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Chemical Structure| 59557-91-4
Chemical Structure| 59557-91-4
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Product Details of [ 59557-91-4 ]

CAS No. :59557-91-4 MDL No. :MFCD01204266
Formula : C7H8BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :WRFYIYOXJWKONR-UHFFFAOYSA-N
M.W :202.05 Pubchem ID :459257
Synonyms :

Calculated chemistry of [ 59557-91-4 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 45.04
TPSA : 35.25 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) : -6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.95
Log Po/w (XLOGP3) : 1.92
Log Po/w (WLOGP) : 2.05
Log Po/w (MLOGP) : 1.91
Log Po/w (SILICOS-IT) : 1.78
Consensus Log Po/w : 1.92

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.68
Solubility : 0.422 mg/ml ; 0.00209 mol/l
Class : Soluble
Log S (Ali) : -2.28
Solubility : 1.05 mg/ml ; 0.0052 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.02
Solubility : 0.192 mg/ml ; 0.000948 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.45

Safety of [ 59557-91-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280 UN#:N/A
Hazard Statements:H302-H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 59557-91-4 ]

* 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 [ 59557-91-4 ]
  • Downstream synthetic route of [ 59557-91-4 ]

[ 59557-91-4 ] Synthesis Path-Upstream   1~25

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Reference: [1] Journal of the American Chemical Society, 2005, vol. 127, # 1, p. 74 - 75
[2] Journal of the Chemical Society, 1957, p. 290,293
[3] Patent: WO2018/178226, 2018, A1,
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  • [ 16817-43-9 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 5, p. 1705 - 1722
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  • [ 55860-22-5 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 49, p. 8563 - 8566
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  • [ 88149-47-7 ]
YieldReaction ConditionsOperation in experiment
83% With 2,4,4,6-tetrabromocyclohexadione In dichloromethane at -10 - 20℃; o-Anisidine (470 mg, 3.60 mmol) was dissolved in dichloromethane (8 mL) and cooled to -10 °C. 2,4,4,6-Tetrabromocyclohexadione (1.56 g, 3.60 mmol) was slowly added into the above stirred solution, while the temperature was kept below -5 °C. The reaction was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was washed with sodium hydroxide (10 mL, 2 M) and then water (15 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed (silica gel, dichloromethane) to afford 2,4-dibromo-6-methoxyaniline (90 mg, 9percent) as a dark brown liquid. 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H, OCH3), 4.20 (br s, 2H, NH2), 6.83 (d, J 2.1 Hz, 1H, ArH), 7.19 (d, J 2.1 Hz, 1H, ArH). The spectral data are in agreement with those reported in the literature.65 Continued elution afforded 4-bromo-2-methoxyaniline (579 mg, 83percent) as a brown solid: mp 57-59 °C (lit.66 56.5-58 °C; lit.65 60-61 °C). 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H, OCH3), 3.85 (br s, 2H, NH2) 6.60 (d, J 7.8 Hz, 2H, ArH), 6.88-6.90 (m, 2H, ArH). The spectral data are in agreement with those reported in the literature.65 J.-M. Chretien, F. Zammattio, E. Le Grognec, M. Paris, B. Cahingt, G. Montavon and J.-P. Quintard, J. Org. Chem. 70 (2005), pp. 2870-2873. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)65
Reference: [1] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
[2] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
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YieldReaction ConditionsOperation in experiment
97% With o-xylylene bis(triethylammonium tribromide) In acetonitrile at 20℃; for 0.05 h; General procedure: To a magnetic solution of aromatic compound (1 mmol)in acetonitrile (5 mL), OXBTEATB (0.233 g, 0.5 mmol) wasadded and stirred at room temperature for the appropriatetime (Table 1). The reaction was monitored by TLC (eluent:n-hexane/ethyl acetate: 5/1). The reaction mixture was transferredinto a separatory funnel after filtration of OXBTEABand was extracted with water (15 mL) and dichloromethane(20 mL). The organic layer was dried over anhydrousNa2SO4, and the solvent was concentrated in a rotary evaporator.The crude product was purified by passing it over acolumn of silica gel using a mixture of n-hexane and ethylacetate as the eluent. In order to regenerate the reagent, whitesolid was treated with liquid bromine. All the product structureswere confirmed by comparison of melting point or 1HNMR spectra with ones reported in the literature [29a-29e].
