Piperazine-2-carboxylicaciddihydrochloride

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To a stirred suspension of piperazine-2-carboxylic acid (SM) (5 g, 24.6 mmol ) in 1, 4-dioxane: water (1 : 1, 100 mL) was added NaHCC>3 (3.1 g, 36.9 mmol) followed by Boc-anhydride (5.6 mL, 24.6 mmol) at 0 C under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (50 mL) and extracted with Et20 (2 x 100 mL). Aqueous layer was acidified with 2N HC1 solution and extracted with n-BuOH. Combined organic layer was dried over Na2S04 and concentrated under reduced pressure to afford compound 1 (5 g, 88%) as white solid. 1H-NMR: (500 MHz, DMSO-ifc): delta 10.18 (br s, 1H), 4.08 (br s, 1H), 3.81-3.71 (m, 2H), 3.63 (t, J = 6.5 Hz, 1H), 3.17-3.15 (m, 2H), 2.91-2.86 (m, 1H), 1.36 (s, 9H), 1.31-1.26 (m, 0.5H), 0.87-0.84 (m, 0.5H). LCMS (ESI): mJz 229.0 [(MM)].General procedure: Target inhibitors were synthesized by the general route previously described with modifications. Briefly, piperazine 2-carboxylic acid 1 was reacted with di-tert-butyl dicarbonate in a 2:1 solution of 1, 4 dioxane and H2O with NaOH. TEA and the desired sulfonyl chloride were then added to install the N1 substituent. The crude reaction was concentrated in vacuo and partitioned between 1M HCl and EtOAc. The organic layer was evaporated then redissolved in MeOH. Thionyl chloride was added to this solution, and the reaction was then washed several times with hexane. The methanol layer was evaporated to give intermediates 2 (a-c) with an overall yield of 30-50% for the two reactions. Subsequent reaction with the desired electrophile in anhydrous dioxane with TEA afforded intermediates 3 (a-u), which were purified by flash chromatography with a resulting yield of 40-90%. Finally, intermediates 3 (a-u) were reacted with methanolic NH2OH to yield the target inhibitors hydroxamic acids 4 (a-u), which were purified by flash chromatography with a yield of 30-75%.General procedure: Target inhibitors were synthesized by the general route previously described with modifications. Briefly, piperazine 2-carboxylic acid 1 was reacted with di-tert-butyl dicarbonate in a 2:1 solution of 1, 4 dioxane and H2O with NaOH. TEA and the desired sulfonyl chloride were then added to install the N1 substituent. The crude reaction was concentrated in vacuo and partitioned between 1M HCl and EtOAc. The organic layer was evaporated then redissolved in MeOH. Thionyl chloride was added to this solution, and the reaction was then washed several times with hexane. The methanol layer was evaporated to give intermediates 2 (a-c) with an overall yield of 30-50% for the two reactions. Subsequent reaction with the desired electrophile in anhydrous dioxane with TEA afforded intermediates 3 (a-u), which were purified by flash chromatography with a resulting yield of 40-90%. Finally, intermediates 3 (a-u) were reacted with methanolic NH2OH to yield the target inhibitors hydroxamic acids 4 (a-u), which were purified by flash chromatography with a yield of 30-75%.General procedure: Target inhibitors were synthesized by the general route previously described with modifications. Briefly, piperazine 2-carboxylic acid 1 was reacted with di-tert-butyl dicarbonate in a 2:1 solution of 1, 4 dioxane and H2O with NaOH. TEA and the desired sulfonyl chloride were then added to install the N1 substituent. The crude reaction was concentrated in vacuo and partitioned between 1M HCl and EtOAc. The organic layer was evaporated then redissolved in MeOH. Thionyl chloride was added to this solution, and the reaction was then washed several times with hexane. The methanol layer was evaporated to give intermediates 2 (a-c) with an overall yield of 30-50% for the two reactions. Subsequent reaction with the desired electrophile in anhydrous dioxane with TEA afforded intermediates 3 (a-u), which were purified by flash chromatography with a resulting yield of 40-90%. Finally, intermediates 3 (a-u) were reacted with methanolic NH2OH to yield the target inhibitors hydroxamic acids 4 (a-u), which were purified by flash chromatography with a yield of 30-75%.Step 1 (piperazin-2-yl)methanol At 0C, to a suspension of lithium aluminum tetrahydrate (5.61 g, 147.74 mmol, 1.5 equivalents) in tetrahydrofuran (300 mL) was added piperazine-2-carboxylic acid (20.00 g, 98.49 mmol. 1.00 equivalent, 2 hydrochloride) in separate portions. The mixture was heated to 70C and stirred for 18 hours. LC/MS showed complete conversion of the starting material and detected the target product. The reaction mixture was cooled to 0C, and quenched with water (5 mL) and an aqueous solution of sodium hydroxide (15%, 5 mL). The mixture was filtered, and the filter cake was washed with dichloromethane (100 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.4 g, 20.66 mmol, 20.98% yield) as a pale yellow oil. 1H NMR (400MHz, CDCl3) delta '3.54 (dd, J = 4.1, 10.7 Hz, 1H), 3.40 (d, J = 7.2 Hz, 1H), 3.02-2.95 (m, 1H), 2.90 (dd, J = 11.9, 2.6Hz, 3H), 2.81-2.75 (m, 4H), 2.47 (dd, J = 11.8, 10.3 Hz, 1H), 1.41 (s. 1H).Example 49 - Preparation of Intermediate 14 The synthesis of Intermediate 14 followed the procedure of General Procedure 10 following: Intermediate 14 To a stirred solution of (+/-)-Example 554-(5-Fluoro-2-trifluoromethyl-benzoyl)-1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-2-carboxylic acid Step 1Synthesis of piperazine-1, 3-dicarboxylic acid 1-benzyl ester copper complex Aqueous 2.5M NaOH solution (4 mL) was added to a clear solution of 7V-Biphenyl-2-yl- 1 , 3-dioxo-2- [^r°ws-2-phenylcyclopr opyll hexahydr oimidazo [ 1 , 5-al pyrazine- 7qH)-carboxamide (A6); Step 1 : l-[(benzyloxy)carbonyll-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Al); A solution 0.164 M of EXAMPLE O; Preparation of Compounds O of Formula 1 General Process for the Preparation of Compound O-In-1 from Piperazine-2- carboxylic acid:[00167] A three necked round bottom flask was charged with piperazine-2- carboxylic acid dihydrochloride (1 eq.), cupric carbonate (1.1 eq.) and water. The reaction mixture was refluxed for about 2h and it was filtered through CELITE bed. The deep blue color filtrate was cooled to O 0C and added sodium bicarbonate (3.7 eq.) into the reaction mixture very slowly. The reaction mixture was stirred at O 0C for 30min and benzyl chloroformate (1.5 eq.) was added to the reaction mixture very slowly. The progress of the reaction was monitored by TLC. After consumption of starting material, the reaction mixture was filtered and a pale blue solid was washed with cold water, ethanol and diethyl ether. The pale blue solid was taken up in water and concentrated hydrochloric acid was added. To this solution, H2S gas was purged for Ih under stirring at room temperature. The excess H2S gas was removed by purging with nitrogen for 30min. The reaction mixture was filtered through

Molecular Weight:203.06
Hydrogen Bond Donor Count:5
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:202.0275830
Monoisotopic Mass:202.0275830
Topological Polar Surface Area:61.4
Heavy Atom Count:11
Complexity:116
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:3
Compound Is Canonicalized:Yes