N-Benzyloxycarbonyl-L-lysinyl-L-proline synthesis

Yield:-

Reaction Conditions:

with trifluoroacetic acid at 20; for 1 h;

Steps:

4

As illustrated in Scheme VI, L-lysine reacts with N benzyloxycarbonyloxy-5-norborene-2,3-dicarboximide to provide N6- (benzyloxycarbonyl)-L-lysine (1). The N2-AMINO group is protected with TERT- butoxycarbonyl using di-tert-butyl dicarbonate to give the fully protected L-lysine (2), which condenses with L-proline TERT-BUTYL ester in the presence of N, N1- DICYCLOHEXYLCARBODIIMIDE to generate N-[N2-(TERT-BUTOXYCARBONYL)-N6- (BENZYLOXYCARBONYL) -L-LYSYL]-L-PROLINE TERT-BUTYL ESTER (3). THE TERT- butoxycarbonyl and tert-butyl ester protecting groups in compound (3) can be Scheme VI 0 NHz O Ph^O''NH J X f O 0 J H2N COOH 1 1 A o 1 lao pu nu JL o Ph O NH 1 0lolo N (OCC) 0 L A 1/'-' . 0 po H 0I'N COOH O H O O--f- 3 g TFA, 1 h, r. t. 0 0'in Ph^0I'NH Ph"0"NH J ho . O-N I vHCOOH 5 COOH N N N? OOH HzN H O O COOH COOH. p-N /6 1. 30-32% HBr/AcOH 2. 2% pyridine-H20 NH2 COOL COOL _ O COOH . O-N N 7 removed by treating compound (3) with trifluoroacetic acid providing N- [N6- (BENZYLOXYCARBONYL)-L-LYSYL]-L-PROLINE (4). Reductive coupling of (4) with 2- OXO-4- (2-OXY-1, 1,3, 3-tetramethyl-2, 3-DIHYDRO-1 H-ISOINDOL-5-YL) BUTYRIC acid (5) from Scheme 2 using sodium cyanoborohydride yields N-{N2-[L (S)-CARBOXY-3-(2- oxy-1,1, 3,3-tetramethyl-2, 3-DIHYDRO-1 H-ISOINDOL-5-YL) PROPYL]-N6-BENZYLOXYCARBO NYL-L-LYSYL}-L-PROLINE (6). Removal of the benzyloxycarbonyl group is achieved by treating compound (6) with 30-32% HBr in glacial acetic acid and then 2% pyridine/H20 solution generating the final product N-{N2-[L (S)-CARBOXY-3-(2- oxy-1,1, 3,3-tetramethyl-2, 3-DIHYDRO-1 H-isoindol-5-yl) propyl]-L-lysyl}-L-proline (7). The nitroxide (5), 2-oxo-4- (2-oxy-1, 1, 3,3-tetramethyl-2, 3-DIHYDRO-1H- isoindol-5-yl) butyric acid, may be synthesized by the method in Scheme 2:

References:

WO2004/50084,2004,A2 Location in patent:Page/Page column 61-63