JPS6072893A - Aminomethyl compound, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2-aminomethylpenem compounds, processes for their production, pharmaceutical formulations containing such compounds and the use of the compounds for the production of pharmaceutical formulations or as pharmacologically active compounds. .

The present invention particularly relates to the general formula (I): [wherein R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, and R2 represents a carboxy group or a carboxy group modified with a functional group] , R3 represents an amino group, a 7mino group substituted with a lower alkyl group, a substituted methylene amino group, or a protected amino group]. The present invention relates to optical isomers of the compound of the general formula (1) having a center of chirality at R1, mixtures of these optical isomers, and salts of the compound of the general formula (I) having a salt-forming group.

Within the scope of this specification, the definitions used above and below preferably have the following definitions.

Carboxy R2 modified with functional groups is in particular an esterified carboxy group or a protected carboxy group R2' which can be decomposed under physiological conditions.

Esterified carboxy group R that can be decomposed under physiological conditions
2 protects the compound of general formula (1) from forming salts in the gastrointestinal tract when administered orally and thus prevents premature excretion, especially when the acyl group is a group of, for example, an organic carboxylic acid. is an acyloxymethoxycarbonyl group which is a lower alkanecarboxylic acid group substituted by , or an acyloxymethoxycarbonyl group in which the acyloxymethyl group forms a lactone group. Such groups are, for example, lower alkanoyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially α-amino-lower alkanoyloxymethoxycarbonyl, 4-crotonolactonyl and 4-crotonolactonyl.
-butyrolactone-4-yl group. Esterified carboxy groups degradable under physiological conditions may further include, for example,
5-indonyloxy carbonyl group, 3-phthalidyloxycarbonyl group, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl group, 1-lower alkoxy lower alkoxycarbonyl group or 2-oxo-1,3
-dioxolene-4-ylm-1-oxycarbonyl group (the 5th position of the dioxolene ring is optionally substituted with a lower alkyl group or a phenyl group).

The amino group R3 substituted with a lower alkyl group is, for example,
It is a lower alkylamino group or a di-lower alkylamino group.

In the substituted methylene amino group R3, one or two methylene groups are preferably substituted. The substituted methylene amino group has, for example, the general formula (IA): 1 / [wherein XI is hydrogen, an optionally substituted amino group,
For example, amino groups, lower alkylamino groups, di-lower alkylamino groups, lower alkylene amino groups, nitroamino groups, hydrazino groups or anilino groups, etherified droxy groups such as lower alkoxy groups or phenyl-lower alkoxy groups, etherified mercapto groups , such as lower alkylthio, optionally substituted lower alkyl, such as lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl or N, N-di-lower alkylamino-lower alkyl, lower alkenyl basis,
a phenyl group or a monocyclic heteroaryl group, such as a corresponding 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms and/or oxygen or sulfur atoms, such as a pyridyl group, such as a 2- or 4- represents a pyridyl group, a chenyl group, such as a 2-chenyl group, or a thiazolyl group, such as a 4-thiazolyl group, and X2 represents an optionally substituted amino group, such as an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower an alkyleneamino group, a cyanamino group, a hydrazino group or anilino group, an etherified hydroxy group such as a lower alkoxy group or a phenyl-lower alkoxy group, or an etherified mercapto group such as a lower alkylthio group.

In preferred groups of general formula (IA), X.

represents hydrogen, an amino group, a lower alkylamino group or a lower alkyl group, and X2 represents an amino group.

A group of general formula (IA) having a hydrogen atom in the α-position of substituent X1 and/or substituent X2, such as X.

is an amino group, a lower alkylamino group, a nitroamino group,
A group of the general formula (TA) representing a hydrazino group, an anilino group, or an optionally substituted lower alkyl group and/or in which X2 represents an amino group, a lower alkylamino group, a hydrazino group, or an anilino group is a group of the formula (I B) or (IC) may be one of the tautomeric forms of (IB) or (IC) [wherein X11 and X21 each represent a corresponding substituted or unsubstituted methylene group or imino group].

In this specification, the term "lower" used in connection with the definitions of groups and compounds means that the number of carbon atoms is 7 unless otherwise specified.
represents up to 4, preferably up to 4 groups and compounds.

The lower alkyl group R1 substituted with a hydroxy group is particularly a lower alkyl group substituted with a hydroxy group at the α-position relative to the penem ring structure, such as a 1-hydroxyprop-I-yl group, a 2-hydroxy Boudo-2-yl or especially hydroxymethyl or 1-hydroxyethyl.

A lower alkanoyloxymethoxycarbonyl group is, for example, an acetoxymethoxycarbonyl group or a pivaloyloxymethoxycarbonyl group.

α-Amino-lower alkanoyloxymethoxycarbonyl group is, for example, glycyloxymethoxycarbonyl group,
L-valyloxymethoxycarbonyl group or L-leucyloxymethoxycarbokyl group.

The 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl group is, for example, an ethoxycarbonyloxymethoxycarbonyl group or a 1-ethoxycarbonyloxyethoxycarbonyl group.

1-lower alkoxy lower alkoxycarbonyl group is
For example, methoxymethoxycarbonyl group or 1-methoxyethoxycarbonyl group.

A 2-oxo-1,3-dioxolen-4-ylmethoxy group optionally substituted in the 5-position of the dioxolene ring by a lower alkyl group or a phenyl group is particularly suitable for 5-phenyl-2-oxo-1,3-dioxolene. -4-ylmethoxy group and more particularly 5-methyl-2-oxo-1,3-
It is a dioxolen-4-ylmethoxy group.

The lower alkylamino group is, for example, a methylamino group, ethylamino group, n-propylamino group, isopropylamine group or n-butylamino group, and the di-lower alkylamino group is, for example, a dimethylamino group, a diethylamino group, a di- It is n-propylamino group or di-n-butylamino group.

A lower alkyleneamino group especially has 4 to 6 carbon chain members and is, for example, a pyrrolidino or piperidino group.

Lower alkoxy groups include, for example, methoxy group, ethoxy group,
n-propoxy group, isopropoxy group, n-butoxy group or tert-butoxy group, and phenyl-lower alkoxy group is, for example, benzyloxy group.

The lower alkylthio group is, for example, a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, or an n-propylthio group.
-butylthio group.

Lower alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl or tert-butyl.

Amino-lower alkyl groups are, for example, 2-aminoethyl or 3-aminopropyl groups.

N-lower alkylamino-lower alkyl group is, for example, 2
-methyl- or 2-ethyl-aminoethyl group, and N,N-di-lower alkylamino-lower alkyl group represents, for example, 2-dimethylaminoethyl group or 2-diethylaminoethyl group.

A lower alkenyl group is, for example, an allyl group, an n-propenyl group or an isopropenyl group.

Preferred esterified carboxy groups R2 that are decomposable under physiological conditions are, for example, phthalidyloxycarbonyl groups,
Lower alkanoyloxy-methoxycarbonyl groups, such as acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl groups, and 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl groups, such as 1
-ethoxycarbonyloxyethoxycarbonyl group.

A preferred embodiment of the invention relates to compounds of general formula (1) in which R1 is a hydroxymethyl group and R2 and R3 have the definitions listed below general formula (1).

A further preferred embodiment of the invention relates to compounds of general formula (T) in which R1 is a 1-hydroxyethyl group and R2 and R3 have the definitions listed under general formula (1).

Functional groups present in the compounds of general formula (1), such as hydroxy groups, carboxy groups or amino groups, in particular the hydroxy group in the group R1 and the carboxy group R2, are optionally used in penems, penicillins, cephalosporins and peptide chemistry. Protected by the protecting group used. Such protecting groups are
During the synthesis of the compound of general formula (I) from its precursors,
The functional group in question is protected from undesired synthesis reactions, substitution reactions, etc.

Such protecting groups can be easily removed, ie, without undesired secondary reactions, for example by solvolysis or reduction, or under physiological conditions.

This type of protecting group and its introduction and removal method are, for example,
Protective Groups in Organic Chemistry by J.F.W. McOmie
ps in Organic Chemistry)
J, (Plenum Press)
, London, New York, 1973], TJl, Greene, Protective Groups in Organic Synthesis.
Organic 5ynthesis ) J (Wiley, New York, published 1981), [The Peptides J
, Volume I (Schroeder and Luebke, Academic Press,
London, New York, 1965] and Tlouben-Weyl, Methods of Organic Chemistry.
chenChemie ) J 1.5 / Volume 1 [Georg Th.
ieme Verlag), Stussotgart, 1
Published in 1974].

In the compounds of general formula (I), the hydroxy group in the radical R+ may be protected, for example by an acyl group. Suitable acyl groups are, for example, lower alkanoyl groups optionally substituted with halogen, such as acetyl or trifluoroacedel groups, benzoyl groups optionally substituted with nitro groups, e.g. benzoyl group, 4-nitrobenzoyl group. or a 2,4-dinitrohenzoyl group, a lower alkoxycarbonyl group optionally substituted with halogen, such as a 2-bromoethoxycarbonyl group or a 2,4-dinitrohenzoyl group;
, 2.21-lichloroethoxy carbonyl group, lower alkenyloxycarbonyl group, such as allyloxycarbonyl group or phenyl- substituted optionally with nitro group.
A lower alkoxycarbonyl group, for example a 4-nitrobenzyloxycarbonyl group. Suitable hydroxy-protecting groups are furthermore, for example, tri-substituted silyl groups, such as tri-lower alkylsilyl groups, such as trimethylsilyl or tert-butyldimethylsilyl, 2-halo-lower alkyl groups, such as 2-chloro-12-bromo- 12
-iodo- and 2,2,2-trichloro-ethyl groups and optionally halogens, such as chlorine, lower alkoxy groups,
For example, phenyl-lower alkyl groups substituted with methoxy and/or nitro groups, such as the corresponding benzyl group.

Tri-lower alkylsilyl groups, lower alkenyloxycarbonyl groups and halo-substituted lower alkoxycarbonyl groups are preferred as hydroxy-protecting groups.

The carboxy group R2 is usually protected in the esterified form, the ester group being subjected to mild conditions, such as mild reduction, such as hydrogenolysis conditions or mild solvolysis conditions, such as acidolysis or especially basic or neutral Easily degraded under hydrolytic conditions. The protected carboxy group may be a carboxy group modified with a different functional group, for example an esterified carboxy group that can be easily converted into a different esterified carboxy group.

Such esterified carboxy groups include, in particular, lower alkyl groups which are branched at the 1-position or suitably substituted at the 1- or 2-position. Preferred carboxy groups in esterified form are:
In particular, it has a lower alkoxycarbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a tert-butoxycarbonyl group, and an aryl group from 1 to 31[1i1] or a monocyclic heteroaryl group. (hetero)arylmethoxycarbonyl radicals, these aryl radicals optionally being substituted one or more times with, for example, lower alkyl radicals, such as tert-lower alkyl radicals, such as tert-butyl radicals, halogens, such as chlorine and/or nitro radicals. It's good that it has been done.

Examples of such groups include benzyloxycarbonyl groups optionally substituted, e.g. as described above, e.g. 4-
a nitrobenzyloxycarbonyl group, an optionally substituted diphenylmethoxycarbonyl group or a triphenylmethoxycarbonyl group, such as a diphenylmethoxycarbonyl group, for example a diphenylmethoxycarbonyl group, or a picolyloxycarbonyl group, such as a 4-picolyloxycarbonyl group, or Mention may be made of furfuryloxycarbonyl groups, such as 2-furfuryloxycarbonyl groups, each of which may be optionally substituted, for example as described above. Furthermore, lower alkanoylmethoxycarbonyl groups, such as acetonyloxycarbonyl groups, aroylmethoxycarbonyl groups (aroyl group preferably represents a benzoyl group optionally substituted, for example by halogen, for example bromine),
For example, phenacyloxycarbonyl group, halo lower alkoxycarbonyl group, e.g. 2-halo lower alkoxycarbonyl group, e.g. 2.2.2-)lichloroethoxycarbonyl group, 2-chloroethoxycarbonyl group, 2-
a bromoethoxycarbonyl group or a 2-iodoethoxycarbonyl group, or an ω-halo lower alkoxycarbonyl group in which the lower alkoxy group contains 4 to 7 carbon atoms,
For example, a 4-chlorobutoxycarbonyl group, a phthalimidomethoxycarbonyl group, a lower alkenyloxycarbonyl group, such as an allyloxycarbonyl group, or a 2-position lower alkylsulfonyl group, a cyano group, or a tri-substituted silyl group, such as a tri-lower alkylsilyl group, or Ethoxycarbonyl group substituted with triphenylsilyl group, such as 2-methylsulfonylethoxycarbonyl group, 2-cyanoethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group or 2-(di-n-butylmethylsilyl)-ethoxycarbonyl group is appropriate.

Other protected carboxy groups in esterified form are
A corresponding organic silyloxycarbonyl group and a corresponding organic stannyloxycarbonyl group. In these groups, the silicon atom or tin atom preferably has a lower alkyl group, particularly a methyl group or an ethyl group, and a lower alkoxy group, such as a methoxy group, as a substituent. Suitable silyl and stannyl groups are especially tri-lower alkylsilyl groups,
Particularly trimethylsilyl or dimethyl-tert-butylsilyl or correspondingly substituted stannyl groups, such as tri-n-butylstannyl.

