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Structure of 1,4-Dibromo butane
CAS No.: 110-52-1
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Tian, Gui-Long ; Hsieh, Chia-Ju ; Taylor, Michelle ; Lee, Ji Youn ; Riad, Aladdin A. ; Luedtke, Robert R. , et al.
Abstract: The difference in the secondary binding site (SBS) between the dopamine 2 receptor (D2R) and dopamine 3 receptor (D3R) has been used in the design of compounds displaying selectivity for the D3R versus D2R. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for D3R versus D2R. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in D3R versus D2R selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing D3R affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for D3R versus D2R and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the D3R. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for D3R versus D2R.
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Keywords: Dopamine 2 receptor ; Dopamine 3 receptor ; Fallypride ; Bitopic ligands ; PET imaging
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Purchased from AmBeed: 89031-84-5 ; 40216-83-9 ; 88-13-1 ; 135042-17-0 ; 110-52-1 ; 488-93-7 ; 18742-02-4 ; 98-98-6 ; 86864-60-0 ; 62-23-7 ; 29886-64-4 ; 59741-04-7 ; 4385-62-0 ; 15268-31-2 ; 134441-72-8 ; 54751-01-8 ; 166173-78-0 ; 213131-32-9 ; 98-98-6 ; 69966-55-8 ; 154342-67-3
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CAS No. : | 110-52-1 |
Formula : | C4H8Br2 |
M.W : | 215.91 |
SMILES Code : | BrCCCCBr |
MDL No. : | MFCD00000261 |
InChI Key : | ULTHEAFYOOPTTB-UHFFFAOYSA-N |
Pubchem ID : | 8056 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301-H315-H318-H335-H412 |
Precautionary Statements: | P261-P280-P301+P310-P305+P351+P338 |
Class: | 8(6.1) |
UN#: | 2922 |
Packing Group: | Ⅲ |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 37.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.28 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.46 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.56 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.96 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.29 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.53 |
Solubility | 0.637 mg/ml ; 0.00295 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.1 |
Solubility | 1.7 mg/ml ; 0.00787 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.21 |
Solubility | 0.133 mg/ml ; 0.000617 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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) |
No |
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 |
-5.87 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 |
2.0 |
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 |
1.0 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) |
2.8 |
* 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 |
---|---|---|
85% | With potassium iodide; sodium hydroxide; In acetonitrile; at 30℃; for 16h; | 5 mmol of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one,5mmol 1,4-dibromobutane,5mmol sodium hydroxide,0.2 mmol of potassium iodide was added to acetonitrile and stirred at 30 ° C for 16 h.After the reaction is filtered,The filtrate is concentrated,85percent by column chromatography7-(4-Bromobutoxy)-3,4-dihydroquinolin-2(1H)-one. |
80.95% | With potassium carbonate; In N,N-dimethyl-formamide; at 30 - 45℃; for 6 - 7h; | 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 6h;Heating / reflux;Product distribution / selectivity; | 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 ethanol;Reflux; | 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 4h;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;Aliquat 336; In toluene; for 2h;Heating / reflux;Product distribution / selectivity; | 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 12h; | 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): delta 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 16h;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) delta 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) upsilon 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]+. |
