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Product Details of [ 24596-19-8 ]

CAS No. :24596-19-8 MDL No. :MFCD00007826
Formula : C8H10BrN Boiling Point : -
Linear Structure Formula :- InChI Key :QGLAYJCJLHNIGJ-UHFFFAOYSA-N
M.W : 200.08 Pubchem ID :90549
Synonyms :

Calculated chemistry of [ 24596-19-8 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 0
Num. H-bond acceptors : 0.0
Num. H-bond donors : 1.0
Molar Refractivity : 48.48
TPSA : 26.02 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) : -5.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.15
Log Po/w (XLOGP3) : 2.66
Log Po/w (WLOGP) : 2.66
Log Po/w (MLOGP) : 2.88
Log Po/w (SILICOS-IT) : 2.7
Consensus Log Po/w : 2.61

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.2
Solubility : 0.126 mg/ml ; 0.000631 mol/l
Class : Soluble
Log S (Ali) : -2.86
Solubility : 0.278 mg/ml ; 0.00139 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.67
Solubility : 0.0428 mg/ml ; 0.000214 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.19

Safety of [ 24596-19-8 ]

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

Application In Synthesis of [ 24596-19-8 ]

* 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 [ 24596-19-8 ]
  • Downstream synthetic route of [ 24596-19-8 ]

[ 24596-19-8 ] Synthesis Path-Upstream   1~22

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Reference: [1] Bulletin of the Chemical Society of Japan, 1971, vol. 44, p. 2248 - 2253
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  • [ 556-96-7 ]
YieldReaction ConditionsOperation in experiment
51%
Stage #1: With sulfuric acid In ethanol at -10 - 20℃; for 1 h;
Stage #2: With sodium nitrite In ethanol; water for 1.5 h;
Stage #3: With copper In ethanol; water at 20℃;
97 ml (1.82 mol) of96percent sulfuric acid was added dropwise to a solution of134.7 g (ca. 673 mmol) of 4-bromo-2,6-dimethylaniline (prepared above, purity ca.90percent) in 1400 ml of95percent ethanol cooled to -10°C, at a such a rate to maintain the reaction temperature below 7°C. After the addition was complete, the solution wasstirred at room temperature for 1 h. Then, the reaction mixture was cooled in an icebath,and a solution of72.5 g (1.05 mol) of sodium nitrite in 150 ml of water wasadded dropwise over ca. 1 h. The formed solution was stirred at the sametemperature for 30 min. Then the cooling bath was removed, and 18 g of copper powder was added. Upon completion of the rapid evolution of nitrogen additionalportions (ca. 5 g each, ca. 50 g in total) of copper powder were added with 10 minintervals until gas evolution ceased completely. The reaction mixture was stirred atroom temperature overnight, then filtered through a glass frit (G3), diluted with twofoldvolume of water, and the crude product was extracted with 4 x 150 ml of dichloromethane. The combined extract was dried over K2C03, evaporated todryness, and then distilled in vacuum (b.p. 60-63°C/5 mm Hg) to give a yellowishliquid. This product was additionally purified by flash-chromatography on silica gel60 (40-63 )lm; eluent: hexane) and distilled once again (b.p. 51-52°C/3 mm Hg) togive 63.5 g (51percent) of 1-bromo-3,5-dimethylbenzene as a colorless liquid. 1H NMR (CDCh): b 7.12 (s, 2H), 6.89 (s, IH), 2.27 (s, 6H). 13CeH} NMR(CDCh): b 139.81, 129.03, 128.61, 122.04, 20.99.
