Sulfur-containing compounds method for their use and prodction

A first embodiment of the invention relates to novel carbapenem compounds, (1R, 5S, 6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxy-ethyl!-1- methylcarbapen-2-em-3-carboxyic acid derivatives. These carbapenem compounds are represented by the following formula having a beta-coordinated methyl group introduced at the 1-position and a 1-(1,3-thia-zolin-2-yl)azetidin-3-yl!thio group introduced at the 2-position. ##STR1## In the formula, R is hydrogen; lower alkyl group which is unsubstituted or substituted by hydroxy, lower alkoxy or lower alkoxy-lower alkoxy group; group --COOR.sup.1 (R.sup.1 is hydrogen or lower alkyl group); or group --CONR.sup.2 R.sup.3 (R.sup.2 and R.sup.3 are, independently each other, hydrogen or lower alkyl), and Y is carboxy, --COO.sup..crclbar. or protected carboxy. These compounds are useful antibiotics for prevention and treatment of bacterial infections. The second embodiment of the invention relates to 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine represented by the following formula and its acid addition salts ##STR2## and to the production process therefor. The above compounds are useful as intermediates for preparing carbapenem compounds, which have strong antibacterial activity, with convenience and high yield.

The substituent designation of the formulae according to the first 
embodiment are specific to the first embodiment and may be the same or 
different than the substituent designation of formulae of the second 
embodiment. 
BACKGROUND OF THE FIRST EMBODIMENT OF THE INVENTION 
1. Field of the Invention 
The first embodiment of the invention relates to 2-1-(1,3-thiozolin-2-yl) 
azetidin-3-yl!thio-carbapenem derivatives. 
The present invention relates to carbapenem antibiotics and, more 
particularly, to 1.beta.-methyl-carbo-penem derivatives having a methyl 
group introduced at the 1-position and 
1-(1,3-thiozolin-2-yl)azetidin-3-yl!thio group introduced at the 
2-position of the carbapenem skeleton, and to antibacterial compositions 
containing the same as an active ingredient. 
2. Description of the Prior Art 
Heretofore, as various antibacterial substances, there have been proposed 
many carbapenem antibiotic substances having, as a basic skeleton, 
carba-2-penem-3-carboxylic acid represented by the following formula (A): 
##STR3## 
For example, an initial generation of carbepenem antibiotics is a naturally 
occurring carbepenem compound such as thienamycin represented by the 
formula (B): 
##STR4## 
The thienamycin may be obtained from a fermentation broth of Streotomyces 
cattleya and has a broad range of antibacterial spectra against 
Gram-positive and Gram-negative bacteria. It has been expected therefore 
to be developed as a highly useful compound, but its poor chemical 
stability has precluded its commercialization. 
With the foregoing background, many researchers have attempted to develop a 
carbapenem compound having antibacterial activities as high as thienamycin 
and ensuring more chemical stability. As a result, there has been 
developed imipenem (INN) represented by the following formula (C): 
##STR5## 
This compound is a practically available antibacterial agent and may be 
obtained by converting an amino group as a side chain at the 2-position to 
a formimidoyl group. 
The imipenem of the formula (C) exhibits anti-bacterial activities higher 
than those of the thienamycin and ensures some degree of chemical 
stability; however, it presents the disadvantage that it is decomposed 
within a short period of time by kidney dehydropeptidase (DHP) in the 
living body. For this reason, it cannot be administered singly, and must 
be used in combination with a DHP inhibitor in order to control its 
decomposition leading to inactivation. Its formulation for clinical 
administration is a combination with cilastatin (INN) that is a DHP 
inhibitor. 
An antibacterial agent preferred for practical clinical use, however, is 
one that alone can demonstrate antibacterial activity. Furthermore, the 
DHP inhibitor to be combined with the antibiotic could exert undesirable 
actions on tissues of the living body. For these reasons, the combined use 
should be avoided wherever possible. Thus there has been a growing demand 
for a carbapenem compound having sufficiently high degrees of both 
antibacterial activity and resistance to DHP. 
Recently, there were proposed some carbapenem compounds of the type that 
could achieve the above objectives. Such carbapenem compounds are 
1-methyl-carbapenem compounds in which a methyl group is introduced at the 
1-position and various heterocyclyl-thio groups at the 2-position of the 
carbapenem skeleton. For example, Japanese Laid-Open Patent Publication 
No. 202,866/1985 to Sankyo discloses 
2-heterocyclyl-thio-1-methylcarbapenem compounds including a compound 
having at the 2-position a (N-methylacetoimidoyl-azetidin-3-yl)thio 
substituent, represented by the formula (D): 
##STR6## 
It is reported that this compound has superior antibacterial activities as 
well as a remarkably improved resistance to decomposition by DHP leading 
to inactivation so that it demonstrates highly useful effects; however, 
the Japanese Patent document does not provide any specific antibacterial 
data or working examples. Therefore, Sankyo does not disclose anything 
about carbapenem compounds having at the 2-position 
1-(1,3-thiazolin-2-yl)azetidin-3-yl-thio substituent according to the 
present invention. Most recently, International Patent Publication Number 
WO 93/23,402 to Fujisawa disclosed 2-(3-azetidinylthio) carbapenem 
compounds represented by the following formula (E): 
##STR7## 
In the specification of this patent publication Fujisawa specifically 
discloses the carbapenem compounds represented by the following formula 
(F): 
##STR8## 
wherein R.sup.4 and R.sup.5 are combined together to form optionally 
substituted imino-containing heterocyclic group: 
however, among the compounds of formula (F), the only one compound is 
supported by working example, and there isn't any specific description of 
antibacterial data whatsoever. No specific compounds according to the 
present invention are disclosed therein, and any prior patent application 
mentioned above does not suggest anything about such compounds as having 
superior pharmacological characteristics as demonstrated and claimed in 
the present invention. Therefore, there was no anticipation of the 
specific compounds disclosed and claimed herein. 
Carbapenem compounds possess a potent antibacterial activity with a broad 
spectrum. However, like other .beta.-lactam antibacterial agents used in 
clinical practice, it is anticipated that carbapenem compounds will be 
uneffective against carbapenem-resistant bacteria. Accordingly, there have 
been proposed some carbapenem compounds having unique substituents at 
2-position of the carbapenem skeleton. Furthermore, even though oral 
formulations of carbapenem compounds are useful for daily administration, 
the carbapenem antibiotics which have been proposed in prior patent 
application are mainly used for injectable formulation. Therefore, there 
has been a demand for orally administrable carbapenem antibiotics. 
SUMMARY OF THE FIRST EMBODIMENT OF THE INVENTION 
The present invention provides carbapenem compounds having high 
antibacterial activities, a strong action of inhibiting .beta.-lactamase 
as well as improved resistance to kidney dehydropeptidase. More 
specifically, the present invention provides the carbapenem compounds 
substituted by a methyl group at the 1-position in the 
.beta.-configuration, in which particularly a 
1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio group is introduced at the 
2-position. 
Accordingly, one object of the present invention is to provide 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylic acid derivative represented by the 
following formula: 
##STR9## 
wherein R is hydrogen; lower alkyl group which is unsubstituted or 
substituted by hydroxy, lower alkoxy or lower alkoxy-lower alkoxy group; 
group --COOR.sup.1 (R.sup.1 is hydrogen or lower alkyl group); or group 
--CONR.sup.2 R.sup.3 (R.sup.2 and R.sup.3 are, independently each other, 
hydrogen or lower alkyl), 
Y is carboxy, --COO.sup..crclbar. or protected carboxy, or a 
pharmaceutically acceptable salt thereof. 
More specifically, the present invention provides 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!-thio-6-(R)-1-hydroxyet 
hyl!-1-methyl-carbapen-2-em-3-carboxylic acid of the following formula: 
##STR10## 
wherein Y has the same meaning as above, or a pharmaceutically acceptable 
salt thereof. 
Still more specifically, the present invention provides 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylic acid of the following formula: 
##STR11## 
or a pharmaceutically acceptable salt thereof. 
Another object of the present invention is to provide orally administrable 
carbapenem compounds which are converted into active carbapenem compounds 
of formula (II) in the body and show potent activities against a number of 
pathogenic microorganisms. For the above purpose of the invention, 
provided is 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylate of the following formula: 
##STR12## 
wherein R.sup.4 is ester moiety of an esterified carboxy, or a 
pharmaceutically acceptable salt thereof. 
Preferable orally administrable carbapenem compound of the present 
invention is 1-(cyclohexyloxy)carbonyloxy!ethyl 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylate of the following formula: 
##STR13## 
or a pharmaceutically acceptable salt thereof. 
The other object of the present invention is to provide antibacterial 
compositions containing the carbapenem compounds represented by formula 
(I) or pharmaceutically acceptable salts thereof, as an active ingredient. 
Preferable antibacterial composition is orally-administrable formulation 
containing the carbapenem compound of formula (IV). 
DETAILED DESCRIPTION OF THE FIRST EMBODIMENT OF THE INVENTION 
The carbapenem compounds according to the present invention are novel 
compounds that are not specifically disclosed in the prior patent 
publications (for instance, Japanese Patent Laid-Open Publication No. 
202,886/1985, and WO 93/23,402). In particular, they are remarkably 
characterized in that the substituent at the 2-position of the carbapenem 
skeleton is a 1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio group and in that 
they have superior antibacterial activities and resistance to DHP. 
In the specification of the present application, the term "lower" 
qualifying a group of a compound means that the group or compound so 
qualified has from 1 to 7, preferably from 1 to 4, carbon atoms. 
The term "alkyl" referred to herein stands for a straight-chained or 
branched-chain hydrocarbon group having preferably from 1 to 20 carbon 
atoms and may include, for example, methyl, ethyl, n-propyl, isopropyl, 
n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, n-hexyl, 
isohexyl, n-heptyl, isoheptyl, octyl, isooctyl, monanyl, dodecanyl, 
pentadecanyl, eicosanyl or the like. 
The term "alkoxy" referred to herein stands for an alkyl-oxy group in which 
the "alkyl" group has the meaning as mentioned above. Examples include 
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 
tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, 
n-heptyloxy, isoheptyloxy or the like. Among them, methoxy, ethoxy, 
isobutoxy, sec-butoxy or tert-butoxy is preferably used. 
The term "protected carboxy" is esterified carboxy which is represented by 
the group --COOR.sup.4 (wherein R.sup.4 is ester moiety of an esterified 
carboxy). Suitable ester moiety of an esterified carboxy represented by 
the group "R.sup.4 " is lower alkyl which may have at least one suitable 
substituent(s), and can be represented by the following group: 
##STR14## 
wherein R.sup.5 is hydrogen or alkyl group, R.sup.6 is alkyl or cycloalkyl 
group in which these groups may be substituted by alkoxy, group: 
--OP(.dbd.O)(OR.sup.7) (wherein R.sup.7 is hydrogen, alkyl, aryl or 
aralkyl), carboxyl or propylglycinamide; and 
n is 0 or 1. 
The term "aryl" may be monocyclic or polycyclic aryl group which may have 
at least one substituent(s) such as alkyl, for example, phenyl, tolyl, 
xylyl, .alpha.-naphthyl or .beta.-naphthyl and the like. 
Suitable "aralkyl" may include aryl substituted alkyl in which the "aryl" 
group and "alkyl" group have the meanings as mentioned above. Examples 
include benzyl, benzhydryl, trityl, phenethyl, .alpha.-methylbenzyl, 
phenylpropyl, naphthylmethyl and the like. 
The term "cycloalkyl" may be saturated monocyclic hydrocarbon group having 
from 3 to 7 ring carbon atoms, and for example cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl, cycloheptyl or the like. 
Therefore, suitable "ester moiety" is for example, lower 
alkanoyloxy(lower)alkyl ester e.g. acetoxymethyl ester, 
propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, 
pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl 
ester, 1-(or 2- or 3-)acetoxypropyl ester, or 1-(or 2- or 3- or 
4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 
3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 
2-)isobutyryloxyethyl ester, 1-(or 2-)pyvaloyloxyethyl ester, 1-(or 
2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 
2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-(or 
2-)pentanoyloxyethyl ester, etc.!, lower alkanesulfonyl(lower)alkyl ester 
(e.g. 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester 
(e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); 
lower alkoxycarbonyloxy(lower)alkyl ester e.g. methoxycarbonyloxymethyl 
ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 
t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 
1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl 
ester, etc.!, cycloalkyloxycarbonyloxy(lower)alkyl ester (e.g. 
cyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)cycloalkyloxycarbonyloxy 
ethyl ester, etc.), phthalidylidene(lower)alkyl ester, or (5-lower 
alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester e.g. 
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 
(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 
(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.!; or the like. More 
preferable example of the protected carboxy thus defined may be 
pivaloyloxymethyloxycarbonyl or 1-(cyclohexyloxycarbonyl)ethyloxycarbonyl. 
Typical examples of the compounds of formula (I) are shown in the following 
Table 1 and Table 2. 
TABLE 1 
______________________________________ 
##STR15## 
R Y 
______________________________________ 
H COOH 
CH.sub.3 COOH 
CH(CH.sub.3).sub.2 
COOH 
CH.sub.2 OH COOH 
CH.sub.2 OCH.sub.2 CH.sub.3 
COOH 
CH.sub.2 OCH.sub.2 OCH.sub.3 
COOH 
COOC.sub.2 H.sub.5 
COOH 
CON(CH.sub.3).sub.2 
COOH 
______________________________________ 
TABLE 2 
______________________________________ 
##STR16## 
R.sup.5 
##STR17## 
______________________________________ 
##STR18## 
CH.sub.3 
##STR19## 
C(CH.sub.3).sub.3 
##STR20## 
H 
##STR21## 
CH.sub.3 
##STR22## 
H 
##STR23## 
(CH.sub.2).sub.5 CH.sub.3 
##STR24## 
H 
##STR25## 
H 
##STR26## 
C(CH.sub.3).sub.3 
##STR27## 
H 
##STR28## 
H 
##STR29## 
CH.sub.3 
##STR30## 
H 
##STR31## 
CH.sub.3 
##STR32## 
H 
##STR33## 
H 
##STR34## 
H 
##STR35## 
H 
##STR36## 
H 
##STR37## 
CH.sub.3 
##STR38## 
H 
##STR39## 
H 
##STR40## 
CH.sub.3 
##STR41## 
H 
##STR42## 
CH.sub.3 
##STR43## 
H 
##STR44## 
CH.sub.3 
##STR45## 
H 
##STR46## 
H 
##STR47## 
H 
##STR48## 
H 
##STR49## 
CH.sub.3 
##STR50## 
H 
##STR51## 
CH.sub.3 
##STR52## 
H 
##STR53## 
H 
##STR54## 
H 
##STR55## 
______________________________________ 
The pharmaceutically acceptable salts of the above listed compounds are 
also included in the examples of the compounds of the present invention. 
