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Product Details of [ 60956-26-5 ]

CAS No. :60956-26-5 MDL No. :MFCD00041243
Formula : C7H6BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :KZNXALJXBRSMFL-UHFFFAOYSA-N
M.W :216.03 Pubchem ID :123546
Synonyms :

Calculated chemistry of [ 60956-26-5 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 47.93
TPSA : 45.82 Ų

Pharmacokinetics

GI absorption : High
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) : -5.41 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.85
Log Po/w (XLOGP3) : 3.11
Log Po/w (WLOGP) : 2.67
Log Po/w (MLOGP) : 1.96
Log Po/w (SILICOS-IT) : 0.8
Consensus Log Po/w : 2.08

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.48
Solubility : 0.0721 mg/ml ; 0.000334 mol/l
Class : Soluble
Log S (Ali) : -3.74
Solubility : 0.0393 mg/ml ; 0.000182 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.02
Solubility : 0.204 mg/ml ; 0.000946 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.89

Safety of [ 60956-26-5 ]

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 [ 60956-26-5 ]

* 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 [ 60956-26-5 ]
  • Downstream synthetic route of [ 60956-26-5 ]

[ 60956-26-5 ] Synthesis Path-Upstream   1~50

  • 1
  • [ 60956-26-5 ]
  • [ 4637-24-5 ]
  • [ 52415-29-9 ]
YieldReaction ConditionsOperation in experiment
36%
Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 110℃; for 1.5 h;
Stage #2: With acetic acid; zinc In water at 75 - 85℃; for 5.5 h;
Step A: To a solution of 4-bromo-2-nitrotoluene (7.9 g, 36.6 mmol) in dimethylformamide (73 mL) were added N,N-dimethylformamide dimethylacetal (14.5 mL, 110 mmol) and pyrrolidine (4.7 mL), and the mixture was heated at 110° C. for 90 minutes. The cooled reaction mixture was diluted with diethyl ether, and washed with water. The aqueous layer was re-extracted with diethyl ether twice, and the combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in aqueous acetic acid (245 mL, 80percent), and heated to 75° C. Zinc powder (20.8 g, 318 mmol) was added to the hot solution in small portions over 2 hours. The reaction mixture was then heated at 85° C. for 3 hours and 30 minutes, cooled to room temperature and then to 0° C. The precipitate formed was removed by filtration, and the filtrate was diluted with ethyl acetate and washed with water twice. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate, then 90:10 hexanes/ethyl acetate) to give 6-bromoindole as a grey solid (2.61 g, 36percent): 1H NMR (500 MHz, CDCl3) δ 8.14 (br s, 1H), 7.53 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.15 (m, 1H), 6.53-6.51 (m, 1H).
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6812 - 6820
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[4] Tetrahedron, 1999, vol. 55, # 4, p. 935 - 942
[5] Patent: US2011/46370, 2011, A1, . Location in patent: Page/Page column 10
[6] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 2
  • [ 123-75-1 ]
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  • [ 4637-24-5 ]
  • [ 52415-29-9 ]
Reference: [1] Tetrahedron, 1992, vol. 48, # 14, p. 2919 - 2924
[2] Patent: US5252732, 1993, A,
[3] Patent: US5310901, 1994, A,
[4] Patent: US5349061, 1994, A,
  • 3
  • [ 25408-61-1 ]
  • [ 60956-26-5 ]
  • [ 52415-29-9 ]
Reference: [1] Patent: EP1859798, 2015, B1, . Location in patent: Paragraph 0144
  • 4
  • [ 60956-26-5 ]
  • [ 52415-29-9 ]
Reference: [1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 2, p. 160 - 167
[2] Tetrahedron, 2002, vol. 58, # 39, p. 7851 - 7861
[3] Journal of the American Chemical Society, 1987, vol. 109, p. 3378
[4] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5106 - 5110
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 1679 - 1680
[6] Chinese Chemical Letters, 2010, vol. 21, # 8, p. 889 - 891
[7] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 5
  • [ 60956-26-5 ]
  • [ 77185-71-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 5, p. 1085 - 1090
[2] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 5, p. 1085 - 1090
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5789 - 5807
  • 6
  • [ 60956-26-5 ]
  • [ 103858-53-3 ]
Reference: [1] Patent: KR101741956, 2017, B1,
  • 7
  • [ 60956-26-5 ]
  • [ 1196-70-9 ]
Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5106 - 5110
[2] Patent: EP1859798, 2015, B1,
  • 8
  • [ 60956-26-5 ]
  • [ 17826-04-9 ]
Reference: [1] Chinese Chemical Letters, 2010, vol. 21, # 8, p. 889 - 891
  • 9
  • [ 60956-26-5 ]
  • [ 51436-99-8 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
  • 10
  • [ 60956-26-5 ]
  • [ 5551-12-2 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: at 0 - 10℃; for 1 h;
Stage #2: With sodium carbonate In water
Stage #3: With hydrogenchloride; water In ethanol for 0.75 h;