85% With N-Bromosuccinimide In dichloromethane at -30 - 20℃; To a solution of o-anisidine (15 g) in dry dichloromethane (250 ml) at -10 0C under argon was added N-bromosuccinimide (22.8 g) portionwise while keeping the internal temperature below -5 0C. The reaction mixture was stirred overnight and then the dichloromethane was evaporated and the residue dissolved in ethyl acetate (300 ml). The organic layer was washed with water (3 x 250 ml), the aqueous combined and extracted with ethyl acetate (150 ml). The combined organic layers were dried (MgSO4) and evaporated and the residue loaded onto six Biotage Si 40+M columns. Purification was carried out on the Biotage SP4 eluting with dichloromethane to afford the title compound (6.0 g and 5.76 g) as a dark red oil.LC/MS (ES) Rt=2.11 min (Method A). Molecular ion observed [M+H]+ 204, consistent with molecular formula C7H8NO81Br; To a solution of (2-methoxyphenyl)amine (125g, 1.01 mol) in dry DCM (2500ml) at - 3O0C was added NBS (19Og, 1.07mol) portionwise while the internal temperature was kept below -250C. The reaction mixture was stirred at rt overnight. Then the solvent was removed and the residue was dissolved in EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. Purification via the CombiFlash system (DCM:MeOH=100:1 ) then afforded the title compound as a red oil (175g, 85percent): LC-MS m/z 203 (M+H)+, 1.56 min (ret time).
75% With trimethylbenzylammonium bromide; calcium carbonate In methanol; dichloromethane at 20℃; for 2 h; o-Anisidine (0.18 ml, 20 mg, 1.63 mmol, 1 eq) is dissolved in a mixture of 10 ml of dichloromethane and 4 ml of methanol.
Subsequently, TBMABr3 (761 mg, 1.95 mmol, 1.2 eq) and calcium carbonate (650 mg, 6.50 mmol, 4 eq) are added, and the mixture is stirred at RT for 2 h.
The calcium carbonate is filtered off, and water is added.
The aqueous phase is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator.
Purification by column chromatography with dichloromethane/hexane 7/3 as the eluent yielded the desired product in a yield of 75percent, 247 mg.
C7H8BrNO; MW 202; 1H-NMR (CDCl3): δ 6.89 (m, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.92 (bs, 1H), 3.82 (s, 3H); 13C-NMR (CDCl3): δ 148.0, 134.9, 123.7, 115.9, 113.8, 109.9, 56.7; IR: 3470, 3375 (amine), 1616, 1503, 1409 (phenyl) 1/cm
59% With bromine In dichloromethane at 0℃; Preparation 80; 4-Bromo-2-methoxy-phenylamine; Add dropwise a solution of bromine (0.83 mL, 16.2 mmol) in CH2Cl2 (130 mL) to a solution of 2-methoxy-phenylamine (2.0 g, 16.2 mmol) in dichloromethane (100 mL) at 0 0C over a period of 45 min. Stir the mixture at 0 0C to RT overnight. Wash the mixture with water, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography eluting with 10percent EtOAc/hexane to give 1.95 g (59percent) of the title compound. GC m/z (81Br) 203 [M+].
55% With N-Bromosuccinimide In acetonitrile at 15℃; for 0.25 h; 2-methoxyaniline (3 g, 24.36 mmol) in acetonitrile (30 mL) was added N- bromosuccinimide (4.34 g, 24.36 mmol) and the reaction mixture was stirred at 15 deg.C for 15 minutes. To the reaction mixture sodium sulfite solution (40 mL) to quench the reaction, the mixture was extracted with ethyl acetate (50ml); the organic layer was dried over sodium sulfate, and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (2.7 g, 55percent yield) as a yellow solid.

