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[ CAS No. 367-24-8 ]

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CAS No. :367-24-8 MDL No. :MFCD00010221
Formula : C6H5BrFN Boiling Point : 210°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :190.01 g/mol Pubchem ID :123050
Synonyms :

Safety of [ 367-24-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 367-24-8 ]

  • Upstream synthesis route of [ 367-24-8 ]
  • Downstream synthetic route of [ 367-24-8 ]

[ 367-24-8 ] Synthesis Path-Upstream   1~32

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Reference: [1] Patent: WO2012/58671, 2012, A1,
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Reference: [1] Patent: WO2007/135527, 2007, A2,
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  • [ 51618-30-5 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 4, p. 727 - 730
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  • [ 140-89-6 ]
  • [ 51618-30-5 ]
Reference: [1] Synthetic Communications, 2007, vol. 37, # 3, p. 369 - 376
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  • [ 30806-83-8 ]
  • [ 21091-98-5 ]
YieldReaction ConditionsOperation in experiment
70% With triethylamine In dichloromethane at 20℃; for 3 h; Step 1: 4- [3-(4-Bromo-2-fluoro-phenyl)-ureido] -benzoic acid ethyl esterTo a solution of 4-bromo-2-fluoroaniline (0.5 g, 0.0026 mol) and TEA (0.38 mL, 0.0026 mol) in DCM (15 mL) was added ethyl 4-isocyanatobenzoate (0.503 g, 0.0026 mol). The reaction mixture was stirred at room temperature for 3 h. The white solid was obtained and was filtered and dried to afford the title compound [0.7 g, 70percent]; LC-MS (ESI): Calculated mass: 380.0; Observed mass: 381.0 [M+H]+ (RT: 1.78 min).
Reference: [1] Patent: WO2012/58671, 2012, A1, . Location in patent: Page/Page column 81
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YieldReaction ConditionsOperation in experiment
90% With N-Bromosuccinimide In chloroform at 25℃; for 2 h; Inert atmosphere This compound was prepared followinga literature procedure.39 To a suspension of 2-fluoroaniline (12)(2.22 g, 20 mmol) in CHCl3 (50 mL) was added NBS (3.56 g, 20 mmol),and the resulting mixture was stirred at RT for 2 h. After completionmonitored by TLC, the mixture was quenched with sat. Na2S2O3 (aq.)and extracted with CH2Cl2 (3×20 mL). The combined organic layerswere dried over MgSO4 and concentrated in vacuo. The crude productwas purified by flash chromatography (hexane/ethyl acetate 10:1) togive the product 13 as an orange oil (3.42 g, 90percent); Rf (hexane/ethylacetate 6:1): 0.35; 1H NMR (300 MHz, CDCl3): δ 7.14 (1H, dd, J=2.1,10.5 Hz), 7.05 (1H, d, J=8.4 Hz), 6.65 (1H, t, J=9.0 Hz), 3.72 (2H,br.s); 13C NMR (75 MHz, CDCl3): δ 151.5 (d, JCF=241.5 Hz), 133.9 (d,JCF=12.8 Hz), 127.5 (d, JCF=3.0 Hz), 118.8 (d, JCF=21.8 Hz), 117.9(d, JCF=3.8 Hz), 109.0 (d, JCF=9.0 Hz). The spectroscopic datamatched that reported in the literature.39
85.6% With tetrabutylammomium bromide In dichloromethane at 30 - 40℃; Synthesis: To a 250 mL three-necked flask were added 7.1 g (0.022 mol) of tetrabutylammonium bromide, 22.2 g (0.20 mol) of o-fluoroaniline and 50 mL of methylene chloride, stirred until all dissolved, and the controlled temperature was lower than 30 ° C (0.21 mol) of bromine was slowly added dropwise over about 30 to 60 minutes, after which the temperature of the material was raised to reflux (about 40 ° C) for about 2.5 hours. Post-treatment: The mixture was cooled to room temperature, filtered, and the filter cake was washed twice with 20 x 2 mL of dichloromethane, followed by dispersing the filter cake in 50 mL of dichloromethane and adding about 80 g of 10percent sodium hydroxide solution To pH = 7 to 8, and the organic phase was allowed to stand apart. The organic phase was washed twice with 50 x 2 mL of deionized water and the solvent was distilled off to give 34.3 g (theoretical 38 g) of 4-bromo-2-fluoroaniline.Gas chromatographic analysis showed that the product content was 94.8percent and the yield was 85.6percent.
