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Chemical Structure| 4068-76-2
Chemical Structure| 4068-76-2
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Product Details of [ 4068-76-2 ]

CAS No. :4068-76-2 MDL No. :MFCD00016460
Formula : C8H7BrO3 Boiling Point : -
Linear Structure Formula :- InChI Key :FJYDBKPPGRZSOZ-UHFFFAOYSA-N
M.W : 231.04 Pubchem ID :77683
Synonyms :

Calculated chemistry of [ 4068-76-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 47.44
TPSA : 46.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.18 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.97
Log Po/w (XLOGP3) : 3.56
Log Po/w (WLOGP) : 1.94
Log Po/w (MLOGP) : 2.06
Log Po/w (SILICOS-IT) : 1.89
Consensus Log Po/w : 2.28

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.75
Solubility : 0.0408 mg/ml ; 0.000176 mol/l
Class : Soluble
Log S (Ali) : -4.22
Solubility : 0.0138 mg/ml ; 0.0000599 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -2.76
Solubility : 0.403 mg/ml ; 0.00175 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 1.56

Safety of [ 4068-76-2 ]

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 [ 4068-76-2 ]

* 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 [ 4068-76-2 ]
  • Downstream synthetic route of [ 4068-76-2 ]

[ 4068-76-2 ] Synthesis Path-Upstream   1~16

  • 1
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Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 583 - 588
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  • [ 66003-76-7 ]
  • [ 56341-31-2 ]
Reference: [1] Chinese Chemical Letters, 2018, vol. 29, # 6, p. 985 - 988
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  • [ 65685-50-9 ]
Reference: [1] Patent: US2015/175560, 2015, A1,
  • 4
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  • [ 323-87-5 ]
Reference: [1] ACS Combinatorial Science, 2015, vol. 17, # 1, p. 32 - 38
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  • [ 91983-31-2 ]
YieldReaction ConditionsOperation in experiment
88% at 0 - 20℃; for 3.5 h; Methyl 5-bromo-2-hydroxybenzoate (231 g, 1 mol) was dissolved in concentrated sulfuric acid (500 mL).The ice bath is cold to 0°C.A mixture of concentrated nitric acid (108 g, 1.1 mol) and concentrated sulfuric acid (120 mL), which had been cooled to 0°C, was slowly added.The dropping rate was controlled so that the temperature of the reaction system was not higher than 5°C.After the addition was complete, the ice bath was removed and the system allowed to naturally warm to room temperature and react at room temperature for 3.5 hours. After completion of the reaction monitored by TLC, the mixture was poured into crushed ice (2 L) and stirred until the crushed ice melted completely and the system precipitated a large amount of pale yellow solid. The solid was filtered, neutralized with stirring in ice water, and dried.Methyl yellow 5-bromo-2-hydroxy-3-nitrobenzoate (243 g) was obtained, yield 88percent.
85% With sulfuric acid; nitric acid In water at 0 - 5℃; Example 114 Bmethyl 5-bromo-2-hydroxy-3-nitrobenzoate; To a mixture of methyl 5-bromo-2-hydroxybenzoate (150 g, 0.65 mol) in concentrated H2SO4 (320 mL) below 0° C. was added dropwise a mixture of concentrated HNO3 (69.2 g, 0.71 mol) and concentrated H2SO4 (97 mL) with stirring below 5° C. After the addition, the mixture was stirred at this temperature for 3 hr. The reaction mixture was poured into crash ice and the precipitate was collected, washed with cold water, hot ethanol and dried to give methyl 5-bromo-2-hydroxy-3-nitrobenzoate (153 g, yield 85percent). 1H-NMR (400 MHz,CDCl3-d) δ 4.04 (s, 3H), 8.25 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 11.92 (s, 1H); LC-MS (ESI) m/z 278 [M+1]+.
Reference: [1] Patent: CN107573336, 2018, A, . Location in patent: Paragraph 0096; 0097; 0098
[2] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 56
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 3, p. 624 - 630
  • 6
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YieldReaction ConditionsOperation in experiment
89% at 0 - 70℃; for 40 h; Heating / reflux Intermediate III: 6- (aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one; Step a) Formation of methyl-5-bromosalicylate; To a solution of 5-BROMOSALICYLIC acid (200 G, 0.92 mol) in METHANE . (2 L) was added thionylchloride (440 g, 3.7 mol) at 0°C with stirring and then allowed to reflux at 70°C for 40H. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10percent cold aqueous NAHC03 solution (2X1 L), brine and dried. The solvent was removed UNDER vacuum to give the title compound as a low melting point solid (190 g, 89percent). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
89% at 0 - 70℃; for 40 h; Heating / reflux To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0°C with stirring and then allowed to reflux at 70°C for 40h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10percent cold aqueous NaHCO3 solution (2 x 1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89percent). TLC: PetEther/EtOAc, 7: 3, Rf: 0. 6