Preferred protected carboxy groups R2' are 4-nitrobenzyloxy carbonyl groups and lower alkenyloxycarbonyl groups, especially allyloxycarbonyl groups and 2-
It is an ethoxycarbonyl group substituted in position with a lower alkylsulfonyl group, a cyano group, or a tri-lower alkylsilyl group, such as a trimethylsilyl group or a di-n-butylsilyl group.

The protected amino group in radical R3 is, for example, in the form of an easily decomposed acylamino, acylimino, etherified mercaptoamino, silylamino or stannylamino group or in the form of an enamino, nitro or azido group. good.

In the corresponding acylamino groups, the acyl group can be, for example,
Acyl groups of organic acids having, for example, up to 18 carbon atoms, in particular alkanecarboxylic acids optionally substituted with, for example, halogens or phenyl groups, or benzoic acids optionally substituted, for example, with halogens, lower alkoxy groups or nitro groups; It is the acyl group of carbonic acid half ester. Such acyl groups are, for example, lower alkanoyl groups such as formyl, acetyl or propionyl groups, halo lower alkanoyl groups such as 2-haloacetyl groups, especially 2-
Fluoro-12-bromo-12-iodo-12,2,2
-) a refluoro- or 2゜2.2-trichloro-acetyl group, an optionally substituted benzoyl group, such as a benzoyl group, a halobenzoyl group, such as a 4-chlorobenzoyl group, a lower alkoxybenzoyl group, such as a 4-
A methoxybenzoyl group or a nitrobenzoyl group, such as a 4-nitrobenzoyl group. Also, lower alkenyloxycarbonyl groups, such as allyloxycarbonyl groups or lower alkoxycarbonyl groups optionally substituted in the 1- or 2-position, such as lower alkoxycarbonyl groups, such as meth-1-oxycarbonyl or ethoxycarbonyl groups, a benzyloxycarbonyl group substituted with, for example a benzyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group, an aroylmethoxycarbonyl group (the aroyl group is optionally substituted with, for example, a halogen,
(preferably represents a benzoyl group substituted with bromine), e.g. a phenacyloxycarbonyl group, a 2-halo lower alkoxycarbonyl group, e.g. 2,2.2-1
-lichloroethoxycarbonyl group, 2-chloroethoxycarbonyl group, 2, bromoethoxycarbonyl group, or 2-chloroethoxycarbonyl group
-iodoethoxycarbonyl group, or 2-(tri-substituted silyl)-ethoxycarbonyl group, such as 2-tri-lower alkylsilylethoxycarbonyl group, such as 2-trimethylsilylethoxycarbonyl group or 2-(di-n
-butylmethylsilyl)-ethoxycarbonyl or 2-triarylsilylethoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl, are particularly suitable.

In the acylimino group, the acyl group is, for example, an acyl group of an organic dicarboxylic acid having, for example, up to 12 carbon atoms, in particular of the corresponding aromatic dicarboxylic acids, such as phthalic acid. Such groups are especially phthalimino groups.

Etherified mercaptoamino groups are in particular phenyl optionally substituted with lower alkyl groups, such as methyl or tert-butyl groups, lower alkoxy groups, such as methoxy groups, halogens, such as chlorine or bromine, and/or nitro groups. It is a thioamino group or a pyridylthioamino group. Corresponding groups are, for example, a 2- or 4-di-lophenylthioamino group or a 2-pyridylthioamino group.

In particular, the silylamino group or stannylamino group preferably has a silicon atom or a tin atom as a substituent, such as a lower alkyl group, such as a methyl group, an ethyl group, an n-butyl group or a tertiary group.
Organic silyl- or stannyl-amino groups containing t-butyl groups and also lower alkoxy groups, such as methoxy groups.

Corresponding silyl or stannyl groups are in particular tri-lower alkylsilyl groups, especially trimethylsilyl groups, and also dimethyl-tert-butylsilyl groups, or correspondingly substituted stannyl groups, such as the l-+J-n-butylstannyl group.

Protected amino groups are also, for example, enamino groups having an electron-withdrawing substituent, such as a carbonyl group, in the 2-position double bond. Protecting groups of this type may be used, for example, if the acyl group is a lower alkanecarboxylic acid, such as acetic acid, optionally, such as a lower alkyl group, such as a methyl group or a te
benzoic acid substituted with r t-butyl groups, lower alkoxy groups, such as methoxy groups, halogens, such as chlorine, and/or nitro groups, or in particular carbonic acid half esters, such as carbonic acid lower alkyl half esters, such as methyl carbonate half esters, or The 1-acyl-lower alk-1-en-2-yl group represents the acyl group of the ethyl half ester, and the lower alk-1-ene particularly represents propane. Corresponding protecting groups are in particular the 1-lower alkanoylprop-1-en-2-yl group, such as the 1-acetylprop-1-en-2-yl group or the 1-lower alkoxylprop-1-en-2-yl group. -yl group, e.g. 1-ethoxycarbonylprop-
It is a 1-en-2-yl group.

Preferred protected amino groups include, for example, an azide group, a phthalimide group, a nitro group, a lower alkenyloxycarbonylamino group, a benzyloxycarbonylamino group optionally substituted with a nitro group, and -lower alkanoyl-lower alk-1-ene-. It is a 2-ylamino group or a 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino group.

Salts of the compounds according to the invention are in particular pharmaceutically acceptable non-toxic salts of compounds of general formula (1). This kind of salt is
For example, formed from acidic groups present in general formula (1), such as the carboxy group R2, in particular metal or ammonium salts, such as alkali metal and alkaline earth metal salts,
For example sodium, potassium, magnesium or calcium salts and ammonia or suitable organic amines, such as lower alkyl amines such as triethylamine, hydroxy-lower alkyl amines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris. -(2-hydroxyethyl)-amines, basic aliphatic esters of carboxylic acids, such as 4-aminobenzoic acid, 2-diethylaminoethyl ester, lower alkylene amines, such as 1-edylpiveridine, cycloalkylamines, such as dicyclohexylamine or benzyl Ammonium salts with amines such as N,N'-dihenzylethylenediamine, dibenzylamine or N-benzyl-β-phenedylamin.

Compounds of general formula (1) having a basic group, for example an amino group, can be used, for example, inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic or sulfonic acids, such as acetic acid, succinic acid, fumaric acid, maleic acid. acid, tartaric acid, oxalic acid,
Acid addition salts can be formed using citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid. The compound of general formula (T) having an acidic group and a basic group may be in the form of an inner salt, that is, in the form of a zwitterion.

It is also possible to use salts that are not pharmaceutically acceptable for isolation or preparation purposes. These are preferred since only pharmaceutically acceptable non-toxic salts are used for treatment.

The penem compound of general formula (I) has R at the 5-position carbon atom.
- configuration, and the carbon atom at the 6-position has an S-configuration. The compound of general formula (1) may further have a center of chirality in the substituent R5, which is R-1S- or racemic R,S-
It may be the arrangement.

Preferred compounds of the general formula (T) have a group R1 which is asymmetrically substituted at the α-position (1'-carbon atom) by a hydroxy group, in particular a 1'-hydroxyethyl group, which has an R-configuration.

The compounds of general formula (T) exist in optically substantially pure form, i.e. are substantially free of isomers having a configuration other than the (5R,63)-configuration, in particular the corresponding (5S,6R )−
Contains no isomers.

In a preferred group of compounds of general formula (1), R1 represents a lower alkyl group substituted with a hydroxy group or a protected hydroxy group, R2 represents a carboxy group or a carboxy group modified with a functional group, and R3 represents a lower alkyl group substituted with a hydroxy group or a protected hydroxy group; Represents an amino group or a protected amino group.

In another group of preferred compounds of general formula (1), R
1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, R2 represents a carboxy group or a carboxy group modified with a functional group, and R3 represents an amino group substituted with a lower alkyl group or a substituted represents a methylene amino group.

The invention particularly provides that R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, and R2 represents a carboxy group, an esterified carboxy group decomposable under physiological conditions, or a protected carboxy group. R2' represents an amino group, a lower alkylamino group, a di-lower alkylamino group, and the formula -N=C(X+,X2) (wherein X1 is hydrogen, an amino group, a lower alkylamino group, a di-lower alkylamino group) group, lower alkylene amino group, nitroamino group, hydrazino group, a, nilino group, lower alkoxy group, phenyl-lower alkoxy group, lower alkylthio group, lower alkyl group, amino-lower alkyl group, N-
lower alkylamino-lower alkyl group, N,N-di-lower alkylamino-lower alkyl group, lower alkenyl group, phenyl group, pyridyl group such as 2- or 4-pyridyl group, thienyl group such as 2-chenyl group, or represents a thiazolyl group, for example a 4-thiazolyl group, and x2 represents an amino group, lower alkylamino group, di-lower alkylamino group, lower alkylene amino group, cyanamino group, hydrazino group, anilino group, lower alkoxy group, phenyl-
(represents a lower alkoxy group or lower alkylthio group), or R3 represents a protected amino group, a compound of the general formula (1) having a center of chirality in the group R1; It relates to salts of compounds of general formula (1) with salt-forming groups, in isomers, mixtures of these optical isomers and in optically substantially pure form.

The present invention more particularly provides that R1 has a hydroxy group, a tri-lower alkylsilyloxy group, a 2-halo lower alkoxy group, a 2-halo lower alkoxycarbonyloxy group, a lower alkenyloxycarbonyloxy group, or an unsubstituted or nitro Represents a lower alkyl group substituted with a substituted phenyl-lower alkoxycarbonyloxy group, and R2
is a carboxyl group, a lower alkenyloxycarbonyl group,
unsubstituted or nitro-substituted benzyloxycarbonyl group, lower alkanoylmethoxycarbonyl group, 2-halo lower alkoxycarbonyl group, 2-1-ly-lower alkylsilylethoxycarbonyl group or esterified carboxy group decomposable under physiological conditions; For example, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl group, lower alkanoyloxymethoxycarbonyl group, α-
represents an amino-lower alkanoyloxymethoxycarbonyl group or a phthalidyloxycarbonyl group, R3 is an amino group, a lower alkylamino group, a di-lower alkylamino group, the formula -N=C(X+, X2) (in the formula, X is hydrogen , amino group, lower alkylamino group, lower furkyl group,
represents a phenyl group or a pyridyl group, such as a 2-pyridyl group, and X2 represents an amino group, a lower alkylamino group, or a di-lower alkylamino group, or R3 represents an azide group, a phthalimino group, a nitro group, Lower alkenyloxycarbonylamino group, unsubstituted or 21,0-substituted benzyloxycarbonylamino group, 1-lower alkanoyl-lower alk-1-en-2-ylamino group, or 1-lower alkoxycarbonyl-lower alk-1-ene- A compound of general formula (1) that does not represent a 2-ylamino group, a group R
optical isomers of compounds of general formula (I) having a center of chirality in 1, mixtures of these optical isomers and optically substantially pure forms of compounds of general formula (I) having a salt-forming group; Regarding salt.

The invention more particularly provides that R1 represents a lower alkyl group substituted in the α-position with a hydroxy group, and R2 represents a carboxy group or an esterified carboxy group decomposable under physiological conditions, such as 1-lower alkoxycarbonyloxy. A compound of the general formula (I) representing a lower alkoxycarbonyl group or a lower alkanoyloxymethoxycarbonyl group, in which R3 represents an amino group, a lower alkylamino group or a formamidino group, a general formula (I) having a center of chirality in the group R1
to optical isomers of the compounds of formula (1), mixtures of these optical isomers and salts of compounds of general formula (1) having salt-forming groups in optically substantially pure form.

The present invention mainly provides that R1 is a hydroxymethyl group or
-represents a hydroxyethyl group, R2 represents a carboxy group, and RE represents an amino group, and relates to compounds of general formula (I) and salts thereof in optically substantially pure form.

Moreover, the present invention particularly provides pure optical isomers of the compound of the general formula (1) having a center of chirality in the substituent R1, particularly the pure optical isomer of the compound of the general formula (1) in which R1 is a 1'-hydroxyethyl group. General formula (1) with 'R)-isomer and salt-forming group
Regarding the salt of the compound.

The present invention particularly relates to compounds of general formula (1) mentioned in the Examples and pharmaceutically acceptable salts thereof.

The compound of the present invention can be produced by a method known per se.

The novel compound is produced, for example, as follows; a) General formula (I'): [wherein R1 has the definition listed under general formula (1), R
2T represents a protected carboxy group and Q represents a group convertible to group R3], or b) general formula (■): 1 [wherein R1 and R3 have the definitions listed under general formula (T), R2' represents a protected carboxy group, Z represents oxygen or sulfur, and XO together with the cation represents a tri-substituted phosphonio group or a diester. or C) general formula (■): [wherein R1 and R3 have the definitions listed under general formula (1), and Z is oxygen or sulfur] and R2' represents a protected carboxy group] is treated with an organic compound of trivalent phosphorus, or d) general formula (I'l+'): [wherein R1 and R3 are the general formula (1), R represents a protected carboxy group and X represents a group -8- or a group -3O2-, as desired or necessary. in the resulting compound of general formula (1), the protected hydroxy group in the group R2 is changed to a free hydroxy group, and/or if desired, the compound of general formula (I)
The protected carboxy group R2' in the generated compound can be replaced with a free carboxy group, an esterified carboxy group that can be decomposed under physiological conditions, or a different protected carboxy group R.
2' or the free carboxy group R2 to an esterified carboxy group or a protected carboxy group R21 that can be decomposed under physiological conditions, and/or if desired, the protected amino group R3 to a free amino or change it to the base
or convert the free amino group R3 into a substituted amino group, and/or, if desired, convert the resulting compound with a salt-forming group into a salt, or convert the resulting salt into the free compound or a different salt, and/or if desired In this case, the resulting mixture of isomeric compounds of general formula (1) is separated into individual isomers.