5 g With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere; Cooling with ice Under room temperature, will be 2-fluoro aniline (3.0 g, 27.0 mmol) dissolved in DMF (15 ml) in. Under nitrogen protection and ice in a mixture obtained to the slowly dropping N-bromo succinimide (5.3 g, 29.7 mmol) of a solution of DMF (15 ml). After the completion of the dropping, the obtained reaction mixture in the 1 hour. Furthermore, the obtained mixture into ice water (100 ml) in. The resulting mixture is extracted with ethyl acetate. The resulting organic phase is concentrated under reduced pressure to obtain 5.0 g brown oily, without purification directly used for the next step reaction.
Reference: [1] Journal of Organic Chemistry, 2005, vol. 70, # 11, p. 4267 - 4271
[2] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 744 - 748
[3] Tetrahedron Letters, 2015, vol. 56, # 41, p. 5646 - 5650
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
[5] Patent: CN106905168, 2017, A, . Location in patent: Paragraph 0026-0029
[6] European Journal of Organic Chemistry, 2006, # 13, p. 2956 - 2969
[7] Synthetic Communications, 2011, vol. 41, # 1, p. 147 - 155
[8] Chemistry - A European Journal, 2017, vol. 23, # 5, p. 1044 - 1047
[9] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190
[10] Patent: US5053542, 1991, A,
[11] Patent: US5149875, 1992, A,
[12] Patent: US4328367, 1982, A,
[13] Patent: US4059434, 1977, A,
[14] Patent: US4111681, 1978, A,
[15] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0266; 0267; 0268
[16] Patent: US3958976, 1976, A,
[17] Patent: US3990880, 1976, A,
[18] Patent: US3992189, 1976, A,
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Reference: [1] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 4, p. 175 - 179
[2] Patent: WO2018/178338, 2018, A1, . Location in patent: Page/Page column 137
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  • [ 65896-11-9 ]
Reference: [1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
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  • [ 20244-61-5 ]
  • [ 367-24-8 ]
Reference: [1] Patent: US4243819, 1981, A,
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  • [ 65896-11-9 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 13, p. 2083 - 2085
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YieldReaction ConditionsOperation in experiment
74.76% at 200℃; Sealed tube Step 1:
Synthesis of 4-amino-3-fluorobenzonitrile
To a solution of 4-bromo-2-fluorobenzenamine (3 g, 15.789 mmol) in NMP (6 mL) was added copper cyanide (2.8 g, 31.578 mmol) and heated overnight at 200° C. in a sealed tube.
Progress of reaction was monitored by TLC.
After reaction completion 1, 2-diaminoethane (3 mL) and reaction mixture was poured into water.
Product was extracted with ethyl acetate and washed with 10percent 1, 2-diaminoethane solution in water and then with water.
Organic layer was dried over sodium sulphate, concentrated under reduced pressure.
Crude was purified by silica (100-200) column chromatography using 15percent ethyl acetate in hexane as eluent to give 4-amino-3-fluorobenzonitrile (1.6 g, 74.76percent) as white solid.
MS: 137.1 [M+1]
Reference: [1] Patent: US2017/291894, 2017, A1, . Location in patent: Paragraph 0533-0535
[2] Patent: US4111681, 1978, A,
[3] Patent: US4120693, 1978, A,
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Reference: [1] Patent: US5200110, 1993, A,
[2] Patent: US5238599, 1993, A,
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  • [ 105-56-6 ]
  • [ 63069-50-1 ]
Reference: [1] Organic Letters, 2012, vol. 14, # 14, p. 3644 - 3647
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YieldReaction ConditionsOperation in experiment
51.5% With hydrogenchloride; sodium nitrite In methanol; water; acetic acid; benzene (1)
sodium nitrite procedure, with water.