With potassium carbonate; In water; | Reference Example 6 To a solution of 4.06 g of potassium carbonate with 400 ml of water was added 40 g of 7-hydroxy-3,4-dihydrocarbostyril and 158 g of 1,4-dibromobutane, then the mixture was refluxed for 3 hours. The reaction mixture thus obtained was extracted with dichloromethane, dried with anhydrous magnesium sulfate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane), and recrystallized from n-hexane-ethanol to yield 50 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril. | |
With potassium carbonate; In acetone; at 60 - 65℃; for 16h; | Example-1 Preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyryl The solution of 7-(4-hydroxy)-3,4-dihydrocarbostyryl (125 g), potassium carbonate (158.75 g) and 1,4-dibromobutane (662.5 g) was prepared in acetone (1375 mL) and refluxed at 60° C.-65° C. for 16 hours. After the completion of the reaction, the reaction mixture was cooled to 15° C.-20° C. and stirred for 1.0 h. Isolated solid was filtered and washed with chilled acetone (250 mL). The filtrate was distilled under vacuum at 60° C. to remove access of acetone and at 120° C. to remove traces of 1,4-dibromobutane. The oily residue were cooled at 40° C.-45° C. and treated with methylene dichloride and stirred for 15-20 minutes till clear solution was obtained. The reaction mixture was treated with 5percent NaOH and process water at 25° C.-35° C. and the organic layer was separated. The organic layer was further charcoalized and filtered through cilete bed. The filtrate was subjected to distillation under vacuum to remove excess of methylene dichloride. The resulting mass was treated with ethyl acetate (125 mL) and cyclohexane (500 mL) at 25° C.-35° C. and stirred for 1 h. The solid thus obtained was filtered, washed with cyclohexane and suck dried. The product was dried in hot air oven at 55° C.-60° C. | |
Example-1Step A:Preparation of Pure 7-(4-Bromobutoxy)-3,4-Dihydro-2(1H)-Quinolinone; (IV):7-Hydroxy-3,4-dihydro-2(1H)-quinolinone (20 g, 0.153 mol) was added to a solution of potassium carbonate (25 g, 0.181 mol) in DM water (400 ml) at 25-35° C. and the contents were heated to 80-90° C. to obtain a clear solution. 1,4-Dibromobutane (200 ml) was added to the reaction mass, heated to reflux temperature (100-105° C.) and stirred for 7 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone having 5percent 1,4-bis[3,4-dihydro-2(1H)quinolinon-7-oxy]butane (by HPLC, by area normalization) was washed with precooled 5percent w/v aqueous sodium hydroxide (75 ml) at 15-20° C., to remove unreacted 7-hydroxy-3,4-dihydro-2(1H)-quinolinone. Organic layer was concentrated at 90-105° C. under reduced pressure varying from 50 to 5 mm of Hg to dryness. The concentrated mass was diluted with toluene (2000 ml) and heated to 60° C. Silica gel (50 g) was added and stirred for 30 min at 60-70° C. Silica gel was removed by filtration and the filtrate was concentrated at 60-80° C. under reduced pressure varying from 200 to 10 mm of Hg. The resulting concentrated mass having 0.3percent of 1,4-bis[3,4-dihydro-2(1H)quinolinon-7-oxy]butane (by HPLC, by area normalization) was diluted with hexanes (50 ml) and stirred for 30 minutes to crystallize the product. Product was filtered and washed with hexanes.Yield: 18 gChromatographic purity: 97.89percent (by HPLC, by area normalization)1,4-Bis[3,4-dihydro-2(1H)quinolinone-7-oxy]butane content: 0.33percent | ||
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetonitrile; at 40 - 45℃; for 24h;Product distribution / selectivity; | Example 1Preparation of 7-(4-bromobutoxy)-3,4-dihvdrocarbostyril7-Hydroxy-3,4-dihydrocarbostyril (60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40- 45°C for 24 hours. Reaction mass was cooled upto room temperature and was filtered off. The resulting filtrate was distilled off under vacuum. The resultant mass was cooled to 25-30°C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The solid was filtered and dried under vacuum at 55-60°C for 20 hours to obtain title compound.Yield: 73-75percent; Purity: 93-95percent | |
93 g | With potassium carbonate; In water; N,N-dimethyl-formamide; at 25 - 30℃; for 19h; | 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 |
---|---|---|
