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[ CAS No. 1072-85-1 ] {[proInfo.proName]}

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Product Details of [ 1072-85-1 ]

CAS No. :1072-85-1 MDL No. :MFCD00000282
Formula : C6H4BrF Boiling Point : -
Linear Structure Formula :- InChI Key :IPWBFGUBXWMIPR-UHFFFAOYSA-N
M.W : 175.00 Pubchem ID :61259
Synonyms :

Calculated chemistry of [ 1072-85-1 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 34.1
TPSA : 0.0 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.44 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.04
Log Po/w (XLOGP3) : 2.71
Log Po/w (WLOGP) : 3.01
Log Po/w (MLOGP) : 3.48
Log Po/w (SILICOS-IT) : 3.0
Consensus Log Po/w : 2.85

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.19
Solubility : 0.114 mg/ml ; 0.00065 mol/l
Class : Soluble
Log S (Ali) : -2.36
Solubility : 0.758 mg/ml ; 0.00433 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.52
Solubility : 0.0522 mg/ml ; 0.000299 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.33

Safety of [ 1072-85-1 ]

Signal Word:Danger Class:3
Precautionary Statements:P261-P305+P351+P338 UN#:1993
Hazard Statements:H225-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1072-85-1 ]

* 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 [ 1072-85-1 ]
  • Downstream synthetic route of [ 1072-85-1 ]

[ 1072-85-1 ] Synthesis Path-Upstream   1~46

  • 1
  • [ 1072-85-1 ]
  • [ 934-32-7 ]
  • [ 28890-99-5 ]
Reference: [1] Patent: WO2017/56053, 2017, A1, . Location in patent: Page/Page column 290
  • 2
  • [ 1072-85-1 ]
  • [ 150879-48-4 ]
  • [ 784-38-3 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 15, p. 4516 - 4520
  • 3
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 1000995-64-1 ]
  • [ 344455-90-9 ]
  • [ 1073-06-9 ]
  • [ 108-36-1 ]
  • [ 106-37-6 ]
  • [ 460-00-4 ]
  • [ 583-53-9 ]
Reference: [1] Patent: US2008/9653, 2008, A1, . Location in patent: Page/Page column 3-4
  • 4
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 1000995-64-1 ]
  • [ 344455-90-9 ]
  • [ 1073-06-9 ]
  • [ 108-36-1 ]
  • [ 106-37-6 ]
  • [ 460-00-4 ]
  • [ 583-53-9 ]
Reference: [1] Patent: US2008/9653, 2008, A1, . Location in patent: Page/Page column 3
  • 5
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 399-94-0 ]
  • [ 1073-06-9 ]
  • [ 348-61-8 ]
  • [ 460-00-4 ]
YieldReaction ConditionsOperation in experiment
0.06 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
  • 6
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 1073-06-9 ]
  • [ 460-00-4 ]
Reference: [1] Journal of the American Chemical Society, 1980, vol. 102, # 10, p. 3511 - 3515
[2] Journal of the American Chemical Society, 1980, vol. 102, # 10, p. 3511 - 3515
[3] Russian Chemical Bulletin, 2015, vol. 64, # 5, p. 1049 - 1052[4] Izv. Akad. Nauk, Ser. Khim., 2015, # 5, p. 1049 - 1052,4
  • 7
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 399-94-0 ]
  • [ 1073-06-9 ]
  • [ 348-61-8 ]
  • [ 460-00-4 ]
YieldReaction ConditionsOperation in experiment
0.06 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
  • 8
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 1000995-64-1 ]
  • [ 344455-90-9 ]
  • [ 1073-06-9 ]
  • [ 108-36-1 ]
  • [ 106-37-6 ]
  • [ 460-00-4 ]
  • [ 583-53-9 ]
Reference: [1] Patent: US2008/9653, 2008, A1, . Location in patent: Page/Page column 3-4
  • 9
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 1000995-64-1 ]
  • [ 344455-90-9 ]
  • [ 1073-06-9 ]
  • [ 108-36-1 ]
  • [ 106-37-6 ]
  • [ 460-00-4 ]
  • [ 583-53-9 ]
Reference: [1] Patent: US2008/9653, 2008, A1, . Location in patent: Page/Page column 3
  • 10
  • [ 3984-22-3 ]
  • [ 1072-85-1 ]
  • [ 1643-26-1 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 50, p. 11533 - 11540