Reference: [1] Russian Journal of Applied Chemistry, 2009, vol. 82, # 9, p. 1570 - 1576
[2] Letters in Organic Chemistry, 2018, vol. 15, # 8, p. 682 - 687
[3] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1936 - 1942
[4] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 744 - 748
[5] Heterocycles, 2010, vol. 81, # 1, p. 73 - 77
[6] Patent: WO2009/50227, 2009, A1, . Location in patent: Page/Page column 17; 76-77
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4016 - 4019
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 15, p. 5444 - 5453
[9] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1222 - 1231
[10] Synthetic Communications, 2010, vol. 40, # 6, p. 868 - 876
[11] Patent: US2010/204234, 2010, A1, . Location in patent: Page/Page column 14
[12] Patent: WO2007/146758, 2007, A2, . Location in patent: Page/Page column 58
[13] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0708; 0709; 0710; 0711
[14] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1013 - 1030
[15] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 254 - 272
[16] Patent: US2005/20619, 2005, A1, . Location in patent: Page 40
[17] Patent: US2007/27125, 2007, A1, . Location in patent: Page/Page column 13
[18] Patent: WO2009/50227, 2009, A1, . Location in patent: Page/Page column 16-17
[19] Patent: US2007/27201, 2007, A1, . Location in patent: Page/Page column 17
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YieldReaction ConditionsOperation in experiment
82.9% at 10℃; for 2 h; To a solution of 2-methoxy-phenylamine (11.27 mL, 12.31 g, 0.1 mol) in glacial acetic acid (250 mL) maintained at about 10 °C a solution of bromine (5.65 mL, 17.58 g, 0.11 mol) in glacial acetic acid (7 mL) was added over 2 h. A purple precipitate was formed, that was filtered on a Buchner funnel and rinsed with glacial acetic acid and petroleum ether (3 x 100 mL) to afford a whitish solid mixture of 4-bromo-2-methoxy-phenylamine and 4,5-dibromo-2-methoxy- phenylamine (26.9 g). The mixture was separated by flash chromatography on silica gel (hexane/EtOAc 40/60) and the desired compound was crystallized from fert-butyl methyl ether (18.73 g, 82.9percent).1H NMR (400 MHz, DMSO-cie) δ ppm 3.83 (s, 3 H) 6.83 (d, J=8.42 Hz, 1 H) 6.98 (dd, J=8.30, 2.08 Hz, 1 H) 7.11 (d, J=1.95 Hz, 1 H).HRMS mil calcd for [M + H] 201.9862; found 201.9866.
Reference: [1] Patent: WO2013/14039, 2013, A1, . Location in patent: Page/Page column 43
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YieldReaction ConditionsOperation in experiment
2 g With water; iron; ammonium chloride In tetrahydrofuran at 65℃; for 4 h; Inert atmosphere Step 3
4-bromo-2-methoxyaniline (Compound 12-5)
At room temperature, the reduced iron powder (4.48 g, 80 mmol) and ammonium chloride (2.65 g, 50 mmol) were added to a mixed solution of compound 12-4 (2.3 g, 10.0 mmol) in 60 ml of THF/water (volume ratio of THF and water is 2:1), and vigorously stirred at 65° C. for 4 h.
After completion of the reaction, the reaction mixture was filtered, the filtrate was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-5 (2.0 g) which was used directly in the next step. MS m/z (ESI): 201.9 [M+H]+.
Reference: [1] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 4, p. 175 - 179
[2] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0207; 0209
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YieldReaction ConditionsOperation in experiment
89% With sodium hydroxide In dichloromethane 4-bromo-2-methoxyaniline
A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at -5° C.
Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature.
Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned.
The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89percent) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1*50 mm; 5percent-95percent acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89percent).
89% With sodium hydroxide In dichloromethane 4-bromo-2-methoxyaniline
A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at -5° C.
Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature.
Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned.
The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89percent) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1*50 mm; 5percent-95percent acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89percent).
Reference: [1] Patent: US2002/156081, 2002, A1,
[2] Patent: US2005/26944, 2005, A1,
[3] Patent: US6921763, 2005, B2,
[4] Patent: US2005/43347, 2005, A1, . Location in patent: Page/Page column 49
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Reference: [1] Patent: US4587341, 1986, A,
[2] Patent: EP96214, 1991, B1,
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Reference: [1] Patent: US2004/58933, 2004, A1, . Location in patent: Page/Page column 5
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Reference: [1] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 440 - 447
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Reference: [1] Journal of the American Chemical Society, 1935, vol. 57, p. 1592,1594
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Reference: [1] Journal of the American Chemical Society, 1935, vol. 57, p. 1592,1594
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Reference: [1] Patent: US1792156, 1929, ,
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 460
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 461
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Reference: [1] Patent: US2017/8889, 2017, A1,
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Reference: [1] Patent: US1792156, 1929, ,
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 460
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 461
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 461
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Reference: [1] Patent: US1792156, 1929, ,
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 460
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 461
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  • [ 5473-01-8 ]
Reference: [1] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 440 - 447
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YieldReaction ConditionsOperation in experiment
91%
Stage #1: With hydrogenchloride; sodium nitrite In water; acetic acid at 10 - 20℃;
Stage #2: With hydrogen bromide; potassium iodide In water; acetic acid at 20℃; for 1 h;
Stage #3: With ammonium hydroxide; sodium carbonate In dichloromethane; water
A stirred solution of NaN02 (5.63 g, 81.7 mmol) in cone. HC1 (6.2 ml) was cooled to 10 °C. 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 °C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48 percent HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H20, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2C03 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgS04), filtered and evaporated to yield a brown solid.The mother liquor (b) was basified by the addition of solid Na2C03 and was then extracted with DCM. The combined organic extracts were washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgS04), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91 percent).
