Home Cart 0 Sign in  
X

[ CAS No. 1493-27-2 ] {[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 1493-27-2
Chemical Structure| 1493-27-2
Chemical Structure| 1493-27-2
Structure of 1493-27-2 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 1493-27-2 ]

Related Doc. of [ 1493-27-2 ]

Alternatived Products of [ 1493-27-2 ]

Product Details of [ 1493-27-2 ]

CAS No. :1493-27-2 MDL No. :MFCD00007048
Formula : C6H4FNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :PWKNBLFSJAVFAB-UHFFFAOYSA-N
M.W : 141.10 Pubchem ID :73895
Synonyms :

Calculated chemistry of [ 1493-27-2 ]

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) : -5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.28
Log Po/w (XLOGP3) : 1.69
Log Po/w (WLOGP) : 2.15
Log Po/w (MLOGP) : 2.1
Log Po/w (SILICOS-IT) : 0.11
Consensus Log Po/w : 1.47

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.16
Solubility : 0.982 mg/ml ; 0.00696 mol/l
Class : Soluble
Log S (Ali) : -2.27
Solubility : 0.763 mg/ml ; 0.00541 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.03
Solubility : 1.31 mg/ml ; 0.00931 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.57

Safety of [ 1493-27-2 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P260-P264-P270-P271-P273-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P314-P391-P405-P501 UN#:2810
Hazard Statements:H302+H332-H311-H372-H411 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1493-27-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 1493-27-2 ]
  • Downstream synthetic route of [ 1493-27-2 ]

