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Chemical Structure| 222978-01-0

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Product Details of [ 222978-01-0 ]

CAS No. :222978-01-0
Formula : C7H6BrFO
M.W : 205.02
SMILES Code : OCC1=CC=C(Br)C(F)=C1
MDL No. :MFCD08236860
Boiling Point : No data available
InChI Key :VQDUFYPJCUBGQW-UHFFFAOYSA-N
Pubchem ID :20682297

Safety of [ 222978-01-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 222978-01-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 40.23
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

20.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.89
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.83
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.35
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.72
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.77
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.31

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.64
Solubility 0.467 mg/ml ; 0.00228 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.88
Solubility 2.73 mg/ml ; 0.0133 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.36
Solubility 0.0887 mg/ml ; 0.000433 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.25 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.39

Application In Synthesis of [ 222978-01-0 ]

* 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.

  • Downstream synthetic route of [ 222978-01-0 ]

[ 222978-01-0 ] Synthesis Path-Downstream   1~35

  • 2
  • [ 153556-42-4 ]
  • [ 222978-01-0 ]
YieldReaction ConditionsOperation in experiment
94% With borane-THF; In tetrahydrofuran; at 25℃; General procedure: BH3.THF (89 mL, 89.49 mmol) was added dropwise to a stirred solution of 4-bromo-3-fluorobenzoic acid (9.8 g, 44.75 mmol) in THF (200 mL) at 25C, over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperaturefor 2 days. The reaction mixture was cautiously quenched with 2M Na2CO3 (200 mL),extracted with Et2O (2 x 500 mL), the organic extratcts were combined, washed with saturated brine (400 mL), dried over MgSO4, filtered and evaporated to afford a paleyellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (4-bromo-3-fluorophenyl)methanol (8.65 g, 94 %) as a white solid.
93% To a solution of commercially available 4-bromo-3-fluoro-benzoic acid (SI-2) (11 g, 50 mmol) in THF (250 mL) was added BH3 (1.0 M in THF, 100 mL, 100 mmol) at 0 oC and then the solution was stirred at 70 oC overnight. Then, the mixture was quenched with MeOH and 1 N HCl, and stirred at room temperature for an additional 2 hours. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography to obtainSI-3 (9.5 g, 93%) as a yellow oil.ESI-MS m/z 205 [M+H]+calc. forC7H6BrFO.This intermediate was used in the next step without further characterization.
93.3% With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere; A solution of 4-bromo-3-fluoro-benzoic acid (15.0 g, 68.5 mmol) in THF (150 mL) was cooled to 0 C. and borane-dimethyl sulfide complex (13.7 mL, 137 mmol, 10 M in THF) was added dropwise under nitrogen atmosphere. The cooling bath was removed and the mixture was stirred at ambient temperature for 12 hours. The mixture was cooled to 0 C., quenched with MeOH (50 mL) and poured into water (30 mL). The mixture was concentrated under vacuum and the residual aqueous mixture was diluted with ethyl acetate (150 mL) and water (150 mL) and stirred for 15 minutes. The organic phase was removed and the aqueous phase was extracted with ethyl acetate (150 mL*2). The organic fractions were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (2-10% ethyl acetate in petroleum ether) to give 4-bromo-3-fluoro-phenyl)methanol (13.1 g, 93.3% yield) as a colorless liquid. LCMS (ESI) m/z 187.0 [MH-18-]. 1H NMR (400 MHz, CDCl3) delta ppm 7.54-7.45 (m, 1H), 7.14 (d, J=9.2 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 4.64 (d, J=4.6 Hz, 2H), 2.20 (br s, 1H).
