Structure of 122794-99-4
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CAS No. : | 122794-99-4 |
Formula : | C12H10BrNO3 |
M.W : | 296.12 |
SMILES Code : | CCOC(=O)C1=C(O)C2=C(C=CC(Br)=C2)N=C1 |
MDL No. : | MFCD00173362 |
InChI Key : | IVZIOBTVAJBBAS-UHFFFAOYSA-N |
Pubchem ID : | 689824 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 67.55 |
TPSA ? Topological Polar Surface Area: Calculated from |
59.42 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.81 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.3 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.88 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.0 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.84 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.77 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.99 |
Solubility | 0.0301 mg/ml ; 0.000102 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.22 |
Solubility | 0.0177 mg/ml ; 0.0000598 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.45 |
Solubility | 0.0105 mg/ml ; 0.0000355 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
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 |
-5.76 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 |
0.0 |
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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.84 |
* 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 |
---|---|---|
100% | In diphenylether; at 250℃; for 0.0833333h;microwave irradiation; | Preparation of Intermediate 4cIntermediate 3c (330mg, 0 879mmoles) was transferred into a microwave vessel and dissolved in 2 ml of diphenylether The experiment was run at 25O0C for 5 minutes Then, petroleum ether was added and the precipitate formed was collected by filtration 1H-NMR confirmed the structure of the desired compound obtained in quantitative yield |
88% | With diphenylether;Reflux; | To a preheated refluxing di-phenol ether (50m1), was added compound 1 (30.5g, 0.0892mo1) in about 1 5mm. The resulting mixture was continue to heat at reflux until the bubbling stopped in about 1 to 2 hours. After cooling to room temperature, the solid was collected and dried to give ethyl 6-bromo-4-oxo- 1,4-dihydroquinoline-3-carboxylate (compound 2, 25.4g, 88%) as an off white solid. |
88% | In diphenylether; for 0.25h;Reflux; | To a preheated refluxing di-phenol ether (50ml), was added compound 1 (30.5g, 0.0892mol) in about 15min. The resulting mixture was continue to heat at reflux until the bubbling stopped in about 1 to 2 hours. After cooling to room temperature, the solid was collected and dried to give ethyl 6-bromo-4-oxo-l,4-dihydroquinoline-3-carboxylate (compound 2, 25.4g, 88%) as an off white solid. |
80% | In diphenylether; at 220℃; for 30h; | A suspension of 38.4 g of the product from the previous step (112mmol) in 200 ml diphenylether was heated up to 220 C internaltemperature and stirring was continued for 30 h. The reactionmixture was then cooled to room temperature and diluted with200 ml Et2O. The precipitate was isolated by filtration and washedsuccessively with EtOH and Et2O. The filter cake was dried in avacuum oven at 60 C overnight to yield 26.4 g (80%) of the titlecompound as off-white crystalline solid. ESI-MS m/z: 317.7[MNa] |
80% | In diphenylether; at 220℃; for 30h; | A suspension of 38.4 g of the product from the previous step (112mmol) in 200 ml diphenylether was heated up to 220 C internaltemperature and stirring was continued for 30 h. The reactionmixture was then cooled to room temperature and diluted with200 ml Et2O. The precipitate was isolated by filtration and washedsuccessively with EtOH and Et2O. The filter cake was dried in avacuum oven at 60 C overnight to yield 26.4 g (80%) of the titlecompound as off-white crystalline solid. ESI-MS m/z: 317.7[MNa] |
77.4% | With trichlorophosphate; In water monomer; at 20 - 70℃; for 12h; | General procedure: To a three-necked flask, 5 (300mg, 0.61mmol), PPA (1.5g) and POCl3 (2.5g) were added at room temperature. The mixture was heated to 70C for 12h and then cooled to room temperature. The mixture was treated with aqueous Na2CO3 solution to remove the remanent acid and filtered, and the solid was washed with water and dried to afford the product, which could be used in next step. m.p. 211-212C; 1H NMR (400MHz, DMSO-d6): δ 12.80 (s, 1H, br), 10.92 (s, 1H), 8.60 (s, 1H), 8.56 (d, 1H, J=2.0Hz), 8.02 (dd, 1H, J1=8.7Hz, J2=2.0Hz), 7.80 (d, 1H, J=8.7Hz), 7.50 (t, 1H, J=7.7Hz), 7.36-7.45 (m, 3H), 4.24 (q, 2H, J=7.2Hz), 1.29 (t, 3H, J=7.2Hz); ESI-MS (m/z): 441 (M+H)+ |
