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CAS No. : | 22246-18-0 | MDL No. : | |
Formula : | C9H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LKLSFDWYIBUGNT-UHFFFAOYSA-N |
M.W : | 163.17 | Pubchem ID : | 2785758 |
Synonyms : |
3,4-Dihydro-7-hydroxy-2(1H)-quinolinone
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 48.56 |
TPSA : | 49.33 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.6 cm/s |
Log Po/w (iLOGP) : | 1.3 |
Log Po/w (XLOGP3) : | 0.98 |
Log Po/w (WLOGP) : | 0.71 |
Log Po/w (MLOGP) : | 0.84 |
Log Po/w (SILICOS-IT) : | 1.61 |
Consensus Log Po/w : | 1.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.84 |
Solubility : | 2.36 mg/ml ; 0.0145 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.6 |
Solubility : | 4.06 mg/ml ; 0.0249 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.58 |
Solubility : | 0.426 mg/ml ; 0.00261 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P273-P280 | UN#: | N/A |
Hazard Statements: | H302-H317-H412 | 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% | With sodium tetrahydroborate In tetrahydrofuran at 0℃; Reflux | 7-Hydroxy-3,4-dihydroquinolin-2(1H)-one(2.00 g, 12.26 mmol) was dissolved in THF (20 mL) and cooled to 0oC. After the addition ofNaBH4 (1.07 g, 28.19 mmol), I2 (3.42 g, 13.48 mmol) dissolved in THF (20 mL) was added to thesolution dropwise via an addition funnel. The reaction was then fitted with a condenser andrefluxed overnight. The solution was then neutralized with 3 M hydrochloric acid and thenextracted with dichloromethane three times, dried over magnesium sulfate. Evaporation ofthe solvent resulted in a viscous yellow oil. The crude material was purified by flash columnchromatography to yield the product as a white crystalline solid (1.80 g) in a 98percent yield. |
66% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 65℃; for 16.25 h; | A solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (12, 5.0 g, 30.64 mmol) in anhydrous THF (30 mL) was added dropwise to a suspended solution of LiAlH4 (1.7 g, 44.80 mmol) in anhydrous THF (70 mL) at 0. After the mixture was stirred for 15 min, the cooled batch was removed, and then the mixture was heated to 65 and stirred for 16 h. The resulting reaction mixture was diluted with THF (50 mL) and quenched with saturated NH4Cl (5 mL) in the ice-water batch. The aqueous solution was adjusted to PH 4-5 with 4 N HCl solution and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1:20-1:10-1:5, v/v), to afford the intermediate 13 (3.03 g, 66percent yield) as a slight yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 2.3 Hz, 1H), 5.97 (d, J = 2.2 Hz, 1H), 4.55 (s, 2H), 3.32-3.13 (m, 2H), 2.67 (t, J = 6.4 Hz, 2H), 1.97-1.80 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 154.68 (s), 145.50 (s), 130.45 (s), 114.45 (s), 104.79 (s), 101.18 (s), 42.04 (s), 26.32 (s), 22.46 (s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.3% | Stage #1: at 155 - 165℃; for 4 h; Stage #2: With methanol; sodium hydroxide In water at 20℃; for 1 h; Heating / reflux |
Example 2; Preparation of 7-HQ in the Presence of a Salt; A 0.5 l reactor was charged with 3-MPCA (40 g, 0.185 mole), AlCl3 (125 g, 0.925 mole, 5 eq.) and anhydrous sodium chloride (20 g) and the reaction mixture was heated under stirring to about 160° C. to obtain a readily stirred slurry. The reaction mixture was held at 155-165° C. for four hours. The reaction mixture was cooled to about 50° C. and quenched by slowly adding ice cold diluted hydrochloric acid (200 ml of 5percent HCl) to the reactor. The suspension thus obtained was heated to 50° C. and a red-violet solid was collected by filtration. The red-violet solid was slurried at 50° C. in water (100 ml) to remove the salts from the compound, and the solid was collected by filtration, washed with water (30 ml) and dried in an oven at 50° C. overnight to yield a red-violet complex of 7-HQ with AlCl3 (27.1 g), containing about 2percent of 5-HQ. The complex (27.1 g) was dissolved in methanol (220 ml) while heating under reflux and 47percent aqueous sodium hydroxide solution was added to produce a pH of about 7. The hot