91%
Stage #1: With hydrogenchloride; sodium nitrite In water; acetic acid at 10 - 20℃; for 0.5 h;
Stage #2: With hydrogen bromide; potassium iodide In water; acetic acid at 20℃; for 1 h;
Stage #3: With sodium carbonate In water
A stirred solution of NaN02 (5.63 g, 81.7 mmol) in cone. HC1 (6.2 ml) was cooled to 10 °C. 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10 °C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48 percent HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H20, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2CC>3 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSC>4), filtered and evaporated to yield a brown solid.The mother liquor (b) was basified by the addition of solid Na2C03 and was then extracted with DCM. The combined organic extracts were washed with a dilutedNH4OH solution until the disappearance of blue colour. The organic phase was dried(MgS04), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91 percent).
91%
Stage #1: at 10 - 20℃; for 0.5 h;
Stage #2: With hydrogen bromide; potassium iodide In water at 20℃; for 1 h;
A stirred solution of NaNO2 (5.63 g, 81.7 mmol) in conc. HCl (6.2 ml) was cooled to 10° C. 4-bromo-2-methoxy-phenylamine (15 g, 74 mmol) in HOAc (100 ml) was added at such a rate that the temperature of the r.m. was maintained below 10° C. After addition was completed, the mixture was stirred at r.t. for 30 min. This solution was added dropwise, to a stirring solution of KI (37 g, 223 mmol) in 48percent HBr (200 ml) at r.t. This mixture was stirred for 1 h and was then diluted with ice water (1000 ml). The resulting white precipitate was collected by filtration and washed with H2O, yielding a solid (a) and the mother liquor (b).The solid (a) was suspended in a mixture of DCM and a sat. aq. Na2CO3 solution. The resulting slurry was filtered over diatomaceous earth. The organic layer of the filtrate was washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSO4), filtered and evaporated to yield a brown solid. The mother liquor (b) was basified by the addition of solid Na2CO3 and was then extracted with DCM. The combined organic extracts were washed with a diluted NH4OH solution until the disappearance of blue colour. The organic phase was dried (MgSO4), filtered and evaporated to give a brown solid.The 2 brown solids were combined, yielding 24.0 g of intermediate 54 (91percent).
78%
Stage #1: With sulfuric acid; sodium nitrite In water at 0 - 10℃; for 1 h;
Stage #2: With potassium iodide In water at 0 - 20℃;
4-Bromo-2-methoxy-aniline (20 g, 99 mmol) was dissolved in water (695 mL) and concentrated sulphuric acid (113 ML). The solution was cooled to 0 °C and sodium nitrite (7.5 g, 109 mmol) dissolved in water (32 mL) was added and stirred for 1 hour at 5-10 °C. POTASSIUM iodide (21.4g, 129 mmol) dissolved in water (100 mL) was added slowly whilst the mixture was virgorously stirred. After addition, the mixture was allowed to warm to room temperature. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted with ethyl acetetate (3 X). The combined organic phases were then washed with 1M NAOH, 1M Na2S203,1M HCl,- 1M saturated NAHCO3 and brine. The separated organic phase was dried (MGS04), filtered and concentrated in vacuo. The product was purified by flash chromatography using silica gel and eluting with HEPTANE/ETHYL acetate 1: 1. The product was identified from relevant fractions which were combined and concentrated IN VACUO. Yield: 24.12g, 78percent
73%
Stage #1: With hydrogenchloride; acetic acid; sodium nitrite In water at 10 - 20℃; for 0.5 h;
Stage #2: With hydrogen bromide; potassium iodide In water at 20℃; for 1 h;
To a mixed solution of 2.0 g (9.0 mmol) of 4-bromo-2-methoxy aniline (Tokyo Chemical Industry Co., Ltd.) in acetic acid (15 ml)-concentrated hydrochloric acid (1 ml) was added 0.75 g (11 mmol) of sodium nitrite under ice cooling while stirring so that the internal temperature did not exceed 10°C, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was added dropwise to a solution of 1.0 g (30 mmol) of potassium iodide in a 48percent by weight aqueous hydrobromic acid solution (30 ml) at room temperature while stirring, and the mixture was stirred at the same temperature for one hour. After completion of the reaction, to a mixture of an aqueous sodium carbonate solution and methylene chloride was added the reaction mixture portionwise, the basicity of the aqueous layer was confirmed, and an extraction with methylene chloride from the mixed solution was subsequently conducted. The organic layer was washed sequentially with a 10percent by weight aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 100:0 to 91:9 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.2 g (7.2 mmol, yield 73percent) of the title compound as an orange solid. Mass spectrum (EI, m/z): 312 [M]+. 1 H-NMR spectrum (400 MHz, CDCl3) δ : 7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s).