A solution of 96 grams (0.50 mole) of crude 4-bromo-2-fluoroaniline and 60.0 grams (1.0 mole) of glacial acetic acid in 100 ml of benzene is added dropwise over 7 hours to a mixture of 69.0 grams (1.0 mole) of sodium nitrite, 69 ml water, and 700 ml of benzene kept at 65° C.
The mixture is then allowed to stir at 65° C. overnight (12 hours) under a nitrogen atmosphere.
The cooled mixture is washed twice with 400 ml of 1 N hydrochloric acid, then heated under reflux overnight (13 hours) with 20 grams (0.36 mole) of iron powder, 250 ml of methanol, and 150 ml (1.8 moles) of concentrated hydrochloric acid.
The resultant solution is cooled and the benzene layer is washed with 490 ml of water, and evaporated at 40° C./40 mm Hg.
The resultant dark oil is distilled at 10 mm Hg pressure to obtain 64.6 grams (51.5percent) of 4-bromo-2-fluorobiphenyl as the entire distillate of boiling point mostly ~132~141° C./8 mm.
The product crystalizes on seeding.
Variations in the sodium nitrite procedure for the preparation of 4-bromo-2-fluorobiphenyl IV1 give corresponding results as shown in Table I.
51.5% With hydrogenchloride; sodium nitrite In methanol; water; acetic acid; benzene (1)
sodium nitrite procedure, with water.
A solution of 96 grams (0.50 mole) of crude 4-bromo-2-fluoroaniline and 60.0 grams (1.0 mole) of glacial acetic acid in 100 ml of benzene is added dropwise over 7 hours to a mixture of 69.0 grams (1.0 mole) of sodium nitrite, 69 ml water, and 700 ml of benzene kept at 65° C.
The mixture is then allowed to stir at 65° C. overnight (12 hours) under a nitrogen atmosphere.
The cooled mixture is washed twice with 400 ml of 1N hydrochloric acid, then heated under reflux overnight (13 hours) with 20 grams (0.36 mole) of iron powder, 250 ml of methanol, and 150 ml (1.8 moles) of concentrated hydrochloric acid.
The resultant solution is cooled and the benzene layer is washed with 490 ml of water, and evaporated at 40° C./40 mm Hg.
The resultant dark oil is distilled at 10 mm Hg pressure to obtain 64.6 grams (51.5percent) of 4-bromo-2-fluorobiphenyl as the entire distillate of boiling point mostly ~132~141° C./8 mm.
The product crystallizes on seeding.
Variations in the sodium nitrite procedure for the preparation of 4-bromo-2-fluorobiphenyl IV1 give corresponding results as shown in Table I.
Reference: [1] Patent: US4443631, 1984, A,
[2] Patent: US4518799, 1985, A,
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Reference: [1] Patent: US4542233, 1985, A,
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  • [ 71-43-2 ]
  • [ 41604-19-7 ]
Reference: [1] Journal of Chemical Research, 2012, vol. 36, # 9, p. 555 - 556
[2] Organic Preparations and Procedures International, 2009, vol. 41, # 6, p. 539 - 541
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  • [ 151-50-8 ]
  • [ 105942-08-3 ]
Reference: [1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364
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Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 16, p. 4817 - 4821
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Reference: [1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364
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  • [ 141474-37-5 ]
  • [ 65896-11-9 ]
Reference: [1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
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  • [ 65896-11-9 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 13, p. 2083 - 2085
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  • [ 196603-96-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3222 - 3226
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5104 - 5107
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YieldReaction ConditionsOperation in experiment
93% With hydrogenchloride In isopropyl alcohol for 2 h; Reflux Hydrogen chloride (6.5 M, 2.54 mL) was added to a mixture of compound 1 (4.51 g, 15.0 mmol) and 4-chloro-2-fluoroaniline (2.40 g, 16.5 mmol) in 2-propanol (160 mL), then the mixture was heated at reflux for 2 h. The mixture was cooled and solid was filtered. The solid was then washed with 2-propanol, followed by Et2O, and dried under vacuum overnight to give 2a (7.9 g, 94percent) as a white solid.
