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CAS No. : | 6942-39-8 | MDL No. : | MFCD00086167 |
Formula : | C8H6BrFO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FCMQMRAFVRTHCR-UHFFFAOYSA-N |
M.W : | 233.03 | Pubchem ID : | 138875 |
Synonyms : |
|
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 : | 0.0 |
Molar Refractivity : | 45.38 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.17 cm/s |
Log Po/w (iLOGP) : | 2.32 |
Log Po/w (XLOGP3) : | 3.59 |
Log Po/w (WLOGP) : | 2.8 |
Log Po/w (MLOGP) : | 3.09 |
Log Po/w (SILICOS-IT) : | 2.79 |
Consensus Log Po/w : | 2.92 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.78 |
Solubility : | 0.0383 mg/ml ; 0.000164 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.83 |
Solubility : | 0.0346 mg/ml ; 0.000148 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.61 |
Solubility : | 0.0569 mg/ml ; 0.000244 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 1.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 0℃; | Methyl 2-bromo-5-fluorobenzoate (159-1). Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0°C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 percent of 159-1 as a yellow oil. |
98% | Stage #1: at 0℃; Stage #2: With acetic acid In methanol; diethyl ether |
Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0°C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 percent of 2λ as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 23℃; for 48 h; Inert atmosphere | DBU(1.7 equiv, 1.16 mL, 7.76 mmol) was added to a solution of 2-bromo-5-fluorobenzoic acid (1.0 equiv, 1.0 g, 4.57 mmol) and iodomethane (2.0 equiv, 0.57 mL, 9.14mmol) in CH3CN (11 mL) at 23 °C. After stirring for 48 h, thereaction was quenched with H2O (10 mL) and extracted with Et2O(2 x 10 mL). The combined organic extracts were washed with water (20 mL),brine (20 mL), dried over Na2SO4 and filtrated.Evaporation of the solvent under reduced pressure followed by flashchromatography (SiO2, 95/5 hexane/EtOAc) afforded the desired ester (1.0g, 98percent of yield) as a colorless oil. Rf = 0.50 (95/5 hexane/EtOAc); 1H NMR (400 MHz, CDCl3,25 °C): d 7.63 (dd, J= 8.8, 5.1 Hz, 1H), 7.53 (ddd, J =8.7, 3.1 Hz, 1H), 7.07 (ddd, J = 8.8, 7.6, 3.1 Hz, 1H), 3.94 (s, 3H)ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | for 24 h; | Preparation 6; test-butyl [2- (aminomethyl)-4-fluorobenzyl] carbamate; (a) Methyl 2-bromo-5-fluorobenzoate; To a solution of 2-bromo-5-fluorobenzoic acid (3.0 g, 13.7 mmol) in methanol (4 mL) was added HCl-saturated methanol (70 mL). The reaction mixture was stirred for 24 hours and then concentrated. The excess of HC1 was removed by co-evaporation from methanol to give the sub-title compound (97percent), which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) 6 3.96 (s, 3H), 7.09 (dt, 1H), 7.55 (dd, 1H), 7.65 (dd, 1H) |
84.7% | for 4 h; Reflux | General procedure: To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3percent.This compound was prepared according to the general procedure reported by Baker.13 The spectral data were consistent with that reported in the literature. |
50 g | for 8 h; Reflux; Inert atmosphere | In the nitrogen atmosphere,2-bromo-5-fluorobenzoic acid (50.0 g) was added,Sulfuric acid (7 ml) and methanol (500 ml) was stirred at reflux temperature for 8 hours.After the reaction solution was cooled to room temperature,The methanol was distilled off under reduced pressure,And then an aqueous solution of ethyl acetate and sodium hydrogencarbonate was added thereto to carry out liquid separation.The solvent of the organic layer was evaporated under reduced pressure to give methyl 2-bromo-5-fluorobenzoate (50.0 g). |
2.7 g | at 0 - 68℃; for 18 h; | Step 1. methyl 2-bromo-5-fluorobenzoate (0904) (0905) To a solution of 2-bromo-5-fluorobenzoic acid (4.00 g, 18.26 mmol) in MeOH (120 mL, anhydrous) was added SOCl2 (3.26 g, 27.40 mmol) dropwise at 0 °C and the mixture was heated at 68 °C for 18 h. TLC (petroleum ether: EtOAc = 5:1) confirmed the desired product. The mixture was concentrated and the residue was mixed with EtOAc (200 mL), washed by NaHCO3 (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give methyl 2-bromo-5-fluorobenzoate as a colorless oil. Yield: 2.7 g LCMS method C: Rt = 0.77 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | Stage #1: With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol at 20℃; Stage #2: With hydrogenchloride; water In tetrahydrofuran; ethanol for 0.166667 h; |
6.24. Synthesis of (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid The mixture of 2-bromo-5-fluoro-benzoic acid methyl ester (1 g, 4.292 mmol), NaBH4 (0.423 g, 11.159 mmol) and LiCl (0.474 g, 11.159 mmol) in THF/EtOH (20 ml/10 ml) was stirred at room temperature overnight. Aqueous HCl (10 ml, 2N) was added and stirred for about 10 min. Then the organic solvent was removed under low vacuum. The residue was diluted with water and extracted by ethyl acetate. The organic layer was washed with aqueous NaHCO3 (10percent), water and brine, and then dried (MgSO4) and concentrated to afford 852 mg (96.8percent crude yield) crude product, (2-bromo-5-fluoro-phenyl)methanol, as a white solid, which was used without further purification. |
96.8% | With hydrogenchloride; sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol | 6.56. Synthesis of (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid The mixture of 2-bromo-5-fluoro-benzoic acid methyl ester (1 g, 4.292 mmol), NaBH4 (0.423 g, 11.159 mmol) and LiCl (0.474 g, 11.159 mmol) in THF/EtOH (20 ml/10 ml) was stirred at room temperature overnight. Aqueous HCl (10 ml, 2N) was added and stirred for about 10 min. Then the organic solvent was removed under low vacuum. The residue was diluted with water and extracted by ethyl acetate. The organic layer was washed with aqueous NaHCO3 (10percent), water and brine, and then dried (MgSO4) and concentrated to afford 852 mg (96.8percent crude yield) crude product, (2-bromo-5-fluoro-phenyl)methanol, as a white solid, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | at 110℃; | A 500 mL round-bottom flask was charged with methyl 2-bromo-5-fluorobenzoate (48 g, 206 mmol), copper cyanide (37 g, 412 mmmol) and DMF (200 mL). The mixture was heated at 110° C. overnight and then cooled to room temperature. Ether (1.5 L) and Celite (100 g) were added and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and the filtrate was washed with brine (3×200 mL) and then dried over MgSO4. The solvent was evaporated under reduced pressure to give the desired product as a colorless solid (31 g, 84percent). MS: (ES) m/z calculated for C9H7FNO2[M+H]+ 180, found 180. |
84% | at 110℃; | A 500 mL round-bottom flask was charged with methyl 2-bromo-5- fluorobenzoate (48 g, 206 mmol), copper cyanide (37 g, 412 mmmol) and DMF (200 mL). The mixture was heated at 110 °C overnight and then cooled to room temperature. Ether (1.5 L) and Celite (100 g) were added and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and the filtrate was washed with brine (3 x 200 mL) and then dried over MgS04. The solvent was evaporated under reduced pressure to give the desired product as a colorless solid (31 g, 84percent). MS : (ES) m/z calculated for C9H7FN02[M+H]+ 180.1, found 180.1. |
84% | at 110℃; | [0126] Step a: A 500 niL round-bottom flask was charged with methyl 2-bromo-5- fluorobenzoate (48 g, 206 mmol), copper cyanide (37 g, 412 mmmol) and DMF (200 mL). The mixture was heated at 110 °C overnight and then cooled to room temperature. Ether (1.5 L) and Celite (100 g) were added and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and the filtrate was washed with brine (3 x 200 mL) and then dried over MgS04. The solvent was evaporated under reduced pressure to give the desired product as a colorless solid (31 g, 84percent). MS: (ES) m/z calculated for C9H7FN02[M + H]+180, found 180. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | for 1.5 h; Heating / reflux | (b) Methyl 2-cyano-5-fluorobenzoate; Methyl 2-bromo-5-fluorobenzoate (3.0 g, 12.87 mmol; see step (a) above) was dissolved in dry DMF (18 mL). The resulting solution was then degassed by flushing with N2 gas for 5 minutes. Copper (I) cyanide (2.3 g, 25.74 mmol) was added and the reaction mixture was degased again before being refluxed for 90 minutes. NaCN (aq, 10percent) was added and the mixture was extracted with DCM. The DCM phase was dried through a phase separator and the solvent was removed in vacuo. The crude product was dissolved in toluene and washed once with water. The organic phase was dried over MgS04 and filtered. The solvent was removed iM vacuo to give the crude sub-title compound (77percent), which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) 5 4.04 (s, 3H), 7.38 (dt, 1H), 7.82-7. 87 (m, 2H) |
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