Reference: [1] Patent: WO2018/91684, 2018, A1, . Location in patent: Page/Page column 49; 50
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YieldReaction ConditionsOperation in experiment
88% With N-Bromosuccinimide In neat (no solvent) at 20℃; for 1 h; Milling; Green chemistry General procedure: 1-Methoxy-3,5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetate and cooled at 0 °C. The product was isolated as filtrate upon paper filtration and waste succinimide as precipitate. The resulting filtrate were concentrated in vacuo to isolate 250 mg (yield: 85percent) of 2b as colourless powder. To test the efficiency in large scale, the reaction was also performed for the mono-bromination of 1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product was isolated in 87percent yield.[1] The milling apparatus was stopped and small portion of the sample was collected from the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
88% With N-Bromosuccinimide In neat (no solvent) at 20℃; for 1 h; Milling; Green chemistry General procedure: 1-Methoxy-3,5-dimethylbenzene (100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reactionwas monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetateand cooled at 0 °C. The product was isolated as filtrate upon paper filtrationand waste succinimide as precipitate. The resulting filtrate were concentrated in vacuoto isolate 250 mg (yield: 85percent) of 2bas colourless powder. To test the efficiency in largescale, the reaction was also performed for the mono-bromination of1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product wasisolated in 87percent yield.[1] Themilling apparatus was stopped and small portion of the sample was collectedfrom the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
75% at 40℃; for 2.33333 h; 21.3 ml (66.1 g, 0.413 mol) of bromine were added dropwise, while vigorously stirring, over ca. 20 minutes to a solution of 50.0 g (0.413 mol) of 2,6-dimethylanilme in 1200 cm3 of glacial acetic acid. This mixture was stirred for 2 hours at 4O0C. The precipitate formed was filtered off, washed with 50 ml of acetic acid, and dried in air. Then, this white solid was added to a solution of 100 g of sodium hydroxide in 600 ml of water. This mixture was stirred for 30 minutes. The crude product was extracted with 3 x 100 ml of dichloromethane. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. Fractional distillation gave a yellow liquid, bp 82-85°C/l mm Hg. Yield 61.7 g (75percent).Anal. calc. for C8H10BrN: C, 48.02; H, 5.04. Found: C, 48.17; H, 5.09.1H NMR (CDCl3): δ 7.03 (s, 2H, 3,5-H), 3.51 (s, 2H, NH2), 2.10 (s, 6H, 2,6-Me).13C NMR (CDCl3): δ 141.8, 130.5, 123.6, 109.4, 17.4.
75% With sodium hydroxide; bromine In water; acetic acid 4-Bromo-2,6-dimethylaniline
21.3 ml (66.1 g, 0.413 mol) of bromine were added dropwise, while vigorously stirring, over ca. 20 minutes to a solution of 50.0 g (0.413 mol) of 2,6-dimethylaniline in 1200 cm3 of glacial acetic acid.
This mixture was stirred for 2 hours at 40° C.
The precipitate formed was filtered off, washed with 50 ml of acetic acid, and dried in air.
Then, this white solid was added to a solution of 100 g of sodium hydroxide in 600 ml of water.
This mixture was stirred for 30 minutes.
The crude product was extracted with 3*100 ml of dichloromethane.
The combined organic fractions were dried over Na2SO4 and evaporated to dryness.
Fractional distillation gave a yellow liquid, bp 82-85° C./1 mm Hg. Yield 61.7 g (75percent).
Anal. calc. for C8H10BrN: C, 48.02; H, 5.04. Found: C, 48.17; H, 5.09.
1H NMR (CDCl3): δ 7.03 (s, 2H, 3,5-H), 3.51 (s, 2H, NH2), 2.10 (s, 6H, 2,6-Me).
13C NMR (CDCl3): δ 141.8, 130.5, 123.6, 109.4, 17.4.
350 g With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; 2) 250 g of 2,6-dimethylaniline (5) and3L N, N- dimethylformamide solution was added to 5L three reaction flask,1 L of 246 g N-bromosuccinimide was slowly added dropwise at about 0 ° CN, N-dimethylformamide, and the mixture was stirred at room temperature for 2 hours.The reaction mixture was introduced into 30 L of water, extracted with 3 L of ethyl acetate twice,The organic phase was washed with 2 L saturated brine, dried over anhydrous sodium sulfate, filtered,Dried to afford 350 g of 2,6-dimethyl-4-bromoaniline (6) as a yellow solid.350 g of product (6), 268 g of potassium acetate, 364 g of bis (pinacolato) diboron, 50 g of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride and 4L of 1,4-bis Oxygen ring, 400mL water was added 5L three-necked flask, nitrogen protection, heating to 80 ° C continued stirring 15h. After the temperature was lowered to room temperature, the mixture was filtered and spin-dried to obtain 414 g of a brown solid borate (7); 332 g of the product (6), 414 g of the product (7), 667 g of cesium carbonate and 50 g of [1,1'- Yl) ferrocene] palladium dichloride, 4L 1,4-dioxane was added to a 5L three-necked flask and heated to 75 ° C under a nitrogen atmosphere for 16 hours. After the temperature was lowered to room temperature, it was filtered and the filtrate was washed with 2 L of water, dried over anhydrous sodium sulfate, filtered and spun dry. Recrystallization from 2 L ethyl acetate: petroleum ether = 1: 4 (volume ratio) solution gave the 210 g white crystals of 2,2 ', 6,6'-tetramethylbiphenylenediamine (8).

Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 51, p. 8959 - 8963
[2] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[3] Synthetic Communications, 2010, vol. 40, # 5, p. 647 - 653
[4] Synthetic Communications, 2009, vol. 39, # 23, p. 4212 - 4220
[5] Journal fuer Praktische Chemie (Leipzig), 1988, vol. 330, # 2, p. 161 - 174
[6] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2154 - 2156
[7] Tetrahedron Letters, 2015, vol. 55, # 13, p. 2154 - 2156
[8] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[9] Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 2001, vol. 498, # 1-2, p. 19 - 37
[10] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 2, p. 597 - 599
[11] Journal of Organic Chemistry, 2012, vol. 77, # 23, p. 10856 - 10869
[12] Patent: WO2007/70040, 2007, A1, . Location in patent: Page/Page column 119
[13] Journal of the Chemical Society, 1927, p. 1106
[14] Chemische Berichte, 1900, vol. 33, p. 1973
[15] Chemische Berichte, 1901, vol. 34, p. 2255
[16] Bulletin of the Chemical Society of Japan, 1971, vol. 44, p. 2248 - 2253
[17] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 3, p. 818 - 820
[18] Journal of Organic Chemistry, 1980, vol. 45, # 19, p. 3892 - 3902
[19] South African Journal of Chemistry, 2006, vol. 59, p. 125 - 128
[20] Patent: US2007/135594, 2007, A1,
[21] Chemical Communications, 2011, vol. 47, # 16, p. 4814 - 4816
[22] Patent: CN106810506, 2017, A, . Location in patent: Paragraph 0039
[23] Patent: WO2018/91684, 2018, A1, . Location in patent: Page/Page column 49
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YieldReaction ConditionsOperation in experiment
64% With potassium hydroxide In dimethyl sulfoxide at 140℃; for 8 h; Green chemistry General procedure: A reaction tube was charged with the 2-aryloxypropanamide (1.0 mmol), potassium hydroxide (112 mg, 2.0 mmol), DMSO (3 mL) and 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU 1 mL).The mixture was heated at 140 C for 3-16 h. The reaction was monitored by TLC. After the reaction period, the reaction mixture was cooled, diluted with saturated brine and extracted with dichloromethane three times. The combined organic layers were washed with three portions of saturated brine and then dried over MgSO4 and filtered. Solvent was removed under reduced pressure. The product was purified through flash column chromatography on 300-400 mesh silica gel with petroleum ether/ethyl acetate as eluent.
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 24, p. 3167 - 3170
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  • [ 3096-70-6 ]
  • [ 87-62-7 ]
Reference: [1] Canadian Journal of Chemistry, 1996, vol. 74, # 7, p. 1321 - 1328
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Reference: [1] Chemische Berichte, 1900, vol. 33, p. 1973
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Reference: [1] Chemische Berichte, 1901, vol. 34, p. 2255
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Reference: [1] Canadian Journal of Chemistry, 1996, vol. 74, # 7, p. 1321 - 1328
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YieldReaction ConditionsOperation in experiment
72%
Stage #1: With hydrogen bromide; sodium nitrite In water at -10℃; for 1 h;
Stage #2: With ferrous(II) sulfate heptahydrate; aminosulfonic acid; hydrogen bromide In water at 80℃; for 1 h;
4-Bromo-2,6-dimethylaniline (6.00 g, 30 mmol) was suspended in 48percent HBr aqueous solution (20 mL), NaNO 2 (2.28 g, 33 mmol) dissolved in water at -10 ° C. was added and stirred for 1 hour And sulfamic acid (0.58 g, 6 mmol) was added. This was treated with FeSO 4 .7H 2 O (4.17 g, 15 mmol) in 48percent HBr aqueous solution (20 mL) and heated gradually to 80 ° C., and the mixture was stirred at 80 ° C. for 1 hour. Water was added to the mixture, the mixture was extracted with hexane, and the organic phase was dried with anhydrous Na 2 SO 4, then the solvent was removed under reduced pressure. Purification with medium pressure (silica gel, hexane) gave 2,5-dibromo-m-xylene (6.19 g, 72percent yield).
72%
Stage #1: With hydrogen bromide; sodium nitrite In water at -10℃; for 1 h;
Stage #2: With ferrous(II) sulfate heptahydrate; aminosulfonic acid; hydrogen bromide In water at 80℃; for 1 h;
4-Bromo-2,6-dimethylaniline (6.00 g, 30 mmol) was suspended in 48percent HBr aqueous solution (20 mL), NaNO 2 (2.28 g, 33 mmol) dissolved in water at -10 ° C. was added and stirred for 1 hour And sulfamic acid (0.58 g, 6 mmol) was added. This was treated with FeSO 4 .7H 2 O (4.17 g, 15 mmol) in 48percent HBr aqueous solution (20 mL) and heated gradually to 80 ° C., and the mixture was stirred at 80 ° C. for 1 hour. Water was added to the mixture, the mixture was extracted with hexane, and the organic phase was dried with anhydrous Na 2 SO 4, then the solvent was removed under reduced pressure. Purification with medium pressure (silica gel, hexane) gave 2,5-dibromo-m-xylene (6.19 g, 72percent yield).
Reference: [1] Journal of the American Chemical Society, 2018, vol. 140, # 18, p. 5925 - 5933
[2] Patent: JP2018/90535, 2018, A, . Location in patent: Paragraph 0072; 0073; 0082; 0083
[3] Patent: JP2018/90536, 2018, A, . Location in patent: Paragraph 0098; 0099; 0100; 0101
[4] Journal of Porphyrins and Phthalocyanines, 2010, vol. 14, # 9, p. 804 - 814
[5] Journal of Organic Chemistry, 2012, vol. 77, # 4, p. 2074 - 2079
[6] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 175[7] Recueil des Travaux Chimiques des Pays-Bas, 1909, vol. 28, p. 93
[8] Bulletin of the Chemical Society of Japan, 1971, vol. 44, p. 2248 - 2253
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Reference: [1] Journal of Organic Chemistry, 1980, vol. 45, # 19, p. 3892 - 3902
[2] Journal of the American Chemical Society, 1941, vol. 63, p. 1679,1681
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  • [ 4198-90-7 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 23, p. 10856 - 10869
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  • [ 54827-17-7 ]
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YieldReaction ConditionsOperation in experiment
63.3% With sodium formate; cetyltrimethylammonim bromide In water EXAMPLE 8
4-Bromo-2,6-dimethylaniline (24.0 parts), 3percent palladium on charcoal (50percent paste; 2.0 parts), cetyltrimethylammonium bromide (4.0 parts), sodium hydroxide liquor (32percent; 13.5 parts), sodium formate (6.8 parts) in water (60 parts) are stirred at the boil under reflux for 3 hours.
Sodium formate (6.8 parts is then added and the mixture boiled for 3 hours when a further charge of sodium formate (6.8 parts) is made.
The reaction mixture is then held at the boil under reflux for a further 23 hours.
The mixture is then steam distilled and from the distillate 2.2 parts (18.2percent) of 2,6-dimethylaniline is recovered by extraction with ether.
The reaction mixture after steam distillation is cooled to room temperature and then filtered.
The residue is extracted continuously with methanol (60 parts) for 5 hours and then the extract cooled.
The colourless crystalline precipitate is filtered off and dried to give 7.7 parts (63.3percent) of 3,3',5,5'-tetramethyl benzidine.
Reference: [1] Patent: US4022795, 1977, A,
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YieldReaction ConditionsOperation in experiment
210 g With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 75℃; for 16 h; Inert atmosphere 2) 250 g of 2,6-dimethylaniline (5) and3L N, N- dimethylformamide solution was added to 5L three reaction flask,1 L of 246 g N-bromosuccinimide was slowly added dropwise at about 0 ° CN, N-dimethylformamide, and the mixture was stirred at room temperature for 2 hours.The reaction mixture was introduced into 30 L of water, extracted with 3 L of ethyl acetate twice,The organic phase was washed with 2 L saturated brine, dried over anhydrous sodium sulfate, filtered,Dried to afford 350 g of 2,6-dimethyl-4-bromoaniline (6) as a yellow solid.Next, 350 g of the product (6), 268 g of potassium acetate,364 g of bis (pinacolato) diboron, 50 g[1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride,4L1,4 - dioxane, 400mL water was added 5L three-necked flask, nitrogen protection,Heated to 80 stirring continued 15h. After falling to room temperature, filtration,Dried to give 414g brown solid boric acid ester (7);332 g of product (6),414 g product (7) 667 g cesium carbonate,50 g of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride,4L 1,4-dioxane was added 5L three-necked flask, a nitrogen atmosphere,Heat to 75 ° C and continue stirring for 16h. After falling to room temperature, filtration,The filtrate was washed with 2 L of water, dried over anhydrous sodium sulfate, filtered and spun dry.Recrystallized from 2 L ethyl acetate: petroleum ether = 1: 4 (volume ratio) solution,The solid was filtered off to give 210 g of white crystals2,2 ', 6,6'-tetramethylbiphenylenediamine(8).
Reference: [1] Patent: CN106810506, 2017, A, . Location in patent: Paragraph 0039
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Reference: [1] Patent: CN106810506, 2017, A,
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YieldReaction ConditionsOperation in experiment
86% at 160℃; The mixture of 4-bromo-2,6-dimethylaniline (1.90 g, 9.50 mmol) and copper (I) cyanide (1.71 g, 19.1 mmol) in NMP (25 mL) was stirred at 160° C. overnight. The reaction mixture was cooled to room temperature. Water (10 mL) and ammonium hydroxide (10 mL) were added and the product was extracted with ethyl acetate (2.x.50 mL). The product was purified by flash chromatography (DCM) to give 1.19 g (86percent, theoretical yield 1.39 g). LCMS (method B) RT 1.925 min., MH+ 147. 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 2H), 2.18 (s, 6H).
35% at 200℃; for 1 h; Microwave irradiation Step 1-Preparation of 4-cyano-2,6-dimethylanilineA mixture of 4-bromo-2,6-dimethylaniline (7.5 mmol, CASRN 24596-19-8) and CuCN (37.5 mmol) in NMP (10 mL) was stirred under microwave irradiation at 200° C. for 1 h. The mixture was poured into a mixture of water (50 mL) and EtOAc (50 mL). The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with EtOAc. The combined extracts were dried (Na2SO4). The solvent was removed in vacuo to afford 0.383 g (35percent) of 107 as light pink solid which could be used without further purification.
Reference: [1] Patent: US2006/287287, 2006, A1, . Location in patent: Page/Page column 34
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3115 - 3126
[3] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 269 - 272
[4] Patent: US2008/146595, 2008, A1, . Location in patent: Page/Page column 29; 30
[5] Patent: WO2006/79656, 2006, A1, . Location in patent: Page/Page column 20
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Reference: [1] Green Chemistry, 2015, vol. 17, # 6, p. 3407 - 3414
[2] Journal of Organic Chemistry, 2012, vol. 77, # 23, p. 10856 - 10869
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YieldReaction ConditionsOperation in experiment
72% With HBF4; sodium nitrite In starch iodide; water Step 1) 1-Bromo-4-fluoro-3,5-dimethylbenzene
To a mixture of 4-Bromo-2,6-dimethylaniline (8.3 g, 42 mmol) at 5° C. and H2 O (50 mL) was added conc H2 SO4 (6.25 mL). NaNO2 (4.1 g) was added in portions until an excess was indicated by starch iodide paper.
Water (30 mL) was added to make the mixture homogeneous.
After transferring to a plastic container, HBF4 (50percent, 13.7 g) was added dropwise with stirring.
The resultant white precipitate was collected by vacuum filtration, washed with H2 O (30 mL), MeOH (30 mL), and Et2 O (60 mL), and dried over P2 O5 under vacuum for 16 h.
The solid was then heated in a glass flask with an open flame until all the solid had decomposed.
The remaining liquid was diluted with Et2 O (50 mL) and 0.5 M NaOH (30 mL).
The organic layer was separated, washed with 0.5 M NaOH (25 mL), H2 O (25 mL), brine (25 mL), dried (MgSO4), and concentrated in vacuo yielding 6.06 g (72percent) of 1-bromo-4-fluoro-3,5-dimethylbenzene as a pale yellow liquid.