[000194] Step A: To a solution of 4-bromo-l-methyl-2-nitrobenzene (300 g, 1.38 mol) in acetic anhydride (2400 mL) at 0 °C, was added slowly concentrated sulfuric acid (324 ml), followed by a solution of chromium tri oxide (384 g, 3.84 mole) in acetic anhydride (2160 ml).The internal temperature was controlled below 10 °C. After stirring for lh, the contents in the flask were poured into a mixture of ice and water. The solid was filtered and washed with water until the washings were colorless. The product was suspended in 1800 ml of 2percent aqueous sodium carbonate solution with stirring. After thorough mixing, the solid was filtered and washed with water and dried under reduced pressure.[000195] A suspension of the diacetate in a mixture of 1360 ml of concentrated hydrochloric acid, 1250 ml of water, and 480 ml of ethanol was refluxed for 45 minutes. The mixture was then cooled to room temperature and the solid was filtered and washed with water. 4-bromo-2- nitrobenzaldehyde (147 g, 45percent for two steps) was afforded as a brown solid without further purification.
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[3] Organic Preparations and Procedures International, 2006, vol. 38, # 3, p. 325 - 331
[4] Synthetic Communications, 2001, vol. 31, # 23, p. 3721 - 3727
[5] Heterocycles, 1994, vol. 39, # 2, p. 767 - 778
[6] Journal of the Chemical Society, 1945, p. 167
[7] Journal fuer Praktische Chemie (Leipzig), 1935, vol. <2> 142, p. 35
[8] Patent: WO2011/22509, 2011, A2,
[9] Patent: WO2011/22508, 2011, A2,
[10] Patent: WO2011/22508, 2011, A2,
[11] Patent: WO2011/22509, 2011, A2,
[12] Patent: WO2012/97177, 2012, A2,
[13] Patent: WO2016/96778, 2016, A1,
[14] Patent: WO2017/46112, 2017, A1,
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Reference: [1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
  • 12
  • [ 106-38-7 ]
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Reference: [1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[3] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[4] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[5] Journal of the American Chemical Society, 1953, vol. 75, p. 3275
  • 13
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Reference: [1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
  • 14
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  • 15
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Reference: [1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
  • 16
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  • 17
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  • [ 53078-85-6 ]
Reference: [1] Patent: WO2003/99275, 2003, A1, . Location in patent: Page 52
  • 18
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  • [ 20776-50-5 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[2] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[3] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
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  • 20
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Reference: [1] Journal of the Chemical Society, 1926, p. 1803
  • 21
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  • [ 6127-11-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 2, p. 421 - 426
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
  • 22
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  • [ 95-92-1 ]
  • [ 6127-11-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1966, vol. 3, p. 95 - 97
  • 23
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Reference: [1] Organic Letters, 2012, vol. 14, # 15, p. 3870 - 3873
[2] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[3] Journal of the Chemical Society, 1929, p. 1255
[4] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 694[5] Recueil des Travaux Chimiques des Pays-Bas, 1929, vol. 48, p. 1137
[6] Journal fuer Praktische Chemie (Leipzig), 1935, vol. <2> 142, p. 35
[7] Justus Liebigs Annalen der Chemie, 1871, vol. 158, p. 339
[8] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
[9] Journal of the American Chemical Society, 1987, vol. 109, p. 3378
  • 24
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Reference: [1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
  • 25
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Reference: [1] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
  • 26
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  • 27
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  • [ 55289-35-5 ]
Reference: [1] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[2] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[3] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[4] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[5] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
  • 28
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Reference: [1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[3] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[4] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[5] Journal of the American Chemical Society, 1953, vol. 75, p. 3275
  • 29
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  • 30
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  • 31
