ethyl 3-amino-3-iminopropanoate;hydrochloride

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

Procedure: After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetate hydrochloride (a publicly known compound described in Liebigs Ann. Chem., 1895 (1977)), the mixture was stirred at room temperature, 22.3 g of sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetate hydrochloride) was added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. To this there was added 49.9 g of 1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound described in Journal of Heterocyclic Chemistry, vol. 2, 310 (1965) and Journal of Medicinal Chemistry, vol. 17, 55(1974)), and the mixture was stirred for 36 hours at room temperature under a nitrogen atmosphere. Water was added, ethyl acetate was used for liquid separation and extraction, and then the organic layer was dried over sodium sulfate and concentrated to dryness to obtain 56.7 g of the title compound. the mixture was stirred for 15 minutes under a nitrogen atmosphere was stirred for 36 hours at room temperature under a nitrogen atmosphere ethyl acetate was used for liquid separation and extraction the organic layer was dried over sodium sulfate concentrated to dryness

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

Procedure: In a dry three-necked flask, under argon, 75 ml of abs. ethanol and 6.5 g (390 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are cooled to 0-5° C. and 2.65 g (390 mmol) of sodium ethanolate are added thereto. Then 5 g (195 mmol) of 2-bromo-1-(4-nitro-phenyl)-ethan-1-one are added and the reaction mixture is allowed to come to RT and then stirred for 48 hours. The reaction mixture is then partitioned between water and ethyl acetate. The ethyl acetate phase is washed three times with water and once with saturated NaCl solution, dried and filtered and the filtrate is concentrated by evaporation. The red-brown residue is suspended in hexane and the title compound precipitates in the form of the crude product (purity 93%), which is used for the next step without further purification; MS: (M)+ =275. to come to RT The reaction mixture is then partitioned between water and ethyl acetate The ethyl acetate phase is washed three times with water once with saturated NaCl solution, dried filtered the filtrate is concentrated by evaporation the title compound precipitates in the form of the crude product (purity 93%), which is used for the next step without further purification

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

Procedure: Analogously to Step 8.1, 1.67 g (10 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 20 ml of abs. ethanol are reacted with 716 mg (10 mmol) of sodium ethanolate and 1.145 g (5.0 mmol) of 4-methoxy-phenacyl bromide (Fluka; Buchs/Switzerland) to form the title compound; m.p. 141-142° C.; TLC-Rf =0.4 (hexane/ethyl acetate [1:1]); FAB-MS: (M+H)+ =261.

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

Procedure: Analogously to Step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 150 ml of abs. ethanol are reacted with 5.9 g (87 mmol) of sodium ethanolate and 10.3 g (44 mmol) of 2-bromo-1-(3-methoxy-phenyl)-ethan-1-one (2-bromo-3'-methoxy-acetophenone; Janssen) to form the title compound; m.p. 96-97oC; TLC-Rf =0.2 (hexane/ethyl acetate [2:1]).

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

Procedure: Analogously to Step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride in 150 ml of abs. ethanol are reacted with 5.9 g (87 mmol) of sodium ethanolate and 10.3 g (44 mmol) of 2-bromo-1-(2-methoxy-phenyl)-ethan-1-one (2-bromo-2'-methoxy-acetophenone; Aldrich; Milwaukee/USA) to form the title compound; m.p.: 128° C.; TLC-Rf =0.25 (hexane/ethyl acetate [2:1]).

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

Procedure: Under an argon atmosphere, 834 mg (5 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are introduced into 10 ml of ethanol and, at 0-5° C., 358 mg (5 mmol) of sodium ethanolate are added thereto. The bright yellow suspension is stirred for 15 min and then 623 mg (2.5 mmol) of 2-bromo-1-(naphth-2-yl)-ethan-1-one (2-bromo-2'-acetonaphthone; Aldrich; Milwaukee/USA) are added thereto. After 3 days' stirring at RT, the reaction mixture is concentrated by evaporation. The residue is taken up in ethyl acetate/water and filtered and the organic phase is separated off and washed with 3 portions of water and brine. The aqueous phases are extracted with ethyl acetate and the organic phases are dried over MgSO4 and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diethyl ether/hexane yield the title compound; m.p. 149-151° C.; TLC-Rf =0.5 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =281. After 3 days' stirring at RT the reaction mixture is concentrated by evaporation filtered the organic phase is separated off washed with 3 portions of water and brine The aqueous phases are extracted with ethyl acetate the organic phases are dried over MgSO4 concentrated by evaporation Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diethyl ether/hexane

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

Procedure: Under an argon atmosphere, 1.65 g (1 0 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride (for preparation see: Liebigs Ann. Chem., 1895 (1977)) are introduced into 10 ml of ethanol and, at 0-5° C., 0.73 g (10 mmol) of sodium ethanolate is added thereto. The bright yellow suspension is stirred for 20 min and then 1.4 g (5 mmol) of 2-bromo-1-(biphen-4-yl)-ethan-1-one (2-bromo-4'-phenyl-acetophenone; Aldrich; Milwaukee/USA) are added thereto. After 48 hours' stirring at RT, the reaction mixture is concentrated by evaporation and the residue is taken up in ethyl acetate and washed with 3 portions of water and brine. The aqueous phases are extracted twice with ethyl acetate and the organic phases are dried over MgSO4 and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diisopropyl ether/hexane yield the title compound; m.p. 186-188° C.; TLC-Rf =0.17 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =306. After 48 hours' stirring at RT the reaction mixture is concentrated by evaporation washed with 3 portions of water and brine The aqueous phases are extracted twice with ethyl acetate the organic phases are dried over MgSO4 concentrated by evaporation Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diisopropyl ether/hexane

