piperazine;hexahydrate

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

Procedure: This compound and its preparation has been described in Great Britain Patents 1,390,014 and 1,390,015. Piperazine hexahydrate (194 g, 1 mole) was dissolved in 250 ml H2O. The solution was acidified to pH 4.5 with 6N HCl. Furoyl chloride (130.5 g, 1 mole, Aldrich) was added along with 10% NaOH solution at such a rate that the pH was maintained at 4.5. After 1 hour, the solution was made basic (pH=8.5) with NaOH solution. The reaction mixture was continuously extracted with chloroform for 36 hours. The CHCl3 extract was dried over MgSO4, and filtered. Distillation gave 108.2 g product (60%), b.p. 132°-138° C./0.6 mm Hg, m.p. 69°-70° C. This compound and its preparation was maintained at 4.5 The reaction mixture was continuously extracted with chloroform for 36 hours The CHCl3 extract was dried over MgSO4 filtered Distillation

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

Procedure: To an aqueous solution of perchloric acid, containing 200 g of said acid in 500 ml of water 40 % solution, the amount of aqueous solution of piperazine hexahydrate required for neutralization is added. The required amount of piperazine hexahydrate is 388.46 g (C4H10N2.6H2O) dissolved in 500 ml of water. Preferably the pH of the neutralizing solution is controlled to a pH close to 6. The piperazine perchlorate solution is mixed with the warm solution of p-dihydroxy benzene disulfonic acid potassium salt, and is stirred until a copious precipitate of potassium perchlorate is formed, which then increases when the solution is left to cool for several hours. After filtering off the potassium perchlorate, the solution of a piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60°C, until crystals begin to form, and it is then left in a refrigerator. The product is filtered and recrystallized in water to give 388 g of bis (piperazine) p-dihydroxy benzene disulfonate, having a melting point of 270°C. is added a pH close to 6 is formed which then increases when the solution is left to cool for several hours After filtering off the potassium perchlorate the solution of a piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60°C, until crystals to form it is then left in a refrigerator The product is filtered recrystallized in water

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

Procedure: To an aqueous solution of perchloric acid, containing 200 g of said acid in 500 ml of water 40 % solution, the amount of aqueous solution of piperazine hexahydrate required for neutralization is added. The required amount of piperazine hexahydrate is 388.46 g (C4H10N2.6H2O) dissolved in 500 ml of water. Preferably the pH of the neutralizing solution is controlled to a pH close to 6. The piperazine perchlorate solution is mixed with the warm solution of p-dihydroxy benzene disulfonic acid potassium salt, and is stirred until a copious precipitate of potassium perchlorate is formed, which then increases when the solution is left to cool for several hours. After filtering off the potassium perchlorate, the solution of a piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60°C, until crystals begin to form, and it is then left in a refrigerator. The product is filtered and recrystallized in water to give 388 g of bis (piperazine) p-dihydroxy benzene disulfonate, having a melting point of 270°C. is added a pH close to 6 is formed which then increases when the solution is left to cool for several hours After filtering off the potassium perchlorate the solution of a piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60°C, until crystals to form it is then left in a refrigerator The product is filtered recrystallized in water

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

Procedure: To an aqueous solution of perchloric acid, containing 200 g of said acid in 500 ml of water 40 % solution), the amount of aqueous solution of piperazine hexahydrate required for neutralization is added. The required amount of piperazine hexahydrate is 388.46 g (C4H10N2.6H2O) dissolved in 500 ml of water. Preferably the pH of the neutralizing solution is controlled to a pH close to 6. The piperazine perchlorate solution is mixed with the warm solution of p-dihydroxy benzene disulfonic acid potassium salt, and is stirred until a copious precipitate of potassium perchlorate is formed, which then increases when the solution is left to cool for several hours. After filtering off the potassium perchlorate, the solution of piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60° C., until crystals begin to form, and it is then left in a refrigerator. The product is filtered and recrystallized in water to give 388 g of bis (piperazine) p-dihydroxy benzene disulfonate, having a melting point of 270° C. is added a pH close to 6 is formed which then increases when the solution is left to cool for several hours After filtering off the potassium perchlorate the solution of piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60° C., until crystals to form it is then left in a refrigerator The product is filtered recrystallized in water

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

Procedure: To an aqueous solution of perchloric acid, containing 200 g of said acid in 500 ml of water 40 % solution), the amount of aqueous solution of piperazine hexahydrate required for neutralization is added. The required amount of piperazine hexahydrate is 388.46 g (C4H10N2.6H2O) dissolved in 500 ml of water. Preferably the pH of the neutralizing solution is controlled to a pH close to 6. The piperazine perchlorate solution is mixed with the warm solution of p-dihydroxy benzene disulfonic acid potassium salt, and is stirred until a copious precipitate of potassium perchlorate is formed, which then increases when the solution is left to cool for several hours. After filtering off the potassium perchlorate, the solution of piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60° C., until crystals begin to form, and it is then left in a refrigerator. The product is filtered and recrystallized in water to give 388 g of bis (piperazine) p-dihydroxy benzene disulfonate, having a melting point of 270° C. is added a pH close to 6 is formed which then increases when the solution is left to cool for several hours After filtering off the potassium perchlorate the solution of piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60° C., until crystals to form it is then left in a refrigerator The product is filtered recrystallized in water

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-dichloro-1,2,5-thiadiazole (4.00 g, 25.8 mmol) and piperazine hexahydrate (25.0 g, 130 mmol) in DMF (25 mL) was heated at 70° C. for 20 minutes. After cooling to ambient temperature, the reaction mixture was basified (11M NaOH) and brine was added. The resulting mixture was extracted with CHCl3 (×3). The combined organic phases were washed twice with brine/water (1:1), dried (MgSO4) and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel using CHCl3 as eluent to give 2.77 g (52%) of the title compound as a colourless oil which was converted to its hydrochloride salt: mp 231° C. (dec). Anal. (C6H9ClN4S.HCl), C calc 29.89, found 30.4, H, N. After cooling to ambient temperature was added The resulting mixture was extracted with CHCl3 (×3) The combined organic phases were washed twice with brine/water (1:1) dried (MgSO4) the solvent was evaporated The resulting oil was purified by column chromatography on silica gel

Conditions: temp:165.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the product from Step 1 above (0.84 g, 3.1 mmol) and piperazine hexahydrate (5.3 g, 27.3 mmol) was heated in a sealed tube at 165° C. for 1 h. After cooling, the mixture was diluted with water (100 mL) and extracted twice with EtOAc. The combined and dried (MgSO4) organic phases were concentrated in vacuo and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting dihydrochloride salt was dried (80° C., 1 mmHg) to afford 0.598 g (52%) of the title compound as a light yellow solid: mp 91-120° C. Anal. (C17H21N3O2.2HCl) C, H, N. After cooling extracted twice with EtOAc dried (MgSO4) organic phases were concentrated in vacuo the residue was purified by chromatography on silica gel

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

Procedure: A mixture of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (22g) and piperazine hexahydrate (160g) was heated at 135°-145° C. in an autoclave for 18.5 hr. The mixture was evaporated to dryness and dissolved in 10% sodium hydroxide. The solution was neutralized with acetic acid. The precipitate was collected, washed with water, dissolved in 30% acetic acid, and filtered. The filtrate was neutralized with 10% sodium hydroxide. The resulting precipitate was collected, washed with water and ethanol, and dried at 140°-145° C. in vacuo for 1.5 hr. to give 14g (54%) of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (II) as colorless powder, m.p. 227°-228° C. was heated at 135°-145° C. in an autoclave for 18.5 hr The mixture was evaporated to dryness dissolved in 10% sodium hydroxide The precipitate was collected washed with water dissolved in 30% acetic acid filtered The resulting precipitate was collected washed with water and ethanol dried at 140°-145° C. in vacuo for 1.5 hr

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.9g), piperazine hexahydrate (15g) and water (15 ml) was heated at 170° C. in a sealed tube for 16 hr. After evaporation of the solvent, the residue was acidified with diluted hydrochloric acid, heated at 100° C., and the hot solution was filtered. The filtrate was evaporated to dryness. The residue was dissolved in 10% sodium hydroxide and neutralized with acetic acid. The precipitate was collected, washed with water, dried, and recrystallized from ethanol to give 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid pentahydrate (I) as colorless powder, m.p.: 226°-227° C. Mass spectrum m/e: 319 (M+). After evaporation of the solvent heated at 100° C. the hot solution was filtered The filtrate was evaporated to dryness The residue was dissolved in 10% sodium hydroxide and neutralized with acetic acid The precipitate was collected washed with water dried recrystallized from ethanol

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of water and 500 ml of methanol are added to 194 g (1 M) of piperazine hexahydrate, while stirring, and the pH is adjusted to 3 with about 163 ml of concentrated hydrochloric acid. The mixture is then cooled to 25° C. and 100 g (0.59 M) of benzyl chloroformate are added dropwise, while stirring, during which the pH is kept between 3 and 4.5 with sodium hydroxide solution (4 M; about 230 ml). About 700 ml are then stripped off on a rotary evaporator and the residue is washed with water, rendered acid with about 1.5 ml of concentrated HCl and extracted twice with 200 ml of toluene each time. The aqueous phase is cooled and brought to pH 12 with about 115 ml of 12.5 N NaOH. The oil which separates out is extracted several times with toluene, and the extract is dried over K2CO3 and concentrated under reduced pressure. Yield: 74 g while stirring, during which the pH About 700 ml are then stripped off on a rotary evaporator the residue is washed with water extracted twice with 200 ml of toluene each time The aqueous phase is cooled The oil which separates out is extracted several times with toluene the extract is dried over K2CO3 concentrated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 250 ml of water and 500 ml of methanol are added to 194 g (1 M) of piperazine hexahydrate, while stirring, and the pH is adjusted to 3 with about 163 ml of concentrated hydrochloric acid. The mixture is then cooled to 25° C. and 100 g (0.59 M) of benzyl chloroformate are added dropwise, while stirring, during which the pH is kept between 3 and 4.5 with sodium hydroxide solution (4 M; about 230 ml). About 700 ml are then stripped off on a rotary evaporator and the residue is washed with water, rendered acid with about 1.5 ml of concentrated HCl and extracted twice with 200 ml of toluene each time. The aqueous phase is cooled and brought to pH 12 with about 115 ml of 12.5 N NaOH. The oil which separates out is extracted several times with toluene, and the extract is dried over K2CO3 and concentrated under reduced pressure. Yield: 74 g while stirring, during which the pH About 700 ml are then stripped off on a rotary evaporator the residue is washed with water extracted twice with 200 ml of toluene each time The aqueous phase is cooled The oil which separates out is extracted several times with toluene the extract is dried over K2CO3 concentrated under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with 12.4 g (66 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile suspended in 40 ml of ethanol. Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and 13.7 ml of water are added and the mixture is refluxed for a further 3.5 hours and kept at ambient temperature for a further 15 hours. Then 43.5 ml of conc. hydrochloric acid are added and the mixture is cooled to 10° C. for 30 minutes with stirring. The precipitate obtained is suction filtered, washed with a little water and dried at 40° C. in the circulating air dryer for 24 hours. the mixture is refluxed for a further 3.5 hours The precipitate obtained filtered washed with a little water dried at 40° C. in the circulating air dryer for 24 hours