ethyl 2-cyanoethanimidate;hydrochloride

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2'- fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). the physical constants of this product were in agreement with those of the product obtained in Example 5-(1). cooling the mixture was then stirred at room temperature overnight the resulting crystals were collected by filtration The crude crystal crop was washed well with n-hexane air-dried purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane) Recrystallization from benzene-n-hexane (1:1)

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C. cooling The mixture was stirred at room temperature overnight concentrated under reduced pressure The resulting crude product was dissolved in ethyl acetate The ethyl acetate layer was washed with water dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) recrystallized from acetone/isopropyl ether

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C. cooling The mixture was stirred at room temperature overnight concentrated under reduced pressure The resulting crude product was dissolved in ethyl acetate The ethyl acetate layer was washed with water dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) recrystallized from acetone/isopropyl ether

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2′-fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). The physical constants of this product were in agreement with those of the product obtained in Example 5-(1). cooling the mixture was then stirred at room temperature overnight the resulting crystals were collected by filtration The crude crystal crop was washed well with n-hexane air-dried purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane) Recrystallization from benzene-n-hexane (1:1)

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2′-fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). The physical constants of this product were in agreement with those of the product obtained in Example 5-(1). cooling the mixture was then stirred at room temperature overnight the resulting crystals were collected by filtration The crude crystal crop was washed well with n-hexane air-dried purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane) Recrystallization from benzene-n-hexane (1:1)

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C. cooling The mixture was stirred at room temperature overnight concentrated under reduced pressure The resulting crude product was dissolved in ethyl acetate The ethyl acetate layer was washed with water dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) recrystallized from acetone/isopropyl ether

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

Procedure: A mixture of 44.70 g (0.302 m) of ethyl 2-cyanoacetimidate hydrochloride and 13.29 g of cyanamide in 400 ml of benzene is stirred under nitrogen for fifteen hours. The cyanamide is purified by ether extraction and concentration of the soluble portion in vacuo. After reaction, the precipitated ammonium chloride is filtered. The residue is washed twice with 50 ml benzene portions. The combined organic phases are concentrated in vacuo to give 41.36 g (100%) of a pale yellow crystalline material. The crystallization is exothermic. The product is very clean by tlc and nmr. The crude crystalline material melts at 51°-63° C. The cyanamide is purified by ether extraction and concentration of the soluble portion in vacuo After reaction the precipitated ammonium chloride is filtered The residue is washed twice with 50 ml benzene portions The combined organic phases are concentrated in vacuo

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

Procedure: A mixture of 44.70 g (0.302 m) of ethyl 2-cyanoacetimidate hydrochloride and 13.29 g of cyanamide in 400 ml of benzene is stirred under nitrogen for fifteen hours. The cyanamide is purified by ether extraction and concentration of the soluble portion in vacuo. After reaction, the precipitated ammonium chloride is filtered. The residue is washed twice with 50 ml benzene portions. The combined organic phases are concentrated in vacuo to give 41.36 g (100%) of a pale yellow crystalline material. The crystallization is exothermic. The product is very clean by tlc and nmr. The crude crystalline material melts at 51°-63° C. The cyanamide is purified by ether extraction and concentration of the soluble portion in vacuo After reaction the precipitated ammonium chloride is filtered The residue is washed twice with 50 ml benzene portions The combined organic phases are concentrated in vacuo

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2'- fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). the physical constants of this product were in agreement with those of the product obtained in Example 5-(1). cooling the mixture was then stirred at room temperature overnight the resulting crystals were collected by filtration The crude crystal crop was washed well with n-hexane air-dried purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane) Recrystallization from benzene-n-hexane (1:1)

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C. cooling The mixture was stirred at room temperature overnight concentrated under reduced pressure The resulting crude product was dissolved in ethyl acetate The ethyl acetate layer was washed with water dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) recrystallized from acetone/isopropyl ether

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2′-fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). The physical constants of this product were in agreement with those of the product obtained in Example 5-(1). cooling the mixture was then stirred at room temperature overnight the resulting crystals were collected by filtration The crude crystal crop was washed well with n-hexane air-dried purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane) Recrystallization from benzene-n-hexane (1:1)

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

Procedure: To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C. cooling The mixture was stirred at room temperature overnight concentrated under reduced pressure The resulting crude product was dissolved in ethyl acetate The ethyl acetate layer was washed with water dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) recrystallized from acetone/isopropyl ether