73%
Stage #1: at 10 - 20℃; for 0.5 h; Cooling with ice
Stage #2: With hydrogen bromide; potassium iodide In water at 20℃; for 1 h;
(Reference Example 3)
4-Bromo-1-iodo-2-methoxybenzene
In an ice bath and while performing stirring, 0.75 g (11 mmol) of sodium nitrite was added to an acetic acid (15 ml)-concentrated hydrochloric acid (1 ml) solution of 2.0 g (9.0 mmol) of 4-bromo-2-methoxyaniline (Tokyo Chemical Industry Co., Ltd.) in such a manner that the inside temperature did not exceed 10°C.
The mixture was stirred at room temperature for 30 minutes.
Next, the reaction mixture liquid was added dropwise to an aqueous solution of 1.0 g (30 mmol) of potassium iodide in a 48 wtpercent aqueous hydrobromic acid solution (30 ml) at room temperature while performing stirring.
The resultant mixture was stirred at the temperature for 1 hour.
After the completion of the reaction, the reaction mixture liquid was added in small portions to a mixture of an aqueous sodium carbonate solution and methylene chloride.
After the basicity of the aqueous phase was confirmed, the liquid was separated.
The organic phase was washed sequentially with a 10 wtpercent aqueous sodium hydrogensulfite solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (eluting solvent: hexane:ethyl acetate = 100:0 to 91:9 (V/V)), and the fraction containing the target compound was concentrated under reduced pressure to give the title compound weighing 2.2 g (7.2 mmol, yield 73percent) as an orange solid.
Mass spectrum (EI, m/z): 312 [M]+.
1H-NMR spectrum (400MHz, CDCl3) δ: 7.61 (1H, d, J = 8.3 Hz), 6.94 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 8.2, 2.1 Hz), 3.88 (3H, s).
62% With toluene-4-sulfonic acid; potassium iodide; sodium nitrite In water; acetonitrile at 10 - 20℃; for 2.16667 h; To a solution of 4-bromo-2-methoxyphenyl)amine (11 Og, 0.54mol) in CH3CN (2000ml) at rt was added TsOH-H2O (281 g, 1.63mol). The mixture was cooled to 10-150C and mixed with a solution of NaNO2 (75g, 1.09mol) and Kl (226g, 1.36mol) in water. The mixture was stirred for 10min, allowed to warm to rt, and stirred for 2h before the reaction was quenched by the addition of water and 2M Na2S2O3 solution. It was then basified to pH of 9-10 by mixing with saturated NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated. Purification via the CombiFlash system (PE) then afforded the title compound as a colorless oil (107g, 62percent): LC-MS 1.87 min (ret time).
