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Product Details of [ 176548-70-2 ]

CAS No. :176548-70-2 MDL No. :MFCD01569540
Formula : C7H4BrFO2 Boiling Point : -
Linear Structure Formula :- InChI Key :KLSLJMGWUPAQGZ-UHFFFAOYSA-N
M.W : 219.01 Pubchem ID :2773339
Synonyms :

Calculated chemistry of [ 176548-70-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.06
TPSA : 37.3 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) : -5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.54
Log Po/w (XLOGP3) : 2.36
Log Po/w (WLOGP) : 2.71
Log Po/w (MLOGP) : 2.79
Log Po/w (SILICOS-IT) : 2.32
Consensus Log Po/w : 2.34

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -3.02
Solubility : 0.208 mg/ml ; 0.00095 mol/l
Class : Soluble
Log S (Ali) : -2.78
Solubility : 0.361 mg/ml ; 0.00165 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.91
Solubility : 0.269 mg/ml ; 0.00123 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.4

Safety of [ 176548-70-2 ]

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 [ 176548-70-2 ]

* 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 [ 176548-70-2 ]
  • Downstream synthetic route of [ 176548-70-2 ]

[ 176548-70-2 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 176548-70-2 ]
  • [ 179898-34-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3243 - 3247
  • 2
  • [ 179898-34-1 ]
  • [ 176548-70-2 ]
YieldReaction ConditionsOperation in experiment
94% for 2 h; Reflux A mixture of 3-bromo-5-fluorobenzonitrile (2.8 g, 13.8 mmol) and aqueous sodium hydroxide (5 M, 28 mL) was heated to reflux for 2 h. After cooling to room temperature, pH was adjusted to 1 by the addition of concentrated hydrochloric acid. The formed precipitate was collected by filtration, the solid was washed with cold water and dried to afford the title compound (2.8 g, 94percent). 1H NMR (400 MHz, CD3OD) d ppm 6.31 (dt, J=8.08, 2.02 Hz, 1 H), 6.37 - 6.43 (m, 1 H), 6.68 (s, 1 H).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6
  • 3
  • [ 124-38-9 ]
  • [ 1435-51-4 ]
  • [ 176548-70-2 ]
Reference: [1] European Journal of Organic Chemistry, 2005, # 24, p. 5242 - 5247
[2] Patent: US6586633, 2003, B1,
  • 4
  • [ 872545-52-3 ]
  • [ 176548-70-2 ]
Reference: [1] European Journal of Organic Chemistry, 2005, # 24, p. 5242 - 5247
  • 5
  • [ 1073-06-9 ]
  • [ 176548-70-2 ]
Reference: [1] European Journal of Organic Chemistry, 2005, # 24, p. 5242 - 5247
  • 6
  • [ 1435-51-4 ]
  • [ 176548-70-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6
  • 7
  • [ 176548-70-2 ]
  • [ 18107-18-1 ]
  • [ 334792-52-8 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: for 1 h;
Stage #2: With acetic acid In methanol; diethyl ether; dichloromethane
To a solution of 3-bromo-5-fluorobenzoic acid (2 g, 9.13 mmol) in DCM/ MeOH (20 ml/ 5 ml) is added trimethylsilyldiazomethane (2M solution in ether; 1 eq, 9.13 mmol) and the mixture is stirred for 1 h. Acetic acid was added dropwise until the yellow colour disappeared. The solvents are then removed in vacuo. The residue is dissolved in DCM and washed with K2CO3. The organic phase is dried (MgSO4) and concentrated in vacuo to give the title compound (1.5 g, 71 percent) LC/MS: 91percent MH+, m/z not ionised, Rt = 1.55 mins.
21% at 20℃; for 0.5 h; Commercially available 3-bromo-5-fmorobenzoic acid (1.Og, 4.57 mmol) was dissolved in methylene chloride (20 mL) trimethylsilyl diazomethane (2M solution in hexane) (5 mL, 10 mmol) was added and the reaction mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography (hexane/methylene chloride 2:1) to yield A101.1 (229mg, 21percent).
Reference: [1] Patent: EP1655283, 2006, A1, . Location in patent: Page/Page column 16-17
[2] Patent: WO2006/122137, 2006, A1, . Location in patent: Page/Page column 124-125
  • 8
  • [ 176548-70-2 ]
  • [ 144-55-8 ]
  • [ 334792-52-8 ]
YieldReaction ConditionsOperation in experiment
80% With sulfuric acid In methanol; diethyl ether Intermediate 25: Methyl 3-bromo-5-fluorobenzoate
Methanol (30 ml) was added to 3-bromo-5-fluorobenzoic acid (3.1 g, 14 mmol) to prepare a solution.
Concentrated sulfuric acid (3.0 ml) was added to the solution, and the mixture was heated under reflux for 1.5 hr.
The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was slowly poured into 400 ml of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction twice with 250 ml of diethyl ether.
The combined organic layers were dried over anhydrous magnesium sulfate and were concentrated under the reduced pressure to give the title compound (2.6 g, 80percent).
Physicochemical properties of intermediate 25
Reference: [1] Patent: EP1229024, 2002, A1,
  • 9
  • [ 176548-70-2 ]
  • [ 67-56-1 ]
  • [ 334792-52-8 ]
YieldReaction ConditionsOperation in experiment
10 g at 0 - 60℃; for 2 h; Step 1: Preparation of methyl 3-bromo-5-fluoro-benzoate To a solution of 3-bromo-5-fluorobenzoic acid (10.0 g, 45.7 mmol) in MeOH (100 mL) was added SOCl2 (6.6 mL, 91.3 mmol) at 0 oC. The reaction mixture was heated to 60 oC and stirred for 2 hrs. The reaction mixture was concentrated in vacuo and the residue was diluted with DCM (250 mL). The resulting mixture was washed with a saturated aqueous solution of NaHCO3 (100 mL), H2O (100 mL) and brine (100 mL) successively, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford methyl 3-bromo-5-fluoro-benzoate (10.0 g) as colorless oil.
