (40:1)) to give compound Y222 (yield, quantitative, 394 mg).
Compound Y491 (mentioned later) (80 mg, 0.18 mmol) was dissolved in dichloromethane (2 ml), compound Y222 (100 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 5 hr.
Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (35:1)) to give the title compound (yield; 68 mg, 64percent).
1H NMR (500 MHz, CDCl3) δ8.40 (s, 1H), 8.0 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.52 (dd, 1H, J=8.0, 7.5 Hz), 6.92 (dd, 2H, J=9.0, 3.5 Hz), 6.77 (dd, 2H, J=9.0, 6.5 Hz), 5.33 (t, 1H, J=6.0 Hz), 4.07 (bs, 2H), 3.11-3.09 (m, 4H), 2.79-2.64 (m, 4H), 1.69-1.53 (m, 10H), 1.43 (s, 9H), 1.09-1.01 (m, 2H)
13C NMR (125 MHz, CDCl3) δ154.9, 141.6, 140.8, 131.4, 130.9, 129.8, 125.8, 125.7, 79.7, 77.4, 48.7, 36.6, 29.6, 28.6, 25.7, 24.2
HRMS (FAB-) m/z: [M-H]- calcd for C28H39N4O6S2, 591.2311. found, 591.2324
97% With potassium carbonate In dimethyl sulfoxide at 120℃; for 20 h; In a 250mL round-bottom flask equipped with a stirring bar, a mixture of 12.8g (0.15mol) of piperidine, 21.2g (0.15mol) of 4-fluoronitrobenzene, and 20.7g (0.15mol) of potassium carbonate (K2CO3) in 100mL of dimethyl sulfoxide (DMSO) was heated with stirring at 120°C for 20h. After cooling, the mixture was poured into 400mL mixed solution of ethanol/water (1:1). The yellow crystals were collected by filtration with a yield of 30.0g (97percent) and a melting point of 100–102°C, measured by differential scanning calorimetry (DSC) at a scan rate of 10°C/min. IR (KBr):1577, 1329cm−1 (−NO2 str.). 1H NMR (500MHz, DMSO-d6, δ, ppm): 8.02 (d, J=9.5Hz, 2H, He), 6.98 (d, J=9.5Hz, 2H, Hd), 3.49 (t, J=5.7Hz, 4H, Hc), 1.63 (m, 2H, Ha), 1.57 (m, 4H, Hb). 13C NMR (125MHz, DMSO-d6, δ, ppm): 154.5 (C4), 135.9 (C7), 125.8 (C6) 112.2 (C5), 47.5 (C3), 24.8 (C2), 23.8 (C1)
75% at 80℃; for 20 h; Synthesis of 1-(4-Nitro-phenyl)-piperidine
Piperidine (362 mg, 0.2 mmol) was added to a solution of 1-fluoro-4-nitro-benzene (200 mg, 1.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80° C. for 20 hours.
The reaction mixture was diluted with water and extracted with ethyl acetate.
The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 220 mg (75percent) of 1-(4-nitro-phenyl)-piperidine.
54% 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).
46% With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 5 h; Inert atmosphere Step Reaction: 15.0g equipped with a mechanical stirring was added a 500mL three-necked flask (176mmol)Piperidine, 24.9g (176mmol) of fluoro nitrobenzene, 24.5g (176mmol) of potassium carbonate was added 250mLOf N, N- dimethylformamide as the solvent, with stirring, under nitrogen, the reaction at 110 5H, coldAfter cooling, ice water discharge, the crude product was washed with water three times, dried, and recrystallized from ethanol to give yellowPiperidin-4-nitrophenyl powder 16.7g, 46percent yield;

Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 18, p. 3634 - 3638
[2] Patent: US2013/45977, 2013, A1, . Location in patent: Paragraph 0211; 0212; 0213; 0214
[3] Reactive and Functional Polymers, 2016, vol. 108, p. 54 - 62
[4] Tetrahedron Letters, 1998, vol. 39, # 17, p. 2471 - 2474
[5] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[6] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[7] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[8] Patent: US2009/239848, 2009, A1, . Location in patent: Page/Page column 24; 25
[9] Journal of Chemistry, 2014, vol. 2014,
[10] Tetrahedron, 2018, vol. 74, # 2, p. 303 - 307
[11] Patent: CN105503775, 2016, A, . Location in patent: Paragraph 0040; 0041
[12] Bulletin de la Societe Chimique de France, 1956, p. 311,315
[13] Organic Magnetic Resonance, 1982, vol. 18, # 2, p. 104 - 108
[14] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1803 - 1806
[15] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[16] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[17] Chemical Communications, 2005, # 22, p. 2857 - 2859
[18] Patent: US5580883, 1996, A,
[19] Patent: WO2005/9978, 2005, A1, . Location in patent: Page 99; 101
[20] Patent: WO2005/42518, 2005, A2, . Location in patent: Page/Page column 99
[21] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3286 - 3295
[22] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
  • 21
  • [ 110-91-8 ]
  • [ 350-46-9 ]
  • [ 10389-51-2 ]
YieldReaction ConditionsOperation 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
  • 22
  • [ 110-91-8 ]
  • [ 350-46-9 ]
  • [ 67-63-0 ]
  • [ 10389-51-2 ]
Reference: [1] Patent: US2003/162787, 2003, A1,
  • 23
  • [ 110-85-0 ]
  • [ 350-46-9 ]
  • [ 6269-89-2 ]
YieldReaction ConditionsOperation 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
  • 24
  • [ 350-46-9 ]
  • [ 6269-89-2 ]
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2549 - 2552
[2] Tetrahedron Letters, 1997, vol. 38, # 23, p. 4091 - 4094
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3086 - 3090
[4] Patent: WO2012/59932, 2012, A1,
  • 25
  • [ 86-74-8 ]
  • [ 350-46-9 ]
  • [ 6299-16-7 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 28, p. 9423 - 9426
  • 26
  • [ 462-06-6 ]
  • [ 70-34-8 ]
  • [ 350-46-9 ]
YieldReaction ConditionsOperation in experiment
7.4% at 50℃; for 4 h; Examples 26-29: Effect of X on the nitration of Ph-X using chloroacetic anhydrideExamples 26 to 29 illustrate the effect of X on the nitration of PhX. The following general procedure was used. A mixture of mono-substituted benzene (35 mmol), nitric acid (120 mmol, 5.04 ml), chloroacetic anhydride (120 mmol, 20.52 g), DCM (10 ml) and zeolite Ηβ (Si/AI = 12.5; 2.0 g) was stirred for 4 h in a bath set at 50 °C. The results are shown in Table 5.Table 5: The effect of X on the nitration of Ph-X
Reference: [1] Patent: WO2012/49513, 2012, A1, . Location in patent: Page/Page column 13
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 654,656
  • 27
  • [ 462-06-6 ]
  • [ 70-34-8 ]
  • [ 350-46-9 ]
  • [ 1493-27-2 ]
YieldReaction ConditionsOperation in experiment
85 %Spectr. at 0 - 50℃; for 4 h; General procedure: Propanoic anhydride (16.90 g, 130 mmol) was added to a stirring mixture of nitric acid (7.65 g, 100percent, 120 mmol), and Hβ (2.0 g, SiO2:Al2O3 = 25) at 0 °C and the mixture was stirred for 5 min at constant temperature. Toluene (3.22 g, 35 mmol) was then added dropwise, and the mixture was allowed to warm to room temperature. The flask was equipped with a water condenser fitted with a calcium chloride guard tube and was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, analytical grade acetone (30 mL) was then added, and the mixture was stirred for 5 min. The zeolite was removed by suction filtration and washed with copious amounts of acetone. The mother liquors were combined, hexadecane (1.00 g) was added, and the mixture was subjected to GC analysis.
