Patent RU-2317297-C2 (RU)
Title: Method for preparing 6-alkylidenepenem derivatives
IPC: C07D519/06
Filed: 2003-04-30
Granted: 2008-02-20
Abstract: 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 R 2 , heteroaryl substituted optionally with one or two R 2 , and so on; R represents H, (C 1 -C 6 )-alkyl, (C 5 -C 6 )-cycloalkyl or -CHR 3 -OCO-(C 1 -C 6 )-alkyl or salt; R 2  represents hydrogen atom, optionally substituted (C 1 -C 6 )-alkyl, optionally substituted (C 2 -C 6 )-alkenyl, and so on; R 3  represents hydrogen atom, (C 1 -C 6 )-alkyl, (C 5 -C 6 )-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: (R 8 )Cl or (R 8 ) 2 O or with tetrahalogen methane of the formula: C(X 1 ) 4  and triphenylphosphine wherein R 8  represents alkyl-SO 2 , aryl-SO 2 , alkyl-CO or aryl-CO; X 1  represents Br, J or Cl atoms to form intermediate compound of the formula ( 19 ):   wherein R 9  represents X 1  or -OR 8 , 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