Process for the production of cephalosporines
AssigneeSandoz Ltd.
InventorsGerd Ascher, Johannes Ludescher, Hubert Sturm
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Abstract
The invention relates to a new, economical and simple process for the production of 3-vinylcephalosporin compounds of formula ##STR1## wherein R.sub.1 and R.sub.2 may be the same or different and denote hydrogen or an organic radical.
Claims11
In a process for the production of a 3-vinyl-cephalosporin derivative of formula I ##STR10## wherein R.sub.1 and R.sub.2 are the same or different and denote hydrogen, or a 3-vinyl-cephalosporin substituent selected from an alkyl group, alkenyl group, lower alkynyl group, lower cycloalkyl radical, (lower cycloalkyl)-lower alkyl radical, aryl radical, aralkyl radical, heterocycle radical, and heterocyclic alkyl radical or R.sub.1 and R.sub.2 form part of a 3-vinyl-cephalosporin ring system, by means of a Wittig reaction comprising the steps of
- i) reacting a compound of formula II ##STR11## wherein R is a protecting group, with a compound of formula VII of VIII ##STR12## where R.sub.4 is a lower alkyl or an aryl group, to produce a compound of formula III ##STR13## where X is --P(R.sub.4).sub.3 I or --P(O)(OR.sub.4).sub.2 and R and R.sub.4 are as defined above;
- ii) reacting the compound of formula III with a base to produce a compound of formula IV ##STR14## where R is as defined above and is X.sup.+ --P(R.sub.4).sub.3 or --P(O)(OR.sub.4).sub.2 Y.sup.+, where R.sub.4 is as defined above and Y is an alkali metal cation or the protonated form of a strong organic base;
- and
- iii) reacting the compound of formula IV with a compound of formula V ##STR15## where R.sub.1 and R.sub.2 are as defined above, the improvement which comprises reacting a silyl protected compound of formula II' ##STR16## where R' is a silyl protecting group, with the compound of formula VII or VIII in step i) and following step iii) removing the protecting groups by hydrolysis or alcoholysis to produce the compound of formula I.
In a process for the production of a 3-vinyl- cephalosporin derivative of formula I ##STR17## wherein one of R.sub.1 and R.sub.2 is hydrogen and the other is i) lower alkyl, lower alkenyl, or lower alkynyl;
- ii) lower cycloalkyl, (lower cycloalkyl)-lower alkyl, aryl, (aryl)-lower alkyl, a heterocyclic group or (heterocyclyl)-lower alkyl, the ring of each of which is optionally substituted by 1 to 3 substituents selected from lower alkoxy, lower alkylthio, halogen, lower alkyl, nitro, hydroxy, acyloxy, carboxy, carbalkoxy, lower alkylcarbonyl, lower alkylsulfonyl, lower alkoxysulfonyl, amino-(lower)-alkyl amino, and acylamido;
- or
- iii) a group of formula --CH.sub.2 Z, wherein Z is:
- a) hydroxy, lower alkoxy, formyloxy, acetyloxy, lower alkylsulfonyloxy, halogen, N-mono(lower)alkylcarbamoyloxy, or N,N-di(lower)alkylcarbamoyloxy,
- b) group of formula --S(O).sub.m R.sub.9 wherein R.sub.9 is an aliphatic, araliphatic, alicyclic, aromatic or heterocyclic group, and m is 0, 1 or 2, or
- c) an acyclic or cyclic ammonium group, by means of a Wittig reaction comprising the steps of
- i) reacting a compound of formula II ##STR18## wherein R is a protecting group for a Wittig reaction, with a compound of formula VII of VIII ##STR19## where R.sub.4 is a lower alkyl or an aryl group, to produce a compound of formula III ##STR20## where X is --P(R.sub.4).sub.3 I or --P(O) (OR.sub.4).sub.2 and R and R.sub.4 are as defined above;
- ii) reacting the compound of formula III with a base to produce a compound of formula IV ##STR21## where R is as defined above and X.sup.+ is --P.sup.+ (R.sub.4).sub.3 or --P(O) (OR.sub.4).sub.2 Y.sup.+, where R.sub.4 is as defined above and Y is an alkali metal cation or the protonated form of a strong organic base;
- and
- iii) reacting the compound of formula IV with a compound of formula V ##STR22## where R.sub.1 and R.sub.2 are as defined above, the improvement which comprises reacting a silyl protected compound of formula II' ##STR23## where R' is a silyl protecting group, with the compound of formula VII or VIII in step i) and following step iii) removing the protecting groups by hydrolysis or alcoholysis to produce the compound of formula I.
Dependencies are inferred from the claim text.