Reference: [1] Journal of Catalysis, 2013, vol. 297, p. 244 - 247
[2] Arkivoc, 2014, vol. 2014, # 4, p. 107 - 123
  • 28
  • [ 1765-93-1 ]
  • [ 70-34-8 ]
  • [ 350-46-9 ]
Reference: [1] Synlett, 2000, # 10, p. 1485 - 1487
  • 29
  • [ 455-17-4 ]
  • [ 70-34-8 ]
  • [ 350-46-9 ]
Reference: [1] Journal of Fluorine Chemistry, 1998, vol. 92, # 1, p. 27 - 32
  • 30
  • [ 350-46-9 ]
  • [ 70-34-8 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1904, vol. 23, p. 261[2] Recueil des Travaux Chimiques des Pays-Bas, 1905, vol. 24, p. 140
  • 31
  • [ 350-46-9 ]
  • [ 3491-12-1 ]
Reference: [1] Arzneimittel-Forschung, 1965, vol. 15, # 6, p. 604 - 608
[2] Dyes and Pigments, 2015, vol. 121, p. 170 - 177
  • 32
  • [ 350-46-9 ]
  • [ 2479-46-1 ]
Reference: [1] Dyes and Pigments, 2015, vol. 121, p. 170 - 177
  • 33
  • [ 350-46-9 ]
  • [ 108-46-3 ]
  • [ 2479-46-1 ]
Reference: [1] Arzneimittel-Forschung, 1965, vol. 15, # 6, p. 604 - 608
  • 34
  • [ 350-46-9 ]
  • [ 6523-49-5 ]
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,
  • 35
  • [ 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,
  • 36
  • [ 693-98-1 ]
  • [ 350-46-9 ]
  • [ 73225-15-7 ]
YieldReaction ConditionsOperation in experiment
89% With caesium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere A mixture of l-fluoro-4-nitrobenzene (10 g, 70.9 mmol), 2-methyl-lH- imidazole (5.8 g, 70.9 mmol), and Cs2C03 (34.7 g, 106.4 mmol) in degassed DMF (200 mL) was heated at 100°C under nitrogen overnight. When TLC indicated that l-fluoro-4-nitrobenzene was consumed, the reaction mixture was concentrated in vacuo. The residue was diluted with water (300 mL), and a grey precipitate was formed and was isolated to give 2-methyl-l-(4- nitrophenyl)-lH-imidazole (12.8 g, yield 89percent).
88% With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 18 h; 5 To 1 -fluoro-4-nitrobenzene (11.0 g, 0.078 mol) in DMF (40 mL) were added 2- methyl-lH-imidazole (6.41 g, 0.078 mol) and potassium carbonate (16.16 g, 0.117 mol) and the reaction stirred at 500C for 18 h. Residual solids were filtered off and the solvent removed from the filtrate. The residues were dissolved in ethyl acetate/water and extracted into ethyl acetate. The solvent was removed and, the residues triturated with 10 diethyl ether to give the title compound (13.93 g, 88percent) as an off-white solid. δη (DMSO- d6) 8.38 (2H, d, J8.8 Hz), 7.78 (2H, d, J9.1 Hz), 7.46 (IH, s), 6.99 (IH, s), 2.38 (3H, s). LCMS (ES+) 204.0 (M+H+).
Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 4, p. 597 - 609
[2] Patent: WO2011/75478, 2011, A1, . Location in patent: Page/Page column 53
[3] Patent: WO2009/71888, 2009, A1, . Location in patent: Page/Page column 83
[4] Patent: US5298520, 1994, A,
[5] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1799 - 1810
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
[8] Patent: US5128351, 1992, A,
[9] Patent: US5077409, 1991, A,
[10] Patent: EP991638, 2005, B1, . Location in patent: Page/Page column 52
  • 37
  • [ 103-76-4 ]
  • [ 350-46-9 ]
  • [ 5521-38-0 ]
YieldReaction ConditionsOperation 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]+.

