Structure of 103291-07-2
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CAS No. : | 103291-07-2 |
Formula : | C7H6BrFO |
M.W : | 205.02 |
SMILES Code : | FC1=C(C=C(C=C1)Br)OC |
MDL No. : | MFCD01861130 |
Boiling Point : | No data available |
InChI Key : | SEVMQEIGENUPIE-UHFFFAOYSA-N |
Pubchem ID : | 13604909 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
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 | 0.0 |
Molar Refractivity | 40.59 |
TPSA ? Topological Polar Surface Area: Calculated from | 9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 2.3 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 2.94 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 3.02 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 2.99 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.92 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 2.83 |
Log S (ESOL):? ESOL: Topological method implemented from | -3.34 |
Solubility | 0.0934 mg/ml ; 0.000456 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.8 |
Solubility | 0.328 mg/ml ; 0.0016 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.66 |
Solubility | 0.0446 mg/ml ; 0.000218 mol/l |
Class? Solubility class: Log S scale | Soluble |
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) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -5.46 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.53 |
* 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 |
---|---|---|
With hydrogen bromide; copper(I) bromide; In water; at 20 - 75℃; for 16h; | Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 C. in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added drop wise during 15 min while maintaining the temperature between 0 and 5 C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d6): delta 7.36 (dd, J=7.78, 2.26 Hz, 1H), 7.23-7.17 (m, 1H), 7.14-7.09 (m, 1H), 3.86 (s, 3H); MS (EI) m/z 204, 206 [M+]. | |
Example 1; 4-Bromo- 1 -fluoro-2-methoxybenzene; Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added drop wise during 15 min while maintaining the temperature between 0-5 0C. The resulting diazoniumsalt solution was added to a suspension of copper (I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with <n="48"/>diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-afo): delta 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) m/z 204, 206 [M+«] | ||
Example 1; 4-Bromo- 1 -fluoro-2-methoxvbenzeneF; Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0 - 5 0C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 0C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d«j): delta 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) 0 >«/z 204, 206 [M+»]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | A mixture OF 4-BROMO-1-FLUORO-2-METHOXYBENZENE (5.0 g, 24.4 mmol), potassium acetate (4.79 g, 48.8 mmol), bis (pinacolato) diboron (7.12 g, 28.0 mmol) and dichloro [1, 1'-BIS (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (1.00 g, 1.22 mmol) in 1, 4-dioxan (50 ML) containing 4. 5 ml of dimethylsulphoxide was degassed with nitrogen for 45 min and then heated at 90C for 16 h. The reaction was allowed to cool to ambient temperature and the solid removed from the reaction by filtration. The filtration cake was washed with diethyl ether (100 ML) AND then the filtrates were combined and concentrated in vacuo. The residue was stirred with 2N sodium hydroxide solution (500 ml) for 45 min and the solid removed by filtration. The aqueous component was cooled (0C) and treated with 36% hydrochloric acid in a dropwise manner to pH 5 over a 15 min period. The precipitate was allowed to stand at 0C for 2 h and then filtered. The resulting solid was washed with ice-cold water (100 ml) and dried at 40C under high vacuum to give the title compound (5.52 g, 90%): ON (400 MHz, CDC13) 1.34 (12H, s), 3.92 (3H, s), 7.03-7. 09 (1H, M), 7.37- 7.39 (2H, M). | |
With potassium acetate; tricyclohexylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; at 150℃; for 1h;Microwave; | Anhydrous 1,2-dimethoxyethane (12 mL) was added to 4-bromo-l-fluoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol), and the mixture was irradiated under an atmosphere of argon in a microwave at 150 0C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the title compound as an oil: MS (EI) (m/z, %) 252 (81), 237 (44), 166 (78), 152 (100) | |
