Structure of 199327-59-8
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CAS No. : | 199327-59-8 |
Formula : | C16H20ClN3O3 |
M.W : | 337.80 |
SMILES Code : | COC1=CC2=NC=NC(Cl)=C2C=C1OCCCN3CCOCC3 |
MDL No. : | MFCD17170922 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319 |
Precautionary Statements: | P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330 |
* 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% | e -Metnoxy- - -mophi o n- -y propoxy - -qu naZo n- -one i w u w phosphorous oxychloride (13.5ml) in a mixture of dichloromethane (150ml), acetonitrile (15ml) and N1N- dimethylformamide (15ml) for 6 hours. After completion of reaction, the reaction mass was quenched in ice (20Og) and the pEta of the resulting reaction mass was adjusted to neutral with potassium carbonate. The layers were separated. The separated organic layer was washed with water and distilled. The resulting compound was crystallized from isopropanol (75 ml) to give 13.5g (85%) of the title compound having purity 99.79% by EtaPLC | |
80.3% | With trichlorophosphate; In dichloromethane; N,N-dimethyl-formamide; acetonitrile; at 40 - 45℃; for 3h; | <strong>[199327-61-2]7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one</strong> 200g, 2000mL of dichloromethane, 200 ml of N,N-dimethylformamide, 200mL of acetonitrile to the reaction mixture was added phosphorus oxychloride (POCl3) 192g by stirring for 3 hours at 40 ~ 45 C prepare a reactant. Preparative cooling the reaction to -10 ~ 0 C and was added dropwise to 25% aqueous potassium carbonate solution was slowly so that the pH is 6-8. After the layers were separated and the organic layer was washed twice with water. After treatment the organic layer over anhydrous magnesium sulfate and activated charcoal, filtered, concentrated and recrystallized isopropanol was added to 2000mL. The resulting solid was filtered and dried under reduced pressure at 50C to 4-chloro-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazoline was obtained 171g. (Yield 80.3%) |
80% | With trichlorophosphate; In acetonitrile; at 100℃; for 12h; | 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine (S3): Take a 100 ml round bottom flask, Put a magnetic charge and add the reactant <strong>[199327-61-2]7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4(3H)-one</strong> (957 mg, 3 mmol), the solvent acetonitrile (20 mL) was added, the reaction tube was stirred in an ice bath, and phosphorus oxychloride (689 g, 4.5 mmol) was slowly added dropwise with a syringe. After the addition was completed, the reaction tube was placed at 100 C for reaction. 12h.After the reaction is over, the reaction is cooled to room temperature.Quench the reaction by adding 30 ml of water.The reaction solution was extracted with dichloromethane (30 mL x 3).The organic phase is dried over anhydrous NaSO4. The solvent was removed using a rotary evaporator.Finally, the product is separated by a chromatography column.The chromatographic conditions were: EtOAc/MeOH (50:1 v/v). The product was a white solid in 80% yield. |
58% | In thionyl chloride; N,N-dimethyl-formamide; toluene; | A solution of 7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin4-one (990 mg, 3.1 mmol) in thionyl chloride (10 ml) and DMF (0.1 ml) was heated at 80 C. for 1.5 hours. The mixture was allowed to cool, toluene was added and the solvent was removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 2M sodium hydroxide solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluding with methylene chloride/methanol (119 followed by 95/5). The purified solid was triturated with hexane, collected by filtration and washed with ether to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (614 mg, 58%). 1H NMR Spectrum: (CDCl3) 2.12(m, 2H); 2.50(br s, 4H); 2.59(t, 2H); 3.73(t, 4H); 4.05(s, 3H); 4.27(t, 2H); 7.33(s, 1H); 7.40(s, 1H); 8.86(s, 1H). |
58% | In thionyl chloride; N,N-dimethyl-formamide; toluene; | Elemental analysis: Found C, 58.6; H, 6.5; N, 12.7% C16H21N3O4 0.5H2O Requires C, 58.5; H, 6.7; N, 12.8% A solution of <strong>[199327-61-2]7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one</strong> (990 mg, 3.1 mmol) in thionyl chloride (10 ml) containing DMF (0.1 ml) was heated at 80 C. for 1.5 hours. After cooling, toluene was added and the solvent was removed by evaporation. The residue was triturated with ether, and the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 2M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by flash chromatography eluding with methylene chloride/methanol (1/9 followed by 95/5). The solid was triturated with hexane, collected by filtration and washed with ether to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (614 mg, 58%). 1H NMR Spectrum: (CDCl3) 2.12(m, 2H); 2.50(br s, 4H); 2.59(t, 2H); 3.73(t, 4H); 4.05(s, 3H); 4.27(t, 2H); 7.33(s, IH); 7.40(s, 1H); 8.86(s, 1H) |
