Hydrochloric Acid → (1R,2S)-2-(cyclopropylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester

Temperature

25 °C

Sodium acetate (0.423 g, 5.16 mmol), powdered 4 Å molecular sieves (0.60 g), cyclopropanecarboxaldehyde (0.193 mL, 2.58 mmol) and sodium cyanoborohydride (0.324 mg, 5.16 mmol) were added sequentially to a solution of (1R,2S)-2-amino-cyclopentanecarboxylic acid ethyl ester hydrochloride (prepared as described in Example 28b, 0.500 g, 2.58 mmol) in methanol (15 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, then was acidified to pH=2 by the addition of 1.0 M aqueous hydrochloric acid solution. After stirring for 5 min at 25° C., the mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (3×50 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 0-40% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(cyclopropylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester (0.101 g, 0.478 mmol, 18%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.00-0.07 (m, 2H), 0.38-0.43 (m, 2H), 0.84-0.91 (m, 1H), 1.23 (t, 3H, J=7.2 Hz), 1.48-1.61 (m, 2H), 1.76-1.87 (m, 3H), 1.91-1.98 (m, 1H), 2.29-2.34 (m, 1H), 2.46-2.51 (m, 1H), 2.84-2.90 (m, 1H), 3.20-3.26 (m, 1H), 3.63 (s, 1H), 4.09 (q, 2H, J=7.0 Hz). LC-MS (ESI) calcd for C12H21NO2 211.16, found 212.4 [M+H+].

1. stirringAfter stirring for 5 min at 25° C.
2. customthe mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (3×50 mL)
3. washThe organic layers were washed with saturated aqueous brine solution (100 mL)
4. dry with materialdried over sodium sulfate
5. filtrationfiltered
6. concentrationwere concentrated in vacuo
7. customThe residue was purified by flash column chromatography (Analogix SuperFlash Column; 0-40% ethyl acetate in hexanes)

ORD record

ord-823676bfd9ab43cb8d6d3cd13b3c2e2e

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582626B2