Reference: [1] Patent: WO2015/92431, 2015, A1, . Location in patent: Page/Page column 236
[2] Patent: WO2015/27222, 2015, A2, . Location in patent: Paragraph 0322
[3] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 112-113
[4] Patent: WO2016/138527, 2016, A1, . Location in patent: Paragraph 00212
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[6] Patent: US2003/13708, 2003, A1,
[7] Patent: US2004/87575, 2004, A1,
[8] Patent: US2004/110745, 2004, A1,
  • 38
  • [ 2759-28-6 ]
  • [ 350-46-9 ]
  • [ 16155-08-1 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In dimethyl sulfoxide 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
  • 39
  • [ 2759-28-6 ]
  • [ 350-46-9 ]
  • [ 16155-08-1 ]
Reference: [1] Patent: US5086055, 1992, A,
  • 40
  • [ 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
  • 41
  • [ 106-48-9 ]
  • [ 350-46-9 ]
  • [ 101-79-1 ]
Reference: [1] Patent: WO2013/63100, 2013, A1,
[2] Patent: WO2013/60029, 2013, A1,
  • 42
  • [ 350-46-9 ]
  • [ 31465-36-8 ]
Reference: [1] Chemical Communications, 2005, # 19, p. 2486 - 2488
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 16, p. 4477 - 4492
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 1023 - 1026
[4] Letters in Drug Design and Discovery, 2012, vol. 9, # 4, p. 379 - 388
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1719 - 1723
[6] MedChemComm, 2015, vol. 6, # 4, p. 671 - 676
  • 43
  • [ 150-76-5 ]
  • [ 350-46-9 ]
  • [ 31465-36-8 ]
Reference: [1] Patent: US2012/46290, 2012, A1,
[2] Patent: EP1047418, 2005, B1,
  • 44
  • [ 350-46-9 ]
  • [ 5521-39-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[2] Patent: WO2012/59932, 2012, A1,
[3] Patent: WO2015/27222, 2015, A2,
[4] Patent: WO2016/138527, 2016, A1,
[5] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
  • 45
  • [ 103-76-4 ]
  • [ 350-46-9 ]
  • [ 5521-39-1 ]
Reference: [1] Patent: WO2015/92431, 2015, A1,
  • 46
  • [ 350-46-9 ]
  • [ 16154-69-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[2] European Journal of Organic Chemistry, 2001, # 16, p. 3105 - 3118
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1092 - 1099
[4] Archives of Pharmacal Research, 2016, vol. 39, # 5, p. 603 - 617
[5] British Journal of Pharmacology, 2018, vol. 175, # 12, p. 2399 - 2413
  • 47
  • [ 350-46-9 ]
  • [ 101349-12-6 ]
Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 10, p. 1704 - 1712
  • 48
  • [ 350-46-9 ]
  • [ 64001-11-2 ]
Reference: [1] Patent: EP3342765, 2018, A1,
  • 49
  • [ 64-17-5 ]
  • [ 350-46-9 ]
  • [ 1128-61-6 ]
  • [ 62-53-3 ]
  • [ 371-40-4 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 2011, vol. 84, # 9, p. 953 - 959
  • 50
  • [ 64-17-5 ]
  • [ 350-46-9 ]
  • [ 1128-61-6 ]
Reference: [1] Catalysis Communications, 2011, vol. 12, # 6, p. 389 - 393
  • 51
  • [ 350-46-9 ]
  • [ 23499-01-6 ]
YieldReaction ConditionsOperation in experiment
38%
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,
  • 52
  • [ 41979-39-9 ]
  • [ 350-46-9 ]
  • [ 23499-01-6 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Synthetic Communications, 1990, vol. 20, # 22, p. 3537 - 3545
[2] Patent: US2011/9390, 2011, A1, . Location in patent: Page/Page column 18
[3] Patent: EP1518855, 2005, A1, . Location in patent: Page/Page column 20
[4] Patent: US5008267, 1991, A,
[5] Patent: WO2014/32, 2014, A1, . Location in patent: Page/Page column 37
  • 53
  • [ 41661-47-6 ]
  • [ 350-46-9 ]
  • [ 23499-01-6 ]
YieldReaction ConditionsOperation in experiment
49.2% 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] Patent: WO2015/38417, 2015, A1, . Location in patent: Paragraph 175; 176
  • 54
  • [ 40064-34-4 ]
  • [ 350-46-9 ]
  • [ 23499-01-6 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 7, p. 2282 - 2284
  • 55
  • [ 675-20-7 ]
  • [ 350-46-9 ]
  • [ 38560-30-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5339 - 5356
  • 56
  • [ 350-46-9 ]
  • [ 190728-25-7 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 1, p. 11 - 17
  • 57
  • [ 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
  • 58
  • [ 350-46-9 ]
  • [ 120-83-2 ]
  • [ 1836-75-5 ]
YieldReaction ConditionsOperation 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
  • 59
  • [ 350-46-9 ]
  • [ 350-30-1 ]
YieldReaction ConditionsOperation 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
  • 60
  • [ 7782-50-5 ]
  • [ 7705-08-0 ]
  • [ 350-46-9 ]
  • [ 350-30-1 ]
Reference: [1] Chem. Zentralbl., 1914, vol. 85, # II, p. 1432
  • 61
  • [ 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
  • 62
  • [ 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
  • 63
  • [ 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
  • 64
  • [ 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
  • 65
  • [ 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
  • 66
  • [ 350-46-9 ]
  • [ 701-45-1 ]
YieldReaction ConditionsOperation in experiment
