2-(4-Methyl-[1,4]diazepan-1-yl)-ethanol synthesis

Yield:59039-64-4 100%

Reaction Conditions:

with N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide at 20 - 100;

Steps:

33 2-(4-Methyl-1,4-diazepan-1-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate

Example 33 2-(4-Methyl-1,4-diazepan-1-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate 1-Methylhomopiperazine (2.00 g, 17.5 mmol) and DIPEA (3.0 mL, 18.4 mmol) were dissolved in DMF (25 mL). 2-bromethanol (1.3 mL, 18.4 mmol) was added slowly over 5 minutes. The reaction mixture was stirred at 100° C. for 2 hours and then at room temperature for 48 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (-300 mL) and then washed sequentially with 1M aq Na₂CO₃ solution (5*200 mL), dried (MgSO₄) and concentrated in vacuo to give 2-(4-methylhomopiperazin-1-yl)ethanol (2.77 g, 100%) as a brown oil which was used without further purification. Analytical LCMS: (System C, R_T=0.33 min), ES⁺: 159.2 [MH]⁺. 2-(4-methylhomopiperazin-1-yl)ethanol from the previous step (2.77 g, 17.5 mmol) was dissolved in DCM (25 mL) and cooled to 0° C. NMM (2.00 mL, 18.4 mmol) and p-nitrophenyl chloroformate (3.71 g, 18.4 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. A solution of 4-(4-methylphenyl)piperazine dihydrochloride (2.84 g, 11.4 mmol) and DIPEA (5.50 mL, 33.3 mmol) in DMF (40 mL) was then added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1 M aq Na₂CO₃ solution (5*200 mL), dried (MgSO₄) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluding with DCM, followed by a 85:15 mixture of DCM:MeOH) followed by reverse phase HPLC (Advanced Chromatography Technologies ACE-122-1030 RP silica 100*30 mm column, packed with Ace 5 C8 (5 μm), Pore Size 100 ?, 30 mL/min, gradient of actonitrile in water, with 0.1% trifluoroacetic acid in each solvent, 8-38%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K₂CO₃ for 20 minutes, filtered and concentrated in vacuo to give 2-(4-methyl-1,4-diazepan-1-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (184 mg, 3.0%) as a pale yellow oil. Analytical HPLC: purity 98.1% (System A, R_T=3.50 min), Analytical LCMS: purity 95.8% (System A, R_T=3.96 min), ES⁺: 361.2 [MH]⁺; HRMS calcd for C₂₀H₃₂N₄O₂: 360.2525, found 360.2542.

References:

US2009/281087,2009,A1 Location in patent:Page/Page column 21