morpholine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 37.07 g (0.3 mole) of morpholine hydrochloride, 57.1 g (0.3 mole) of p-tert.-butyl-propiophenone and 15.01 g (0.5 mole) of paraformaldehyde were heated under reflux in 150 ml of ethanol for 1 hour. After adding 0.5 ml of concentrated hydrochloric acid, the reaction mixture was stirred under reflux for a further 15 hours. It was then concentrated, the residue was taken up in chloroform, the chloroform mixture was washed twice with water and the organic phase was dried over sodium sulphate and concentrated. The crystalline residue was suspended in hot ethyl acetate, filtered off and dried. 60 g (61.5% of theory) of p-tert.-butyl-2-methyl-3-morpholin-4-yl-propiophenone hydrochloride of melting point 189° to 91° C. were obtained. under reflux for a further 15 hours It was then concentrated the chloroform mixture was washed twice with water the organic phase was dried over sodium sulphate concentrated filtered off dried

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-]imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained. Yield: 85%. M.P.: 195°-196° C. The solid mass obtained The mixture is filtered hot the filtrate is concentrated until a solid suspension The mixture is then cooled to room temperature 200 ml of diethyl ether are added The reaction product crystallizes It is filtered washed with diethyl ether dried

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-]imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained. Yield: 85%. M.P.: 195°-196° C. The solid mass obtained The mixture is filtered hot the filtrate is concentrated until a solid suspension The mixture is then cooled to room temperature 200 ml of diethyl ether are added The reaction product crystallizes It is filtered washed with diethyl ether dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium azide (65 g; 1.0 mol), 4-phenyl-1-(2-cyanoethyl)-piperazine (215 g; 1.0 mol), and morpholine hydrochloride (124 g; 1.0 mol) were dissolved in 1 liter of morpholine, and heated at 120°-125° C with stirring for 4 hours. After the reaction mixture was allowed to cool to room temperature, it was filtered, and the solvent was removed in vacuo. The residue was mixed in water, and the pH of the resulting solution was adjusted to 5. Crude 5-[(4-phenyl-1-piperazyl)ethyl]tetrazole was collected by filtration and was dried; yield -- 170 g. The crude product was recrystallized from water and dried; yield -- 155 g (60% yield; m.p. 190°-194° C). heated at 120°-125° C it was filtered the solvent was removed in vacuo The residue was mixed in water Crude 5-[(4-phenyl-1-piperazyl)ethyl]tetrazole was collected by filtration was dried The crude product was recrystallized from water dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 23.6 grams of 2-phenyl-3- acetylbenzofuran, 70 milliliters of isopropanol, 4.2 grams of paraformaldehyde, and 17.3 grams of morpholine hydrochloride were heated under reflux at the boiling point for 12 hours, after which the solvent was evaporated therefrom under vacuum and the residue was triturated with dilute hydrochloric acid and the hydrochloride of the compound named in the heading of this example, which separated in the form of crystals therefrom, was separated from the mixture by suction filtration and dried. In this manner, 23.8 grams of the specified hydrochloride, which had a melting point of 177°-179°C, was obtained. were heated under reflux at the boiling point for 12 hours after which the solvent was evaporated under vacuum and the residue was triturated with dilute hydrochloric acid separated in the form of crystals was separated from the mixture by suction filtration dried was obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 37.07 g (0.3 mole) of morpholine hydrochloride, 57.1 g (0.3 mole) of p-tert.-butyl-propiophenone and 15.01 g (0.5 mole) of paraformaldehyde were heated under reflux in 150 ml of ethanol for 1 hour. After adding 0.5 ml of concentrated hydrochloric acid, the reaction mixture was stirred under reflux for a further 15 hours. It was then concentrated, the residue was taken up in chloroform, the chloroform mixture was washed twice with water and the organic phase was dried over sodium sulphate and concentrated. The crystalline residue was suspended in hot ethyl acetate, filtered off and dried. 60 g (61.5% of theory) of p-tert.-butyl-2-methyl-3-morpholin-4-yl-propiophenone hydrochloride of melting point 189° to 91° C. were obtained. under reflux for a further 15 hours It was then concentrated the chloroform mixture was washed twice with water the organic phase was dried over sodium sulphate concentrated filtered off dried