(Left below) In the starting compounds of the general formulas (Io), (TI) and (III), the functional groups, such as the free hydroxy group in the group R1, and in particular the free amino group R3, can be replaced by conventional protecting groups, such as those described above. Preferably it is protected with one of the protecting groups.

a) Groups Q convertible into lb(λ-introducing groups R3 are in particular corresponding groups which can be converted by nucleophilic reactions. Such groups Q are in particular esterified hydroxy groups, for example hydrohalic acid , di-lower alkyl phosphoric acid, diaryl phosphoric acid, lower alkane carboxylic acid optionally substituted with an oxo group or halogen, lower alkanesulfonic acid optionally substituted with halogen, or benzenesulfonic acid optionally substituted with halogen or lower alkyl group. Such groups Q are, for example, halogens, such as chlorine, bromine or iodine, di-lower alkyl- or diaryl-phosphoryloxy groups, such as dimethyl-, diethyl- or diphenyl-phosphoryloxy groups. , lower alkanoyloxy groups optionally substituted with halogen or oxo groups, such as formyloxy, acetoxy or acetoacetoxy groups,
a lower alkanesulfonyloxy group optionally substituted with a halogen, such as a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, or a henzenesulfonyloxy group optionally substituted with a halogen or a lower alkyl group, such as a henzenesulfonyloxy group, 4-chloro-, 4-promo or 4-methyl-henzenesulfonyloxy group.

The reaction is carried out using a compound of the formula R3H (wherein R3 is as defined above) or a salt thereof, such as an alkali metal salt, such as a sodium salt or a potassium salt, i.e. hydrogen azide or phthalimide or an alkali metal salt thereof, such as a salt thereof.・Rium salt or potassium salt, and further ammonia, lower alkyl amine, di-lower alkyl amine, amidine,
This is carried out using guanidine, etc. (each may optionally be present in a protected form, but it is necessary that at least one hydrogen atom be present in the amino group to be reacted). The reaction is carried out in an inert solvent, such as a lower alkanol, dimethylformamide, a cyclic ether, such as dioxane or dimethyl sulfoxide, at room temperature or at slightly elevated or reduced temperatures, for example from about 0 to 40° C1, especially at room temperature.

The starting compound of the general formula (■'') is prepared in a manner analogous to that described in method b) with the general formula (IT'): 1 [wherein Z and X■ are the definitions listed under the general formula (n)] can be produced by ring closure of a phosphorane having

b)] The group X in the starting material of the general formula (I[) of the formula N+) is a phosphonio group or a phosphono group commonly used in the Wittig condensation reaction. One, in particular, a trifluoride group, such as a triphenyl- or tri-lower alkyl-1, such as a tri-n-butyl-phosphonio group, or a phosphono group diesterified with a lower alkyl group, such as an ethyl group, in the case of a phosphono group; The radical X○ further includes strong basic cations, in particular suitable metal ions, such as alkali metal ions, such as lithium, sodium or potassium ions. On the one hand, a triphenylphosphonio group and, on the other hand, a diethylphosphono group together with an alkali metal ion, for example a sodium ion, are preferred as radicals X■.

In the phosphonio compound of general formula (11), negative charges are neutralized by the positively charged phosphonio group. In the phosphono compounds of general formula (II), the negative charge is neutralized by strong basic cations, which cations can be, for example, alkali metal ions,
For example, it may be sodium, lithium or potassium ions. The phosphono starting material is therefore used in the reaction in salt form. The ring closure reaction can occur naturally, ie, during the preparation of the starting materials, or can be carried out by heating, for example, at a temperature range of about 30 to 160<0>C, preferably about 50'C to about 100<0>C. The reaction is carried out in a suitable inert solvent,
For example, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as cyclohexane, benzene or l-toluene, halogenated hydrocarbons, such as methylene chloride, ethers, such as diethyl ether, cyclic ethers, such as dioxane or tetrahydrofuran, carboxylic acid amides, such as Preference is given to carrying out in dimethylformamide, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, or lower alkanols, such as ethanol, or mixtures thereof, optionally under an inert gas atmosphere, such as nitrogen atmosphere.

C)-〇 ■ A of 1 The organic compound of trivalent phosphorus is derived from, for example, phosphorous acid,
Especially lower alkanols, such as methanol or ethanol, and/or esters with optionally substituted aromatic hydroxy compounds, such as phenol or pyrocatechol, or esters of the formula P(○Ra )2 N (Rh
)2 (wherein Ra and Rb each independently represent a lower alkyl group, such as a methyl group, or an aryl group, such as a phenyl group). Preferred compounds of trivalent phosphorus are tri-lower alkylbosphites,
For example trimethyl phosphite or triethyl phosphite.

The reaction is carried out in an inert solvent, such as an aromatic hydrocarbon, such as toluene or xylene, an ether, such as dioxane or tetrahydrofuran, or a halogenated hydrocarbon, such as methylene chloride or chloroform, for about 20 minutes.
'C to about 150°C1 preferably about 20'C to about 120
Preferably carried out at a temperature of 0.degree. C., 1 molar equivalent of a compound of general formula (TIE) is reacted with 2 molar equivalents of a phosphorus compound. Preferably, the compound of general formula (Ill) is placed in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over an extended period of time, for example from 2 to 4 hours.

In a preferred embodiment, a starting material of general formula (T[T) is prepared as follows and is reacted with an organic compound of trivalent phosphorus without isolation from the reaction mixture to form a compound of general formula (I). to produce the final product.

d) Type 1 Go] "Yu J Kari Kaimono Gyozu Kari [℃9 removed.

Compounds of general formula (■') are correspondingly substituted 2-thia-3-cephem-4-carboxylic acids or especially 2-thia-3
-cephem-4-carboxylic acid 1°1-dioxide.

The reaction for removing sulfur from 2-thia-3-cephem-4-carboxylic acid (X=S) of the general formula (■'') can be carried out using, for example, an organic compound of trivalent phosphorus, such as the compound listed in method C). Suitable compounds of trivalent phosphorus are, for example, tri-lower alkyl phosphites, such as triethyl phosphite and especially triphenyl phosphite.The removal is carried out at room temperature or at slightly elevated temperatures, e.g. at 60 °C in an inert solvent or solvent mixture, e.g.
It is carried out, for example, in benzene, chlorinated hydrocarbons, such as chloroform, or lower alkanones, such as acetone, optionally in an inert gas atmosphere, such as nitrogen.

The reaction of removing sulfur dioxide from the compound of the general formula (■") in which X represents SO2 can be carried out by mild to moderate heating in a solution containing the compound, for example, heating to about 0°C to about 80°C. Suitable solvents are inert solvents, such as optionally chlorinated hydrocarbons, such as chloroborum, aliphatic ethers, or aromatic hydrocarbons, such as benzene.

Preference is given to using starting materials of the general formulas (Io), (TI), (III) and (■") which produce compounds of the general formula (I) mentioned at the outset as particularly preferred.

In the resulting compounds of general formula (1) in which one or more functional groups are protected, the protected functional groups, such as protected carboxy groups, hydroxy groups and amino groups, are removed by themselves, optionally in several steps or simultaneously. It can be liberated in known manner by solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by reduction, especially hydrogenolysis or chemical reduction.

The protected carboxy group in the compound of general formula (1) in which R2 represents a protected carboxy group obtained by the method of the present invention can be liberated by a method known per se. That is, ter is -lower alkoxycarbonyl group,
or a lower alkoxycarbonyl group substituted in the 2-position with a tri-substituted silyl group or substituted in the 1-position with a lower alkoxy group, or an optionally substituted diphenylmeth-1-oxycarbonyl group, e.g. Nuclear compounds such as phenol or anisole can be added and converted into free carboxy groups by treatment with carboxylic acids such as formic acid or trifluoroacetic acid.

Optionally substituted bezyloxycarbonyl groups can be decomposed, for example, by hydrogenolysis, ie, treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst. Furthermore, a suitably substituted benzyloxycarbonyl group, such as 4-nitropenzyloxycarbonyl, can be treated with chemical reduction, for example with an alkali metal dithionite, such as sthorium dithionite, or is usually treated with a nascent metal. Hydrogen generators capable of producing hydrogen, such as suitable carboxylic acids, such as lower alkane carboxylic acids optionally substituted with e.g. Tin or reducing metal salts, such as chromium (IT) salts, such as chromium chloride (H
) can be converted into a free carboxy group.

Removal of the allyl protecting group is carried out, for example, by reaction with a palladium compound, for example tetrakis(triphenylphosphine)-palladium, in the presence of triphenylphosphine and by addition of a carboxylic acid, for example 2-ethylhexanoic acid or a salt thereof. 2-halo lower alkoxycarbonyl group (optionally after converting the 2-bromo-lower alkoxycarbonyl group to the corresponding 2-iodo-lower alkoxycarbonyl group) by treatment with a reducing metal or metal salt, as described above. Alternatively, the aroylmethoxycarbonyl group can be converted into a free carboxy group, and the aroylmethoxycarbonyl group can likewise be converted to a nucleophilic, preferably salt-forming reagent,
For example, it can be decomposed by treatment with sodium thiophenolate or sodium iodide. The substituted 2-silylethoxycarbonyl group is treated with a salt of hydrofluoric acid, such as an alkali metal fluoride, such as sodium fluoride, which yields a fluoride anion in the presence of a macrocyclic polyether ("crown ether"), or It can be converted to a free carboxy group by treatment with a fluoride of an organic quaternary base, such as a tetra-lower alkylammonium fluoride, such as tetrabutylammonium fluoride. Carboxyls esterified with organosilyl or suphnyl groups, such as tri-lower alkylsilyl or tri-lower alkylstannyl groups, can be liberated in the usual manner by solvolysis, for example by treatment with water or alcohol. A lower alkoxycarbonyl group substituted with a lower alkylsulfonyl group or a cyano group at the 2-position,
For example, basic reagents such as alkali metal or alkaline earth metal hydroxides or carbonates, such as thorium hydroxide,
It can be converted to free carboxy groups by treatment with potassium hydroxide, sodium carbonate or potassium carbonate.

Further, the compound of the general formula (1) in which R2 represents a carboxyl group may be converted to a compound of the general formula (I ) can be converted into a compound. The free carboxy group is treated with a suitable diazo compound, for example a diazo-lower alkane, for example diazomethane, or a phenyl-diazo-lower alkane, for example diphenyldiazomethane, optionally in the presence of a Lewis acid, for example boron trifluoride. or by reaction with an alcohol suitable for esterification in the presence of an esterification agent, such as a carbodiimide, such as dicyclohexylcarbodiimide and carbonyldiimidazole. Esters may also be prepared by reacting salts of acids (optionally prepared in situ) with reactive esters of alcohols and strong inorganic acids, such as sulfuric acid or strong organic sulfonic acids, such as 4-toluenesulfonic acid. can. Furthermore, acid halides - e.g. chlorides (prepared e.g. by treatment with oxalyl chloride)
, active esters (e.g. formed using N-hydroxy nitrogen compounds, e.g. N-hydroxysuccinimide), or mixed anhydrides (e.g. haloformic acid lower alkyl esters, e.g. chloroformic acid ethyl ester or chloroformic acid isobutyl ester, or haloacetic acid halides). (obtained for example using trichloroacetyl chloride) can be converted into an esterified carboxy group by reaction with a suitable alcohol, optionally in the presence of a base, for example pyridine.

This group in compounds of general formula (1) having an esterified carboxy group can be changed to a different esterified carboxy group. For example, a 2-chloroethoxycarbonyl group or a 2-promoethoxycarbonyl group can be converted into a 2-iodoethoxycarbonyl group by treatment with an iodide salt, such as sodium iodide. Furthermore, the carboxy protecting group in the compound of general F(T) containing a protected carboxy group in esterified form can be removed as described above, and the carboxyl protecting group in the compound of general formula (1) having a free carboxy group can be removed as described above.
General formula (1) in which R2 represents an esterified carboxy group that can be decomposed under physiological conditions by reacting the resulting compound or its salt with a reactive ester of the corresponding alcohol
can be converted into compounds of

In the compounds of general formula (1) obtained by the process of the invention, the protected hydroxy group present in the group R1 can be converted into a free hydroxy group by methods known per se. For example, a hydroxy group protected with a suitable acyl group or an organosilyl group or stannyl group is liberated in the same way as a correspondingly protected amine, no group (see description below). The tri-lower furkylsilyl group can also be removed using, for example, tetrabutylammonium fluoride and acetic acid (under these conditions, the carboxy group protected by the I-ly substituted silylethoxy group is not decomposed). 2-
Halo lower alkyl groups and optionally substituted benzyl groups are removed by reduction.