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,2-dimethoxyethane; at 150℃; for 1h; | Anhydrous 1,2-dimethoxyethane (12 mL) was added to <strong>[103291-07-2]4-bromo-1-fluoro-2-methoxybenzene</strong> (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (1.14 g, 4.5 mmol) and the resulting mixture was irradiated in a microwave at 150 C. for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+]. |
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,2-dimethoxyethane; at 150℃; for 1h;Microwave irradiation; | Example 2 2-(4-Fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane; Anhydrous 1,2-dimethoxy ethane (12 mL) was added to 4-bromo-l-fiuoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol) and the resulting mixture was irradiated in a microwave at 150 C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+»] | |
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,2-dimethoxyethane; at 150℃; for 1h;Microwave irradiation; | Example 2; 2-(4-Fluoro-3-methoxvphenvlV4,4,5.5-tetramethvl-1.3,2-dioxaborolane; <n="47"/>Anhydrous 1,2-dimethoxy ethane (12 mL) was added to 4-bromo-l-fluoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol) and 5 the resulting mixture was irradiated in a microwave at 150 C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+*]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With boron tribromide; In dichloromethane; at 20℃; | To a stirred solution OF 4-BROMO-1-FLUORO-2-METHOXYBENZENE (1.00 g, 4.88 mmol) in anhydrous CH2CL2 (20 ml) was added dropwise in an ice bath BBR3 (1 M solution in CH2Cl2, 9.75 ml, 9. 75 mmol), and the mixture was stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched by adding MEOH (1.0 ml) dropwise. The solvent was evaporated and the residue purified by flash chromatography eluting with ISOHEXANE/CH2CL2/MEOH (70: 20: 10) to leave 0.802 g (86%) of the title compound: BH (400 MHz, CDCL3) 5.24 (1 H, s), 6.96 (2 H, m), 7.16 (1 H, DD, J7. 7,2. 0 HZ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 65h; | Reference Example-13 Potassium carbonate (18.8 g, 136 mmol) and methyl iodide (19.3 g, 136 mmol) were added to a solution of 5-bromo-2-fluorophenol (13.0 g, 68.1 mmol) in DMF (120 mL), followed by stirring at room temperature for 65 hours. After the reaction was completed, water (150 mL) was added to the reaction solution, and the resultant product was extracted with ethyl acetate (100 mL*1, 50 mL*2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby a pale yellow oily crude product (29.0 g) was obtained. This was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), whereby 5-bromo-2-fluoroanisole (14.2 g, yield: quantitative) was obtained as a colorless oily material. 1H-NMR (400 MHz, CDCl3): delta3.88 (s, 3H), 6.95 (dd, J=8.6 and 10.8 Hz, 1H), 7.02 (ddd, J=2.2, 4.2 and 8.6 Hz, 1H), 7.08 (dd, J=2.2 and 7.6 Hz, 1H). 19F-NMR (376 MHz, CDCl3): delta-137 (s, 1F). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 40℃; for 2h; | 100204] To a solution of 23 A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 niL, 23.4 mmol) at rt. The mixture was heated at 400C for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgS O4. The crude residue was purified by flash column chromatography (EtOAc:hexanes = 1 : 6) to give 2.74 g(77%) of 23B as a viscous oil. 1H NMR (400 MHz, CDCl3) delta ppm 3.89 (s, 3 H), 6.95 - 7.00 (m, 3 H). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 40℃; | To a solution of 7A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40 C. for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77%) of 7B as a viscous oil. 1H NMR (400 MHz, CDCl3) delta ppm 3.89 (s, 3H), 6.95-7.00 (m, 3H). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 2h; | To a solution of 64A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40 C. for 2.0 h. After cooled to rt, it-was diluted with ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77%) of 69A as viscous oil. 1H NMR (400 MHz, CDCl3) delta ppm 3.89 (s, 3 H), 6.95-7.00 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.3 g (79%) | With hydrogenchloride; potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; water; | PREPARATION 12 3-(4-Fluoro-3-methoxyphenyl)pyridine A solution of 15.6 g (76.1 mmole) of <strong>[103291-07-2]1-bromo-4-fluoro-3-methoxybenzene</strong> in 67 ml of tetrahydrofuran was added dropwise, with stirring, under nitrogen, to 1.92 g (79.1 mmole) of dried magnesium turnings. Stirring was continued for 1 hour and then the supernatant liquid was removed to give a solution of 4-fluoro-3-methoxyphenylmagnesium bromide. In a separate flask, 