81% for 12 h; Reflux 5-Bromo-2-hydroxybenzoic acid (2.17 g, 10 mmol) was dissolved in methanol (50 ml_) and sulfuric acid (100percent, 1 ml_) and heated at rx for 12 h. After cooling and neutralization (NaHCO3, aq, sat), the white precipitate was filtered off and washed with water and dried, furnishing 1.92 g (81percent) of intermediate I.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2621 - 2625
[2] Journal of Materials Chemistry, 1996, vol. 6, # 8, p. 1297 - 1307
[3] Organic Letters, 2014, vol. 16, # 19, p. 5140 - 5143
[4] Patent: WO2005/12280, 2005, A1, . Location in patent: Page/Page column 46-47
[5] Patent: WO2005/11685, 2005, A1, . Location in patent: Page/Page column 41
[6] Organic Letters, 2009, vol. 11, # 21, p. 4790 - 4793
[7] Journal of the American Chemical Society, 2001, vol. 123, # 43, p. 10429 - 10435
[8] Patent: WO2009/138758, 2009, A2, . Location in patent: Page/Page column 73
[9] Journal of Fluorine Chemistry, 1995, vol. 74, p. 69 - 76
[10] Gazzetta Chimica Italiana, 1886, vol. 16, p. 402
[11] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
[12] Synthetic Communications, 2000, vol. 30, # 4, p. 689 - 699
[13] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 583 - 588
[14] Angewandte Chemie, International Edition, 2009, vol. 48, # 23, p. 4226 - 4228
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1555 - 1564
[16] Medicinal Chemistry Research, 2014, vol. 23, # 7, p. 3274 - 3286
[17] Polyhedron, 2017, vol. 128, p. 18 - 29
[18] Journal of the American Chemical Society, 2018, vol. 140, # 9, p. 3412 - 3422
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YieldReaction ConditionsOperation in experiment
99.6% With bromine; sodium hydrogencarbonate In chloroform REFERENCE EXAMPLE 2
Synthesis of methyl 5-bromosalicylate STR22
To a mixture of 152 g (1.0 mole) of methyl salicylate and 500 ml of chloroform were added dropwise with stirring a solution of 172 g (1.08 mole) of bromine in 300 ml of chloroform at about 10° C. over a period of 6 hours.
After the addition, the mixture was stirred at the same temperature for 1 hour.
The reaction mixture was washed with water and then with an aqueous solution of sodium bicarbonate.
Removal of the solvent gave 230 g of substantially pure methyl 5-bromosalicylate in 99.6percent yield, M.P. 59° to 61.5° C.
98% With bromine In dichloromethane at 20℃; for 6 h; To a solution of methyl salicylate S1(15.2 g, 0.1 mol) in dichloromethane (100 ml) was added dropwise bromine (1 N solution in dichloromethane, 1.1 equiv) for 6h, then concentrated, the residue was poured into the saturated sodium sulphite, The resulting yellow precipitate was recovered by filtration and washed with petroleum ether to obtain the light yellow solid S2. (yield: 98percent). 1H-NMR (300MHz, CDCl3): δ ppm 10.7(s, 1H), 7.97 (d, J = 2.52 Hz, 1H), 7.55 (dd, J = 8.91, 2.52 Hz, 1H), 6.90 (d, J = 8.91 Hz, 1H), 3.98 (s, 3H).
87.4% With bromine In chloroform at 10 - 20℃; Methyl paraben (152 g, 1 mol) was dissolved in chloroform (600 mL).Under ice-cooling, a solution of liquid bromine (176 g, 1.1 mol) in chloroform (300 mL) was carefully added dropwise. The dropping rate was controlled so that the temperature of the system was not higher than 10°C. After the addition, the system was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC on the following day. After removing the solvent and excess bromine in vacuo, the system was dissolved in dichloromethane (1 L). Separately washed with water (1L), saturated aqueous sodium hydrogencarbonate solution, 1percent sodium dithionite solution, and water (1L), dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was recrystallized from methanol to give 201 g of white crystals in a yield of 87.4percent.
84% With N-Bromosuccinimide; thiourea In acetonitrile at 20℃; for 2 h; General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
83% With bromine In acetic acid (a)
Methyl 5-bromo-2-hydroxybenzoate
Br2 (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 mL acetic acid.
The reaction mixture was stirred at rt.
for 10 h, poured on ice-water and the precipitate recrystallized from MeOH, giving the sub-title compound in a 83percent yield.
83% With bromine In chloroform at 10 - 20℃; Example 114 Amethyl 5-bromo-2-hydroxybenzoate; To a solution of methyl 2-hydroxybenzoate (152 g, 1.0 mol) in chloroform (500 mL) was added dropwise with stirring a solution of bromine (172 g, 1.08 mol) in chloroform (300 mL) at 10° C. After the addition, the solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (500 mL), washed with water (1 L.x.3), saturated sodium bicarbonate solution (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was re-crystallized from methanol to give methyl 5-bromo-2-hydroxybenzoate (192 g, yield 83percent) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.89 (d, J=8.8 Hz, 1H), 7.52-7.55 (dd, J=8.8 Hz, J=2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 10.7 (s, 1H); LC-MS (ESI) m/z 233 [M+1]+.
83% With bromine In acetic acid at 20℃; for 10 h; [0312] Br2 (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 mL acetic acid. The reaction mixture was stirred at rt. for 10 h, poured onto ice-water and the precipitate recrystallized from MeOH, giving the sub-title compound in a 83percent yield.

