(R)-N-Boc-piperazine-2-carboxylic acid methyl ester

Trimethylsilyl diazomethane (2M in hexane, 14 ml) was added dropwise to a solution of (2R)-L-(TERT-BUTOXYVARBONYL) piperazine-2-carboxylic acid (5 g) in methanol (100 ml) and DCM (115 ml), and the solution stirred at room temperature for 16 hours. The solvent was concentrated in vacuo and the residue purified by chromatography, eluting with ethyl acetate then 5percent methanol / 7N ammonia in ethyl acetate, to give 1-tert-butyl 2-methyl (2R)- PIPERAZINE-1, 2-dicarboxylate as an oil (2.55 g, 48percent); NMR spectrum (DMSO-d6) 1.40 (s, 9H), 2.10 (bs, 1H), 2.52 (m, 1H), 2.72 (dd, 1H), 2.82 (d, 1H), 2.97 (m, 1H), 3.29 (d, 1H), 3.61 (d, 1H), 3.67 (s, 3H), 4.43 (m, 1H) ; Mass spectrum MH+ 245.Step 1 To a stirred solution of A mixture of Compound 13A (605 mg, 2.46 mmol), l-(/er/-butyl) 2-methyl (f?)-piperazine-l, 2-dicarboxylate (500 mg, 2.05 mmol), and K2CO3 (424 mg, 3.07 mmol) in DMF (10 mL) was stirred at 60 C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to yield Compound 13B-1: LC-MS (ESI) m/z: 411 [M+H]+.In a sealed tube, 1-tert-butyl 2-methyl (2R) -piperazine-1, 2-dicarboxylate (500 mg)1-Bromo-4-chlorobenzene (383 mg), palladium (II) acetate(15 mg), BINAP (75 mg), And sodium tert-butoxide (442 mg) were added toluene in a nitrogen stream, and the mixture was stirred at 80 C. for 18 hours.The reaction solution was cooled to room temperature, filtered through celite with ethyl acetate, The solvent was evaporated under reduced pressure to obtain a residue, Silica gel column chromatography (hexane-ethyl acetate)Made, 1-tert-butyl 2-methyl (2R) -4- (4-chlorophenyl)Piperazine-1, 2-dicarboxylate240 mg (yield 34%) was obtained (120 mg, 0.49 mmol) and 2-Bromo-5-trifluoromethyl-pyridine (133 mg, 0.59 mmol) were dissolved into 2.0 mL of anhydrous toluene (degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol), 1, 3-bis(2, 6-di-i-propylphenyl)imidazolium chloride (42 mg, 0.1 mmol) and sodium t-butoxide (57 mg, 0.59 mmol). This 'catalytic' vial was equipped with a magnetic stir bar and flushed with dry nitrogen. The reactant solution was next transferred to the 'catalytic' vial and the mixture was stirred at 100 C. for 5 h. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was evaporated in vacuo and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 110 mg (58%) of (R)-4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, intermediate IX-B, as a yellow residue. 1H NMR (400 MHz, CDCl3) delta 8.39-8.38 (m, 1H), 7.65 (d, 1H), 6.68 (m, 1H), 4.89-4.68 (m, 2H), 4.29 (dd, 1H), 3.95 (dd, 1H), 3.69 (s, 3H), 3.43-3.26 (m, 2H), 3.12-2.97 (m, 1H), 1.51-1.46 (m, 9H).

Molecular Weight:244.29
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:244.14230712
Monoisotopic Mass:244.14230712
Topological Polar Surface Area:67.9
Heavy Atom Count:17
Complexity:298
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes