Intermediates for and synthesis of 3-methylene cephams

Details Intermediates for and synthesis of 3-methylene cephams Intermediates for and synthesis of 3-methylene cephams

2001-12-31

2004-01-27

Berch, Mark L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S222000, C540S226000, C540S228000, C540S229000, C540S230000, C540S359000

Reexamination Certificate

active

06683176

ABSTRACT:

BACKGROUND OF THE INVENTION
Since the early 1940's penicillins, and more recently cephalosporins, have been utilized in man's fight against bacterial infections. These two classes of molecules were the first effective treatments for life threatening infections. Over the past 50 years a tremendous effort has been expended by the scientific community to develop increasingly effective forms of these antibiotics. This effort has led to the identification of specific molecules of great importance to the global medical community. Cefaclor and cephalexin are two examples of cephalosporin antibiotics that have been developed through this process. Despite years of continuing research on new antibiotics, many penicillins and cephalosporins are still widely utilized in the every day fight against pathogenic bacteria.
The primary drawbacks associated with cephalosporins relate to the difficulty and expense of their synthetic production. Several of these important compounds are derived through the synthetic transformation of a penicillin substrate which is itself acquired through a fermentation process. Many steps in the conversion of penicillins to cephalosporins are typically performed using reagents which pose a number of health and environmental risks. In addition, these reagents present economic disadvantages of high outright cost as well as a high cost associated with disposal of the generated waste. These factors significantly affect the overall cost of producing cephalosporin antibiotics.
The present invention relates to novel processes for the preparation of 3-methylenecephams. The present invention utilizes specific catalysts and novel intermediates which have a member of advantages over the analogous procedures known in the art. These catalysts are typically utilized in a less than stoichiometric amount, which may also be recovered and reused, thereby allowing for lower material costs as well as significantly lower waste disposal costs. These two important features combine to lower the overall production cost of 3-methylenecephams and some novel starting materials even eliminate the need for catalysts at all. More specifically, the present invention relates in part to the intramolecular cyclization of penicillin sulfoxide derived monocyclic azetidinone derivatives either thermally or with metal salt catalysts.
SUMMARY OF THE INVENTION
The present invention is directed to a process of preparing compounds of the formula I:
said process comprising the step of reacting a compound of the formula II;
with a catalyst of the formula III in an inert solvent;
wherein:
M is Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi, or In;
E is O[SO
2
(C
1
-C
6
polyfluoroalkyl)], N[SO
2
(C
1
-C
6
polyfluoroalkyl)]
2
, or C[SO
2
(C
1
-C
6
polyfluoroalkyl)]
3
;
x is the common oxidation state of the metal M;
y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
R is a carboxylic acid protecting group;
R′ is hydrogen or a carboxylic acid protecting group;
R
1
is a group of the formula;
R
2
is C
2
-C
4
alkenylene, C
2
-C
4
alkylene, 1,2-phenylene, or 1,2-cyclohexenylene;
R
2
′ is C
1
-C
3
alkyl, C
1
-C
6
haloalkyl, C
1
-C
3
alkoxy, or 2,2,2-trichloroethoxy;
R
3
is hydrogen, C
1
-C
3
alkyl, halomethyl, cyanomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, 4-methoxybenzyloxy, phenyl, substituted phenyl, a group of the formula R
0
—(Q)
m
—CH
2
—, a heteroarylmethyl group of the formula R″CH
2
—, or a substituted arylalkyl group of the formula
R
0
is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or 1,4-cyclohexyldienyl;
R″ is 2-furyl, 3-furyl, 2-thiazolyl, or 5-isoxazolyl;
m is 0 or 1,
Q is O or S;
W is protected hydroxy, or protected amino;