91.6% With dimethylsulfide borane complex; In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 6h; Step 1 (MT-Si):Boranmethyl sulfide in ether (5.0 M; 38.3 mL, 191.8 mmol) was added to a solution of 4- bromo-3-fluorobenzoic acid (21.0 g, 95.9 mmol) in dry tetrahydrofuran (250 mL) at 0C and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate, and the combined organic layers were washed with water, brine; dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum to afford 18 g (91 .6%) of MTSi as a colorless liquid, further used without any purification.
87% With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 72h; Step A: (4-Bromo-3-fluorophenyl methanolA 0C solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5 ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1 M solution in THF, 15.75 mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with IN HC1, stirred for 20 minutes, then extracted with DCM. Concentration and silica gel chromatography (10-50% EtOAc/hexanes) yields the title compound 1.87 g (87 % yield) as colorless needles. 1H NMR (500 MHz, CDC13) delta 7.55 (m, IH), 7.04 (d, J9.4 Hz, IH), 7.04 (d, J 8.3 Hz, IH), 4.70 (d, 2H).
87% With borane-THF; In tetrahydrofuran; at 20℃; for 72h; A ooc solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1M solution in THF, 15.75mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with20 IN HCl, stirred for 20 minutes, then extracted with DCM. Concentration and silica gelchromatography (10-50% EtOAc/hexanes) yields the title compound 1.87 g (87% yield) ascolorless needles. 1H NMR (500 MHz, CDCh) 8 7.55 (m, IH), 7.04 (d, J9.4 Hz, IH), 7.04 (d, J8.3 Hz, IH), 4.70 (d, 2H).
84% To a suspension of sodium borohydride (10.4 g, 0.27 mol) in tetrahydrofuran (200 mL) was added boron trifluoride etherate (44.3 mL, 0.36 mol) followed by 4-bromo-3- fluoro-benzoic acid (10.0 g, 0.04 mol) in THF (200 mL) at ice temperature. The mixture was allowed to stir at room temperature over a period of 2 h. The resulting reaction mixture was quenched with methanol and methanol was removed under reduced pressure. The residue obtained upon evaporation of methanol was diluted with ethyl acetate (1.0 L), washed with water (700 mL), dried over sodium sulphate and concentrated to give (4- bromo-3-fluoro-phenyl)-methanol as off-white solid (7.9 g, 84%)
84% To a suspension of sodium borohydride (10.4 g, 0.27 mol) in tetrahydrofuran (200 mL) was added boron trifluoride etherate (44.3 mL, 0.36 mol) followed by 4-bromo-3-fluoro-benzoic acid (10.0 g, 0.04 mol) in THF (200 mL) at ice temperature. The mixture was allowed to stir at room temperature over a period of 2 h. The resulting reaction mixture was quenched with methanol and methanol was removed under reduced pressure. The residue obtained upon evaporation of methanol was diluted with ethyl acetate (1.0 L), washed with water (700 mL), dried over sodium sulphate and concentrated to give (4-bromo-3-fluoro-phenyl)-methanol as off-white solid (7.9 g, 84%).
73% A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4x 3 mL to rinse) under N2 was added drop- wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous TIIF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2x 3 mL) was added drop- wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10% HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4x 50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50% CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73%) as a white solid: mp (CH2Cl2/petroleum ether) 39-40 C; 1H NMR (CDCl3) delta 7.52 (dd, J = 8.0, 7.2 Hz, 1 H), 7.16 (dd, J = 9.3, 1.8 Hz, 1 H), 7.02 (dd, J = 8.2, 1.8 Hz, 1 H), 4.67 (d, J = 5.9 Hz, 2 H), 1.75 (t, J = 5.9 Hz, 1 H); HREIMS calcd for C7H6BrFO mlz (M+) 205.9567, 203.9586, found 205.9566, 203.9580.