Reference: [1] Patent: US4634768, 1987, A,
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4537 - 4543
[3] Patent: CN107573336, 2018, A, . Location in patent: Paragraph 0093; 0094; 0095
[4] Synthetic Communications, 2007, vol. 37, # 4, p. 581 - 585
[5] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572
[6] Patent: US6291475, 2001, B1,
[7] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 56
[8] Patent: US2004/229900, 2004, A1, . Location in patent: Page 16
[9] Journal of Organic Chemistry, 1985, vol. 50, # 23, p. 4468 - 4473
[10] Chemische Berichte, 1869, vol. 2, p. 275
[11] Gazzetta Chimica Italiana, 1886, vol. 16, p. 402
[12] Roczniki Chemii, 1954, vol. 28, p. 139,141[13] Chem.Abstr., 1955, p. 8869
[14] Patent: EP1308439, 2003, A1,
[15] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
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Reference: [1] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
  • 9
  • [ 89-55-4 ]
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Reference: [1] Organic Letters, 2015, vol. 17, # 18, p. 4550 - 4553
[2] Organic Letters, 2018, vol. 20, # 5, p. 1316 - 1319
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Reference: [1] Annales de Chimie (Cachan, France), 1844, vol. <3> 10, p. 329,336, 353[2] Justus Liebigs Annalen der Chemie, 1843, vol. 48, p. 65
[3] Patent: US4420476, 1983, A,
[4] Patent: CN107573336, 2018, A,
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Reference: [1] Annales de Chimie (Cachan, France), 1844, vol. <3> 10, p. 329,336, 353[2] Justus Liebigs Annalen der Chemie, 1843, vol. 48, p. 65
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Reference: [1] Annales de Chimie (Cachan, France), 1844, vol. <3> 10, p. 329,336, 353[2] Justus Liebigs Annalen der Chemie, 1843, vol. 48, p. 65
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Reference: [1] Tetrahedron, 2010, vol. 66, # 34, p. 6928 - 6935
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  • [ 54450-20-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4537 - 4543
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 3, p. 624 - 630
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  • [ 1131587-78-4 ]
YieldReaction ConditionsOperation in experiment
50% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24 h; To a solution of methyl 5-bromo-2-hydroxybenzoate (409 mg, 1.77 mmol) in DMF (5 mL) was added potassium carbonate (367 mg, 2.67 mmol) and ethyl 2-bromo-2,2-difluoroacetate (280 μ^, 2.13 mmol). The resulting mixture was heated at 80 °C for 24 hrs. The resulting solution was cooled to RT, diluted with ether and washed sequentially with water, 10percent aq. HCl, water and brine. The organic extract was then dried over Na2S04, filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (S1O2, gradient elution, Hex to 2:1 (v/v) Hex: EtOAc) afforded methyl 5-bromo-2- (difluoromethoxy)benzoate as a yellow oil (250 mg, 50percent yield).
Reference: [1] Patent: WO2013/134562, 2013, A1, . Location in patent: Paragraph 00294
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