1 H NMR (500 MHZ, CDCl3) δ 7.17 (d, 2H, J=6.2 Hz), 2.21 (s, 6H) ppm.
72% With HBF4; sodium nitrite In starch iodide; water Step 1) 1-Bromo-4-fluoro-3,5-dimethylbenzene
To a mixture of 4-Bromo-2,6-dimethylaniline (8.3 g, 42 mmol) at 5° C. and H2 O (50 mL) was added conc H2 SO4 (6.25 mL). NaNO2 (4.1 g) was added in portions until an excess was indicated by starch iodide paper.
Water (30 mL) was added to make the mixture homogeneous.
After transferring to a plastic container, HBF4 (50percent, 13.7 g) was added dropwise with stirring.
The resultant white precipitate was collected by vacuum filtration, washed with H2 O (30 mL), MeOH (30 mL), and Et2 O (60 mL), and dried over P2 O5 under vacuum for 16 h.
The solid was then heated in a glass flask with an open flame until all the solid had decomposed.
The remaining liquid was diluted with Et2 O (50 mL) and 0.5 M NaOH (30 mL).
The organic layer was separated, washed with 0.5 M NaOH (25 mL), H2 O (25 mL), brine (25 mL), dried (MgSO4), and concentrated in vacuo yielding 6.06 g (72percent) of 1-bromo-4-fluoro-3,5-dimethylbenzene as a pale yellow liquid.
1 H NMR (500 MHZ, CDCl3) δ 7.17 (d, 2H, J=6.2 Hz), 2.21 (s, 6H) ppm.
Reference: [1] Patent: US5962462, 1999, A,
[2] Patent: US6013652, 2000, A,
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Reference: [1] Journal of Medicinal Chemistry, 1986, vol. 29, # 2, p. 170 - 181
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YieldReaction ConditionsOperation in experiment
95.7%
Stage #1: With potassium acetate; acetic anhydride In chloroform at 0 - 20℃; for 1 h; Inert atmosphere
Stage #2: With tert.-butylnitrite In chloroform at 60℃;
To a solution of 4-bromo-2,6- dimethylaniline (51-51, 10 g, 0.05 mol) and potassium acetate (5.88 g, 0.06 mol) in CHC13 (120 mL) was added acetic anhydride (15.3 g, 0.15 mol) dropwise at 0 °C under an atmosphere ofnitrogen and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was heated to 60 °C and tert-butyl nitrite (10.3 g, 0.1 mol) was added dropwise. The resulting mixture was stirred overnight at 60 °C. The mixture was cooled to room temperature, diluted with H20, and extracted with DCM twice. The combined organic layers were washed by brine, dried over anhydrous Na2SO4, and concentrated to dryness. The remaining residue was dissolved inMeOH and 6 N aqueous HC1 (50 mL, v/v= 1:1) and the resulting mixture was stirred at room temperature for 4 hour. The reaction mixture was basified with 10 N aqueous NaOH and extracted with DCM. The organic layer was washed by brine, dried over anhydrous Na2SO4, and concentrated to afford 51-S2 (10.1 g, 95.7percent yield) as light a yellow solid. LC/MS (ESI) m/z: 212 (M+H) .
Reference: [1] Patent: WO2018/160889, 2018, A1, . Location in patent: Page/Page column 516; 517
[2] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1953 - 1966
[3] Synlett, 2008, # 20, p. 3216 - 3220
[4] Patent: US2011/59954, 2011, A1,
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1870 - 1873
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5129 - 5140
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YieldReaction ConditionsOperation in experiment
96% With hydrogenchloride; potassium iodide; sodium nitrite In water; acetonitrile at 0℃; In 0 ° C in acetonitrile with sodium nitrite and hydrochloric acid 4-bromo-2,6-dimethylanilinewas diazotized, by converting theamino group to iodine by the addition of potassium iodide, 4-bromo-2,6-dimethyliodobenzene was obtained in 96percent yield.This method is a known method of the literature (NonPatentDocument 2) describes.
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7202 - 7217
[2] Patent: JP5959171, 2016, B2, . Location in patent: Paragraph 0258-0260
[3] Bulletin of the Chemical Society of Japan, 2001, vol. 74, # 11, p. 2207 - 2218
[4] Patent: WO2009/74314, 2009, A1, . Location in patent: Page/Page column 168-169
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  • [ 1092352-34-5 ]
Reference: [1] Patent: US2011/59954, 2011, A1,
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  • [ 1393124-08-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 10, p. 3051 - 3058
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