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Chemical Structure| 2105-94-4
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Product Details of [ 2105-94-4 ]

CAS No. :2105-94-4 MDL No. :MFCD00011722
Formula : C6H4BrFO Boiling Point : -
Linear Structure Formula :- InChI Key :RYVOZMPTISNBDB-UHFFFAOYSA-N
M.W : 191.00 Pubchem ID :2724981
Synonyms :

Calculated chemistry of [ 2105-94-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 36.12
TPSA : 20.23 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) : -5.6 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.91
Log Po/w (XLOGP3) : 2.63
Log Po/w (WLOGP) : 2.71
Log Po/w (MLOGP) : 2.67
Log Po/w (SILICOS-IT) : 2.48
Consensus Log Po/w : 2.48

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.17
Solubility : 0.128 mg/ml ; 0.000669 mol/l
Class : Soluble
Log S (Ali) : -2.71
Solubility : 0.377 mg/ml ; 0.00197 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.96
Solubility : 0.211 mg/ml ; 0.00111 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.25

Safety of [ 2105-94-4 ]

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 [ 2105-94-4 ]

* 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 [ 2105-94-4 ]
  • Downstream synthetic route of [ 2105-94-4 ]

[ 2105-94-4 ] Synthesis Path-Upstream   1~32

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YieldReaction ConditionsOperation in experiment
90% With bromine In dichloromethane; water EXAMPLE 5
Preparation of 2-[4-(4-bromo-2-fluorophenoxy)phenoxy]propionic acid methyl ester STR29
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mol) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mol).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.
90% With bromine In dichloromethane; water EXAMPLE 5
Preparation of 2-[4-(4-bromo-2-fluorophenoxy)phenoxy propionic acid methyl ester STR29
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mmol) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mol).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.
90% With bromine In dichloromethane; water STR34
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.
The gc of this material showed that it contained only a trace of the 2,6-isomer.
This material was used directly in the following step without additional purification.
90% With bromine In dichloromethane; water EXAMPLE 5
Preparation of α[4(4'-bromo-2'-fluorophenoxy)phenoxy]propionic acid methyl ester STR30
To a stirred solution of 2-fluorophenol (22.4 g, 0.2 mole) in methylene chloride (250 ml) which was cooled to ~3° C. in an ice bath, was added, all at once, bromine (31.97 g, 0.2 mole).
The resulting solution was stirred at ice bath temperature for two hours and then at room temperature for 1 hour.
The mixture was poured into water (600 ml) containing excess sodium bisulfite.
The organic phase was separated and the aqueous phase was washed with additional methylene chloride (200 ml).
The combined organic extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and the solvent evaporated to give the desired 2-fluoro-4-bromophenol as a colorless oil (34.5 g, 90percent).
The NMR (CDCl3) was consistent with the assigned structure.