solution was filtered and activated carbon (0.8 g) was added to the filtrate. The mixture was heated under reflux for half an hour and the activated carbon was collected by filtration. Methanol (about 190 ml) was removed from the filtrate by evaporation and water (30 ml) was added to the residue thus obtained. The mixture was stirred at ambient temperature for half an hour and the colorless crystals were collected by filtration, washed with a cold methanol-water (1:1) mixture (20 ml) and dried at 50° C. overnight to yield 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (18.8 g, 62.3percent yield, having a purity of 99.4percent by HPLC). |
61.3% | Stage #1: With N,N-dimethyl acetamide In water at 95 - 165℃; for 5.5 h; Stage #2: With methanol; sodium hydroxide In water at 20℃; for 1 h; Heating / reflux |
Example 1; Preparation of 7-HQ in a Mixture Containing a High Boiling Solvent; A 3.0 l reactor was charged with 3-MPCA (300 g, 1.4 mole), AlCl3 (920 g, 7.0 mole, 5 eq.) and N,N-dimethylacetamide (65 ml, 61 g, 0.5 eq.) and the reaction mixture was heated under stirring to about 160° C. to obtain a readily stirred liquid. The reaction mixture was held at 155-165° C. for about four hours under stirring, then cooled to about 50° C. Cold water (1500 ml) was added for a time period of half an hour and the mixture was stirred under heating to about 95° C. for one hour. The suspension thus obtained was cooled to about 50° C. and a red-violet solid was collected by filtration, washed with water (400 ml) and dried in an oven at 50° C. overnight to yield a red-violet complex of 7-HQ with AlCl3 (202 g), containing about 2percent of 5-HQ. The complex (202 g) was dissolved in methanol (1600 ml) while heating under reflux and 47percent aqueous sodium hydroxide solution was added to produce a pH of about 7. The hot solution was filtered and activated carbon (6 g) was added to the filtrate. The mixture was heated under reflux for half an hour and the activated carbon was collected by filtration. Methanol (about 1400 ml) was removed from the filtrate by evaporation and water (200 ml) was added to the residue thus obtained. The mixture was stirred at ambient temperature for half an hour and the colorless crystals were collected by filtration, washed with a cold methanol-water (1:1) mixture (10 ml) and dried at 50° C. overnight to yield 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (140.5 g, 61.3percent yield, having a purity of 99.3percent by HPLC). Re-crystallization from methanol gave colorless crystals: mp 230-231.5° C. |
61.3% | Stage #1: at 95 - 165℃; for 5.5 h; Stage #2: With methanol; sodium hydroxide In water at 20℃; for 1 h; Heating / reflux |
Example 3; Preparation of 7-HQ in a Melt; A 2.0 l reactor was charged with 3-MPCA (150 g, 0.69 mole) and AlCl3 (460 g, 3.45 mole, 5 eq.).The reaction mixture was heated under stirring to about 160° C. to obtain a liquid. The reaction mixture was stirred and held at 155-165° C. for about four hours. Stirring was stopped and the reaction mixture was cooled to 50° C. Ice cold diluted hydrochloric acid (750 ml of 5percent HCl) was added to the reactor during half an hour and the mixture was stirred while heating to about 95° C. for one hour. The suspension thus obtained was cooled to about 50° C. and a red-violet solid was collected by filtration, washed with water (200 ml) and dried in an oven at 50° C. overnight to yield the red-violet complex of 7-HQ with AlCl3 (100 g), containing about 2percent of 5-HQ. The complex (100 g) was dissolved in methanol (800 ml) while heating under reflux and 47percent aqueous sodium hydroxide solution was added to produce a pH of about 7. The hot solution was filtered and activated carbon (3 g) was added to the filtrate. The mixture was heated under reflux for half an hour and the activated carbon was collected by filtration. Methanol (about 700 ml) was removed from the filtrate by evaporation and water (100 ml) was added to the residue thus obtained. The mixture was stirred at ambient temperature for half an hour and the colorless crystals were collected by filtration, washed with a cold