  • 11
  • [ 1072-85-1 ]
  • [ 120-12-7 ]
  • [ 217-59-4 ]
  • [ 477-75-8 ]
Reference: [1] Chemische Berichte, 1958, vol. 91, p. 873,881
[2] Org. Synth. Coll. Vol., 1963, vol. IV, p. 964
  • 12
  • [ 462-06-6 ]
  • [ 1072-85-1 ]
  • [ 1435-53-6 ]
  • [ 359-90-0 ]
  • [ 460-00-4 ]
Reference: [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406
  • 13
  • [ 462-06-6 ]
  • [ 1072-85-1 ]
  • [ 1435-53-6 ]
  • [ 3925-78-8 ]
  • [ 359-90-0 ]
  • [ 460-00-4 ]
Reference: [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406
  • 14
  • [ 1072-85-1 ]
  • [ 348-52-7 ]
Reference: [1] Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6904 - 6906
[2] Catalysis Science and Technology, 2017, vol. 7, # 10, p. 2110 - 2117
  • 15
  • [ 1072-85-1 ]
  • [ 701-45-1 ]
YieldReaction ConditionsOperation in experiment
89% With sulfuric acid; nitric acid In water at 10 - 20℃; To a solution of l-bromo-2-fluorobenzene (35.0 g, 200 mmol) in 200 mL of concentrated sulfuric acid was added 20 mL of 68percent nitric acid. The temperature of the mixture was maintained below 20 0C. After the addition was completed, the <n="140"/>mixture was stirred at 10 0C overnight, then diluted with ice water. The resulting solid was collected by filtration. The solid was recrystallized from petroleum ether to give the title compound 0602 as a yellow solid (38 g, 89percent): m.p.55.8-56.7 0C, 1U NMR (DMSO-J6): δ 7.66 (t, J= 9 Hz, IH), 8.32 (m, IH), 8.58 (dd, J= 3 Hz, 6 Hz, IH).
89% at 10 - 20℃; Step 31a.
2-Bromo-1-fluoro-4-nitrobenzene (compound 0602)
To a solution of 1-bromo-2-fluorobenzene (35.0 g, 200 mmol) in 200 mL of concentrated sulfuric acid was added 20 mL of 68percent nitric acid.
The temperature of the mixture was maintained below 20° C.
After the addition was completed, the mixture was stirred at 10° C. overnight, then diluted with ice water.
The resulting solid was collected by filtration.
The solid was recrystallized from petroleum ether to give the title compound 0602 as a yellow solid (38 g, 89percent): m.p. 55.8-56.7° C., 1H NMR (DMSO-d6): δ 7.66 (t, J=9 Hz, 1H), 8.32 (m, 1H), 8.58 (dd, J=3 Hz, 6 Hz, 1H).
89% at 10 - 20℃; Example 31Preparation of 7-(4-(3-ethynyl-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (Compound 75)Step 31a. 2-Bromo-1-fluoro-4-nitrobenzene (compound 0602); To a solution of 1-bromo-2-fluorobenzene (35.0 g, 200 mmol) in 200 mL of concentrated sulfuric acid was added 20 mL of 68percent nitric acid. The temperature of the mixture was maintained below 20° C. After the addition was completed, the mixture was stirred at 10° C. overnight, then diluted with ice water. The resulting solid was collected by filtration. The solid was recrystallized from petroleum ether to give the title compound 0602 as a yellow solid (38 g, 89percent): m.p. 55.8-56.7° C., 1H NMR (DMSO-d6): δ 7.66 (t, J=9 Hz, 1H), 8.32 (m, 1H), 8.58 (dd, J=3 Hz, 6 Hz, 1H).
82.2% at 0 - 40℃; for 3 h; 100 g (0.57 mol) of 1-bromo-2-fluorobenzene and 570 mL of concentrated sulfuric acid were placed in a 1 L four-necked round bottom flask equipped with a stirrer, a Liebig condenser, a 50 mL dropping funnel and a thermometer, , Cooled to 0 ° C. and then 47 mL of 68percent nitric acid was added dropwise at a temperature not exceeding 40 ° C. Subsequently, the mixture was cooled to 20 ° C. and postreacted at the same temperature for 3 hours. The obtained reaction solution was poured into 3150 g of crushed ice, the precipitated crystals were recovered by filtration, further washed thoroughly with 1.5 L of water, and dried overnight in a vacuum dryer at 40 ° C. Subsequently, the resulting crude crystals were further recrystallized with petroleum ether to obtain 103.1 g (yield 82.2percent) of the title compound.