73% R. Synthesis of (6S)-6-[2-fluoro-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-6][1,3]oxazine (15) by the method of Scheme 11 A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4×3 mL to rinse) under N2 was added drop-wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous THF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2×3 mL) was added drop-wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10% HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50% CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73%) as a white solid: mp (CH2Cl2/petroleum ether) 39-40 C.; 1H NMR (CDCl3) delta 7.52 (dd, J=8.0, 7.2 Hz, 1H), 7.16 (dd, J=9.3, 1.8 Hz, 1H), 7.02 (dd, J=8.2, 1.8 Hz, 1H), 4.67 (d, J=5.9 Hz, 2H), 1.75 (t, J=5.9 Hz, 1H); HREIMS calcd for C7H6BrFO m/z (M+) 205.9567, 203.9586, found 205.9566, 203.9580.
In tetrahydrofuran; water; Step B Preparation of 4-bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
In tetrahydrofuran; water; Step B Preparation of 4-bromo-3-fluorobenzyl alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
In tetrahydrofuran; water; Step B Preparation of 4-bromo-3-fluorobenzyl alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
In tetrahydrofuran; water; Step B: Preparation of 4-bromo-3-fluorobenzyl alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol), prepared as described in Step A, was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
In tetrahydrofuran; water; Step B Preparation of 4-Bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) delta 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
In tetrahydrofuran; water; Step B: Preparation of 4-bromo-3-fluorobenzyl alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) d 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
With borane; In tetrahydrofuran; water; Step I Preparation of 4-Bromo-3-fluorobenzyl Alcohol To a solution of the product from Step H (14.69 g, 67.0 mmol) in 40 mL of tetrahydrofuran at 0 C. was added borane in THF (141 mL, 141 mmol, 1M) dropwise, keeping the reaction temperature below 5 C. The solution was allowed to warm to room temperature, then stirred for one hour. The reaction was cautiously quenched at 0 C. with 50 mL of water, concentrated in vacuo, and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
In tetrahydrofuran; water; Step B Preparation of 4-Bromo-3-fluorobenzyl Alcohol 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10 C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3*100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing. 1H NMR (CDCl3) d 7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02 (d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).
With sodium hydrogencarbonate; In tetrahydrofuran; water; ethyl acetate; Reference Example 65 (4-Bromo-3-fluorophenyl)methanol A solution of 4-bromo-3-fluorobenzoic acid (39.422 g) in THF (240 mL) was cooled to 0 C. under a nitrogen atmosphere. A borane-tetrahydrofuran complex (0.9 M solution in THF, 400 mL) was added dropwise thereto, and the mixture was stirred for 2 hours and then stirred at room temperature for 20 hours. The reaction mixture was cooled to 0 C., and water (40 mL) was added dropwise thereto. The reaction mixture was concentrated, and water (200 mL), ethyl acetate (100 mL), and a saturated aqueous solution of sodium bicarbonate (100 mL) were added to the residue in this order, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and saturated aqueous sodium chloride in this order, dried over anhydrous magnesium sulfate, and then concentrated to obtain the title compound (36.71 g). 1H NMR (CDCl3, 400 MHz): delta (ppm) 7.53 (dd, J=8.1, 7.3 Hz, 1H), 7.14-7.19 (m, 1H), 7.00-7.06 (m, 1H), 4.68 (d, J=5.7 Hz, 2H), 1.75 (t, J=5.9 Hz, 1H)