Furthermore, when the compounds of the present invention have an asymmetric 
carbon in the side chain at the 2-position or 3-position, these optically 
active compounds can be stereo-selectively obtained by using the optically 
active starting materials (see the examples described below), or they can 
be also obtained by resolution of the diastereoisomeric mixture of these 
compounds by ordinary methods. Therefore, the optically active and 
stereoisomeric mixture of the compounds (I) should be included in the 
compounds of the present invention. 
The compounds of the present invention of the formula (I) may be prepared 
in accordance with the processes as illustrated by the reaction schemes 
shown below. 
The compound of formula (I) in which the group "Y" is carboxy or 
--COO.sup..crclbar. may be prepared by the following Reaction Scheme A: 
##STR56## 
wherein L is a leaving group; and R has the same meaning as above. 
The "leaving group" represented by L in the formula (VI) may, for example, 
be an azido group; a halogen atom such as chlorine, bromine or fluorine; 
lower alkanoyloxy group such as acetoxy or propionyloxy; sulfonyloxy group 
such as benzenesulfonyloxy, tosyloxy or methanesulfonyloxy; lower alkoxy 
group such as methoxy or ethoxy; lower alkylthio group such as methylthio 
or ethylthio. 
The reaction of 
(1R,5S,6S)-2-(azetidin-3-yl)!thio-6-(R)-1-hydroxyethyl!-1-methyl-carbape 
n-2-em-3-carboxylic acid of formula (V) with the compound of formula (VI) 
may be carried out, for instance, by reacting the compound of formula (V) 
with the compound (VI) in an appropriate buffer-solvent of pH 5 to 7 such 
as a phosphate buffer solution, an acetate buffer solution, a citrate 
buffer solution, a morpholino-propane sulfonate buffer solution, an 
N-methylmorpholino phosphate buffer solution or the like. The reaction can 
be carried out by adding the compound of formula (VI) into the solution 
mixture of the compound of formula (V) and by stirring the reaction 
mixture for an appropriate time. 
The quantity of the compound of formula (VI) is not critical and may vary 
appropriately in a range from approximately 1 to approximately 10 moles, 
preferably in a range from approximately 1 to approximately 5 moles, per 
mole of the compound of formula (V). If necessary, an organic solvent, 
alcohol such as methanol, ethanol or isopropanol; ether such as diethyl 
ether or tetrahydrofuran; acetonitrile; dimethylformamide; or 
dimethylacetamide can be used as the reaction solvent together with the 
above buffer solution. The reaction temperature is not limited to a 
particular range and many vary in a wide range according to the starting 
material of (VI) to be used. It may range generally from about -78.degree. 
C. to about 50.degree. C., preferably from about -20.degree. C. to about 
0.degree. C. The reaction may be finished in approximately 5 minutes to 
approximately 5 hours. 
The compounds of formula (V) to be employed as a starting compound in the 
above reaction are known compounds or may be prepared in accordance with 
the known method described in Japanese Patent Publication No. 
255,280/1988. 
Furthermore, the compound of the present invention of the formula (I) in 
which the group "Y'" is carboxy or --COO.sup..crclbar. may also be 
prepared in accordance with the following Reaction Scheme B. 
##STR57## 
wherein R.sup.a is an acyl group; R' is a carboxyl protecting group; and R 
has the same meaning as above. 
The term "acyl group" represented by R.sup.a may be, in a narrower sense, a 
moiety obtainable by removing the hydroxyl group from the carboxyl group 
of an organic carboxylic acid as well as, in a broader sense, any acyl 
group derived from an organic sulfonic acid or an organic phosphoric acid. 
Such an acyl group may include, for example, a lower alkanoyl group such 
as acetyl, propionyl, butyryl or the like, a (halo)lower alkyl sulfonyl 
group such as methanesulfonyl, trifluoromethanesulfonyl or the like; a 
substituted or unsubstituted arylsulfonyl group such as benzenesulfonyl, 
p-nitrobenzenesulfonyl, p-bromo-benzenesulfonyl, toluenesulfonyl, 
2,4,6-triisopropylbenzenesulfonyl or the like; and diphenylphosphoryl. 
The term "carboxyl protecting group" represented by R' stands for any group 
capable of protecting the carboxyl group of the compound involved without 
adversely affecting any other substituents and the reactions that follow 
and may include, for example, an ester residue such as a lower alkyl ester 
residue including, for example, methyl ester, ethyl ester, n-propyl ester, 
isopropyl ester, n-, iso-, sec- or tert-butyl ester, n-hexyl ester or the 
like; an aralkyl ester residue including, for example, benzyl ester, 
n-nitrobenzyl ester, o-nitrobenzyl ester, p-methoxybenzyl ester or the 
like; and a lower aliphatic acyloxymethyl ester residue including, for 
example, acetoxymethyl ester, propionyloxymethyl ester, n- or 
iso-butyryloxymethyl ester, pivaloxyloxymethyl ester or the like. 
The reaction of the compound of formula (VIII) with 
1-(1,3-thiazolin-2-yl)azetidin-3-yl!thiol of the formula (IX) may be 
carried out, for instance, by reacting the compound of formula (VIII) with 
the compound of formula (IX) in an amount ranging from approximately 0.5 
molar to approximately 5 molar, preferably from approximately 0.8 molar to 
approximately 3 molar amount in an appropriate solvent such as 
tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, 
dimethylsulfoxide; acetonitrile, hexamethylene phosphoramide or the like, 
preferable in the presence of a base such as sodium hydrogen carbonate, 
potassium carbonate, triethylamine, diisopropylethyl amine or the like at 
a temperature ranging from approximately -40.degree. C. to approximately 
25.degree. C. for approximately 30 minutes to approximately 24 hours. 
Preferably, the reaction may be carried out in an inert atmosphere, for 
example in an atmosphere of nitrogen gas or argon gas. 
The reaction described above provides the compound of formula (X), and the 
resulting reaction mixture containing the compound of formula (X) may be 
used for the next reaction without further purification; or the compound 
(X) may be isolated from the reaction mixture by ordinary methods, if 
necessary. 
In the reaction of the compound of formula (VIII) with the compound of 
formula (IX), another compound (IX') wherein the mercapto group of the 
formula (IX) is protected by a merecapto-protecting group may be used 
instead of the compound (IX). The reaction may be carried out in the 
following manner: the mercapto-protecting group of the compound (IX') is 
removed by ordinary methods used in the amino acid chemistry, then, 
without isolating the resulting compound (IX), to the reaction mixture the 
compound of formula (VIII) is added. The reaction condition is the same as 
above. 
The carbapenem compounds of the present invention of the formula (VII) may 
be obtained by removal of the carboxyl protecting group R' of the 
compounds of the formula (X) obtained by the reaction method described 
above. The removal of the protecting group R' may be made by a reaction 
known per se for removing a protective group, such as solvolysis or 
hydrogenolysis. In a typical reaction, the compound represented by formula 
(X) may be treated, for instance, in a mixture of solvents such as 
tetrahydrofuran-water, tetrahydrofuran-ethanol-water, dioxane-water, 
dioxane-ethanol-water, n-butanol-water or the like containing a acetate 
buffer solution (pH 5.5), morpholino-propane sulfonic acid-sodium 
hydroxide buffer solution (pH 5.5), a phosphate buffer solution (pH 5.5), 
dipotassium phosphate, sodium bicarbonate or the like, using hydrogen 
under 1 to 4 atmospheric pressures, in the presence of a catalyst for 
hydrogenation such as platinum oxide, palladium-activated carbon or 
palladium hydroxide-activated carbon at temperatures ranging from 
approximately 0.degree. C. to approximately 50.degree. C. for 
approximately 0.25 to approximately 5 hours. 
Furthermore, the removal of the protecting group R' of the compound of 
formula (X) may also be carried out by reacting the compound (X) with zinc 
in a buffer. In a typical reaction, the compound of formula (X) may be 
treated with zinc in an appropriate buffer solvent of pH 5 to 7 such as a 
phosphate buffer solution, an acetate buffer solution, a citrate buffer 
solution, a morphorinopropanesulfonate buffer solution, or an 
N-methylmorphorine buffer solution. Zinc used in the reaction may include, 
for example, elemental zinc in the form of powder, flower or granule or 
the like. 
The amount of zinc used in this reaction is not strictly limited; however, 
in general, it is conveniently about 1 to 10 parts by weight, preferably 1 
to 5 parts by weight per part by weight of the compound of formula (X) to 
be reacted. 
In this reaction, an organic solvent may be used in combination. Examples 
of the solvent are alcohols such as ethanol, propanol and n-butanol; 
ethers such as diethyl ether and tetrahydrofuran; acetonitrile, 
dimethylformamide and dimethylacetamide. Usually, the reaction may be 
finished in approximately 5 minutes to approximately 5 hours in a reaction 
temperature from about -20.degree. C. to about 50.degree. C., preferably 
from the room temperature to about 30.degree. C. 
The compound of formula (VIII) to be employed as a starting compound in the 
above reaction is known per se and may be prepared in such a manner as 
disclosed, for example, in Japanese Laid-Open Patent Publication No. 
123,985/1981 or, more preferably, in accordance with the 
stereo-selectivity method as disclosed in Japanese Laid-Open Patent 
Publication No. 284,176/1988. 
Furthermore, 1-(1,3-thiazolin-2-yl)azetidin-3-yl!thiol of the formula (IX) 
may be prepared in accordance with the method described in the synthetic 
examples or working examples mentioned later, or may be easily prepared 
from commercially available compounds. 
As a result, (1R,5S,.sup.6 
S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyethyl!-1-me 
thylcarbapen-2-em-3-carboxylic acids represented by formula (I) in which 
"Y" is carboxy are produced in extremely high yield. These compounds may 
be isolated by using ion-exchange resins or polymer resins. 
The present invention provides orally administrable ester derivatives of 
carbapenem compounds, that is, 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!-thio-6-(R)-1-hydroxyet 
hyl!-1-methyl-carbapen-2-em-3-carboxylates of formula (I) in which the 
group "Y" is protective carboxy. The ester derivatives of the present 
invention of the formula (I) may be prepared in accordance with the 
following Reaction Scheme C: 
##STR58## 
wherein X is halogen; and R, R.sup.5, R.sup.6 and n have the same meanings 
as above. 
In the Reaction Scheme C, halogen represented by X may be chlorine, iodine, 
bromine or fluorine. 
The reaction of 
(1R,5S,6S)-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyethyl 
!-1-methylcarbapen-2-em-3-carboxylic acid of formula (VII) with the 
compound of formula (XI) may be carried out, for instance, first by 
obtaining an alkali metal salt of formula (VII) in water by reacting the 
compound of formula (VII) with an appropriate alkali metal bases such as 
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium 
carbonate, sodium bicarbonate, potassium bicarbonate or the like. Then, 
the alkali metal salt of formula (VII) thus obtained is reacted with the 
compound of formula (XI) in inert organic solvent, for example, ethers 
such as diethyl ether, tetrahydrofuran, dioxane; carbon hydrides such as 
benzene, toluene, xylene, cyclohexane; N,N-dimethylformamide, 
dimethylsulfoxide, acetonitrile, preferably in dimethylformamide under 
stirring. 
The quantity of the alkali metal base is not critical and may vary 
appropriately in a range from approximately 1 to approximately 10 moles, 
preferably in a range from approximately 1 to approximately 5 moles, per 
mole of the compound (VII). The reaction temperature is not limited to a 
particular range and may vary from about 0.degree. C. to room temperature. 
The reaction may be finished in approximately 2 or 3 minutes to 
approximately 1 hour under these conditions. 
Furthermore, the quantity of the compound of formula (XI) is not critical 
and may vary appropriately in a range from approximately 1 to 
approximately 3 moles, preferably in a range from approximately 1 mole to 
approximately 1.5 moles, per mole of the alkali metal salt of formula 
(VII). The reaction temperature is not limited and generally may vary in a 
range from about -20.degree. C. to about 50.degree. C., preferably in a 
range from 0.degree. C to room temperature, and the reaction may be 
finished in approximately 10 minutes to approximately 2-3 hours. 
Thus, 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylates represented by the formula (I) in 
which Y is protected carboxy compounds of formula (XII)! are produced and 
these compounds may be isolated and purified by usual method, for example, 
filtration, decantation, extraction, washing, removal of the solvent, 
column chromatography, thin-layer chromatography, recrystallization, 
distillation, sublimation or the like. 
The compounds of formula (VII) to be employed as a starting compound in the 
above Reaction Scheme C can be prepared in accordance with the method 
described in the examples mentioned later. 
The compounds of the present invention represented by formula (I) may be 
converted to a pharmaceutically acceptable acid addition salt thereof with 
inorganic or organic acids; these include, for example, aliphatic acid 
such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, 
trichloroacetic acid or the like; substituted or unsubstituted benzoic 
acid such as benzoic acid, p-nitrobenzoic acid or the like; 
lower(halo)alkylsulfonic acid such as methanesulfonic acid, 
trifluoromethanesulfonic acid or the like; substituted or unsubstituted 
arylsulfonic acid such as benzensulfonic acid, p-nitro benzenesulfonic 
acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 
2,4,6-triisopropylbenzensulfonic acid or the like; organic phosphinic acid 
such as diphenylphosphinic acid; and inorganic acid such as hydrochloric 
acid, sulfuric acid, hydrobromic acid, hydriodic acid, borofluoric acid, 
nitrous acid or the like. 
The desired compounds of formula (I) in accordance with the present 
invention are novel compounds that are not disclosed specifically in the 
above-mentioned publication and that are extremely stable against 
dehydropeptidase (DHP) known as a kidney enzyme and have superior 
antibacterial activities. Furthermore, the orally administrable carbapenem 
compounds of the present invention show good intestinal absorption in the 
body and easily converted to active carbapenem compound which is highly 
active against a number of pathogenic microorganisms. Therefore, the 
carbapenem compounds of the present invention of formula (I) in which the 
group Y is protective carboxy may be used as pro-drug type antibiotics for 
oral administration and are useful for practical clinical use. The 
remarkably high antibacterial activities, intestinal absorption and 
stability against the kidney DHP of the compounds of formula (I) according 
to the present invention have been determined by biological tests 
described below. 