In diphenylether;Reflux; | General procedure: The quinolone derivatives 1 were prepared by treating the appropriate aniline (100 mmol) with diethyl ethoxymethylenemalonate (100 mmol) under reflux in ethanol (5 mL) for 2-10 h to obtain the enamine derivatives that were then cyclized in refluxing diphenyl ether for 30 min-6 h [29]. These quinolones (13 mmol) were refluxed in thionyl chloride (20 mL), for 17 h, affording the corresponding chloro-derivatives 2a-g [22]. Reaction of 2a-g (4 mmol) with 2-hydrazinobenzothiazole (8 mmol) in toluene (30 mL), for 3 h, followed by a 2 h reflux in acetic acid gave the corresponding 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones 3a-g as solids which were collected by filtration under vacuum, washed with water and subsequent purified by washing with hot ethyl alcohol. | |
In diphenylether; for 1h;Reflux; | General procedure: Substituted aniline 1 (0.01 mol) and diethylethoxy methylene malonate 2 (0.01 mol) weremixed and heated at 125-130 0C for 2 h. Ethanolwas evaporated off from the resulting mixture ofethyl anilinomethylene malonate 3. The crude solidwas filtered on sintered funnel, dried and recrystallized from n-hexane. The malonate 3 (0.01mol) was refluxed with diphenylether (50 mL) for 1h to give 1,4-dihydro-4-oxoquinoline-3-carboxylicacid ethyl ester 4. After 1 h the solution was cooledand the resulting precipitate was filtered off, washedwith n-hexane, and dried. The solid wasrecrystallized from DMF to give substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethylester 4. | |
In diphenylether; at 240℃; for 1h;Dean-Stark; | Diphenyl ether (870mL) was heated to 240C then diethyl 2-[[(4- bromophenyl)amino]methylidene]propanedioate (75g, 219.18mmol) added portionwise. The mixture was stirred at 240C for 60 minutes in a flask fitted with dean-stark apparatus. After cooling (25C) a crystallized solid was formed. The mixture was diluted with Et20 and the solid was collected by filtration, washed with Et20 and dried to afford the desired material (59.9g) as a beige crystallized solid, which was used without purification or characterisation. | |
In diphenylether; at 260℃; for 9.5h; | Diphenyl ether (100 g) was then added to the crude solid and the mixture was refluxed at 260C for 8 hours. After 1.5 hours a white solid started crushing out of solution in the reaction flask. T.l.c. analysis (ethyl acetate cyclohexane, 1: 4) showed the presence of one UV-active product (Rf 0.75) andcomplete consumption of the intermediate starting material 1 (Rf 0.49). Upon cooling of the reaction solution to room temperature, more ethyl 6-bromo-4-oxo-1,4- dihydroquinoline-3-carboxylate 2 crushed out of solution as a white powder (at 230C). The white solid was filtered, washed with toluene and dried in vacuo to afford ethyl 6-bromo-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate 2 (2.5 87g, 43.4%) asa pale yellow/white powder. M.p. 285-290C (decomposition: gas evolved); HRMS(El): found 294.983 14 [M] C12H10NO379Br requires 294.98386; found 296.98073[M] C12H10NO381Br requires 296.98 152; peak ratio: 49.5% : 50.5%; Vmax (Ge): 3421(br s, NH), 3149, 3088 (w, ArC-H), 2981 (m, alkyl C-H), 1694 (s, 2 xintramolecularly hydrogen-bonded C=O conjugated with C=C), 1615 (s, CCconjugated with C=O) cm’; Elemental Analysis: found C 48.36%, H 3.34%, N 4.64%; required C 48.67%, H 3.40%, N 4.73%. | |