7.3 ml (76.1 mmole) of 3-bromopyridine was dissolved in 23 ml of tetrahydrofuran and 880 mg (0.76 mmole) of tetrakis-triphenylphosphine palladium was added. This latter mixture was heated to reflux, and the above Grignard solution was added dropwise, during 10 minutes, with stirring. The resulting mixture was refluxed for 1 hour and then it was stirred overnight at room temperature. The reaction mixture was diluted with 100 ml of water, followed by 100 ml of 10% hydrochloric acid, and the resulting solution was washed with dichloromethane. The aqueous phase was basified with sodium bicarbonate and then it was extracted with dichloromethane. The combined extracts were dried using potassium carbonate and evaporated in vacuo to give 12.3 g (79%) of the title compound as a reddish oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0-5 0C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound.: 1H-NMR (DMSO-J6): delta 7.36 (dd, J= 7.78, 2.26 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.14-7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) (m/z, %) 204,206 (100), 189,191 (23), 161,163 (45) | |
With hydrogen bromide; copper(I) bromide; sodium nitrite; In water; | PREPARATION 13 1-Bromo-4-fluoro-3-methoxybenzene To a stirred suspension of 20.8 g (0.147 mole) of 4-fluoro-3-methoxyaniline (Mulvey et al., Tetrahedron Letters, 16, 1419 [1978]) in 200 ml of water was added 50.2 ml of 48% hydrobromic acid. The resulting mixture was cooled to 0 C., and a solution of 11.2 g (0.162 mole) of sodium nitrite in 100 ml of water was added dropwise during 1 hour, with stirring, maintaining the temperature between 0 and 5 C. The solution of the diazonium salt thus obtained was then added to a suspension of 23.2 g (0.162 mole) of cuprous bromide in 100 ml of water which had been preheated to 75 C. The mixture was shaken thoroughly and then 251 ml of 48% hydrobromic acid was added. The resulting mixture was stirred overnight at room temperature and then it was diluted with an excess of water. The product was extracted into diethyl ether, and the extract was washed with saturated sodium chloride solution and dried (MgSO4). Evaporation of the dried ethereal solution in vacuo afforded a black liquid, which was distilled under reduced pressure. This afforded 23 g of the title compound as a yellow liquid, b.p. 82-85 C. (8 mm of Hg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | To a solution of 7B (2.7 g, 13.1 mmol) in THF (25 mL) at -78 C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at -78 C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from -78 C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 7C (0.75 g, 35% yield) was collected as a white solid. 1H NMR (400 MHz, Methanol-d4) delta ppm 3.86 (s, 3H) 7.03-7.45 (m, 3H). | |
35% | To a solution of 69A (2.7 g, 13.1 mmol) in THF (25 mL) at -78 C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at -78 C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from -78 C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 69B (0.75 g, 35% yield) was collected as a white solid. 1H NMR (400 MHz, Methanol-d4) delta ppm 3.86 (s, 3 H) 7.03-7.45 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 5h;Heating / reflux; | [0413] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo- l-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol), Xaniphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (0.3 g, 14%) as a beige solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Add sodium hydride (2.77 g, 60% w/w, 69.2 mmol) to a solution of 3-hydroxy- azetidine-1-carboxylic acid tert-butyl ester (10.9 g, 62.9 mmol) in dimethyl sulfoxide (100 mL). Stir the mixture for 30 min and then add 3-bromo-6-fluoroanisole (15.5 g, 75.5 mmol). Heat the mixture to 65 0C overnight. Cool the mixture to room temperature and then dilute the solution with saturated ammonium chloride and brine and extract with ethyl acetate. Wash the organics five times with brine, then dry over sodium sulfate and filter. Concentrate and purify via silica gel chromatography using a 0-45% gradient of ethyl acetate/hexane to give 10.4 g (46%) of the title compound as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Example 41i 1-(3-Bromophenyl)-4-fluoro-1-(4-fluoro-3-methoxyphenyl)-1H-isoindol-3-amine tert-Butyllithium (3.68 mL, 5.89 mmol) was added dropwise to THF (10 mL) at -100 C. under an argon atmosphere. A solution of <strong>[103291-07-2]4-bromo-1-fluoro-2-methoxybenzene</strong> (0.604 