[ 1493-27-2 ] Synthesis Path-Upstream   1~70

  • 1
  • [ 3536-96-7 ]
  • [ 1493-27-2 ]
  • [ 387-44-0 ]
Reference: [1] Patent: US5929072, 1999, A,
[2] Patent: EP897921, 1999, A1,
  • 2
  • [ 1826-67-1 ]
  • [ 1493-27-2 ]
  • [ 387-44-0 ]
Reference: [1] Tetrahedron Letters, 1989, vol. 30, # 16, p. 2129 - 2132
  • 3
  • [ 1493-27-2 ]
  • [ 5755-07-7 ]
Reference: [1] Patent: WO2012/151512, 2012, A2,
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 145 - 150
  • 4
  • [ 1493-27-2 ]
  • [ 29026-74-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5795 - 5800,6
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5795 - 5800
  • 5
  • [ 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
  • 6
  • [ 1493-27-2 ]
  • [ 6433-72-3 ]
Reference: [1] Patent: US2014/315889, 2014, A1,
[2] Patent: WO2013/62344, 2013, A1,
  • 7
  • [ 1493-27-2 ]
  • [ 28890-99-5 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1987, vol. 96, # 10, p. 787 - 792
  • 8
  • [ 1493-27-2 ]
  • [ 5719-08-4 ]
Reference: [1] Patent: WO2011/56739, 2011, A1,
  • 9
  • [ 1493-27-2 ]
  • [ 2688-84-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 20, p. 2779 - 2782
[2] Chemical Communications, 2011, vol. 47, # 27, p. 7845 - 7847
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5795 - 5800,6
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5795 - 5800
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10317 - 10323[6] Angew. Chem., 2015, vol. 127, p. 10457 - 10461,5
[7] Organic Letters, 2017, vol. 19, # 14, p. 3855 - 3858
[8] Patent: US2018/155312, 2018, A1,
[9] European Journal of Organic Chemistry, 2018, vol. 2018, # 34, p. 4740 - 4747
  • 10
  • [ 1493-27-2 ]
  • [ 53786-10-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1687 - 1691
  • 11
  • [ 109-01-3 ]
  • [ 1493-27-2 ]
  • [ 180605-36-1 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 27, p. 7381 - 7383
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 27, p. 7381 - 7383
  • 12
  • [ 109-01-3 ]
  • [ 1493-27-2 ]
  • [ 180605-36-1 ]
  • [ 62208-63-3 ]
Reference: [1] Patent: US6258953, 2001, B1,
  • 13
  • [ 1493-27-2 ]
  • [ 180605-36-1 ]
Reference: [1] Patent: WO2013/55949, 2013, A2,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5099 - 5119
  • 14
  • [ 1493-27-2 ]
  • [ 105-53-3 ]
  • [ 10565-14-7 ]
Reference: [1] Australian Journal of Chemistry, 2013, vol. 66, # 9, p. 1112 - 1114
[2] Chemical Communications, 2007, # 22, p. 2264 - 2266
  • 15
  • [ 996-82-7 ]
  • [ 1493-27-2 ]
  • [ 10565-14-7 ]
Reference: [1] Synthesis, 2000, # 12, p. 1659 - 1661
  • 16
  • [ 1493-27-2 ]
  • [ 2836-03-5 ]
Reference: [1] Dalton Transactions, 2011, vol. 40, # 35, p. 8906 - 8911
[2] Organic Letters, 2012, vol. 14, # 24, p. 6366 - 6369
[3] Organic Letters, 2015, vol. 17, # 3, p. 402 - 405
[4] Organic and Biomolecular Chemistry, 2015, vol. 13, # 27, p. 7381 - 7383
[5] Organic and Biomolecular Chemistry, 2015, vol. 13, # 27, p. 7381 - 7383
[6] European Journal of Inorganic Chemistry, 2016, vol. 2016, # 31, p. 4974 - 4987
  • 17
  • [ 1493-27-2 ]
  • [ 2217-65-4 ]
YieldReaction ConditionsOperation in experiment
77% With tributylphosphine; palladium diacetate In 5,5-dimethyl-1,3-cyclohexadiene for 24 h; Reflux; Inert atmosphere General procedure: A mixture of fluorobenzene (1.0 mmol), PBu3 (2.0 mmol), Pd(OAc)2 (2 molpercent), K2CO3/ZrO2 (1.5 equiv., based on K2CO3, 2.070 g) in xylene (10 mL) was stirred at reflux under nitrogen for 24 h or according to the TLC. On completion, the resulting mixture was filtered and washed with DCM. The combined organic solvent layers were separated, the solvent evaporated and the product purified by column chromatography with dichloromethane/n-hexane (1:1–1:2) as the eluent to provide the corresponding product 2.
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1992, # 3, p. 377 - 382
[2] Chemistry - An Asian Journal, 2015, vol. 10, # 2, p. 468 - 473
[3] Journal of Chemical Research, 2016, vol. 40, # 11, p. 691 - 693
[4] Journal of Organic Chemistry, 2018, vol. 83, # 24, p. 14882 - 14893
  • 18
  • [ 1493-27-2 ]
  • [ 88-75-5 ]
  • [ 2217-65-4 ]
Reference: [1] Synthesis, 1996, # 8, p. 930 - 940
[2] Zeitschrift fur Anorganische und Allgemeine Chemie, 2015, vol. 641, # 1, p. 128 - 135
  • 19
  • [ 298-14-6 ]
  • [ 1493-27-2 ]
  • [ 2217-65-4 ]
Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, p. 1122 - 1125
[2] Journal of Organic Chemistry, 1984, vol. 49, p. 1122 - 1125
  • 20
  • [ 95-56-7 ]
  • [ 1493-27-2 ]
  • [ 2217-65-4 ]
Reference: [1] Australian Journal of Chemistry, 1988, vol. 41, # 6, p. 995 - 1001
  • 21
  • [ 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
  • 22
  • [ 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
  • 23
  • [ 141-43-5 ]
  • [ 1493-27-2 ]
  • [ 4926-55-0 ]
YieldReaction ConditionsOperation in experiment
82.9% With potassium carbonate In ethanolReflux 2-fluoronitrobenzene (0.92 g, 6.53 mmol) and ethanolamine (1.19 g, 19.59 mmol) were dissolved in 20 mL ethanol, potassium carbonate (1.08 g, 7.83 mmol) was added and stirred under reflux for 5-6 hours, after the reaction solution was cooled, filtered, the filtrate was concentrated under reduced pressure, to obtain an orange solid, and 20 mL saturated brine was added, extracted with ethyl acetate (3×40 mL), the organic phases were combined, washed with a saturated brine, dried on anhydrous sodium sulfate, rotary evaporated, purified by silica gel column chromatography to obtain 2-nitro-N-(2-hydroxyethyl)aniline (0.98 g, yield 82.9percent).
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 17, p. 2362 - 2365
[2] Tetrahedron, 1998, vol. 54, # 18, p. 4647 - 4654
[3] Green Chemistry, 2013, vol. 15, # 3, p. 798 - 810
[4] Chemical Communications, 2013, vol. 49, # 85, p. 9935 - 9937
[5] Patent: US2017/114085, 2017, A1, . Location in patent: Paragraph 0053
[6] Tetrahedron, 1998, vol. 54, # 18, p. 4647 - 4654
