Cycloalkylamino Acid Derivatives
a technology of cycloalkylamino acid and derivatives, which is applied in the field of new carboxycycloalkylamino derivatives, can solve the problems of affecting angiogenesis, proliferation, and interference with tumor neovascularization, and achieves the effects of preventing neovascularization, preventing neovascularization, and preventing neovascularization
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preparation 1
[0508]
1A. 3-Oxo-cyclobutanecarboxylic acid ethyl ester
[0509]A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80% yield) as an oil.
[0510]1H NMR (400 MHz, DMSO-d4) δ1.23 (t, 3H), 3.30 (m, 5H), 4.14 (q, 2H).
1B. 3-Dibenzylamino-cyclobutanecarboxylic acid ethyl ester
[0511]Dibenzyl amine (0.150 g, 0.77 mmol) and sodium triacetoxyborohydride (0.300 g, 1.4 mmol) were added to a solution of 3-oxo-cyclobutanecarboxylic acid ethyl ester (0.100 g, 0.700 mmol) and acetic acid / THF (10%, 4.4 mL), stirred at room temperature for 72 hours and concentrated in vacuo. The resulting residue was dissolved in ...
preparation 2
[0517]
2A. Ethyl 4-isobutylbenzoate
[0518]Triethylorthoacetate (15.4 mL, 84.2 mmol) was added slowly to a solution of isobutyl benzoic acid (5.0 g, 28.1 mmol) and toluene (60 mL) at room temperature. The resulting heterogeneous solution was heated to 115° C. and stirred for 24 hours. The reaction mixture was cooled to room temperature and quenched with 1N HCl (60 mL). The organic layer was separated, washed with saturated NaHCO3 (1×30 mL) and brine (1×30 mL), dried (MgSO4), filtered and concentrated in vacuo to obtain the title compound (5.59 g, 97% yield) as a clear oil.
[0519]ESI-MS: 207.3 (MH+); HPLC Rf: 2.9 minutes (HPLC method 1); HPLC purity: 95%.
2B. 4-Isobutylbenzohydrazide
[0520]Hydrazine monohydrate (2.43 g, 48.5 mmol) was added slowly to a heterogeneous solution of ethyl 4-isobutylbenzoate (5.0 g, 24.2 mmol) and H2O and stirred at reflux for 12 hours. The reaction mixture was cooled to room temperature and filtered. The yellow solid was washed with cold water (1×20 mL) and dri...
preparation 3
[0524]
3A. 5-Chloro-2-(methylsulfonyl)pyrimidine-4-carboxylic acid
[0525]A stirred mixture of 5-chloro-2-(methylthio)pyrimidine-4-carboxylic acid (8.0 g, 39 mmol) and acetic acid (30 mL) was treated dropwise with 25% aqueous hydrogen peroxide (11.5 mL, 85 mmol) over 1 hour and stirred at room temperature for four days. The reaction mixture was filtered and the solid was washed with cold water (2×50 mL) and dried to afford the title compound (5.8 g, 63% yield) as a white solid.
[0526]1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 2.71 (s, 3H).
3B. 5-Chloro-2-(methylsulfonyl)pyrimidine
[0527]5-Chloro-2-(methylsulfonyl)pyrimidine-4-carboxylic acid (5.7 g, 24 mmol) was refluxed in anisole (8 mL) until the evolution of carbon dioxide ceased. The reaction mixture was cooled to room temperature and filtered. The solid was washed with light petroleum ether (1×50 mL) and dried to obtain the title compound (4.10 g, 88% yield) as a light orange solid.
[0528]ESI-MS: 193.5 (MH+); HPLC Rf: 1.8 minutes (HPLC m...
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