Patent ID: 6489471
Filing Date: 2002-12-03
Classification: A61P,C07D,Y02P

Abstract:
A process of synthesizing a carbapenem compound of formula 6: is disclosed wherein:R represents H or methyl, COOP* represents H, negative charge (which is balanced by a positively charged Râ€² group or pharmaceutically acceptable counterion) or a carboxy protecting group; P represents hydrogen, hydroxyl, or hydroxy-protecting group; and each R1 is independently selected from: â€”R*; â€”Q; hydrogen; halo; â€”CN; â€”NO2; â€”NRaRb; â€”ORc; â€”SRc; â€”C(O)NRaRb; â€”C(O)ORh; â€”S(O)Rc; â€”SO2Rc; â€”SO2NRaRb; â€”NRaSO2Rb; â€”C(O)Ra; â€”OC(O)Ra; â€”OC(O)NRaRb; â€”NRaC(O)NRbRc; â€”NRaCO2Rh; â€”OCO2Rh; â€”NRaC(O)Rb; â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and â€”C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups, with the proviso that at least one R group contains a positive charge and no more than two positive charges are present on the molecule, said positive charge(s) balanced by a negatively charged counterion and/or P* when it is a negative charge; each Ra, Rb and Rc independently represents hydrogen, â€”R*, â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or â€”C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; or Ra and Rb taken together with any intervening atoms represent a 4-6 membered saturated heterocyclic ring optionally interrupted by one or more of O, S, NRc, with Rc as defined above, or â€”C(O)â€”, said ring being unsubstituted or substituted with one to four Ri groups; or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated heterocyclic ring optionally interrupted by one to three of O, S, NRa, with Ra as defined above, or â€”C(O)â€”, said ring being unsubstituted or substituted with one to four Ri groups; each Rd independently represents halo; â€”CN; â€”NO2; â€”NReRf; â€”ORg; â€”SRg; â€”CONReRf; â€”COORg; â€”SORg; â€”SO2Rg; â€”SO2NReRf; â€”NReSO2Rf; â€”CORe; â€”NReCORf; â€”OCORe; â€”OCONReRf; â€”NReCONRfRg; â€”NReCO2Rh; â€”OCO2Rh; â€”C(NRe)NRfRg; â€”NReC(NH)NRfRg; â€”NReC(NRf)Rg; â€”R* or â€”Q; Re, Rf and Rg represent hydrogen; â€”R*; â€”C16 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated heterocyclic ring optionally interrupted by one to three of O, S, â€”C(O)â€”or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups; each Ri independently represents halo; â€”CN; â€”NO2; phenyl; â€”NHSO2Rh; â€”ORh, â€”SRh; â€”N(Rh)2; â€”N+(Rh)3; â€”C(O)N(Rh)2; â€”SO2N(Rh)2; heteroaryl; heteroarylium; â€”CO2Rh; â€”C(O)Rh; â€”OCORh; â€”NHCORh; guanidinyl; carbamimidoyl or ureido; each Rh independently represents hydrogen, a â€”C1-6 straight or branched-chain alkyl group, a â€”C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated heterocyclic ring, optionally interrupted by one or two of O, S, SO2, â€”C(O)â€”, NH and NCH3; Q is selected from the group consisting of: â€ƒwherein: a and b are 1, 2 or 3; Lâˆ’ is a pharmaceutically acceptable counterion; &agr; represents O, S or NRs; &bgr;, &dgr;, &lgr;, &mgr; and &sgr; represent CRt, N or N+Rs, provided that no more than one of &bgr;, &dgr;, &lgr;, &mgr; and &sgr; is N+Rs; R* is selected from the group consisting of: â€ƒwherein: d represents O, S or NRk; e, g, x, y and z represent CRm, N or N+Rk, provided that no more than one of e, g, x, y and z in any given structure represents N+Rk; Rk represents hydrogen; â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or â€”(CH2)nQ where n=1, 2 or 3 and Q is as previously defined; each Rm independently represents a member selected from the group consisting of: hydrogen; halo; â€”CN; â€”NO2; â€”NRnRo; â€”ORn; â€”SRn; â€”CONRnRo; â€”COORh; â€”SORn; â€”SO2Rn; â€”SO2NRnRo; â€”NRnSO2Ro; â€”CORn; â€”NRnCORo; â€”OCORn; â€”OCONRnRo; â€”NRnCO2Rh; â€”NRnCONRoRh; â€”OCO2Rh; â€”CNRnNRoRh;â€”NRnCNHNRoRh; â€”NRnC(NRo)Rh; â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; â€”C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and â€”(CH2)nQ where n and Q are as defined above; Rn and Ro represent hydrogen, phenyl; â€”C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; each Rs independently represents hydrogen; phenyl or â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; each Rtindependently represents hydrogen; halo; phenyl; â€”CN; â€”NO2; â€”NRuRv; â€”ORu; â€”SRu; â€”CONRuRv; â€”COORh; â€”SORu; â€”SO2Ru; â€”SO2NRuRv; â€”NRuSO2Rv; â€”CORu; â€”NRuCORv; â€”OCORu; â€”OCONRuRv; â€”NRuCO2Rv; â€”NRuCONRvRw; â€”OCO2Rv; â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; Ru and Rv represent hydrogen or â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated heterocyclic ring optionally interrupted by one or more of O, S, NR w [w] or â€”C(O)â€”, said ring being unsubstituted or substituted with one to four Ri groups; each Rwindependently represents hydrogen; â€”C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four RI groups; C3-6 cycloalkyl optionally substituted with one to four Ri groups; phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 Ri groups; or Rh and Rw taken together with any intervening atoms represent a 5-6 membered saturated heterocyclic ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3; Rx represents hydrogen or a C1-8 straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or â€”C(O)â€”, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRw, SORw, SO2Rw, NRhRw, N+(Rh)2Rw, â€”C(O)â€”Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups; Ry and Rz represent hydrogen; phenyl; â€”C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NRw, N+RhRwor â€”C(O)â€”; or Rx and Ry together with any intervening atoms represent a 4-6 membered saturated heterocyclic ring optionally interrupted by O, S, SO2, NRw, N+RhRwor â€”C(O)â€”, unsubstituted or substituted with 1-4 Ri groups, and when Rx and Ry together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered heterocyclic ring fused to the ring represented by Rx and Ry taken together, optionally interrupted by O, S, NRwor â€”C(O)â€”, said rings being unsubstituted or substituted with one to four Ri groups; comprising reacting a carbapenem of formula 4â€²: with a compound of formula 7: wherein R, R1, P and P* are as previously defined and R2 represents C(O)ORâ€², C(O)Râ€² or P(O)(ORâ€³)2, wherein Râ€² and Râ€³ independently represent C1-6 alkyl, aryl or benzyl, in the presence of a palladium catalyst selected from the group consisting of Pd(OAc)2, Pd(PPh3)4 PdCl2, PdCl2(PPh3)2, PdCl2(CH3CN)2 or Pd2DBA(dibenzylidene acetone)3, to produce a compound of formula 6.