I. Antibacterial Tests 
Test Procedures 
The antibacterial activities were tested by an agar plate dilution method 
in accordance with the standard method of The Japanese Chemotherapy 
Society Chemotherapy, Vol. 29, 76-79 (1981)!. 
A Mueller-Hinton (MH) agar liquid medium of a test microorganism was 
cultured overnight at 37.degree. C. and the resultant culture medium was 
diluted with a buffered saline gelatin (BSG) solution to contain 
approximately 10.sup.6 cells of the test microorganisms per milliliter, 
and then the diluted solution was inoculated with a microplanter at the 
rate of approximately 5 microliters on a MH agar medium containing a test 
compound. This medium was then incubated at 37.degree. C. for 18 hours. 
The minimum inhibitory concentration (MIC) is determined as a minimum 
concentration in which no test microorganism could grow. It is noted here 
that the test organisms used were all standard strains. 
Results 
Table 3 shows the test results. The test compounds used therein were the 
Compound (28) obtained in Example 2, which is the active compound of the 
Compound (33) obtained in Example 6, and the Compound (31) obtained in 
Example 4. 
TABLE 3 
______________________________________ 
MINIMUM INHIBITORY CONCENTRATIONS (MIC) 
MIC (.mu.g/ml) 
Test Compounds 
Test Organisms (28) (31) 
______________________________________ 
S. aureus FDA209P JC-1 
0.013 0.05 
S. aureus Terajima .ltoreq.0.006 
.ltoreq.0.006 
S. aureus MS353 .ltoreq.0.006 
0.025 
S. pyogenes Cook .ltoreq.0.006 
.ltoreq.0.006 
B. subtilis ATCC 6633 
0.025 0.025 
M. luteus ATCC 9341 0.2 0.2 
E. coli NIHJ JC-2 0.013 0.05 
E. coli K-12 C600 0.1 0.2 
E. cloacae 963 0.05 0.2 
E. aerogenes ATCC 13048 
0.1 0.39 
K. pneumoniae PCI-602 
0.013 0.013 
S. typhimurium 11D971 
0.025 0.1 
S. typhi 901 .ltoreq.0.006 
0.05 
S. paratyphi 1015 0.05 0.05 
S. schottmuelleri 8006 
0.025 0.2 
S. enteritidis G14 0.39 0.2 
S. marcescens IAM 1184 
0.05 0.39 
M. morganii IFO 3848 
0.39 0.2 
P. mirabilis IFO 3849 
0.39 0.78 
P. vulgaris OX-19 0.1 0.1 
P. vulgaris HX-19 0.1 0.39 
P. rettgeri IFO 3850 
0.39 6.25 
______________________________________ 
The foregoing results clearly demonstrate that the carbapenem compounds 
according to the present invention have superior antibacterial activities 
against Staphylococcus, Streptococcus, Klebsiella and Proteus. 
II. Antibacterial Activities against Clinically Isolated Microorganism 
Test Procedures 
1. Strains of Test organisms 
The following strains clinically isolated freshly in Japan were used in 
this test. 
______________________________________ 
MRSA 28 strains 
S. epidermidis 23 strains 
E. faecalis 16 strains 
E. coli 20 strains 
E. cloacae 14 strains 
K. pneumoniae 23 strains 
S. marcescens 27 strains 
______________________________________ 
2. The test was carried out by the agar plate dilution method in accordance 
with the standard method of The Japanese Chemotherapy Society. The minimum 
inhibitory concentration (MIC) was determined in substantially the same 
manner as the test procedures described in Test I. 
Results 
The Compound (28) obtained in Example 2 was used in this test. The control 
compounds used were ceftazidime (CAZ) as a cephalosporin compound, and 
imipenem as a carbapenem compound, which are widely used in clinical 
practice. 
Table 4 shows the test results. In the table, 50% inhibitory concentrations 
MIC.sub.50 against test strains are listed. 
TABLE 4 
______________________________________ 
MIC.sub.50 against CLINICALLY 
ISOLATED MICROORGANISM 
(.mu.g/ml) 
______________________________________ 
Test Species 
Test Compounds 
MRSA S. epidermidis 
E. fasecalis 
______________________________________ 
Compound (28) 
0.78 0.39 0.39 
Imipenem 3.13 0.2 0.78 
CAZ 100 12.5 25 
______________________________________ 
Test Species 
Test Compounds 
E. coli* E. cloacae K. pneumoniae 
______________________________________ 
Compound (28) 
0.05 0.1 0.025 
Imipenem 0.78 0.2 0.2 
CAZ 3.13 1.56 0.2 
______________________________________ 
Test Species 
Test Compounds 
S. marcescens 
______________________________________ 
Compound (28) 
0.2 
Imipenem 1.56 
CAZ 0.39 
______________________________________ 
*In the case of E. coli, MIC.sub.100 data are shown. 
The foregoing results clearly demonstrate that the carbapenem compounds 
according to the present invention have superior antibacterial activities. 
III. Stability Test against Renal Dehydropeptidase-1: 
Test Procedures 
The stability of the carbapenem compounds of the present invention was 
measured with a purified enzyme extracted from the swine kidney cortex. As 
a substrate, the compound was adjusted to give a final concentration of 35 
.mu.g/ml and was then added to the enzyme solution in 50 mM MOPS buffer 
(pH 7.0). The reaction mixture was incubated at 30.degree. C. for 2 hours 
and then diluted with an equal volume of methanol. The residual antibiotic 
activity in the supernatant after centrifugation at 1,000.times. g for 20 
minutes was determined by a bioassay method by using Staphylococcus aureus 
Terajima. Standard curves were calculated by using inactivated enzyme as a 
control. 
Compound (28) obtained in Example 2 below was used as a test compound and 
imipenem was used as a control compound. 
Results 
Table 5 below shows the results of the stability test of the compound 
according to the present invention and imipenem against swine renal 
dehydropeptidase-1. 
TABLE 5 
______________________________________ 
STABILITY TO SWINE RENAL DHP-1 
Test Compounds 
0 30 60 120 240 (min) 
______________________________________ 
Compound (28) 
100 100 82.9 67.1 40.0 
Imipenem 100 35 10 3 0 
______________________________________ 
*Residual activity (%) 
The stability test results against DHP-1 clearly show that the carbapenem 
compound according to the present invention was more stable than imipenem. 
IV. In Situ Experiments on Absorption from Rat Intestinal Loop 
Method 
7-week-old male rats of Wistar strain were used after fasting overnight. 
After anesthetizing the animals with ether, the intestine was exteriorized 
and an acute loop of 30 cm length was prepared from the upper part of 
jejunum by ligature of both ends. 0.2% physiological saline solutions of 
the test compounds were injected at a dose of 20 mg/kg into the loop with 
a syringe, and the loop was returned. About 0.4 ml blood was taken from 
the vena jugularis at 10, 30, 60 and 120 minutes after dosing. Then the 
plasma concentrations of the test compounds or the active metabolite were 
measured by HPLC. And the area under the plasma concentration level-time 
curve (AUC) for 2 hours after administration was calculated. 
As the test compounds, the Compounds (28), (32) and (33) obtained in the 
Examples 2, 5 and 6, respectively, were used. 
Results 
Table 6 shows the test results. In the table, the maximum concentrations of 
the test compounds in plasma (C max) and the AUCs (.mu.g.hr/ml) are shown. 
After administration of the Compounds (32) and (33), these compounds were 
undetectable and the deesterified active compound Compound (28)! was only 
detected. Therefore, in the cases of these compounds, the test results are 
shown as those of Compound (28). 
TABLE 6 
______________________________________ 
INTESTINAL ABSORPTION 
Test Compounds 
Test Items (28) (32) (33) 
______________________________________ 
C max (.mu.g/ml) 
0.8 8.4 12.3 
AUC (.mu.g .multidot. hr/ml) (0-2 hr) 
1.0 9.4 15.7 
______________________________________ 
The foregoing results clearly show that the orally administrable carbapenem 
compounds of the present invention have superior intestinal absorption. 
That is, after administration of Compounds (32) and (33), these compounds 
were easily absorbed in the body and then quickly converted to the active 
carbapenem compound Compound (28)!. 
V. Oral Absorption Study 
Method 
5-week-old male mice of ddY strain were used after fasting overnight. The 
test compounds in 1% physiological saline solution at a dose of 100 mg/kg 
were administered orally to a group of 2 mice. Blood was taken from the 
vena jugularis at 15, 30, 60 and 120 minutes after dosing. Then the 
concentrations of the test compounds or the active metabolite and the area 
under the plasma concentration level-time curve (AUC) were calculated in 
the same way mentioned above. 
As the test compounds, the Compounds (28), (32) and (33) of the present 
invention obtained in the Examples 2, 5 and 6 were used. 
Results 
Table 7 shows the test results. In the table, the maximum concentrations of 
the test compounds in plasma (C max) and the AUCs (.mu.g.hr/ml) are shown. 
After administration of the Compounds (32) and (33), these compounds were 
undetectable and the deesterified active compound Compound (28)! was only 
detected. Therefore, in the cases of these compounds, the test results are 
shown as those of Compound (28). 
TABLE 7 
______________________________________ 
ORAL ABSORPTION (.mu.g/ml) 
Test Compounds 
Test Items (28) (32) (33) 
______________________________________ 
C max (.mu.g/ml) 
3.5 131.2 128.3 
AUC (.mu.g .multidot. hr/ml ) (0-2 hr) 
5.0 147.8 150.2 
______________________________________ 
From the in vivo test results, the orally administrable carbapenem 
compounds of the present invention showed a good oral absorption. 
VI. Toxicity 
Toxicological studies were carried out using a group of 10 male mice of 
CrjCD(SD) strain weighing from 20 to 23 grams. Solutions containing each 
of the carbapenem Compounds (28), (31), (32) and (33) of the present 
invention were administered subcutaneously to the mice and subjected to 
observations for one week. 
The results have revealed that the group of mice to which the carbapenem 
compounds of the present invention had been administered in the amount of 
500 mg/kg were alive without any abnormal findings. 
As described above, the carbapenem compounds according to the present 
invention demonstrate a wider scope of antibacterial spectra than do 
conventional cephalosporin compounds, and remarkable antibacterial 
activities comparable to imipenem as well as an overwhelmingly higher 
resistance against DHP than imipenem. 
Therefore, the carbapenem compounds of formula (I) according to the present 
invention permit a single administration without combination with any 
other compounds and without a risk of any side effect that might be caused 
in their combined use with a DHP inhibitor, unlike imipenem that was led 
for the first time to a practically useful antibacterial agent in 
combination with cilastatin acting as a DHP inhibitor. The carbapenem 
compounds are accordingly extremely useful as antibacterial agents for 
therapy and prevention of infectious diseases from various pathogenic 
organisms. 
The carbapenem compound of formula (I) according to the present invention 
may be administered as an antibacterial agent to the human being and other 
mammalian animals in the form of a pharmaceutically acceptable composition 
containing an antibacterially effective amount thereof. The administration 
dose may vary in a wide range with ages, patients, weights and conditions 
of patients, forms or routes of administration, physicians' diagnoses or 
the like and may be orally, parenterally or topically administered, to 
adult patients usually in a standard daily dose range from approximately 
200 to approximately 3,000 mg once or in several installments per day. 
The pharmaceutically acceptable composition of the carbapenem compound of 
formula (I) according to the present invention may contain an inorganic or 
organic, solid or liquid carrier or diluent, which is conventionally used 
for preparation of medicines, particularly antibiotic preparations, such 
as an excipient, e.g., starch, lactose, white sugar, crystalline 
cellulose, calcium hydrogen phosphate or the like; a binder, e.g., acacia, 
hydroxypropyl cellulose, alginic acid, gelatin, polyvinyl pyrrolidone or 
the like; a lubricant, e.g., stearic acid, magnesium stearate, calcium 
stearate, talc, hydrogenated plant oil or the like; a disintegrator, e.g., 
modified starch, calcium carboxymethyl cellulose, low substituted 
hydroxypropyl cellulose or the like; or a dissolution aid, e.g., a 
non-ionic surface active agent, an anionic surface active agent or the 
like, and may be prepared into forms suitable for oral, parenteral or 
topical administration. The formulations for oral administration may 
include solid preparations such as tablets, coatings, capsules, troches, 
powders, fine powders, granules, dry syrups or the like or liquid 
preparations such as syrups or the like; the formulations for parenteral 
administration may include, for example, injectable solutions, drip-feed 
solutions, depositories or the like; and the formulations for topical 
administration may include, for example, ointments, tinctures, creams, 
gels or the like. These formulations may be formed by procedures known per 
se to those skilled in the art in the field of pharmaceutical 
formulations. 
The carbapenem compounds of formula (I) according to the present invention 
are suitably administered in the form of oral or parenteral formulations, 
particularly in the form of oral formulations. 
The production of the carbapenem compounds of the formula (I) according to 
the present invention will be described more in detail by way of working 
examples. 
In the following description, the following symbols are used to have the 
particular meanings. 