In the compounds of the general formula (1) obtainable according to the invention which have a protected amino group R3, this group can be liberated in a manner known per se, for example, depending on the nature of the protecting group, preferably by solvolysis or reduction. Can be converted to amine group. For example, a 2-halo lower alkoxycarbonylamino group (optionally after changing the 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), an aroylmethoxycarbonylamino group or a 4-nitrobenzyloxy The carbonylamino group can be cleaved by treatment with a suitable chemical reducing agent, such as zinc, in the presence of an aqueous solution of a suitable carboxylic acid, such as acetic acid, or by contact with hydrogen in the presence of a palladium catalyst.

aroylmethoxycarbonylamino group, a nucleophilic reagent,
Preferably, the 4-nitrobenzyloxycarbonylamino group can also be decomposed by treatment with a salt-forming reagent, such as sodium thioferlate, and the 4-nitrobenzyloxycarbonylamino group can be decomposed by treatment with an alkali metal-faced dithionate, such as sodium dithionite. . The optionally substituted benzyloxycarbonylamino group can be decomposed, for example, by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst,
The allyloxycarbonylamino group can be converted into a palladium compound, such as tetrakis (
(triphenylphosphine)-palladium and a carboxylic acid such as 2-ethylhexanoic acid or a salt thereof. Amino groups protected with organosilyl or stannyl groups can be liberated, for example by hydrolysis or alcoholysis, and amino groups protected with 2-halo lower alkanoyl groups, e.g. 2-chloroacetyl groups, can be liberated in the presence of a base. with thiourea or with a thiolate salt of thiourea, for example an alkali metal thiolate, and the resulting condensation product can then be liberated by solvolysis, for example alcoholysis or hydrolysis. With the presence of a macrocyclic polyether (“crown ether”), an amino group protected by a 2-substituted silylethoxycarbonyl group,
Salts of hydrofluoric acid, such as those treated with alkali metal fluorides, such as sodium fluoride, yielding fluoride anions, or fluorides of organic quaternary bases, such as tetra-lower alkylammonium fluorides, such as tetraethylammonium. It can be converted to a free amino group by treatment with fluoride. Amino groups protected in the form of an azide group or a nitro group can be removed, for example, by reduction, e.g. catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, e.g. platinum or palladium oxide, or treatment with zinc in the presence of an acid, e.g. acetic acid. converted into a free amino group by Amino groups protected in the form of phthalimide groups can be converted into free amino groups by reaction with hydrazine. Moreover, it's over.
A ruthioamino group can be converted to an amine group by treatment with a nucleophilic reagent, such as sulfite.

Furthermore, the free amine group R3 can be converted into a substituted amino group by a method known per se. For example, an amino group is converted into an acylamino group R3 by reacting with the corresponding acyl halide, e.g. chloride, and a 1-lower Alkanoyl- or 1-lower alkoxy groups can be converted into luponylprop-1-en-2-yl-amino groups. The reaction for converting an amino group into an amidino group, a guanidino group, an iturea group, an imidoether group, or an imidothioether group is described, for example, in German Patent Application Publication No. 265
This is carried out by one of the methods described in Japanese Patent No. 2679. For example, a compound of the general formula (1) in which R3 represents an amino group is represented by the formula: C(XI, Yt) C=X2H]0Y2
0 [In the formula, X represents hydrogen, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a phenyl group, or a monocyclic heteroaryl group, Xl represents an optionally substituted imino group, Yl represents a halogen, For example, it represents chlorine, or a lower alkoxy group, such as an ethoxy group, and Yl is an anion,
for example by reaction with an imidohalide or imidoester of chlorine ion], or by reaction with an imidoester of the formula:
XI C(=S)
3 represents a lower alkoxy group or a lower alkylthio group,
Xl represents an optionally substituted amino group and X21 represents an optionally substituted imino group) can be converted to guanidine by reaction with isourea or isothiourea. Furthermore, the free amino group R3 can be converted into a hepano- or di-substituted amino group with a lower alkyl group.

The introduction of lower alkyl groups can be achieved, for example, in the presence of a basic condensing agent, such as an alkali metal or alkaline earth metal hydroxide or carbonate, such as potassium hydroxide or sodium carbonate, in an inert solvent, such as a lower alkanol. reactive lower alkyl esters, such as halides, such as chlorides or bromides, or sulfonates, such as methanesulfonate or p-)luenesulfonate, at room temperature or at elevated or lower temperatures, e.g. from about -20°C to
This is carried out by reacting at +80°C.

A salt of the compound of general formula (1) having a salt-forming group can be produced by a method known per se. That is, the salt of the compound of general formula (1) having a free carboxy group or sulfo group is
For example, with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, such as the sodium salt of α-ethylcaproic acid, or inorganic alkali metal or alkaline earth metal salts, such as sodium bicarbonate, or ammonia or suitable organic amines. It is preferred to use the salt-forming agent in stoichiometric amounts or in small excess. The acid addition salt of the compound of general formula (I) can be prepared by a conventional method,
For example, it can be obtained by treatment with a suitable acid or a suitable anion exchange reagent.

Inner salts of compounds of general formula (I) can be formed, for example, by neutralizing the salts, for example acid addition salts, to their isoelectric point, for example with a weak base or by treatment with an ion exchanger.

The salt can be converted into the free compound in a conventional manner.

Thus, metal salts and ammonium salts can be converted into the free compounds, for example by treatment with a suitable acid, and acid addition salts can be converted into the free compounds, for example by treatment with a suitable basic reagent.

The resulting mixture of isomeric compounds can be separated into the individual isomers by methods known per se.

For example, the resulting racemate is reacted with an optically active auxiliary, the resulting mixture of two diastereomeric compounds is separated by appropriate physicochemical methods (e.g. fractional crystallization, adsorption chromatography), and then the individual diastereomeric compounds are separated Separation of stereomeric compounds into optically activated metals.

Racemates suitable for separation into enantiomers are those containing an acidic group, for example, the general formula (1) in which R2 represents a carboxy group.
It is a racemate of the compound. These acidic racemates are treated with optically active bases, such as esters of optically active amino acids, or (-)-brucine, (+)-quinidine, (-)-quinine, (+)-cinchonine, (+)-dehydroabiethylamine, (+) and (-)-ephedrine, (+) and (
1-1-phenylethylamine or their N-mono-
Alternatively, it can be reacted with an N,N-di-alkylated derivative to form a mixture of two diastereomeric salts.

In the racemate containing a carboxyl group, the carboxyl group is replaced with an optically active alcohol, such as (-)-menthol, (
It is also possible to esterify with -)-borneol (-)-2-octatool and then liberate the carboxy group when isolation of the desired diastereomer is complete.

To separate the racemates, the hydroxy present can also be esterified with an optically active acid or a reactive functional derivative thereof to form diastereomeric esters. Such acids are, for example, (-)-abietic acid, D(+)-
and L(-)-malic acid, N-acylated optically active amino acid, (+)- and (-)-camphanic acid, (+)- and (=)-ketopic acid, L(→-)-ascorbic acid ,(
+)-camphoric acid, (+)-camphor-10-sulfonic acid (β)
, (+) or (-)-α-bromocamphor-π-sulfonic acid, D(=)-quinic acid, D(-)-isoascorbic acid,
D(-)- and L(+)-mandelic acid, (→-)-1-men-1-xyacetic acid, D(-)- and L(+)-tartaric acid and its di-O-henzoyl derivatives and di-O-p- 1
It is a luoyl derivative.

Optically active isocyanates, such as (+) or (-)-1
- By reacting with phenylethyl isocyanate, the general formula (I
) can be converted into a mixture of diastereomeric urethanes.

A basic racemate, for example, R3 does not represent an amino group and the general formula (
The compound of 1) can be converted into a diastereomeric salt using the optically active acid described above.

The separated diastereomers can be divided into optically active compounds of general formula (1) by a conventional method. The acid or base is liberated from the salt, for example by treatment with a stronger acid or base than the one originally used.

The desired optically active compounds are obtained from the esters or urethanes, for example after alkaline hydrolysis or reduction with complex hydrides, such as lithium aluminum hydride.

Another racemate separation method involves chromatography on an optically active adsorption layer, such as sucrose.

In the third method, the racemate is dissolved in an optically active solvent, and the less soluble optical antipode can be crystallized.

A fourth method exploits the differences in the reactivity of optically active enantiomers towards biological materials, such as microorganisms or isolated enzymes.

In a fifth method, one optical enantiomer is crystallized by dissolving the racemate and inoculating with a small amount of the optically active product obtained in the above method.

The racemate can be produced in any operating step, i.e. for example with the general formula (
■'), (II), (II[) or (■1) at the stage of the starting materials or the production of the starting compounds of the general formula (lo), (II), (III) or (■“) as described below. The optical antipodes can be separated at any stage of the process.

In all subsequent transformation reactions of the resulting compounds of general formula (I), preference is given to carrying out these reactions under alkaline or especially neutral conditions.

The process of the present invention includes embodiments in which the compound produced as an intermediate is used as a starting material and the remaining process steps are carried out, or embodiments in which the process is interrupted at any stage. Furthermore, the starting materials can be used in the form of derivatives or prepared in situ, optionally under reaction conditions.

Starting compounds of general formulas (TI) and (III) can be prepared as shown in Scheme I below.

(Left below) Reaction formula I 2 In the compounds of general formulas (n), (V) and (Vl),
R4 is group R3 or group Q.

Thioazetidinones of the general formula (V) can be obtained by reacting a compound of the general formula (IV) with a compound that introduces a group -3-C(-Z)CH2R4.

In the starting material of general formula (IV), the W group-3-C (
-Z) Nucleofugal (
nucleofugal) group. Such a group W
is, for example, an acyloxy group, a sulfonyl group ROSO2 (
In the formula, R6 represents an organic group), an azide group, or a halogen. The acyl group in the acyloxy group W is, for example, an organic carboxylic acid group, such as a lower alkanoyl group, such as an acetyl group or a propionyl group, an optionally substituted benzoyl group, such as a hendiyl group or a 2.4
- represents a dinitrohendiyl group, or a phenyl-lower alkanoyl group, such as a phenylacetyl group. Sulbonyl group R8-302 (wherein R6 is a lower alkyl group optionally substituted with a hydroxy group, such as a methyl group,
Ethyl group, tert-butyl group, 1-hydroxy-2
-yl group, 1-hydroxy-2-methylprop-2-yl group or 2-hydroxyethyl group, benzyl group or optionally substituted phenyl group, such as phenyl group,
4-bromophenyl group or 4-methylphenyl group. Halogens are, for example, bromine, iodine or especially chlorine. W is a methylsulfonyl group, a tert-butylsulfonyl group, or a 2-hydroxyethylsulfonyl group,
Preferably, it is an acetoxy group or chlorine.

Compounds introducing the group -3C(=Z) CH2R4 are, for example, acids of the formula R4CH2C(=Z) SH or salts thereof, such as alkali metal salts, such as sodium or potassium salts. Substitution is carried out using organic solvents such as lower alkanols,
It can be carried out, for example, in methanol or ethanol, lower alkanones such as acetone, lower alkanecarboxylic acid amides such as dimethylformamide, cyclic ethers such as tetrahydrofuran or dioxane or similar inert solvents. The reaction is usually carried out at room temperature, but the temperature may be increased or decreased, e.g.
It can also be carried out at ~40°C. The reaction can be accelerated by adding salts of hydriodic acid or hydrothiocyanic acid, for example alkali metal salts, eg sodium salts.

Group to be introduced -3-〇 (=Z) CI (2R4 is group R
1 is preferentially directed to the trans-position. Therefore, (33,4R)- and (3S,43) of general formula (IV)
)-configuration starting compounds can be used. Primarily, the trans-isomer is formed, but occasionally also small amounts of the cis-isomer. The cis-isomers are separated by enrichment methods as described above, in particular by chromatography and/or crystallization.

Suitable starting compounds of the general formula (IV) are, for example, those described in European Patent Application No. 82113, German Patent Application No. 3013997 or German Patent Application No. 3224.05.
5 or can be produced by similar methods. These compounds can also be produced by the methods described in the Examples.

Processing process The azetidinone of general formula (V) in which R4 represents a radical R3 is prepared in an inert solvent, for example the solvent mentioned for reacting the compound of general formula (III) to form the compound of general formula (I'). -20°C to 80°C, preferably -20°C to 40°C
The starting compounds of the general formula (nl) are obtained by treatment with an acid of the formula R2'-COOH or in particular a reactive derivative thereof, such as an ester or an acid halide, such as an acid chloride, at a temperature of .degree. When acid halides are used, the operation is carried out with acid binders, such as tertiary aliphatic amines such as triethylamine or diisopropylethylamine ("Iluenig bases"), aromatic amines such as pyridine or especially alkali metals or alkali Preference is given to working in the presence of earth metal carbonates or bicarbonates, such as potassium carbonate or calcium carbonate.

"1 [Shadow Xo is a reactive esterified hydroxy group, especially a halogen,
For example, chlorine or bromine, or organic sulfonyloxy groups, such as lower alkanesulfonyloxy groups, such as methanesulfonyloxy groups, or arenesulfonyloxy groups, such as benzene-sulfonyloxy groups or 4-
General formula (V
Compound l) is a compound of general formula (V)
2' glyoxylic acid compound or a suitable derivative thereof, such as a hydrate, hemihydrate or hemisecur, such as a lower alkanol such as methanol or ethanol, resulting in a general It is produced by changing the hydroxy group in the compound of formula (Vl) to a reactive esterified hydroxy group.