73.3% With sulfuric acid; nitric acid In water at 20℃; for 1 h; Step 1a.
2-Bromo-1-fluoro-4-nitrobenzene (Compound 102)
To a sulfuric acid (50 ml) solution of compound 101 (8.75 g, 500 mmol) was added 68percent HNO3 (4 mL) in such a way that the temperature of the reaction was maintained below 40° C.
After the addition, the mixture was stirred at 20° C. for 1 h.
The mixture was diluted with 300 mL of ice-water and filtered.
The collected solid was recrystallized from petroleum ester to yield the title compound 102 as a white solid (8.06 g, 73.3percent): 1H NMR (DMSO-d6): δ 8.6 (dd, 1H), 8.3 (m, 1H), 7.7 (t, 1H).

Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2280 - 2286
[2] Patent: WO2008/33747, 2008, A2, . Location in patent: Page/Page column 138-139
[3] Patent: US2009/76022, 2009, A1, . Location in patent: Page/Page column 78
[4] Patent: US2009/111772, 2009, A1, . Location in patent: Page/Page column 76-77
[5] Patent: JP2018/90561, 2018, A, . Location in patent: Paragraph 0088
[6] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 25
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2538 - 2548
  • 16
  • [ 1072-85-1 ]
  • [ 701-45-1 ]
  • [ 185331-69-5 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 17
  • [ 1072-85-1 ]
  • [ 40920-16-9 ]
  • [ 19614-16-5 ]
  • [ 116865-00-0 ]
Reference: [1] Chemische Berichte, 1988, vol. 121, p. 2251 - 2254
  • 18
  • [ 1072-85-1 ]
  • [ 74-88-4 ]
  • [ 19614-16-5 ]
  • [ 116865-00-0 ]
Reference: [1] Chemische Berichte, 1988, vol. 121, p. 2251 - 2254
  • 19
  • [ 1072-85-1 ]
  • [ 78-82-0 ]
  • [ 57775-06-1 ]
YieldReaction ConditionsOperation in experiment
5.2 %Chromat.
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 65℃; for 1 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran
Example 4; Reaction of haloarenes and 2-methylpropionitrile in the presence of various bases in THF. The reaction tubes of Mettler Toledo MiniBlock.(TM). were independently charged with the haloarenes (0.01 mol) identified below and a solution of 2-methylpropionitrile in THF (8.5 mL, 0.01 mol) which was prepared from the nitrile (14 g) and THF (160 mL). An equimolar amount of the base (0.01 mol) was independently added to each tube dropwise at ambient temperature. The reaction mixtures were heated to 65° C. over 1 hour, cooled to ambient temperature and quenched with 5percent HCl (6 mL). The organic phases were separated and the solvents were evaporated. The crude product mixtures were examined using gas chromatography (GC)/mass spectroscopy (MS) and proton nuclear magnetic resonance (1H-NMR).F. haloarene: 1-bromo-2-fluorobenzene; base: sodium hexamethyldisilazide (1M in THF); product: 2-(2-bromophenyl)-2-methylpropionitrile (5.2percent by GC/MS) and residual haloarene (76.8percent)
Reference: [1] Patent: US2006/247441, 2006, A1, . Location in patent: Page/Page column 17
  • 20
  • [ 1072-85-1 ]
  • [ 766-49-4 ]
Reference: [1] Synthesis, 1996, # 5, p. 589 - 590
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
  • 21
  • [ 1072-85-1 ]
  • [ 95-92-1 ]
  • [ 1813-93-0 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; Inert atmosphere
Stage #2: at -70 - 20℃;
To a stirring solution of 1- bromo-2-fluorobenzene (lOg, 57 mmol) in tetrahydrofuran (100 mL) at -70 °C under nitrogen was added a solution of n-butyllithium (25 mL, 62.9 mmol, 2.5 M in hexane). After 20 minutes, this solution was added to a solution of diethyl oxalate (39 mL, 285 mmol) in tetrahydrofuran (100 mL) at -70 °C. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature. After one hour at ambient temperature, the reaction mixture was poured into water (150 mL) and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined and concentrated at reduced pressure. The resulting crude product was purified by column chromatography through silica gel cartridge (240 g) eluting with ethyl acetate/hexane(1 :49) to give the product as a colorless oil (5.6 g, 50percent). 1H NMR (CDC13) δ 7.95 (m, 1H,), 7.62 (m, 1H), 7.35-7.13 (m, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). MS(ES+) = 197(M+H)+.
Reference: [1] Patent: WO2012/74784, 2012, A2, . Location in patent: Page/Page column 23-24
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3726 - 3732
[3] Angewandte Chemie - International Edition, 2014, vol. 53, # 10, p. 2658 - 2661[4] Angew. Chem., 2014, vol. 126, # 10, p. 2696 - 2699,4
  • 22
  • [ 1072-85-1 ]
  • [ 109-72-8 ]
  • [ 75716-82-4 ]
  • [ 1813-93-0 ]
Reference: [1] Patent: EP386940, 1990, A1,
  • 23
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  • [ 316-61-0 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 2, p. 346 - 349
  • 24
  • [ 1072-85-1 ]
  • [ 656-64-4 ]
Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2280 - 2286
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2538 - 2548
[3] Patent: JP2018/90561, 2018, A,
  • 25
  • [ 1072-85-1 ]
  • [ 1993-03-9 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 1.5 h;
Stage #2: With Triisopropyl borate In tetrahydrofuran at 20℃; for 4 h;
Stage #3: With hydrogenchloride In tetrahydrofuran
10.0 g (57.1 mmol) of 1-bromo-2-fluorobenzene and dehydrated tetrahydrofuran were placed, followed by cooling to -70° C. To the resulting mixture, 44.2 ml (68.5 mmol) of 1.55M-normalbutyllithium was added dropwise. The resulting mixture was stirred at -70° C. for 1.5 hours, and 21.5 g (114.2 mmol) of triisopropyl borate was added dropwise, and the temperature was elevated to room temperature, followed by stirring for 4 hours. An aqueous hydrochloric acid solution was added to the reaction mixture, and extracted with dichloromethane. The solvent in the organic phase was removed under reduced pressure, thereby to obtain a crude product of the compound (f). This crude product was purified by column chromatography (hexane: acetone), whereby 4.8 g (yield: 61percent) of compound (f) was obtained.
48%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #3: With hydrogenchloride; water; ammonium chloride In tetrahydrofuran; n-heptane; water at 0℃; Acidic aqueous solution
EXAMPLE IV
2-Fluorophenylboronic Acid
Under argon, 155 g (0.86 mol) of 2-fluorobromobenzene are initially charged in 732 ml of absolute tetrahydrofuran and, at -78° C., mixed slowly with 600 ml of 1.6 M n-butyllithium in hexane.The mixture is then stirred at -78° C. for 2 h.At -78° C., 298 ml (1.28 mol) of trimethyl borate are then added dropwise.After 1 h, cooling is removed, and the reaction mixture is stirred overnight and warmed to room temperature.For work-up, the mixture is, at 0° C., mixed with 346 ml of saturated ammonium chloride solution, the PH is adjusted to PH 6 using 1N HCl and the aqueous phase is extracted 3 times with in each case 250 ml of methylene chloride.The combined organic phases are washed with saturated sodium chloride solution and dried with magnesium sulphate.This gives Example IV in the form of a beige solid.
Yield: 60.0 g (48percent)
MS (EI, m/z): 140 (80percent, [M]+), 96 (100percent, [C6H5F]+)
Reference: [1] Patent: US2012/273770, 2012, A1, . Location in patent: Page/Page column 24
[2] Patent: US2004/6076, 2004, A1, . Location in patent: Page 15
[3] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
  • 26
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  • [ 5419-55-6 ]
  • [ 1993-03-9 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 0.5 h; Inert atmosphere; Autoclave; Large scale
Stage #2: at -70℃; Large scale
Under nitrogen atmosphere, 14 kg (22.9 mol) of the compound and 20 L of THF were sequentially added to the 50 L autoclave, and the temperature was lowered to -70 ° C.Temperature control -70 the following dropping n-BuLi6.8kg, after dropping at -70 below stirring 0.5 hours. Temperature -70 below the dropBoric acid isopropyl ester 4.75kg, drop back after the natural warm night. Poured into 20L (1N) dilute hydrochloric acid, liquid, water phase and thenEA10L. The combined organic phases were washed once with saturated brine 10 L, dried over anhydrous sodium sulfate, filtered and concentratedTo give 22.4 kg of the compound in 85percent yield.