52.2% With toluene-4-sulfonic acid; potassium iodide; sodium nitrite In water at 10 - 20℃; for 1 h; 4-Bromo-2-methoxy-phenylamine (2.02 g, 10 mmol) was added to a solution of p-toluensulphonic acid monohydrate (3.80 g, 20 mmol) in acetonitrile (30 mL). The mixture was cooled in an ice bath and treated with an solution of sodium nitrite (0.69 g, 10 mmol) and potassium iodide (4,15 g, 25 mmol) in water (7 mL) over 15 min maintaining the internal temperature below 10 °C. After stirring at that temperature for 15 min and then for 0.5 h at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (5 x 50 mL). The combined organic extracts were washed with 2M sodium thiosulfate (10 mL), brine (4 x 20 mL), water (20 mL), anhydrified over sodium sulphate, and evaporated to dryness affording a black oil that was purified by flash chromatography (petroleum ether/ferf-butylmethyl ether 5/1) to yield the title compound (1.63 g, 52.2percent).1H NMR (400 MHz, DMSO-cie) δ ppm 3.85 (s, 3 H) 6.95 (dd, J=8.24, 2.14 Hz, 1 H) 7.19 (d, J=2.08 Hz, 1 H) 7.69 (d, J=8.18 Hz, 1 H).

Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1222 - 1231
[2] Patent: WO2011/86098, 2011, A1, . Location in patent: Page/Page column 77
[3] Patent: WO2011/86099, 2011, A1, . Location in patent: Page/Page column 66
[4] Patent: US2012/295891, 2012, A1, . Location in patent: Page/Page column 31
[5] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1013 - 1030
[6] Patent: WO2004/96761, 2004, A1, . Location in patent: Page 43
[7] Patent: EP2940013, 2015, A1, . Location in patent: Paragraph 0513
[8] Patent: EP3162801, 2017, A1, . Location in patent: Paragraph 0149; 0150
[9] Patent: WO2009/50227, 2009, A1, . Location in patent: Page/Page column 77
[10] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4016 - 4019
[11] Patent: WO2013/14039, 2013, A1, . Location in patent: Page/Page column 43
[12] Journal of the American Chemical Society, 1935, vol. 57, p. 1592,1594
[13] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 3981 - 3984
[14] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 3248
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YieldReaction ConditionsOperation in experiment
83% With 2,4,4,6-tetrabromocyclohexadione In dichloromethane at -10 - 20℃; o-Anisidine (470 mg, 3.60 mmol) was dissolved in dichloromethane (8 mL) and cooled to -10 °C. 2,4,4,6-Tetrabromocyclohexadione (1.56 g, 3.60 mmol) was slowly added into the above stirred solution, while the temperature was kept below -5 °C. The reaction was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was washed with sodium hydroxide (10 mL, 2 M) and then water (15 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed (silica gel, dichloromethane) to afford 2,4-dibromo-6-methoxyaniline (90 mg, 9percent) as a dark brown liquid. 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H, OCH3), 4.20 (br s, 2H, NH2), 6.83 (d, J 2.1 Hz, 1H, ArH), 7.19 (d, J 2.1 Hz, 1H, ArH). The spectral data are in agreement with those reported in the literature.65 Continued elution afforded 4-bromo-2-methoxyaniline (579 mg, 83percent) as a brown solid: mp 57-59 °C (lit.66 56.5-58 °C; lit.65 60-61 °C). 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H, OCH3), 3.85 (br s, 2H, NH2) 6.60 (d, J 7.8 Hz, 2H, ArH), 6.88-6.90 (m, 2H, ArH). The spectral data are in agreement with those reported in the literature.65 J.-M. Chretien, F. Zammattio, E. Le Grognec, M. Paris, B. Cahingt, G. Montavon and J.-P. Quintard, J. Org. Chem. 70 (2005), pp. 2870-2873. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (25)65
Reference: [1] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
[2] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
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Reference: [1] Russian Journal of Applied Chemistry, 2009, vol. 82, # 9, p. 1570 - 1576
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Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 254 - 272
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  • [ 122833-04-9 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 11, p. 2809 - 2812
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YieldReaction ConditionsOperation in experiment
26% With tetrakis(triphenylphosphine) palladium(0); potassium acetate In dimethyl sulfoxide at 150℃; for 0.666667 h; Microwave irradiation Example 27E (500 mg, 2.47 mmol) in DMSO (5mL) solution was added bis(pinacolato)diboron(628.4 mg, 2.47 mmol), tetrakis triphenylphosphine palladium (150 mg, 0.13 mmol ) and potassium acetate (485 mg, 4.95 mmol) and the reaction mixture was stirred at 150 deg.C by microwave for 40 minutes. The reaction mixture was diluted with ethyl acetate (50mL) and water (30mL). The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether 1:: ethyl acetate = 10) to give the title compound (160 mg, 26percent yield) as a yellow oil.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 966 - 970
[2] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0712; 0713; 0714; 0715
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Reference: [1] Patent: CN107954989, 2018, A,
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