59.9 g | In diphenylether; at 240℃; for 1h;Dean-Stark; Inert atmosphere; | Diphenyl ether (870 mL) was heated to 240C then diethyl [(4- bromophenyl)amino]methylidene}propanedioate (75 g, 219.18 mmol) added portionwise. The mixture was stirred at 240C for 60 minutes in a flask fitted with Dean-Stark apparatus. After cooling ,the mixture was diluted with Et20 and the solid was collected by filtration, washed with Et20 and dried to afford ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate (59.9g) as a beige crystallized solid, which was used without purification or characterisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide; In ethanol; water monomer; for 3h;Reflux; | 77ml aqueous NaOH (2 N) were added at ambient temperature to asuspension of 15.2 g of the product from the previous step (51.2mmol) in 77 ml EtOH. The mixture was heated to reflux for 3 h andthen concentrated to approx. 50% of the starting volume. The yellowsolution was diluted with water and cooled with an ice bath.The mixture was acidified to pH 2 with hydrochloric acid to precipitatethe product. The resulting suspension was stirred for 10min at low temperature and was then filtered via a Buchner funnel.The filter cakewaswashed with H2O and dried in a convection ovenat 80 C to yield 13.5 g (99%) of the title compound as white solid. 1HNMR (200 MHz, DMSO) d 14.97 (br s, 1H), 13.56 (br s, 1H), 8.90 (s,1H), 8.30 (d, J 2.3 Hz, 1H), 8.00 (dd, J 8.9, 2.3 Hz, 1H), 7.75 (d, J 8.9 Hz, 1H) 13C NMR (50 MHz, DMSO) d 177.1, 166.0, 145.6, 138.4,136.6, 127.1, 125.9, 122.1, 119.0, 108.1. ESI-MS m/z: 265.6 [M H]-HPLC (Method A) tret 6.16 min. |
99% | With sodium hydroxide; In ethanol; water monomer; for 3h;Reflux; | 77ml aqueous NaOH (2 N) were added at ambient temperature to asuspension of 15.2 g of the product from the previous step (51.2mmol) in 77 ml EtOH. The mixture was heated to reflux for 3 h andthen concentrated to approx. 50% of the starting volume. The yellowsolution was diluted with water and cooled with an ice bath.The mixture was acidified to pH 2 with hydrochloric acid to precipitatethe product. The resulting suspension was stirred for 10min at low temperature and was then filtered via a Buchner funnel.The filter cakewaswashed with H2O and dried in a convection ovenat 80 C to yield 13.5 g (99%) of the title compound as white solid. 1HNMR (200 MHz, DMSO) d 14.97 (br s, 1H), 13.56 (br s, 1H), 8.90 (s,1H), 8.30 (d, J 2.3 Hz, 1H), 8.00 (dd, J 8.9, 2.3 Hz, 1H), 7.75 (d, J 8.9 Hz, 1H) 13C NMR (50 MHz, DMSO) d 177.1, 166.0, 145.6, 138.4,136.6, 127.1, 125.9, 122.1, 119.0, 108.1. ESI-MS m/z: 265.6 [M H]-HPLC (Method A) tret 6.16 min. |
96% | With water monomer; sodium hydroxide; In ethanol; at 75℃; for 1.5h; | 2N Sodium hydroxide (506mL, 1011.43mmol) was added to a stirred suspension of ethyl 6-bromo-4-oxo-lH-quinoline-3-carboxylate (59.9g, 202.29mmol) in EtOH (590mL) and the resulting solution stirred at 75C for 1.5 h. Water was added and the mixture cooled to 0C. The pH of the solution was adjusted to 3 using hydrochloric acid and the precipitate collected by filtration. The solid was washed with water, EtOH/water (1 : 1) then Et20 before being dried to afford the desired material (51.9g, 96%) as a beige solid. NMR Spectrum: 1H MR (500MHz, DMSO-d6) δ 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+ = 270. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; In acetonitrile; at 60 - 70℃; for 3h;Inert atmosphere; | General procedure: A stirred solution of 1,4-dihydro-4-oxo-quinolines 4 (4.0 mmol), anhydrous acetonitrile (5.0 mL) and BSTFA (3.0 mL, 11.2 mmol) containing 1% of trimethylchlorosilane (TMCS), was heated at 60-70 oC, under nitrogen, for 3 h. The resulting mixture was allowed to cool to room temperature and a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2.020 g, 4 mmol) in 15 mL of acetonitrile was added, followed by dropwise addition of TMSOTf (0.4 mL, 2.09 mmol). After having been stirred for 4 h, at room temperature, the solution was poured into ice-cold water (20 g), and neutralized with saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with methylene chloride (3 x 20 mL) and the combined organic layers were washed with water (3 x 20 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to leave the corresponding products as white crystals, which were recrystallized from ethanol to produce the protected ribonucleosides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.8% | With trichlorophosphate; for 1h;Reflux; | Compound 2 (19.4g, 0.O6mol) was suspended in POC13 (45m1) and heated at reflux for 1 hour. The excess solvent was evaporated under reduced pressure and the deep brown residue was taken up in dichloromethane (1 50m1) and washed sequentially by water (1 OOml), saturated sodium bicarbonate (lOOml), and brine (lOOml). The organic phase was dried over sodium sulfate, the solid was filtered off and the filtrate was concentrated to give ethyl 6-bromo-4-chloroquinoline-3-carboxylate (compound 3, 17.67g, 93.8%) as a yellowish solid. |