With sodium hydroxide; tetrabutylammomium bromide; In water; | Preparation Example 2 Into a 2 liter glass flask, 317 g of <strong>[3452-97-9]3,5,5-trimethylhexanol</strong>, 216 g of 1,4-dibromobutane, 14.3 g of tetrabutylammonium bromide and 442 g of a 52percent by mass aqueous solution of sodium hydroxide were placed, and the reaction was allowed to proceed at 70° C. for 8 hours under stirring. After the reaction was completed, the reaction mixture was transferred to a separatory funnel, and the aqueous phase was removed by filtration. The remaining organic phase was washed with 500 ml of water 5 times. From the organic phase, 1,4-bis(3,5,5-trimethylhexoxy)butane was separated by distillation under a reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.4 g (76%) | With potassium tert-butylate; In tetrahydrofuran; water; | 1.1. 43.7 g of potassium tert-butylate (0.39 mol) were added portionwise at -78° C. to a solution of 32.0 g of 7-fluoro-l,2,3,4-tetrahydro-naphthalen-1-one (0.19 mol) in 320 ml of THF while gassing with argon. The mixture was stirred at -78° C. for 2 hrs. and then a solution of 40 ml of 1,4-dibromobutane (73 g, 0.338 mol) in 40 ml of THF was added dropwise. The cooling bath was removed and the mixture was stirred at RT for 16 hrs. Water was added, the mixture was extracted with ether, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over MgSO4, filtered, concentrated and the residue was chromatographed over silica gel with toluene. The product was distilled through a 20 cm Vigreux column. Yield: 29.4 g (76percent) of 7'-fluoro-3'4'-dihydro-spiro[cyclopentan-1,2'(1'H)-naphthalen]-1'-one as a colourless liquid; b.p. 98°-102° C./0. 11 Torr. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.4 g (55%) | With potassium tert-butylate; In tetrahydrofuran; water; | EXAMPLE 10 10.1.93.8 g of potassium tert-butylate (0.837 mol) were added portionwise at -78 C. to a solution of 75.6 g of 5-chloro-l,2,3,4-tetrahydro-naphthalen-1-one (0.419 mol) in 760 ml of THF while gassing with argon. The mixture was stirred at -78 C. for 2 hrs. and then a solution of 84 mi of 1,4-dibromobutane (134 g, 0.711 mol) in 350 ml of THF was added dropwise. The cooling bath was removed and the mixture was stirred at RT for 16 hrs. Water was added, the mixture was extracted with ether, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over MgSO4, filtered off, concentrated and the residue was chromatographed over silica gel with hexane/toluene 1:1. Yield: 54.4 g (55%) of 5'-chloro-3'4'-dihydro-spiro[cyclopentane-1,2'(1'H)-naphthalen]-1'-one as a colourless oil. MS: m/e (% basic peak)=234 (C14 H15 ClO+, 21), 193 (100), 165 (13), 152 (21), 124 (14), 89 (14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.8% | EXAMPLE-XIII: Preparation of Aripiprazole p-toluenesulfonate; Step-1; Sodium hydroxide (29.5 g, 0.737 mole) is added to a suspension of 7-Hydroxy carbostyril (100 g, 0.613 mole) in isopropyl alcohol (1850 ml) and mixed at 250C to 300C for about 30 min. Tetra butyl ammonium bromide is added (5 g, 0.015 mole) followed by 1,4-Dibromo butane (530 g, 2.45 mole), raised to reflux and maintained at reflux temperature 8O0C - 850C for 3 hrs. The insolubles are filtered in hot condition, and isopropyl alcohol is distilled off from the filtrate under vacuum at temperature up to 1100C - 115°C. The reaction mass is .cooled and isopropyl alcohol (300 ml) is added to the reaction mass, maintained at 300C - 35°C for 1 hr. The mass is further cooled and maintained at 2O0C- 22°C for 2 hrs, filtered, washed with isopropyl alcohol (50 ml) to give the wet cake of about 250 g. The wet cake (250 g) is suspended in n- hexane (300 ml) , raised the temperature to reflux and maintained for about 60min. The reaction mass is cooled to a temperature of 250C - 35°C and maintained for 1 hr. The mass is filtered; washed and dried the wet cake at 40°C to 500C till becomes constant weight.The dry weight of 7- (4-bromobutoxy) -3, 4-dihydrocarbostyril is 135 g (Yield: 73.8percent) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.0 - 8.0%; 66.8% | With sodium hydroxide; In ISOPROPYLAMIDE; at 36 - 40℃; for 4h;Product distribution / selectivity; | 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% | 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% | 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). |
