4-Boc-piperazine-2-carboxylic acid

To a sealed tube was added tert-Butyl N-[(lS)-l-(3-bromophenyl)but-3-en-l-yl] carbamate, prepared as described in intermediate 2 (1 g, 2.78 mmol), (R)-4-(tert- butoxycarbonyl)piperazine-2-carboxylic acid (0.767 g, 3.33 mmol), K2CO3 (1.151 g, 8.33 mmol) and DMSO (2.78 ml). The reaction was purged with Ar and then Cul (0.026 g, 0.139 mmol) was added. The reaction was sealed and stirred at 110 C for 30 h. The reaction was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was separated, washed with saturated aqueous NH4CI (40 ml), water (40 ml) and brine (40 ml), dried over MgS04, filtered and concentrated to give crude mixture as greenish gum. The residue was purified using ISCO system (0-100% EtO Ac/Hex gradient) to give (R)-l-(3- ((S)-l-(((benzyloxy)carbonyl)amino)but-3-en-l-yl)phenyl)-4-(teri- butoxycarbonyl)piperazine-2-carboxylic acid (400 mg, 0.785 mmol, 28.3 % yield) as a white solid. (ESI) m/z: 510.2 (M+H)+. NMR (400MHz, CDCh) delta 7.43 - 7.30 (m, 5H), 7.23 (d, J=7.0 Hz, 1H), 6.87 - 6.71 (m, 3H), 5.68 (br. s., 1H), 5.19 - 4.99 (m, 5H), 4.76 (br. s., 1H), 4.66 - 4.33 (m, 2H), 4.16 - 3.99 (m, 1H), 3.59 - 3.47 (m, 1H), 3.39 (br. s., 2H), 3.16 (br. s., 1H), 2.54 (br. s., 2H), 1.48 (s, 9H).Preparation 7.5(2R)-2-(Cyclobutylcarbamoyl)-1 -methylpiperazine ditrifluoroacetate.0.39 ml of a solution of formaldehyde at 37% in water, 0.32 g of sodium cyanoborohydride and 0.994 ml of acetic acid are added to a solution of 1 g of fe/f-butyl (3R)-piperazine-1 , 3-d icarboxy late in 26 ml of MeOH and stirred for 3 hours at RT. The reaction mixture is diluted by adding a saturated solution of K2CO3, extracted with DCM, the organic phase is dried over MgS04 and the solvent is evaporated under vacuum. The residue is dissolved in 4 ml of DMF, 0.19 g of HOAT, 0.267 g of EDC and 0.1 g of cyclobutylamine are added and it is stirred for 16 hours at RT. The reaction mixture is diluted by adding a saturated solution of NaHC03, extracted with DCM, the organic phase is dried over MgS04 and the solvent is evaporated under vacuum. The residue is purified by preparative HPLC, the fractions containing the product are concentrated under vacuum and lyophilized, obtaining 0.31 g of a white solid. The solid is dissolved in 2 ml of DCM, 2.5 ml of TFA is added and stirred for 4 hours at RT. It is diluted by adding 100 ml of toluene and the solvents are concentrated under vacuum. 0.94 g of the expected compound is obtained.(R)-Piperazine-l, 3-dicarboxylic acid l-tert-buty ester (4.94 g, 21.5 mmol) was dissolved in water (10 mL) and dioxane (20 mL) and cooled to 0 C. Sodium hydroxide (1.72 g, 43.0 mmol) in water (4 mL) and di-tert-buty dicarbonate (5.20 g, 23.8 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was suspended in DCM (400 mL) and stirred for 30 minutes at room temperature, filtered and the filtrate was concentrated in vacuo to give (R)-2-piperazine- 1, 2, 4-tricarboxylic acid 1 , 4-di-tert-buty{ ester (9.78 g, 138%) as a pale yellow oil which was used without further purification. Analytical LCMS: purity -90% (System C, Rtau = 1.56 min), ES+: 131.7 [M+H-2Boc]+.[4-BOC-PIPERAZINE-2- (R)-CARBOXYLIC] acid (933mg, 4. [05MOL), ] CH2Cl2 (12ml), DMF (6ml), and DIEA (2. 5ml, 14. [3MMOL)] were combined under N2. TMS-Cl (810mul, 6. [38MMOL)] was added slowly and the mixture stirred at room temperature for approximately 2 hrs. [4- (4-] fluorophenoxy) -3, 5-difluorophenyl)] sulfonyl chloride (1.43g, 4. [43MMOL)] dissolved in a minimum of [CH2CL2] was added and the mix- ture stirred at room temperature for another 2 hrs. The reaction mixture was diluted with EtOAc and washed with 0.5N HCl (3x), sat'd NaCl [(LX), ] dried [(NA2SO4), ] and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (6: 4 hexanes: EtOAc + [1%] AcOH) to give the desired product (1.37g, [65%).] LC/MS Calcd [FOR [M+H] 517.] 1, found 417.0 (-Boc).(a) 2(R)-N-hydroxy-1-(4-(4-chlorophenoxy)benzenesulfonyl)-4-(t-butoxycarbonyl)-piperazine-2-carboxamide To a solution of 2(R)-piperazine-2-carboxylic acid (1.30 g) and triethylamine (3.50 mL) in 25 mL of 3:2 acetonitrile:water at -15 C. was added BOC-ON (2.70 g) in one portion. The mixture was allowed to warm slowly to 25 C. overnight, and then concentrated to a volume of ca. 10 mL. The resulting mixture was partitioned between 25 mL of water and 50 mL of 4:1 ethyl acetate:hexane. The aqueous layer was further washed with dichloromethane (3*10 mL) and then concentrated. The semi-solid residue was triturated with ethanol and filtered to give 1.18 g of 2(R)-4-(t-butoxycarbonyl)piperazine-2-carboxylate. Concentration of the filtrate gave a second crop of 0.58 g; total yield of

Molecular Weight:230.26
XLogP3:-2.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:230.12665706
Monoisotopic Mass:230.12665706
Topological Polar Surface Area:78.9
Heavy Atom Count:16
Complexity:285
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes