EXAMPLE 2
(1) (2)
(iii), (iv)
(l-Aminomethyl-cyclobutyl)-acetic acid hydrochloride
Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeNO2, Bu4N+F"; (iii) H2, Ni; (iv) HCl
Synthesis of Cyclobutylidene-acetic acid ethyl ester (2)
NaH
(60%) dispersion in oil, 1.80 g, 44.94 mmol) was suspended in dry
tetrahydrofuran (80 mL) and cooled to 0°C. Triethylphosphonoacetate
(9.33 mL, 47.08 mmol) was added and the mixture stirred at 0°C for 15
minutes. Cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was then
added and the mixture allowed to warm to room temperature. After 2
hours, the mixture was partitioned between diethyl ether (200 mL) and
water (150 mL). The organic phase was separated, washed with brine,
dried (MgSO4), and the solvent removed in vacuo at 600 mm Hg. The
residue was purified by flash chromatography (silica, ethyl acetate
:pentane 1 : 19) to give 5.81 g (96%) of (2) as a colorless oil. iH NMR,
400 MHz (CDCI3): δ 1.27 (3H, t, J=6Hz), 2.09 (2H, m), 2.82 (2H, m),
3.15 (2H, m), 4.14 (2H, q, J = 6 Hz), 5.58 (IH, s).
MS (ES+) m/e: 141 ([MH+], 100%). IR (film) v cm"1: 1088, 1189, 1336, 1673, 1716,2926. Synthesis of (l-Nitromethyl-cyclobutyl)-acetic acid ethyl ester (3)
The
unsaturated ester (2) (5.79 g, 41.4 mmol) was dissolved in
tetrahydrofuran (20 mL) and stirred at 70°C with nitromethane (4.67 mL,
86.4 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 55
mL, 55.0 mmol). After 18 hours, the mixture was cooled to room
temperature, diluted with ethyl acetate (150 mL), and washed with 2N HCl
(60 mL) followed by brine (100 mL). The organic phase was collected,
dried (MgSO4), and the solvent removed in vacuo. The residue was
purified by flash chromatography (silica, ethyl acetate:heptane 1 :1) to
give 4.34 g (52%) of a clear oil. !H NMR 400 MHz (CDC13): δ 1.27 (3H, t, J = 6 Hz), 1.96-2.20 (6H, m), 2.71
(2H, s), 4.15 (2H, q, J = 6 Hz), 4.71 (2H, s).
MS (ES+) m/e: 202 ([MH+], 100%).
IR Cfiln- v cm-1 : 1189, 1378, 1549, 1732, 2984.
Synthesis
of (l-Aminomethyl-cyclobutyl)-acetic acid hydrochloride (4) The
nitroester (3) (2.095 g, 10.4 mmol) was dissolved in methanol
(50
mL) and shaken over Raney nickel catalyst under an atmosphere of
hydrogen (45 psi) at 30°C. After 6 hours, the catalyst was removed by
filtration through celite. The solvent was removed in vacuo to give 1.53
g of a pale yellow oil which was used without purification. The oil was
dissolved in 1 ,4-dioxane (5 mL) and 6N HCl (15 mL) and heated to
reflux. After 5 hours, the mixture was cooled to room temperature,
diluted with water (20 mL), and washed with dichloromethane (3 x 30 mL).
The aqueous phase was collected and the solvent removed in vacuo. The
residue was triturated with ethyl acetate to give 1.35 g (72%) of a
white solid after collection and drying. !H NMR 400 MHz (de-DMSO): δ 1.80-2.03 (6H, m), 2.59 (2H, s), 3.02 (2H, s),
8.04 (3H, br s), 12.28 (IH, br s).
MS (ES+) m/e: 144 ([MH-HC1J+, 100%). Microanalysis calculated for C7H14NO2CI:
C, 46.80%; H, 7.86%; N, 7.80%. Found: C, 46.45%; H, 7.98%; N, 7.71%.
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