Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-15
2002-05-28
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S302000
Reexamination Certificate
active
06395894
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for synthesizing 1-&bgr;-methyl-2-hydroxymethyl carbapenem intermediates. Generally the carbapenems are substituted at the 2-position. The intermediate compounds are included as well.
European applications 0330108, 0102239, 0212404, 0695753 and 0476649 disclose methods for synthesizing various antibiotic derivatives.
Many of the carbapenems are useful against gram positive microorganisms, especially methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant
Staphylococcus epidermidis
(MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
SUMMARY OF THE INVENTION
The invention describes a short and high yielding synthesis of protected 1-&bgr;-methyl-2-hydroxymethyl substituted carbapenems as key intermediates for the synthesis of anti-MRSA carbapenem antibiotics. The synthesis involves a highly diastereoselective addition of a titanium, zirconium or hafnium enolate of a suitably protected 1-hydroxy-2-butanone derivative with 4-acyl-2-azetidinone. Using this enolate, the resulting derivatized 2-azetidinone product is obtained largely as a single diastereomer rather than a mixture. Additionally, the two chiral centers which are produced are of the correct absolute stereochemical configuration for subsequent synthesis of 1-&bgr;-methyl-2-hydroxymethyl substituted carbapenems.
In one aspect of the invention, a process of synthesizing a compound of formula 2:
is disclosed wherein R
1
represents H or a suitable protecting group for an alcohol; R
2
represents a benzyl, C
1-6
alkyl or aryl; Y represents C
1-3
alkyl, O, NH or S; and X represents O, NH, or S comprising reacting a compound of formula 1:
wherein R
1
is described above and R
4
represents C
1-15
alkyl, aryl or C
1-6
aralkyl;
with a compound of formula 3:
wherein R
2
, X and Y are as previously defined in the presence of WZ
4
and an amine to produce a compound of formula 2, wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for making protected 1-&bgr;-methyl-2-hydroxymethyl substituted carbapenems which are key intermediates in the synthesis of anti-MRSA carbapenem antibiotics (such as those disclosed in U.S. Ser. No. 08/825,786 filed on Apr. 8, 1997 now U.S. Pat. No. 5,756,725, the teachings of which are hereby incorporated by reference). The intermediates can be readily coupled to a wide range of functional groups (see U.S. Ser. No. 08/825,786 now U.S. Pat. No. 5,756,725).
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term “alkyl” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from R
d
and R
i
, as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”.
Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
The term “alkenyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The term “alkynyl” refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 5 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
Aryl also refer to heteroaryl, which is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a polycyclic aromatic group having 8 to 16 atoms, containing at least one heteroatom, O, S, S(O), SO
2
or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole and the like.
As used herein, “aralkyl” is intended to mean an aryl or heteroaralkyl moiety, as defined above, attached through a C
1-6
alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphtylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2-quinolinylmethy, 2-imidazolylmethyl and the like.
Examples of polycyclic heteroaromatics include benzopyrans, benzofurans, benzopyrroles, benzimidazoles, benzothiazoles, quinolines, purines, isoquinolines, benzopyrimidines, dibenzofurans, dibenzothiophenes, 1,8-naphthosultams.
The term “heterocycle” (heterocyclyl) refers to a 5-16 membered cycloalkyl group (nonaromatic) with 1-4 rings, in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by heteroatoms.
The term “heteroatom” means O, S, S(O), S(O)
2
or N, selected on an independent basis.
Halogen and “halo” refer to bromine, chlorine, fluorine and iodine.
When a group is termed “protected”, such as R
1
, R
5
and the like, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al.
Protective Groups in Organic Synthesis
Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
In some of the compounds of the present invention, R
1
and R
5
represent alcohol and carboxyl protecting groups, respectively. Likewise, Y may represent a protecting group for X, which in turn represents O or N. These groups are generally removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
Examples of carboxyl protecting groups R
5
include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl (pNB), 4-pyridylmethyl an
Pye Philip J.
Reider Paul J.
Rossen Kai
Volante Ralph P.
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
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