Aluminium lithium hydride → HCID 67492507, compound

2-Bromo-2-methylpropionic acid ethyl ester (155 μL, 1.06 mmol) was added to a solution of potassium carbonate (145 mg, 1.05 mmol) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in anhydrous acetonitrile (1 mL) The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 98:2) to give (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a pale brown oil. To a solution of (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (1 mmol) in anhydrous THF (5 mL) at 0° C., a solution of LiAlH4 (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a brown oil (168 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 3.37 (bs, 1H); 3.31 (d, J=10.2 Hz, 1H); 3.21 (d, J=10.2 Hz, 1H); 3.15-3.00 (m, 2H); 2.81-2.61 (m, 2H); 2.45 (s, 2H); 1.76 (d, J=10.0 Hz, 1H); 1.56 (d, J=10.0 Hz, 1H); 1.46 (t, J=5.02 Hz, 1H); 1.03 (s, 3H) and 1.00 (s, 2H).

1. washwashed with MeOH before the desired product
2. washwas eluted
3. customThe product was collected
4. concentrationconcentrated in vacuo

ORD record

ord-e674e3564b77421aa2213796f47c60a8

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08173650B2