g, 2.95 mmol) in THF (5 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1 g, 2.46 mmol) in THF (5 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (11.78 mL, 14.73 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluding with 0-10% 0.1 M NH3 in MeOH in DCM to afford 0.98 g (93%) of the title compound. MS (ES+) m/z 429, 431 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc(II) fluoride; tri-tert-butyl phosphine;bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 80 - 90℃; for 5h;Inert atmosphere; | To a solution <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (109 g, 0.54 mol), ZnF2 (2.52 g, 24.39 mmol), Pd(dba)2 (3.08 g, 5.35 mmol), and PT^ (5.2 mL of a 50% solution in toluene, 11 mmol) in DMF (1 L) was added trimethylsilyl methyl ketene acetal (121 g, 0.7 mol). The reaction mixture was stirred at 80-90 C for 5 h under nitrogen atmosphere and then was allowed to cool to room temperature and diluted with EtOAc. The reaction mixture was filtered through Celite. The filtrate was washed with H20 (2 L) and the aqueous layer was extracted with EtOAc (2.5 L). The combined extracts were washed with brine (2 L x 2), dried over MgSC^, and concentrated at reduced pressure to give methyl 2-(4-fluoro-3- methoxyphenyl)-2-methylpropanoate (151 g), which was used for the next step without further purification. 1H NMR (400MHz, CDC13): delta 7.04-6.98 (m, 1H), 6.95-6.92 (dd, 1H), 6.88-6.85 (m, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 1.57 (s, 6H). | |
With zinc(II) fluoride;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; toluene; at 80 - 90℃; for 5h;Inert atmosphere; | To a solution <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (109 g, 0.54 mol), ZnF2 (2.52 g, 24.39 mmol), Pd(dba)2 (3.08 g, 5.35 mmol), and P^Bu3 (5.2 mL of a 50% solution in toluene, 11 mmol) in DMF (1 L) was added trimethylsilyl methyl ketene acetal (121 g, 0.7 mol). The reaction mixture was stirred at 80-90 0C for 5 h under nitrogen atmosphere and then was allowed to cool to room temperature and diluted with EtOAc. The reaction mixture was filtered through Celite. The filtrate was washed with H2O (2 L) and the aqueous layer was extracted with EtOAc (2.5 L). The combined extracts were washed with brine (2 L x 2), dried over MgSO4, and concentrated at reduced pressure to give methyl 2-(4-fluoro-3- methoxyphenyl)-2-methylpropanoate (151 g), which was used for the next step without further purification. 1U NMR (400MHz, CDCl3): delta 7.04-6.98 (m, IH), 6.95-6.92 (dd, IH), 6.88-6.85 (m, IH), 3.89 (s, 3H), 3.67 (s, 3H), 1.57 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (1.00 g, 4.88 mmol, 1 equiv) in anhydrous THF was added granules of magnesium (125 mg, 5.12 mmol, 1.05 equiv) under nitrogen. The mixture was heated to 60 C for 2 h. After cooling to room temperature, 5-bromo-2-formylpyridine (1.09 g, 5.86 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 80 C overnight. The reaction was cooled to room temperature, quenched with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was used in the next step without further purification. C13H11BrFNO2; MW 312. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (200 mg, 0.98 mmol, 1 equiv) in anhydrous THF was added granules of magnesium (24 mg, 0.98 mmol, 1 equiv) under nitrogen. The mixture was heated to 60 C for 2 h. After reaching room temperature, 6-bromopyridin-2-yl carboxaldehyde (182 mg, 0.98 mmol, 1 equiv) was added and the reaction mixture was heated to 80 C and stirred overnight at 80 C. The reaction was cooled to room temperature, quenched with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was used in the next step without further purification. C13H11BrFNO2; MW 312. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (547 mg, 2.67 mmol, 1 equiv) in anhydrous THF was added granules of magnesium (68 mg, 2.80 mmol, 1.05 equiv) under nitrogen. The mixture was heated to 60 C for 2 h. After cooling to room temperature, 4-bromobenzaldehyde (592 mg, 3.20 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 80 C overnight. The reaction was cooled to room temperature, quenched with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was used in the next step without further purification. C14H12BrFO2; MW 311. |
Tags: 103291-07-2 synthesis path| 103291-07-2 SDS| 103291-07-2 COA| 103291-07-2 purity| 103291-07-2 application| 103291-07-2 NMR| 103291-07-2 COA| 103291-07-2 structure
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