methanol-water (1:1) mixture (50 ml) and dried at 50° C. overnight to yield 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (70.2 g, 61.3percent yield, having a purity of 99.5percentby HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 66℃; for 4 h; | Into a 1000mL reaction flask put 100g of 3, 4-dihydro-7-hydroxyl-2-quinolinone, and add 500mL of tetrahydrofuran, and then add 140g of DDQ, after that heated at 66 ° C, stirred and refluxed for 4 hours, after the reaction is complete, add 1mol / L sodium thiosulfate 500mL aqueous solution, and then filtered and dried, and then obtained 7-hydroxyl-2-quinolinone as an off-white powder 88g, yield 89percent, purity 99.7percent. |
75% | Stage #1: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 20 - 50℃; for 2 h; Inert atmosphere Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 1 h; Inert atmosphere |
To a solution of compound 4 (25 g, 0.153 mol, 1.0 eq) in THF (125 mL) at room temperature under a nitrogen atmosphere and stirred for 10-15 min, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) added portion wise (37.16 g, 0.163, 1.07 eq) to the reaction mixture. Stirred the reaction at 45-50 °C for 2 h. The progress of the reaction monitored by TLC, reaction mixture was cooled to 25-30 °C, added NaHCO3 (27.5 g, 0.327, 2.14 eq) and water (250 mL) to the reaction mixture, stirred for 1 h at room temperature, solid filtered and washed with water (50 mL). Wet cake was triturated with Isopropyl alcohol (75 mL), filtered and washed with isopropyl alcohol (25 mL) to obtain pure compound 1 (18.5 g, 0.114 mol, 75 percent) as an off-white solid, m.p. 233-235 °C. 1H NMR (400 MHz, DMSO-d6)δ (ppm) 11.47 (br s, 1H), 10.07 (s, 1H), 7.73 (d, J) 9.44 Hz, 1H), 7.43 (d, J) 8.52 Hz, 1H) 6.67 (s, 1H) 6.61 (d, J) 6.48 Hz, 1H), 6.20 (d, J) 9.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)δ (ppm) 162.3, 159.5, 140.7, 140.0, 129.2, 117.4, 112.3, 111.5, 99.8; C9H7NO2 [M-1] calcd. 160.1. |
20.3 g | With 2,3-dichloro-5,6-dicyanohydroquinone In tetrahydrofuran at 0 - 30℃; for 11 h; | A solution of 4,5-dichloro-3,6-dihydroxyphthalonitrile (40.86 gm) in tetrahydrofuran (100 ml) was added to a pre-cooled mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (25 gm) and tetrahydrofuran (50 ml) at 0-5°C and stirred the reaction mixture for 20 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 1 1 hrs at the same temperature. Filtered the solid, washed with tetrahydrofuran and suck dried the material. Methanol (125 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with methanol and dried the material to get the title compound. (0289) Yield: 20.3 gm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.95% | With potassium carbonate In N,N-dimethyl-formamide at 30 - 45℃; for 6 - 7 h; | Example-l; <n="10"/>Preparation of 7-(4-bromobutoxy)- 3,4- dihydro carbostyril [ BBQ]:In a 3 -Liter capacity multi necked flask equipped with mechanical stirrer, condenser, thermometer, were charged 100 gm of 7 - HQ, 397.5 gm of 1,4- dibromobutane, 42.33 gm of potassium carbonate and 300 ml of N,N-dimethyl formamide at RT (30 - 35°C).The reaction mass was heated up to 40-45 0C and maintained for 1 hour at 40 - 450C. After that second lot of potassium carbonate (42.33 gm) was added. The reaction mass was further maintained for 1 hour. After that third lot of potassium carbonate (42.33 gm) was added and further maintained at 40 - 450C for 4 - 5 hours. The reaction mass was cooled to room temperature and dumped into 1500 ml of water. The reaction mass was stirred for 30 minutes and to it were added 500 ml of chloroform , layers were separated and aq. phase is further extracted with 500 ml of chloroform. Layers were separated and organic phases were combined and washed with 10 percent NaOH solution. Layers were separated and chloroform layer was washed with 1500 ml water and organic phase was distilled out under vacuum. The traces were swapped with 2x250 ml of cyclohexane. To the reaction mass were added 300 ml of cyclohexane and stirred for 3 hours. The solid material was filtered and washed with 200 ml of cyclohexane. T he material was dried in tray dryer at about 65-700C for about 10 to 12 hours till loss on diying was less than 1 percentWeight of product: 148 gms Yield is 80.95percent; Purity 86.09 percent by HPLC |