With potassium carbonate; In water; at 25 - 105℃; for 5 - 7h;Heating / reflux;Product distribution / selectivity; | 7-Hydroxy-3,4-dihydro-2(lH)-quinolinone (2Og, 0.153mol) was added to a solution of potassium carbonate (25g, O.l Slmol) in DM water (400ml) at 25-350C and the contents <n="8"/>were heated to 80-900C to obtain a clear solution. 1 ,4-Dibromobutane (200ml) was added to the reaction mass, heated to reflux temperature (100-1050C) and stirred for 7 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing 7-(4- bromobutoxy)-3,4-dihydro-2(lH)-quinolinone having 5percent l,4-bis[3,4-dihydro- 2(lH)quinolinon-7-oxy]butane (by HPLC, by area normalization) was washed with precooled 5percentw/v aqueous sodium hydroxide (75ml) at 15-200C, to remove unreacted 7- hydroxy-3?4-dihydro-2(lH)-quinolinone. Organic layer was concentrated at 90-1050C under reduced pressure varying from 50 to 5 mm of Hg to dryness. The concentrated mass was diluted with toluene (2000ml) and heated to 6O0C. Silica gel (50g) was added and stirred for 30 min at 60-700C. Silica gel was removed by filtration and the filtrate was concentrated at 60-800C under reduced pressure vaiying from 200 to 10 mm of Hg. The resulting concentrated mass having 0.3percent of l,4-bis[3,4-dihydro-2(lH)quinolinon-7- oxy]butane (by HPLC, by area normalization) was diluted with hexanes (50ml) and stirred for 30 minutes to crystallize the product. Product was filtered and washed with hexanes. Yield: 18gChromatographic purity: 97.89percent (by HPLC, by area nopinalization) EXAMPLE-2PREPARATION OFPURE 7-(4-BROMOBUTOXY)-SJ-DIHYDROOUINOLINONE7-Hydroxy-3,4-dihydroquinolinone (2Og, 0.153mol) was added to a solution of potassium carbonate (25g, O.ldeltalmol) in DM water (140ml) at 25-35°C and the contents were heated to 65-7O0C to obtain a clear solution. 1,4-Dibromobutane (200ml) was added to the reaction mass and again heated to reflux temperature (95-1000C) and stirred for 5 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing l,4-bis[3,4- dihydro-2(lH)quinolinon-7-oxy]butane was washed with precooled 5percentw/v aqueous sodium hydroxide (75ml) at 10-150C, to remove unreacted 7-hydroxy-3,4- dihydroquinolinone. Organic layer was concentrated at 100-1200C under reduced pressure varying from 50 to 5 mm of Hg. The concentrated mass was diluted with toluene (500ml) and heated to 6O0C. Silica gel (6Og) was added and stirred for 30 min at 60-700C. Silica gel was removed by filtration and treated again with preheated toluene (l x400ml, lx200ml, 60-700C). The combined filtrate was concentrated at 60-700C under reduced pressure vary ing from 200 to 10 mm of Hg. Thus, obtained concentrated mass was diluted with hexanes (150ml) and stirred for 30 minutes upon which the product crystallized out. Product was filtered and washed with hexanes. Yield: 17g Chromatographic purity: 97.31percent (by HPLC, by area normalization) l,4-Bis[3,4-dihydiO-2(lH)quinolinon-7-oxy]butane content: 0.44percentEXAMPLE-3PREPARATION OFPURE 7-(4-BROMOBUTOXY)-3,4-DIHYDROOUINOLINONE7-Hydroxy-3,4-dihydroquinolinone (50g, 0.306mol) was added to a solution of potassium carbonate (62.5g, 0.453mol) in DM water (350ml) at 25-350C and the contents were heated to 65-7O0C to obtain a clear solution. 1,4-Dibromobutane (500ml) was added to the <n="10"/>reaction mass and again heated to reflux temperature (95-100°C) and stirred for 5 hours at the same temperature. After completion of reaction, reaction mass was cooled to ambient temperature and organic layer was separated. Organic layer containing l,4-bis[3,4- dihydro-2(lH)quinolinon-7-oxy]butane was washed with precooled 5percentw/v aqueous sodium hydroxide (195ml) at 10~15°C, to remove unreacted 7-hydroxy-3,4- dihydroquinolinone. Organic layer was concentrated at 100-120°C under reduced pressure varying from 50 to 5 mm of Hg. The concentrated mass was diluted with toluene (1000ml) and heated to 600C. Silica gel (165g) was added and stirred for 30 min at 60-700C. Silica gel was removed by filtration and treated again with preheated toluene (2x750ml, 60- 7O0C). The combined filtrate was concentrated at 60-700C under reduced pressure varying from 200 to 10 mm of Hg. Thus, obtained concentrated mass was diluted with cyclohexane (150ml) and stirred for 30 minutes to crystallize the product. Product was filtered and washed with cyclohexane. Yield: 42.5g Chromatographic purity: 97.5percent (by HPLC, by area normalization) l,4-Bis[3,4-dihydro-2(lH)quinolinon-7-oxy]butane content: 0.55percentEXAMPLE-4PREPARATION OFPURE 7-(4-BROMOBUTOXY)-3,4-DIHWROQUINOUNONE7-Hydroxy-3,4-dihydroquinolinone (30g, 0.184mol) was added to a solution of potassium carbonate (37g, 0.268mol) in DM water (1200ml) at 25-35°C and the contents were heated to 65-700C to obtain a clear solution. 