[7] Bulletin de la Societe Chimique de France, 1956, p. 311,315
[8] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4790 - 4793
[9] Tetrahedron Letters, 2006, vol. 47, # 38, p. 6899 - 6902
[10] Journal of Physical Organic Chemistry, 2011, vol. 24, # 8, p. 714 - 719
  • 24
  • [ 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
  • 25
  • [ 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
  • 26
  • [ 1493-27-2 ]
  • [ 363-51-9 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 9, p. 872 - 877
  • 27
  • [ 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
  • 28
  • [ 1493-27-2 ]
  • [ 364-73-8 ]
YieldReaction ConditionsOperation in experiment
40% at 65℃; reaction was completed. The reaction was cooled to room temperature and poured onto ice. The product, 2-fluoro-5-bromo-nitrobenzene, was extracted with 200 mL of ethyl acetate and evaporated to a brown solidCrude. The crude product was recrystallized from petroleum ether, the GC was 98percent, dried to obtain pure 227.1g, yield 40.0percent
Reference: [1] Journal of the American Chemical Society, 2004, vol. 126, # 48, p. 15770 - 15776
[2] Patent: CN104530107, 2016, B, . Location in patent: Paragraph 0026
  • 29
  • [ 1493-27-2 ]
  • [ 4273-98-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5795 - 5800,6
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5795 - 5800
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4614 - 4627
  • 30
  • [ 1493-27-2 ]
  • [ 364-75-0 ]
YieldReaction ConditionsOperation in experiment
66% at 0 - 20℃; for 1 h; Intermediate Example 3.1 -Fluoro-4-iodo-2-nitrobenzene To a solution of l-fluoro-2-nitrobenzene (5 g, 35.43 mmol) in triflic acid (15.6 ml, 177.15 mmol, 5 eq.) at 0 °C was added N-iodosuccinimide (9.57 g, 42.5 mmol, 1.2 eq.) portionwise and the mixture was stirred at RT for 1 h. The mixture was quenched by the addition of water and extracted with diethylether (3 χ 150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 5 percent ethyl acetate in hexane) to afford the compound in 66 percent yield (6.2 g). lK NMR (300 MHz, DMSO-i/6): δ 8.42 (dd, 1H), 8.18- 8.13 (m, 1H), 7.46-7.39 (m, 1H).
66% at 0 - 20℃; for 1 h; To a solution of 1-fluoro-2-nitrobenzene (5 g, 35.43 mmol) in triflic acid (15.6 ml, 177.15 mmol, 5 eq.) at 0° C. was added N-iodosuccinimide (9.57 g, 42.5 mmol, 1.2 eq.) portionwise and the mixture was stirred at RT for 1 h.
The mixture was quenched by the addition of water and extracted with diethylether (3*150 ml).
The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate.
The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 5percent ethyl acetate in hexane) to afford the compound in 66percent yield (6.2 g).
1H NMR (300 MHz, DMSO-d6): δ 8.42 (dd, 1H), 8.18-8.13 (m, 1H), 7.46-7.39 (m, 1H).
Reference: [1] Journal of the American Chemical Society, 2004, vol. 126, # 48, p. 15770 - 15776
[2] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 30
[3] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0132
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1973, p. 595 - 599
  • 31
  • [ 1493-27-2 ]
  • [ 345-18-6 ]
Reference: [1] Journal of the American Chemical Society, 2004, vol. 126, # 48, p. 15770 - 15776
  • 32
  • [ 1493-27-2 ]
  • [ 34883-46-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10317 - 10323[2] Angew. Chem., 2015, vol. 127, p. 10457 - 10461,5
[3] Patent: US2018/155312, 2018, A1,
  • 33
  • [ 1493-27-2 ]
  • [ 100-46-9 ]
  • [ 5729-06-6 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; EXAMPLE 16 [00244] Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]acetyl}amino)propanoic acid. [00245] Step One: A mixture of 1-fluoro 2-nitrobenzene (0.50 g, 3.54 mmol), benzylamine (0.38 g, 3.54 mmol) and K2CO3 (0.98 g, 7.08 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated to dryness to give 49 (0.79 g, 98percent) as an orange solid.
90% With potassium carbonate In N,N-dimethyl-formamide at 80℃; General procedure: A solution of 1-fluoro-2-nitrobenzene (5mmol) and arylamine (5 mmol) in 10 mL DMFcontaining K2CO3 (5.5 mmol) was stirred at 80 °C for 5-6 h. After cooling to room temperaturethe mixture reaction was filtered through Celite. Then the filtrate was concentrated and added toa saturated aq. solution of NaCl and then extracted with ethyl acetate. The organic phases wasdried over sodium sulfate and then evaporated under vacuum. The products were purified bycolumn chromatography over silica gel.
78% With sodium t-butanolate In water at 20℃; for 3 h; General procedure: To the aryl halide (1.0 equiv.) and the nucleophile (1.0 - 1.1 equiv.) in a 5 mL microwave vial was added a 2wtpercent solution of HPMC (40-60 cps) in Millipore water (1 mL). After the addition of sodium tert-butoxide (1.1 equiv) the mixture was vigorously stirred (1200 rpm) at room temperature until LCMS or TLC showed full conversion of the aryl halide. The mixture was diluted with EtOAc (3 mL) followed by the addition of a saturated aqueous solution of sodium sulfate (2 mL). After 5-15 min of stirring (200 rpm) the precipitated solids were filtered off and washed with EtOAc (3 x 15 mL). ). After extraction, the organic layer was dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.; Following the general procedure using benzylamine (53.6 mg, 0.50 mmol, 1.0 equiv.), l-fluoro-2-nitrobenzene (70.5 mg, 0.50 mmol, 1.0 equiv.) and sodium tert-butoxide (72.1 mg, 0.75 mmol, 1.5 equiv) the reaction was allowed to stir for 3 h at room temperature. After column chromatography (0-30 percent ethyl acetate - cyclohexane), the product was obtained as a white solid (89 mg, 0.39 mmol, 78 percent). ESI-MS: m/z (percent): 229.20 (100, [M]+). 1H NMR (600MHz, CDC13): δ [ppm]: 8.44 (s, 1H), 8.20 (dd, J = 8.6, 1.6 Hz, 1H), 7.44 - 7.27 (m, 7H), 6.83 - 6.79 (m, 1H), 6.69 - 6.64 (m, 1H), 4.55 (d, J= 5.7 Hz, 2H).
Reference: [1] Patent: EP1213288, 2002, A1, . Location in patent: Page 35
[2] Patent: US6723711, 2004, B2, . Location in patent: Page column 48