Reference: [1] Patent: CN105801553, 2016, A, . Location in patent: Paragraph 0093; 0094; 0095
[2] Organic Letters, 2015, vol. 17, # 2, p. 346 - 349
  • 27
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  • [ 121-43-7 ]
  • [ 1993-03-9 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 15, p. 3630 - 3633
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  • [ 109-72-8 ]
  • [ 5419-55-6 ]
  • [ 1993-03-9 ]
YieldReaction ConditionsOperation in experiment
63% With hydrogenchloride In tetrahydrofuran Preparation 3
2-Fluorobenzeneboronic Acid
A solution of 50 g (285.6 mmol) of 2-fluorobromobenzene in 400 mL of tetrahydrofuran was cooled to -78° C. and 200 mL (320.0 mmol) of 1.6M n-Butyllithium was added via a cannula.
The mixture was stirred at -78° C. for 60 minutes, then 98.9 mL (428.4 mmol) of triisopropyl borate was added via a cannula and stirring was continued for 60 minutes.
The cooling bath was removed and the mixture was stirred at ambient temperature for 1.5 hours, then 150 mL of 6N hydrochloric acid was added and stirring was continued for 1.5 hours.
To the mixture was added 100 mL of brine, and then the organic layer was separated and the aqueous layer was extracted three times with 30 mL each of ether.
The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo.
The residue was recrystallized from water to afford 25.2 g (63percent) of the title compound.
63% With hydrogenchloride In tetrahydrofuran PREPARATION 3
2-Fluorobenzeneboronic Acid
A solution of 50 g (285.6 mmol) of 2-fluorobromobenzene in 400 mL of 15 tetrahydrofuran was cooled to -78° C. and 200 mL (320.0 mmol) of 1.6M n-Butyllithium was added via a cannula.
The mixture was stirred at -78° C. for 60 minutes, then 98.9 mL (428.4 mmol) of triisopropyl borate was added via a cannula and stirring was continued for 60 minutes.
The cooling bath was removed and the mixture was stirred at ambient temperature for 1.5 hours, then 150 mL of 6N hydrochloric acid was added and stirring was continued for 1.5 hours.
To the mixture was added 100 mL of brine, and then the organic layer was separated and the aqueous layer was extracted three times with 30 mL each of ether.
The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo.
The residue was recrystallized from water to afford 25.2 g (63percent) of the title compound.
Reference: [1] Patent: US6303816, 2001, B1,
[2] Patent: US6500865, 2002, B1,
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  • [ 13675-18-8 ]
  • [ 1993-03-9 ]
Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
  • 30
  • [ 1072-85-1 ]
  • [ 603-35-0 ]
  • [ 2751-90-8 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1970, vol. 732, p. 97 - 106
  • 31
  • [ 1072-85-1 ]
  • [ 132715-69-6 ]
Reference: [1] Patent: CN108003016, 2018, A,
  • 32
  • [ 1072-85-1 ]
  • [ 77123-60-5 ]
Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2280 - 2286
[2] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2280 - 2286
[3] Patent: US2009/111772, 2009, A1,
  • 33
  • [ 1072-85-1 ]
  • [ 161957-61-5 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141
[2] Tetrahedron Letters, 1995, vol. 36, # 6, p. 881 - 884
  • 34
  • [ 1072-85-1 ]
  • [ 124-38-9 ]
  • [ 161957-56-8 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 2 h;
Stage #3: With hydrogenchloride In water
INTERMEDIATE PREPARATION 76-bromo-7-fluoro-1 /-/-indole-2,3-dione3-bromo-2-fluorobenzoic acidTo a solution of diisopropylamine (84.3 mL, 600 mmol) in THF (500 mL) at -30°C was added n-BuLi (240 mL of a 2.5M solution, 600 mmol) dropwise. The resulting solution was stirred at -30°C for 30 min. This mixture was added dropwise to a solution of 1-bromo-2- fluorobenzene (100 g, 571 .43 mmol) in THF (500 mL) at -78°C. After the addition was complete, the resulting solution was stirred at -78°C for 2 h and poured over crushed solid C02. After removal of the solvent in vacuo, the resulting residue was diluted with water and washed with diethyl ether (2 x 500 mL). The aqueous phase was acidified with 1 N HCI to pH 2. The precipitate was collected by filtration and dried to afford 3-bromo-2-fluorobenzoic acid (90 g, 64percent yield) as a white solid. MS (m/z) 221.0 (M+H+).