70% With sulfuric acid; bromine; silver sulfate In water at 10 - 35℃; for 30 - 32 h; In a 20 L 4- necked RB flask, fitted with a mechanical stirrer, reflux condenser, add DM water (550 ml), cone. Sulphuric acid (6.2 L, 113 M), 4- EPO <DP n="28"/>fluronitrobenzene(1.0 kg, 7.09 M) at 25-350C under stirring. The reaction mixture was cooled to 1O0C and bromine (1.13 kg, 7.06 M) was added to reaction mixture under stirring. The reaction mixture was brought to temp.25-35°C, silver sulfate (1.1 kg, -3.53 M) was added in one portion to the reaction mixture at 25-350C and maintained for 30- 32 h under stirring. Monitor the progress of the reaction by GC and after ascertaining completion, the reaction mixture was poured slowly into ice cold water (12 L) and dichloromethane (12 L) mixture. Filter the insoluble and wash the inorganic with dichloromethane (2 L). Combine the organic layer, wash with 10percent sodium bicarbonate (3 L), water (5 L). The dichloromethane layer was distilled below 4O0C under vacuum and add n-Hexane (4.5 L) to the residue. The resulting mass was stirred at 25-350C for 4-5hr, filter the product and dried in vacuum oven below 350C till LOD reaches <1percent. The dried product appears as white lustrous crystalline solid, weighs about 1.1-1.2 kg, yield 70-77percent, purity 97-98percent by HPLC, m.p. 56-580C. The structure assigned to the product is in agreement with spectral data.
67% at 140℃; for 16 h; Sodium nitrate (20 g, 0.235 mol) was added to 200 mL of concentrated sulfuric acid under stirring and cooling with an ice bath. Fluorobenzene (20 g, 0.21 mol) was added dropwise (at a temperature bellow 10 °C). After 2 h the resulting mixture was poured out into crushed ice and transferred to a separatory funnel using EtOAc (2 100 mL). Organic phase was washed with sat. aq. NaHCO 3 (50 mL) and brine (50 mL) and dried over MgSO 4 . After evaporation of solvent the residue was distilled in vacuo to give 1-fluoro-4-nitrobenzene. Yield 16.7 g (57percent); yellowish oil; bp 94−98 °C (15 mmHg) (lit. [7] bp 90−92 °C (13−14 mmHg)); 1 H NMR (400 MHz, CDCl 3 ): δ 8.25–8.34 (m, 2H), 7.19–7.24 (m, 2H). Bromine (18 mL, 0.19 mol) was added dropwise to the mixture of iron powder (0.20 g, 3.6 mmol) and 1-fluoro-4-nitrobenzene (16.6 g, 0.12 mol) being stirred and heated at 140 °C during 10 h. The second portion of the iron (1 g, 18 mmol) was added and the mixture was heated further at 140 °C for 6 h. After cooling to the ambient temperature the resulting mixture was poured out into water with sodium sulfite and transferred to a separatory funnel using Et 2 O (2 × 100 mL). Organic phase was washed with sat. aq. Na 2 SO 3 (50mL) and brine (50 mL), dried over MgSO 4 and concentrated in vacuo. The residue was treated with hexane (50 mL), the resulting crystals were filtered and air-dried. Yield: 17.7 g (67percent); pale purple solid; mp 58–60 °C (lit. [8] mp 58–59 °C); 1 H NMR (400 MHz, CDCl 3 ): δ 8.53 (dd, J = 5.8, 2.8 Hz, 1), 8.22–8.29 (m, 1), 7.32 (t, J = 7.2 Hz, 1).
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 4, p. 1235 - 1238
[2] Patent: WO2006/40652, 2006, A2, . Location in patent: Page/Page column 26-27
[3] Synthesis (Germany), 2016, vol. 48, # 17, p. 2851 - 2862
[4] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 14, p. 1659 - 1664
[5] Journal of Organic Chemistry, 1956, vol. 21, p. 934,937[6] Organic Syntheses, 1963, vol. Coll. Vol. IV, p. 114,116
[7] Journal of Organic Chemistry, 1978, vol. 43, p. 441 - 447
[8] Organic Process Research and Development, 2000, vol. 4, # 1, p. 30 - 33
  • 67
  • [ 7439-89-6 ]
  • [ 350-46-9 ]
  • [ 701-45-1 ]
YieldReaction ConditionsOperation in experiment
55.8% With bromine In hexane EXAMPLE 4
3.0 g (0.054 mol) of iron powder are added to 250 g (1.77 mols) of 4-fluoronitrobenzene and the mixture is heated to a temperature of 140° C. During 9 hours, 450 g (2.81 mols) of bromine are added dropwise, while additionally adding portionwise a total of another 15 g (0.27 mol) of iron powder.
Subsequently, stirring of the mixture is continued for 6 hours.
After filtration, the filtrate is taken up in 530 g of hot n-hexane.
After cooling of the solution, 220 g of crystalline 3-bromo-4-fluoronitrobenzene (55.8percent of theory) with a melting range of 55.5° to 56.5° C. and a purity degree of 99.0 are obtained.
Reference: [1] Patent: US4446075, 1984, A,
  • 68
  • [ 350-46-9 ]
  • [ 701-45-1 ]
Reference: [1] Patent: US5734073, 1998, A,
  • 69
  • [ 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
  • 70
  • [ 109-86-4 ]
  • [ 350-46-9 ]
  • [ 22483-40-5 ]
YieldReaction ConditionsOperation 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
  • 71
  • [ 33311-29-4 ]
  • [ 350-46-9 ]
  • [ 22483-40-5 ]
Reference: [1] Patent: US5880130, 1999, A,
  • 72
  • [ 350-46-9 ]
  • [ 2657-87-6 ]
Reference: [1] Journal of the American Chemical Society, 1934, vol. 56, p. 117,118
  • 73
  • [ 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. &lt;5&gt; 7, p. 536[2] Chem. Zentralbl., 1922, vol. 93, # I, p. 22
  • 74
  • [ 350-46-9 ]