Reference: [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 5, p. 508 - 513
[2] Patent: WO2016/177655, 2016, A1, . Location in patent: Page/Page column 235; 236
  • 10
  • [ 176548-70-2 ]
  • [ 334792-52-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6
  • 11
  • [ 176548-70-2 ]
  • [ 216755-57-6 ]
Reference: [1] Patent: US2011/34450, 2011, A1,
[2] Patent: US2012/172448, 2012, A1,
[3] Patent: WO2016/54728, 2016, A1,
[4] Patent: WO2016/74068, 2016, A1,
[5] Patent: CN104447730, 2017, B,
  • 12
  • [ 176548-70-2 ]
  • [ 105515-20-6 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With methyllithium In diethyl ether at -78 - -10℃;
Stage #2: With ammonium chloride In diethyl ether
1-(3-Bromo-5-fluorophenyl)-ethanone
Methyllithium (1.3 M in diethyl ether, 35 mL) was added dropwise to 3-bromo-5-fluorobenzoic acid (5 g) in diethyl ether at -78° C. keeping the temperature below -60° C.
The reaction was then left to warm to -10° C. and was stirred for 1 h before being carefully quenched with saturated ammonium chloride (100 mL) until pH=3.
The product was extracted with diethyl ether (2*100 mL), dried over sodium sulfate and the solvent removed by evaporation to yield 1-(3-bromo-5-fluorophenyl)ethanone as an off-white solid (4.67 g, 94percent).
1H NMR (CDCl3): 2.59 (3H, s, ArCOCH3), 7.44 (1H, dd, Ar), 7.59 (1H, dd, Ar), 7.87 (1H, s, Ar).
Reference: [1] Patent: US2009/209529, 2009, A1, . Location in patent: Page/Page column 35
  • 13
  • [ 176548-70-2 ]
  • [ 216755-56-5 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃;
Stage #2: With methanol In tetrahydrofuran at 0℃;
(3-Bromo-5-fluorophenyl)methanol. 3-Bromo-5-fluorobenzoic acid (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 9 mL, 9.0 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2.x.), then brine (2.x.), dried over sodium sulfate, and concentrated to afford 0.88 g (95percent) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.29 (s, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).
95% With borane-THF In tetrahydrofuran at 0 - 20℃; To a solution of 3-bromo-5-fluorobenzoic acid (4.38 g, 20.0 mmol) Of tetrahydrofuran(20 mL)A solution of 1M borane tetrahydrofuran complex in tetrahydrofuran (30 mL,30. Ommol).Continue stirring at 0 ° C for 1.5 hours,Then stirred at room temperature overnight. Methanol was slowly added to it at room temperature until no gas had escaped to quench. The solvent was evaporated under reduced pressureThe crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1), A pale yellow liquid (3.9 g, 95percent)
67% With borane-THF In tetrahydrofuran at 0 - 20℃; for 23.3667 h; Inert atmosphere [00127] A solution of 3-bromo-5-fluorobenzoic acid (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0°C under nitrogen, was treated with borane-tetrahydrofuran complex (1M, 15 mL, 15 mmol) in small portions over 12 mm, and the reaction was then stirred at 0°C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5-fluorobenzyl alcohol (1.79 g, 67percent). 1H NMR (400 MHz, CDCI3): ö 7.29 (s, IH), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1H), 4.66 (s, 2H), 2.04 (br s, 1 H); 19F NMR (377 MHz, CDCI3): -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); 13C NMR (101 MHz, CDCI3):162.87 (d, JCF 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, JCF = 9.2 Hz), 118.01 (d, JCF = 24.6 Hz), 112.51 (d, JCF = 21.5 Hz), 63.60 (d, JCF = 2.3 Hz).
67% With borane-THF In tetrahydrofuran at 0 - 20℃; for 23.4 h; Inert atmosphere A solution of 3-bromo-5-fluorobenzoic acid (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0°C under nitrogen, was treated with borane-tetrahydrofuran complex (1 M, 15 mL, 15 mmol) in small portions over 12 min, and the reaction was then stirred at 0°C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5- fluorobenzyl alcohol (1.79 g, 67percent). 1H NMR (400 MHz, CDCI3): δ 7.29 (s, 1 H), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1 H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1 H), 4.66 (s, 2H), 2.04 (br s, 1 H); 19F NMR (377 MHz, CDCI3): δ -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); 13C NMR (101 MHz, CDCI3): δ 162.87 (d, JCF = 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, JCF = 9.2 Hz), 118.01 (d, JCF = 24.6 Hz), 112.51 (d, JCF = 21.5 Hz),

Reference: [1] Patent: US2007/249607, 2007, A1, . Location in patent: Page/Page column 81
[2] Patent: CN104447730, 2017, B, . Location in patent: Paragraph 0146-0147
[3] Patent: WO2016/54728, 2016, A1, . Location in patent: Paragraph 00127
[4] Patent: WO2016/74068, 2016, A1, . Location in patent: Paragraph 00121
[5] Patent: WO2006/79791, 2006, A1, . Location in patent: Page/Page column 44
[6] Patent: US6586633, 2003, B1,
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1864 - 1868
[8] Patent: US2011/34450, 2011, A1, . Location in patent: Page/Page column 96
[9] Patent: US2012/172448, 2012, A1, . Location in patent: Page/Page column 19
[10] Patent: US9242996, 2016, B2, . Location in patent: Page/Page column 271; 272
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