55% With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -75 - -10℃; for 3.5 h; Example 16
3-Bromo-2-fluorobenzoic acid
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10° C.
The mixture was stirred for 1.5 h at -10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75° C.
The mixture was stirred for 2 h at -75° C., before being poured on excess of CO2 gas.
Then the reaction mixture was warmed to room temperature and stirred over night.
After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2*50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).
55%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane; water at -75 - -10℃;
Stage #2: at -75 - 20℃;
Stage #3: With hydrogenchloride In water
Example 16
3-Bromo-2-fluorobenzoic Acid
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10° C.
The mixture was stirred for 1.5 h at -10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75° C.
The mixture was stirred for 2 h at -75° C., before being poured on excess of CO2 gas.
Then the reaction mixture was warmed to room temperature and stirred over night.
After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2*50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).
55%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -75℃; for 2 h;
Stage #2: at -75 - 20℃;
Example 19
3-Bromo-2-fluorobenzoic Acid
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10° C.
The mixture was stirred for 1.5 h at -10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75° C.
The mixture was stirred for 2 h at -75° C. and an excess of freshly CO2 gas bubbled into the reaction mixture.
Then the reaction mixture was warmed to room temperature and stirred over night.
After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2*50 mL), acidified (to pH 1) and the solid was filtered off, dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).
55%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -75℃; for 2 h;
Stage #2: at -75 - 20℃;
Stage #3: Acidic conditions
Example 16 3-Bromo-2-fhiorobenzoic acidTo a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10 0C. The mixture was stirred for 1.5 h at -10 0C and the fluoroarene (l-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75 0C. The mixture was stirred for 2 h at -75 0C, before being poured on excess of CO2 gas. Then the reaction mixture was warmed to room temperature and stirred over night. After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2 x 50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).

Reference: [1] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141
[2] Patent: WO2011/119704, 2011, A1, . Location in patent: Page/Page column 39-40
[3] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 12, p. 4158 - 4181
[4] Patent: US2009/203657, 2009, A1, . Location in patent: Page/Page column 47
[5] Patent: US2009/203677, 2009, A1, . Location in patent: Page/Page column 50
[6] Patent: US2009/197871, 2009, A1, . Location in patent: Page/Page column 49
[7] Patent: WO2009/100169, 2009, A1, . Location in patent: Page/Page column 125
[8] Tetrahedron Letters, 1995, vol. 36, # 6, p. 881 - 884
[9] Tetrahedron Letters, 1996, vol. 37, # 36, p. 6551 - 6554
[10] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 18, p. 2115 - 2118
[11] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 10001 - 10012
  • 35
  • [ 1072-85-1 ]
  • [ 109-72-8 ]
  • [ 161957-56-8 ]
YieldReaction ConditionsOperation in experiment
57% With lithium; diisopropylamine In tetrahydrofuran; water Intermediate 38: 3-Bromo-2-fluorobenzoic acid
Tetrahydrofuran (60 ml) was added to diisopropylamine (9.6 ml, 68 mmol) in an argon atmosphere. n-Butyllithium (hexane solution, 1.5 M, 38 ml, 57 mmol) was added dropwise thereto at -10°C, and the mixture was stirred for one hr.
Separately, 55 ml of tetrahydrofuran was added to 1-bromo-2-fluorobenzene (10 g, 57 mmol) to prepare a solution which was then added dropwise to the lithium reagent solution at -78°C.
The mixture was stirred for 2 hr and was then stirred for additional 30 min while blowing carbon dioxide thereinto.
The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was concentrated under the reduced pressure.
Water (200 ml) was added to the residue to prepare a solution, and the solution was washed twice with 100 ml of diethyl ether.The aqueous layer was adjusted to pH 1 by the addition of 1.0 M hydrochloric acid, was extracted twice with 300 ml of methylene chloride, was dried over anhydrous magnesium sulfate, and was concentrated under the reduced pressure to give the title compound (7.1 g, 57percent).