Me: methyl group 
Et: ethyl group 
Ac: acetyl group 
Ph: phenyl group 
PNB: p-nitrobenzyl group 
PNZ: p-nitrobenzyloxycarbonyl group 
i-Pr: isopropyl 
t-But: tert.-butyl 
Boc: t-butoxycarbonyl 
Preparation 1 
##STR59## 
(a) To a solution of 109 mg of 3-hydroxyazetidine.HCl Compound (1)! in 5 
ml of ethanol was added a mixture of 133 mg of 2-methylthiazoline 
Compound (2)! and sodium methoxide, and the reaction mixture was refluxed 
for 8 hours. After removal of the solvent under reduced pressure, the 
resulting residue was dissolved in chloroform and washed with 50% aqueous 
potassium carbonate solution. The solvent was removed under reduced 
pressure to give 119 mg (81.5%) of 3-hydroxy-1-(thiazolin-2-yl)azetidine 
Compound (3)! as a crystaline. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 3.356 (t, 2H, J=7.26 Hz), 
3.70.about.4.00 (m, 4H), 4.211 (t, 2H, J=8.21 Hz), 4.622.about.4.705 (m, 
1H), 4.971 (s, 1H) 
(b) To a mixture solution of triphenylphosphine and diethyl 
azodicarboxylate in 10 ml of tetrahydrofuran was added a mixture of 119 mg 
of Compound (3) and thioacetic acid under ice-cooling, and the reaction 
mixture was stirred for 1 hour at the same condition, then for 1 hour at 
room temperature. After the reaction solvent was removed under reduced 
pressure, the resulting residue was purified by silica gel column 
chromatography (chloroform:ethanol=1:1) to give 107 mg (65%) of 
3-acetylthio-1-(thiazolin-2-yl)azetidine Compound (4)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.333 (s, 3H), 3.352 (t, 2H, J=7.26 Hz), 
3.885 (dd, 2 H, J=8.24, 5.28 Hz), 4.012 (t, 2H, J=7.26 Hz), 
4.250.about.4.374 (m, 1H), 4.426 (t, 2H, J=8.25 Hz) 
Preparation 2 
##STR60## 
(a) To a mixture solution of 4.88 g of 
4(R)-hydroxymethyl-2-mercapto-1,3-thiazoline Compound (5)! and 22.8 ml of 
diisopropylethylamine in 65 ml of dry methanol was added 14.00 g of methyl 
iodide under refluxing condition, and the reaction mixture was refluxed 
for 1 hour. After removal of the solvent under reduced pressure, the 
resulting residue was dissolved in ethyl acetate and the organic layer was 
washed with saturated sodium bicarbonate solution, water and saturated 
saline solution and dried over magnesium sulfate. The solvent was removed 
under reduced pressure and the resulting residue was purified by silica 
gel column chromatography (chloroform-acetone) to give 3.14 g (59%) of 
4(R)-hydroxymethyl-2-methylthio-1,3-thiazoline Compound (6)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.53 (s, 3H), 3.30 (dd, 1H, J=8.6, 10.6 
Hz), 3.44 (dd, 1H, J=7.6, 10.6 Hz), 3.67-3.73 (m, 1H), 3.86-3.92 (m, 1H), 
4.51-4.68 (m, 1H) 
(b) 3.14 g of Compound (6) obtained in the step (a) and 6.7 ml of 
diisopropylethylamine were dissolved in 40 ml of dry dichloromethane 
solution. 2.33 g of chloromethylmethyl ether was added to the above 
mixture under ice-cooling and the reaction mixture was stirred for 1 hour 
under the same condition and for 15 hours at room temperature. After the 
reaction, the reaction mixture was washed with water, saturated sodium 
bicarbonate solution and saturated saline solution, and dried over 
magnesium sulfate. After removal of the solvent, the resulting residue was 
purified by silica gel column chromatography (chloroform-ethyl acetate) to 
give 1.42 g (36%) of 
4(R)-methoxy-methyloxymethyl-2-methylthio-1,3-thiazoline Compound (7)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.55 (s, 3H), 3.35 (dd, 1 H, J=7.3, 10.9 
Hz), 3.38 (s, 3H), 3.42 (dd, 1 H, J=8.3, 10.9 Hz), 3.474 (dd, 1H, J=7.6, 
9.9 Hz), 3.78 (dd, 1H, J=5.0, 9.9 Hz), 4.66-4.70 (m, 1H), 4.67 (s, 2H) 
(c) A mixture solution of 0.924 g of Compound (7) obtained in the above 
step (b), 0.540 g of 3-hydroxyazetidine.HCl Compound (1)!, 0.490 g of 
sodium bicarbonate and 0.160 g of acetic acid in 20 ml of ethanol was 
refluxed for 24 hours. After removal of the solvent, the resulting residue 
was dissolved in chloroform and washed with 50% potassium carbonate 
aqueous solution. The organic layer was dried over magnesium sulfate and 
then removed under reduced pressure. The resulting residue was purified by 
silica gel column chromatography (10% methanol in chloroform) to give 
0.590 g (57%) of 
1-(4(R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)-3-hydroxyazetidine 
Compound (8)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 3.25-3.32 (m, 1H), 3.37 (s 3H), 
3.40-3.46 (m, 1H), 3.47-3.52 (m, 1H), 3.63 (dd, 1H, J=5.3, 9.9 Hz), 
3.79-3.89 (m, 2H), 4.16-4.22 (m, 2H), 4.38-4.45 (m, 1H), 4.61-4.68 (m, 3H) 
(d) To a solution of 1.40 g of triphenylphosphine in 15 ml of dry 
tetrahydrofuran was added 0.800 ml of diethyl azodicarboxylate under 
ice-cooling and the mixture solution was stirred for 0.5 hour. Then, a 
mixture solution of 0.588 g of Compound (8) obtained in the above step (c) 
and 0.361 ml of thioacetic acid in 15 ml of dry tetrahydrofuran was added 
dropwise to the above solution under ice-cooling and the reaction mixture 
was stirred for 1 hour under the same condition and for 1 hour at room 
temperature. After removal of the solvent, the resulting residue was 
purified by silica gel column chromatography (chloroform-acetone) to give 
0.600 g (82%) of 
2-acetyl-thio-1-(4(R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidine 
Compound (9)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.33 (s, 3H), 329 (dd, 1H, J=6.3, 10.9 
Hz), 3.37 (s 3H), 3.43 (dd, 1H, J=7.6, 10.9 Hz), 3.50 (dd, 1H, J=7.9, 9.9 
Hz), 3.67 (dd, 1H, J=4.6, 9.9 Hz), 3.86-3.91 (m, 2H), 4.25-4.34 (m, 1H), 
4.39-4.51 (m, 3H), 4.66 (s, 2H) 
##STR61## 
(a) 0.3 g of sodium hydroxide was added to 64.8 g of benzylalcohol and the 
reaction mixture was cooled to 0.degree. C. To this reaction mixture was 
added 12.9 g of .beta.-butyrolactone and the mixture was stirred for 5 
minutes at 0.degree. C. and for 2 hours at room temperature. After 
reaction, the reaction solution was neutralized by adding 15 ml of 1N-HCl 
solution and the separated organic layer was washed with saturated sodium 
bicarbonate aqueous solution and saline, and dried over magnesium sulfate. 
The resulting organic layer was distilled under reduced pressure to give 
23.3 g (79%) of benzyl 3-hydroxybutanoate Compound (11)! as oil. 
Boiling point : 134.degree. C./8 mmHg 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.22 (d, 3H, J=6.3 Hz), 2.41.about.2.58 
(m, 2H), 2.95 (brs, 1H), 4.15.about.4.24 (m, 1H), 5.14 (s, 2H), 
7.30.about.7.36 (m, 5H) 
(b) A mixture solution of 1.0 g of benzyl 3-hydroxybutanoate obtained in 
the step (a), 1.0 ml of triethylamine and 63 mg of 4-dimethylaminopyridine 
in 10 ml of methylene chloride was cooled to 0.degree. C. To this solution 
was added 1.79 g of diphenyl phosphorochloridate under nitrogen atmosphere 
and the reaction mixture was stirred for 3 hours at room temperature. 
After reaction, the reaction mixture was washed with 1N-HCl solution, 
saturated sodium bicarbonate aqueous solution and saline, and dried over 
magnesium sulfate. The solvent was removed under reduced pressure and the 
resulting residue was purified by silica gel column chromatography with 
methylene chloride to give 1.85 g (84%) of 
3-diphenoxyphosphoryloxybutanoate Compound (12)! as colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.32 (d, 3H, J=6.3 Hz), 2.52 (dd, 1H, 
J=6.3 Hz, 15.8 Hz), 2.72 (dd, 1H, J=6.3 Hz, 15.8 Hz), 4.92 (d, 1H, J=12.9 
Hz), 4.98 (d, 1H, J=12.9 Hz), 4.9-5.1 (m, 1H), 7.06.about.7.20 (m, 15H) 
(c) To a solution of 1.23 g of Compound (12) obtained in the step (b), 8 ml 
of ethyl acetate and 8 ml of ethanol was added 61 mg of 10% 
palladium-carbon, and the reaction mixture was stirred for 1 hour under 
H.sub.2 gas atmosphere at room temperature. Then, palladium-carbon was 
filtrated off and the organic layer was removed under reduced pressure. 
The resulting residue was dissolved in 8 ml of methylene chloride and to 
this solution was added a mixture of 847 mg of sodium bicarbonate, 8 ml of 
water, 98 ml of tetrabutylammonium phosphate and 570 mg of chloromethyl 
chlorosulfonate, and the reaction mixture was stirred for 2 hours at room 
temperature. After reaction, the organic layer was separated and washed 
with saline and dried over magnesium sulfate. The solvent was removed 
under reduced pressure and the resulting residue was purified by silica 
gel column chromatography with methylene chloride to give 1.10 g (99%) of 
chloromethyl 3-diphenylphosphoryloxybutanoate Compound (13)! as colorless 
oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.46 (d, 3H, J=6.3 Hz), 2.66 (dd, 1H, 
J=6.3 Hz, 15.8 Hz), 2.85 (dd, 1H, J=6.3 Hz, 15.8 Hz), 5.09.about.5.18 (m, 
1H), 5.58 (d, 1H, J=6.0 Hz), 5.61 (d, 1H, J=6.0 Hz), 7.16.about.7.37 (m, 
10H) 
Preparation 4 
##STR62## 
(a) To a solution of 12.0 g of .epsilon.-hexanolactone in 20 ml of ethanol 
was added a solution of 11.7 g of potassium hydroxide in 20 ml of water 
under ice-cooling and the reaction mixture was stirred for 2.5 hours at 
40.degree. C. After reaction, the reaction mixture was adjusted to pH 9 by 
adding 1N-HCl solution and washed with ethyl acetate (twice). The aqueous 
layer was concentrated under reduced pressure and the residue was adjusted 
to pH 1 by adding 1N-HCl solution and extracted by ethyl acetate. The 
organic layer was dried over magnesium sulfate and the solvent was removed 
under reduced pressure to give 11.5 g of 6-hydroxyhexanoic acid. A mixture 
of 1 g of 6-hydroxyhexanoic acid obtained above, 0.72 mg of sodium 
bicarbonate in 20 ml of water was stirred for 15 minutes. After reaction, 
the solvent was removed and the resulting residue was washed with 
acetonitrile to give 1.24 g of sodium 6-hydroxyhexanoic acid. Then, 276 mg 
of this compound was dissolved in 2.7 ml of dimethylformamide and to this 
solution was added 161 mg of methoxymethyl chloride and the reaction 
mixture was stirred for 1.5 hours at room temperature. After adding 10 ml 
of ethyl acetate to the reaction mixture, the organic layer was washed 
with saline, saturated sodium bicarbonate aqueous solution and saline 
respectively and dried over magnesium sulfate. The solvent was removed to 
give 190 mg (59%) of methoxymethyl 6-hydroxyhexanoate Compound (15)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.36.about.1.72 (m, 6H), 2.34 (t, 2H, 
J=7.2 Hz), 3.45 (s, 3H), 4.07 (t, 2H, J=6.7 Hz), 5.16 (s, 2H), 5.19 (s, 
2H), 5.22 (s, 2H), 7.53 (d, 4H, J=8.7 Hz), 8.23 (d, 4H, J=8.7 Hz) 
(b) To a solution of 25 g of phosphorus trichloride in 70 ml of diethyl 
ether was added dropwise during 30 minutes a mixture of 51 ml of 
diisopropylamine and 60 ml of diethyl ether at -10.degree. C., then the 
reaction mixture was stirred for 1 hour at room temperature. After 
reaction, unsolved substance was filtrated off and the filtrate was 
distilled under reduced pressure to give 19.8 g (53%) of phosphorus 
diisopropylamino dichloride as oil. b.p. 57.degree. C./4 mmHg. 
To a solution of 2.06 g of phosphorus diisopropylamino dichloride in 40 ml 
of methylene chloride was added 4.19 ml of diisopropylamine at -30.degree. 
C. under nitrogen atmosphere and 3.06 g of p-nitrobenzylalcohol was added. 
The reaction mixture was stirred for 0.5 hour at the same temperature and 
further 0.5 hour at room temperature. After removal of the solvent, the 
resulting residue was dissolved in 40 ml of diethyl ether and washed with 
saturated saline solution and dried over magnesium sulfate. The solvent 
was removed to give 4.50 g (100%) of 
diisopropylamino-di-p-nitrobenzylphosphite Compound (16)! as yellowish 
solid. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.23 (d, 12H, J=6.6 Hz), 3.71 (q, 1H, 
J=6.6 Hz), 3.73 (q, 1H, J=6.6 Hz), 4.75.about.4.91 (m, 4H), 7.51 (d, 4H, 
J=8.2 Hz), 8.21 (d, 4H, J=8.2 Hz) 
(c) A mixture solution of 100 mg of Compound (15) obtained in the step (a), 
87.4 mg of tetrazole and 274 mg of Compound (16) obtained in the step (b) 
in 10 ml of methylene chloride was stirred for 1.5 hour at room 
temperature. Then, the reaction mixture was cooled to -40.degree. C. and 
215 mg of 3-chloroperbenzoic acid was added to the reaction mixture and 
the reaction mixture was stirred for 30 minutes. After reaction, the 
mixture was washed with saturated saline solution, 10% sodium thiosulfate 
aqueous solution, saturated sodium bicarbonate aqueous solution and 
saturated saline solution respectively. The organic layer was dried over 
magnesium sulfate and the solvent was removed under reduced pressure to 
give 306 mg (95%) of methoxymethyl 6-di-p-nitrobenzyloxy 
phosphoryloxyhexanoate Compound (17)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.36.about.1.72 (m, 6H), 2.34 (t, 2H, 
J=7.2 Hz), 3.45 (s, 3H), 4.07 (t, 2H, J=6.8 Hz), 5.16 (s, 2H), 5.19 (s, 
2H), 5.22 (s, 2H), 7.53 (d, 4H, J=8.7 Hz), 8.23 (d, 4H, J=8.7 Hz) 
(d) To a solution of 206 mg of Compound (17) obtained in the step (c) above 
in 2 ml of tetrahydrofuran was added 1 ml of 4N-HCl solution and the 
reaction mixture was stirred for 1.5 hour at room temperature. After 
reaction, the reaction mixture was adjusted to pH 1 by adding 1N-NaOH 
solution and washed with diethyl ether. Then, the water layer was adjusted 
to pH 1 by adding 1N-HCl solution and extracted with ethyl acetate. The 
organic layer was dried over magnesium sulfate and the solvent was removed 
to give 96 mg (51%) of 6-di-p-nitrobenzyloxy-phosphoryloxyhexanoic acid. 
Then, 96 mg of this hexanoic acid was dissolved in 4.8 ml of methylene 
chloride and to this solution was added a mixture solution of 51.3 mg of 
sodium bicarbonate in 4.8 ml of water, 6.6 mg of tetrabutylammonium 
hydrogen sulfate and 40.4 mg of chloromethyl chlorosulfonate, and the 
reaction mixture was stirred for 1 hour at room temperature. After 
reaction, the organic layer was separated and washed with saturated sodium 
bicarbonate aqueous solution and saline, and dried over magnesium sulfate. 