  • [ 13080-86-9 ]
Reference: [1] Macromolecules, 2014, vol. 47, # 2, p. 659 - 667
[2] Patent: US9644071, 2017, B1,
  • 75
  • [ 98-95-3 ]
  • [ 402-67-5 ]
  • [ 369-34-6 ]
  • [ 364-74-9 ]
  • [ 350-46-9 ]
  • [ 1493-27-2 ]
YieldReaction ConditionsOperation in experiment
0.05 mmol at 0 - 25℃; Cooling with ice 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
  • 76
  • [ 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
  • 77
  • [ 350-46-9 ]
  • [ 156150-67-3 ]
Reference: [1] Journal of the American Chemical Society, 1971, vol. 93, # 5, p. 1190 - 1198
  • 78
  • [ 350-46-9 ]
  • [ 1435-48-9 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
  • 79
  • [ 350-46-9 ]
  • [ 75-05-8 ]
  • [ 405-67-4 ]
Reference: [1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 2, p. 293 - 304
  • 80
  • [ 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
  • 81
  • [ 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
  • 82
  • [ 350-46-9 ]
  • [ 33311-29-4 ]
Reference: [1] Patent: WO2015/131080, 2015, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5177 - 5181
[3] Patent: WO2017/102014, 2017, A1,
  • 83
  • [ 350-46-9 ]
  • [ 6052-10-4 ]
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
  • 84
  • [ 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
  • 85
  • [ 5382-16-1 ]
  • [ 350-46-9 ]
  • [ 79421-45-7 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 1 h; Reference Example 5 Synthesis of Compound 12 [Show Image] Compound 11 (2.12 g, 15.0 mmol) and Compound 8 (1.82 g, 18.0 mmol) were dissolved in DMF (15 ml), potassium carbonate (2.52 g, 18.0 mmol) was added, and the mixture was stirred at 85°C for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with chloroform. After dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-acetonitrile) to obtain Compound 12 (3.10 g, yield 93percent). mp 115.6-117°C 1H-NMR (CDCl3 / TMS) δppm: 1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82-3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H).
92% With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃; Step: 3A-1Synthesis of l-(4-Nitro-phen -piperidin-4-ol.Procedure:K2C03 (2.44g, 0.0177mol) followed by l-Fluoro-4-nitro-benzene (lg, 0.00708mol) was added to a stirred solution of Piperidin-4-ol (0.86g, 0.00850mol) in DMF (5ml) and stirred at RT. The resulting reaction mixture was heated at 60°C. The reaction was monitored by the TLC (50percent EtOAc: hexane). The reaction mixture was cooled to RT, and ice was added into it to precipitate a solid which was collected to afford 1.45g (92percent yield) of l-(4- Nitro-phenyl)-piperidin-4-ol.
86.14% With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 5 h; Weigh the compound 18 (10.00 g, 70.87 mmol) in a reaction flask,Piperidinol 26 (7.87 g, 77.96 mmol) was added sequentially,Potassium carbonate (11.74 g, 85.04 mmol),85 mL of DMF,70 heating and stirring,5h, stop reaction; filter,Filter insoluble solids,And rinsed with a small amount of DMF,The filtrate was poured into 650 mL of water,Static precipitation, solidification,The filter cake was dried at 60 ° C under vacuum for 14.56 gOrange solid 33, the yield was 86.14percent.
78% With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 1 h; To a solution of 14.1g (0.10mol) of 4-fluoronitrobenzene in 200mL of N, N-dimethylformamide were added 20.73 (0.15mol) of potassium carbonate and 10.1g (0.10mol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 140°C. The reaction mixture was cooled to room temperature and the mixture was treated with chloroform, then insoluble substances were removed off by filtration. The filtrate was condensed and the residue was recrystallized from ethanol to give 17. 27g (78percent) of the title compound.
71% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 105℃; for 48 h; The 1-(4-Amino-phenyl)-piperidin-4-ol is prepared from p-fluoronitrobenzene by using the following multiple step procedure: Step 1: 1-(4-Nitro-phenyl)-piperidin-4-ol.; A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.500 mL, 4.71 mmol), Piperidin-4-ol (0.619 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution, diisopropyl ethyl amine (0.463 mL, 6.12 mmol) was added dropwise, and the reaction was allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3.x.50 mL), and brine (2.x.50 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10percent MeOH/90percent CHCl3) affording a yellow solid (0.742 g, 3.34 mmol, 71percent yield).
1.025 g With N-ethyl-N,N-diisopropylamine In acetonitrile for 8 h; Reflux A solution of 1-fluoro-4-nitrobenzene (0.658 g, 4.66 mmol), 4-hydroxypiperidine (0.590 g, 5.81 mmol) and DIEA (1.24 mL, 7.12 mmol) in anhyd CH3CN (7 mL) was refluxed for 8 hours. The volatiles were removed in vacuo and the residue was suspended in water (15 mL) to give a bright yellow suspension. The solid was collected by vacuum filtration, washed with water and dried in vacuo to give 1.025 g 1-(4-nitro-phenyl)-piperidin-4-ol. MS (MH+): 223