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-]imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained. Yield: 85%. M.P.: 195°-196° C. The solid mass obtained The mixture is filtered hot the filtrate is concentrated until a solid suspension The mixture is then cooled to room temperature 200 ml of diethyl ether are added The reaction product crystallizes It is filtered washed with diethyl ether dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 100 ml. of ethanol is dissolved a mixture of 1 g. of 6-methoxy-5-nitro-3,4-dihydro-1(2H)-naphthalenone and 3 g. of morpholine hydrochloride and the mixed solution is reacted at 80° C. for 10 hours. The reaction mixture is cooled and, following addition of 500 ml. of water, it is shaken with 100 ml. of diethyl ether. The water layer is neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract is dried and distilled under reduced pressure to remove the solvent. By the above procedure is obtained 6-methoxy-2-morpholinomethyl-5-nitro-3,4-dihydro-1(2H)-naphthalenone as an oily product. This product is dissolved in 50 ml. of methanol and, after addition of 1 g. of sodium borohydride, the solution is stirred at room temperature for 30 minutes. To this reaction mixture is added 500 ml. of water and the mixture is extracted with chloroform. The extract is dried and distilled under reduced pressure to remove the solvent. The above procedure provides an oil of 6-methoxy-2-morpholinomethyl-5-nitro-1,2,3,4-tetrahydro-1-naphthalenol. This product is dissolved in 20 ml. of ethanolic hydrochloric acid and the solution is heated at 80° C. for 1 hour. Following the addition of 50 ml. of ethyl acetate, the solution is cooled, whereupon 0.35 g. of 7-methoxy-3-morpholinomethyl-8-nitro-1,2-dihydronaphthalene hydrochloride is obtained as pale-yellow prisms melting at 200°-270° C. (gradually decomposed). a mixture of 1 g The reaction mixture is cooled addition of 500 ml extracted with chloroform The extract is dried distilled under reduced pressure to remove the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 100 ml. of ethanol is dissolved a mixture of 1 g. of 6-methoxy-5-nitro-3,4-dihydro-1(2H)-naphthalenone and 3 g. of morpholine hydrochloride and the mixed solution is reacted at 80° C. for 10 hours. The reaction mixture is cooled and, following addition of 500 ml. of water, it is shaken with 100 ml. of diethyl ether. The water layer is neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract is dried and distilled under reduced pressure to remove the solvent. By the above procedure is obtained 6-methoxy-2-morpholinomethyl-5-nitro-3,4-dihydro-1(2H)-naphthalenone as an oily product. This product is dissolved in 50 ml. of methanol and, after addition of 1 g. of sodium borohydride, the solution is stirred at room temperature for 30 minutes. To this reaction mixture is added 500 ml. of water and the mixture is extracted with chloroform. The extract is dried and distilled under reduced pressure to remove the solvent. The above procedure provides an oil of 6-methoxy-2-morpholinomethyl-5-nitro-1,2,3,4-tetrahydro-1-naphthalenol. This product is dissolved in 20 ml. of ethanolic hydrochloric acid and the solution is heated at 80° C. for 1 hour. Following the addition of 50 ml. of ethyl acetate, the solution is cooled, whereupon 0.35 g. of 7-methoxy-3-morpholinomethyl-8-nitro-1,2-dihydronaphthalene hydrochloride is obtained as pale-yellow prisms melting at 200°-270° C. (gradually decomposed). a mixture of 1 g The reaction mixture is cooled addition of 500 ml extracted with chloroform The extract is dried distilled under reduced pressure to remove the solvent

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.0 g (32.3 mmoles) of N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmoles) of morpholine hydrochloride is heated at 160° C. under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a solid suspension appears. The mixture is then cooled to room temperature and 200 ml of diethyl ether are added. The reaction product crystallizes. It is filtered, washed with diethyl ether and dried. 6.8 g of N-[imino(cyclopropylamino)methyl]-4-morpholinecarboximidamide hydrochloride are obtained. The solid mass obtained The mixture is filtered hot the filtrate is concentrated until a solid suspension The mixture is then cooled to room temperature 200 ml of diethyl ether are added The reaction product crystallizes It is filtered washed with diethyl ether dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a manner similar to Preparation 11 react 2,6-difluorobenzeneacetonitrile with morpholine hydrochloride and paraformaldehyde to obtain the title compound. In a manner similar to Preparation 11

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction was carried out similarly as described in the preparation of compound 112, using compound 111 (0.12 mmol) and morpholine hydrochloride (0.12 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 5:95 as the eluent to afford the title compound as almost yellow syrup. 13C NMR (CDCl3) δ 196.0, 163.5, 147.9, 147.3, 139.8, 138.0, 135.3, 133.7, 131.9, 129.2, 128.0, 127.7, 126.5, 124.4 (dd), 124.2 (dd), 121.4, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 66.6, 66.4, 50.9, 45.9, 42.6, 20.2 The crude product was purified by continuous gradient flash chromatography