The compound of general formula (Vl) usually has two isomers [~C
H(R2') N-X, with respect to the group] is obtained in the form of a mixture. However, it is also possible to isolate the pure isomers, for example by chromatography.

The reaction of adding the glyoxylic acid ester compound to the nitrogen atom of the lactam ring in the compound of general formula (V) is carried out at room temperature or, if necessary, with heating, for example at about 100°C.
Performed in the absence of actual condensing agent. If a hydrate of a glyoxylic acid compound is used, the water formed is optionally removed by distillation, for example azeotropic distillation, or by using a suitable dehydrating agent, for example molecular sieves.

Preferably, the operation is carried out in the presence of a suitable solvent, such as dioxane, toluene or dimethylformamide, or a mixture of solvents, if necessary in an inert gas atmosphere, for example nitrogen gas.

In the compounds of general formula (Vl), the conversion of the hydroxy group Xo into the reactive esterified hydroxy group X0 is preferably carried out using a basic reagent, especially an organic basic reagent, such as an aliphatic tertiary amine, such as triethylamine or diisopropylamine. , or in the presence of a heterocyclic base of the pyridine type, such as pyridine or collidine, suitable esterifying agents, such as thionyl halides, such as thionyl chloride, phosphorous oxyhalides, especially phosphorous oxychloride, halobosphonium halides, This is carried out, for example, by treatment with triphenylphosphonium dibromide or dichloride, or with a suitable organic sulfonic acid halide, such as chloride. The operation is carried out in a suitable solvent, such as dioxane or tetrahydrofuran, or a solvent mixture, with optional cooling, e.g. from about -30° C. to about 30° C., optionally in an inert gas atmosphere, e.g. nitrogen gas atmosphere. is preferable.

Step ↓ The starting material for general formula (n) is a compound of general formula (VI) which is combined with a suitable phosphine compound, such as a 1-di-lower alkylphosphine, such as tri-n-butylphosphine, or a triarylphosphine, such as triphenylphosphine. or a suitable phosphite compound, such as tri-lower alkyl phosphite, such as triethyl phosphite,
or alkali metal di-lower alkyl phosphatide 1-1
For example, it can be obtained by treatment with an alkali metal diethylbosphite.

The above reaction can be carried out in a suitable inert solvent, such as a hydrocarbon such as cyclohexane or benzene, or an ether.
Preferably, it is carried out, for example, in the presence of dioxane or a solvent mixture. Depending on the reactivity, the operation is carried out with cooling or at elevated temperature, from about 10° C. to +100° C., preferably from about 20 to 80° C., and/or in an inert gas atmosphere, for example a nitrogen gas atmosphere. is preferable. To prevent oxidation reactions from occurring, catalytic amounts of antioxidants, such as hydroquinone, can be added.

The reaction is usually carried out in the presence of a basic reagent, such as an organic base, such as an amine, such as triethylamine, diisopropylethylamine, pyridine, lutidine or "polystyrene Hunig's base", or an inorganic base, such as an alkali metal carbonate, such as sodium carbonate or potassium carbonate. The general formula (ITa) initially produced is: cJ In the entire blank formula, X'' represents a phosphono group or an anion (depending on the definition of the group X0, for example, a chloride ion) and a phosphonio group. ] into the ylide starting material of general formula (n). Then, the reaction is carried out in the absence of a base and the compound of general formula (Ila), in particular the corresponding phosphono compound, is isolated and the compound can also be converted into the starting material of the general formula (IT) in situ during the preparation of the desired product of the general formula (T).

Step j Furthermore, a compound of general formula (II) can be obtained by treating the mercaptide of general formula (■) in which M represents a metal cation with an acylating agent that introduces a group R4-CH2C(=Z)-. can.

In the starting material of general formula (■), the metal cation M is
For example, cations of 2M or M++/2, in which M+ especially represents a silver ion and M'' especially a divalent cation of a suitable transition metal, such as copper, lead or mercury.

Acylating agents introducing the group R4-C)(z C(-Z)- are, for example, the acid R4CH2C(=Z)-OH or especially its reactive functional derivatives, such as acid halides, such as acid chlorides or bromides, or its azide or anhydride.

When using reactive functional derivatives of acids of the formula R4CH2C(=Z)OH, such as acid chlorides, the acylation is carried out in an inert solvent, such as a chlorinated hydrocarbon, such as methylene chloride, or an ether, such as diethyl ether or in dioxane at room temperature or with heating or cooling, for example from about -50°C to about +60°C, especially from about -30°C to about +20°C.
Conducted in a temperature range of

Starting compounds of general formula (■) can be prepared, for example, by reacting an azetidinone of general formula (■) with a thio-lower alkanecarboxylic acid, such as thioacetic acid, or an alkali metal salt, such as the storium salt, of I.riphenylmethylmercabutan. [In the formula, W' represents a triphenylmethylthio group or a lower alkanoylthio group, such as an acetylthio group], and this compound was treated in the same manner as described in reaction steps 3 and 4. to give a compound of the general formula (■): which is prepared in a suitable solvent such as diethyl ether or methanol in the presence of a base such as pyridine or tri-n-butylamine to a compound of formula MA (where M represents , in particular silver ions, A is prepared by reacting with a salt of a customary anion, such as nitrate, acetate or fluoride, which promotes the dissolution of the salt MA in the chosen solvent.

In the ring-closing reaction to produce the target substance of the general formula (N),
) can be used directly.

However, if R1 is a protected hydroxy group, e.g. a protected hydroxy group that can be easily decomposed by hydrolysis,
For example, the hydroxy protecting group in the compound of general formula (It) representing a lower alkyl group substituted with a tri-substituted silyloxy group is first removed, and then the hydroxy protecting group in the compound of general formula (II) representing a lower alkyl group substituted with a hydroxy group is removed. The resulting compounds can also be used in ring closure reactions.

Starting compounds of general formula (■") in which X does not represent a group -8- are known (for example, Belgian Patent No. 898382 and Tetrahedron
tters), 1983.1631-1634)
or can be produced in a similar manner. A compound of the general formula (■°) in which X does not represent a sulfonyl group -302- is a compound of the general formula (X): [wherein R2 and R3 have the definitions listed under the general formula (I), and R2' represents a protected carboxy group] in an inert solvent or solvent mixture, such as a halogenated hydrocarbon, such as chloroform, an ether, or an aromatic hydrocarbon, such as benzene, at a temperature of from about 60°C to about 60°C. peracetic acid, m-chloroperbenzoic acid or monoperphthalic acid.

General formulas (l゛), (II), (m), (■“) and (I
The functional groups present in the starting materials and intermediates of V) to (X) can be protected with customary protecting groups in a manner analogous to that described for the desired products of general formula (1).

In the compounds of general formulas (Tl) to (X), the functional groups can be changed into protected functional groups or the protected functional groups can be changed into free radicals or different protecting groups. Furthermore, in the compounds of general formulas (II), (m), (■"), (V) and (Vl), the group R3 can be changed to a different group R3. When carrying out these conversion reactions, the molecule Taking into account the further substituents present therein, the same methods as indicated for the corresponding transformation to compounds of general formula (1) can be used.

General formulas (Io), (II>, (TIT) and (V) - (
The diastereomer mixture produced by carrying out the method described in reaction formula 1 for the production of the compound of Alternatively, the optically active compound according to the invention can be isolated from the racemate by any desired processing steps as described above.

The present invention further provides new starting compounds and new intermediates obtainable by the process of the present invention, such as general formulas (IT), (1), (
V) - (■), (IX) and (X) and their production methods.

The starting materials used and the reaction conditions chosen are preferably those which give rise to the compounds already mentioned as particularly preferred.

Does the compound of general formula (I) have a useful pharmacological action?
Alternatively, it can be used as an intermediate for producing compounds with useful pharmacological effects. R2 represents a hydroxy-lower alkyl group, R2 represents a carboxy group or an esterified carboxy group decomposable under physiological conditions, and R3 represents an amino group, a lower alkylamino group, a di-lower alkylamino group, or as described above. Compounds of general formula (1) representing a methylene amino group substituted with and pharmaceutically acceptable salts of the compounds having a salt-forming group have antibacterial activity. For example, these compounds can be used, for example, in vitro to infect Durham-positive and Gram-negative cocci, such as Staphylococcus aureus (Staphylococcus aureus).
hylococcus aureus), Streptococcus pyogenes (St, reptococcus pyoBen)
es), Streptococcus pneumoniae
us pneumoniae), Streptococcus faecalis (Streptococcus faecalis)
alis), meningococcus (N, eisseria me
njnHitidis) and Neisseria gonorrhoeae (Neisseria
gonorr) + oeae ), and also enterobacteria, such as Escherichia coli (lEsc'nerichiaco
li) , Proteus mirabilis
mirabilis) and Klebsiella pneumoniae (Klebsie)
llapneumoniae), Haemophilus influenzae (
Haemoph i Iusinfluenzae) and Pseudomonas aeruginos
a) as well as anaerobes, such as Bactheroides sp.
Clostridium sp.) and Clostridium sp.
Effective at a minimum concentration of 02-64 μg/m+. In vivo, for example in the case of systemic infection of mice with Staphylococcus aureus, Escherichia coli or Streptococcus pyogenes, an ED50 of approximately 0.3-30 mg/kg is obtained by subcutaneous or oral administration.

That is, (5R,6S)-2-aminomethyl-6-((1
'R)-1-hydroxyethyl]-2-benem-3-carboxylic acid (Compound A) and (5R56S)-2-amitumedel-6-hydroxymethyl-2-benem-3-carboxylic acid (Compound C) are U.S. Patent No. 4,272,437
Racemic body known from the specification (1'R, 5R, 6s+1
'S, 5S, 6R)-2-aminomethyl-6-(
Compared to 1″-hydroxyethyl)-2-penem-3-carboxylic acid (compound B), it exhibits the following superior activities:
(Leaving space below) Antibiotic activity of the compound of general formula (1) and known control compound B in vitro Table 1 (continued) Table 1 (continued) All exhibit 2-4 times higher 'activity compared to the corresponding known racemate (compound B). The optically active compound C according to the invention shows a remarkably consistent activity in all tested strains and is 2 to 8 times better than the known racemic homolog (compound B), especially in the Gram-negative region.

The stability of compounds A, B and C against the enzyme dehydropeptidase from human kidney is as follows (denoted by half-life t'A).

tV2 (hours) Compound A 6.75 Compound 8 2.20 Compound C 5,50 Compounds A and C according to the invention surprisingly exhibit lower resistance under the action of renal dehydropeptidase than the known racemate (compound B). It has a significantly longer half-life.

The novel compounds can therefore be used as orally or parenterally administrable antibacterial antibiotics for the treatment of infections, for example in the form of corresponding pharmaceutical preparations.

Compounds of general formula (I) in which at least one of the functional groups present is present in protected form (the protected carboxy group is other than an ester carboxy group which can be decomposed under physiological conditions) are generally It can be used as an intermediate for the preparation of the abovementioned pharmacologically active compounds of formula (I).

The pharmaceutically acceptable compounds of the invention may be, for example, inorganic or organic solids or liquids suitable for oral or parenteral administration, i.e. intramuscular, subcutaneous or intraperitoneal administration of an effective amount of the active ingredient. It can be used in the preparation of pharmaceutical formulations containing, together with or in admixture with, pharmaceutically acceptable excipients.

For oral administration, the active ingredient may be combined with diluents such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and/or glycine and lubricants such as silica, talc, stearic acid or its salts, such as stearic acid. Tablets or gelatin capsules containing magnesium or calcium and/or polyethylene glycol are used. The tablets may further contain binders such as aluminum magnesium silicate, starches such as corn starch, wheat starch, rice starch or waste starch, gelatin, tragacanth, methyl heptulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and optionally disintegrants, such as starch, agar, alginic acid or its salts, such as sodium alginate, and/or foaming mixtures or adsorbents, colorants, flavors or sweeteners. .

For parenteral administration, infusion solutions, preferably isotonic aqueous solutions or suspensions, are particularly suitable, which can be prepared, for example, by lyophilization before use, containing the active ingredient alone or together with excipients, such as mannitol. It can be prepared from formulations. Such formulations may be sterile and/or contain auxiliary agents such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers,
Osmotic pressure regulating salts and/or buffers may be included.

The pharmaceutical preparations according to the invention, which optionally contain other pharmaceutically useful substances, are prepared in a manner known per se, for example by conventional mixing, dissolving or lyophilizing processes, containing about 0% of the active ingredient.
．． It comprises from 1% to 100%, especially from about 1% to about 50%, or in the case of a lyophilizate up to 100%.

Depending on the type of infection and the condition of the infected organism, it weighs approximately 7
1 for use in the treatment of 0 kg warm-blooded animals (human or animal)
The daily dose is from 125 g to about 5 g.

The following examples are merely illustrative of the invention. Temperatures are given in degrees Celsius.