1 ,4-Dibromobutane (150ml) was added to the reaction mass and again heated to reflux temperature (95-1000... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In DMF (N,N-dimethyl-formamide); for 168h; | 4- (DIMETHYLAMINO) phenyldiphenylphosphine (1.73 mmoles, 0.529 g) and 1,4-dibromobutane (1.73 mmoles, 0.207 g) were dissolved in DMF (1 ml) and shaken for 1 week. A viscous liquid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 60% | With potassium carbonate; In ethanol; for 38h;Reflux; | Example 7; 4-tetramethylene aminophenoxyisobutyric acidA mixture of 1.2 ml of 1,4-dibromobutane, 1.95 g <strong>[117011-70-8]4-aminophenoxyisobutyric acid</strong>, 5.3 g potassium carbonate and 50 ml ethanol was refluxed and stirred for 38 hours. After evaporation of most of the ethanol, some unreacted dibromobutane and some water were added to dissolve the solid. The solution was acidified with acetic acid and charcoaled. A solid with a melting point of 94-96 C. was formed. The solid was soluble in ethylacetate and chloroform and the structure was confirmed by NMR spectroscopy. The yield was approximately 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g | To stirred solution of 7-Azaoxindole 1(0.5 g ,3.73mmol ) in anhydrous THF(10 ml ) was added n-butyl lithium (0.47g,7.42 mmol)at -78C followed by TMEDA(0.865 g, 7.42mmol). After lh ,1,4dibromobutane (0.571 g, 3.73 mmol ) was added slowly and mixture was allowed to come up to room temperature. After stirring for 15h, saturated aqueous ammonium chloride was added and the crude material was partitioned between water and ethyl acetate. Organic layer was separated, dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by column chromatography by eluting with 50% ethyl acetate in pet ether to get the desired compound 2 (0.1 g) | |
0.1 g | Step-1 [0059] To stirred solution of 7-Azaoxindole 1 (0.5 g, 3.73 mmol) in anhydrous THF (10 ml) was added n-butyl lithium (0.47 g, 7.42 mmol) at -78 C. followed by TMEDA (0.865 g, 7.42 mmol). After 1 h, 1,4 dibromobutane (0.571 g, 3.73 mmol) was added slowly and mixture was allowed to come up to room temperature. After stirring for 15 h, saturated aqueous ammonium chloride was added and the crude material was partitioned between water and ethyl acetate. Organic layer was separated, dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by column chromatography by eluting with 50% ethyl acetate in pet ether to get the desired compound 2 (0.1 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23%; 16% | General procedure: To L1 (2.00 g, 13.6 mmol) dissolved in acetonitrile (60 mL) was added potassium carbonate (18.8 g, 136 mmol). The resulting solution was heated at reflux temperature for 30 min and to the hot solution was added 1,n-dibromoalkane (48.0 mmol, n=3, 4, 6 or 8). The reaction mixture was then stirred at reflux temperature for a further 24 . After cooling, the inorganic solids were removed by filtration and the solvent was removed under reduced pressure to afford an oil, which was purified by column chromatography on silica gel (initially at a ratio of petroleum ether:ethyl acetate 80:20, followed by the ratio of 60:40). This gave the products L2A-D and L3A-D. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In acetone;Reflux; | General procedure: 1,3-dibromopropane (1,4-dibromobutane; 1,5-dibromopentane; 1,6-dibromohexane; 20 mmol) was added to asolution of compounds 6 (10 mmol) and potassium carbonate(20 mmol) in acetone (100 mL), and the mixture was refluxed for4e6 h. The progress of the reaction was monitored by TLC. Aftercooling to room temperature, the mixture was filtered, the solventwas evaporated under reduced pressure. The crude product waspurified by means of chromatography (petroleum ether/EtOAc 10/1) to yield compounds 8ae8d. 6.1.1.2. 