Reference: [1] Patent: US4642338, 1987, A,
[2] Patent: US4725683, 1988, A,
[3] Patent: US4808750, 1989, A,
[4] Patent: US4550192, 1985, A,
[5] Chemistry - A European Journal, 2017, vol. 23, # 5, p. 1044 - 1047
[6] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
[7] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3112 - 3129
[9] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[10] Patent: WO2005/123748, 2005, A1, . Location in patent: Page/Page column 84 - 85
[11] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 58
[12] Patent: WO2006/137770, 2006, A1, . Location in patent: Page/Page column 33
[13] Canadian Journal of Chemistry, 2011, vol. 89, # 3, p. 364 - 384
  • 2
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
  • [ 576-86-3 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 46, p. 9456 - 9463
  • 3
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
Reference: [1] Patent: US5225607, 1993, A,
[2] Patent: EP240121, 1991, B1,
  • 4
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
Reference: [1] Patent: US4829074, 1989, A,
  • 5
  • [ 2357-52-0 ]
  • [ 2105-94-4 ]
Reference: [1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
  • 6
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
  • [ 576-86-3 ]
  • [ 2040-89-3 ]
Reference: [1] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
  • 7
  • [ 403-19-0 ]
  • [ 2105-94-4 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
  • 8
  • [ 366-99-4 ]
  • [ 2105-94-4 ]
Reference: [1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
  • 9
  • [ 348-61-8 ]
  • [ 2105-94-4 ]
  • [ 112204-58-7 ]
Reference: [1] Synlett, 2009, # 4, p. 633 - 637
  • 10
  • [ 106-41-2 ]
  • [ 2105-94-4 ]
  • [ 104197-13-9 ]
Reference: [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
  • 11
  • [ 95-56-7 ]
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Reference: [1] Patent: CN104844399, 2016, B,
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Reference: [1] Patent: CN104844399, 2016, B,
  • 13
  • [ 1073-06-9 ]
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Reference: [1] Xenobiotica, 1994, vol. 24, # 8, p. 759 - 774
  • 14
  • [ 399-96-2 ]
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Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
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  • [ 394-50-3 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
  • 16
  • [ 367-12-4 ]
  • [ 2105-94-4 ]
  • [ 576-86-3 ]
  • [ 2040-89-3 ]
Reference: [1] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
  • 17
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  • [ 350-29-8 ]
Reference: [1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
  • 18
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  • [ 341-27-5 ]
Reference: [1] Synthesis, 1999, # 11, p. 1878 - 1880
  • 19
  • [ 557-21-1 ]
  • [ 2105-94-4 ]
  • [ 405-04-9 ]
YieldReaction ConditionsOperation in experiment
98% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; for 2 h; To a solution of 4-bromo-2-fluoro phenol 14-I (500 mg, 2.62 mmol) in DMF (15 mL) was addedzinc cyanide (492 mg, 4.2 mmol) and terakis(triphenylphosphine)palladium (302 mg ,0.262mmol) and the solution was stirred at 120 °C for 2 h. The reaction mixture was cooled to roomtemperature and the black precipitate was removed by filteration. After concentrating the filtrate,saturated aqueous NaHCO3 solution was added into the residue mixture was extracted with ethylacetate (3 × 20 mL). The organic layer was washed with brine, dried over anhyd. Na2SO4 andconcentrated to get crude product which was purified by column chromatography using pet.Ether:EtOAc (8:2) to give 250 mg 4-cyano-2fluoro phenol 14-II.
Reference: [1] Synlett, 2016, vol. 27, # 9, p. 1339 - 1343
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  • [ 437-83-2 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
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  • [ 74-88-4 ]
  • [ 2357-52-0 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In N,N-dimethyl-formamide at 20℃; [000274] To a solution of 4-bromo-2-fluorophenol (15 g, 78.5 mmol) in DMF (200 mL) was added K2CO3 (32.25 g, 235.6 mmol), CH3I (12.3 mL, 96.3 mmol). The mixture was stirred at rt overnight. Water (500 mL) was added to the mixture and the mixture was extracted with ethyl acetate (200 mL x 3), dried over anhydrous Na2S04, and purified by column chromatography on silica gel (petroleum 100percent) to obtain Compound 4A (11.3 g, 70percent)) as a colorless oil. 1H-NMR (CDCI3, 400 MHz) major characteristic peaks: δ (ppm) 3.86 (s, 3H), 6.83 (t, J= 8.8 Hz, 1H), 7.20 (m, 2H).
Reference: [1] Patent: WO2015/42397, 2015, A1, . Location in patent: Paragraph 000274
[2] Patent: WO2005/123748, 2005, A1, . Location in patent: Page/Page column 85
[3] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 58
[4] Patent: WO2006/137770, 2006, A1, . Location in patent: Page/Page column 33
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  • [ 320-76-3 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
