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Latamoxef

latamoxef sodium injection, latamoxef
Latamoxef or moxalactam is an oxacephem antibiotic usually grouped with the cephalosporins In oxacephems such as latamoxef, the sulfur atom of the cephalosporin core is replaced with an oxygen atom

Latamoxef has been associated with prolonged bleeding time, and several cases of coagulopathy, some fatal, were reported during the 1980s Latamoxef is no longer available in the United States As with other cephalosporins with a methylthiotetrazole side chain, latamoxef causes an antabuse reaction when mixed with alcohol Additionally, the methylthiotetrazole side chain inhibits γ-carboxylation of glutamic acid; this can interfere with the actions of vitamin K

It has been described as a third-generation cephalosporin

Synthesis

Oxa-substituted third generation cephalosporin antibiotic oxacephalosporin

Moxalactam synthesis: excerpt from Lednicer book 3

The benzhydrol ester of 6-Aminopenicillanic acid 6-APA is S-chlorinated and treated with base whereupon the intermediate sulfenyl chloride fragments to 2 Next, displacement with propargyl alcohol in the presence of zinc chloride gives predominanntly the stereochemistry represented by diastereoisomer 3 The side chain is protected as the phenylacetylamide; the triple bond is partially reduced with a 5% Pd-CaCO3 Lindlar catalyst and then epoxidized with mCPBA to give 4 The epoxide is opened at the least hindered end with 1-methyl-1H-tetrazole-5-thiol to put in place the future C-3 side chain and give intermediate 5 Jones oxidation followed in turn by ozonolysis reductive work-up with zinc-AcOH and reaction with SOCl2 and pyridine give halide 6 The stage is now wet for intramolecular Wittig reaction Displacement with PPh3 and Wittig olefination gives 1-oxacephem 7 Next a sequence is undertaken of side chain exchange and introduction of a 7-methoxyl group analogous to that which is present in cephamycins and gives them the enhanced beta-lactamase stability First 7 is converted to the imino chloride with PCl5 and then to the imino methyl ether with methanol and next hydrolyzed to the free amine 8 Imine formation with 3,5-di-t-butyl-4-hydroxybenzaldehyde is next carried out leading to 9 Oxidation with nickel peroxide gives iminoquinone methide 10, to which methanol is added in a conjugate sense and in the sterechemistry represented by formula 11 The imine is exchanged with Girard's reagent T to give 12, and this is acylated by a suitable protected arylmalonate, as the hemiester hemiacid chloride so as to give 11 Deblocking with aluminium chloride and anisole gives moxalactam 14

References

  1. ^ Weitekamp MR, Aber RC 1983 "Prolonged bleeding times and bleeding diathesis associated with moxalactam administration" JAMA 249 1: 69–71 doi:101001/jama249169 PMID 6217353 
  2. ^ Brown RB, Klar J, Lemeshow S, Teres D, Pastides H, Sands M 1986 "Enhanced bleeding with cefoxitin or moxalactam Statistical analysis within a defined population of 1493 patients" Arch Intern Med 146 11: 2159–64 doi:101001/archinte146112159 PMID 3778044 
  3. ^ Salem RR, McIndoe A, Matkin JA, Lidou AC, Clarke A, Wood CB June 1987 "The hematologic effects of latamoxef sodium when used as a prophylaxis during surgical treatment" Surg Gynecol Obstet 164 6: 525–9 PMID 3296254 
  4. ^ M Narisada, W Nagata, DE 2713370 ; eidem, US Patent 4,138,486 1977, 1979 both to Shionogi
  5. ^ Narisada, Masayuki; Yoshida, Tadashi; Onoue, Hiroshi; Ohtani, Mitsuaki; Okada, Tetsuo; Tsuji, Teruji; Kikkawa, Ikuo; Haga, Nobuhiro; Satoh, Hisashi; et al 1979 "Synthetic studies on β-lactam antibiotics Part 10 Synthesis of 7β--7alpha-methoxy-3-methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt 6059-S and its related 1-oxacephems" Journal of Medicinal Chemistry 22 7: 757–9 doi:101021/jm00193a001 PMID 448673 
  6. ^ Otsuka, H; Nagata, W; Yoshioka, M; Narisada, M; Yoshida, T; Harada, Y; Yamada, H 1981 "Discovery and development of moxalactam 6059-S: The chemistry and biology of 1-oxacephems" Medicinal Research Reviews 1 3: 217 doi:101002/med2610010302 PMID 6213825 
  7. ^ Narisada, Masayuki; Onoue, Hiroshi; Nagata, Wataru 1977 "Synthetic Studies on b-Lactam Antibiotics Part 5 A Synthesis of 7b-Acylamino-3-methyl-1-oxadethia-3-cephem-4-carboxylic Acids" Heterocycles 7 2: 839 doi:103987/S-1977-02-0839 


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    Latamoxef beatiful post thanks!

    29.10.2014


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