7-(4-Bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (8b).Yield: 91percent. White solid, m. p. 110e112 C. 1H NMR (400 MHz, CDCl3)d 10.05 (s, 1H), 7.01 (d, J 8.2 Hz, 1H), 6.49 (dd, J 8.2, 2.3 Hz, 1H),6.45 (d, J 2.2 Hz, 1H), 3.91 (t, J 6.0 Hz, 2H), 3.45 (t, J 6.6 Hz, 2H),2.87 (t, J 7.5 Hz, 2H), 2.61 (t, J 7.5 Hz, 2H), 2.05e1.98 (m, 2H),1.91e1.84 (m, 2H). 13C NMR (100 MHz, CDCl3) d 173.00, 158.47,138.41, 128.55, 115.75, 108.71, 102.35, 66.94, 33.65, 31.04, 29.45,27.89, 24.53. MS (ESI) m/z 298.1 ([M H]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 80℃; for 24h; | General procedure: Dicationic imidazolium ionic liquids were prepared by refluxing-N-hexadecylimidazole (5.85 g, 20 mmol) and 1,4-dibromobutane (2.16 g, 10 mmol) in isopropanol (50 mL) at 80 °C for 24 h. Then, the products were washed with diethyl ether four times under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.711 g | To a stirred solution of <strong>[7321-93-9]4,6-dichloropyridin-3-amine</strong> (3.9 g, 0.0239 mol) in dry DMF (35 mL) was added sodium hydride (1.914 g, 0.0478 mol, 60 percent suspension in mineral oil) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at this temperature for 30 min. Then 1 ,4-dibromobutane (4.134 g, 0.0191 mol) was added dropwise. The reaction mixture was stirred at RT overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction was quenched by addition of ice-water (50 mL) and the product was extracted with EtOAc (2x150 mL). The organic layer was again washed with water (2x50 mL) and brine solution (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afforded an oily residue that was purified by column chromatography on silica gel (100-200 mesh) using 0.5-1percent EtOAc-hexane to afford 2,4-dichloro-5-pyrrolidin-l-yl-pyridine (3.711 g) as an off- white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With caesium carbonate; 1-butyl-3-methylimidazolium Tetrafluoroborate; In acetonitrile; at 20℃; | 1,4-Dibromobutane (2.4 mL, 20. mmol) was added to a mixture of <strong>[42726-73-8]tert-butyl methyl malonate</strong> (1.74 g, 10.0 mmol), cesium carbonate (9.8 g, 30. mmol) and 1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate (0.4 g, 2 mmol) in acetonitrile (20 mL). The resulting mixture was stirred at room temperature overnight then diluted with diethyl ether and filtered. The filtrate was concentrated and the residue was dissolved in diethyl ether then washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography on a silica gel column eluting with 0 to 10percent EtOAc in hexanes to give the desired product (1.7 g, 75percent). LC-MS calculated for C8H13O4 (M-tBu+2H)+: m/z=173.1. found 173.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; | General procedure: Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; | General procedure: To a solution of 1,4-dibromobutane (4.88g, 22.5mmol) and methyl 2-(6-chloropyridin-3-yl)acetate (2.79g, 15.0mmol) in THF (150mL) was added a 1.0M solution of LHMDS in THF (18.8mL, 18.8mmol) dropwisely at 0C. The reaction mixture was stirred at rt for 2.0h, then was added a 1.0M solution of LHMDS in THF (18.8mL, 18.8mmol) slowly at rt. The reaction mixture was stirred at rt overnight, quenched with brine, and extracted with ethyl acetate (30mL, 3×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography with pre-packed silica gel disposable column to afford the title compound 2a (2.26g, 63%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.1% | In acetone; at 50℃;Inert atmosphere; | General procedure: 1,4-dibromobutane (36.0 mmol, 7.70 g) was dissolved indry acetone (50 mL) and the obtained N-alkyl imidazole(9.0 mmol of N-hexyl imidazole, <strong>[21252-69-7]N-octyl imidazole</strong>, Ndecylimidazole, or N-dodecyl imidazole) was addedgradually. The reaction mixture was refluxed at 50° Cunder nitrogen atmosphere and the reaction was monitoredby TLC analysis. After the reaction finished, the solventwas removed under reduced pressure, and subsequently theun-reacted 1, 4-dibromobutane was washed thoroughlywith hexane. The collected viscous liquid was purified bysilica column chromatography with mixtures of acetone/methanol (10:1, by vol) as eluent to afford 1-(4-bromobutyl)-3-alkylimidazolium bromide. The yields of 