After removal of the solvent under reduced pressure, the resulting residue 
was purified by silica gel column chromatography (methylene 
chloride-acetone) to give 69 mg (55%) of chloromethyl 
6-di-p-nitrobenzyloxyphosphoryloxyhexanoate Compound (18)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.37.about.1.71 (m, 6H), 2.37 (t, 2H, 
J=7.2 Hz), 4.07 (t, 2H, J=6.6 Hz), 5.16 (s, 2H), 5.19 (s, 2H), 5.69 (s, 
2H), 7.54 (d, 4H, J=8.5 Hz), 8.23 (d, 4H, J=8.5 Hz) 
Preparation 5 
##STR63## 
To a solution of 10 g of azelaic acid in 200 ml of acetonitrile were added 
16.2 mg of triethylamine and 11.4 g of p-nitrobenzylbromide at nitrogen 
atmosphere under ice-cooling and the reaction mixture was stirred for 3 
hours. After reaction, the reaction mixture was concentrated and 100 ml of 
water was added. The solution was adjusted to pH 2 by adding 1N-HCl 
solution and extracted 50 ml of ethyl acetate (twice). The organic layer 
was washed with saturated saline solution and dried over magnesium 
sulfate. The solvent was removed under reduced pressure and the resulting 
residue was purified by silica gel column chromatography (methylene 
chloride-methanol) to give 4.51 g (26%) of mono-p-nitrobenzylazelate. 
Then, to a solution of 550 mg of this azelate in 10 ml of methylene 
chloride were added 428 mg of sodium bicarbonate in 10 ml of water. 57 mg 
of tetrabutylammonium hydrogen sulfate and 336 mg of chloromethyl 
chlorosulfonate, and the reaction mixture was stirred vigorously for 2 
hours at room temperature. After reaction, the reaction mixture was washed 
with saturated sodium bicarbonate aqueous solution and saturated saline 
solution, and dried over magnesium sulfate. After removal of the solvent, 
the resulting residue was purified by silica gel column chromatography 
(methylene chloride) to give 450 mg (74%) of p-nitrobenzyl 
chloromethylazelate Compound (20)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.20.about.1.40 (m, 10H), 2.37 (t, 2H, 
J=7.3 Hz), 2.39 (t, 2H, J=7.2 Hz), 5.20 (s, 2H), 5.70 (s, 2H), 7.51 (d, 
2H, J=8.7 Hz), 8.23 (d, 2H, J=8.7 Hz) 
Preparation 6 
##STR64## 
(a) A mixture solution of 5.0 g of L-proline, 9.91 g of p-toluenesulfonic 
acid monohydrate and 6.65 g of p-nitrobenzyl alcohol in 100 ml of benzene 
was refluxed for 2 days by using Dean-Stark trap. After reaction, the 
solvent was removed under reduced pressure and the resulting residue was 
washed with diethyl ether to give 21.7 g of L-proline p-nitrobenzyl ester 
p-toluenesulfonic acid salt as oil. Then, a mixture solution of 12.17 g of 
Boc-glycine and 13.32 g of 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride in 150 ml of 
ethylene chloride was stirred for 25 minutes under ice-cooling at nitrogen 
atmosphere. To this reaction mixture was added a solution of 29.36 g of 
the compound obtained above in 100 ml ethylene chloride and the reaction 
mixture was stirred overnight at room temperature. After reaction, the 
reaction mixture was washed with 10% citric acid aqueous solution, 4% 
sodium bicarbonate aqueous solution and saline, and dried over magnesium 
sulfate. The solvent was removed under reduced pressure and the resulting 
residue was purified by silica gel column chromatography 
(chloroform-methanol) to give 8.00 g of 
N-(t-butoxycarbonyl)glycyl!L-proline p-nitrobenzyl ester Compound (22)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.45 (s, 9H), 1.96.about.2.33 (m, 4H), 
3.43.about.3.70 (m, 2H), 3.93.about.4.01 (m, 2H), 4.59 (d, 1H, J=40 Hz, 
8.6 Hz), 5.23 (d, 1H, J=13.5 Hz), 5.30 (d, 1H, J=13.5 Hz), 5.37 (br, 1H), 
7.52 (d, 2H, J=8.9 Hz), 8.23 (d, 2H, J=8.9 Hz) 
(b) To a solution of 4.10 g of Compound (22) obtained in the step (a) in 5 
ml of methylene chloride was added 2.5 ml of trifluoroacetic acid under 
ice-cooling and the reaction mixture was stirred for 1 hour, then, 4 ml of 
trifluoroacetic acid was added to the reaction mixture and the stirring 
was continued for 2 hours. After reaction, the solvent was removed to give 
5.82 g of glycyl-L-proline p-nitrobenzyl ester trifluoroacetic acid salt 
as pale brownish oil. 
Then, to an ice-cooled solution of 5.54 g of the compound obtained above 
and 1.499 g of glutaric anhydride in 50 ml of methylene chloride was added 
1.83 ml of triethylamine, and the reaction mixture was stirred for 20 
minutes at the same temperature. After reaction, 60 ml of 10% citric acid 
aqueous solution and 200 ml of ethyl acetate were added to the reaction 
mixture and the organic layer was separated. The organic layer was 
extracted with 300 ml of 4% sodium bicarbonate aqueous solution, and the 
extraction was adjusted to pH 4 and extracted with ethyl acetate. The 
organic solvent was removed under reduced pressure to give 3.43 g of 
N-(4-carboxybutanoyl)glycyl!-L-prolin p-nitrobenzyl ester Compound (23)! 
as pale yellowish oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.90.about.2.20 (m, 3H), 1.97 (quintet, 
2H, J=7.3 Hz), 2.20.about.2.34 (m, 1H ), 2.41 (t, 2H, J=7.3 Hz), 2.44 (t, 
2H, J=7.3Hz), 3.53.about.3.75 (m, 2H), 4.04 (dd, 1H, J=4.3 Hz, 17.5 Hz), 
4.22 (dd, 1H, J=4.9 Hz, 17.5 Hz), 4.58 (dd, 1H, J=4.0 Hz, 8.9 Hz), 5.20 
(d, 1H, J=13.5 Hz), 5.32 (d, 1H, J=13.5 Hz), 6.85 (br, 1H), 7.50 (d, 2H, 
J=8.6 Hz), 8.22 (d, 2H, J=8.6 Hz) 
(c) To a solution of 3.09 g of Compound (23) obtained in the step (b) in 70 
ml of methylene chloride were added 1.85 g of sodium bicarbonate in 70 ml 
of water, 249 mg of tetrabutylammonium hydrogen sulfate and 1.57 g of 
ClCH.sub.2 SO.sub.3 Cl, and the reaction mixture was stirred for 140 
minutes at room temperature. After reaction, the organic layer was 
separated and washed with 4% sodium bicarbonate aqueous solution and 
saline, and dried over magnesium sulfate. The solvent was removed under 
reduced pressure to give 3.00 g of 
N-(4-chloromethyloxycarbonylbutanoyl)glycyl!-L-proline p-nitrobenzyl 
ester as pale yellowish oil. Then, a mixture solution of 2.86 g of the 
compound obtained above and 1.83 g of sodium iodide in 20 ml of 
acetonitrile was refluxed for 2 hours. After reaction, the solvent was 
removed and the resulting residue was dissolved in 70 ml of ethyl acetate. 
The organic layer was washed with 0.1N sodium thiosulfate aqueous solution 
and saline, and dried over magnesium sulfate. The solvent was removed 
under reduced pressure and the resulting residue was purified by silica 
gel column chromatography (methylene chloride-acetone) to give 2.35 g of 
N-(4-iodomethyloxycarbonylbutanoyl)glycyl!-L-proline P-nitrobenzyl ester 
Compound (24)! as yellowish oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.92.about.2.17 (m, 5H), 2.17.about.2.37 
(m, 1H), 2.33 (t, 2H, J=7.3 Hz), 2.42 (t, 2H, J=7.3 Hz), 3.46-3.74 (m, 
2H), 4.02 (dd, 1H, J=4.0 Hz, 17.8 Hz), 4.12 (dd, 1H, J=4.4 Hz, 17.8 Hz), 
4.59 (dd, 1H, J=4.0 Hz, 8.9 Hz), 5.24 (d, 1H, J=13.5 Hz), 5.32 (d, 1H, 
J=13.5 Hz), 5.91 (s, 2H), 6.45 (br, 1H), 7.53 (d, 2H, J=8.9 Hz), 8.24 (d, 
2H, J=8.9 Hz)

EXAMPLE 1 
##STR65## 
770 mg of 28% sodium methoxide-methanol solution was added to a mixture 
solution of 862 mg of Compound (4) obtained in the step (c) of Preparation 
1 in 20 ml of anhydrous methanol under ice-cooling and nitrogen gas 
stream. Then the reaction mixture was stirred for 10 minutes under the 
same conditions. After reaction, 4 ml of 2N-HCl was added to the reaction 
mixture and the solvent was removed under reduced pressure to give the 
crude Compound (25). Then, the crude Compound (25) was dissolved in the 
mixture solution of anhydrous aceton-chloroform and to this solution were 
dded 2430 mg of p-nitrobenzyl 
(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-(R)-1-hydroxyethyl!-1-methyl-carba 
pen-2-em-3-carboxylate Compound (26)! and 2.8 ml of diisopropylethylamine 
under ice-cooling and nitrogen gas stream. After stirring the reaction 
mixture for 2 hours under the same conditions, ethyl acetate was added and 
the separated organic layer was washed with saturated sodium bicarbonate 
aqueous solution and saturated saline solution. The solvent was removed 
and the resulting residue was purified by silica gel column chromatography 
with chloroform:aceton (1:2) to give 1339 mg (65% from Compound (4)) of 
p-nitrobenzyl 
(1R,5S,6S)-2-1-(thiazolin-2-yl)azetidin-3-yl!-thio-6-(R)-1-hydroxyethyl! 
-1-methyl-carbapen-2-em-3-carboxylate Compound (27)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.235 (d, 3H, J=7.26 Hz), 1.349 (d, 3H, 
J=6.27 Hz), 3.160 (quintet, 1H, J=7.26 Hz), 3.265 (dd, 1H, J=2.3, 6.26 
Hz), 3.367 (t, 2H, J=7.26 Hz), 3.898-4.038 (m, 4H), 4.071.about.4.147 (m, 
1H), 4.212.about.4.278 (m, 2H), 4.372 (2H, J=7.92 Hz), 5.2555.517 (d (A 
B), 2H, J=13.85 Hz), 7.665 (d, 2H, J=8.58 Hz), 8.226 (d, 2H, J=8.58 Hz) 
EXAMPLE 2 
##STR66## 
To a mixture solution of 1339 mg of Compound (27) obtained in Example 1 in 
2 ml of tetrahydrofuran were added 60 ml of 0.38M phosphate buffer 
solution and 11.2 g of zinc powder, and the reaction mixture was 
vigorously stirred for 2 hours. After the reaction, unsolved substance was 
removed by using Celite.RTM. and the filtrate was washed with ethylacetate 
and the pH of the filtrate was adjusted to 5.5. Then, the filtrate was 
concentrated and the resulting residue was purified by using Diaion HP-40R 
column (5% isopropylalcohol-water) to give 630 mg (64%) of 
(1R,5S,6S)-2-1-(thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyethyl!- 
1-methyl-carbapen-2-em-3-carboxylic acid Compound (28)!. 
.sup.1 H-NMR (D.sub.2 O) .delta.: 1.093 (d, 3H, J=6.93 Hz), 1.207 (d, 3H, 
J=6.27 Hz), 3.05.about.3.20 (m, 1H), 3.357 (dd, 1H, J=2.3, 5.94 Hz), 3.558 
(t, 2H, J=7.26 Hz), 3.920 (t, 2H, J=7.26 Hz), 4.00.about.4.20 (m, 5H), 
4.20-4.30 (m, 1H), 4.60.about.4.70 (m, 1H) 
IR (KBr): 1740, 1640, 1590 cm.sup.-1 
EXAMPLE 3 
##STR67## 
To a solution of 600 mg of Compound (9) obtained in the step (d) in 
Preparation 2 in 10 ml of anhydrous methanol was added 400 mg of 28% 
sodium methoxide-methanol solution under ice-cooling and nitrogen 
atmosphere, and the reaction mixture was stirred for 5 minutes under the 
same conditions. After the reaction, 0.355 ml of acetic acid was added and 
the solvent was removed under reduced pressure. The resulting residue was 
dissolved in 5 m of anhydrous acetonitrile and the unsolved substance was 
removed by filtration. Then, this filtrate was added to a solution of 
1.230 g of p-nitrobenzyl 
(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-(R)-1-hydroxyethyl!-1-methyl-carba 
pen-2-em-3-carboxylate Compound (26)! in 5 ml of anhydrous acetonitrile 
under ice-cooling, and 2.2 ml of diisopropylethylamine was further added 
dropwise to the reaction mixture. After stirring the reaction mixture for 
1.5 hour under the same condition. The solvent was removed under reduced 
pressure. The resulting residue was dissolved in ethyl acetate and the 
organic layer was washed with saturated sodium bicarbonate aqueous 
solution, and dried over magnesium sulfate. After removal of the solvent, 
the resulting residue was purified by silica gel column chromatography 
(chloroform-acetone) to give 0.788 g (64% from Compound (26)) of 
p-nitrobenzyl 
(1R,5S,6S)-2-1-(4(R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidin-3 
-yl!thio-6-(R)-1-hydroxyethyl!-1-methyl-carbapen-2-em-3-carboxylate 
Compound (30)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.24 (d, 3H, J=7.3 Hz), 1.36 (d, 3H, 
J=6.3 Hz), 3.16 (dq, 1H, J=7.3, 9.2 Hz), 3.25-3.34 (m, 2H), 3.37 (m, 2H), 
3.43-3.47 (m, 1H), 3.51 (dd, 1H, J=7.9, 9.9 Hz), 3.67 (dd, 1H, J=5.0, 9.9 
Hz), 2.94-4.00 (m, 2H), 4.07-4.17 (m, 1H), 4.23 (dd, 1H, J=2.6, 9.2 Hz), 
4.20-4.30 (m, 1H), 4.30-4.51 (m, 3H), 4.66 (s, 2H), 5.25 (d, 1H, J=13.9 
Hz), 5.51 (d, 1H, J=13.9 Hz), 7.66 (d, 2H, J=8.6 Hz), 8.23 (d, 2H, J=8.6 
Hz) 
EXAMPLE 4 
##STR68## 
To a solution of 756 mg of Compound (30) obtained in Example 3 in 10 ml of 
tetrahydrofuran and 30 ml of 0.35M phosphate buffer (pH 6.0) solution was 
added 6.0 g of zinc powder, and the reaction mixture was stirred for 2 
hours at room temperature. After removal of the zinc powder by filtration, 
the filtrate was washed with ethyl acetate and the pH of the filtrate was 
adjusted to 5.5, then the filtrate was concentrated. The resulting residue 
was purified by using Diaion HP-40R column (10% isopropanol-water) to give 
415 mg (71%) of 
(1R,5S,6S)-2-1-((4R)-methoxymethyloxymethyl-1,3-thiazolin-2-yl)azetidin-3 
-yl!thio-6-(R)-1-hydroxyethyl!-1-methyl-carbapen-2-em-3-carboxylic acid 
Compound (31)!. 