[3] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6097 - 6099
[4] Organic Letters, 2015, vol. 17, # 19, p. 4734 - 4737
[5] Green Chemistry, 2013, vol. 15, # 3, p. 798 - 810
[6] ACS Combinatorial Science, 2018, vol. 20, # 5, p. 282 - 291
[7] Synthetic Communications, 2015, vol. 45, # 4, p. 534 - 540
[8] Organic and Biomolecular Chemistry, 2009, vol. 7, # 24, p. 5173 - 5183
[9] Synlett, 2003, # 4, p. 564 - 566
[10] Patent: WO2017/129796, 2017, A1, . Location in patent: Page/Page column 249; 250
[11] Tetrahedron Letters, 2002, vol. 43, # 43, p. 7707 - 7710
[12] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 20, p. 5652 - 5655
[13] Patent: WO2006/60737, 2006, A2, . Location in patent: Page/Page column 123
[14] Patent: US6420410, 2002, B1,
[15] Patent: US2003/229074, 2003, A1, . Location in patent: Page 20 - 21
[16] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3138 - 3141
[17] Bioorganic Chemistry, 2015, vol. 61, p. 7 - 12
[18] European Journal of Organic Chemistry, 2017, vol. 2017, # 44, p. 6499 - 6504
[19] Advanced Synthesis and Catalysis, 2018, vol. 360, # 2, p. 290 - 297
  • 34
  • [ 1493-27-2 ]
  • [ 100-46-9 ]
  • [ 883-93-2 ]
  • [ 5729-06-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 50, p. 13808 - 13812[2] Angew. Chem., 2014, vol. 126, # 50, p. 14028 - 14032,5
  • 35
  • [ 1493-27-2 ]
  • [ 28458-68-6 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 2387 - 2391
[2] Patent: US2011/39893, 2011, A1,
  • 36
  • [ 75-64-9 ]
  • [ 1493-27-2 ]
  • [ 28458-68-6 ]
Reference: [1] Organometallics, 2015, vol. 34, # 11, p. 2624 - 2631
[2] Dalton Transactions, 2016, vol. 45, # 8, p. 3285 - 3293
  • 37
  • [ 108-24-7 ]
  • [ 1493-27-2 ]
  • [ 399-31-5 ]
Reference: [1] Tetrahedron Letters, 2003, vol. 44, # 1, p. 77 - 79
  • 38
  • [ 1493-27-2 ]
  • [ 76697-50-2 ]
Reference: [1] Patent: WO2011/140338, 2011, A1,
[2] Patent: EP2257637, 2015, B1,
[3] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 80 - 89
[4] Patent: WO2016/199020, 2016, A1,
[5] Patent: CN106146468, 2016, A,
[6] Patent: CN106336382, 2017, A,
[7] Patent: CN104356112, 2017, B,
[8] Patent: CN107151233, 2017, A,
[9] Patent: CN106083670, 2016, A,
[10] Patent: CN106854200, 2017, A,
  • 39
  • [ 1493-27-2 ]
  • [ 68817-71-0 ]
Reference: [1] Molecules, 2012, vol. 17, # 4, p. 4545 - 4559
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8409 - 8417,9
[4] Patent: WO2012/151512, 2012, A2,
[5] Chinese Journal of Chemistry, 2013, vol. 31, # 12, p. 1473 - 1482
[6] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 145 - 150
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4475 - 4486
[8] Patent: WO2012/3190, 2012, A1,
  • 40
  • [ 106-47-8 ]
  • [ 1493-27-2 ]
  • [ 68817-71-0 ]
Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 2, p. 452 - 464
  • 41
  • [ 106-47-8 ]
  • [ 1493-27-2 ]
  • [ 23008-56-2 ]
YieldReaction ConditionsOperation in experiment
93.9% at 105 - 115℃; for 12 h; 107.6 g of triethylamine, 150 g of o-fluoronitrobenzene,P-chloroaniline (203.4 g), the system was heated to 105-115 ° C for 12 hours,HPLC showed that the reaction was complete,After cooling to 20-30 ° C,The filter cake was washed with 150 mL of methanol,Drying, get 248g products. Purity 99.8percentYield 93.9percent.
72.3%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: at 25℃; for 16 h;
General procedure: To the suspension of NaH (75 mol) in DMF (60 mL), substitutedamines (50 mmol) was added at 0 C. The mixture was stirred for30 min at the same temperature, and then 2-fluoronitrobenzene(60 mmol) diluted in DMF (30 mL) was added slowly. The mixturewas warmed to room temperature and stirred for 16 h. The reactionmixture was carefully poured into stirring saturated NH4Cl(500 mL), then filtered. The filter cake was washed with water,and recrystallized from methanol to afford corresponding N-aryl-2-nitroanilines 15a–15n.6.2.8
N-(4-chlorophenyl)-2-nitroaniline (15h)
Orange solid; Yield: 72.3percent; M.p.: 135.1-137.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.12 (d, J = 8.0, 1H), 7.53(t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H); MS (ESI) m/z (percent): 247.2 [M-H]-.
72% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 120 - 125℃; for 8 h; Inert atmosphere In the reaction flask,Put 87 g of o-fluoronitrobenzeneAnd 200 grams of DMAC,94 grams of diisopropylethylamine was added with stirring,After warming to 120 degrees under nitrogen.71 grams of p-chloroaniline was dissolved in 100 grams of DMAC to prepare a solution,After that, the solution was slowly added dropwise to the above reaction system.Dropping temperature will rise during the process,The reaction temperature should be controlled by cooling within 125 degrees.The reaction was continued at 120 to 125 degrees for 8 hours,HPLC monitors the progress of the reaction.When the content of chloroaniline is not declining,At the end of the reaction, about 11percent of the chloroaniline remained.Cool to 60 degrees.After the same way with the first embodiment,Finally, 100 g of the condensate intermediate N- (4-chlorophenyl) -2-nitro-1-aniline,Yield 72percentHPLC purity> 98percent.
52% With potassium fluoride; potassium carbonate In dichloromethane at 220℃; for 0.466667 h; Microwave irradiation N-(4-chlorophenyl)-2-nitrobenzenamineA mixture of 2-fluoronitrobenzene (3.5 g, 24.8 mmol), 4-chlorobenzenamine (3.05 g, 24.0 mmol), K2C03 (3.45 g, 25.0 mmol) and KF (1.5 g, 25.8 mmol) was heated at 220 °C for 28 min under microwave condition. The solid was dissolved in DCM (150 mL), washed with water (50 mL x 3), dried over Na2S04. The solvent was evaporated in vacuo, and then the mixture was purified by Combi-flash (PE : EA = 20 : 1) to give N-(4-chlorophenyl)-2-nitrobenzenamine (3.2 g, 52percent) as a scarlet solid. 1H NMR (300 MHz, CD3OD): δ 6.82-6.87 (m, 1H), 7.27-7.31 (m, 2H), 7.41-7.45 (m, 3H), 7.70-7.73 (m, 1H), 8.15-8.18 (m, 1H).