78% for 4 h; Heating / reflux A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (8. 35g, 27.8mmol) and 4- bromo-2-fluoroaniline (5.65g, 29. 7MMOL) in 2-propanol (200ML) was heated at reflux for 4 hours. The resulting precipitate was collected by filtration, washed with 2-propanol and then ether and dried under vacuum to give 7-BENZYLOXY-4- (4-BROMO-2-FLUOROANILINO)-6- methoxyquinazoline hydrochloride (9.46g, 78percent). 1H NMR Spectrum: (DMSOd6; CD3COOD) 4.0 (s, 3H); 5.37 (s, 2H); 7.35-7. 5 (M, 4H); 7.52- 7.62 (m, 4H); 7. 8 (d, 1H); 8. 14 (9s, 1H); 8.79 (s, 1H) MS-ESI: 456 [MH] + Elemental analysis: Found C 54.0 H 3.7 N 8.7 C22HI7N302BRF 0. 9HC1 Requires C 54.2 H 3.7 N 8. 6percent
74% at 80℃; for 4 h; 4-Bromo-2-fluorobenzenamine (3.1 g, 16.1 mmol, 1.10 equiv) was added to a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (4.5 g, 12 mmol, 1.00 equiv) and isopropyl alcohol (100 mL).
The solution was stirred at about 80° C. for about 4 hours.
The resulting solids were collected by filtration, the filter cake was washed with isopropyl alcohol and diethyl ether, and then dried in vacuo to give the title product as a gray solid (4.5 g, yield 74percent). LC-MS: m/z=454/456 (MH)+.
45% for 24 h; Heating / reflux (7-Benzyloxy-6-methoxyquinazolin-4-yl)-(4-bromo-2-fluorophenyl)- amine A mixture of 2-2 (7-benzyloxy-4-chloro-6-methoxyquinazoline, obtained from J. W. Pharmlab, 2.05 g, 6.81 mmol) and 4-bromo-2-fluoroaniline (3.04 g, 15.9 mmol) was heated to reflux in isopropyl alcohol (80 mL) for 24 hours. After cooling to room temperature, the mixture was made basic with sodium bicarbonate (1.0 g) in DIUF water (10 mL). The mixture was concentrated under reduced pressure and dried under high vacuum before purification by flash column chromatography on silica gel (80 g), eluting with 1-10percent methanol in dichloromethane. The procedure produced 2-3 as a light yellow solid (1.37 g, 45percent yield). (at)H NMR (300 MHz, DMSO-d6): 6 9.48 (s, 1H), 8.33 (s, 1H), 7.80 (s, 1H), 7.56-7.33 (m, 8H), 7.26 (s, 1 H), 5.26 (s, 2H), 3.94 (s, 3H). 13C NMR (75 MHz, DMSO-d6): No. 156.69, 156.46 (d, J = 249.6 Hz), 153.10,152.77, 148.92, 146.64, 136.14, 129.42, 128.37, 127.89, 127.39,126.23 (d, J = 12.0 Hz), 119.21 (d, J = 23.2 Hz), 117.45 (d, J = 9.0 Hz), 108.65, 108.22, 101.91, 69.92,56.12.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3222 - 3226
[2] Patent: WO2005/13998, 2005, A1, . Location in patent: Page/Page column 75
[3] Patent: US2010/75916, 2010, A1, . Location in patent: Page/Page column 16
[4] Patent: WO2005/97134, 2005, A2, . Location in patent: Page/Page column 16-17; figure 2
[5] Patent: US2009/238808, 2009, A1,
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
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YieldReaction ConditionsOperation in experiment
62% for 2 h; Reflux The compound obtained in <Step 6> was dissolved in isopropanol (50 mL), 4- bromo-2-fluorophenylamine (3.22g, 16.94 mmol) was added thereto, and the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature, filtered, and the resulting solid was filtered to obtain the title compound as a brown solid (4.0g, 62percent). NMR(300 MHz, CDC13):+, m/z): 454[M+H]+
Reference: [1] Patent: WO2012/30160, 2012, A2, . Location in patent: Page/Page column 52
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389
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  • [ 321436-06-0 ]
Reference: [1] Patent: US2011/112067, 2011, A1,
[2] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 788 - 796
[3] Patent: WO2009/135651, 2009, A1,
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  • [ 133059-44-6 ]
Reference: [1] Patent: US2017/291894, 2017, A1,
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  • [ 262444-42-8 ]
Reference: [1] Patent: US2002/156081, 2002, A1,
[2] Patent: US6921763, 2005, B2,
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  • [ 262444-42-8 ]
Reference: [1] Patent: WO2007/147574, 2007, A1,
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  • [ 56-81-5 ]
  • [ 127827-52-5 ]
YieldReaction ConditionsOperation in experiment
44% at 140℃; for 12 h; To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml), con.sulphuric acid (9.15 ml) was added slowly and the reaction mixture was heated to 140°C. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 10-12 with 10percent sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44percent). 'H-NMR (δ ppm, CDC13, 400 MHz): 8.96 (dd, J = 4.3, 2.7 Hz, 1H), 8.15 (m, 2H), 7.81 (d, J = 9.5 Hz, 1H), 7.42 (dd, J = 8.3,4.3 Hz, 1H).
