Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-29
2002-05-07
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06384214
ABSTRACT:
BACKGROUND OF THE INVENTION
Certain &Dgr;2 double bond cephalosporin derivatives are known to be valuable intermediates for the manufacture of pharmacologically useful cephalosporins as described in EP-A-620 225 and in EP-A-849 269. In a known process these cephalosporin derivatives are prepared from a phosphonium salt and a &Dgr;2 double bond aldehyde in the presence of a base such as 1,2-butyleneoxide or triethylamine in an inert solvent to yield the &Dgr;3-isomer of the cephalosporin derivative. This is due to the fact that the &Dgr;2 double bond is very sensitive towards bases in solution and readily migrates to the 3-position. The formation of the &Dgr;3-reaction product necessitates the correction of the position of the double bond to the desired 2-position by a two-step redox sequence. In the known process this is effected by oxidation to the corresponding sulfoxide with hydrogen peroxide or a peracid and deoxygenation thereof with phosphorus tribromide. These reagents, in particular the latter, are corrosive and dangerous to use on a large scale.
Efforts to obtain these cephalosporin derivatives directly via reaction of the phosphonium salt and &Dgr;2 aldehyde are hampered by the sensitivity of &Dgr;2 cephalosporins to bases in solution. Therefore, it would be useful to develop a process in which this isomerization does not occur.
SUMMARY OF THE INVENTION
The present invention is concerned with a process for producing compounds of formula
wherein
R
1
is an amino protecting group,
R
2
is a carboxy protecting group, and
R is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl and the heterocyclyl moieties being unsubstituted or substituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl
which comprises treating a phosphonium salt of formula
in a toluene reaction mixture with a base, said base being present in a molar amount which is less than the molar amount of said phosphonium salt, to form an ylide of formula
coupling the ylide of formula III with an aldehyde of formula
by adding to the reaction mixture a solution of the aldehyde of formula IV in a polar solvent at a temperature of from about −80° C. to about 0° C.; to produce the compound of formula I.
Preferably, the process involves the manufacture of cephalosporin derivatives of the formula
wherein
R
1
is an amino protecting group,
R
2
is a carboxy protecting group, and
R is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl and the heterocyclyl moieties being unsubstituted or substituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and allyloxycarbonyl which is substituted on a ring nitrogen of pyrrolidinyl.
The process is characterized in that it comprises converting a phosphonium salt of the formula
wherein R is as above and Ph represents phenyl,
in toluene by treatment with a base into the corresponding ylide of the formula
wherein R and Ph are as above,
and reacting same with a solution in a polar solvent of an aldehyde of the formula
wherein R
1
and R
2
are as above,
at a temperature of from about −80° C. to about 0° C., the phosphonium salt II, base and aldehyde IV being employed in a molar ratio of about 1.15:1.1:1.0 to 1.3:1.25:1.0. The molar amount of base is less than that of the phosphonium salt.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, this invention is directed to a method of producing a compound of formula
wherein
R
1
is an amino protecting group,
R
2
is a carboxy protecting group, and
R
2
is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl and the heterocyclyl moieties being unsubstituted or substituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and allyloxycarbonyl which is substituted on a ring nitrogen of pyrrolidinyl
which comprises treating a phosphonium salt of formula
in a toluene reaction mixture with a base, said base being present in a molar amount which is less than the molar amount of said phosphonium salt, to to form an ylide of formula
coupling the ylide of formula III to the aldehyde of formula
by adding to the reaction mixture a solution of the aldehyde of formula IV in a polar solvent at a temperature of from about −80° C. to about 0° C. (preferably about −80° C. to about −60° C., most preferably about −70° C.); wherein said base, ylide, and aldehyde are present in the reaction mixture during the formation of the compound of formula I in molar ratio of about 1.15:1.1:1.0 to 1.3:1.25:1.0, and preferably about 1.2:1.15:1.0, to produce the compound of formula I. It is important that the molar amount of base is less than that of the phosphonium salt.
A preferred polar solvent is tetrahydrofuran. Preferred bases include aqueous sodium hydroxide and potassium tert.butoxide in tetrahydrofuran.
When the base is potassium tert.butoxide in tetrahydrofuran, it is preferable that the toluene reaction mixture further comprises methylene chloride and the polar solvent is tetrahydrofuran, in the preferred weight ratio of about 2:1:1 to 5:2:1. Under these conditions, a preferred R is N-substituted 3-pyrrolidinyl, especially N-allyloxycarbonyl-3-pyrrolidinyl.
Preferred aldehydes of formula IV are diphenylmethyl (6R,7R)-7-(1-tert-butoxyformamido)-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate and 4-methoxybenzyl (6R,7R)-7-phenylacetylamino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
It is preferred that R is selected from substituted lower alkyl (such as 2,2,2-trifluoroethyl), or unsubstituted or substituted cycloalkyl (such as cyclopropyl or cyclopropylmethyl). Heterocyclyl is also a preferred R, such as 5 or 6-membered rings containing one or two heteroatoms (preferably nitrogen), especially substituted heterocyclyl such as N-substituted 3-pyrrolidinyl (such as N-allyloxycarbonyl-3-pyrrolidinyl).
As used herein, the terms “lower alkyl” and “optionally substituted lower alkyl” refer to both straight and branched chain saturated hydrocarbon groups having 1 to 8, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like. The lower alkyl groups can be unsubstituted or substituted by at least one substituent such as halogen. Preferred substituents are fluoro, examples of substituted lower alkyl are trifluoromethyl, 2,2,2-trifluoroethyl, perfluorohexyl and the like.
By term “lower alkoxy” is meant an ether group wherein alkyl is as defined above. Examples are methoxy, ethoxy, propyloxy and the like.
By the term “cycloalkyl” is meant a 3-7 membered saturated carbocyclic ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. “Cycloalkyl-lower alkyl” is an alkyl group as defined above with an attached cycloalkyl ring. Preferred cycloalkyl-lower alkyls are for example cyclopropylmethyl and cyclopropylethyl. By the term “cycloalkenyl” is meant a 4-7 membered carbocyclic ring having at least one olefinic double bond, e.g. cyclopentenyl.
As used herein, “lower alkenyl” refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one
Spurr Paul
Trickes Georg
Basilea Pharmaceutica AG
Berch Mark L.
Ebel Eileen M.
Johnston George W.
Rocha-Tramaloni Patricia S.
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