FIELD: organic chemistry, chemical technology, antibiotics.
SUBSTANCE: invention relates to a method for synthesis of compounds of the formula (I): wherein one of substitutes A or B means hydrogen atom (H) and another one means aryl substituted optionally with one or two R2, heteroaryl substituted optionally with one or two R2, and so on; R represents H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl or -CHR3-OCO-(C1-C6)-alkyl or salt; R2 represents hydrogen atom, optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, and so on; R3 represents hydrogen atom, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Method for synthesis of these compounds involves the following steps: (a) condensation of substituted aldehyde of the formula: (A'-CHO) (17) wherein A' represents A, such as given above when B represents hydrogen atom; or B, such as given above when A represents hydrogen with derivative of 6-bromopenem of the formula (16):
wherein R represents p-nitrobenzyl in the presence of Lewis acid and a weak base at low temperature that results to formation of intermediate aldol product of the formula (18):
; (b) interaction of intermediate compound of the formula (18) with chloroanhydride or acid anhydride of the formula: (R8)Cl or (R8)2O or with tetrahalogen methane of the formula: C(X1)4 and triphenylphosphine wherein R8 represents alkyl-SO2, aryl-SO2, alkyl-CO or aryl-CO; X1 represents Br, J or Cl atoms to form intermediate compound of the formula (19):
wherein R9 represents X1 or -OR8, and conversion of intermediate compound of the formula (19) to the end compound of the formula (I). Also, invention relates to 4-nitrobenzyl-(5R,6S)-6-bromopenem-3-carboxylate of the formula (16) and to a method for its synthesis. Method involves the following steps: (A) (i) interaction of 6-aminopenicillanic acid with hydrobromic acid in organic solvent and water to form 6-bromopenicillanic acid of the formula (21):
and its conversion to p-nitrobenzyl-6-bromopenicillanate of the formula (22):
wherein R represents p-nitrobenzyl by interaction with 4-nitrobenzyl bromide in the presence of a base in organic solvent; (B) oxidation of compound of the formula (22) to form p-nitrobenzyl-6-bromopenicillanate-1-oxide of the formula (23) given in the invention description; (C) boiling compound of the formula (23) with 2-mercaptobenzothiazole in aromatic solvent to form 4-nirobenzyl-(2R)-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-3-enoate of the formula (24) given in the invention description; (D) dissolving compound of the formula (24) in organic solvent and interaction with an organic tertiary base to form 4-nitrobenzyl-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (25) given in the invention description; (E) conversion of compound of the formula (25) to 4-nitrobenzyl-2-[(3S,4R)-3-bromo-4-formylthio-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (26) given in the invention description as result of interaction of with organic acid in aromatic organic medium in the presence of a mixture acetic anhydride/organic tertiary base and trialkyl- or triarylphosphine in the range of temperature from about -10°C to about -30°C, and (F) passing ozonized oxygen through solution of compound of the formula (26) in organic solvent for 3-4 h at temperature from -70°C to -90°C and the following the intramolecular cyclization reaction using a phosphite reagent. Invention provides the increased yield and economy method for synthesis of derivatives of 6-alkylidenepenem.
EFFECT: improved method of synthesis.
41 cl, 2 tbl, 42 ex
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Authors
Dates
2008-02-20—Published
2003-04-30—Filed