93.8% | With trichlorophosphate; for 1h;Reflux; | Compound 2 (19.4g, 0.06mol) was suspended in POCI3 (45ml) and heated at reflux for 1 hour. The excess solvent was evaporated under reduced pressure, the deep brown residue was taken up in dichloromethane (150ml) and washed sequentially by water (100ml), saturated sodium bicarbonate (100ml), and brine (100ml). The organic phase was dried over sodium sulfate, the solid was filtered off and the filtrate was concentrated to give ethyl 6-bromo-4-chloroquinoline-3- carboxylate (compound 3, 17.67g, 93.8%) as a yellowish solid. |
88.49% | With trichlorophosphate; at 0 - 110℃; for 3h; | ethyl 6- bromo-4-oxo-1H-quinoline-3-carboxylate (1.5 g, 5.07 mmol, 1.0 eq) was added into POCl3 (15 mL) at 0 C, then stirred for 3 h at 110 C. LCMS showed ~2% starting material was remained. The mixture was cooled to room temperature, concentrated in vacuo to remove excess solvents. The residual was added dropwise into a mixture of ice-water (10 mL) and ethyl acetate (10 mL), separated, extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with 10% NaHCO3, concentrated in vacuo. ethyl 6-bromo-4-chloro-quinoline-3-carboxylate (1.41 g, 4.48 mmol, 88.49% yield) was obtained as a off-white solid. 1H NMR (400MHz, CHLOROFORM-d) d = 9.20 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.91 (dd, J=2.1, 8.9 Hz, 1H), 4.51 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H). |
With thionyl chloride; for 17h;Reflux; | General procedure: The quinolone derivatives 1 were prepared by treating the appropriate aniline (100 mmol) with diethyl ethoxymethylenemalonate (100 mmol) under reflux in ethanol (5 mL) for 2-10 h to obtain the enamine derivatives that were then cyclized in refluxing diphenyl ether for 30 min-6 h [29]. These quinolones (13 mmol) were refluxed in thionyl chloride (20 mL), for 17 h, affording the corresponding chloro-derivatives 2a-g [22]. Reaction of 2a-g (4 mmol) with 2-hydrazinobenzothiazole (8 mmol) in toluene (30 mL), for 3 h, followed by a 2 h reflux in acetic acid gave the corresponding 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones 3a-g as solids which were collected by filtration under vacuum, washed with water and subsequent purified by washing with hot ethyl alcohol. | |
With trichlorophosphate; for 1h;Reflux; Inert atmosphere; Schlenk technique; | General procedure: A solution of compounds 3a-d (1.0 mmol) in POCl3 (6 mL) was refluxed for 1 h. The mixture was evaporated in vacuo and the residue was extracted with methylene chloride, crushed ice and aqueous NH3.The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, EA: n-Hex) to get key intermediates 4a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 48h; | General procedure: The appropriate oxoquinoline derivative 5 (1.75 mmol) was stirred for 15 minutes in the presence of 750.0 mg of K2CO3 and 5.0mL of DMF, followed by the addition of diisopropyl(tosylmethoxy)phosphonate 4 (3.50 mmol). The reaction mixture was additionally stirred for 48 h at 80 C. Afterwards, the resulting mixture was poured into water (30 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated, giving rise to ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k which were purified by crystallization from ethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Dowtherm A; for 0.5h;Reflux; | General procedure: A solution of the appropriate meta or para-substituted anilines (100 mmol), 20.4 mL (100 mmol) of diethyl ethoxymethylenemalonate and 20 mL of ethanol was heated under reflux for 2 hours. The mixture was allowed to cool and then was poured into ice-cold water. The precipitate was collected by filtration and the corresponding enamine-type derivatives (3.0 g) were refluxed for 30 minutes in 30 mL of Dowtherm A, leading to crude oxoquinolines 4 that were recrystallized from dimethylformamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate; In