Process for synthesizing carbapenem intermediates

Details Process for synthesizing carbapenem intermediates Process for synthesizing carbapenem intermediates

1999-06-04

2001-02-27

Berch, Mark L. (Department: 1611)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06194568

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention described herein relates to a process for synthesizing 1&bgr;-methyl-2-hydroxymethyl carbapenem intermediate compounds that are useful in the synthesis of carbapenems. 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. Likewise, U.S. Pat. No. 4,350,631 issued to Christensen, et al. on Sep. 21, 1982 and in U.S. Pat. No. 4,994,568 issued to Christensen on Feb. 19, 1991 also discloses various antibiotic derivatives and methods of making.
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 an improved process for synthesizing 1&bgr;-methyl-2-hydroxymethyl substituted carbapenems as key intermediates for the synthesis of anti-MRSA carbapenem antibiotics. Previously, intermediates of 1p-methyl-2-hydroxymethyl substituted carbapenems were prepared by a Stille-type cross-coupling reaction using BuSnCH
2
OH and HMPA (see U.S. Ser. No. 60/056967, filed Aug. 26, 1997, Merck case number 19988PV). This new synthesis eliminates the use of Bu
3
SnCH
2
OH and HMPA. The novel intermediates are also within the scope of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for making 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. Pat. No. 5,756,725, issued May 26, 1998, 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. Pat. No. 5,756,725).
In one aspect of the invention, a process of synthesizing a compound of formula 3:
is disclosed wherein
R
1
represents H or a suitable protecting group for an alcohol; R
2
represents H or methyl; and R
5
represents a carboxy protecting group
comprising adding a compound of formula 2:
wherein
R
1
, R
2
and R
5
are described above and R and R′ independently represent H, alkyl, O-alkyl, S-alkyl, N-alkyl, O-aryl, S-aryl, N-aryl, or aryl; said alkyl or aryl optionally substituted with 1-3 groups of N, S, O, and halo;
to a solvent in the presence of a catalyst to produce a compound 3.
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 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 specie 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 “O-alkyl” refers to an oxygen atom attached to an alkyl such as an alkoxy.
The term “N-alkyl” refers to a nitrogen atom attached to an alkyl.
The term “S-alkyl” refers to an sulfur atom attached to an alkyl.
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.
The term “S-aryl” refers to an sulfur atom attached to an aryl.
The term “N-aryl” refers to an nitrogen atom attached to an aryl.
The term “Oaryl” refers to an oxygen atom attached to an aryl.
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, N.Y. (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. 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 and t-butyl, preferably pNB.
Examples of suitable alcohol protecting groups R
1
include trialkylsilyl, diarylalkylsilyl, aryldialkylsilyl or trityl such as TMS, TES, TBDMS, carbonates and alkyl carbonates such as benzyl carbonate, benzyl ether, diarylalkylsilyl, aryldialkylsilyl and the like. Preferred R
1
groups are TMS, TES, TBDMS.
In still another aspect of the process the synthesis of a compound of formula 4:
is disclosed wherein
R
1
represents H or a suitable protecting group for an alcohol; R
2
represents H or methyl; and R
5
represents a carboxy protecting group
c

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