75.5% | With potassium carbonate In propan-1-ol for 6 h; Heating / reflux | Example 10; Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (7-BBQ) by Reaction of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-dibromobutane in 1-propanol in the Presence of potassium carbonate; A mixture of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (10 g, 0.061 mole), 1,4-dibromobutane (22.2 ml, 39.75 g, 0.184 mole. 3 eq.) and potassium carbonate (9.32 g, 0.067 mole, 1.1 eq.) in 1-propanol (100 ml) was heated under reflux for 6 hours (the reaction mixture contained 9.6percent of BQB after reaction completion). The hot reaction mixture was then filtered and the solid was washed with hot 1-propanol (3.x.20 ml). The solvent and the excess of 1,4-dichlorobutane were removed to dryness by evaporation in vacuum. 2-Propanol (50 ml) was added to the residue thus obtained and the mixing was maintained at 5-10° C. for 3 hours. A precipitate was then collected by filtration and dried at 50° C. under reduced pressure overnight to give crude 7-BBQ (16.5 g, 90.7percent yield, containing 11.0percent of BQB). The crude 7-BBQ (16.5 g) was slurried in ethyl acetate (230 ml) at room temperature for 8 hours. A precipitate (BQB) was collected by filtration and washed with ethyl acetate (3.x.15 ml). The ethyl acetate was removed to dryness by evaporation under reduced pressure to give 7-BBQ (13.72 g, 75.5percent total yield, containing 1.8percent of BQB). Melting point=110-111° C. |
74% | With potassium carbonate In ethanolReflux | Intermediate 4:[0118] 7-hydroxy-3,4-dihydroquinolin-2(lH)-one (163 mg, 1.0 mmol), 1,4- dibromobutane (0.36 mL, 3.0 mmol) and anhydrous K2C03 (138 mg, 1.0 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHC03, brine, dried over anhydrous Na2S04, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE EtOAc = 2: 1) to give 7-(4-bromobutoxy)-3,4-dihydroquinolin- 2(lH)-one (intermediate 4) (220 mg, 74percent) as a white solid, mp: 106-109°C. |
73.3% | With potassium carbonate In water; acetonitrile for 4 h; Reflux | 40 g of acetonitrile was added to 82 g (0.5 mol) of 7-hydroxy-3,4-dihydrocarbostyril,to this,After adding a potassium carbonate aqueous solution (a solution obtained by dissolving 69 g (0.5 mol) of potassium carbonate in 204 g of water)further,324 g (1.5 mol) of 1,4-dibromobutane was added,Refluxed for 6 hours.This reaction solution was concentrated under reduced pressure,408 g of 2-propanol was added to the residue,After stirring at 10 ° C. or less for 1 hour,204 g of water was added,The mixture was stirred at 10 ° C. or less for 1 hour for crystallization and filtration.The obtained crystals were dried at 80 ° C.,109 g (yield: 73.3percent) of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril was obtained. |
72% | With potassium carbonate; sodium sulfate In toluene for 2 h; Heating / reflux | Example 11; Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (7-BBQ) by reaction of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-dibromobutane in the Presence of Phase Transfer Catalyst; A reactor was charged with 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (50 g, 0.307 mole), 1,4-dibromobutane (98percent purity, 110.8 ml, 198.7 g, 0.92 mol, 3 eq.), potassium carbonate (55.1 g, 0.399 mole, 1.3 eq.), tricaprylylmethylammonium chloride (Aliquat.(R). 336) (5 g), sodium sulfate (30 g), water (250 ml) and toluene (75 ml) and the mixture was heated under reflux for 2 hours (the reaction mixture contained 12.1percent of BQB after reaction completion). The organic phase was collected and the solvent and an excess of 1,4-dibromobutane were removed from to dryness by evaporation in vacuum. 2-Propanol (270 ml) was added to the residue thus obtained and the mixture was stirred at 5-10° C. for 5 hours. A precipitate was then collected by filtration, washed with cold 2-propanol (2.x.35 ml) and dried at 50° C. overnight to give crude 7-BBQ (82.3 g, 90.0percent yield, containing 14.3percent of BQB). The crude 7-CBQ (82.3 g) was slurried in ethyl acetate (1150 ml) at room temperature for 8 hours. A precipitate (BQB) was collected by filtration and washed with ethyl acetate (2.x.100 ml). The ethyl acetate was removed from the filtrate to dryness by evaporation under reduced pressure and the colorless solid thus obtained was dried at 60° C. overnight to give 7-BBQ (65.9 g, 72.0percent total yield, containing 1.9percent of BQB). Melting point=110-111° C. |
72% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12 h; | Example 1; 7-(4-Bromobutoxy)-3,4-dihydroquinolinone-2(1H)-one (3) (Scheme 1); To a stirred suspension of anhydrous potassium carbonate (K2CO3) (10.50 g, 0.075 mol) in 100 mL of anhydrous N,N-dimethylformamide (DMF) was added 7-hydroxyquinolinone 1 (10.00 g, 0.06 mol) followed by 1,4-dibromobutane 2 (25.91 g, 0.12 mol). The resulting mixture was heated at 60° C. for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC) technique. After cooling to room temperature, the reaction mixture was filtered through a sintered funnel and the precipitate was washed with ethyl acetate (25 mL.x.2). The combined filtrate was concentrated on a rotavapor. The residue was diluted with 250 mL of ethyl acetate, washed with water (100 mL.x.2), dried over anhydrous magnesium sulfate and evaporated the solvent. The residue was triturated with hexane and then filtered the precipitate to give the pure title compound 3. White solid, 12.88 g (72percent). 1H NMR (400 MHz, CDCl3): δ 1.92-1.97 (m, 2H); 2.05-2.10 (m, 2H); 2.64 (t, J=9.2 Hz, 2H); 2.92 (t, J=9.2 Hz, 2H); 3.50 (t, J=7.6 Hz, 2H); 3.98 (t, J=7.6 Hz, 2H); 6.37 (d, J=3.2 Hz, 1H); 6.50-6.54 (m, 1H); 7.04 (d, J=11.2 Hz, 1H), 8.61 (broad s, 1H). |
68.7% | With potassium carbonate In acetonitrile at 60 - 65℃; Inert atmosphere | General procedure: The appropriate dibromoalkane derivative 2a–2d (4.4 mmol)was added to a mixture of the starting material 7-hydroxy-3,4-dihydro-2(1H)-quinoline (1) (2.0 mmol), anhydrous K2CO3(290 mg, 2.1 mmol) in CH3CN (8 mL). The reaction mixture washeated to 60–65 C and stirred for 8–10 h under an argon atmosphere.After complete reaction, the solvent was evaporated underreduced pressure. Water (30 mL) was added to the residue and themixture was extracted with dichloromethane (30 mL 3). Thecombined organic phases were washed with saturated aqueoussodium chloride, dried over sodium sulfate, and filtered. The solventwas evaporated to dryness under reduced pressure. The residuewas purified on a silica gel chromatography usingdichloromethane/acetone (50:1) as eluent to give the intermediates3a–3d. |
55% | With potassium hydroxide In isopropyl alcohol for 16 h; Reflux | Potassium hydroxide (0.120 g, 2.139 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (0.200 g, 1.226 mmol) in 2-propanol (3 mL). After a clear solution was obtained, 1,4-dibromobutane (0.44 mL, 3.685 mmol) was added and the mixture was refluxed for 16 h. It was then cooled, diluted with ethyl acetate and filtered. The filtrate was concentrated to provide a crude residue which was purified by chromatography on neutral alumina (20percent acetone in dichloromethane) to give the title compound as a white solid (0.200 g, 55percent). 1H NMR (400 MHz, CDCl3) δ 1.87-1.98 (m, 2H), 2.00-2.10 (m, 2H), 2.62 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.5 Hz, 2H), 3.49 (t, J=6.8 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 6.29 (d, J=2.1 Hz, 1H), 6.52 (dd, J=8.3, 2.5 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 7.69 (br, exchangeable with D2O, 1H); IR (KBr) υ 2928, 1677, 1631, 1594, 1383 cm-1; MS 298, 300 [(M+1), (M+3)]. |
32% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; | To a mixture of 7-hydroxy-3,4-dihydroquinolin-2(lH)-one (23-1) (14.0 g, 85.9 mmol, 1.0 eq) and potassium carbonate (17.8 g, 129 mmol, 1.5 eq) in N,N-dimethylformamide (200 mL) was added 1,4-dibromobutane (46.0 g, 215 mmol, 2.5 eq). The mixture was stirred at 50 °C overnight. The reaction mixture was poured into 500 mL of water, extracted with ethyl acetate (200 mL x 2), dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5: 1) to give compound 23-2 as a white solid (8.2 g, yield: 32 percent). MS (ESI): m/z 298, 300 [M+H]+. |
