2-[4-(2-methoxyphenyl)piperazin-1-yl]ethanamine

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

Procedure: The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification. The resulting mixture was refluxed for 18 hours The layers were separated the aqueous layer was made basic by careful addition of 50% aqueous NaOH The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate The combined organic layers were washed with brine (50 mL) dried over anhydrous sodium sulfate Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the was used without further purification

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

Procedure: This compound was prepared by the similar procedure as in the case of Example 8, excepting that 4-(2-aminoethyl)-1-(2-methoxyphenyl)pyperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) were employed. This compound was prepared by the similar procedure as in the case of Example 8

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

Procedure: 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine (9.4 g, 40 mmol) and 2-chloroquinoline (6.5 g, 40 mmol) were heated at 160° C. for 3 h, then at 120° C. for 18 h in a sealed vessel. The resultant brown tar was taken up into dilute hydrochloric acid (300 ml), washed with dichloromethane (3×100 ml) basified with sodium hydroxide, extracted into dichloromethane (3×100 ml), dried (MgSO4) then evaporated in vacuo to give a brown oil. The oil was purified by chromatography [alumina; ethyl acetate-toluene (1:4)] to give the product (1.8 g) as a clear oil. washed with dichloromethane (3×100 ml) extracted into dichloromethane (3×100 ml) dried (MgSO4) then evaporated in vacuo to give a brown oil The oil was purified by chromatography [alumina; ethyl acetate-toluene (1:4)]

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

Procedure: 5.8 g (23.4 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 50 ml of ethanol were mixed with 5.5 g (23.4 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine and refluxed for 2 h. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 30 ml of ethyl acetate, heated to boiling and left to cool with stirring. The solid which crystallized out was filtered off with suction after cooling in an ice bath and was washed with ethyl acetate. 8.7 g (80%) of product with melting point 170-172° C. were isolated. refluxed for 2 h The mixture was then concentrated in a rotary evaporator heated left to cool The solid which crystallized out was filtered off with suction after cooling in an ice bath was washed with ethyl acetate

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

Procedure: 2.5 g (7.3 mmol) of 2-carboethoxyamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine were heated with 1.7 g (7.3 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine at 180° C. for 2 h under nitrogen while stirring the melt efficiently. After cooling, the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/ methanol 95/5). 0.7 g (20%) of product with melting point 135-137° C. was isoldted. After cooling the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/ methanol 95/5)

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

Procedure: 1.9 g (6.2 mmol) of ethyl N-(3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ethanimidate in 30 ml of ethanol were mixed with 1.5 g (6.2 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine and refluxed for 7 h. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 20 ml of ethyl acetate. 2.1 g of crude product crystallized out overnight and were filtered off with suction and purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 92/8). 0.8 g (29%) of product was isolated. refluxed for 7 h The mixture was then concentrated in a rotary evaporator 2.1 g of crude product crystallized out overnight were filtered off with suction purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 92/8)

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

Procedure: 1.1 g (4.8 mM) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine were added to 1.6 g (4.8 mM) of 2-ethoxymethyleneamino-3,5-dicarbethoxy-4,6-dihydrothieno[3,2-c]pyrrole in 25 ml of ethanol and refluxed for 2 h. The mixture was then concentrated in a rotary evaporator, and the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 96/4). After recrystallization from ethyl acetate, 1.1 g (47%) of product were isolated with melting point 153-155° C. refluxed for 2 h The mixture was then concentrated in a rotary evaporator the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 96/4) After recrystallization from ethyl acetate

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

Procedure: 1.1 g (4.8 mM) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine were added to 1.6 g (4.8 mM) of 2-ethoxymethyleneamino-3,5-dicarbethoxy-4,6-dihydrothieno[3,2-c]pyrrole in 25 ml of ethanol and refluxed for 2 h. The mixture was then concentrated in a rotary evaporator, and the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 96/4). After recrystallization from ethyl acetate, 1.1 g (47%) of product were isolated with melting point 153-155° C. refluxed for 2 h The mixture was then concentrated in a rotary evaporator the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 96/4) After recrystallization from ethyl acetate

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

Procedure: The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification. The resulting mixture was refluxed for 18 hours The layers were separated the aqueous layer was made basic by careful addition of 50% aqueous NaOH The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate The combined organic layers were washed with brine (50 mL) dried over anhydrous sodium sulfate Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the was used without further purification

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

Procedure: The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification. The resulting mixture was refluxed for 18 hours The layers were separated the aqueous layer was made basic by careful addition of 50% aqueous NaOH The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate The combined organic layers were washed with brine (50 mL) dried over anhydrous sodium sulfate Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the was used without further purification

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

Procedure: This compound was prepared by the similar procedure as in the case of Example 8, excepting that 4-(2-aminoethyl)-1-(2-methoxyphenyl)pyperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) were employed. This compound was prepared by the similar procedure as in the case of Example 8

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

Procedure: This compound was prepared by the similar procedure as in the case of Example 8, excepting that 4-(2-aminoethyl)-1-(2-methoxyphenyl)pyperazine and (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1) were employed. This compound was prepared by the similar procedure as in the case of Example 8