With thionyl chloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 1.5h; | The 4-amino-7-methoxy-6-(3-morpholinopropoxy)quinazolile used as a starting material was prepared as follows :- A mixture of 4-(3-chloro-4-fluoroanhino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (International Patent Application WO 96/33 980, Example 1 therein; 6 g) and 6N aqueous hydrochloric acid solution (120 ml) was stirred and heated to reflux for 6 hours. The mixture was cooled to 0 C. and carefully, with cooling, was neutralised by the addition of concentrated aqueous ammonium hydroxide solution. The No. resultant precipitate was isolated, washed in turn with a dilute aqueous ammonium hydroxide solution and with water and dried under vacuum. There was thus obtained <strong>[199327-61-2]7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one</strong> (4.2 g); NMR Spectrum: (DMSOd6) 2.4 (m, 6H), 3.59 (t, 4H), 3.75 (t, 2H), 3.9 (s, 3H), 4.12 (t, 2H), 7.12 (s, 1H), 7.43 (s, 1H), 7.98 (s, 1H), 12.0 (br s, 1H); Mass Spectrum: M + H+ 320. A mixture of a portion (0.99 g) of the material so obtained, thionyl chloride (10 ml) and DMF (0.1 ml) was stirred and heated to 80 C. for 1.5 hours. The mixture was cooled to ambient temperature, toluene (10 ml) was added and the mixture was evaporated. The residue was partitioned between ethyl acetate and water (the acidity of the aqueous layer being adjusted to pH 7.5 by the addition of 2N aqueous sodium hydroxide solution). The organic layer was washed No. with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. The solid so obtained was triturated under hexane, reisolated and washed with diethyl ether. There was thus obtained 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.614 g); NMR Spectrum: (CDCl3) 2.12 (m, 2H), 2.5 (br s, 4H), No. 2.59 (t, 2H), 3.73 (t, 4H), 4.05 (s, 3H), 4.27 (t, 2H), 7.33 (s, 1H), 7.4 (s, 1H), 8.86 (s, 1H). A mixture of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (1.6 g) and isopropanol (50 ml) was placed in a Carius tube which was cooled to -78 C. prior to the addition of liquid ammonia (10 ml). The Carius tube was sealed and heated to 130 C. for 20 hours. The Carius tube was cooled to ambient temperature, opened and the mixture was evaporated. The residue was triturated under diethyl ether. There was thus obtained 4- No.amino-7-methoxy-6-(3-morpholinopropoxy)quinazoline (containing 2.9 equivalents of ammoniuin chloride; 1.54 g) which was used without further purification. A portion of the material was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent. The purified product gave the following data :- NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.5 (m, 6H), 3.6 (m, 4H), 3.9 (s, 3H), 4.1 (m, 2H), 7.05 (s, 1H), 7.4 (br s, 2H), No. 7.6 (s, 1H), 8.25 (s, 1H); Mass Spectrum: M + H+ 319. | |
With oxalyl dichloride; In chloroform; N,N-dimethyl-formamide;Reflux; | i) Preparation of 4-Chloro-6-[3-(4-morpholinyl)propoxy-4-quinazoline (Ilia); Into a clean and dried 5-Litre four necked round bottomed flask equipped with a mechanical stirrer, reflux-condenser, pressure equalizing addition funnel, and thermometer socket were charged chloroform (3000 ml), dimethyl formamide (30 ml) followed by 7-methoxy-6-(3-morpholino propoxy)-3,4-dihydro-quinazolin-4-one (Ha) (15Og), obtained according to the process given in Example-l of PCT international application published as WO.2005/070909Ai. Oxalyl Chloride (120 g) was slowly added and the reaction mass was heated to reflux temperature and maintained at reflux temperature for about 5 hours. Reaction was found to be completed by HPLC test. The solvent chloroform and excess oxalyl chloride were distilled off by applying mild vacuum. The reaction mass was cooled to about 4O0C and added chloroform (300 ml) and again distilled out the solvent by applying mild vacuum . The reaction mixture was cooled to room temperature and acetonitrile (3000 ml) was added and stirred for 10-15 minutes and kept under nitrogen atmosphere to proceed to the next step. | |
With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 15h; | A mixture of a portion (0.99 g) of the material so obtained, thionyl chloride (10 ml) and DMF (0.1 ml) was stirred and heated to 80 C. for 1.5 hours.. The mixture was cooled to ambient temperature, toluene (10 ml) was added and the mixture was evaporated.. The residue was partitioned between ethyl acetate and water (the acidity of the aqueous layer being adjusted to PH 7.5 by the addition of 2N aqueous sodium hydroxide solution).. The organic layer was washed with brine, dried over magnesium sulphate and evaporated.. The residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent.. The solid so obtained was triturated under hexane, re-isolated and washed with diethyl ether.. There was thus obtained 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.614 g); NMR Spectrum: (CDCl3) 2.12 (m, 2H), 2.5 (br s, 4H), 2.59 (t, 2H), 3.73 (t, 4H), 4.05 (s, 3H), 4.27 (t, 2H), 7.33 (s, 1H), 7.4 (s, 1H), 8.86 (s, 1H). | |
