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[ CAS No. 433939-27-6 ] {[proInfo.proName]}

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Chemical Structure| 433939-27-6
Chemical Structure| 433939-27-6
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Product Details of [ 433939-27-6 ]

CAS No. :433939-27-6 MDL No. :MFCD07783710
Formula : C6H4BrFO Boiling Point : -
Linear Structure Formula :- InChI Key :JCPJGUPQZDEZQH-UHFFFAOYSA-N
M.W : 191.00 Pubchem ID :21904636
Synonyms :

Calculated chemistry of [ 433939-27-6 ]

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) : -5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.72
Log Po/w (XLOGP3) : 2.36
Log Po/w (WLOGP) : 2.71
Log Po/w (MLOGP) : 2.67
Log Po/w (SILICOS-IT) : 2.48
Consensus Log Po/w : 2.39

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.0
Solubility : 0.189 mg/ml ; 0.00099 mol/l
Class : Soluble
Log S (Ali) : -2.43
Solubility : 0.718 mg/ml ; 0.00376 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 : 1.42

Safety of [ 433939-27-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 433939-27-6 ]

* 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 [ 433939-27-6 ]
  • Downstream synthetic route of [ 433939-27-6 ]

[ 433939-27-6 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 461-96-1 ]
  • [ 433939-27-6 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With 2-(methylsulfonyl)ethyl alcohol; potassium <i>tert</i>-butylate In dimethyl sulfoxide at 0 - 20℃; for 3 h;
Stage #2: With hydrogenchloride In water; dimethyl sulfoxide
Stage #3: With sodium hydroxide In diethyl ether; water
To a solution of l-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and 2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was added potassium tert-butoxide (76.6 g, 0.682 mole) at 00C. The resulting mixture was stirred at room temperature for 3h and quench with 4N HCl slowly to pH < 1. The desired product was extracted with Et2O (12 L) until no product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure to one third the amount of the <n="223"/>solvent and washed with IN NaOH (12 L). Then, the NaOH solution was adjusted to pH= 3 and extracted with Et2O until no desired product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure and passed through an Al2O3 column eluted with Et2O to afford 3-bromo-5-fluorophenol as a colorless oil (48 g, 94percent yield). LC-MS 190.33 (M+H); Analytical HPLC = 2.26 minutes (0-100percent CH3CN in H2O witfi 0.1percent TFA in a 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 6.88 - 6.64 (m, 2H), 6.58 - 6.30 (m, 1 H), 4.99 (s, 1 H).
Reference: [1] Patent: WO2007/62308, 2007, A2, . Location in patent: Page/Page column 220-221
[2] Synlett, 2009, # 4, p. 633 - 637
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 22, p. 9010 - 9026
[4] Patent: WO2007/62342, 2007, A1, . Location in patent: Page/Page column 176; 205
[5] Patent: US2007/161685, 2007, A1, . Location in patent: Page/Page column 115
[6] Journal of Medicinal Chemistry, 2012, vol. 55, # 13, p. 6162 - 6175
  • 2
  • [ 130722-44-0 ]
  • [ 433939-27-6 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0℃; for 2.16667 h;
Stage #2: With hydrogenchloride In dichloromethane; water
To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N,N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous CH2Cl2 (1.0 L) at 0° C. was added aluminium chloride (156.0 g, 1.17 mol).
After 10 min, the ice bath was removed and the stirring was continued for 2 h.
The reaction was quenched by the cautious addition of 3N HCl (600 mL).
The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2*150 mL).
The combined organic extracts were washed with 2N HCl (250 mL) and H2O (3*250 mL).
To the organic layer was added 15percent KOH (500 mL), and the layers were separated.
The organic layer was further extracted with 2 N KOH (2*70 mL).
The combined aqueous layers were washed with CH2Cl2 (3*100 mL) and then acidified with 4N HCl.
The aqueous layer was extracted with Et2O (3*125 mL) then, the combined Et2O extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92percent) as a brown oil that was used without further purification.
Mp: 33-35° C.
Rf=0.25 (CHCl3)