.sup.1 H-NMR (D.sub.2 O) .delta.: 1.10 (d, 3H, J=7.3 Hz), 1.21 (d, 3H, 
J=6.6 Hz), 3.06-3.18 (m, 1H), 3.22-3.33 (m, 1H), 3.33 (s, 3H), 3.36-3.47 
(m, 1H), 3.61-3.75 (m, 3H), 4.09-4.31 (m, 6H), 4.33-4.56 (m, 1H), 
4.60-4.68 (m, 3H) 
IR (KBr: 1735, 1640, 1580 cm.sup.-1 
EXAMPLE 5 
##STR69## 
A mixture solution of 430 mg (1.12 mM) of Compound (28) obtained in the 
Example 2 and 94.1 mg (1.12 mM) of sodium bicarbonate in 15 ml of water 
was lyophilized. The resulting amorphous solid was dissolved in 5 ml of 
dimethylformamide, and 285 mg (1.18 mM) of pivalic acid iodomethyl ester 
was added to this solution and the reaction mixture was stirred for 1 hour 
at room temperature. After reaction, ethyl acetate was added to the 
reaction mixture and the organic layer was washed with saturated sodium 
bicarbonate aqueous solution and saline, and dried over magnesium sulfate. 
After removal of the solvent, the resulting residue was purified by silica 
gel column chromatography (10% methanol-chloroform) to give 415 mg of 
(74.6%) of pivaloyloxymethyl 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylate Compound (32)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.229 (s, 9H), 1.229 (d, 3H, J=7.3 Hz), 
1.339 (d, 3H, 6.3 Hz), 3.165 (dd, 1H, J=7.3 Hz, 9.2 Hz), 3.227 (dd, 1H, 
J=2.6 Hz, 6.9 Hz), 3.369 (t, 2H, 7.3 Hz), 3.952 (dd, 2H, 5.6 Hz, 8.6 Hz), 
3.988.about.4.043 (m, 2H), 4085.about.4.162 (m, 1H), 4.183.about.4.274 (m, 
2H), 4.346-4.426 (m, 2H), 5.842 (d, 1H, J=5.6 Hz), 5.972 (d, 1H. J=5.6 Hz) 
EXAMPLE 6 
##STR70## 
A mixture solution of 500 mg (1.30 mM) of Compound (28) obtained in the 
Example 2 and 109.4 mg (1.30 mM) of sodium bicarbonate in 15 ml of water 
was lyophilized. The resulting amorphous solid was dissolved in 5 ml of 
dimethylformamide, and 379.5 mg (1.30 mM) of 
1-iodoethylcyclohexylcarbonate prepared by the method described in The 
Journal of Antibiotics, vol. XL, No. 1, page 81! was added to this 
solution, and the reaction mixture was stirred for 2 hours at room 
temperature. After reaction, ethyl acetate was added to the reaction 
mixture and the organic layer was washed with saturated sodium bicarbonate 
aqueous solution and saline, and dried over magnesium sulfate. The solvent 
was removed under reduced pressure and the resulting residue was purified 
by silica gel column chromatography (10% methanol-chloroform) to give 309 
mg of (43%) of 1-(cyclohexyloxy)carbonyloxy! ethyl 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methylcarbapen-2-em-3-carboxylate Compound (33)!. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.219 (d, 3H, J=7.3 Hz), 1.323 (d, 3H, 
J=6.3 Hz), 1.37.about.1.50 (m, 2H), 1.563 (d, 1.5H, J=5.3 Hz), 1.611 (d, 
1.5H, J=5.3 Hz), 1.67.about.1.82 (m, 4H), 1.90.about.2.05 (m, 4H), 3.20 
(m, 1H), 3.216 (dd, 1H, J=2.7 Hz, 6.9 Hz), 3.367 (t, 2H, J=7.6 Hz), 
3.92.about.4.04 (m, 4H), 4.08.about.4.25 (m, 3H), 4.34.about.4.43 (m, 2H), 
4.59.about.4.71 (m, 1H), 6.880 (q, 0.5H, J=5.3 Hz), 6.890 (q, 0.5H, J=5.3 
Hz) 
EXAMPLE 7 
##STR71## 
Other ester compounds of 
(1R,5S,6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyeth 
yl!-1-methyl-carbapen-2-em-3-carboxylic acid represented by the above 
formula were obtained by reacting Compound (28) with Compound (18) 
obtained in the Preparation 4!, Compound (20) obtained in the 
Preparation 5! and Compound (24) obtained in the Preparation 6! 
respectively. 
EXAMPLE 8 
##STR72## 
Compound (34) was obtained in substantially the same manner as that of 
Examples 1 and 2. 
.sup.1 H-NMR (D.sub.2 O) .delta.: 1.16 (d, 3H, J=6.9 Hz), 1.27 (d, 3H, 
J=6.3 Hz), 2.95 (s, 3H), 3.11 (s, 3H), 3.19 (m, 1H), 3.41 (dd, 1H, J=2.5 
Hz, 6.1 Hz), 3.57 (dd, 1H, J=5.9 Hz, 11.5 Hz), 3.89 (dd, 1H, J=8.6 Hz, 
11.5 Hz), 4.11.about.4.37 (m, 5H), 4.62.about.4.80 (m, 2H), 5.37 (dd, 1H, 
J=5.9 Hz, 8.6 Hz) 
The carbapenem compounds according to the present invention may be 
formulated in various preparation forms. 
Formulation Example 1 (Injection) 
______________________________________ 
(1) Injectable suspension: 
______________________________________ 
Compound (28) 25.0 g 
Methy cellulose 0.5 g 
Polyvinyl pyrrolidone 0.05 g 
Methyl p-oxybenzoate 0.1 g 
Polysolvate 80 0.1 g 
Lidocaine hydrochloride 
0.5 g 
Distilled water to make 100 ml 
______________________________________ 
The above components were formulated into 100 ml of an injectable 
suspension. 
(2) Lyophilization 
An appropriate amount of distilled water was added to 20 g of the sodium 
salt of Compound (28) to make a total volume of 100 ml. The above solution 
(2.5 ml) was filled in vials so as for each vial to contain 500 mg of the 
sodium salt of Compound (28) and lyophilized. The lyophilized vial was 
mixed in situ with approximately 3-4 ml of distilled water to make an 
injectable solution. 
(3) Powder 
Compound (28) was filled in an amount of 250 ml in a vial and mixed in situ 
with about 3-4 ml of distilled water to make an injectable solution. 
Formulation Example 2 (Tablets) 
______________________________________ 
Compound (33) 25 g 
Lactose 130 g 
Crystalline cellulose 20 g 
Corn starch 20 g 
3% aqueous solution of 100 ml 
hydroxypropyl cellulose 
Magnesium stearate 2 g 
______________________________________ 
Compound (33), lactose, crystalline cellulose, and corn starch were 
screened through a 60-mesh sieve, homogenized, and charged into a kneader. 
A 3% aqueous solution of hydroxypropyl cellulose was added and the mixture 
was kneaded. The product was granulated by a 16-mesh sieve, dried in air 
at 50.degree. C., and again granulated by a 16-mesh sieve. Magnesium 
stearate was added to the granule and mixed. The mixture was tabletted to 
produce tablets weighing 200 mg each and having an 8 mm diameter. 
Formulation Example 3 (Capsules) 
______________________________________ 
Compound (33) 25 g 
Lactose 125 g 
Corn starch 48.5 g 
Magnesium stearate 1.5 g 
______________________________________ 
The above components were finely pulverized and thoroughly mixed to produce 
a homogeneous mixture. The mixture was filled in gelatin capsules, 0.2 g 
per capsule, to obtain capsules for oral administration. 
Formulation Example 4 (Tablets) 
______________________________________ 
Compound (32) 25 g 
Lactose 130 g 
Crystalline Cellulose 20 g 
Corn starch 20 g 
3% aqueous hydroxypropyl cellulose 
100 ml 
Magnesium stearate 2 g 
______________________________________ 
Compound (32), lactose, crystalline cellulose, and corn starch were 
screened through a 60-mesh sieve, homogenized, and charged into a kneader. 
The 3% aqueous solution of hydroxypropyl cellulose was added and the 
mixture was kneaded. The product was granulated by a 16-mesh sieve, dried 
in air at 50.degree. C., and again granulated by a 16-mesh sieve. 
Magnesium stearate was added to the granule and mixed. The mixture was 
tabletted to produce tablets weighing 200 mg each and having an 8 mm 
diameter. 
Formulation Example 5 (Troche) 
______________________________________ 
Compound (33) 200 mg 
Sugar 770 mg 
Hydroxypropyl cellulose 
5 mg 
Magnesium stearate 20 mg 
Flavor 5 mg 
1,000 mg/troche 
______________________________________ 
The components were mixed with each other and formulated into troches by 
punching in conventional manner. 
Formulation Example 6 (Capsules) 
______________________________________ 
Compound (33) 500 mg 
Magnesium stearate 10 mg 
510 mg/capsule 
______________________________________ 
The components were mixed with each other and filled in conventional hard 
gelatin capsules. 
Formulation Example 7 (Dry Syrup) 
______________________________________ 
Compound (33) 200 mg 
Hydroxypropyl cellulose 
2 mg 
Sugar 793 mg 
Flavor 5 mg 
1,000 mg 
______________________________________ 
The above components were mixed with each other and formulated into dry 
syrups in conventional manner. 
Formulation Example 8 (Powders) 
______________________________________ 
(1) Compound (33) 200 mg 
Lactose 800 mg 
1,000 mg 
(2) Compound (33) 250 mg 
Lactose 750 mg 
1,000 mg 
______________________________________ 
The components were mixed with each other and formulated in powders in 
conventional manner. 
Formulation Example 9 (Suppository) 
______________________________________ 
Formulation Example 9 (Suppository): 
______________________________________ 
Compound (33) 500 mg 
Witepsol H-12 700 mg 
(Product of Dynamite Noble) 
1,200 mg 
______________________________________ 
The above components were mixed with each other and formulated into 
suppositories in conventional manner. 
SECOND EMBODIMENT OF THE INVENTION 
The substituent designation of the formulae according to the second 
embodiment are specific to the second embodiment and may be the same or 
different than the substituent designation of formulae of the first 
embodiment. 
The second embodiment of the present invention relates to thiol compounds, 
and, more detailedly, to novel thiol compounds which are useful as 
synthesis intermediates for a certain kind of orally administrable 
carbapenem compound which shows strong antibacterial activity, and to acid 
addition salts of said thiol compounds, and further to the processes for 
the production of these compounds, and, moreover, to novel synthesis 
intermediates which are useful in said production processes. 
There have heretofore been found out a lot of compounds having what is 
called a carbapenem skeleton, and, from among such compounds, there have 
been proposed some ones having excellent antibacterial activity. On 
account of their low absorbability from alimentary canal, however, most of 
the carbapenem compounds which have so far been proposed are clinically 
though to be administered as injections only. 
In view of the purpose of therapy or circumstances on the side of patients, 
it is desirable in clinical practice that several dosage routes can be 
selected for the administration of medicines. Compared with injections, 
oral drugs are especially preferable and clinically quite useful since 
they can be administered easily and conveniently, and since they can be 
administered also in one's own home. 
Clinically, therefore, there have bene strong demands for the development 
of carbapenem compounds which have a wide range of antibacterial spectrum 
and strong antibacterial activity and which can orally be administered. 
Under the above-mentioned circumstances, the authors of this invention made 
studies over and over again about orally administrable carbapenem 
compounds, and found that compounds which have, as a substituent at the 
2-position of carbapenem skeleton, a 
1-(1,3-thiazolin-2-yl)azetidin-3-ylthio group represented by the following 
formula (X) 
##STR73## 
or, typically, such a carbapenem compound as is represented by the 
following formula (IX) 
##STR74## 
exhibits per se high antibacterial activity, and that, moreover, an ester 
derivative which is prepared by esterifying the carboxyl group at 
3-position of the above compound with a specific ester residue has 
excellent absorbability from alimentary canal and, besides, is converted 
again to the compound of the above formula (IX) when rapidly hydrolyzed in 
vivo, and thus found that, therefore, the above-mentioned ester derivative 
can be used as a clinically excellent antibacterial agent, especially, for 
oral administration, in the form of a prodrug of the compound of the above 
formula (IX), and, thus, they have already applied for a patent with 
regard to the compound of the above formula (IX) and their ester 
derivatives (Japanese Patent Application No. 6-170496; U.S. patent 
application Ser. No. 8/267397; EP-A-632039 etc.). 
The main object of the present invention is to provide a synthesis 
intermediate for the purpose of efficiently introducing a 
1-(1,3-thiazolin-2-yl)azetidin-3-ylthio group represented by the above 
formula (X), which is a characteristic substituent at the 2-position of 
the compounds of the above formula (IX), into a carbapenem skeleton. 
The other objects of this invention will be seen clearly from the following 
description: 
This invention provides 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine which is 
represented by the following formula (I) and its acid addition salts: 
##STR75## 
The compound which is represented by the above formula (I) and its acid 
addition salts are quite useful as key intermediates for the 
industrial-scale efficient production of the clinically quite useful 
carbapenem compound represented by the above formula (IX) which exhibits 
per se high antibacterial activity, and which becomes orally administrable 
when esterified. 
