Patent FR-2796641-A1 (FR)
Title: Preparation of new fused ethano-perhydroisoindole optically active derivatives, for use e.g. as antitumor agent, includes enzymatic preparation of optically active cyclohexenone derivative avoiding the need for a resolution stage
Inventor: MAILLIET PATRICK
IPC: A61P35/00
Filed: 1999-07-22
Abstract: Preparation of fused ethano-perhydroisoindole derivatives (I) in optical isomer form involves   various new optically active intermediates, including an ethano-perhydroisoindole derivative (III), an isoindoline derivative (IX), an optically active cyclohexenone derivative (X') and an isoindolinone derivative (XIII). Preparation of fused ethano-perhydroisoindole derivatives of formula (I), in optical isomer form, or their salts comprises: (1) preparing an optically active cyclohexenone derivative of formula (X') from a racemic analog of formula (X) using an enzyme; (2) converting (X') into an isoindoline derivative of formula (IX) by reaction with an amino-protected N-trialkylsilylmethyl-N-alkoxymethylamine; and (3) converting (IX) into (I) by either:  (i) (i) cyclizing to give an ethano-perhydroisoindole derivative of formula (III), coupling the side-chain and optionally interconverting R; or (ii) coupling the side-chain to give an isoindolinone derivative of formula (XIII), cyclizing to give a ethano-perhydroisoindole derivative and optionally interconverting R.    A  = fused phenyl ring (optionally substituted (os) by 1-2 of halo, alkyl, OH, alkoxy, alkylcarbonyloxy, alkylthio, alkylsulfonyl, alkylsulfinyl, NH2, mono- or dialkylamino, alkoxycarbonylamino, COOH, alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, CHO, alkylcarbonyl, CN or CF3); or a fused mono-, bi- or tricyclic ring system in which each ring is 4-7 membered, provided that at least one ring contains 1-4 heteroatom(s);  Ar  = phenyl (os by one or more of halo, alkyl, 2-4C alkenyl, OH, SH, alkylthio, alkylsulfonyl, alkylsulfinyl, NH2, mono- or dialkylamino, CHO, alkylcarbonyl, COOH, alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, CN, CF3, alkoxy or perhaloalkoxy); phenyl fused with a 4-7 membered heterocycle containing one or more heteroatom(s); an aromatic or non-aromatic polycyclic group; a C-bonded 5-12C heterocyclic group containing one or more heteroatom(s) (os by one or more of halo, alkyl, 2-4C alkenyl, OH, alkoxy, SH, alkylthio, alkylsulfonyl, alkylsulfinyl, NH2, mono- or dialkylamino, CHO, alkylcarbonyl, COOH, alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, CN or CF3);  R  = -(CH2)m-X1-(CH2)n-Z (optionally having one or more CH2 groups substituted by COOH, alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, NH2 or mono- or dialkylamino);  X1 = direct bond, O or S;  m  = 0 or 1;  n  = 0-2;  Z  = COOH, COOR6, P(O)(OR9)2, NHCOT or pyridinio-methyl (having a counter-anion such as CF3SO3<->);  R6  = 1-3C alkyl;  R7, R9  = H or 1-6C alkyl;  R8  = H, OH, arylsulfonyl (os by one or more of halo, alkyl and alkoxy), 5-7 membered heterocyclyl containing one or more heteroatom(s), NH2 (os by 1 or 2 of alkyl, aryl (os by one or more of alkyl and alkoxy), 5-7 membered heterocyclyl containing one or more heteroatom(s) and arylcarbonyl (os by one or more of alkyl and alkoxy)), 1-6C alkoxy (os by Ph), 1-6C alkyl (os by one or more of NH2, mono- or dialkylamino, OH, alkoxy, SH, alkylthio, alkoxycarbonyl, COOH, CN or os 5-12 membered mono- or polycyclic aryl (optionally containing heteroatom(s)), phenyl (os by one or more of halo, OH, NH2, CF3, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, alkylcarbonyl or alkoxycarbonyl or 2-4C, CONH2, mono- or di-(1-8C alkyl)-carbamoyl or CHO) or 1- or 2-naphthyl;  T  = H or 1-6C alkyl (os by NH2, COOH, alkoxycarbonyl, OH, alkoxy, SH or alkylthio);  R1, R2  = H or halo; alkyl or alkylamino (both os by dialkylamino or by saturated 5- or 6-membered N-heterocyclyl); or alkylthio or alkoxycarbonyl; or  R1 + R2 (in ortho position)  = heterocycle containing 1-2 of O and N (os by halo, alkyl or alkoxy);  R5  = H, alkyl or alkylthio;  X  = O, S, NH, CO, CH2, alkene-1,1-diyl (e.g. C=CH2) or 3-6C cycloalkane-1,1-diyl;  Y  = O or S; and G  = amino-protecting group; unless specified otherwise alkyl moieties have 1-4C and heteroatoms are N, O or S. Independent claims are included for:  (a) intermediates (III), (IX), (X'), (XIII) and (XV) (all as optical isomers, specifically in the dextrorotatory for (III) and the levorotatory form for the others) as new compounds; (b) the preparation of (X') by treating the racemate (X) with an enzyme in a mixture of a hydrocarbon solvent and an aqueous solution; and (c) (I) (in optical isomer form) and their salts when prepared by the present process.