Reference: [1] Patent: CN106916069, 2017, A, . Location in patent: Paragraph 0016; 0017; 0018; 0019; 0020; 0021; 0022-0024
[2] Organic Process Research and Development, 2016, vol. 20, # 2, p. 452 - 464
[3] Molecules, 2012, vol. 17, # 4, p. 4545 - 4559
[4] Synlett, 2003, # 4, p. 564 - 566
[5] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4475 - 4486
[6] Patent: CN107445845, 2017, A, . Location in patent: Paragraph 0033; 0034; 0035; 0036; 0037; 0038; 0039-0045
[7] Synthesis, 1980, # 3, p. 215
[8] Chinese Journal of Chemistry, 2013, vol. 31, # 12, p. 1473 - 1482
[9] Patent: WO2012/151512, 2012, A2, . Location in patent: Page/Page column 103
[10] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 145 - 150
[11] Liebigs Annalen, 1995, # 7, p. 1275 - 1282
[12] Patent: US6403607, 2002, B1,
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3138 - 3141
[14] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 18, p. 5443 - 5448
[15] Patent: WO2012/3190, 2012, A1, . Location in patent: Page/Page column 44-45
[16] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[17] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8409 - 8417,9
  • 42
  • [ 1493-27-2 ]
  • [ 399-95-1 ]
YieldReaction ConditionsOperation in experiment
40.7% With oxalic acid; aluminium In water at 80 - 85℃; for 1.5 h; 2-Fluoronitrobenzene (300 g) was added to the solution of oxalic acid dihydrate (858 g) in DM water (7.5 L) at 25°C and heated to 80°C. Aluminum powder (98.8 g) was added to the reaction mass at 80-85°C and stirred for 90 mm. After completion of reaction, reaction mass was cooledto 50°C. Activated carbon (30 g) was added to the reaction mass, stirred for 30 mm and filtered through hyflo bed. The filtrate was washed with ethyl acetate (2 x 1500 ml) at 40°C, treated with sodium sulfite (300 g) and adjusted pH to 7.5-8.0 with aqueous ammonia solution. The product was extracted with ethyl acetate (2 x 1500 ml), washed with DM water (300 ml) and concentrated under vacuum at below 50°C. The concentrated mass was stirred in the mixtureof ethyl acetate (60 ml) and hexane (1140 ml) and filtered the solid. The wet solid was suspended in the mixture of isopropyl alcohol (150 ml) and toluene (600 ml) and added IPAHC1 (198 g, 24percent w/w). The slurry was heated to 50°C and stirred for lh, cooled to 0-5°C and filtered the solid. The wet solid was dissolved in DM water (700 ml) and adjusted pH to 7.5-8.0 with aqueous ammonia solution at 0-5°C. The solid product was filtered and dried at 40-45°C (109.9 g; 40.7percent). HPLC purity: 99.867percent
Reference: [1] Patent: WO2017/125941, 2017, A1, . Location in patent: Page/Page column 6; 7
[2] Bulletin de la Societe Chimique de France, 1966, p. 1848 - 1858
  • 43
  • [ 7784-21-6 ]
  • [ 144-55-8 ]
  • [ 1493-27-2 ]
  • [ 399-95-1 ]
YieldReaction ConditionsOperation in experiment
86% With sulfuric acid In water PRODUCTION EXAMPLE 5
2.03 Grams of o-fluoronitrobenzene, 0.70 g of aluminum powder, 43 ml of water and 4.4 g of conc. sulfuric acid were added to a reactor and stirred at an inner temperature of from 90° to 95° C. for 40 minutes.
After cooling the reaction solution, a 5percent aqueous sodium hydrogencarbonate solution was added to make the reaction solution weakly alkaline.
The reaction solution was then extracted with three 100-ml portions of diethyl ether.
The ether layers were combined, dried and concentrated to obtain a crude product.
This crude product was subjected to chromatography on silica gel to obtain 1.58 g of 3-fluoro-4-aminophenol.
Yield: 86percent.
m.p.: 137°-138° C.
86% With sulfuric acid In water PRODUCTION EXAMPLE 5
2.03 Grams of o-fluoronitrobenzene, 0.70 g of aluminum powder, 43 ml of water and 4.4 g of conc. sulfuric acid were added to a reactor and stirred at an inner temperature of from 90° to 95° C. for 40 minutes.
After cooling the reaction solution, a 5percent aqueous sodium hydrogencarbonate solution was added to make the reaction solution weakly alkaline.
The reaction solution was then extracted with three 100-ml portions of diethyl ether.
The ether layers were combined, dried and concentrated to obtain a crude product.
This crude product was subjected to chromatography on silica gel to obtain 1.58 g of 3-fluoro-4-aminophenol.
Yield: 86percent
m.p.: 137°-138° C.
Reference: [1] Patent: US4904696, 1990, A,
[2] Patent: US4985460, 1991, A,
  • 44
  • [ 1493-27-2 ]
  • [ 348-54-9 ]
  • [ 367-25-9 ]
Reference: [1] Journal of Fluorine Chemistry, 1995, vol. 74, # 2, p. 251 - 254
  • 45
  • [ 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
  • 46
  • [ 1493-27-2 ]
  • [ 2369-13-3 ]
  • [ 142564-54-3 ]
Reference: [1] Journal of Organic Chemistry, 1992, vol. 57, # 18, p. 4784 - 4785
  • 47
  • [ 865-47-4 ]
  • [ 1493-27-2 ]
  • [ 83747-12-0 ]
  • [ 2369-13-3 ]
  • [ 88-74-4 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
  • 48
  • [ 1493-27-2 ]
  • [ 2369-13-3 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
  • 49
  • [ 1493-27-2 ]
  • [ 83747-12-0 ]
  • [ 2369-13-3 ]
  • [ 88-74-4 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
  • 50
  • [ 1493-27-2 ]
  • [ 2770-11-8 ]
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 40, p. 14060 - 14067
[2] Organic Letters, 2017, vol. 19, # 14, p. 3855 - 3858
  • 51
  • [ 1493-27-2 ]
  • [ 24878-25-9 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; 1,2-bis-(diphenylphosphino)ethane; bis(pinacol)diborane; copper dichloride In N,N-dimethyl-formamide at 140℃; for 10 h; In a 50 ml reaction flask by adding 2- fluoro-nitrobenzene (7.06 mg, 0 . 05mmol), pinacone ester boric acid (12.7 mg, 0 . 05mmol), copper chloride (0.68 mg, 10percent * 0.05mmol), 1,2(Diphenylphosphino) ethane(2.00 mg, 10percent * 0.05mmol), potassium carbonate (2.76 mg, 40percent * 0.05mmol). DMF added in the reaction solvent, the reaction temperature 140 °C, the reaction time is 10h, is dissolved with water to produce a dark brown solution, then using ethyl acetate extraction, the solution of the ethyl acetate layer reservations, hangs does, then using the 200 - 300 mesh silica gel column separation (elution agent is 1:1 of dichloromethane/hexane), after removing the solvent, to obtain 2 - nitro -2 ' - phenylaniline ether, the structural formula:
Reference: [1] Patent: CN103012027, 2016, B, . Location in patent: Paragraph 0050-0052
[2] Zeitschrift fur Anorganische und Allgemeine Chemie, 2015, vol. 641, # 1, p. 128 - 135
[3] Chemical Communications, 2016, vol. 52, # 80, p. 11995 - 11998
  • 52
  • [ 348-54-9 ]
  • [ 1493-27-2 ]
  • [ 28898-02-4 ]
YieldReaction ConditionsOperation in experiment
74.1%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: at 25℃; for 16 h;
General procedure: To the suspension of NaH (75 mol) in DMF (60 mL), substitutedamines (50 mmol) was added at 0 C. The mixture was stirred for30 min at the same temperature, and then 2-fluoronitrobenzene(60 mmol) diluted in DMF (30 mL) was added slowly. The mixturewas warmed to room temperature and stirred for 16 h. The reactionmixture was carefully poured into stirring saturated NH4Cl(500 mL), then filtered. The filter cake was washed with water,and recrystallized from methanol to afford corresponding N-aryl-2-nitroanilines 15a–15n.6.2.10
2-Fluoro-N-(2-nitrophenyl)aniline (15j)
Red solid; Yield: 74.1percent; M.p.: 74.4-75.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.51 (m, 2H), 7.35 (m, 3H), 6.90 (m, 2H); MS (ESI) m/z (percent): 231.1 [M-H]-.