In the examples, the following abbreviations are used:

TLCn thin y distillation chromatography ■R: Infrared spectrum UV: Ultraviolet spectrum NMR: Nuclear magnetic resonance spectrum DBU = 1,5-diazabicycloC5,4,0) undec-5-ene THF: Tetrahydrofuran DMF Nidimethylformamide Anhydrous toluene 200ml 2-C(3s,4R)3 in
(tert-butyldimethylsilyloxymethyl)-4
-(allyloxycarbonylaminoacetylthio)-2
A solution of 3.05 g of -oxo-azetidin-1-yl]-2-1-liphenylphosphoranylidene acetic acid allyl ester is stirred at reflux temperature for 90 minutes under an argon atmosphere. The solvent is then concentrated by evaporation and the crude product is purified by chromatography on silica gel (in MIt
Qi 1. l-ruene/ethyl acetate 9:1). I R(
CH2CI2): 3435.1785.1710
．． A 1580 cm″1° starting material is produced as follows.

12.5 g of triphenylmethyl mercaptan are suspended in 70 ml of methanol at 0° C. and a total of 2.2 g of a 55% sodium hydride suspension in oil are added portionwise over 10 minutes. Then (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-methylsulfonylazetidin-2-one (European Patent Application No. 82113) 11 in 70 ml acetone and 70 ml water Add .1 g of emulsion dropwise over 30 minutes. After stirring for 30 minutes at 0° C. and 1 hour at room temperature, the reaction mixture is concentrated in a rotary evaporator, to which methylene chloride is added and the aqueous phase is separated off. Wash the organic solution with brine and dry over sodium sulfate. After concentration, the crude title compound is purified by chromatography on silica gel (eluent toluene/ethyl acetate 19:1), T
LC() toluene/ethyl acetate 19: 1): Rf
=0.64, TR (methylene chloride)-3390,176
0,1117,835 cm-”.

Molecular sieve (4 people) 27g to anhydrous toluene 17g
8.4 g of (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-)liphenylmethylthioazetidin-2-one and 8.23 g of glyoxylic acid allyl ester ethyl hemiacetal in 0 ml
g and the whole is stirred at 55° C. for 10 hours. After washing and concentrating under reduced pressure in a rotary evaporator, the crude title compound is purified by chromatography on silica gel (eluent toluene/ethyl acetate 95:5). T
L C (silica gel, toluene/ethyl acetate 10
: 1): Rf=0.37 and 0.27, I R(CH
2C12) :3520.1760.1745cm-”
.

l-((33,4R) in tetrahydrofuran 5n+1
3 (tert-butyldimethylsilyloxymethyl)-4-)riphenylmethyl 10-2-oxo-azetidin-1-yl]-2-hydroxyacetic acid allyl ester 604μ 80 μe of thionyl chloride and 88 μl of pyridine are added sequentially over minutes. The white suspension is then stirred at -10° C. for 1 hour and passed on a Hyflo. After washing the residue with toluene, concentration is carried out in a rotary evaporator. The residue was dissolved in 3 ml of dioxane, 293 ml of triphenylphosphine and 0.13 ml of 2,6-lutidine were added thereto, and the whole was stirred at a bath temperature of 115 DEG C. for 2 hours. The mixture is filtered once on Hyflow and the residue is then washed with toluene. The combined f'P liquids are concentrated by evaporation. Chromatography of the residue on silica gel gives the pure product (eluent, toluene/ethyl acetate 9
5:5). TLC (silica gel, toluene/ethyl acetate 1:1): Rf=0.1.8, Ill (CH2CI2
): 1745.1605cm-12((3S, 4
R) 7.5 g of 3 (tert-butyldimethylsilyloxymethyl)-4,-(triphenylmethyl 10-2-oxo-azetidin-1-yl 3-2-1-riphenylphosphoranylidene acetic acid allyl ester) was dissolved in ether. 87
ml, and add 0.5M silver nitrate aqueous solution 7 at room temperature.
Add 0ml. A mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether is then added and the reaction mixture is stirred for a further 20 minutes. The solid material is filtered off with suction and washed with ether, water and ether. For purification, the solid substance was mixed with 40 ml of ether and 40 ml of water.
Make a slurry, filter it with suction, and dry it. I R(C
H2C12): 1'760.1620 cm-'.

2-((3S,4R)3 in 20 ml of anhydrous methylene chloride
-(tert-butyldimethylsilyloxymethyl)-
1.7 ml of pyridine was added to 5 g of silver salt of 4-mercap I.-2-oxo-azetidin-1-yl)-1-)riphenylphosporanilidene acetic acid allyl ester, and then heated at 0°C.
Allyloxycarbonylaminoacetyl chloride 1.
A mixture of 87 g and 10 ml of anhydrous methylene chloride is added dropwise. After stirring for 30 minutes, the solid material is removed (on high flow) and the solution is washed with an aqueous solution of Na It C03 and then with brine.

After drying over Na2SO4, concentrate in vacuo. The residue is purified by chromatography on silica gel (eluent toluene/ethyl acetate 4:1). TR(C
H2C12): 3435.1750.1735.1
695.1615cm"".

The starting material, allyloxycarbonylaminoacetyl chloride, can be produced as follows.

ea) Armyloxycarbonyla LJIJE.

12 ml of allyl chloroformate and 20 ml of water and 5
7.51 g of glycine in 44 ml of N Na0ll solution
Add dropwise to the solution at Q'C. The suspension is then stirred for 16 hours at room temperature. After removing insoluble substances by filtration, the 5f solution was diluted with 100 ml of water and diluted with 2 ml of CH2Cl2.
Wash twice. The aqueous phase is adjusted to pH 2 with 4 N 1 rcl and extracted twice with CI (2 ch. The combined organic extracts are washed once with brine, dried over MgSO4 and concentrated by evaporation to give the title compound. White crystals form.

TR in 01 CH2CI2: 3450.1715cm
-'.

eb) Allyloxycarbonylaminoacetyl chloride 3.18 g of allyloxycarbonylaminoacetic acid at 0°C
Add 5.7 ml of thionyl chloride. The mixture is stirred for 2 hours under protective gas. The mixture is then diluted with anhydrous toluene and concentrated in a rotary evaporator.

IR(CH2CI2): 3435.1800.
1725cm-1° (5R
, 6S)-2-(allyloxycarbonylaminomethyl)-6-(tert-butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester 1.
A solution of 79 g with 1.83 ml of acetic acid and 0.0 ml of acetic acid in THF was added. I
80 ml of N-tetrabutylammonium fluoride solution are added in sequence. After stirring for 4.5 hours, the mixture was dissolved in CH
2Cl21.41! diluted with 200 ml of saturated Na1
Wash with lCOi aqueous solution. The organic phase is then washed with brine, dried over MBSO, filtered and concentrated by evaporation. The product is purified by chromatography on silica gel (1 volume toluene/ethyl acetate 1:1 to anhydrous ethyl acetate).

T R (CH2C12): 3600.3435.1
785.1695.1615 cm-'.

(5R,6S)-2-allyloxycarbonylaminomethyl-6-hydroxymethyl- in 20 ml of anhydrous THF
To a solution of 55 parts of 2-penem-3-carboxylic acid allyl ester was added 60 parts of tetrakis-(triphenylphosphine)-halacium and 1 part of tributyltin hydride at -10°C.
Add ml.

After stirring for 20 minutes at −10° C., 0.2 ml of acetic acid is added and, after removing the cooling bath, the reaction mixture is stirred for a further 30 minutes. After concentration on a rotary evaporator, the residue is taken up in water/ethyl acetate, the aqueous phase is removed and the organic phase is extracted three more times with water. After brief concentration on a rotary evaporator, the combined aqueous phases are lyophilized. UV (phosphate 03 buffer, pl+7.4): λmax=309nm.

2- ((3S, 4.R) in 300ml of anhydrous toluene
-:l((1'R)-1-allyloxycarbonyloxyethyl)-4-(allyloxycarbonylaminoacetylthio)-2-oxo-azetidin-1-yl)-2
-) Riphenylphosboranylidene acetic acid allyl ester 2
．． 4.2 g of the solution was heated at reflux temperature under an argon atmosphere for 2 hours.
Stir for 4 hours. The solvent is then concentrated by evaporation and the crude product is purified by chromatography on silica gel (solvent MIt agent, toluene/ethyl acetate 9:1).

IR(CH2C12) 3435.1790.1740
．． 1720.1580 cm-'' starting material is prepared as follows.

04 Sue(p-methoxybenzyl)-hexahydro-1,3
, 5-) Reazine (Federal Republic of Germany Patent Application Publication No. 2
A solution of 69 g (23.9 mmol) of 2.8 ml of hydrogen chloride in 20 ml of acetonitrile at room temperature was added to a solution of 69 g (23.9 mmol) of
8 g (78.8 tl mol) of solution and 6.45 g (71.66 mmol) of tert-butyl mercaptan are added in succession. Stir the mixture for 22 hours. The insoluble material is aspirated and the dental fluid is concentrated under reduced pressure. The crystalline residue obtained is stirred with ether and filtered with suction. Melting point 142°C0 (2S, 3R)-2-promo 3
-Hydroxybutyric acid (Shimo Higashi et al., Bull, Ch.
em, Soc, Japan52.949 (197
Produced in the same manner as described in 9)) 1.83
g (10 mmol) at room temperature, add 2.76 g (10 mmol) of N-p-methoxybenzyl-N-tert-butylthiomethylammonium chloride 05 and 2.06 g (10 mmol) of dicyclohexylcarbodiimide, 1.40 ml (10 mmol) of triethylamine are added dropwise.

The resulting reaction mixture is stirred at room temperature for 2 hours. The separated dicyclohexyl urea is filtered off with suction, the r-liquid is diluted with methylene chloride and washed with water and a phosphate buffer solution of p+I8. The organic phase is dried over sodium sulfate, concentrated by evaporation and the oily residue is chromatographed on silica gel using toluene/ethyl acetate. The title compound is obtained in the form of a colorless viscous oil. Rf () Ruen/
Ethyl acetate 1:1): 0.55, IR (methylene chloride)
: 3550-3200.2950-2850.163
2.1608.1508.1457.1438.140
7.1360.1242.1202.1175.115
0.1028cm-”.

<23,3R)-N-p-methoxybenzyl-N tert-butylthiome 06 thyl-2-bromo-3-hydroxybutyramide 1.9 in 50 ml of methylene chloride
Add 2.06 g of 90% m-chloroperbenzoic acid (2.06 g) to 1 g solution of 7 g (4.89 mmol) at -14°C while stirring.
approximately 2.2 equivalents). The reaction mixture is stirred at 0° C. for 80 minutes. The separated m-chlorobenzoic acid was removed by iP
The solution is diluted with methylene chloride and shaken sequentially with a 3% aqueous sodium bisulfite solution and an 8% aqueous sodium bicarbonate solution.

The organic phase is dried over sodium sulfate, concentrated by evaporation under reduced pressure and the residue is chromatographed on silica gel with toluene/ethyl acetate (71) and (6:1.). The title compound is obtained in the form of a colorless viscous oil. Rf (toluene/ethyl acetate 1:1) 0.43, [
α)=+88±1° (1.01% in chloroborum).

I H-NMR spectrum (CDC) 400 Ml in 3
lz) indicates that two rotamers exist in a ratio of 3:1.

07 (2S,3R)-N-p in 8 ml of tetrahydrofuran
-Methoxybenzyl-N-tert-butylsulfonylmethyl-2-bromo-3-hydroxybutyramide 4
A solution of 1,5-diazabicycloC5,4,O)undec-5-ene 340 in 1 ml of te-1-rahydrofuran at -14°C with exclusion of water was added to a solution of
Add m1. The solution was stirred at room temperature for 75 minutes. After addition of methylene chloride, the organic phase is extracted by shaking with 15% aqueous citric acid and 8% aqueous sodium bicarbonate.

The organic phase is dried over sodium sulfate and concentrated by evaporation under reduced pressure. After chromatography of the residue on silica gel with 1-toluene/ethyl acetate (4:1), the title compound is obtained in the form of a colorless viscous oil. Rf
() toluene/ethyl acetate 1:1): 0.29, [α)
=+45±1" (1.065% in CIlCI3).'
H-NMR spectrum (CI) in CI3 4. OOM
llz) indicates that the two rotamers are present in a ratio of 1:2.8.

e)-←L5-! LB ---' 08 -3- ((1'R)-1-Hydroxyethyl-(2S,3R)-N- in 2.5 ml of tetrahydrofuran)
p-Methoxybenzyl-N tert-butylsulfonylmethyl-2,3-epoxybutyramide 398■ (1
, 12 mmol) in THF with stirring at 0° C. without excluding water, add 5 g of dehydrated tetra-n-butylammonium fluoride trihydrate (tetra-n-butylammonium fluoride trihydrate) in THF. 55℃, Q, 111
Dehydrated with 11111111 and 20% with tetrahydrofuran.
(manufactured by making it m1)? 'ml is fed-batch.

4 active molecular sieves were added to the reaction mixture;
Stir the whole thing for 2 hours. suction ir for molecular sieve
” and washed four times with 20 ml of methylene chloride each time.

Add 5 parts of diethyl ether to each IR solution and wash the IR solution sequentially with an aqueous phosphate buffer solution of p'l18. The combined organic phases are dried over magnesium sulphate and concentrated by evaporation under reduced pressure. The residue is chromatographed on 20 g of silica gel with toluene/ethyl acetate (3:1) to give the crystalline title compound.

Melting point 112~] 13°C (from Koffler, methylene chloride, diethyl ether, pentane); Rf (toluene/
Ethyl acetate 1:1): 0.27, [α]-19±1°
(1.105% in chloroform). I H-NMR spectrum (400 Mllz in CDCI3): 4 (R
) - δ-4 with respect to the proton (a) at the position of the carbon atom,
65,3(S)-δ-3,6L for the proton (b) at the position of the carbon atom and 1″ (R
) - δ for the proton (C) at the position of the carbon atom = 4.
09; J a-b: about 2, Jb-c: about 7.

Tetra-n-butylammonium hydrogen sulfate 0.68g
(2 mmol) in 20 ml of methylene chloride (33,4
R)-1,-p-methoxybenzyl-3-((1'R)
-1-Hydroxyethyl]-410 ter t-butylsulfonyl-2-azetidinone 1.
77 g (5 mmol) of solution and 20 ml of IN aqueous sodium hydroxide solution are added to a two-phase system.

With vigorous stirring, at 0° C., 0.8 ml (7.5 mmol) of chloroformic acid allyl ester are added. 2 for this
After 0 minutes and 40 minutes, allyl chloroformate 0.
Add 8ml. After a reaction time of 60 minutes, methylene chloride is added to the mixture, the aqueous phase is separated and the organic phase is washed successively with 5% aqueous citric acid and 8% aqueous sodium bicarbonate. After drying the organic phase over sodium sulfate and concentrating by evaporation under reduced pressure, the crude product is obtained as a residue. This is purified by chromatography on Merck silica gel using 1 to toluene/ethyl acetate (9:1). Melting point 90-91"c, Rf (toluene/ethyl acetate 4:1): 0.43, [α) = +46±1° (1.49% in chloroborm).

11 (3S,4R)-1-p in 1.2 ml of acetonitrile
-Methoxybenzyl-3-[(1'R)-1-allyloxycarbonyloxyethyl]-4-tert-butylsulfonyl-2-azetidinone in a solution of 518 μm (1.18 mmol) in 6 ml of water at 0°C. A solution of 2.46 g (4.48 mmol) of ammonium cerium nitrate (rV) is added and the whole is stirred for 1 hour at room temperature. Extracted with ethyl acetate, dried the organic phase over sodium sulfate,
After concentration by evaporation under reduced pressure, the crude product is obtained. This is purified by chromatography on 20 g of Merck silica gel using toluene/ethyl acetate (4:1 and 1:1). Melting point 137-138℃, [α]-+
49+1' (1.067% in Rioo*rum), Rf(
Toluene/ethyl acetate 1:1): 0.48° (3s) in a similar manner as described in Example 1a).

0.86 g of 4R)-3-((1'R)-1-allyloxycarbonyloxyethyl)-4-tert-butylsulfonylazetidin-2-one are converted to the title compound.

IR(CH2CI2): 3395.1770.
1750 cu-1° (3S) in a similar manner as described in Example 1b).

4, R)-3-C(1°R)-1-allyloxycarbonyloxyethyl) 4 0.82 g of tert-butylsulfonylazedecin-2-one is converted to the title compound.

I R(CH2C12): 3510.1770.1
745cm-”.

13 In a similar manner as described in Example 1c), 2-((3S,
4R) -3-((1'R)-1-allyloxycarbonyloxyethyl)-4=)liphenylmethylthio2-oxo-azetidin-1-yl]-2-hydroxyacetic acid allyl ester (1 g) of the title convert into a compound.

IR(CH2CI2): 1745.1620
cm-1° In a similar manner as described in Example 1d), 2-
((33,4R)-3-((1'R)-1-allyloxycarbonyloxyethyl)-4-)rifle methylthio-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylidene Acetic acid allyl ester 0.46
Replace g with the title compound. I R(CH2CI2
): 1765.1745.1630cm-1゜)
-,3S R--[LL1Ynee14 1-allyloxycarbonyloxyethyl]-4 Example 1e
), 2-((3S,4R)
-3-C(1'R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl2-triphenylphosphoranylidene acetic acid allyl ester (silver salt) 0.385 g Conversion to the title compound using allyloxycarbonylaminoacetyl chloride. , IR(CH2CI2):3440.
1750.1740.1700, 1620cm -'
.

(5R,63)-2-allyloxycarbonylaminomethyl-6-((1'R)- in 20 ml of anhydrous TIIF
To a solution of 15 425 μl of 1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester was added at -10° C. 60 mg of tetrakis-(triphenylphosphine)-palladium and then 1.07 ml of tributyltin hydride. Add.

After stirring for 20 minutes at −10° C., 0.3 ml of acetic acid is added and, after removing the cooling bath, the reaction mixture is stirred for a further 30 minutes. After concentration on a rotary evaporator, the residue is taken up in water/ethyl acetate, the aqueous phase is separated off and the organic phase is further extracted three times with water.

After brief concentration on a rotary evaporator, the combined aqueous phases are lyophilized. UV (phosphate buffer, pl+7.4): λmax
=308 nm; α2D (0.07% in water): +
220°±11°.

ester 2-C (3S) in a similar manner as described in Example 4.

4R)-3-C(1'R)-1-allyloxycarbonyloxyethyl)-4-(N-methyl-N-allyloxycarbonylaminoacetylthio)16 -2-oxo-azetidin-1-yl)- 2-1 ~ rifhenylphosphoranylidene acetic acid allyl ester 2, 42
Replace g with the title compound.

TR (methylene chloride) X1780.1745.1705
．． The 1580 cm −1° starting material is prepared as follows.

a) 347 N-allyloxycarbonyl salts 1. ea
15 g of sarcosine are converted to the title compound in a similar manner as described in ).

IR (methylene chloride): 1705 cm-'.

In a similar manner as described in Example 1eb), 3.46 g of N-allyloxycarbonylsarcosine are converted to the title compound using 6.27 ml of thionyl chloride. IR(
Methylene chloride): 1800.1710 cm-1°17 ■-yl)-2-) Liphenylphosporanylidene Example 1e
), 2-((33,4R)
-3-((1'R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylidene acetic acid allyl ester (see Example 41) 3 .75g of N-allyloxylponylaminosarcosyl chloride 1.55g
g to give the title compound. IR (methylene chloride): 1750.1700.1620 cm-1° In a similar manner as described in Example 5, (5R,6S)-2-(N
-methyl-N-allyloxycarbonylaminomethyl)
Convert 1.3 g of -6-((1'R) -1-allyloxycarbonyloxyethyl]-2-benem-3-carboxylic acid allyl ester to the title compound. UV (phosphate buffer, pH 18 7.4 ) λIIIax = 311 nm (5R,6S)-2-aminomethyl-6- in 1 ml of water
Hydroxymethyl-2-benem-3-carboxylic acid 23■
A solution of 8.4μ of sodium bicarbonate and 4n+ of water at room temperature.
109.5 mg of ethylpormimide-1 hydrochloride in l
and 84 μm of sodium bicarbonate. After stirring for 50 minutes at room temperature, 191 ml of IN salt are added and the whole is concentrated by evaporation under high vacuum. OPT crude materials
Purify by chromatography on I-UPC, 2. UV (phosphate buffer, pH 7,4) λmax=3
06.5nm.

In a similar manner as described in Example 8, (5R,6S)-2
-Aminomethyl-6-((1'R)-1-hydroxyethyl]-2-benem-3-carbo]19 Convert 51 mg of phosphoric acid to the title compound. UV (phosphate buffer, pll '7. 4) λmax = 310
nm.

In a similar manner as described in Example 1, 2-CC3S, 4.
R) 3 (tert-methylenemethylene/L/SiIJ
0.71 g of liphenylphosphoranylidene acetic acid allyl ester are converted into the title compound. IR (methylene chloride): 1790.1
705.1560 cm-1° The starting material is prepared as follows.

De-2-C(3S,4-R)-3-(tert-butyldimethylsilyloxymethyl)-4-mercapto-20 2-oxo-azetidin-1-yl)-2-1-liphenylphosphoranylidene Silver salt of acetic acid 2-allyl ester [
Example 1 d)) 30 g are dissolved in 600' ml of anhydrous methylene chloride, the solution is cooled to O'c and 120 mg of 4-dimethylaminopyridine and 6.8 ml of pyridine are added thereto. After adding 5.04 ml of chloroacetyl chloride and a further 1.5 ml of pyridine, the reaction mixture was heated at 0°C for 30
Stir for a minute. Remove the precipitate from one unit, and reduce the 1F liquid to Na II.
Wash with aqueous CCh solution and then with brine, dry over sodium sulfate and concentrate by evaporation. After purification on silica gel (eluent, toluene/ethyl acetate 9:1), the pure title compound is obtained. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.5;
I R(CH2C12): 1750.1680.1
610cm-'.

4,04 g of (5R,6S)-2-chloromethyl-6
-(tert-butyldimethylsilyloxymethyl)-2-benem-3-carboxylic acid allyl ester
Dissolve in 40ml of MF and add 0.9 ml of sodium azide to this.
Add g. After stirring for 6 hours, the solvent is reduced to a volume of 115 and the residue is partitioned between ethyl acetate and water. Dry over sodium sulfate and evaporate the solvent. The crude mixture is purified by chromatography on silica gel (eluent toluene/acetic acid). I R(CH2C
I2): 2110.1790.1705.158
5cm-1° (5R
, 6S)-2-azidomethyl-6-(tert-butyldimethylsilyloxymethyl)-2-benem-3-carboxylic acid allyl ester are converted into the title compound. IR (methylene chloride): 3595.2120.179
0.1710.1585cm-”.

22 In a similar manner as described in Example 3, (5R,6S)-2
-azidomethyl-6-hydroxymethyl-2-penem-
0.89 g of 3-carboxylic acid allyl ester are converted to the title compound. UV (phosphate buffer, pH 7, lI) λ
max=309nm.

0.53 g of (5R,6S)-2-azidomethyl-6-hydroxymethyl-2-penem-3-carboxylic acid was dissolved in THF.
/water (1:1) in the presence of 0.53 g of activated carbon with 10% palladium at room temperature at normal pressure.
Hydrogenate for an hour. ) Filtration and concentration are carried out and the crude mixture is purified by reverse phase column chromatography (eluent, water). UV (phosphate buffer, pH 7,4) λma
x=309nrn.

This product is identical to the compound prepared according to Example 3.

Sonoue upper: and R65--1'' Bow LL Ward 23 Rubonylaminomethyl)-6-((1'R)-1(
3S, 4R)-1(1-allyloxycarbonyloxyethyl)-4-allyloxycarbonylaminoacetylthio-azetidin-2-one (317 mmol) was dissolved in 5 ml of methylene chloride, and the solution was evaporated. 15°
Cool to C. This was then added with 0.143 ml of allyloxyoxalyl chloride and 0.217 ml of Hunig's base.
m1 is added and the whole is stirred at -15°C for 30 minutes. The reaction solution was reduced to 0. Wash once with IN hydrochloric acid (cooled) and twice with saturated sodium chloride solution, dry over sodium sulfate and concentrate in a rotary evaporator. The residue is extracted twice with toluene in a rotary evaporator.

Crude 1-C(33,4R)-3-((1'R)=1
The oily residue containing allyl ester of -allyloxycarbonyloxyethyl]-4-allyloxycarbonylaminoacetylthio=2-oxo-azetidin-1-yl]-2-oxoacetate was dissolved in 20 ml of toluene and triethyl phosphatide was dissolved. Fight 0.3
2 ml was added and the whole was heated under argon at 103°C for 17 ml.
Heat for an hour. The solution was concentrated and subjected to preparative thin layer chromatography on silica gel (system: toluene/ethyl acetate 3:
Purify according to 1). The product is identical to the compound described in Example 4.

The starting material (33,4.R)-3-(1-allyloxycarbonyloxyethyl)-4-allyloxycarbonylaminoacetylthio-azetidin-2-one is
It is manufactured as follows.

Allyloxycarbonylaminothioacetic acid 450■ (2,
57 mmol) in 7 ml of water and 2.5 ml of IN sodium hydroxide are added at room temperature under a nitrogen atmosphere. Then (3s in methylene chloride 51).

4R)-3-((1'R)-1-Roxycarbonyloxyethyl) 4 A solution of 585 μm (1,83 mmol) of tert-butylsulfonyl azetidin-2-one was added and the emulsion was placed in a nitrogen atmosphere. Stir vigorously for 1 hour at room temperature. The reaction mixture is partitioned and the organic phase is washed 225 times with saturated sodium chloride solution. The aqueous phase is extracted twice with methylene chloride.

The organic solution is dried over sodium sulfate and concentrated in a rotary evaporator. The crude product is purified by flilli thin layer chromatography (system: hexane/ether 1:9).

The following compounds can be prepared in a manner similar to that described in the examples above using the corresponding starting compounds. : (5R,6S)-2-(N-acetamidinomethyl)-
6-Hydroxymethyl-2-penem-3-carboxylic acid UV (phosphate buffer, pH 7,4), λmax 5307
nm.

(5R,63)-2-(N-acetamidinomethyl)-
6-((1'R)-1-hydroxyethyl]-2-penem-3-carboxylic acid UV (phosphate buffer, pl+7.4), λmax=31
1 nm.

(5R,63)-2-(N-guanidinylmethyl)26-6-hyroxymethyl-2-benem-3-carboxylic acid UV (phosphate buffer, pH 7,4), λll1ax=3
06 nm.