Reference: [1] Patent: EP1988077, 2008, A1, . Location in patent: Page/Page column 64
[2] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 112
[3] Patent: CN106905245, 2017, A, . Location in patent: Paragraph 0277; 0278; 0279; 0280
[4] Synthesis, 1981, # 8, p. 606 - 608
[5] Patent: EP1775298, 2007, A1, . Location in patent: Page/Page column 38-39
[6] Patent: US2007/32478, 2007, A1, . Location in patent: Page/Page column 147
[7] Journal of Physical Chemistry B, 2000, vol. 104, # 44, p. 10191 - 10195
[8] Patent: US2009/54425, 2009, A1, . Location in patent: Page/Page column 24
[9] Patent: WO2009/131687, 2009, A2, . Location in patent: Page/Page column 133
[10] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0356; 0357
[11] Patent: WO2014/183300, 2014, A1, . Location in patent: Page/Page column 30
[12] Patent: KR2016/8881, 2016, A, . Location in patent: Paragraph 0120; 0121; 0122; 0123
  • 86
  • [ 350-46-9 ]
  • [ 98105-79-4 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1989, vol. 54, # 8, p. 2181 - 2189
[2] Collection of Czechoslovak Chemical Communications, 1989, vol. 54, # 8, p. 2181 - 2189
  • 87
  • [ 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
  • 88
  • [ 350-46-9 ]
  • [ 74852-81-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[3] Patent: WO2011/75478, 2011, A1,
[4] Advanced Synthesis and Catalysis, 2016, vol. 358, # 4, p. 597 - 609
  • 89
  • [ 350-46-9 ]
  • [ 77-76-9 ]
  • [ 70441-63-3 ]
YieldReaction ConditionsOperation in experiment
98% With 3 % platinum on carbon; hydrogen; toluene-4-sulfonic acid In toluene at 70 - 80℃; for 4 h; 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.
Reference: [1] Patent: CN103553934, 2016, B, . Location in patent: Paragraph 0016; 0020; 0021
  • 90
  • [ 350-46-9 ]
  • [ 67-64-1 ]
  • [ 70441-63-3 ]
YieldReaction ConditionsOperation in experiment
93% at 60℃; 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 δ 7.04 benzene ring, hydrogen chemical signal on δ 4.96 tertiary carbon CH-, δ 1.04 is 6 hydrogen signals on two methyl groups); yield (93percent, Purity 94percent).
Reference: [1] Patent: CN107721948, 2018, A, . Location in patent: Paragraph 0036-0038
  • 91
  • [ 350-46-9 ]
  • [ 70441-63-3 ]
Reference: [1] Patent: US5616799, 1997, A,
[2] Patent: US5712414, 1998, A,
  • 92
  • [ 350-46-9 ]
  • [ 57260-71-6 ]
  • [ 182618-86-6 ]
YieldReaction ConditionsOperation 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
  • 93
  • [ 56621-48-8 ]
  • [ 350-46-9 ]
  • [ 112559-81-6 ]
YieldReaction ConditionsOperation 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,
  • 94
  • [ 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
  • 95
  • [ 350-46-9 ]
  • [ 57260-71-6 ]
  • [ 170911-92-9 ]
Reference: [1] Patent: CN106905245, 2017, A,
  • 96
  • [ 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,
  • 97
  • [ 350-46-9 ]
  • [ 109384-19-2 ]
  • [ 138227-63-1 ]
Reference: [1] Patent: WO2015/92431, 2015, A1,
  • 98
  • [ 350-46-9 ]
  • [ 13143-47-0 ]
Reference: [1] Patent: WO2014/135471, 2014, A1,
  • 99
  • [ 350-46-9 ]
  • [ 425378-68-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 4, p. 1235 - 1238
  • 100
  • [ 350-46-9 ]
  • [ 431980-38-0 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 6, p. 465 - 469
  • 101
  • [ 350-46-9 ]
  • [ 159184-15-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 13, p. 2871 - 2876
  • 102
  • [ 26690-80-2 ]
  • [ 350-46-9 ]
  • [ 159184-14-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 13, p. 2871 - 2876
  • 103
  • [ 350-46-9 ]
  • [ 442549-42-0 ]
Reference: [1] Patent: WO2012/59932, 2012, A1,
  • 104
  • [ 5308-25-8 ]
  • [ 350-46-9 ]
  • [ 115619-00-6 ]
YieldReaction ConditionsOperation 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
  • 105
  • [ 4606-65-9 ]
  • [ 350-46-9 ]
  • [ 166438-83-1 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Patent: WO2015/38417, 2015, A1, . Location in patent: Page/Page column 100
  • 106
  • [ 350-46-9 ]
  • [ 898543-06-1 ]
Reference: [1] Patent: CN103980221, 2016, B,
  • 107
  • [ 350-46-9 ]
  • [ 959795-70-1 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2018, vol. 66, # 3, p. 251 - 262
[2] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
  • 108
  • [ 350-46-9 ]
  • [ 444796-09-2 ]
Reference: [1] Polymer, 2011, vol. 52, # 8, p. 1748 - 1754
  • 109
  • [ 350-46-9 ]
  • [ 1357470-29-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
  • 110
  • [ 350-46-9 ]
  • [ 1402238-32-7 ]
Reference: [1] Patent: WO2012/158764, 2012, A1,
[2] Patent: WO2014/22569, 2014, A1,
[3] Patent: US8673925, 2014, B1,
  • 111
  • [ 350-46-9 ]
  • [ 1439934-41-4 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 113, p. 93433 - 93437
Recommend Products
Same Skeleton Products
Historical Records