52% at 180℃; for 48 h; General procedure: 4-Fluoroaniline or 2-fluoroaniline, respectively (1 mmol), anhydrous KF (1 mmol), and K2CO3 (1 mmol) were well powdered with a mortar and a pestle, then 1-fluoro-2-nitrobenzene (1 mmol) was added and the mixture was stirred for 2 days at 180 °C. Thereafter, water (5 mL) and CH2Cl2 (5 mL) were added and the organic layer was washed with 10percent HCl (5 mL) and brine (5 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness prior to purification by column chromatography.
Reference: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4475 - 4486
[2] Molecules, 2015, vol. 20, # 1, p. 1712 - 1730
[3] Archiv der Pharmazie, 1997, vol. 330, # 11, p. 353 - 357
[4] Patent: WO2008/73459, 2008, A1, . Location in patent: Page/Page column 95
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 11, p. 4511 - 4521
  • 53
  • [ 12775-96-1 ]
  • [ 88-74-4 ]
  • [ 1493-27-2 ]
  • [ 28898-02-4 ]
YieldReaction ConditionsOperation in experiment
72% With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene; ethyl acetate Step 1
Preparation of N-(2-nitrophenyl)-2-fluoroaniline
2-Nitroaniline (14.9 g), 2-fluoronitrobenzene (29 g), potassium carbonate (14.9 g), copper powder (6.9 g) and xylene (100 ml) was mixed, the mixture was refluxed for 39 hours under argon atmosphere.
The reaction mixture was allowed to cool, filtrated, and the filtrate was concentrated under reduced pressure.
The residue was dissolved ethyl acetate, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby obtain 18.0 g of the titled compound as orange color crystals (Yield: 72percent).
1H-NMR(CDCl3) δ: 6.80-6.86(1H, m), 7.05-7.44(6H, m), 8.22(1H, dd), 9.30(1H, brs)
Reference: [1] Patent: US6239131, 2001, B1,
  • 54
  • [ 1493-27-2 ]
  • [ 2924-09-6 ]
Reference: [1] Patent: CN104530107, 2016, B,
  • 55
  • [ 1493-27-2 ]
  • [ 403-21-4 ]
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 394 - 400
[2] Tetrahedron, 2001, vol. 57, # 22, p. 4753 - 4757
  • 56
  • [ 107-14-2 ]
  • [ 1493-27-2 ]
  • [ 105003-88-1 ]
Reference: [1] Bulletin of the Polish Academy of Sciences, Chemistry, 1985, vol. 33, # 9-10, p. 427 - 432
  • 57
  • [ 1493-27-2 ]
  • [ 1019453-85-0 ]
Reference: [1] Patent: WO2014/161976, 2014, A1,
[2] Patent: WO2015/155153, 2015, A1,
[3] Patent: WO2016/79751, 2016, A2,
[4] Patent: WO2016/125191, 2016, A2,
[5] Patent: CN105669594, 2016, A,
[6] Patent: US2017/189394, 2017, A1,
[7] Patent: CN107915694, 2018, A,
  • 58
  • [ 1493-27-2 ]
  • [ 138564-58-6 ]
  • [ 138564-59-7 ]
YieldReaction ConditionsOperation in experiment
77% With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 18 h; Inert atmosphere; Cooling with ice A solution of 1-fluoro-2-nitrobenzene (34.5 g, 244 mmol) and compound 1 (33.1 g, 240 mmol) in dry THF (160 mL) was added dropwise under N2 atmosphere to a vigorously stirred suspension of NaH (13.5 g, 60percent dispersion in oil, 336 mmol) in dry THF (100 mL) in an ice bath. After the reaction mixture was stirred at room temperature (RT) for 10 h, additional NaH (1.53 g, 95percent, 72 mmol) was slowly added to above reaction mixture. The mixture was stirred for another 8 h at rt, and poured into cracked ice, adjusted pH value to 8 with saturated NH4Cl. The resulting precipitate was filtered, and dried; and the crude product was purified by column chromatography (10percent EtOAc/hexanes) on silica gel to obtain 2 (47.9 g, 77percent) as a darkened solid; Rf = 0.62 (25percent EtOAc/hexanes); mp 105–107 °C. 1H NMR (CDCl3): δ 2.47 (d, J = 1.0 Hz, 3H, CH3), 6.78 (q, J = 1.0 Hz, 1H, Ar-H), 6.95 (ddd, J = 1.0, 7.0, 8.5 Hz, 1H, Ph-H), 7.18 (dd, J = 1.0, 8.5 Hz, 1H, Ph-H), 7.50 (ddd, J = 1.5, 7.0, 8.5 Hz, 1H, Ph-H), 8.24 (dd, J = 1.5, 8.5 Hz, 1H, Ph-H), 9.61 (s, 1H, NH). MS (ESI): 258 ([M−H], 100percent).
64%
Stage #1: With sodium hydride In tetrahydrofuran at -10 - 20℃; for 7.25 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃;
Step 2; 5-Methyl-2-(2-nitrophenylamino) thiophene-3-carbontrile: At about -10° C. and over a period of 15 minutes, a solution of 2-fluoro-nitro benzene (10.23g, 72.36 mmol), 2-amino -5-methylthiophene-3-carbonitrile (10 g, 72.36 mmol), and tetrahydrofuran (100 mL) was added dropwise to a suspension of sodium hydride (4.35 g, 108.69 mmol) and dry tetrahydrofuran. The resulting mixture was stirred for about 7 hours at ambient temperature and then cooled to about 0° C. Ice-cold water (100 mL) was slowly added, and then 5 N hydrochloric acid was added. Following standard extractive workup with dichloromethane (2.x.100 mL), the resulting residue was triturated with a mixture of n-pentane and diethyl ether (10:1), filtered, and dried to give the title compound as a dark brown color solid (12.0 g, yield=64percent). m.p. 100-103° C. 1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 6.78 (s, 1H), 6.96 (t, J=7.8 Hz, 1H), 7.2 (d, J=8.4 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H) 8.25 (d, J=8.4 Hz, 1H), 9.61 (s, exchangeable with D2O, 1H); IR (KBr) υ 3279, 3080, 3027, 2917, 2854, 2226, 1612, 1491, 1402, 1335, 1270, 736 cm-1; MS 258 (M-1).
60%
Stage #1: With sodium hydride In tetrahydrofuran at 30℃;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃;
For a general synthesis see He, X.; Griesser, U. J.; Stowell, J. G.; Borchrdt, T. B.; Byrn, S. R. J. Pharm. Sd. 2001, 90, 371.B To NaH (3 equivalents, from 55percent suspension in oil, rendered oil-free by washing with hexane) was added 1 ml of dry THF. 2-amino-5-methyl-3- thiophenecarbonitrile (A, as prepared above, 0.5 g, 3.6 mmol) and 4-fluoro-3- nitotoluene (0.51 g, 3.6 mmol) were dissolved in dry THF (1.5 ml) and added in a dropwise manner to the suspension while the temperature was maintained below 30°C. The reaction mixture was allowed to stir overnight under N2 purge. The mixture was then poured into 11 ml of ice- water mixture, neutralized with concentrated HCl, and extracted with 36 ml of DCM. The DCM solution was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel (elution with 1 :9 EtOAc/ Hexanes) to give compound B (yield 60percent).1H NMR (200 MHz, CDCl3): δ 9.61 (br s, IH), 8.25 (dd, J = 8.5 Hz, J = 1.5 Hz, IH), 7.52 (dt, J = 7.8 Hz, J = 1.4 Hz, IH), 7.19 (dd, J = 8.5 Hz, J = 1.1 Hz, IH)5 6.97 (dt, J = 7.8 Hz, J = 1.2 Hz5 IH), 6.78 (d, J = 1.1 Hz, IH), 2.48 (s, 3H).
60% With potassium hydroxide In DMF (N,N-dimethyl-formamide) at 0 - 25℃; for 5 h; To a stirred mixture of potassium hydroxide (59.1 g), benzyltriethylammonium chloride (1.2 g) and N,N-dimethylformamide (70 mL) in a 250 mL flask was added dropwise a solution of 2-amino-5-methylthiophene-3- carbonitrile (73 g) and 1-fluoro-2-nitrobenzene (74.5 g) in N,N dimethylformamide (175 mL) while maintaining the temperature between at 20-25 °C with an ice/salt bath. After the addition was complete, the mixture was stirred between 20-25°C for 5 hours, then poured onto ice/water (400 mL), and extracted with dichloromethane (480 mL). The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (240 mLx2). Water (400 mL) was added to the combined organic extracts, and the pH was adjusted between 8-9 with 2N hydrochloric acid. The organic layer was separated and washed with water (400 mL). The solvent was removed under reduced pressure to afford a residue that was crystallized from ethanol (300 mL) to give 2- (2-nitroanilino)-5-methylthiophene-3- carbonitrile (82.2 g). Yield: 60percent

