(1-methylpyrrolidin-2-yl)methanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (1-methylpyrrolidin-2-yl)methylamine similar to as described in Example 2 to afford 7.6 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-[(1-methylpyrrolidin-2-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.27 (s, 1H), 7.01 (d, J=10.4, 4.6 Hz, 1H), 4.67-4.44 (m, 2H), 4.44-4.14 (m, 2H), 2.96 (s, 2H), 2.36 (s, 1H), 2.02-1.86 (m, 2H), 1.83 (s, 1H), 1.78-1.62 (m, 1H), 1.49 (s, 6H).

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

Procedure: To 30 ml. of toluene were added 3.0 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 3.0 g. of 2-aminomethyl-1-methylpyrrolidine and the mixture was refluxed for 4 days. The reaction mixture was acidified with hydrochloric acid at room temperature and then extracted twice each time with 30 ml. of water. From the toluene layer, 0.9 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate used as the starting material was recovered. The extracts were combined, basified with aqueous ammonia and extracted three times each time with 30 ml. of chloroform. The extracts were combined and evaporated to dryness. By adding 50 ml. of ether to the residue formed, 1.0 g. of crystals of N-(1-methylpyrrolidin-2-ylmethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide were obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 126°-127° C. extracted twice each time with 30 ml was recovered extracted three times each time with 30 ml evaporated to dryness By adding 50 ml of ether to the residue formed

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

Procedure: To 30 ml. of toluene were added 3.0 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 3.0 g. of 2-aminomethyl-1-methylpyrrolidine and the mixture was refluxed for 4 days. The reaction mixture was acidified with hydrochloric acid at room temperature and then extracted twice each time with 30 ml. of water. From the toluene layer, 0.9 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate used as the starting material was recovered. The extracts were combined, basified with aqueous ammonia and extracted three times each time with 30 ml. of chloroform. The extracts were combined and evaporated to dryness. By adding 50 ml. of ether to the residue formed, 1.0 g. of crystals of N-(1-methylpyrrolidin-2-ylmethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide were obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 126°-127° C. extracted twice each time with 30 ml was recovered extracted three times each time with 30 ml evaporated to dryness By adding 50 ml of ether to the residue formed

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

Procedure: In a similar manner to that of the above example, 71 g of levorotatory 1-methyl-2-aminomethyl-pyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 175 g of levorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 187°-187.5° C.; yield: 77%).

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

Procedure: 61 g of dextrorotatory 1-methyl-2-aminomethylpyrrolidine, 465 ccm of chloroform and, in portions, 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the temperature being maintained at 5°-10° C., were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture and the addition of 1,850 cm3 of water, chloroform was distilled and the remaining solution was filtered. The base was precipitated by the addition of 65 cm3 of 20% ammonia. The crystals formed were dried off, washed and dried. 154 g of dextrorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 187°-188° C.; yield: 78.5%). were introduced into a balloon flask provided with an agitator was distilled the remaining solution was filtered The base was precipitated by the addition of 65 cm3 of 20% ammonia The crystals formed were dried off washed dried

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

Procedure: 169 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1,250 ml of water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 100 ml of 20% ammonia. The crystals were dried off, washed with water and dried. 182 g of N-(1-methyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 189°-190° C.; yield: 83.6%). provided with a reflux condenser The mixture was heated on a water bath until a test sample the solution was filtered over carbon black the base was reprecipitated by the addition of 100 ml of 20% ammonia The crystals were dried off washed with water dried

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

Procedure: In a similar manner to that of the above example, 71 g of levorotatory 1-methyl-2-aminomethyl-pyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 175 g of levorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 187°-187.5° C.; yield: 77%).

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

Procedure: 61 g of dextrorotatory 1-methyl-2-aminomethylpyrrolidine, 465 ccm of chloroform and, in portions, 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the temperature being maintained at 5°-10° C., were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture and the addition of 1,850 cm3 of water, chloroform was distilled and the remaining solution was filtered. The base was precipitated by the addition of 65 cm3 of 20% ammonia. The crystals formed were dried off, washed and dried. 154 g of dextrorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 187°-188° C.; yield: 78.5%). were introduced into a balloon flask provided with an agitator was distilled the remaining solution was filtered The base was precipitated by the addition of 65 cm3 of 20% ammonia The crystals formed were dried off washed dried

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

Procedure: 169 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1,250 ml of water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 100 ml of 20% ammonia. The crystals were dried off, washed with water and dried. 182 g of N-(1-methyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 189°-190° C.; yield: 83.6%). provided with a reflux condenser The mixture was heated on a water bath until a test sample the solution was filtered over carbon black the base was reprecipitated by the addition of 100 ml of 20% ammonia The crystals were dried off washed with water dried

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

Procedure: 2-Methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid, 5.0 g, is dissolved in a mixed solvent of 50 ml of dimethylformamide and 50 ml of acetone, 6.5 ml of triethylamine is added and the solution is stirred. Under cooling at 15°-18° C., 2.2 g of ethyl chlorocarbonate is added dropwise for 10 minutes, and the solution is stirred at room temperature for one hour. Thereafter, 2.7 g of 1-methyl-2-aminomethylpyrrolidine is added and the whole is stirred at room temperature for 3 hours and allowed to stand for 15 hours. Excess triethylamine and acetone are distilled off under reduced pressure and the resulting residue is poured into 300-400 ml of water. The aqueous layer is extracted via with chloroform three times and the extract layer is washed with aqueous sodium bicarbonate solution, water and sodium chloride saturated water in this sequence. After drying, the chloroform is distilled off under reduced pressure and the residue obtained is recrystallized from ethyl acetate to give crystals of N-(1-methyl-2-pyrrolidinyl-methyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 187°-189° C. is added Under cooling at 15°-18° C. the solution is stirred at room temperature for one hour the whole is stirred at room temperature for 3 hours Excess triethylamine and acetone are distilled off under reduced pressure the resulting residue is poured into 300-400 ml of water The aqueous layer is extracted via with chloroform three times the extract layer is washed with aqueous sodium bicarbonate solution, water and sodium chloride saturated water in this sequence After drying the chloroform is distilled off under reduced pressure the residue obtained is recrystallized from ethyl acetate