1-N-BOC-4-(2-CHLORO-4-PYRIDINYL) PIPERAZINE synthesis

Yield:633283-63-3 100%

Reaction Conditions:

with sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium⁽⁰⁾;4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in toluene at 85; for 20 h;Inert atmosphere;

Steps:

16

xample 16: N-CyclopentyW-piperazin-i-ylpyridin^-amine. 4-(2-Chloro-pyridin-4-yl)-piperazine-1 -carboxylic acid tert-butyl ester. To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.5 mmol) in toluene (100 ml_) was added piperazine-1-carboxylic acid tert-butyl ester (3.2 g, 17.2 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask was evacuated and flushed with N₂(g) twice. A mixture of Xantphos (600 mg, 1.0 mmol) and Pd₂(dba)₃ (318 mg, 0.35 mmol) was added in one portion and the mixture was heated at 85 ⁰C for 20 h. The mixture was cooled to rt, diluted with H₂O (75 -->ml_), and extracted with EtOAc (3x). The combined organic layers were dried and concentrated to give a clear golden oil. The oil was purified on FCC (O to 5% 2 M NH₃ in MeOH/CH₂CI₂) to give the title product as a beige solid (5.1 g, 100%). MS (ESI): mass calcd. for Ci₄H₂₀CIN₃O₂, 297.1 ; m/z found, 298.2 [M+H]⁺. ¹H NMR (DMSO-d₆): 7.95 (d, J = 5.9, 1 H), 6.88-6.78 (m, 2H), 3.46- 3.32 (m, 8H), 1.42 (s, 9H). terf-Butyl 4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1 -carboxylate. To a stirring solution of 4-(2-chloro-pyridin-4-yl)-piperazine-1-carboxylic acid tert- butyl ester (163 mg, 0.55 mmol) in toluene (2 ml_) in a vial was added cyclopentylamine (136 μl_, 1.38 mmol) and sodium tert-butoxide (161 mg, 1 .68 mmol). A mixture of racemic BINAP (20 mg, 0.032 mmol) and Pd(OAc)₂ (18 mg, 0.027 mmol) was added in one portion and the mixture was heated at 85 ⁰C for 20 h. The mixture was cooled to rt and purified directly by FCC (0 to 5% 2 M NH₃ in MeOH/CH₂CI₂) to provide the title compound as a white solid (34 mg, 17%). MS (ESI): mass calcd. for Ci₉H₃₀N₄O₂, 346.2; m/z found, 347.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 7.65 (d, J = 6.0, 1 H), 6.10 (d, J = 6.0, 1 H), 5.92 (d, J = 7.1 , 1 H), 5.78 (s, 1 H) 4.08-4.02 (m, 1 H), 3.41 (t, J = 5.4, 4H), 3.16 (t, J = 5.4, 4H), 1.89-1.82 (m, 2H), 1.67-1 .61 (m, 2H), 1 .59-1.48 (m, 2H), 1.42 (s, 9H), 1.43-1.35 (m, 2H). N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine dihydrochloride. To a stirring solution of tert-butyl 4-[2-(cyclopentylamino)pyhdin-4-yl]piperazine-1 - carboxylate (34 mg, 0.1 mmol) in 96% formic acid (4 ml_) was added 6 N aq HCI (2 drops). The mixture was stirred for 2 h and concentrated to give the desired product as a white solid (26 mg, 93%). MS (ESI): mass calcd. for Ci₄H₂₂N₄, 246.2; m/z found, 247.2 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.32 (s, 2H), 7.89 (d, J = 7.1 , 1 H), 7.69 (d, J = 7.5, 1 H), 6.58 (d, J = 7.6, 1 H), 6.04 (s, 1 H), 4.03-3.96 (m, 1 H), 3.73 (t, J = 4.9, 4H), 3.20 (t, J = 5.0, 4H), 2.03-1.95 (m, 2H), 1.73-1.68 (m, 2H), 1.64-1 .52 (m, 2H), 1.50-1.42 (M, 2H).

References:

WO2009/152325,2009,A1 Location in patent:Page/Page column 47-48