1,4-BIS(N-BOC)PIPERAZINE-2-CARBOXYLIC ACID

White powder

Intermediate 140: (+/-VI ^-bislfd .i-dimethylethvDoxyicarbonvD^-piperazinecarboxylic acid; In a 1 L round-bottomed flask 15.76 g of NaOH (394 mmole) were poured in 390 mL of 1, 4-di(tert-Butoxycarbonyl)piperazine-2-carboxylic acid To an aqueous (100 ml) sodium hydroxide (4.0 g, 100 mmol) solution of piperazine-2-carboxylic acid dihydrochloride (5 g, 24.63 mmol) is added a solution of di-tert-butyl dicarbonate (11.0 g, 50.45 mmol) in dioxan (50 ml) at 0° C. over a period of half an hour. The reaction mixture is stirred at 0° C. for 1 hr. followed by stirring at room temperature (25° C.) for another 2 hrs. Neutralized (pH 6-7) with aqueous 2N HCl, extracted with ethyl acetate. Organic layer washed with brine solution, dried (Na2SO4) and evaporated in vacuo to yield an oil which solidifies on cooling. (Yield 8.02 g, 98.76percent).EXAMPLE-6 2-Cyano-1-(4-isopropyl-2-piperazinyl)-carbonyl Pyrrolidine Trifluoroacetate (Compound No.2). Step-1 To an aqueous (100 ml) sodium hydroxide (4.0 g, 100 mmol) solution of piperazine-2-carboxylic acid dihydrochloride (5 g, 24.63 mmol) is added a solution of di-tert-butyl dicarbonate (11.0 g, 50.45 mmol) in dioxan (50 ml) at 0° C. over a period of half an hour. The reaction mixture is stirred at 0° C. for 1 hr. followed by stirring at room temperature (25° C.) for another 2 hrs. Neutralized (pH 6-7) with aqueous 2N HCl, extracted with ethyl acetate. Organic layer washed with brine solution, dried (Na2SO4) and evaporated in vacuo to yield an oil which solidifies on cooling. (Yield 8.02 g, 98.76percent).A solution of di-tert-butyldicarbonate (63 g, 290 mmol) in MeOH (100 mL) was added portionwise to a solution of piperazine-2-carboxyilic acid dihydrochloride (25.0 g, 123 mmol) and triethylamine (48 mL, 340 mmol) in MeOH (150 mL) over 30 minutes. Upon complete addition, the reaction mixture was heated to 50 Pyrazine-2-carboxylic acid hydrochloride (2 g, 9.8 mmol)And (Boc) 2O (8.6 g, 39.4 mmol)Was dissolved in THF (40 mL) and water (40 mL)Sodium bicarbonate (8.31 g, 79.8 mmol) was added, The reaction mixture was stirred magnetically at room temperature for 4 hours and then added with ethyl acetate.Poured into a separatory funnel, and the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, The solvent was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 2.5 g of 1, 4-di-tert-butoxycarbonylpiperazine-2-carboxylic acid (13-2) in a yield of 78percentTo a solution of piperazine-2-carboxylic acid dihydrochloride (25.0 g, 123 mmol), dioxane (180 ml) and 5N aqueous sodium hydroxide solution (90 ml) was added dropwise di-tert-butyl dicarbonate (62.7 g, 288 mmol) under ice-cooling. To a stirring solution of piperazine-2-carboxylic acid dihydrochloride (SMI) (5 g, 24.6 mmol) in 1, 4-dioxane (40 mL) were added 5 N NaOH solution (3.5 g, 88.6 mmol) and Boc-anhydride (12.9 mL, 56.6 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), volatiles were evaporated under reduced pressure. Obtained crude was dissolved in water (50 mL) and extracted with EtPiperazine-2-carboxyilc acid dihydrochloride (15.0 g, 73.9 mmol) was dissolved in HStep 1 Intermediate 140: (+/-VI ^-bislfd .i-dimethylethvDoxyicarbonvD^-piperazinecarboxylic acid; In a 1 L round-bottomed flask 15.76 g of NaOH (394 mmole) were poured in 390 mL of 1, 4-di(tert-Butoxycarbonyl)piperazine-2-carboxylic acid To a solution of piperazine-2-carboxylic acid (21.2 g, 0.16 mol) in 1, 4-dioxane at 0 C., NaOH (80 mL, 400 mmol) was added slowly (over 15 min) followed by (Boc)2O (71 g, 33 mol) and the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in water (100 mL), acidified with conc. HCl at 0 C. to adjust the pH to 2-3 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the product (44.2 g, 83.7% yield) as an off-white solid.3-carboxypiperazine (10gm, 49.2mm) was dissolved in 200ml of 50% methanol/water and the pH adjusted to 9.5 with 50% sodium hydroxide. Di-tert.butyldicarbonate (21 gm) was added and the pH kept at 9.5 with 1N sodium hydroxide. The reaction was monitored by tlc and more di-tert.butyldicarbonate added if needed. The reaction mixture was acidified with conc. Hydrochloric acid to pH=7 and then with citric acid to pH 3.8 and extracted with methylenechloride to obtain 15.4 gm of solid product.Synthesis of 4-(4-Chloro-3-methoxy-phenyl)-piperazine-2-carboxylic acid (-)-menthol ester 8.75 g (43.4 mmol) of 2-piperazine carboxylic acid and 16.4 g (195 mmol) of sodium hydrogencarbonate were dissolved in 140 mL of water, 140 mL of acetonitrile was added, and the mixture was cooled to 0 C. To this was added 20.9 g (95.4 mmol) of Di-tert-butyldicarbonate, and the mixture was allowed to warm to ambient temperature after 2 hours. After stirring for twelve hours, the mixture was concentrated in vacuo to remove the acetonitrile, and the mixture was washed with ether. The aqueous solution was acidified with 1M NaHSO4, and was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give Piperazine-1, 2, 4-tricarboxylic acid 1, 4-di-tert-butyl ester.Intermediate 140: (+/-VI ^-bislfd .i-dimethylethvDoxyicarbonvD^-piperazinecarboxylic acid; In a 1 L round-bottomed flask 15.76 g of NaOH (394 mmole) were poured in 390 mL of 1, 4-di(tert-Butoxycarbonyl)piperazine-2-carboxylic acid To a solution of piperazine-2-carboxylic acid (21.2 g, 0.16 mol) in 1, 4-dioxane at 0 C., NaOH (80 mL, 400 mmol) was added slowly (over 15 min) followed by (Boc)2O (71 g, 33 mol) and the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in water (100 mL), acidified with conc. HCl at 0 C. to adjust the pH to 2-3 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the product (44.2 g, 83.7% yield) as an off-white solid.3-carboxypiperazine (10gm, 49.2mm) was dissolved in 200ml of 50% methanol/water and the pH adjusted to 9.5 with 50% sodium hydroxide. Di-tert.butyldicarbonate (21 gm) was added and the pH kept at 9.5 with 1N sodium hydroxide. The reaction was monitored by tlc and more di-tert.butyldicarbonate added if needed. The reaction mixture was acidified with conc. Hydrochloric acid to pH=7 and then with citric acid to pH 3.8 and extracted with methylenechloride to obtain 15.4 gm of solid product.Synthesis of 4-(4-Chloro-3-methoxy-phenyl)-piperazine-2-carboxylic acid (-)-menthol ester 8.75 g (43.4 mmol) of 2-piperazine carboxylic acid and 16.4 g (195 mmol) of sodium hydrogencarbonate were dissolved in 140 mL of water, 140 mL of acetonitrile was added, and the mixture was cooled to 0 C. To this was added 20.9 g (95.4 mmol) of Di-tert-butyldicarbonate, and the mixture was allowed to warm to ambient temperature after 2 hours. After stirring for twelve hours, the mixture was concentrated in vacuo to remove the acetonitrile, and the mixture was washed with ether. The aqueous solution was acidified with 1M NaHSO4, and was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give Piperazine-1, 2, 4-tricarboxylic acid 1, 4-di-tert-butyl ester.A mixture of tert-butyl 5-bromo-2-(7, 8-dimethyl-[1, 2, 4]triazolo[1, 5-a]pyridin-6-yl)-3-isopropyl-1H-pyrrolo[3, 2-b]pyridine-1-carboxylate (72.3 mg, 0.100 mmol),

Molecular Weight:330.38
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:5
Exact Mass:330.17908655
Monoisotopic Mass:330.17908655
Topological Polar Surface Area:96.4
Heavy Atom Count:23
Complexity:477
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes