Structure of 1246548-95-7
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CAS No. : | 1246548-95-7 |
Formula : | C10H8BrNO |
M.W : | 238.08 |
SMILES Code : | COC1=CC2=CC=C(Br)C=C2N=C1 |
MDL No. : | MFCD18253949 |
InChI Key : | UOSVBHOMCFHOSP-UHFFFAOYSA-N |
Pubchem ID : | 53393239 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
* 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 |
---|---|---|
61% | With p-toluenesulfonic acid monohydrate; In toluene; for 3h;Reflux; | General procedure: A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-de) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H). |
61% | With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; | General procedure: a) 7-bromoquinoline-3 -carbonitrileA mixture of 3,3-diethoxypropanenitrile (1.801 mL, 12.00 mmol),2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Starkapparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. NaHCO3 solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethylether provided the title compound (1.75 g, 75%). ‘H NMR (400 MHz, DMSO-d6) ö ppm7.95 (dd, J8.72, 1.89 Hz, 1 H) 8.08 (d, J8.84 Hz, 1 H) 8.38 (d, J2.02 Hz, 1 H) 9.13 (d, J1.52 Hz, 1 H) 9.21 (d, 1 H). |
61% | With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark; | General procedure: A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H) |
19% | With toluene-4-sulfonic acid; In toluene; for 3h;Dean-Stark; Reflux; | General procedure: A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatusfor 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of N,N-dimethylformamide, diluted with chloroform, and washed with aq sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification of the residue by flash chromatography (0-3%methanol in dichloromethane) followed by trituration in diethyl ether provided the titlecompound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89Hz, 1H) 8.08 (d, J=8.84 Hz, 1H) 8.38 (d, J=2.02 Hz, 1H) 9.13 (d, J=1.52 Hz, 1H) 9.21(d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26%; 23% | A solution of methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa- 4,9-diazaspiro[5.5]undecan-9-yl)acetate (0.626 mmol) in 1,4-dioxane (2.5 mL) was treated with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.751 mmol), potassium acetate (0.939 mmol), and PdCi2(dppf)-CH2Ci2 adduct (0.031 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 80 C overnight. The reaction mixture was cooled to room temperature and was treated with 7- bromo-3-methoxyquinoline (0.626 mmol), PdCl2(dppf)-CH2Ci2 adduct (0.031 mmol), and 2M aq potassium carbonate (1.878 mmol). The solution was degassed with a stream of nitrogen for 3 min, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 C for 15 min. The resulting black mixture was diluted with water (100 mL) and was extracted three times with chloroform. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chiralpak I A column, methanol :acetonitrile-l : 1) and lyophilization from water (w/ 25%) acetonitrile) afforded the title compound as a white solid (94 mg, 26%>). MS(ES)+ m/e 534.2 [M+H]+, >99% ee, aD = +58 deg (c = 0.05, methanokacetonitrile 1 : 1). Example 47 (-)-methyl 2-(4-cyclopropyl-3-oxo- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4- (3-methoxyquinolin-7-yl)phenyl)acetate a) From Example 46b, the title product was isolated as a solid in >99% ee using chiral HPLC (Chiralpak I A column, methanol: acetonitrile 1 : 1) followed by lyophilization from water (w/ 25% acetonitrile) (84 mg, 23% yield). MS(ES)+ m/e 534.2 [M+H]+. aD = -62 deg (c = 0.03, methanol: acetonitrile 1 : 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19%; 21% | a) A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetamide (266 mg, 0.47 mmol) in dry 1,4-dioxane (3 mL) was treated with bis(pinacolato)diboron (142 mg, 0.56 mmol), potassium acetate (49 mg, 0.5 mmol) and PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol). The reaction mixture was degassed with nitrogen for ~3 min and the vessel was purged with nitrogen, sealed, and heated to 110 C for 3 h. Analysis of a reaction mixture aliquot indicated complete conversion of the starting material to the boronate intermediate. To the cooled reaction mixture was added 7-bromo-3-fluoroquinoline (105 mg, 0.47 mmol), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol) and 2M aq K2CO3 (0.7 mL, 1.4 mmol). The reaction mixture was purged with nitrogen, sealed, and heated at 120 C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC (5-75% acetonitrile: water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Lux Cell 4, methanol) to afford the title product in 95% ee (29 mg, 12% yield). aD = +26 deg (c =0.14, methanol); MS(ES)+ m/e 495 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 1.06 - 1.18 (m, 3 H) 1.63 - 1.84 (m, 2 H) 1.90 - 1.97 (m, 2 H) 2.27 - 2.39 (m, 1 H) 2.53 - 2.73 (m, 2 H) 2.80 (d, J=11.37 Hz, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.95 - 4.08 (m, 2 H) 4.53 (s, 1 H) 6.28 (br. s., 1 H) 7.29 (br. s., 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.55 (dd, J=11.24, 1.89 