Detail of "3082-64-2"

Reference

Synthesis of enantiomerically pure amino-substituted fused bicyclic rings

Synthesis of enantiomerically pure amino-substituted fused bicyclic rings. McEachern, Ernest J.; Bridger, Gary J.; Skupinska, Krystyna A.; Skerlj, Renato T. (Anormed Inc., Can.). PCT Int. Appl. WO 2003022785 A2 20 Mar 2003, 85 pp. DESIGNATED STATES: W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM; RW: AT, BE, BF, BJ, CF, CG, CH, CI, CM, CY, DE, DK, ES, FI, FR, GA, GB, GR, IE, IT, LU, MC, ML, MR, NE, NL, PT, SE, SN, TD, TG, TR. (English). (World Intellectual Property Organization). CODEN: PIXXD2. CLASS: ICM: C07C. APPLICATION: WO 2002-US29372 12 Sep 2002. PRIORITY: US 2001-PV323201 12 Sep 2001. DOCUMENT TYPE: Patent CA Section: 27 (Heterocyclic Compounds (One Hetero Atom)) This invention describes various processes for synthesis and resoln. of racemic amino-substituted fused bicyclic ring systems (shown as I; variables defined below), primarily 5,6,7,8-tetrahydroquinolines (shown as II; e.g. 8-amino-2-methyl-5,6,7,8-tetrahydroquinoline) and 5,6,7,8-tetrahydroisoquinolines (e.g. 5-amino-5,6,7,8-tetrahydroisoquinoline). One process uses selective hydrogenation of an amino-substituted fused bicyclic arom. 3082-64-2 is the cas registry number of certain chemical which is used as reagents here. ring system; for example, 8-amino-5,6,7,8-tetrahydroquinoline was obtained in 2 steps (100, 54 and 91% yields) from 8-aminoquinoline via intermediates 8-acetylaminoquinoline and 8-acetylamino-5,6,7,8-tetrahydroquinoline using PtO2/trifluoroacetic acid/H2 for the hydrogenation. An alternative process preps. the racemic amino-substituted fused bicyclic ring system via nitrosation; for example, 5,6,7,8-tetrahydroquinoline was converted with LDA/MTBE at -30° followed by isoamyl nitrite to 8-hydroxyimino-5,6,7,8-tetrahydroquinoline (75%) that was hydrogenated using H2/Pd/C/MeOH to give 8-amino-5,6,7,8-tetrahydroquinoline (100%). The present invention describes the enzymic resoln. of a racemic mixt. to produce the (R)- and (S)- forms of amino-substituted fused bicyclic rings as well as a racemization process to recycle the unpreferred enantiomer. For example, 8-amino-5,6,7,8-tetrahydroquinoline was half reacted with EtOAc in iPr2O at 60° in the presence of Candida antarctica lipase to give (R)-(-)-N-(5,6,7,8-tetrahydroquinolin-8-yl)acetamide (97% ee) and unreacted (S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline (96% ee). The amine could be racemized at 150° in a sealed tube under Ar with 87% yield. Further provided by this invention is an asym. synthesis of the (R)- or (S)- enantiomer of primary amino-substituted fused bicyclic ring systems. For example, (R)-(-)-8-amino-5,6,7,8-tetrahydroquinoline (98% ee) was obtained in 4 steps (82, 95, 93 and 59% yields) starting from 8-hydroxy-5,6,7,8-tetrahydroquinoline via intermediates 6,7-dihydro-5H-quinolin-8-one, (R)-(-)-(6,7-dihydro-5H-quinolin-8-ylidene)(1-phenylethyl)amine, and (-)-((1R)-1-Phenylethyl)-(8-(R)-5,6,7,8-tetrahydroquinolin-8-yl)amine using (R)-(+)-a-methylbenzylamine as chiral auxiliary. For I: ring A is a heteroarom. 5- or 6-membered ring, P is N, S or O; ring B is a 5- or 6-membered cycloalkyl or heterocycloalkyl; NH2 is located at a position on ring B; and R2 is located at any other H position on the fused bicyclic ring; m is 0-4; R2 = halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxy, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an arom. group and a heterocyclic group. The variable definitions for II and the isoquinolines are the same as for I. .