(5R,6S)-2-(N-guanidinylmethyl)-6
-C(1'R)-1-hydroxyethyl]-2-penem-3-carboxylic acid UV (phosphate buffer, pl+7.4), λmax=31
0 nm.

(5R,63)-2-(N-ethylaminomethyl)-6
-((1'R)-1-hydroxyethyl]-2-benem-3-carboxylic acid UV (phosphate buffer, pl+7.4), λmax=31
0 nm.

(5R,6S)-2-(N-ethylaminomethyl)-6
~Hydroxymethyl-2-benem-3-carboxylic acid UV (phosphate buffer, pl+7.4), λmax =
311 nm.

(5R,6S)-2-(N-propylaminomethy12ful)-6-((1“R)-1-hydroxyethyl]=2
-Benem-3-carboxylic acid UV (phosphate buffer, pl+ 7.4), λmax=
312 nm.

(5R,6S)-2-(N-propylaminomethyl)-
6-Hydroxymethyl-2-benem-3-carboxylic acid UV (phosphate buffer, pl+7.4), λmax=31
1 nm.

(5R,6S)-2-(N-methylaminomethyl)-〇-hydroxymethyl-2-penem-3-carboxylic acid UV (phosphate buffer, pH 7,4), λmax=306
nm.

Dissolve 1.2 g of thorium iodide in 3.7 ml of acetone, and add 0.2 g of ethyl-1-chloroethyl carbonate to this solution.
Add 75ml. The mixture is stirred at room temperature for 3 hours. Next, the solution was added to 15.0 ml of methylene chloride to remove one precipitated inorganic salt. The methylene chloride solution was concentrated to a volume of 2 ml and dissolved in dimethylacetamide 4 at 0°C.
0.23 g of (5R,63)-2-aminomethyl-6-hydroxymethyl-2-benem-3-carboxylic acid in ml
(1 mmol). Next, mix the mixture with O'
Stir at C for 3 hours, dilute with ethyl acetate and wash three times with water. The organic phase is dried over sodium sulfate and concentrated in a rotary evaporator. The crude product is purified on 10 g of silica gel using ethyl acetate as eluent. The title compound is obtained in the form of a white foam. IR (methylene chloride):
Suction hand at 1790 and 1740 cm-1.

Dissolve 0.6 g of sodium iodide in 2 ml of acetone,
Add 0.15 ml of pivalic acid chloromethyl ester. The mixture was stirred at room temperature for 3 hours, then diluted with methylene chloride, 7
．． Add to 5 ml. 29) Remove the precipitated inorganic salt. Concentrate the methylene chloride solution to a volume of 1 ml and prepare 0.092 g of (5R,6S)-2-aminomethyl-6-hydroxymethyl-2-benem-3-carboxylic acid in N,N-dimethylacetamide 4n+1 at 0 °C. (0,
4 mmol) and diisopropylethylamine 0.07
m1 solution. The mixture is then stirred at 0° C. for 3 hours, then diluted with ethyl acetate and washed three times with water. The organic phase is dried over thorium sulfate and concentrated in a rotary evaporator. The crude product is purified on 10 g of silica gel using ethyl acetate as eluent. The title compound is obtained in the form of a white foam. IR (methylene chloride) = 17
Adsorption hunt at 90 and 1730 cm-1.

Separate-19- The following compound is obtained in the same manner as described in the above example.

(5R,6S)-2-aminomethyl~6-((1'R)
-1-Hydroxyethyl]-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester 30 T R (CH2CI2) 41785.1.740c
m-'.

(5R,6S)-2-aminomethyl-6-((1'R)
-1-Hydroxyethyl]-2-penem-3-carboxylic acid pivaloyloxymethyl ester TR (CH2C1
2): 1790.1735cm-”.

As an active ingredient, (5R,6S)-2-aminomethyl-6
Dry ampoules or vials each containing 0.5 g of -((1'R)-1-hydroxyethyl]-2-penem-3-carboxylic acid are prepared as follows.

(per ampoule or vial): Active ingredient 0
．． 5g Mannitol 0.05g A sterile aqueous solution of the active ingredient and Mannitol was prepared under aseptic conditions.
lyophilized in ml ampoules or 5 ml vials;
Melt and check the ampoule or vial.

Instead of the active ingredients mentioned above, it is also possible to use the same amount of another active ingredient from the examples above, such as (5R,63)-2-amythyl-31-thyl-6-hydroxymethyl-2-penem-carboxylic acid. .

Margin below +32

Claims (1)

[Claims] 1. General formula (■): [In the formula, R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, and R2 is a carboxy group or a carboxy group modified with a functional group. and R3 represents an amino group, an amino group substituted with a lower alkyl group, a substituted methylene amino group or a protected amino group], an optically substantially pure (5R,6S)-configured compound,
Optical isomers of the compound of general formula (1) having a chirality center in the group R3, mixtures of these optical isomers, and salts of the compound of general formula (1) having a salt-forming group. 2, R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, R2 represents a carboxy group, an esterified carboxy group that can be decomposed under physiological conditions, or a protected carboxy group R21; R3 is an amino group, a lower alkylamino group, a di-lower alkylamino group, 2N-C(X+, X2) (wherein X1 is hydrogen, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkylene amino group , nitroamino group, hydrazino group, anilino group, lower alkoxy group, phenyl-lower alkoxy group, lower alkylthio group, lower alkyl group, amino-lower alkyl group, N-lower alkylamino-lower alkyl group, N, N-di lower alkylamino-lower alkyl groups, lower alkenyl groups, phenyl groups, pyridyl groups, such as 2- or 4-pyridyl groups,
represents a chenyl group, such as a 2-chenyl group, or a thiazolyl group, such as a 4-thiazolyl group;
anilino group, lower alkoxy group, phenyl-lower alkoxy group or lower alkylthio group),
or a compound of the general formula (T) according to claim 1, in which R3 represents a protected amino group, optical isomers of the compound of the general formula (1) having a center of chirality in the group R1, and optical isomers thereof. Salts of compounds of general formula (1) having salt-forming groups in mixtures of compounds and in optically substantially pure form. 3. R1 is a hydroxy group at the α-position, a tri-lower alkylsilyloxy group, a 2-halo lower alkoxy group, a 2-
halo represents a lower alkoxycarbonyloxy group, a lower alkenyloxycarbonyloxy group, or a lower alkyl group substituted with an unsubstituted or nitro-substituted phenylene group, and R2 represents a carboxy group, a lower alkenyloxycarbonyl group, a Substituted or nitro-substituted benzyloxycarbonyl groups, lower alkanoylmethoxycarbonyl groups, 2-halo lower alkoxycarbonyl groups, 2-tri-lower alkylsilylethoxycarbonyl groups or esterified carboxy groups decomposable under physiological conditions, such as 1-lower Alkoxycarbonyloxy-lower alkoxycarbonyl group, lower alkanoyloxymethoxycarbonyl group, α-amino-lower alkanoyloxymethoxycarbonyl group or phthalidyloxycarbonyl group, R3 is an amino group, a lower alkylamino group, a di-lower alkylamino group, Formula-N-C
(X+, (represents an alkylamino group), or R3 represents an azide group, a phthalimino group, a nitro group, a lower alkenyloxycarbonylamino group, an unsubstituted or nitro-substituted benzyloxycarbonylamino group, a 1-lower alkanoyl-lower alk-1 The compound of the general formula (1) according to claim 1, which does not represent an -en-2-ylamino group or a 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino group, has a chirality center in the group R1. Optical isomers of compounds of the general formula (T) having a salt-forming group, mixtures of these optical isomers and optically substantially pure forms of the compound of the general formula (T) having a salt-forming group
Salts of compounds of I). 4. R1 represents a lower alkyl group substituted with a hydroxy group at the α-position, and R2 is a carboxy group or an esterified carboxy group that can be decomposed under physiological conditions, such as a 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl group. or represents a lower alkanoyloxy-methoxycarbonyl group, and R3 represents an amino group, a lower alkylamino group, or a formamidino group, a compound of the general formula (1) according to claim 1, having a center of chirality in the group R1 Optical isomers of compounds of general formula (1), mixtures of these optical isomers and salts of compounds of general formula N) with salt-forming groups in optically substantially pure form. 5. The compound of the general formula (1) according to claim 1, in which R1 represents a hydroxymethyl group or a 1-hydroxyethyl group, R2 represents a carboxy group, and R3 represents an amino group, and an optically substantially its salt in its pure form. 6. A pure optical isomer of the compound of general formula (1) according to claim 1, which has a center of chirality in the group R. 7. 1"R of the compound of the general formula (1) according to claim 1, in which R1 represents a 1-hydroxyethyl group and R2 and R3 represent the compounds described in claim 1
) - isomer. 8. A pharmaceutically acceptable salt of a compound of general formula CI) according to claim 1. 9. Ester of the compound of general formula (I) which decomposes under physiological conditions. The compound according to claim 1. 10, (5R,6S)-2-aminomethyl-6-hydroxymethyl-2-benem-3-carboxylic acid and the pharmaceutically acceptable salts thereof in optically substantially pure form. A compound according to scope 1. 1.1.2-(N-methylaminomethyl)-6-((1
'R)-1-Hydroxyethyl-2-benem-3-carboxylic acid and the pharmaceutically acceptable salt thereof in optically substantially pure form. 12, (5R,6S)-1-(N-formamidinomethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and its optically substantially pure form, pharmaceutically acceptable salts. The compound according to claim 1, which is ], 3. (5R,6S)-2-(N-polamidinomethyl)-6-((1'R)-1-hydroxyethyl-2-benem-3-carboxylic acid and its optically substantially pure form The compound according to claim 1, which is a pharmaceutically acceptable salt of 14, (5R,63)-2-(N-acetamidinomethyl)-6-((1'R)-1- Hydroxyethyl two 2
-Benem-3-carboxylic acid and its pharmaceutically acceptable salts in optically substantially pure form. 15. (5R,6S)-2-(N-methylaminomethyl)-6-hydroxymethyl-2-benem-3-carboxylic acid and pharmaceutically acceptable salts thereof in optically substantially pure form The compound according to claim 1, which is 16, (5R,63)-2-aminomethyl-6-((1
'R)-1-Hydroxyethyl-2-penem-3-carboxylic acid and its pharmaceutically acceptable salts in optically substantially pure form. 17, General formula (■); [In the formula, R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, R2 represents a carboxy group or a carboxy group modified with a functional group, and R3 represents an amino or a pharmaceutically acceptable salt of said compound having a salt-forming group. 18. The general formula (
1. A method for treating bacterial infections in mammals, which comprises administering a therapeutically effective amount of the compound of 1) or a pharmaceutically acceptable salt thereof. 19. General formula (■): [In the formula, R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, R2 represents a carboxy group or a carboxy group modified with a functional group, and R3 represents an amino group, representing an amino group substituted with a lower alkyl group, a substituted methylene amino group or a protected amino group], a compound having chirality in the group R1 For producing optical isomers of compounds of general formula (I) having a center, mixtures of these optical isomers and salts of compounds of general formula (1) having a salt-forming group, a) general formula (I') : [In the formula, R7 has the definition given below in general formula (I), and R
2T represents a protected carboxy group and Q represents a group convertible to group R3], or b) general formula (■): 1 [wherein R1 and R3 have the definitions listed under general formula (T), R21 represents a protected carboxy group, Z represents oxygen or sulfur, and X, together with the cation, represents a tri-substituted phosphonio group or or C) general formula (■): [wherein R1 and R3 have the definitions listed under general formula (1), and Z is oxygen or sulfur and R2' represents a protected carboxy group] with an organic compound of trivalent phosphorus, or d) a compound of the general formula (III'): [wherein R1 and R3 are of the general formula ( I), R21 represents a protected carboxy group and X represents a group -8- or a group -3O2-] by removing the group If desired, in the resulting compound of general formula N) the protected hydroxy group in the group R1 is changed to a free hydroxy group and/or if desired, in the resulting compound of general formula N
) protected carboxy group R2' in the compound produced
into a free carboxy group, an esterified carboxy group that can be decomposed under physiological conditions or a different protected carboxy group R2', or an esterified carboxy group or a protection that can decompose the free carboxyl group R2 under physiological conditions. and/or, if desired, changing the protected amino group R3 to a free amino group or changing the free amino group R3 to a substituted amino group, and/or
or, if desired, converting the resulting compound with a salt-forming group into a salt, or converting the resulting salt into a free compound or a different salt, and/or, if desired, creating the general formula (1)
A method for producing a 2-aminomethyl compound, which comprises separating a mixture of isomeric compounds into individual isomers. 20. General formula (V'): [In the formula, R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, Z represents oxygen or sulfur, and R3 is an amino group, a lower alkyl-substituted amino group ,
Represents a substituted methylene amino group or a protected amino group]
optically substantially pure (3R,43)-configured compounds, optical isomers of compounds of general formula (Vl) having a center of chirality in the group R1 and mixtures of these optical isomers. 21. General formula (■): [In the formula, R1 represents a hydroxy group or a lower alkyl group substituted with a protected hydroxy group, R2' represents a protected carboxy group, and R3 is an amino group, a lower alkyl substituted represents an amino group, a substituted methylene amino group or a protected amino group, and Z represents oxygen or sulfur], having a center of chirality in the group R1 Optical isomers of the compound of general formula (III) and mixtures of these optical isomers.