ethanol; for 4.5h;Reflux; | General procedure: Substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 4 (0.01 mol) wasrefluxed for 12 h with hydrazine monohydrate (0.01mol) in absolute ethanol ( 9 mL) to give substituted-4-oxo-1,4-dihydroquinoline-3-carbohydrazide 5.The excess solvent was evaporated off and theresulting mixture was poured into crushed ice. Thesolid separated was filter on sintered funnel,washed with water and dried. The crude solid waspurified by recrystallized from Dioxane: ethanol togive 5 as white solid. Purity of the compound waschecked on silica gel TLC plates. TLC was run inchloroform-methanol (9:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.92% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 12h;Reflux; Inert atmosphere; | A mixture of o-tolyl boronic acid (760mg, 5.58mmol), 11 (1.5g, 5.08mmol), K2CO3 (1.05g, 7.66mmol), Pd(PPh3)4 (295mg) and H2O (3.8mL) in THF (30mL) was heated to reflux under N2 atmosphere for 12h. After the mixture was cooled to room temperature, filtered, the crude solid product 12 was purified by recrystallization with ethyl acetate. (1.2g, 76.92% yield). m.p. 208-209C; 1H NMR (400MHz, DMSO-d6): δ 12.59 (s, 1H), 8.60 (s, 1H), 8.06 (s, 1H), 7.71 (s, 2H), 7.22-7.37 (m, 4H), 4.23 (q, 2H, J=7.2Hz), 2.26 (s, 3H), 1.29 (t, 3H, J=7.2Hz); HRMS (ESI) for C19H17NO3: calcd. 308.12812 (M+H)+, found: 308.12776 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h; | To the quinoline compound shown above (2.94 g, 10 mmol) in DMF (60 mL) wasadded K2C03 (5.5 g, 40 mmol) followed by 4-chloromethylmethlsulfone (Fluorochem) (2.04 g, 10 mmol) and the reaction mixture heated to 900 for 4 h. The DMF was removed on a rotary evaporator (1 mm Hg) and water (200 mL) and ethyl acetate (100 mL) added. The mixture was stirred for 30 mins and the light grey solid product filtered off and washed with ethyl acetate (100 mL). 3.58 g, 82 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.280 g | Crude 6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate 2 (1.000 g, 3.377 mMol) was stirred in DMF (6.7 mL) with potassium carbonate (1.159 g, 8.386 mMol) at 40C. After 5 minutes benzyl bromide (1.99 mL, 16.771 mMol) was added dropwise and the temperature raised to 80C. After 24.5 hours, LCMS analysis showed thepresence of one product only (mlz 3 85-387) and complete consumption of the starting material (m/z 297-299). The reaction mixture was concentrated in vacuo and coevaporated twice (toluene). The residue was partitioned between water and dichloromethane and the aqueous layer was washed with dichloromethane 3 times. The organic layers were collected, dried (magnesium sulphate), filtered andconcentrated in vacuo to give crude ethyl 1-benzyl-6-bromo-4-oxo-1,4- dihydroquinoline-3-carboxylate 3 as a sticky bright pale yellow solid. The solid residue was then dissolved in dichloromethane, pre-absorbed onto silica gel and purified by flash-chromatography (ethyl acetate to ethyl acetate : methanol 5% to ethyl acetate : methanol 10%) to afford ethyl 1-benzyl-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate 3 (1.280 g, 98.1%) as a white crystalline solid. M.p.166-168C (ethyl acetate/methanol); HRMS (El): found 385.03131 [M]C19H16NO379Br requires 385.03081; found 387.02894 [M] C19H16NO381Br requires387.02847; peak ratio: 5 1.9% : 48.1%; Vmax (thin film): 3035 (w, ArC-H), 2964,2928, (m, alkyl C-H), 1725 (s, C=O ketone), 1686 (s, C=O ester, conjugated with C=C), 1623, 1606 (s, C=C conjugated with C=Os) cm’; 6H (CDC13, 300 MHz): 1.32(3H, t, JCH3,CH2 7.2 Hz, CH3), 4.30 (2H, q, JCH2,CH3 7.2 Hz, CH2), 5.30 (2H, s, CH2,Bn), 7.04-7.09 & 7.22-7.32 (5H, 2 x m, 5 x ArHs, Bn), 7.10 (1H, d, JH-C,H-B 9.0 Hz,ArHC), 7.50 (1H, dd, JH-B,H-C 9.0 Hz, JH-B,H-A 2.3 Hz, ArHB), 8.47 (1H, 5, CH-N-Bn),8.50 (1H, d, JHA,HB 2.3 Hz, ArHA); 6c (CDC13, 75 MHz): 14.4 (CH3), 57.6 (CH2,Bn), 61.0 (OCH2CH3), 111.5 (O=C-C-C=O), 118.6 (ArCquatC), 119.2 (Br-Cq), 126.0, 128.7, 129.4 (5 x ArCs, Bn), 130.4 (CA), 130.5 (CACqC=O), 133.9 (Cq (Bn)), 135.5 (CB), 138.0 (CCCqNBn), 149.7 (CD), 165.2 (CO2tBu), 173.1 (0C-CC). Soluble in DCM and a bit soluble in acetone. |
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