With oxalyl dichloride; In chloroform; N,N-dimethyl-formamide; for 5h;Reflux; | EXAMPLE-1Preparation of N-(3-ethylnylphenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine (I, NRC-2694); i) Preparation of 4-Chloro-6-[3-(4-morpholinyl)propoxy-4-quinazoline (IIIa)Into a clean and dried 5-Litre four necked round bottomed flask equipped with a mechanical stirrer, reflux-condenser, pressure equalizing addition funnel, and thermometer socket were charged chloroform (3000 ml), dimethyl formamide (30 ml) followed by 7-methoxy-6-(3-morpholino propoxy)-3,4-dihydro-quinazolin-4-one (IIa) (150 g), obtained according to the process given in Example-1 of PCT international application published as WO.2005/070909A1. Oxalyl Chloride (120 g) was slowly added and the reaction mass was heated to reflux temperature and maintained at reflux temperature for about 5 hours. Reaction was found to be completed by HPLC test. The solvent chloroform and excess oxalyl chloride were distilled off by applying mild vacuum. The reaction mass was cooled to about 40 C. and added chloroform (300 ml) and again distilled out the solvent by applying mild vacuum. The reaction mixture was cooled to room temperature and acetonitrile (3000 ml) was added and stirred for 10-15 minutes and kept under nitrogen atmosphere to proceed to the next step. | |
With thionyl chloride; potassium carbonate; at 80℃;Microwave irradiation; | 1mmol7-methoxy-6 - [3 - (4-morpholinyl) propoxy] quinazoline-4-one with 2mmol chlorination reagent and 2mmol microwave the presence of a base to obtain the intermediate 4-chloro-7-methoxy-6 - [3 - (4-morpholinyl) propoxy] quinazoline. Wherein the reagent is thionyl chloride, the catalyst is K 2 CO 3, the reaction temperature is 80 C, microwave power 150W. After the reaction cooled to room temperature, filter to get the solid powder. | |
With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 2h; | The compound (IV) (10 g, 31.31 mmol) and thionyl chloride (20 mL) were stirred well and slowly added dropwiseDMF (2.25 g, 34.44 mmol). After completion of the addition, stirring was continued and the temperature was raised to 80 C. The reaction was completed after 2 h. After cooling to room temperature, most of the thionyl chloride and DMF were removed under reduced pressure, and then 30 mL of toluene was added to the mixture under reduced pressure to give the residue as Compound (V) without further purification and transferred directly to another clean Isopropanol (150 mL) and compound (VI) (9.12 g, 62.62 mmol) were sequentially added and the mixture was heated to reflux. After 1.5 h, the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The cake was dried under reduced pressure. The resulting pale yellow solid was stirred with water (200 mL) and heated to 60 C. The pH was adjusted to 9-10 by the addition of a saturated solution of sodium hydroxide. The resulting filter cake was recrystallized to give the title compound (I) (11.90 g, 85%) as a white solid of high purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; for 2h; | a) DI-TERT-BUTYL azodicarboxylate (1.44 g, 6.26 mmol) was added portionwise at room temperature to a stirred suspension of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (1.20 g, 5.70 mmol), 3-MORPHOLIN-4-YLPROPAN-1-OL (0.91 g, 6.27 mmol) and triphenylphosphine (1.8 g, 6. 87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hours and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 5% methanol in dichloromethane to give 4-CHLORO-7-METHOXY-6- (3-MORPHOLIN-4- ylpropoxy) quinazoline (1. 28 g, 67% yield) as a pale yellow solid: 1H-NMR (CDC13) : 8. 86 (s, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 4.28 (t, 2H), 4.05 (s, 3H), 3.73 (m, 4H), 2.60 (t, 2H), 2.50 (m, 4H), 2.13 (quintet, 2H); MS (+ve ESI) : 338 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide; at 100℃; for 6h;Microwave irradiation; Sealed tube; | The preparation method of the 4-indolequinazoline compound III-29 includes:Take the raw material 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine 0.5mmolAnd <strong>[55577-25-8]2-(4-methylphenyl)-1H-indole</strong> 1.5mmol, and added to a 10mL microwave reaction tube,Add 1 mL of hexafluoroisopropanol and bistrifluoromethanesulfonimide 0.05 mmol, seal and heat at 100C with stirring, and react for about 6 hours.Use TLC to monitor the completion of the reaction. After the system has cooled to room temperature, add silica gel to stir the sample.Separate and purify by column chromatography to obtain yellow solid III-29, yield 75%, |