Reference: [1] Patent: WO2011/145035, 2011, A1, . Location in patent: Page/Page column 109-110
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YieldReaction ConditionsOperation in experiment
96.9%
Stage #1: With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 110℃;
Stage #2: at 95 - 140℃;
Stage #3: With ammonia In water
A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water (49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol (commercially available, for example, from Fluka) (52 ml, 720 mmol) to give a thick grey suspension. This was heated to 110 0C. 4-Bromo-2- fluoroaniline (commercially available, for example, from Fluorochem) (38 g, 200 mmol) was added portion wise over 10 min, during which the temperature rose to 95 0C. The reaction was heated to 140 0C and stirred overnight. The reaction mixture was cooled and then poured into water (1000 ml) and basified to pH 7 with aqueous ammonia (0.88 s.g., 190 ml). The brown precipitated that formed was collected by filtration and partially dried. This solid <n="50"/>(63 g) was loaded onto a Silica column (1500 ml) and eluted with EtOAc to give the title compound (43.8 g, 96.9percent) LCMS RT = 2.87 min, ES+ve m/z 226/228 [M+H]+.
88% With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 95 - 140℃; A solution of concentrated H2504 (0.63 ml, ii .82 mmoi) in H20 (0.48 ml, 26.6 mmoi) was treated with 3-Nitrohenzenesulfonic acid, sodium salt ( 0.48g. 2.132 nrniol) and glycerol (0.516 ml. 706 mmoi) to give a thick grey suspension, the mixture was heated to 110 °C. 4-Bromo2fluoroaniline was added portion wise over 10 mm, during which the temperature rose to 95 °C. The reaction was heated to 140 °C and stirred overnight. The reaction mixture was cooled and then poured into water and basified to pH 7 with aqueous ammonia. The brown precipitated that formed was collected by filtration and partially dried. This solid (0.63 g) was purified by flash column chromatography givethe 6-bromo-8-fluoroquinohne (04 g, 1770 mmoi, 88 percent yield) compound.
81.2% With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 110 - 140℃; Glycerol (14.5 g, 158 mmol) And the catalyst sodium 3-nitrobenzenesulfonate (14.2 g, 63 mmol) were added to the sulfuric acid Aqueous solution (20 mL of concentrated sulfuric acid + 15 mL of water), The mixture was heated to 110 ° C and 2-fluoro-4-bromoaniline C-1 (10 g, 52.6 mmol) was added slowly and stirred at 140 ° C overnight. After dropping to room temperature, pour into crushed ice, adjust the pH to about 8 with concentrated aqueous ammonia, extract with ethyl acetate, wash with water, Washed with saturated saline, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography to obtain 9.65 g of white solid compound C-2, yield 81.2percent
60%
Stage #1: With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 135℃;
Stage #2: With sodium hydroxide In waterCooling with ice
5.00 g (26.3 mmol) of 4-bromo-2-fluoroaniline, 5.31 g (57.89 mmol) glycerol and 9.89 g (43.94 mmol) of 3-nitrophenylsulfonic acid-sodium salt were prepared and homogenized. Then 25 ml of 70percent sulfuric acid was added dropwise. The mixture was stirred overnight at 135°C. The cooled black reaction mixture was made alkaline, cautiously and with ice cooling, with 50percent sodium hydroxide solution, and then filtered on a large bed of silica gel and kieselguhr. It was washed again with water and ethyl acetate. The phases collected were combined, then the organic phase was separated. The aqueous phase that remained was then extracted with ethyl acetate (2x). Then the organic phases thus obtained and the phase already separated previously were combined. It was dried over magnesium sulfate and the volatile components were removed in a rotary evaporator. The residue was finally purified by MPLC (Puriflash Analogix: 4OM: isohexane / ethyl acetate = 4 / 1). We obtained 3.56 g (60percent of theor.) of the target compound. IH-NMR (400 MHz, DMSO-D6): δ [ppm] = 7.70 (dd, 2H), 7.89 (dd, IH), 8.17 (s, IH), 8.44 (d, IH), 9.00 (d, IH).

Reference: [1] Patent: WO2009/50204, 2009, A1, . Location in patent: Page/Page column 15; 48-49
[2] Patent: WO2018/116072, 2018, A1, . Location in patent: Page/Page column 97; 98
[3] Patent: CN105968115, 2016, A, . Location in patent: Paragraph 0449-0451
[4] Patent: WO2010/20363, 2010, A1, . Location in patent: Page/Page column 131-132
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 4066 - 4084
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YieldReaction ConditionsOperation in experiment
97%
Stage #1: With sulfuric acid; glycerol In water at 85 - 133℃;
Intermediate 16-Bromo-8-fluoroquinoline A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water (49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol (commercially available, for example, from Fluka and/or Aldrich) (52 ml, 720 mmol) to give a thick grey suspension. This was heated to 110° C. (internal temperature was 85° C.). 4-Bromo-2-fluoroaniline (commercially available, for example, from Fluorochem and/or Aldrich) (38 g, 200 mmol) was added over 10 min in portions, during which the internal temperature rose to 95° C. The reaction was heated to 140° C. (internal temperature was 133° C.) and stirred overnight. The reaction mixture was cooled and then poured into water (1000 ml) and basified to pH 7 with aqueous ammonia (0.88 s.g, approximately 190 ml). The brown precipitate that formed was collected by filtration and partially dried. This solid (63 g) was loaded onto a column of silica (1500 ml) and eluted with EtOAc to give the title compound as a light brown solid (43.8 g, 97percent). LCMS RT=2.87 min, ES+ve m/z 226/228 [M+H]+.
Reference: [1] Patent: US2009/270355, 2009, A1, . Location in patent: Page/Page column 21
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  • [ 367-24-8 ]
  • [ 107-02-8 ]
  • [ 220513-46-2 ]
YieldReaction ConditionsOperation in experiment
22%
Stage #1: With hydrogenchloride In water; toluene at 100℃;
Stage #2: With sodium hydroxide In water
Intermediate 3
6-Bromo-8-fluoroquinoline
4-Bromo-2-fluoroaniline (commercially available, for example, from Aldrich) (5.788 g, 30.46 mmol) was dissolved in hydrochloric acid (5M, 137 ml), toluene (40 ml) and acrolein (6 ml, 91 mmol) were added. The solution was stirred at 1000C overnight. The aqueous was separated and 10M sodium hydroxide was added until the solution became basic. The compound which appeared in the shape of a powder was dissolved in dichloromethane, and the organic layer was separated, washed with water and brine. The organic layer was dried with sodium sulphate, filtered and evaporated. The sample was dissolved in dichloromethane and purified by flashmaster (100 g column, 0-100percent ethyl acetate-cyclohexane, 60 min). The pure fractions were combined and evaporated to give the title compound (1.512 g, 22percent). LCMS RT=2.87 min, ES+ve m/z 226/228 (M+H)+.
Reference: [1] Patent: WO2010/94643, 2010, A1, . Location in patent: Page/Page column 42-43
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