  • 23
  • [ 106-41-2 ]
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  • [ 104197-13-9 ]
Reference: [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
  • 24
  • [ 348-61-8 ]
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  • [ 112204-58-7 ]
Reference: [1] Synlett, 2009, # 4, p. 633 - 637
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  • [ 73183-34-3 ]
  • [ 760990-08-7 ]
YieldReaction ConditionsOperation in experiment
93% With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane for 4 h; Inert atmosphere; Reflux 4-bromo-2-fluorophenol (1,9 g, 9.9 mmol), bis(pinacolato)diboron (2.9 g, 11.4 mmol), potassium acetate (3.90g, 39.7 mmol) and DPPF (0.27 g, 0.49 mmol) were dissolved in 32 mL of 1,4-dioxane, and charged with N2 gas for 5minutes. PdCl2(dppf)-DCM (0.4 g, 0.49 mmol) was added thereto, and the mixture was stirred for 4 hours under refluxstirred. The reaction solution was filtered through Celite and purified by column chromatography to obtain the titlecompound (2.2 g, 93 percent).1H NMR (CDCl3) δ 7.49 (2H, m), 6.98 (1H, t), 5.31 (1H, brs), 1.33 (12H, s)
90% With potassium acetate In 1,4-dioxane at 85℃; for 17 h; Inert atmosphere Intermediate 6-6: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
A solution of 4-bromo-2-fluorophenol (1.032 mL, 9.42 mmol) in dioxane (60.2 mL) was degassed with nitrogen for a period of 10 minutes.
Potassium acetate (3.70 g, 37.70 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.59 g, 14.14 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.465 g, 0.57 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0.317 g, 0.57 mmol) were added.
The resulting mixture was stirred at 85° C. under nitrogen for 17 hours (overnight).
The reaction mixture was concentrated and diluted with EtOAc (100 mL), and the mixture was acidified with 1N citric acid (75 mL) and the mixture was filtered through celite.
The aqueous phase was separated and extracted with EtOAc (150 mL) and organic extracts were combined, washed with saturated brine (150 mL), dried over MgSO4, filtered and evaporated to afford crude product which was filtered through a pad of silica, washing through with EtOAc.
The filtrate was evaporated to afford crude product.
The crude product was purified by flash silica chromatography, elution gradient 0 to 20percent EtOAc in isohexane.
Pure fractions were evaporated to dryness to afford 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.020 g, 90percent) as a pale brown oil which solidified on standing.
1H NMR (400.132 MHz, CDCl3) δ 1.33 (12H, s), 5.38 (1H, s), 6.98 (1H, t), 7.47-7.51 (2H, m).
m/z (ES-) (M-H)-=237
19.9 g With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane for 4 h; Inert atmosphere; Reflux 2a:To 4-bromo-2-fluoro-phenol (25.30g, 128 . 0mmol) and bis(pinacolato)diboron(29.00g, 114 . 0mmol) in 300 ml of 1,4-dioxane , added solution of potassium acetate (38.00g, 387 . 0mmol). Argon degassing after the full used, added bis(triphenylphosphine)-palladium chloride (II) (2.8g, 3 . 80mmol). The reaction mixture is heated to reflux and stirred for 4 hours. After the cooling to room temperature, add 800 ml distilled water. Methyl tert-butyl ether and separate the aqueous phase used for extraction. Combined with the phase and drying with anhydrous sodium sulfate, and through the silica gel filter. After removing the solvent in a vacuum, through the use of 3:2 the heptane/methyl tert-butyl ether as eluant of oily residue by silica gel column chromatographic purification. The obtained crude product is recrystallized from heptane to further obtain the white crystalline 2a (19.9g).
Reference: [1] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0417
[2] Patent: US2010/324068, 2010, A1, . Location in patent: Page/Page column 30
[3] Patent: WO2014/209034, 2014, A1, . Location in patent: Paragraph 432; 433; 434
[4] Patent: CN105384638, 2016, A, . Location in patent: Paragraph 0678; 0679; 0680; 0681
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10479 - 10497
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Reference: [1] Patent: WO2008/63300, 2008, A2, . Location in patent: Page/Page column 198
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  • [ 61676-62-8 ]
  • [ 760990-08-7 ]
Reference: [1] Chemical Communications, 2006, # 24, p. 2589 - 2591
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  • [ 253429-19-5 ]
  • [ 286836-04-2 ]
Reference: [1] Patent: EP1204654, 2003, B1,
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  • [ 279263-10-4 ]
Reference: [1] Patent: EP2484658, 2012, A1,
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  • [ 156487-13-7 ]
Reference: [1] Patent: EP2399896, 2011, A1,
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  • [ 1532533-67-7 ]
Reference: [1] Patent: WO2014/6572, 2014, A1,
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  • [ 1532533-69-9 ]
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