1H NMR (300 MHz, DMSO-d6) δ10.38 (s, 1H), 6.90 (dd, JH-F=11 Hz, J=2 Hz, 1H), 6.81 (s, 1H), 6.59 (dt, JH-F=11 Hz, J=2 Hz, 1H).
92% With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0℃; for 2.16667 h; To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N, N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous [CH2CI2] (1.0 L) at [0°C] was added aluminium chloride (156.0 g, 1.17 mol). After 10 min, the ice bath was removed and the stirring was continued for 2 h. The reaction was quenched by the cautious addition of 3N HC1 (600 mL). The layers were separated, and the aqueous layer was extracted with [CH2CI2] (2 x 150 mL). The combined organic extracts were washed with 2N HCI (250 mL) and [H2O] (3 x 250 mL). To the organic layer was added 15percent KOH (500 mL), and the layers were separated. The organic layer was further extracted with 2 N KOH (2 x 70 mL). The combined aqueous layers were washed with [CH2CI2] (3 x 100 [ML)] and then acidified with 4N HCI. The aqueous layer was extracted with [ET,] O [X 1 ? 5] mL) then, the combined Et20 extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92percent) as a brown oil that was used without further purification. Mp: [33-35°C] Rf = 0.25 (CHC13) 'H NMR (300 MHz, DMSO-d6) 8 10.38 (s, 1H), 6.90 (dd, [JH-F] = [11 HZ, J] = 2 Hz, 1H), 6.81 (s, [1H),] 6.59 (dt, JH-F = 11 Hz, [J] = 2 Hz, [1H).] APCI-MS: (M-1) = 189 m/z
66.6%
Stage #1: With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0 - 20℃; for 2.16667 h;
Stage #2: With hydrogenchloride In dichloromethane; water
3-bromo-5-fluoro-phenol
Add aluminum chloride (13.51 g, 101.38 mmol) to 1-benzyloxy-3-bromo-5-fluoro-benzene (9.50 g, 33.79 mmol, prepared according to WO 03/101956) and dimethylaniline (40.96 g, 337.92 mmol) in dichloromethane (84 mL) at -0° C. under nitrogen and stir 10 minutes.
Remove ice-bath and stir 2 hours.
Add 60 mL 2N hydrochloric acid dropwise.
Separate layers and wash the organic layer with 2N hydrochloric acid (4*50 mL).
Extract the organic layer with 3N potassium hydroxide (4*50 mL).
Acidify with 5N hydrochloric acid and extract with dichloromethane (3*50 mL).
Dry the dichloromethane layer (sodium sulfate) and concentrate to give 4.3 g (66.6percent) of the desired compound as an oil.
Reference: [1] Patent: US2004/19033, 2004, A1, . Location in patent: Page/Page column 32
[2] Patent: WO2003/101956, 2003, A1, . Location in patent: Page 88; 89
[3] Patent: US2007/225267, 2007, A1, . Location in patent: Page/Page column 62
  • 3
  • [ 29578-39-0 ]
  • [ 433939-27-6 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With boron tribromide In dichloromethane at -30 - 5℃; for 3 h;
Stage #2: With water; sodium hydrogencarbonate In dichloromethane
Step 2
3-Bromo-5-fluorophenol
To a solution of 1-bromo-3-fluoro-5-methoxybenzene (3.0 g, 0.015 mol) in dry CH2Cl2 (80 mL) under an inert atmosphere and cooled to -30° C. was added 1 M BBr3 (4.27 mL, 0.045 mol) in 21 mL of CH2Cl2 dropwise while maintaining temperature at -30° C.
The reaction was stirred for 3 h at 0-5° C. and then the reaction mixture was quenched with aqueous saturated NaHCO3.
Water was added and the mixture was extracted with CH2CO2 three times.
The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.54 g, 91percent).
85% With boron tribromide In dichloromethane at -78 - 20℃; for 3 h; To a stirred suspension of l-bromo-3-fluoro-5-methoxybenzene (5.0 g, 25 mmol) in DCM (50 mL) was added BBr3 (12.2 g, 50 mmol) at -78°C. The resulting mixture was stirred at -78°C to r.t for 3hrs, then the mixture was poured into ice-water and extracted with EtOAc. The organics was dried and concentrated to give 3-bromo- 5-fluorophenol (4 g, 85percent yield) as yellow oil. lH NMR: (CDC13 400MHz) δ 6.82- 6.80 (m, 2H), 6.53-6.51(m, 1H), 6.20-6.15(m, 1H).
Reference: [1] Patent: US2008/261941, 2008, A1, . Location in patent: Page/Page column 43
[2] Patent: WO2017/151489, 2017, A1, . Location in patent: Paragraph 0248
  • 4
  • [ 15205-66-0 ]
  • [ 461-96-1 ]
  • [ 433939-27-6 ]
Reference: [1] Patent: US2010/41717, 2010, A1, . Location in patent: Page/Page column 45
  • 5
  • [ 433939-27-6 ]
  • [ 216755-56-5 ]
Reference: [1] Patent: US5446055, 1995, A,
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