* 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.
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃;
Step 5: 8-Chloro-6-methoxyquinoline To a solution of 3.3 g of 8-chloro-6-hydroxyquinoline (Step 4, 3.3 g) in dimethylformamide was added K2CO3 (3.8 g), followed by iodomethane (5.2 g). The mixture was stirred at room temperature overnight. Water was then added and the aqueous mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2, to give 2.2 g of the desired product as a beige solid; MP=74-75 C.; MS (ES) m/z (relative intensity): 194 (M+H)+ (100).
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃;
Example 11 Intermediate 11-8-chloro-6-methoxy-quinoline To a solution of 15 g of 8-chloro-6-hydroxy-quinoline in (50 ml) DMF, 23 g of K2CO3 were added followed by 18 g iodomethane. The mixture was stirred at room temperature overnight. Water was added and the product was extracted with CH2Cl2 dried and the solvent removed. The crude product was filtered through 250 ml of silica gel using 50% ethyl acetate/hexane to give 11 g of the desired product.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20.0℃;
To a solution of 15 g of 8-chloro-6-hydroxy-quinoline in (50 ml) DMF, 23 g OF K2C03 were added followed by 18 g iodomethane. The mixture was stirred at room temperature overnight. Water was added and the product was extracted with CH2C12 dried and the solvent removed. The crude product was filtered through 250 ml of silica gel using 50% ethyl acetate/hexane to give 11 g of the desired product.
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃;
To a solution of 3.3 g of 8-chloro-6-hydroxyquinoline (Step 1, 3.3 g) in dimethylformamide was added K2CO3 (3.8 g), followed by iodomethane (5.2 g). The mixture was stirred at room temperature overnight. Water was then added and the aqueous mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2, to give 2.2 g of the desired product as a beige solid; MP=74-75 C.; MS (ES) m/z (relative intensity): 194 (M+H)+ (100).
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃;
Step 5: 8-Chloro-6-methoxyquinolineTo a solution of 3.3 g of 8-chloro-6-hydroxyquinoline (Step 4, 3.3 g) in dimethylformamide was added K2CO3 (3.8 g), followed by iodomethane (5.2 g). The mixture was stirred at room temperature overnight. Water was then added and the aqueous mixture <n="30"/>was extracted with CH2CI2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using 100% CH2Cl2, to give 2.2 g of the desired product as a beige solid; MP = 74-75C; MS (ES) m/z (relative intensity): 194 (M+H)+ (100).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 5.0h;Heating / reflux;
Step 6: 6-Methoxy-8-[1-(tert-butoxycarbonyl)-4-piperazino]quinoline To a mixture of <strong>[796851-15-5]8-chloro-6-methoxyquinoline</strong> (Step 5, 2.7 g) in anhydrous tetrahydrofuran, was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.064 g), sodium tert-butoxide (1.9 g), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (CYMAP, 0.08 g) and tert-butoxycarbonylpiperazine (3.4 g). The mixture was refluxed for 5 hours under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with ether, filtered through Celite and concentrated on a rotary evaporator. The crude material was purified by flash chromatography using 100% CH2Cl2 to give 4.0 g of the desired product as a beige solid; mp=92-93 C.; MS (ES) m/z (relative intensity): 344 (M++H) (100).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 5.0h;Heating / reflux;
Example 12 Intermediate 12-6-methoxy-8-(t-Boc)-piperazino-quinoline To a mixture of 9 g of <strong>[796851-15-5]8-chloro-6-methoxy-quinoline</strong> in 75 ml dry THF, was added 0.64 g Pd2(dba)3, 6.2 g NaOt-Bu, 0.274 g of 2-Dicyclohexylphosphino-2'-(N,N-dimethyl-amino)biphenyl (also known as cymap) and 11.2 g t-Boc piperazine. The mixture was refluxed for 5 hrs. The reaction mixture was then cooled to room temperature, diluted with ether, and filtered through celite. The filtrate was concentrated in vacuo. The crude material was then purified by flash chromatography using 300 ml of silica gel and 100% CH2Cl2 then 50% ethyl acetate/hexane to give 16.5 g of the desired product.
With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; for 5.0h;Heating / reflux;
To a mixture of 9 g of 8-CHLORO-6-METHOXY-QUINOLINE in 75 ml dry THF, was added 0.64 g Pd2 (dba) 3,6. 2 g NaOt-Bu, 0.274g of 2-DICYCLOHEXYLPHOSPHINO-2 -(N, N-DIMETHYL- amino) biphenyl (also known as CYMAP) and 11.2 g t-Boc piperazine. The mixture was refluxed for 5 hrs. The reaction mixture was then cooled to room temperature, diluted with ether, and filtered through celite. The filtrate was concentrated in vacuo. The crude material was then purified by flash chromatography using 300 ml of silica gel and 100% CH2CI2 then 50% ethyl acetate/hexane to give 16.5 g of the desired product.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 5.0h;Heating / reflux;
To a mixture of <strong>[796851-15-5]8-chloro-6-methoxyquinoline</strong> (Step 2, 2.7 g) in anhydrous tetrahydrofuran, was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.064 g), sodium tert-butoxide (1.9 g), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (CYMAP, 0.08 g) and tert-butoxycarbonylpiperazine (3.4 g). The mixture was refluxed for 5 hours under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with ether, filtered through celite and concentrated on a rotary evaporator. The crude material was purified by flash chromatography using 100% CH2Cl2 to give 4.0 g of the desired product as a beige solid; mp=92-93 C.; MS (ES) m/z (relative intensity): 344 (M++H) (100).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 5.0h;Heating / reflux;
Step 6: 6-Methoxy-8-[l-(tert-butoxycarbonyl)-4-piperazino]quinolineTo a mixture of <strong>[796851-15-5]8-chloro-6-methoxyquinoline</strong> {Step 5, 2.7 g) in anhydrous tetrahydrofuran, was added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.064 g) , sodium tert-butoxide (1.9 g), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (CYMAP, 0.08 g) and ferf-butoxycarbonylpiperazine (3.4 g). The mixture was refluxed for 5 hours under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with ether, filtered through Celite and concentrated on a rotary evaporator. The crude material was purified by flash chromatography using 100% CH2Cl2 to give 4.0 g of the desired product as a beige solid; mp = 92-93C; MS (ES) m/z (relative intensity): 344 (M++H) (100).
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