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

Procedure: In a dry three-necked flask, under argon, 75 ml of abs. ethanol and 6.5 g (390 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [preparation see: Liebigs Ann. Chem., 1895 (1977)] are cooled to 0-5° C. and 2.65 g (390 mmol) of sodium ethanolate are added. 5 g (195 mmol) of 2-bromo-1-(4-nitro-phenyl)-ethan-1-one are then added and the mixture is allowed to rise to room temperature and is stirred for a further 48 hours. The reaction mixture is then partitioned between water and ethyl acetate. The ethyl acetate phase is washed three times with water and once with sat. NaCl solution, dried and filtered, and the filtrate is concentrated by evaporation. The reddish-brown residue is made into a slurry in hexane, the title compound precipitating in the form of a crude product (purity 93%) which is used for the next step without further purification; MS: (M)+ =275. to rise to room temperature The reaction mixture is then partitioned between water and ethyl acetate The ethyl acetate phase is washed three times with water once with sat. NaCl solution, dried filtered the filtrate is concentrated by evaporation the title compound precipitating in the form of a crude product (purity 93%) which is used for the next step without further purification

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A glass microwave reaction vessel was charged with ethyl 3-amino-3-iminopropanoate hydrochloride (1.248 g, 7.49 mmol, Tyger Scientific, Inc., Ewing, N.J.) in EtOH (5 mL) and the solution was cooled to 0° C. Sodium ethoxide (21% w/w solution in EtOH; 2.80 mL, 7.49 mmol) was added dropwise and a precipitate was formed. After 10 min, 2-bromo-1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (Example 126h; 1.06 g, 3.74 mmol) was added, and the reaction was stirred at RT for 3 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (10-25% EtOAc in Hexanes) to give ethyl 2-amino-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (615 mg, 1.957 mmol, 52% yield) as an orange solid. MS (ESI, pos. ion) m/z: 315.0 (M+1). A glass microwave reaction vessel a precipitate was formed The reaction was quenched with water extracted with DCM The combined organic layers were dried (MgSO4) filtered concentrated The residue was purified with silica gel chromatography (10-25% EtOAc in Hexanes)

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

Procedure: After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetate hydrochloride (a publicly known compound described in Liebigs Ann. Chem., 1895(1977)), the mixture was stirred at room temperature, 22.3 g of sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetate hydrochloride) was added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. To this there was added 49.9 g of 1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound described in Journal of Heterocyclic Chemistry, vol. 2, 310(1965) and Journal of Medicinal Chemistry, vol. 17, 55(1974)), and the mixture was stirred for 36 hours at room temperature under a nitrogen atmosphere. Water was added, ethyl acetate was used for liquid separation and extraction, and then the organic layer was dried over sodium sulfate and concentrated to dryness to obtain 56.7 g of the title compound. the mixture was stirred for 15 minutes under a nitrogen atmosphere was stirred for 36 hours at room temperature under a nitrogen atmosphere ethyl acetate was used for liquid separation and extraction the organic layer was dried over sodium sulfate concentrated to dryness

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

Procedure: After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetate hydrochloride (a publicly known compound described in Liebigs Ann. Chem., 1895 (1977)), the mixture was stirred at room temperature, 22.3 g of sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetate hydrochloride) was added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. To this there was added 49.9 g of 1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound described in Journal of Heterocyclic Chemistry, vol.2, 310 (1965) and Journal of Medicinal Chemistry, vol.17, 55 (1974)), and the mixture was stirred for 36 hours at room temperature under a nitrogen atmosphere. Water was added, ethyl acetate was used for liquid separation and extraction, and then the organic layer was dried over sodium sulfate and concentrated to dryness to obtain 56.7 g of the title compound. the mixture was stirred for 15 minutes under a nitrogen atmosphere was stirred for 36 hours at room temperature under a nitrogen atmosphere ethyl acetate was used for liquid separation and extraction the organic layer was dried over sodium sulfate concentrated to dryness

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

Procedure: Sodium (0.20 g) was dissolved in dry ethanol (10 ml) and the thus-obtained sodium ethylate solution was added dropwise to a solution of 2-(4-benzhydryl-1-piperazinyl)ethyl 2-(3-nitrobenzylidene)acetoacetate (4.37 g) and ethyl amidinoacetate hydrochloride (1.42 g) in dry ethanol (10 ml) with stirring under reflux over a period of about 15 minutes. The mixture was further refluxed for 5 minutes. The resulting NaCl was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g). From the eluate with ethyl ether-ethyl acetate (10:1, v/v), there was obtained 5-[2-(4-benzhydryl-1-piperazinyl)ethyl] 3-ethyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate as a yellow powder. Yield 3.22 g. To a solution of 2.48 g of this product in ethanol was added a solution of oxalic acid in ethanol to give the oxalate as crystals. Yield 2.52 g. Recrystallization from ethanol-ethyl ether gave yellow crystals (1.83 g). m.p. 152°-153° C. under reflux over a period of about 15 minutes The mixture was further refluxed for 5 minutes The resulting NaCl was filtered off the filtrate was concentrated under reduced pressure The residue was purified by column chromatography on silica gel (120 g)