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  • [ 75508-75-7 ]
Reference: [1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
  • 32
  • [ 106-38-7 ]
  • [ 108-24-7 ]
  • [ 5326-34-1 ]
  • [ 60956-26-5 ]
  • [ 75508-75-7 ]
Reference: [1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
  • 33
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  • [ 52414-97-8 ]
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Reference: [1] Journal of the Chemical Society, 1926, p. 1803
  • 34
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  • 35
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Reference: [1] Justus Liebigs Annalen der Chemie, 1871, vol. 158, p. 340
  • 36
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  • [ 7647-18-9 ]
  • [ 7726-95-6 ]
  • [ 60956-26-5 ]
  • [ 55289-35-5 ]
Reference: [1] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
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Reference: [1] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
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Reference: [1] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[2] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[3] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[4] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
[5] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
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Reference: [1] Journal of the University of Bombay, Science: Physical Sciences, Mathematics, Biological Sciences and Medicine, 1942, vol. 10/5, p. 99
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Reference: [1] Journal of the American Chemical Society, 2002, vol. 124, # 50, p. 14844 - 14845
  • 42
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  • [ 350-28-7 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
  • 43
  • [ 60956-26-5 ]
  • [ 99277-71-1 ]
YieldReaction ConditionsOperation in experiment
32.8%
Stage #1: With potassium permanganate In pyridine; water at 60℃; for 32 h;
Stage #2: for 0.5 h; Heating / reflux
1.1.a.
4-Bromo-2-nitro-benzoic acid
To a reaction mixture of 82 g (0.379 mol) 4-bromo-2-nitro-toluene in 700 ml of pyridine and 500 ml of water are added batchwise 174.5 g (1.104 mol) of potassium permanganate within eight hours.
The reaction mixture is stirred for 12 hours at 60° C. Then a further 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are added one after another.
The reaction mixture is stirred for 12 hours at 60° C., combined with 200 ml of ethanol and refluxed for 30 minutes.
Then the reaction mixture is filtered hot and the filtrate is evaporated down in the rotary evaporator.
The residue remaining is made alkaline with 10percent sodium hydroxide solution and extracted with diethyl ether.
The aqueous phase is separated off and acidified with dilute hydrochloric acid.
The crystals formed are filtered off, washed with water, azeotropically dried with tetrahydrofuran and stirred with diisopropylether.
26% With potassium permanganate; sodium carbonate In water at 105℃; Heating / reflux Sodium carbonate (4.53 g, 42 mmol) was added to a suspension of 4-bromo-2- nitrotoluene (2.00 g, 9.26 mmol) in 140 mL of water. The mixture was heated to 80°C. Potassium permanganate (5.85 g, 37 mmol) was added and the temperature was raised to 105°C and heating was continued under a reflux condenser overnight. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was acidified with 6N aqueous HCI and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 0.59 g (26percent yield) of desired product as a beige solid.
22% With potassium permanganate In waterHeating / reflux A. 4-bromo-2-nitrobenzoic acid A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with water. The basic filtrate was acidified to pH1 with concentrated HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide pure benzoic acid (1.22 g, 22percent). 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). MS (ESI): neg. ion m/z 244 [M-H]-.
22%
Stage #1: With potassium permanganate In waterHeating / reflux
Stage #2: With hydrogenchloride In water
A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (1 g, 70 mmol), and H2O (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with H2O. The basic filtrate was acidified to pH 1 with concentrated HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure benzoic acid (1.22 g, 22percent). MS (ESI) calculated for C7H4BrNO4, 244.9; found, m/z 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H).
22% Heating / reflux A. 4-Bromo-2-nitrobenzoic acid. ; A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight. The mixture was filtered through a pad of diatomaceous earth, washing with water. The basic filtrate was acidified to pH1 with conc. HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated to provide the desired benzoic acid (1.22 g, 22percent). MS (ESI-): mass calcd. for C7H4BrNO4, 244.9; m/z found, 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9, 1H), 7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).

