Patent AU-2004212029-B2 (AU)
Title: Method for the production of bicyclic aromatic amino acids and intermediate products thereof
Inventor: WIESNER MATTHIAS
IPC: C07D413/12
Filed: 2004-01-14
Granted: 2010-01-21
Abstract: A multi-stage process is claimed for preparing 2-amino-3-(2-(substituted ethyl)-3-oxo-3,4-dihydro-2H-benz-(1,4)-oxazin-6-yl)-propionic acid derivatives (I), starting from 5-oxo-tetrahydrofuran-2-carboxylic acid and based on construction and cyclization of new 2-(4-(2-amino-2-carboxy-ethyl)-2-nitrophenoxy)-pentanedicarboxylate diesters (VII). Preparation of benzoxazinones of formula (I) or their derivatives, solvates or stereoisomers involves: (1) reacting 5-oxo-tetrahydrofuran-2-carboxylic acid with a benzylating or alkylating agent of formula R 7>-L (II) to give a hydroxy-glutaric acid diester of formula R 7>OCO-CH 2CH 2CH(OH)-COOR 7>(III); (2) optionally reacting (III) with a sulfonating agent of formula R 8>-L (IV) to give an O-sulfonyl derivative of formula R 7>OCO-CH 2CH 2CH(OR 8>)-COOR 7>(V); (3) reacting (III) or (V) with a nitrophenol derivative of formula (VI) to give an O-(nitrophenoxy) compound of formula (VII); (4) converting (VII) into benzoxazinyl-propionic acid derivative of formula (VIII); (5) reacting (VIII) (optionally after conversion of the COOH group into COL') with R 5>-H (IX) or R 6>-NH 2(X) to give (I); and (6) optionally interconverting groups R 2>in the product by reaction of (I; R 2>= H) with L-R 1>0>, L-CO-R 1>0>, L-COOR 6>, L-COOR 1>0>, R 1>0>-NCO or R 1>0>-SO 2L. [Image] R 1>H, 1-6C alkyl or benzyl; R 2>R 1>0>, COR 1>0>, COOR 6>, COOR 1>0>, CONHR 1>0>, SO 2R 6>or SO 2R 1>0>; R 3>H or 1-6C alkyl; R 4>H, halo, OA, NHR 1>0>, N(R 1>0>) 2, -NH-acyl, -O-acyl, CN, NO 2, OR 1>0>, SR 1>0>, R 2>or CONHR 1>0>; R 5>H, NH 2, C(=NH)NH 2or NHC(=NH)NH 2(where primary amino groups are optionally protected or optionally substituted (os) by 1-3 of R 1>0>, COR 1>0>, COOR 1>0>or SO 2R 1>0>); or R 6>; X : direct bond or NH; R 6>mono- or bicyclic, saturated, unsaturated or aromatic heterocycle containing 1-4 N, O and/or S atoms (os by 1-3 of halo, A, COA, CN, COOH, COOA, CONHA, NO 2, =NH or O); R 9>H, halo, OA, NHA, NAA', NH-acyl, O-acyl, CN, NO 2, SA, SOA, SO 2A, SO 2Ph' or SO 3H; R 1>0>H, A, Ar or 7-14C aralkylene; A, A' : H; or 1-15C alkyl or 3-15C cycloalkyl (both os by 1-3 R 6>and optionally having 1-3 CH 2groups replaced by N, O and/or S); Ar : mono- or bicyclic aromatic ring system (os by 1-3 of A and/or R 9>and optionally containing 1-4 of N, O and/or S); Ph' : phenyl (os by 1-3 A); R 7>benzyl or 1-6C alkyl; L : Cl, Br, I or free of functionally modified OH; R 8>1-6C alkylsulfonyl or 6-10C arylsulfonyl; L' : as for L but not free OH. Independent claims are included for: (a) the intermediates (VII) and their salts, solvates and stereoisomers as new compounds; and (b) the preparation of (VII) by the first three stages of the above process. ACTIVITY : Thrombolytic; Anticoagulant; Cardiant; Antiarteriosclerotic; Antiinflammatory; Cerebroprotective; Antianginal; Cytostatic; Osteopathic; Ophthalmological; Antidiabetic; Antirheumatic; Antiarthritic; Antiulcer; Antipsoriatic; Vasotropic; Virucide; Antibacterial; Fungicide; Nephrotropic; Vulnerary. MECHANISM OF ACTION : Integrin inhibitor; Vitronectin receptor antagonist; Angiogenesis inhibitor.