Y is hydrogen, acetyl, or nitroso;
X is chloro, bromo, —OR
4
, —SR
5
, or —NR
6
R
7
wherein: (a) R
6
is hydrogen and R
7
is hydrogen, phenyl, substituted phenyl, or —NHR
8
; or wherein (b) R
6
is —COOR
9
or —COR
9
and R
7
is —NH—COOR
9
or —NH—COR
9
; or wherein (c) R
6
, R
7
, and the nitrogen to which each is attached combine to form an imido group of the formula
R
4
is hydrogen, C
1
-C
10
alkyl, (C
1
-C
3
alkyl)aryl, C
1
-C
6
haloalkyl, or —COR
10
;
R
5
is C
1
-C
6
alkyl, phenyl, substituted phenyl, (C
1
-C
3
alkyl)phenyl, or (C
1
-C
3
alkyl)substituted phenyl;
R
8
is aminocarbonyl, C
1
-C
3
alkylaminocarbonyl, C
1
-C
3
alkoxycarbonyl, C
1
-C
3
alkylcarbonyl, or tosyl;
R
9
is C
1
-C
6
alkyl, or phenyl;
R
10
is C
1
-C
6
alkyl, C
1
-C
6
polyfluoroalkyl, C
3
-C
6
cycloalkyl, adamantyl, phenyl, substituted phenyl, (C
1
-C
3
alkyl)phenyl, or (C
1
-C
3
alkyl)substituted phenyl, or a group of the formula
Z is solid polymer support; and
Z
1
is one or two groups independently selected from the group consisting of hydrogen, halo, hydroxy, protected hydroxy, nitro, cyano, trifluoromethyl, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy.
The present invention is also directed towards the novel compounds of Formula IIA below:
R is a carboxylic acid protecting group;
R
1
is a group of the formula;
R
2
is C
2
-C
4
alkenylene, C
2
-C
4
alkylene, 1,2-phenylene, or 1,2-cyclohexenylene;
R
2
′ is C
1
-C
3
alkyl, C
1
-C
6
haloalkyl, C
1
-C
3
alkoxy, or 2,2,2-trichloroethoxy;
R
3
is hydrogen, C
1
-C
3
alkyl, halomethyl, cyanomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, 4-methoxybenzyloxy, phenyl, substituted phenyl, a group of the formula R
0
—(Q)
m
—CH
2
—, a heteroarylmethyl group of the formula R″CH
2
—, or a substituted arylalkyl group of the formula
R
0
is phenyl, substituted phenyl, 2-thienyl, 3-thienyl, or 1,4-cyclohexyldienyl;
R″ is 2-furyl, 3-furyl, 2-thiazolyl, or 5-isoxazolyl;
m is 0 or 1,
Q is O or S;
W is protected hydroxy, or protected amino;
Y is hydrogen, acetyl, or nitroso;
R
10
is C
1
-C
6
alkyl, C
1
-C
6
polyfluoroalkyl, C
3
-C
6
cycloalkyl, adamantyl, phenyl, substituted phenyl, (C
1
-C
3
alkyl)phenyl, diphenylmethyl, or (C
1
-C
3
alkyl)substituted phenyl, or a group of the formula
Z is solid polymer support; and
Z
1
is one or two groups independently selected from the group consisting of hydrogen, halo, hydroxy, protected hydroxy, nitro, cyano, trifluoromethyl, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy.
The present invention is also directed towards a process of preparing a compound of Formula I, as described above, wherein said process comprises heating a compound of the Formula IIA, as described above, to a temperature of about 40° C. to about 200° C.
DETAILED DESCRIPTION OF THE INVENTION
The term “C
1
-C
10
alkyl” as used herein includes both straight and branched alkyl groups; including but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like. Included within the definition of “C
1
-C
10
alkyl” are also the groups “C
1
-C
8
alkyl”, “C
1
-C
6
alkyl”, “C
1
-C
5
alkyl”, “C
1
-C
4
alkyl”, and “C
1
-C
3
alkyl”.
The term “alkoxy” as used herein designates an alkyl group attached through an oxygen atom. Examples include but are not intended to be limited to methoxy, ethoxy, pentoxy, and the like.
The term “C
1
-C
3
alkoxycarbonyl” as used herein includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and isopropoxycarbonyl.
The term “C
1
-C
6
polyfluoroalkyl” as used herein includes both straight and branched alkyl groups; including but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, which are substituted with from 2-13 fluorine atoms. The number of fluorine atoms will never exceed the available valency of the alkyl group. For example, a methyl group could be substituted with 2 or 3 fluorine atoms, an ethyl group with 2-5 fluorine atoms, and a propyl group with 2-7 fluorine atoms. Substitution can occur independently at any of the available cites.
The term “halo” as used herein includes fluoro, bromo, chloro, and iodo.
The ter

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