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[8] Journal of the Chemical Society, 1926, p. 1803
[9] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[10] Journal of the American Chemical Society, 1952, vol. 74, p. 5621
[11] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
[12] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6905 - 6909
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  • 45
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  • [ 39478-78-9 ]
YieldReaction ConditionsOperation in experiment
93% With stannous chloride hydrate In ethyl acetate at 30℃; First, into a 250-mL round-bottom flask, was placed 4-bromo-1-methyl-2-nitrobenzene (5 g, 23.14 mmol, 1.00 equiv), ethyl acetate (100 mL), SnCl2.H2O (20 g). The resulting solution was stirred overnight at 30° C. The pH value of the solution was adjusted to 10 with sodium hydroxide (5 mol/L). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4 g (93percent) of 5-bromo-2-methylaniline as brown oil.
92% With iron; ammonium chloride In water for 48.5 h; Heating / reflux The mixture of iron powder (9. 31g, 167 mmol) and [NH4C1] (2.48g, 46.3 mmol) in water (50 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-2-nitrotoluene (10 g, 46.3 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3 x 100 mL). The organic solution was washed with [H20] (3 x 200 mL) and brine (200 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 15percent EtOAc in hexanes) to give 7.9g (92percent) of title compound as a pale yellow [OIL.APOS;H] nuclear magnetic resonance (NMR) [(CDC13)] : 300 MHz [6] 6.88 (m, [1H),] 6.81 (m, 2H), 3.63 (bs, 2H), 2.09 (s, 3H).
80.7% With tin(ll) chloride In ethyl acetate at 0 - 80℃; for 4.16667 h; Example 1 5-BROMO-8-METHYL-1-PROPYL-3, 4-DIHYDRO-LH-BENZOTHIENO [2, 3-CLPYRAN-1- yl] acetic acid 5-BROMO-2-METHYLANILINE [0082] 4-bromo-2-nitrotoluene (25.0 g, 0.1157 mol) in EtOAc (250 mL) was cooled to 0°C. Tin (IN chloride dihydrate (87.76 g, 0.4623 mol) was then added portionwise over 10 min while stirring. The reaction mixture was allowed to come to room temperature and then refluxed at 80°C for 4 h. The mixture was cooled to 0°C and neutralized with 5 N NAOH while stirring. EtOAc layer was filtered and remaining portions were extracted with EtOAc. The organic solution was washed with brine, dried with Na2SO4, and concentrated. The residue was purified by flash chromatography (silica, 10percent ETOAC in hexanes) to give 17. 367 g (80.7percent) of the ANILINE.
Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 19, p. 3116 - 3127
[2] Patent: US2015/366198, 2015, A1, . Location in patent: Paragraph 0132
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 26, p. 6603 - 6608
[4] Patent: WO2003/99824, 2003, A1, . Location in patent: Page 23
[5] Patent: US6337351, 2002, B1, . Location in patent: Example 14
[6] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[7] Patent: WO2005/16932, 2005, A1, . Location in patent: Page/Page column 33
[8] Journal of Chemical Research - Part S, 2000, # 6, p. 290 - 291
[9] Synlett, 1998, # 9, p. 1028 - 1028
[10] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 9, p. 955 - 977
[11] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1869, vol. 69, p. 477[12] Zeitschrift fuer Chemie, 1869, p. 636
[13] Justus Liebigs Annalen der Chemie, 1870, vol. 154, p. 294
[14] Justus Liebigs Annalen der Chemie, 1871, vol. 158, p. 340
[15] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[16] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[17] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[18] Helvetica Chimica Acta, 1946, vol. 29, p. 872,876
[19] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 34
[20] ChemMedChem, 2016, vol. 11, # 23, p. 2607 - 2620
[21] Patent: WO2018/52903, 2018, A1, . Location in patent: Page/Page column 81
  • 46
  • [ 60956-26-5 ]
  • [ 7439-89-6 ]
  • [ 39478-78-9 ]
Reference: [1] Patent: US6300352, 2001, B1,
  • 47
  • [ 60956-26-5 ]
  • [ 59278-65-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
  • 48
  • [ 60956-26-5 ]
  • [ 82420-34-6 ]
YieldReaction ConditionsOperation in experiment
54% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 18 h; Reflux (1) Production of 4-bromo-1-(bromomethyl)-2-nitrobenzene (0145) To carbon tetrachloride (100 mL) were added 2-nitro-6-bromotoluene (25.0 g, 116 mmol), N-bromosuccinimide (28.2 g, 162 mmol), and 2,2-azobis(2-methylpropionitrile) (1.90 mg, 11.6 mmol) to cause the reactants to react with each other for 18 hours while the reaction system was refluxed. Thereafter, the reaction liquid was filtrated, and the resultant filtrate was concentrated under a reduced pressure. The resultant was purified through silica gel column chromatography (AcOEt/n-hexane = 1/9) to yield 18.5 g (54percent) of the target compound. 1H-NMR (CDCl3); 4.78 (s, 2H, CH2), 7.46 (d, J=8.0, 1H, Ar), 7.74 (dd, J =2.0, 8.1, 1H, Ar), 8.18 (d, J =1.7, 1H, Ar).