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.83 - 7.93 (m, 2 H) 7.93 - 8.00 (m, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.88 (d, J=2.53 Hz, 1 H). Example 91 (-)-2-(4-ethyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3- fluoroquinolin-7-yl)phenyl)acetamide a) From Example 90a, the title product was also isolated in 99.2% ee using chiral HPLC (Lux Cell 4, methanol) (17mg, 7% yield). aD = -26 deg (c =0.12, methanol); MS(ES)+ m/e 495 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 1.06 - 1.18 (m, 3 H) 1.61 - 1.83 (m, 2 H) 1.87 - 1.96 (m, 2 H) 2.34 (td, J=11.12, 2.27 Hz, 1 H) 2.53 - 2.74 (m, 2 H) 2.74 - 2.85 (m, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.16 Hz, 2 H) 3.92 - 4.10 (m, 2 H) 4.53 (s, 1 H) 6.19 (d, J=3.28 Hz, 1 H) 7.29 (d, J=3.79 Hz, 1 H) 7.42 - 7.51 (m, 1 H) 7.55 (dd, J=11.24, 1.89 Hz, 1 H) 7.62 (dd, J=8.08, 1.77 Hz, 1 H) 7.83 - 7.92 (m, 2 H) 7.92 - 8.03 (m, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.88 (d, J=2.53 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With hydrogen bromide; acetic acid; at 120.0℃; for 96.0h; | A solution of 7-bromo-3-methoxyquinoline (1.1 g, 4.62 mmol) in acetic acid (20mL) was treated with 48% hydrobromic acid (5.0 mL, 92 mmol) and heated under reflux at 120 C for 4 days. Analysis by LCMS then showed the reaction had progressed to approximately 50% completion. The mixture was poured onto ice and adjusted to a basic pH with ammonium hydroxide solution. The aqueous mixture was extracted with diethyl ether (3x), the combined extracts were evaporated, and the residue was purifiedby flash chromatography (10-50% ethyl acetate/hexanes) to give the title product (500 mg, 2.232 mmol, 48% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.55 (d, J=2.53 Hz, 1H), 7.63 (dd, J=8.59, 2.02 Hz, 1H), 7.80 (d, J=8.84 Hz, 1H), 8.10 (d, J=1.77 Hz, 1H), 8.60 (d, J=2.78 Hz, 1H), 10.51 (s, 1H). |
48% | With hydrogen bromide; In acetic acid; at 120.0℃; for 96.0h;Reflux; | A solution of 7-bromo-3-methoxyquinoline (1.1 g, 4.62 mmol) in acetic acid (20 mL) was treated with 48% hydrobromic acid (5.0 mL, 92 mmol) and heated under reflux at 120 C for 4 days. LCMS then showed the reaction had progressed about 50%>. The mixture was poured onto ice and basified with ammonium hydroxide solution. The aqueous mixture was extracted with diethyl ether (x3) and the combined extracts were evaporated under reduced pressure. Purification by flash chromatography (10-50% ethyl acetate in hexanes) provided the title compound (500 mg, 48 %) as a tan solid. 1H NMR (400 MHz, DMSO- 6) delta ppm 7.55 (d, J=2.53 Hz, 1 H) 7.63 (dd, J=8.59, 2.02 Hz, 1 H) 7.80 (d, J=8.84 Hz, 1 H) 8.10 (d, J=1.77 Hz, 1 H) 8.60 (d, J=2.78 Hz, 1 H) 10.51 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | a) A microwave vial was charged in succession with 9-((5-bromo-3-fluoropyridin-2- yl)methyl)-4-cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (122 mg, 0.306 mmol), bis(pinacolato)diboron (85 mg, 0.335 mmol), potassium acetate (120 mg, 1.223 mmol), Ι, - bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.024 mmol), and ethanol (2 mL). The vial was capped, purged with nitrogen, and stirred at 100 C. After 1 h, the reaction mixture was cooled to room temperature, and 7-bromo-3- methoxyquinoline (80 mg, 0.336 mmol) and 2M aq. potassium carbonate (1 mL) were added to the vial. The vial was capped, purged with nitrogen, and allowed to stir overnight at 100 C. The reaction mixture was cooled to room temperature. The ethanol layer was decanted and passed through a plug of Celite and sodium sulfate (with a small amount of Si-Thiol resin). The plug was washed with ethanol (4 mL). The combined ethanol filtrate was concentrated in vacuo. Purification by flash chromatography (0-10% methanol/dichloromethane) then reverse phase HPLC (10-70% acetonitrile /water w/ 0.1% NH4OH) afforded the title compound (14 mg, 9%). MS(ES)+ m/e 477.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | a) A 5 mL microwave vial was charged in succession with tra/?s-9-((5-bromo-3- fluoropyridin-2-yl)methyl)-4-cyclopropyl-7-fluoro-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (100 mg, 0.240 mmol), bis(pinacolato)diboron (65 mg, 0.256 mmol), potassium acetate (100 mg, 1.019 mmol), l, -bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.024 mmol), and 1,4-dioxane (2 mL). The vial was capped, purged with nitrogen, and stirred at 80 C. After 1 h, the reaction mixture was cooled and <strong>[1246548-95-7]7-bromo-3-methoxyquinoline</strong> (60 mg, 0.252 mmol) and 2M aqueous potassium carbonate solution (1.000 mL) were added to the mixture. The vial was capped, purged with nitrogen, and returned to stirring at 80 C. After 1 h, the reaction mixture was cooled to room temperature and two layers formed. The dioxane layer was decanted. This was purified via direct injection onto flash chromatography (0-10% methanol/dichloromethane) followed by reverse phase HPLC (10-70% acetonitrile /water w/ 0.1% NH4OH) to afford the title compound as the trans racemate (22 mg, 18%). MS(ES)+ m e 495.4 [M+H]+. |