  • 3
  • [ 358-23-6 ]
  • [ 222978-01-0 ]
  • [ 476494-04-9 ]
  • 1-(4-bromo-3-fluoro-benzyl)-5-{2-[4-(7-methanesulfonyloxy-naphthalen-1-yl)-3-oxo-piperazin-1-yl]-ethyl}-3-trityl-3<i>H</i>-imidazol-1-ium; trifluoro-methanesulfonate [ No CAS ]
  • 4
  • [ 13154-24-0 ]
  • [ 222978-01-0 ]
  • [ 1009334-17-1 ]
YieldReaction ConditionsOperation in experiment
89% With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h; To a solution of <strong>[222978-01-0](4-bromo-3-fluoro-phenyl)-methanol</strong> (410 mg, 2.0 mmol) and imidazole (163 mg, 2.4 mmol) in DMF (10 mL) was added triisopropylsilyl chloride (0.472 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. The organic layer was isolated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-SPE, pentane) to provide the title compound as a colourless oil (643 mg, 89%). IH NMR (CDCl3, 400MHz) 7.48 (dd, J=8.1, 7.0 Hz, IH), 7.16 (d, J = 9.7 Hz, IH), 6.99 (d, J=8.7 Hz, IH), 4.78 (s, 2H), 1.04-1.24 (m, 21H).
  • 8
  • [ 222978-01-0 ]
  • 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile [ No CAS ]
  • 9
  • [ 222978-01-0 ]
  • [ 101048-76-4 ]
  • 12
  • [ 222978-01-0 ]
  • N-[(4-cyano-3-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methylene]-2-methyl-[S(R)]-propanesulfinamide [ No CAS ]
  • 13
  • [ 222978-01-0 ]
  • N-[(4-cyano-3-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methylene]-2-methyl-[S(S)]-propanesulfinamide [ No CAS ]
  • 15
  • [ 222978-01-0 ]
  • [ 222978-25-8 ]
  • 17
  • [ 222978-01-0 ]
  • 1-(S)-N-[1-(4-cyano-3-fluorophenyl)-1-(3-methyl-3H-imidazol-4-yl)ethyl]-2-methyl-[S(S)]-propanesulfinamide [ No CAS ]
  • 18
  • [ 222978-01-0 ]
  • 1-(R)-N-[1-(4-cyano-3-fluorophenyl)-1-(3-methyl-3H-imidazol-4-yl)ethyl]-2-methyl-[S(R)]-propanesulfinamide [ No CAS ]
  • 19
  • [ 222978-01-0 ]
  • 1-(R)-N-[1-(4-cyano-3-fluorophenyl)-1-(3-methyl-3H-imidazol-4-yl)ethyl]-2-methyl-[S(S)]-propanesulfinamide [ No CAS ]
  • 20
  • [ 222978-01-0 ]
  • [ 275807-74-4 ]
  • 21
  • [ 222978-01-0 ]
  • 4-imidazol-1-ylmethyl-2-[3-(2-oxo-azepan-3-yl)-phenoxy]-benzonitrile [ No CAS ]
  • 22
  • [ 222978-01-0 ]
  • 4-imidazol-1-ylmethyl-2-[3-(1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile [ No CAS ]
  • 23
  • [ 222978-01-0 ]
  • [ 275806-03-6 ]
  • 24
  • [ 222978-01-0 ]
  • [ 222978-23-6 ]
  • 25
  • [ 222978-01-0 ]
  • 2-[3-(3-ethyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile [ No CAS ]
  • 26
  • [ 222978-01-0 ]
  • [ 222978-24-7 ]
  • 27
  • [ 222978-01-0 ]
  • 2-[3-(3(S)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile [ No CAS ]
  • 28
  • [ 222978-01-0 ]
  • 2-[3-(3(R)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile [ No CAS ]
  • 29
  • [ 222978-01-0 ]
  • (R)-(+)-4-[1-amino-1-(1-methyl-1H-imidazol-5-yl)ethyl]-2-fluorobenzonitrile bishydrochloride [ No CAS ]
  • 30
  • [ 222978-01-0 ]
  • (S)-(-)-4-[1-amino-1-(1-methyl-1H-imidazol-5-yl)ethyl]-2-fluorobenzonitrile bishydrochloride [ No CAS ]
  • 31
  • [ 222978-01-0 ]
  • 2-[3-(3-ethyl-1-methyl-2-oxoazepan-3-yl)phenoxy]-4-(1H-imidazol-5-ylmethyl)benzonitrile [ No CAS ]
  • 32
  • [ 222978-01-0 ]
  • 2-[3-(1-acetyl-3-ethyl-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile [ No CAS ]
  • 33
  • [ 222978-01-0 ]
  • 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(3-methyl-3<i>H</i>-imidazol-4-ylmethyl)-benzonitrile [ No CAS ]
 

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