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 7, p. 1953 - 1956
[2] Patent: US2010/266711, 2010, A1, . Location in patent: Page/Page column 14
[3] Patent: WO2008/50341, 2008, A2, . Location in patent: Page/Page column 33
[4] Patent: WO2004/94390, 2004, A1, . Location in patent: Page 13-14
[5] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 378 - 382
[6] Tetrahedron, 2010, vol. 66, # 41, p. 8203 - 8209
[7] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 1, p. 25 - 30
[8] Patent: WO2006/6180, 2006, A1, . Location in patent: Page/Page column 10
[9] Patent: US5229382, 1993, A,
[10] Patent: US5605897, 1997, A,
[11] Patent: US5627178, 1997, A,
[12] Patent: US5817655, 1998, A,
[13] Patent: US5817657, 1998, A,
[14] Patent: US5817656, 1998, A,
[15] Patent: WO2006/25065, 2006, A1, . Location in patent: Page/Page column 7-8
[16] Patent: US2009/5556, 2009, A1, . Location in patent: Page/Page column 5
[17] Patent: US2010/317849, 2010, A1, . Location in patent: Page/Page column 4
[18] Patent: US2014/57303, 2014, A1, . Location in patent: Page/Page column
[19] Patent: WO2014/31656, 2014, A1, . Location in patent: Paragraph 00189; 00190
[20] Patent: WO2014/31587, 2014, A1, . Location in patent: Page/Page column 57
  • 59
  • [ 1493-27-2 ]
  • [ 202859-73-2 ]
Reference: [1] Patent: WO2015/65338, 2015, A1,
[2] Patent: WO2015/65336, 2015, A1,
[3] Patent: EP3216786, 2017, A1,
  • 60
  • [ 1493-27-2 ]
  • [ 132539-06-1 ]
Reference: [1] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 378 - 382
[2] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 1, p. 25 - 30
  • 61
  • [ 1493-27-2 ]
  • [ 406233-31-6 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: at 120℃;
Stage #2: With ammonium hydroxide In isopropyl alcohol at -60℃; for 1 h;
37. Synthesis of intermediate 23 (0486) (0487) [00160] The solution of 22 (4.0 g, 28.4 mmol) in CISO3H (25 mL) was stirred at (0488) 120 °C overnight, and the reaction was cooled to room temperature and poured into ice water. Then the resultant was extracted with EA (50 mL x 3), combined the organic layers, removed the solvent at reduced pressure, and the crude residue was re-dissolved in i-PrOH. The solution was cooled to -60°C. Ammonium hydroxide was added drop-wise, and stirred at this temperature for 1 hour, HC1 (6M, 8 mL) was added to quenched the reaction, the reaction was warmed to room temperature and concentrated to dryness. The intermediate 23 (5.1 g, 82 percent) was obtained as white solid. 1H NMR (400MHz, DMSO-d6): 58.52 (dd, 1H), 8.20(dq, 1H), 7.84 (dt, 1H), 7.73(s, 2H).
Reference: [1] Patent: WO2017/123616, 2017, A1, . Location in patent: Paragraph 00160
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5207 - 5211
[3] Chemistry - A European Journal, 2018, vol. 24, # 52, p. 13762 - 13766
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 1165 - 1181
[5] Patent: US2011/237553, 2011, A1, . Location in patent: Page/Page column 19
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 39 - 44
[7] Patent: US2012/35134, 2012, A1,
[8] Patent: US2012/129897, 2012, A1, . Location in patent: Page/Page column 21
[9] Patent: US2012/129872, 2012, A1, . Location in patent: Page/Page column 32
[10] Patent: US2012/129843, 2012, A1, . Location in patent: Page/Page column 40-41
[11] Patent: US2012/129842, 2012, A1, . Location in patent: Page/Page column 59
[12] Patent: US2012/129811, 2012, A1, . Location in patent: Page/Page column 42; 43
[13] Patent: US2012/302569, 2012, A1, . Location in patent: Page/Page column 24
  • 62
  • [ 1336-21-6 ]
  • [ 1493-27-2 ]
  • [ 406233-31-6 ]
Reference: [1] Patent: US2002/55631, 2002, A1,
[2] Patent: US2002/86887, 2002, A1,
  • 63
  • [ 1493-27-2 ]
  • [ 252758-94-4 ]
Reference: [1] Patent: WO2007/123516, 2007, A1,
  • 64
  • [ 1493-27-2 ]
  • [ 761440-16-8 ]
Reference: [1] Patent: WO2011/140338, 2011, A1,
[2] Patent: EP2257637, 2015, B1,
[3] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 80 - 89
[4] Patent: CN105622520, 2016, A,
[5] Patent: WO2016/199020, 2016, A1,
[6] Patent: CN106146468, 2016, A,
[7] Patent: CN106336382, 2017, A,
[8] Patent: CN104356112, 2017, B,
[9] Patent: CN107151233, 2017, A,
[10] Patent: CN106854200, 2017, A,
[11] Patent: CN108383799, 2018, A,
  • 65
  • [ 1493-27-2 ]
  • [ 757251-39-1 ]
Reference: [1] Patent: WO2017/125941, 2017, A1,
  • 66
  • [ 1493-27-2 ]
  • [ 760212-58-6 ]
Reference: [1] Green Chemistry, 2013, vol. 15, # 3, p. 798 - 810
[2] Tetrahedron, 2014, vol. 70, # 18, p. 2992 - 2998
[3] Patent: CN102977129, 2016, B,
[4] Patent: US9548460, 2017, B2,
  • 67
  • [ 1493-27-2 ]
  • [ 867044-33-5 ]
Reference: [1] Patent: CN102977129, 2016, B,
  • 68
  • [ 1493-27-2 ]
  • [ 873566-75-7 ]
Reference: [1] Patent: CN104530107, 2016, B,
  • 69
  • [ 56-84-8 ]
  • [ 1493-27-2 ]
  • [ 136584-14-0 ]
Reference: [1] Patent: US6369057, 2002, B1,
  • 70
  • [ 1493-27-2 ]
  • [ 1097871-99-2 ]
Reference: [1] Patent: WO2013/68461, 2013, A1,
Same Skeleton Products
Historical Records

Similar Product of
[ 1493-27-2 ]

Chemical Structure| 2230123-14-3

A1267848[ 2230123-14-3 ]

o-Nitrofluorobenzene-13C6

Reason: Stable Isotope

Related Functional Groups of
[ 1493-27-2 ]

Fluorinated Building Blocks

Chemical Structure| 2369-13-3

[ 2369-13-3 ]

3-Fluoro-4-nitroaniline

Similarity: 0.98

Chemical Structure| 446-35-5

[ 446-35-5 ]

2,4-Difluoro-1-nitrobenzene

Similarity: 0.98

Chemical Structure| 369-35-7

[ 369-35-7 ]

2-Fluoro-4-nitroaniline

Similarity: 0.94

Chemical Structure| 113269-06-0

[ 113269-06-0 ]

4-Fluoro-5-nitrobenzene-1,2-diamine

Similarity: 0.92

Chemical Structure| 567-63-5

[ 567-63-5 ]

3-Fluoro-2-nitroaniline

Similarity: 0.92

Aryls

Chemical Structure| 2369-13-3

[ 2369-13-3 ]

3-Fluoro-4-nitroaniline

Similarity: 0.98

Chemical Structure| 446-35-5

[ 446-35-5 ]

2,4-Difluoro-1-nitrobenzene

Similarity: 0.98

Chemical Structure| 369-35-7

[ 369-35-7 ]

2-Fluoro-4-nitroaniline

Similarity: 0.94

Chemical Structure| 113269-06-0

[ 113269-06-0 ]

4-Fluoro-5-nitrobenzene-1,2-diamine

Similarity: 0.92

Chemical Structure| 567-63-5

[ 567-63-5 ]

3-Fluoro-2-nitroaniline

Similarity: 0.92

Nitroes

Chemical Structure| 2369-13-3

[ 2369-13-3 ]

3-Fluoro-4-nitroaniline

Similarity: 0.98

Chemical Structure| 446-35-5

[ 446-35-5 ]

2,4-Difluoro-1-nitrobenzene

Similarity: 0.98

Chemical Structure| 369-35-7

[ 369-35-7 ]

2-Fluoro-4-nitroaniline

Similarity: 0.94

Chemical Structure| 113269-06-0

[ 113269-06-0 ]

4-Fluoro-5-nitrobenzene-1,2-diamine

Similarity: 0.92

Chemical Structure| 567-63-5

[ 567-63-5 ]

3-Fluoro-2-nitroaniline

Similarity: 0.92