1-(4-bromobutyl)-3-hexylimidazolium bromide, 1-(4-bromobutyl)-3-octylimidazolium bromide, 1-(4-bromobutyl)-3-decylimidazolium bromide and 1-(4-bromobutyl)-3-dodecylimidazoliumbromide are 72.5, 74.1, 76.8 and 80.3 percent,respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 3h;Sonication; Microwave irradiation; Heating; | 50 mL of N, N-dimethylformamide, 10.0 g of 3-cyano-4-trifluoromethylsulfinyl-5-amino-1- (2,6-di- Dichloro-4-trifluoromethylphenyl) -1H-pyrazole, 2g KOH, then add 4.3g 1,4-dibromobutane, ultrasonic vibration at room temperature for 60min, open the spray switch after the shock, through the trachea to mist The microwave reactor was turned on and the power was adjusted to 300W to start the heating reaction. When the solvent in the ultrasonic atomizer was about to atomize, the atomization was stopped and the inlet of the microwave reactor was shut down and the reaction was continued for 120 min.After completion of the reaction, the product was washed with water and dried by filtration to obtain 13.6 g of compound 6.Yield: 95.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 72h; | General procedure: A solution of 1a, 1b or 11 (2.3 mmol) in acetonitrile (20 mL) wasstirred with DBU (5.7 mmol) and 1-2-dibromoethane, 1-bromo-3-chloropropane, 1,4-dibromobuthane or 1,5-dibromopenthane(16 mmol) at room temperature. After completion of the reaction the reaction mixture was concentrated under reduced pressure. The residuewas diluted with water (25 mL) and extracted with chloroform(3×25 mL). The combined organic layers were washed with water(50 mL), dried over anhydrous MgSO4, filtered, and the solvent wasremoved under reduced pressure. The residue was purified as specifiedin each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 72h; | General procedure: A solution of 1a, 1b or 11 (2.3 mmol) in acetonitrile (20 mL) wasstirred with DBU (5.7 mmol) and 1-2-dibromoethane, 1-bromo-3-chloropropane, 1,4-dibromobuthane or 1,5-dibromopenthane(16 mmol) at room temperature. After completion of the reaction the reaction mixture was concentrated under reduced pressure. The residuewas diluted with water (25 mL) and extracted with chloroform(3×25 mL). The combined organic layers were washed with water(50 mL), dried over anhydrous MgSO4, filtered, and the solvent wasremoved under reduced pressure. The residue was purified as specifiedin each case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | With n-butyllithium; | Preparation of 1,3-di(thiophen-2-yl) butane Thiophene (10.6 g, 125.7 mmol) was dissolved in anhydrous tetrahydrofuran (126 mL) at room temperature, and n-BuLi (50.3 mL, 125.7 mmol) was added at -78 C. After stirring at room temperature for 2 hours, 1,4-dibromobutane (9.04 g, 41.9 mmol) was slowly added at 0 C. After stirring at room temperature overnight, 100 mL of distilled water was added. An organic layer was extracted with diethyl ether and water, water was removed with MgSO4, and a solid was filtered. The filtrate was concentrated to obtain a product in the form of orange oil (8.5 g, a yield of 92.1%). 1H-NMR (500 MHz, CDCl3): 7.11 (dd, J1=5.0 Hz, J2=1.0 Hz, 2H), 6.91 (dd, J1=5.0 Hz, J2=3.5 Hz, 2H), 6.78-6.77 (m, 2H), 2.88-2.85 (m, 4H), 1.78-1.73 (m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
for 48.0h;Reflux; | General procedure: A volume of 0.022 mol of N, N-bis (hydroxyethyl) tertiaryamine, 0.01 mol 1,3-dibromopropane or 1,4-dibromobutane,and 15 mL dry ethanol or 1-propanol were added to a 50 mLround-bottom flask. The reactants were stirred by a magneticstirrer for 48 h at reflux temperature. The extent of reactionwas followed by thin-layer chromatography (silica gel plates)with a mixture of 4:1:1 of ethyl acetate, methanol, and wateras the eluent. After the reaction was completed, the solid atlow temperature was precipitated from the solvent and filtered.The filtered solid was recrystallized in ethanol and ethylacetate and then dried under vacuum to obtain a white solid. |
Tags: 110-52-1 synthesis path| 110-52-1 SDS| 110-52-1 COA| 110-52-1 purity| 110-52-1 application| 110-52-1 NMR| 110-52-1 COA| 110-52-1 structure
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P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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