Physicochemical properties of intermediate 38
Reference: [1] Patent: EP1229024, 2002, A1,
  • 36
  • [ 1072-85-1 ]
  • [ 701-45-1 ]
  • [ 185331-69-5 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 37
  • [ 1072-85-1 ]
  • [ 78782-17-9 ]
  • [ 517920-60-4 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 13, p. 3368 - 3371
  • 38
  • [ 1072-85-1 ]
  • [ 68-12-2 ]
  • [ 149947-15-9 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 1.16667 h;
Was added to 1-bromo-2-fluoro-benzene 5.0 g (28.57 mmol) of 2.0 M LDA 18.6 ml (37.14 mmol) at minus 78 was dissolved in 50 ml of tetrahydrofuran solution was stirred for 1 hour. And then added to N, N- dimethylformamide, 3.30 ml (42.86 mmol) and stirred for 10 minutes at minus 78 , which was stirred for 1 hour at room temperature. It was added to 100 ml of water After stirring for 5 minutes and extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure, the filtrate was purified by silica gel column chromatography (n-hexane: ethyl acetate, 50: 1, v / v) to give a yield of 73percent of the title compound a yellow solid. to give 4.22 g (20.79 mmol) in .Rf = 0.29 (n-hexane: ethyl acetate, 10: 1, v / v)
34 g With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Inert atmosphere 2,2,6,6-Tetramethylpiperidine (30 g, 212 mmol) and 150 ml of anhydrous THF are introduced into a 500 ml three-necked flask. The medium is cooled to 0 °C under argon and a 1 .6M solution of n-butyllithium in hexane (131 ml, 210 mmol) is added dropwise. After stirring at 0 °C for 30 min, the medium is coded to -78 °C and a solution of 1 -bromo- 2-fluorobenzene (35 g, 200 mmol) in 150 ml of THF is added dropwise. After stirring at - 78°C for 1 hour, 32 ml of anhydrous DMF (412 mmol)are added. The medium is stirred at -78°C for 30 min. It is run on to a saturated aqueous ammonium chloride solution (300 ml) and extracted with 3 x 200 ml of ether. The organic phases are washed with a saturated aqueous sodium chloride solution and dried over MgS04. The slurry is filtered and the filtrate concentrated. 34 g of an oil are obtained. Rf = 0.4 (cyclohexane/ethyl acetate; 90:10).
Reference: [1] Patent: KR2015/117318, 2015, A, . Location in patent: Paragraph 0181; 0182; 0183; 0184
[2] Patent: JP2005/350455, 2005, A, . Location in patent: Page/Page column 17
[3] Patent: WO2013/92756, 2013, A1, . Location in patent: Page/Page column 42; 43
  • 39
  • [ 1072-85-1 ]
  • [ 130286-84-9 ]
  • [ 149947-15-9 ]
Reference: [1] Patent: US2005/255258, 2005, A1,
  • 40
  • [ 1072-85-1 ]
  • [ 19075-59-3 ]
Reference: [1] Patent: KR2015/117318, 2015, A,
  • 41
  • [ 1072-85-1 ]
  • [ 550998-53-3 ]
Reference: [1] Patent: KR2015/117318, 2015, A,
  • 42
  • [ 1072-85-1 ]
  • [ 5419-55-6 ]
  • [ 731817-89-3 ]
Reference: [1] Patent: WO2004/65388, 2004, A1, . Location in patent: Page 49-50
  • 43
  • [ 1072-85-1 ]
  • [ 811842-30-5 ]
Reference: [1] Patent: JP2018/90561, 2018, A,
  • 44
  • [ 1072-85-1 ]
  • [ 86-74-8 ]
  • [ 902518-11-0 ]
YieldReaction ConditionsOperation in experiment
87% With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 24 h; General procedure: A mixture of a fluorinated aryl halide (2.0 mmol), a carbazole (0.5 mmol), and a base (2.0 mmol) in solvent (2 mL) was allowed to react under air atmosphere. The reaction mixture was heated to the specified temperature for 24 h. After reaction completion, the mixture was added to brine (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined extract was concentrated under reduced pressure and the product was isolated by short chromatography on a silica gel (200–300 mesh) column.
Reference: [1] Synthesis (Germany), 2016, vol. 48, # 5, p. 737 - 750
[2] Journal of Materials Chemistry C, 2018, vol. 6, # 15, p. 4300 - 4307
  • 45
  • [ 1072-85-1 ]
  • [ 1336963-95-1 ]
Reference: [1] Patent: WO2011/119704, 2011, A1,
  • 46
  • [ 1072-85-1 ]
  • [ 1378388-20-5 ]
Reference: [1] Patent: CN105801553, 2016, A,
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