Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-19
2002-01-22
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S216000, C548S221000, C548S225000, C548S230000, C548S551000, C544S071000, C544S097000
Reexamination Certificate
active
06340751
ABSTRACT:
FIELD OF THE INVENTION
The present application is based on Japanese Application No. Hei. 10-223724, which is incorporated herein by reference.
The present invention relates to a process for the preparation of a 4-substituted azetidinone derivative which is important as an intermediate for the synthesis of a carbapenem compound.
BACKGROUND OF THE INVENTION
Since a 1-&bgr;-methylcarbapenem derivative exhibits excellent antibacterial activity against a wide range of bacteria including Gram positive bacteria and Gram negative bacteria and has excellent in vivo stability, it has attracted attentions as an antibacterial agent. For the synthesis of this 1-&bgr;-methylcarbapenem derivative, various processes are known. In particular, an azetidinone compound having a &bgr;-methyl group at the 1′-position of the 4-side chain, said compound being represented by the following formula (A):
wherein R
1
represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group, is an especially important intermediate for the synthesis of the derivative. It has so far been synthesized by a 1′-deprotonation of the acetic acid residue at the 4-position by using a strong base and then introducing a methyl group [
Heterocycles
, 21, 29(1984)]. By the above-described process, however, it is difficult to stereo-selectively prepare a compound having a &bgr;-configuration at the 1′-position of the 4-side chain. Various processes are therefore proposed now.
For example, Fuentes, et al. has proposed a process in which a 4-acetoxyazetidinone compound and a certain propionamide derivative are reacted in the presence of a reagent complex composed of a certain base and a Lewis acid, for example, tin triflate—ethylpiperidine—zinc bromide or diethylborane triflate—diisopropylethylamine—zinc bromide [L. M. Fuentes, et al.,
J. Am. Chem. Soc
., 108, 4675(1986), JP-A-61-275267 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”)]. A similar process has been proposed by Nagao, et al. [Y. Nagao, et al.,
J. Am. Chem. Soc
., 108, 4673(1986), JP-A-63-170377] and also by Hara, et al. [WO 93/13064, JP-A-7-70116]. Iwasaki, et al. has proposed a process in which reaction is performed in the presence of a predetermined base [JP-A-7-97381].
The above-described process using a reagent complex of a base and a Lewis acid however lacks in environmental harmony because as the Lewis acid, that containing an expensive boron reagent or a heavy metal is employed. It is therefore impossible to deny the industrial disadvantage of this process. In addition, the use of a predetermined base, for example, a base typically employed in this is reaction such as sodium or lithium brings about a marked decrease in the yield under the reaction conditions at around room temperature. Very low temperature conditions at −60° C. or lower become essential, which also makes the process industrially disadvantageous.
With a view to overcoming the above-described problems of the conventional process and to finding a process permitting the selective preparation of an intermediate for the synthesis of a carbapenem antibacterial agent having a desired 1′-&bgr; configuration, the present inventors have proceeded with various investigations. As a result, it has been found that a compound having a desired 1′-&bgr; configuration can be prepared only by reacting in the presence of a predetermined magnesium compound without using a reagent complex of a base and a Lewis acid as described in the conventional process or without using a base requiring predetermined low-temperature reaction conditions.
SUMMARY OF THE INVENTION
In the present invention, there is provided a process for selectively preparing a desired 1′-&bgr; configuration, which comprises reacting an azetidinone compound and a predetermined alkanamide compound in the presence of a magnesium compound without using a reagent complex composed of a base and a Lewis acid or a base which requires predetermined low-temperature reaction conditions.
Described specifically, the present invention provides a process for the preparation of a 4-substituted azetidinone derivative represented by the following formula (IV):
wherein R represents a hydrogen atom or a protecting group for N, R
1
represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group, R
2
represents a hydrogen atom or a lower C
1-4
alkyl group, R
3
represents (1) a C
1-12
alkyl group, (2) a C
2-5
alkenyl group, (3) a C
1-6
organosilyl group, (4) a phenyl group which may be substituted by a lower C
1-4
alkyl group, a lower C
1-4
alkoxy group, a nitro group or a halogen atom, (5) a C
6-13
aralkyl group which may be substituted by a lower C
1-4
alkyl group, (6) a 5- to 8-membered alicyclic group which may be substituted by a lower C
1-4
alkyl group or (7) a naphthyl group, and R
4
represents an electron withdrawing group; or R
3
and R
4
may form a heterocyclic ring together with the adjacent nitrogen atom,
which comprises reacting an azetidinone derivative represented by the following formula (I):
wherein R represents a hydrogen atom or a protecting group for N, R
1
has the same meaning as described above, Z represents an eliminative group,
with an amide compound represented by the following formula (II):
wherein R
2
, R
3
and R
4
have the same meanings as described above,
in the presence of a magnesium compound represented by the following formula (III):
MgR
5
R
6
(III)
wherein R
5
represents (1) a C
1-12
alkyl group, (2) a C
2-5
alkenyl group, (3) a 5- to 8-membered alicyclic group which may be substituted by a lower C
1-4
alkyl group, (4) a phenyl group which may be substituted by a lower C
1-4
alkyl group, a lower C
1-4
alkoxy group or a halogen atom, or (5) a benzyl group which may be substituted by a lower C
1-4
alkyl group, a lower C
1-4
alkoxy group or a halogen atom, and R
6
represents (1) a halogen atom, (2) a methanesulfonyloxy group, (3) a benzenesulfonyloxy group, (4) a p-toluenesulfonyloxy group, (5) a trifluoromethanesulfonyloxy group, (6) an acetoxy group which may be substituted by a halogen atom or a cyano group, or (7) an OR
7
group wherein R
7
represents a lower C
1-4
alkyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will next be described more specifically.
In the formula (I) of the present invention, R represents a hydrogen atom or a protecting group for N, R
1
represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group and Z represents an eliminative group.
Specific examples of the protecting group for N include organosilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylhexylsilyl and dimethylthexylsilyl, a benzyl group, a p-nitrobenzyl group, a p-nitrobenzoylmethyl group, a benzhydryl group, a p-methoxybenzyl group and a 2,4-dimethoxybenzyl group.
Specific examples of the protecting group for the hydroxyl group which is a substituent of the lower alkyl group represented by R
1
include organosilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylhexylsilyl, trimethylsilyl and dimethylthexylsilyl; oxycarbonyl groups such as p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and allyloxycarbonyl; an acetyl group; a triphenylmethyl group; a benzoyl group and a tetrahydropyranyl group.
Here, the lower alkyl group of R
1
means a lower C
1-4
alkyl group and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl, with the ethyl being preferred.
Preferred specific examples of R
1
include 1-tert-butyldimethylsilyloxyethyl, 1-tert-butyldiphenylsilyloxyethyl, 1-triethylsilyloxyethyl, 1-triisopropylsilyloxyethyl, 1-trimethylsilyloxyethyl, 1-dimethyl
Matsumoto Takaji
Miura Takashi
Murayama Toshiyuki
Saito Takao
Berch Mark L.
Sughrue & Mion, PLLC
Takasago International Corporation
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