48.8% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 76℃; for 16 h; Inert atmosphere To a mixture of 4-bromo-1-methyl-2-nitro-benzene (60 g, 277 mmol, 1.0 eq) and NBS (59.3 g, 333 mmol, 1.2 eq) in CC14(600 mL) was added AIBN (5.47 g, 33.3 mmol, 0.12 eq) at rt under N2. The mixture was stirred at 76°C for 16 h. The reaction mixture was filtered and the filtrate was washed with 2M NaHC03(2 x 250 ml) and brine (400 ml), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0~5percent EtOAc/PE) to provide 4-bromo-l-(bromomethyl)-2-nitro-benzene (40 g, 135 mmol, 48.8percent yield) as a yellow solid. 1HNMR (400 MHz, CDC13) δ ppm: 8.19 (d, J=1.6 Hz, 1H), 7.75 (dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 4.78 (s, 2H).
Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 401 - 406
[2] Organic Letters, 2012, vol. 14, # 15, p. 3870 - 3873
[3] Patent: EP2907818, 2015, A1, . Location in patent: Paragraph 0145
[4] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 20, p. 6574 - 6595
[5] Heterocycles, 1994, vol. 39, # 2, p. 767 - 778
[6] Patent: WO2017/149313, 2017, A1, . Location in patent: Page/Page column 47
[7] Patent: US2009/226398, 2009, A1,
[8] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 602 - 606
  • 49
  • [ 60956-26-5 ]
  • [ 642494-36-8 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6812 - 6820
[2] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6812 - 6820
  • 50
  • [ 60956-26-5 ]
  • [ 1826-67-1 ]
  • [ 936092-87-4 ]
YieldReaction ConditionsOperation in experiment
43% at -40℃; for 0.666667 h; Inert atmosphere A solution of 4-bromo-1 -methyl-2-nitrobenzene (1 1 .57 mmol, 2.5 g) in THF (1 16 mL) under nitrogen atmosphere was cooled to -40 5C and vinylmagnesium bromide (46.28 mmol, 46 mL) was added. The reaction mixture was stirred for 40 min and quenched with saturated aqueous NH4CI. The aqueous layer was extracted with ethyl acetate twice and the combined organic layers were dry with Na2S04, filtered and concentrated. The crude product thus obtained was dissolved in THF (35 mL) and cooled to 0 5C. 0.5 N HCI (4.4 mL) was added and the reaction mixture stirred at 05C for 1 h, when it was quenched with NaHC03 (44 mL). The aqueous layer was extracted with ethyl acetate twice and the combined organic extracts were dried with Na2S04, filtered and concentrated. Purification of the crude material by flash chromatography on silica gel using an elution of 1 1 percent ethyl acetate in hexanes afforded the pure title compound (1 .05 g. Yield: 43percent) 1 H NMR (400 MHz, CDCI3) δ 8.21 (1 H, brs), 7.28-7.26 (1 H, m), 7.21 (1 H, d, J = 7.2 Hz), 6.87 (1 H, d, J = 6.8 Hz), 6.63-6.61 (1 H, m), 2.47 (3H, s). LC-MS: tR = 3.58 [M+H]+=not ion (method 3)
43%
Stage #1: at -40℃; for 0.666667 h; Inert atmosphere
Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃; for 1 h;
A solution of 4-bromo-1-methyl-2-nitrobenzene (11.57 mmol, 2.5 g) in THF (116 mL) under nitrogen atmosphere was cooled to −40 °C and vinyl magnesium bromide (46.28 mmol, 46 mL) was added. The reaction mixture was stirred for 40 min and quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with ethyl acetate twice and the combined organic layers were dried with Na2SO4, filtered and concentrated. The crude product thus obtained was dissolved in THF (35 mL) and cooled to 0 °C. 0.5 N HCl (4.4 mL) was added and the reaction mixture was stirred at 0 °C for 1 h, then it was quenched with NaHCO3 (44 mL). The aqueous layer was extracted with ethyl acetate twice and the combined organic extracts were dried with Na2SO4, filtered and concentrated. Purification of the crude material by flash chromatography over silica gel using an elution of 11percent ethyl acetate in hexanes afforded 1.05 g (Yield: 43percent) of the pure title compound 25. 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, brs), 7.28-7.26 (1H, m), 7.21 (1H, d, J = 7.2 Hz), 6.87 (1H, d, J = 6.8 Hz), 6.63-6.61 (1H, m), 2.47 (3H, s).
Reference: [1] Patent: WO2013/149997, 2013, A1, . Location in patent: Page/Page column 120-121
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 9, p. 1117 - 1130
[3] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 93
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