Process for preparing cephalosporin intermediates

Details Process for preparing cephalosporin intermediates Process for preparing cephalosporin intermediates

1987-03-23

1989-09-19

Rizzo, Nicholas S.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540225, C07D50146, A61K 31545

Patent

active

048682942

DESCRIPTION:

BRIEF SUMMARY
SUMMARY OF THE INVENTION

This invention relates to temperature stable, crystalline salts of a cephalosporin intermediate having the formula ##STR2## wherein X is HI or HCl, which are substantially free of the .DELTA..sup.2 isomer, and which are convertible into broad spectrum cephalosporin antibiotics without the necessity of a carboxyl group deblocking step. This invention also relates to methods for making salts of Formula I, to intermediates in the preparation of the salts of Formula I, and to a method of converting a salt of Formula I into broad spectrum cephalosporin antibiotics.


DESCRIPTION OF THE PRIOR ART

Aburaki, et al., U.S. Pat. No. 4,406,899, issued Sept. 27, 1983 discloses compounds of the formulae ##STR3## wherein Ph is phenyl, and ##STR4## or an N-silyl derivative thereof, wherein B.sup.1 is hydrogen or a conventional carboxyl-protecting group. These compounds are not exemplified in the patent, but are disclosed by structural formulae only, as intermediates in an alternate reaction scheme for the preparation of certain cephalosporins (by acylation and then deblocking of the protected carboxyl group). The reaction scheme actually exemplified did not utilize these compounds (and also required deblocking of the protected carboxyl group as the final step). Each of the final products of U.S. Pat. No. 4,406,899 required a chromatographic purification step to separate the mixture of .DELTA..sup.2 and .DELTA..sup.3 isomers which were produced.
Barry E. Ayres, U.S. Pat. No. 4,168,309, issued Sept. 18, 1989 discloses compounds of the formula ##STR5## wherein R'" is a carboxyl-protecting group; R.sup.1, taken together with the carbon atom to which it is attached, forms an optionally substituted saturated or partially saturated 4-10 membered heterocyclic ring which may contain one or more further hetero-atoms selected from O, N and S; the dotted line indicating a ceph-2-em or a ceph-3-em compound; and X.sup.31 representing an anion; and acid addition salts or an N-silylated derivative thereof.
These compounds are not exemplified but are disclosed by structural formula only as intermediates in an alternative synthesis of certain cephalosporins (by acylation and then deblocking of the protected carboxyl group). The reaction scheme actually exemplified did not utilize these compounds (and also required deblocking of the protected carboxyl group as a final step).
The use of blocked carboxyl groups in the processes of the above two patents has the disadvantage of requiring deblocking after acylating whereby acyl group is lost in the deblocking step due to less than 100% yield in the deblocking step.
Derek Walker et al., U.S. Pat. No. 4,223,135, issued Sept. 16, 1980 discloses compounds of the formula ##STR6## in which B is chloro, methoxy or --CH.sub.2 E, E is hydrogen, ##STR7## in which Z is an optionally substituted 5- or 6- membered heterocyclic ring containing 2-4 N atoms and zero or one atom selected from O and S, the S atom of --SZ being connected to a carbon atom of the heterocyclic ring Z, and A is trimethylsilyl or an easily cleavable ester-protecting group.
The compounds are prepared by adding dry carbon dioxide to a solution of a compound of the formula ##STR8## wherein A and B are as described above, in an inert organic solvent which is preferably methylene chloride.
U.S. Pat. No. 4,316,017, which is a continuation-in-part of a division of U.S. Pat. No. 4,223,135, has a substantially identical disclosure.
William H. W. Lunn, U.S. Pat. No. 4,336,253, issued June 22, 1982 discloses compounds of the formula ##STR9## and their preparation by reaction of a compound of the formula ##STR10## with a silylating agent such as trimethylsilylacetamide, bistrimethylsilylacetamide, or the like, to produce a compound of the formula ##STR11## reacting the compound of formula III with trimethylsilyl iodide to produce a compound of the formula ##STR12## and then reacting the compound Formula IV with ##STR13## to produce a compound of Formula I.
Solvents suitable for the reactions to produce Compounds III and I

REFERENCES:
patent: 4168309 (1979-09-01), Aynes
patent: 4223135 (1980-09-01), Walker et al.
patent: 4316017 (1982-02-01), Walker et al.
patent: 4336253 (1982-06-01), Lunn et al.
patent: 4379787 (1983-04-01), Lunn et al.
patent: 4382931 (1983-05-01), Lunn et al.
patent: 4382932 (1983-05-01), Lunn et al.
patent: 4406899 (1983-09-01), Aburaki et al.
patent: 4667028 (1987-05-01), Schwab et al.
patent: 4703118 (1987-10-01), Lord et al.

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