93 g | With potassium carbonate In water; N,N-dimethyl-formamide at 25 - 30℃; for 19 h; | A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (75 gm), 1 ,4-dibromobutane (196.6 gm), potassium carbonate (90 gm), dimethylformamide (375 ml) and water (37.5 ml) was stirred for 19 hrs at 25-30°C. Dichloromethane was added to the reaction mixture at 25- 30°C and stirred for 30 min at the same temperature. Filtered the unwanted solid and extracted the desired compound trapper in the unwanted solid by using dichloromethane. Combined the obtained dichloromethane solution with the above obtained filtrate. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cyclohexane (75 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound. Yield: 93.0 gm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.8% | With sodium hydroxide In ISOPROPYLAMIDE at 36 - 40℃; for 4 h; | 1,4-dibromo butane (509 ml) was added to a stirred solution of 7-hydroxy-3,4-dihydrocarbostyril (100 gm) in dimethylacetamide (500 ml) at ambient temperature. The reaction mixture was heated at 36° to 40° C. Sodium hydroxide (33.1 gm) was added to the reaction mixture at the interval of 30 min (Complete the addition of sodium hydroxide in 9 equal fractions in 4.0 hours). The reaction mixture was cooled at ambient temperature and D.M Water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5percent brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure (10 mm) at 45° C. to obtain residue. To the residue cyclohexane (1000 ml) was added to give of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril. Yield: 122.0 gms (66.8percent) Dimer content: 5.0-8.0percent |
66% | Stage #1: With potassium carbonate In acetonitrile for 2 h; Heating / reflux Stage #2: With tetra-(n-butyl)ammonium iodide In acetonitrile for 2 - 4 h; Heating / reflux |
Example 1; A mixture of 7-hydroxy 3,4-dihydrocarbostyril (5Og, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-3O0CA mixture of dibromo butane (20Og, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the <n="10"/>0003109above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture was heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4- dihydrocarbostyril is present less than 1.0percent, (the reaction mixture contained 14-15 percent of the dimer impurity), mixture was cooled to 25-3O0C1 filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, Hydrogen chloride gas was purged into it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 percent, carbon (5g) was added to the solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20percent potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20percent brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-100C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-450C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (62 g, yield 66percent, purity by HPLC 97.4 percent, dimer impurity 0.28percent). |
55% | Stage #1: With potassium carbonate In acetonitrile for 2 h; Heating / reflux Stage #2: With tetra-(n-butyl)ammonium iodide In acetonitrile for 2 - 4 h; Heating / reflux |
Example 2; A mixture of 7-hydroxy 3,4-dihydrocarbostyril (5Og, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-300CA mixture of dibromo butane (20Og, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4- dihydrocarbostyril is present less than 1.0percent, (the reaction mixture contained 14-15 percent of the dimer impurity), mixture was cooled to 25-300C, filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, sulphuric acid (55g) was added to it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 percent, carbon (5g) was added to the <n="11"/>N2007/00031010solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20percent potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20percent brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-100C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-450C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (52 g, yield 55percent, purity by HPLC 98.05 percent, dimer impurity 0.08percent). |