Similar Product of
[ 350-46-9 ]

Chemical Structure| 1958100-79-2

A812339[ 1958100-79-2 ]

1-Fluoro-4-nitrobenzene-1,2,3,4,5,6-13C6

Reason: Stable Isotope

Related Functional Groups of
[ 350-46-9 ]

Fluorinated Building Blocks

Chemical Structure| 108159-96-2

[ 108159-96-2 ]

3-Fluoro-5-nitrobenzaldehyde

Similarity: 0.77

Chemical Structure| 17417-09-3

[ 17417-09-3 ]

2-Fluoro-5-nitrobenzonitrile

Similarity: 0.76

Chemical Structure| 402-67-5

[ 402-67-5 ]

1-Fluoro-3-nitrobenzene

Similarity: 0.76

Chemical Structure| 364-75-0

[ 364-75-0 ]

1-Fluoro-4-iodo-2-nitrobenzene

Similarity: 0.73

Chemical Structure| 394-33-2

[ 394-33-2 ]

4-Fluoro-2-nitrophenol

Similarity: 0.73

Aryls

Chemical Structure| 108159-96-2

[ 108159-96-2 ]

3-Fluoro-5-nitrobenzaldehyde

Similarity: 0.77

Chemical Structure| 17417-09-3

[ 17417-09-3 ]

2-Fluoro-5-nitrobenzonitrile

Similarity: 0.76

Chemical Structure| 402-67-5

[ 402-67-5 ]

1-Fluoro-3-nitrobenzene

Similarity: 0.76

Chemical Structure| 364-75-0

[ 364-75-0 ]

1-Fluoro-4-iodo-2-nitrobenzene

Similarity: 0.73

Chemical Structure| 394-33-2

[ 394-33-2 ]

4-Fluoro-2-nitrophenol

Similarity: 0.73

Nitroes

Chemical Structure| 108159-96-2

[ 108159-96-2 ]

3-Fluoro-5-nitrobenzaldehyde

Similarity: 0.77

Chemical Structure| 17417-09-3

[ 17417-09-3 ]

2-Fluoro-5-nitrobenzonitrile

Similarity: 0.76

Chemical Structure| 402-67-5

[ 402-67-5 ]

1-Fluoro-3-nitrobenzene

Similarity: 0.76

Chemical Structure| 364-75-0

[ 364-75-0 ]

1-Fluoro-4-iodo-2-nitrobenzene

Similarity: 0.73

Chemical Structure| 394-33-2

[ 394-33-2 ]

4-Fluoro-2-nitrophenol

Similarity: 0.73