Examples of the acid addition salts of the compound of the above formula 
(I) include addition salts with organic acids like lower aliphatic acids 
such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid 
and trichloroacetic acid; substituted or unsubstituted benzoic acids such 
as benzoic acid and p-nitrobenzoic acid; (halo)lower alkylsulfonic acids 
such as methanesulfonic acid and trifluoromethanesulfonic acid; 
substituted or unsubstituted aryl sulfonic acids such as benzenesulfonic 
acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, 
toluenesulfonic acid and 2,4,6-triisopropylbenzenesulfonic acid; and 
organic phosphoric acids such as diphenylphosphoric acid; as well as 
addition salts with inorganic acids like hydrochloric acid, sulfuric acid, 
hydrobromic acid, hydroiodic acid, fluoroboric acid, perchloric acid and 
nitrous acid. 
The compound of the above formula (I) can be efficiently produced by any of 
the following three characteristic processes A, B and C, for example: 
Process variant A 
In this process, the compound of the above formula (I) is produced from 
2-halomethyl aziridine as a starting material by the path shown in the 
following reaction scheme (A): 
##STR76## 
In the above formulae, R denotes an acyl group, a substituted or 
unsubstituted lower alkyl group or an aryl group; and X denotes a halogen 
atom. 
In this specification, the term "lower" means that the number of the carbon 
atoms to which this term is attached is six or less, preferably four or 
less. 
"Lower alkyl group" may be either straight-chain one or branched-chain one. 
Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, 
n-heptyl and isoheptyl. Preferable among them are methyl, ethyl, n-propyl, 
isopropyl n-butyl, isobutyl, sec-butyl and tert-butyl. Under 
circumstances, these lower alkyl groups may be substituted with a phenyl 
group which may further be substituted with at least one, preferably one 
or two, substituent which is selected from the group consisting of 
hydroxy, methoxy, acetoxy and nitro. 
"Acyl group" may be such one as is left after hydroxyl group is removed 
from the carboxyl portion of organic carboxylic acids. Examples of acyl 
groups include lower alkanoyl groups such as acetyl, propionyl and 
butyryl, or a substituted or unsubstituted benzoyl group. 
"Aryl group" may be monocyclic or polycyclic, and, further, may have one or 
more substituent such as lower alkyl group, nitro group and halogen atom 
on its ring. Examples of aryl group include phenyl, tolyl, xylyl, 
.alpha.-naphtyl and .beta.-naphtyl groups. 
"Halogen atom" includes fluorine, chlorine, bromine and iodine atoms, and, 
among these, chlorine, bromine and iodine atoms are preferable. 
In the following, the method shown by Scheme (A) is minutely explained in 
accordance with each step: 
Step (a) 
In this step, 2-halomethyl aziridine is made to react with a base, and, 
thus, is converted into 1-azabycyclo1.1.0!butane which is represented by 
formula (VII). 
The above reaction is conducted as follows: 2-halomethyl aziridine is 
dissolved or suspended in a reactionally inert solvent selected from among 
alcohol type solvent such as methanol, ethanol, propanol and n-butanol; 
ether type solvent such as diethyl ether and tetrahydrofuran; hydrocarbon 
type solvent such as n-heptane, n-hexane, cyclohexane, pentane and 
cyclopentane; ester type solvent such as methyl acetate ester and ethyl 
acetate ester; halogen type solvent such as dichloromethane, chloroform 
and carbontetrachloride; or acetonitrile, dimethylformamide, 
dimethylacetamide, dimethylsulfoxide and the like; preferably, ether type 
solvent such as diethyl ether and tetrahydrofuran, and, to the resultant 
solution or suspension, there are added suitable bases selected from 
organic and inorganic bases like alkaline metals such as lithium, sodium 
and potassium; alkaline earth metals such as calcium and magnesium; 
alkaline metal hydrides such as lithium hydride and sodium hydride; 
alkaline earth metal hydrides such as calcium hydride; alkaline metal 
hydroxides such as sodium hydroxide and potassium hydroxide; alkaline 
metal carbonates such as sodium carbonate and potassium carbonate; 
alkaline metal hydrogencarbonates such as sodium hydrogencarbonate and 
potassium hydrogencarbonate; alkaline metal alkyls such as methyllithium 
and n-butyllithium; alkyl Grignard reagents; alkaline metal amides such as 
lithiumamide, lithiumdiisopropylamide, sodiumamide and potassiumamide; 
alkaline metal alkoxides such as sodiummethoxide, sodiumethoxide and 
potassium tertiary butoxide; alkaline metal alkanoates such as sodium 
acetate; alkaline earth metal carbonates such as magnesium carbonate and 
calcium carbonate; tri(lower)alkylamine such as trimethylamine, 
triethylamine, N,N-diisopropyl-N-ethylamine; pyridine compounds such as 
pyridine, picoline, lutidine, N,N-di(lower)alkylaminopyridine like 
N,N-dimethylaminopyridine; quinolines; N-(lower)alkylmorpholine such as 
N-methylmorpholine; N,N-di(lower)alkylbenzylamine such as 
N,N-dimethylbenzylamine; and DMSO salts which are made from DMSO and 
sodium hydride or lithium hydride: preferably, alkyl lithium such as 
methyl lithium and n-butyllithium, and alkaline metal amides such as 
lithium amide and lithium diisopropylamide, and, then, the resultant 
mixture is stirred. 
The amount of the above bases used in this reaction is not especially 
restricted. Usually, the bases are used at the proportion of about 1 to 
about 20 moles, preferably about 1.5 to about 5 moles, per mole of 
2-halomethylaziridine. The reaction temperature is not strictly limited, 
and may be adequately changed according to the species and amount of the 
bases used. Usually, the reaction is suitably carried out at the 
temperature in the range of about -78.degree. C. to about 100.degree. C. 
preferably about -78.degree. C. to about 60.degree. C., and, under such 
conditions, the reaction can be completed in about 10 minutes to several 
days. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
The above-mentioned step gives the compound of formula (VII) with a good 
yield, and the reaction liquid can be employed as it is for the subsequent 
step. If necessary, by means of subjecting the reaction liquid to a 
conventional purification measure such as distillation, extraction, 
washing, solvent evaporation, and column or thin-layer chromatography, the 
compound of formula (VII) can be isolated and purified. 
Examples of 2-halomethylaziridine as a synthesis material used in the above 
reaction include 2-chloromethylaziridine, 2-bromomethylaziridine and 
2-iodomethylaziridine. These compounds can be easily synthesized from 
allylamine on the market in accordance with the method mentioned in the 
following Examples 1 or 2. 
Step (b) 
In this step, 1-azabicyclo1.1.0!butane of formula (VII) obtained in the 
above step (a) is made to react with a carboxylic acid, and the resultant 
compound is subjected to solvolysis, and, thus, is converted into 
3-hydroxyazetidine of formula (IV). 
In this reaction, the compound of formula (VII) is firstly dissolved in a 
reactionally inert solvent like ether type solvent such as diethyl ether 
and tetrahydrofuran which are mentioned in the above step (a), and, then, 
a carboxylic acid is added to the resultant solution, and the mixture is 
stirred. 
The aforementioned carboxylic acid may be appropriately selected from among 
formic acid and the organic acids which are mentioned above as forming 
acid addition salts of the compound of formula (I). Especially preferable 
are formic acid and acetic acid. 
The amount of the carboxylic acid used in this reaction is not especially 
restricted. Usually, the carboxylic acid is used at the proportion of 
about 1 to about 20 moles, preferably about 1.5 to about 5 moles, per mole 
of the compound of formula (VII). The reaction temperature is not strictly 
limited, and may be adequately changed according to the species and amount 
of the carboxylic acid used. Usually, the reaction is suitably carried out 
at a temperature in the range of about -78.degree. C. to about 100.degree. 
C., preferably about -78.degree. C. to about 60.degree. C., and, under 
such conditions, the reaction can be completed in about 10 minutes to 
several days. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
Next, the compound obtained by the above reaction is subjected to 
solvolysis such as hydrolysis, and, thus, there can be produced 
3-hydroxyazetidine of formula (IV). 
Said solvolysis reaction is conducted by treating the compound obtained 
from the above reaction either in water or in alcohol type solvent such as 
methanol, ethanol and isopropanol or in a mixed solvent composed of water 
and organic solvent such as acetonitrile, tetrahydrofuran and dioxane, and 
in the presence of suitable base or inorganic acid such as hydrochloric 
acid, sulfuric acid, hydrobromic acid and hydroiodic acid which are 
mentioned in the above step (a), at a temperature in the range of about 
-20.degree. C. to about 50.degree. C. preferably at a comparatively as low 
as about 0.degree. C. to a room temperature, for about 10 minutes to 
several hours. 
If necessary, the reaction liquid obtained by the above step may be 
subjected to a conventional purification measure such as extraction, 
washing, solvent evaporation, column or thin-layer chromatography or 
recrystallization, and then the desired compound of formula (IV) can be 
isolated and purified. However, without such isolation step, the reaction 
liquid can be employed as it is for the subsequent step. 
Step (c) 
In this step, 3-hydroxyazetidine of formula (IV) obtained in the above step 
(b) is converted into 3-hydroxy-1-(1,3-thiazol in-2-yl)azetidine of 
formula (III). 
This step can be conducted by either the method (i) or (ii) as follows: 
(i) The above conversion is carried out by stirring 3-hydroxyazetidine of 
formula (IV) together with a 2-substituted thiazoline derivative 
represented by the following formula (V) 
##STR77## 
wherein L denotes a leaving group in the above-mentioned reactionally 
inert solvent, preferably alcohol type solvent such as methanol or 
ethanol, and, preferably, in the presence of the above-mentioned suitable 
base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium 
carbonate or potassium carbonate. 
Examples of the leaving group denoted by the mark L in the compounds of the 
above formula (V) include azido group; halogen atoms such as chlorine, 
bromine and fluorine; lower alkanoyloxy groups such as acetoxy and 
propionyloxy; sulfonyloxy groups such as benzenesulfonyloxy, tosyloxy and 
methanesulfonyloxy; lower alkoxy groups such as methoxy and ethoxy; and 
lower alkylthio groups such as methylthio and ethylthio. Especially 
preferable among these are lower alkylthio groups. 
The amount of the base and the compound of formula (V) used in this react 
on is not especially restricted. Usually, the base and the compound of 
formula (V) are each used at the proportion of about 1 to about 3 moles, 
preferably about 1 to about 1.5 mole, per mole of the compound of formula 
(IV). The reaction temperature is not strictly limited, and may be 
adequately changed according to the species and amount of the solvent, the 
base and the compound of formula (V) used. Usually, however, the reaction 
is suitably carried out at a temperature in the range of a room 
temperature to about 100.degree. C., preferably a room temperature to 
about 80.degree. C., and, under such conditions, the reaction can be 
completed in about 1 to about 24 hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
(ii) The conversion from the compound of formula (IV) into the compound of 
formula (III) can also be carried out by stirring the compound of formula 
(IV) together with haloethylisothiocyanate in the above-mentioned suitable 
solvent, preferably in acetonitrile, and, preferably, in the presence of 
the above-mentioned organic base such as triethylamine. 
Examples of the haloethylisothiocyanate used here as a raw material include 
chloroethylisothiocyanate, bromoethylisothiocyanate and 
iodoethylisothiocyanate. 
The amount of the base and the haloethylisothiocyanate used in this 
reaction is not especially restricted. Usually, however, the base and the 
haloethylisothiocyanate are each used at the proportion of about 1 to 
about 3 moles, preferably about 1 to about 1.5 mole, per mole of the 
compound of formula (IV). The reaction temperature is not strictly 
limited, and may be adequately changed according to the species and amount 
of the base and haloethylisothiocyanate. Usually, however, the reaction is 
suitably carried out at a temperature in the range of about -20.degree. C. 
to about 50.degree. C. preferably comparatively as low as about 0.degree. 
C. to a room temperature, and, under such conditions, the reaction can be 
completed in about 10 minutes to several hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
Whichever method (i) or (ii) is carried out, the reaction liquid may be 
subjected to a conventional purification measure such as extraction, 
washing, solvent evaporation, column or thin-layer chromatography or 
recrystallization if need be, and then the compound of formula (III) can 
be isolated and purified. Moreover, also when stirred together with the 
organic and inorganic acids which are mentioned above as forming acid 
addition salts of the compound of formula (I) in a suitable solvent, the 
compound of formula (III) can be isolated as an acid addition salt. 
The compound of formula (III) prepared in the above manner is a novel 
compound which has never been mentioned in any other literatures, and 
constitutes a part of the present invention. 
Step (d) 
In this step, 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine of formula (III) 
obtained in the above step (c) is converted into 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine derivatives of formula (II). 
This step can be conducted by either the method (i) or (ii) as follows: 
(i) The above conversion can be carried out by activating the hydroxyl 
group of the compound of formula (III), and, thereafter, by making the 
resultant activated derivative react with a compound represented by 
formula RSH (wherein R is as defined above) or with its salt. 
Examples of the thiol compound represented by formula RSH include 
thioacetic acid, thiopropionic acid, thiobenzoic acid, t-butylmercaptan, 
benzylmercaptan, benzhydrylmercaptan, tritylmercaptan, benzylmercaptan 
whose phenyl group is substituted with one or two hydroxy, methoxy, 
acetoxy or nitro, phenylmercaptan which may be substituted with lower 
alkyl group, nitro group or halogen atom, or naphthyl mercaptan. 
Preferable among these are thiol compounds whose R denotes lower alkanoyl 
group or substituted or unsubstituted benzoyl group. Furthermore, this 
thiol compound may take the form of a salt with alkaline metal such as 
sodium and potassium. 
The reaction to activate the hydroxyl group of the compound of formula 
(III) can be conducted by allowing the compound of formula (III) to react 
with an hydroxyl group-activating reagent like organic sulfonylhalide such 
as methanesulfonyl chloride and 4-toluenesulfonyl chloride or acylhalide 
such as acetylchloride in the above-mentioned inert solvent like ether 
type solvent such as diethylether and tetrahydrofuran, and, preferably in 
the presence of the above-mentioned suitable base like organic bases such 
as triethylamine, diisopropylethylamine and N,N-dimethylaminopyridine, or 
a combination thereof. 
