Patent TW-200403248-A (TW)
Title: Process for preparing 6-alkylidene penem derivatives
Inventor: ABE TAKAO
IPC: C07D499/897
Filed: 2003-04-29
Abstract: The present invention provides a process of making compounds of formula I, which are useful for the treatment of bacterial infection or disease. A process for the preparation of compounds of the formula I, wherein: one of A and B denotes hydrogen and the other is an aryl optionally substituted with one or two R2, heteroaryl optionally substituted with one or two R2, fused bicyclic heteroaryl optionally substituted with one or two R2, fused tricyclic heteroaryl optionally substituted with one or two R2, cycloalkyl optionally substituted with one or two R2, alkyl optionally substituted with one or two R2, alkenyl optionally substituted with one or two R2, alkynyl optionally substituted with one or two R2, saturated or partially saturated heteroaryl optionally substituted with one or two R2; R5 is H, C1-C6 alkyl, C5-C6 cycloalkyl, or CHR3OCOC1-C6alkyl; R1 is H, optionally substituted -C1-C6 alkyl, optionally substituted -aryl, optionally substituted -heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted -C3-C7 cycloalkyl, optionally substituted -C3-C6 alkenyl, optionally substituted -C3-C6 alkynyl with the proviso that both the double bond and the triple bond should not be present at the carbon atom which is directly linked to N; optionally substituted -C1-C6 per fluoro alkyl, -S(O)p optionally substituted alkyl or aryl where p is 2, optionally substituted -C=Oheteroaryl, optionally substituted -C=Oaryl, optionally substituted - C=O (C1-C6) alkyl, optionally substituted -C=O (C3-C6) cycloalkyl, optionally substituted -C=O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkyl aryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, -CONR6R7, -SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkyl aryloxyheteroaryl , optionally substituted alkyl aryloxy alkylamines, optionally substituted alkoxy carbonyl, optionally substituted aryloxy carbonyl, optionally substituted heteroaryloxy carbonyl. R3 is hydrogen, C1-C6 alkyl, C5 - C6 cycloatkyl, optionally substituted aryl, optionally substituted heteroaryl; R6 and R7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, R6 and R7 can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms such as N-R1, O, S=(O)n n=O-2; said process comprising (a) condensing an appropriately substituted aldehyde 17, wherein A is defined as above (when B is hydrogen) with 6-bromo-penem derivative of structure 16, wherein R is p-nitrobenzyl in the presence of a Lewis acid, etherate and a mild base, at low temperature to form an intermediate aldol product 18, wherein A and R are as defined above, (b) reacting intermediate 18 with an acid chloride or anhydride, (R8)Cl or (R8)2O, or with tetrahalomethane, C(X1)4, and triphenyl phosphine, to form intermediate compound 19 wherein R8 is alkylSO2, arylSO2, alkyICO, or arylCO; X1 is Br, I, or Cl; A and R are as defined above: and R9 is X1 or OR8; and (c) converting the intermediate compound 19 to the desired formula I compound by a reductive elimination process.