The amount of the base and the hydroxyl group-activating reagent used in 
this reaction is not especially restricted. Usually, however, the base and 
the activating reagent are each used at the proportion of about 1 to about 
3 moles, preferably about 1 to about 1.5 mole, per mole of the compound of 
formula (III). The reaction temperature is not strictly limited, and may 
be adequately changed according to the species and amount of the base and 
the activating reagent. Usually, however, the reaction is suitably carried 
out at a temperature in the range of about -20.degree. C. to about 
50.degree. C., preferably comparatively as low as about 0.degree. C. to a 
room temperature, and, under such conditions, the reaction can be 
completed in about 10 minutes to several hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
Then, the compound of formula (III) whose hydroxyl group has been activated 
is stirred together with the above compound represented by formula RSH or 
its salt in the above-mentioned suitable solvent such as 
dimethylformamide, and, thus, there can be obtained the desired compounds 
of formula (II) intended in this step. 
The amount of the thiol compound represented by formula RSH or its salt 
used in this reaction is not especially restricted. Usually, however, the 
compound or its salt is used at the proportion of about 1 to about 8 
moles, preferably about 1 to about 6 moles, per mole of the compound whose 
hydroxyl group has been activated. The reaction temperature is not 
strictly limited, and may be adequately changed according to the species 
and amount of the thiol compound or its salt. Usually, however, the 
reaction is suitably carried out at a temperature in the range of about 
0.degree. C. to about 150.degree. C., preferably a room temperature to 
about 120.degree. C., and, under such conditions, the reaction can be 
completed in about 10 minutes to several hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
(ii) The conversion of the compound of formula (III) to the compounds of 
formula (II) can be also conducted by making the compound of formula (III) 
react with di(lower)alkylazodicarboxylate, triphenylphosphine and the 
above compound represented by RSH. 
Examples of di(lower)alkylazodicarboxylate used here include 
diethylazodicarboxylate and diisopropylazodicarboxylate. As for the 
compound represented by RSH, there can be employed those mentioned in the 
above (i). 
The reaction can be carried out by stirring the compound of formula (III) 
together with di(lower)alkylazodicarboxylate, triphenylphosphine and the 
compound represented by RSH in the above-mentioned suitable solvent like 
ether type solvent such as diethylether and tetrahydrofuran. 
The amount of the di(lower)alkylazodicarboxylate, triphenylphosphine and 
the compound represented by RSH used in this reaction is not especially 
restricted. Usually, however, these compounds are each used at the 
proportion of about 1 to about 3 moles, preferably about 1 to about 2 
moles, per mole of the compound of formula (III). The reaction temperature 
is not strictly limited, and may be adequately changed according to the 
species and amount of the reagent and compounds. Usually, however, the 
reaction is suitably carried out at a temperature in the range of about 
-20.degree. C. to about 50.degree. C., preferably about 0.degree. C. to a 
room temperature, and, under such conditions, the reaction can be 
completed in about 10 minutes to several hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
Whichever method (i) or (ii) is carried out, the reaction liquid may be 
subjected to a conventional purification measure such as extraction, 
washing, solvent evaporation, column or thin-layer chromatography or 
recrystallization if need be, and then the compounds of formula (II) can 
be isolated and purified. Moreover, also when stirred together with the 
above-mentioned organic acids or inorganic acids in a suitable solvent, 
the compounds of formula (II) can be isolated in the form of adequate acid 
addition salts. 
Thus obtained compounds of formula (II) are also novel compounds which have 
never been mentioned in any other literatures, and constitute a part of 
the present invention. 
Step (e) 
In this step, 3-mercapto-1-(1,3-thiazolin-2-yl )azetidine derivatives of 
formula (II) or its acid addition salts obtained in the above step (d) are 
converted, by means of cleaving off the group R therefrom, into 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine of formula (I) or its acid 
addition salts of the present invention. 
The group R can be cleaved off from the compounds of formula (II) by means 
of the above-mentioned solvolysis reaction such as hydrolysis, or by the 
following hydrogenolysis reaction. 
Hydrogenolysis can be conducted by treating the compounds of formula (II) 
in, for example, a buffer solution of pH 5-7 such as an acetate buffer 
solution, a morpholinopropanesulfonate-sodium hydroxide buffer solution or 
a phosphate buffer solution; a mixed solvent composed of these buffer 
solutions and alcoholic solvent; or in a mixed solvent such as 
tetrahydrofuran-water, tetrahydrofuran-ethanol-water, dioxane-water, 
dioxane-ethanol-water and n-butanol-water each containing dipotassium 
phosphate, sodium bicarbonate, and the like; with use of hydrogen of about 
1 to 4 atm, in the presence of a hydrogenation catalyst such as platinum 
oxide, palladium-activated carbon or palladium hydroxide-activated carbon, 
at a temperature in the range of about 0.degree. C. to about 50.degree. 
C., for about 0.25 to about 5 hours. 
The above step gives the compound of formula (I) of the present invention 
with a good yield. The reaction liquid may be subjected to a conventional 
purification measure such as extraction, washing, solvent evaporation, 
column or thin-layer chromatography or recrystallization if need be, and 
then the compound of formula (I) can be isolated and purified. 
Process variant 8 
In the secondarily proposed process, the compound of formula (I) is 
produced from the compound of formula (VII), which can be prepared by the 
above-mentioned manner from 2-halomethylaziridine, by the reaction path 
shown in the following Scheme (B). 
##STR78## 
In the following, the method shown in Scheme (B) is minutely explained in 
accordance with each step: 
Step (a) 
In this step, 2-(azetidin-3-ylthio)-1,3-hiazoline of formula (VI) is 
produced by making 1-azabicyclo1.1.0!butane of formula (VII) react with 
1,3-thiazolidine-2-thione. 
This reaction can be conducted by stirring 1-azabicyclo1.1.0!butane of 
formula (VII) and 1,3-thiazolidine-2-thione in the above-mentioned 
suitable solvent, preferably in tetrahydrofuran, and preferably in the 
presence of the above-mentioned suitable base like alkaline metal hydride 
such as sodium hydride or alkaline metal alkoxide such as sodium 
methoxide. 
The amount of 1,3-thiazolidine-2-thione and the base used in this reaction 
is not especially restricted. Usually, however, they are each used at the 
proportion of about 1 to about 3 moles, preferably about 1 to about 1.5 
mole, per mole of 1-azabicyclo1.1.0!butane of formula (VII). The reaction 
temperature is not strictly limited, and may be adequately changed 
according to the species and amount of 1,3-thiazolidine-2-thione and the 
base. Usually, however, the reaction is suitably carried out at a 
temperature in the range of about -78.degree. C. to about 100.degree. C., 
preferably -78.degree. C. to a room temperature, and, under such 
conditions, the reaction can be completed in about 1 hour to about 24 
hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
The above step gives the compound of formula (VI) with a good yield. The 
reaction liquid may be subjected to a conventional purification measure 
such as extraction, washing, solvent evaporation, column or thin-layer 
chromatography or recrystallization if need be, and then the compound of 
formula (VI) can be isolated and purified. Moreover, when stirred together 
with the above organic or inorganic acid in a suitable solvent, the 
compound of formula (VI) can be isolated as a suitable acid addition salt. 
The obtained compound of formula (VI) is a novel compound which has never 
been mentioned in any other literatures, and constitutes a part of the 
present invention. 
Step (b) 
In this step, 2-(azetidin-3-ylthio)-1,3-thiazoline of formula (VI) obtained 
in the above step (a) is treated with acid, and, thus, is converted into 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine of formula (I) in accordance 
with the present invention. 
This reaction can be carried out by stirring the above compound of formula 
(VI) and an acid in the above-mentioned suitable solvent, preferably in 
tetrahydrofuran. Examples of the above mentioned acid include the organic 
and inorganic acids which are mentioned above as forming acid addition 
salt of the compound of formula (I). Preferably used among them are lower 
alkylsulfonic acids such as methylsulfonic acid. 
The amount of acid used in this reaction is not especially restricted. 
Usually, however, it is used at the proportion of about 0.1 to about 3 
moles, preferably about 0.1 to about 1 mole, per mole of the compound of 
formula (VI). The reaction temperature is not strictly limited, and may be 
adequately changed according to the species and amount of the acid. 
Usually, however, the reaction is suitably carried out at a temperature in 
the range of a room temperature to about 100.degree. C., preferably a room 
temperature to about 80.degree. C., and, under such conditions, the 
reaction can be completed in about 10 minutes to about several hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
The above step gives the compound of formula (I) with a good yield. The 
reaction liquid may be subjected to a usual purification measure such as 
extraction, washing, solvent evaporation, column or thin-layer 
chromatography or recrystallization if need be, and then the compound of 
formula (I) can be isolated and purified. 
Process variant C 
In the thirdly proposed process, the compound of formula (I) is produced 
from the compound of formula (VII), which can be prepared by the 
above-mentioned manner from 2-halomethylaziridine, by the reaction path 
shown in the following Scheme (C). 
##STR79## 
In the following, the method shown in Scheme (C) is minutely explained in 
accordance with each step. 
Step (a) 
In this step, 1-azabicyclo1.1.0!butane of formula (VII) is converted into 
3-mercaptoazetidine of formula (VIII). 
The above reaction can be carried out by stirring the compound of formula 
(VII) together with the aforementioned compound represented by formula RSH 
or its salts in such a suitable solvent as mentioned above, and, then, 
cleaving off the group R from the resultant compound. 
Examples of the compound represented by formula RSH or its salts include 
the above-mentioned compounds. Preferably used among these are compounds 
whose R denotes a lower alkanoyl group or a substituted or unsubstituted 
benzoyl group, or salts thereof with sodium and potassium. 
The amount of the compound RSH used in this reaction with the compound of 
formula (VII) is not especially restricted. Usually, however, it is used 
at the proportion of about 1 to about 5 moles, preferably about 1 to about 
3 moles, per mole of the compound of formula (VII). The reaction 
temperature is not strictly limited, and may be adequately changed 
according to the species and amount of the compound RSH. Usually, however, 
the reaction is suitably carried out at a temperature in the range of 
about -78.degree. C. to about 80.degree. C., preferably -50.degree. C. to 
a room temperature, and, under such conditions, the reaction can be 
completed in about 10 minutes to several hours. 
The reaction is preferably conducted in the stream of inert gas such as 
nitrogen or argon gas. 
Next, the reaction to cleave off the group R from the compound obtained in 
the above reaction can be carried out in accordance with the method shown 
in step (e) of the above process variant A. 
Incidentally, when the above reaction is conducted with use of a thiol 
compound whose R is acyl group as a starting material, there is added a 
group R in two molar equivalents to the compound of formula (VII) under 
circumstances (See: Example 9 which is mentioned later). In this case, 
however, the group R can also be cleaved off in accordance with the method 
shown in step (e) of the above process variant A (See: Example 10 which is 
mentioned later). 
The above step gives the compound of formula (VIII) with a good yield. The 
reaction liquid may be subjected to a conventional purification measure 
such as extraction, washing, solvent evaporation, column or thin-layer 
chromatography or recrystallization if need be, and then the compound of 
formula (VIII) can be isolated and purified. Moreover, when stirred 
together with the above organic or inorganic acid in a suitable solvent, 
the compound of formula (VIII) can be isolated as a suitable acid addition 
salt. 
Step (b) 
In this step, the compound of formula (VIII) obtained in the above step (a) 
is made to react with the above mentioned 2-substituted-1,3-thiazoline 
derivatives of formula (V), and, thus, there is produced the compound of 
formula (I) in accordance with the present invention. 
This step can be conducted in the same manner as the method (i) or (ii) of 
step (c) in the above process variant A. 
Whichever method (i) or (ii) is employed, the reaction liquid may be 
subjected to a conventional purification measure such as extraction, 
washing, solvent evaporation, column or thin-layer chromatography or 
recrystallization if need be, and then the compound of formula (I) can be 
isolated and purified. 
When stirred together with the above organic or inorganic acid in a 
suitable solvent, the compound of formula (I) which is obtained by the 
above process variants A to C can be isolated in the form of acid addition 
salts. Among thus obtained acid addition salts, the salt with inorganic 
acid, especially hydrochloric acid, can easily be obtained in the form of 
crystal having excellent storage stability as shown in Examples stated 
below, and is quite useful as a synthesis intermediate for long-period 
storage. 
In the above stated manner, there can be produced 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine of formula (I) or its acid 
addition salts which is intended in the present invention. 
As stated concretely in Example 13 mentioned below, when Scheme (D) 
mentioned below is followed with use of the compound of formula (I) which 
is provided by the present invention, there can be obtained, with good 
yield, the carbapenem compound of formula (IX) which has excellent 
antibacterial activity and which becomes orally administrable when 
esterified. 
##STR80## 
In the following, this invention is more detailedly explained by Examples, 
Production Examples and Experimental Examples. This invention is, however, 
not restricted at all by the following descriptions. 
Incidentally, the marks in the descriptions have the following meanings: 
Ac: acetyl 
PNB: p-nitrobenzyl 
Example 1 
##STR81## 
In 94 ml of bromine solution dissolved in 110 ml of diethylether, there was 
added 80 g of allylamine (1) dropwise at a temperature of 15.degree. C. or 
less, and was stirred for a day at a room temperature. After the reaction 
was over, the crystal which had deposited was taken out by filtration, and 
was washed with 55 ml of diethyl ether, and, then, was subjected to vacuum 
drying, and, thus, there was obtained 302.6 g (yield: 99.6%) of 
2-bromomethylaziridine hydrobromide (2). 
H-NMR (CD.sub.3 OD) .delta.: 3.35 (dd, 1H, J=9.89 Hz, 14.19 Hz), 3.71 (dd, 
1H, J=3.30 Hz, 14.19 Hz), 3.86 (dd, 1H, J=8.58 Hz, 10.89 Hz), 4.01 (dd, 
1H, J=4.62 Hz, 10.89 Hz), 4.4-4.6 (m, 1H) 
Example 2 
##STR82## 
A 900 ml dried solution of dichloromethane containing 9.64 ml of sulfuryl 
chloride and a catalytic amount of iodine dissolved therein was subjected 
to reflux at 40.degree. C., and, to this solution, there was added 
dropwise a 100 ml dried solution of dichloromethane containing 7.6 ml of 
allylamine (1) dissolved therein, and, after the addition was over, the 
solution was stirred at the same temperature for two hours. After the 
reaction was over, the reaction liquid was left still until it had a room 
temperature, and, then, a residue which was obtained by filtration was 
washed with dichloromethane and n-hexane, and, next, was subjected to 
vacuum drying, and, thus, there was obtained 8.37 g (yield: 65.8%) of 
2-chloromethylaziridine hydrochloride (3). 
.sup.1 H-NMR (D.sub.2 O) .delta.: 3.26 (dd, 1H, J=9.57 Hz, 13.85 Hz), 3.53 
(dd, 1H, J=3.30 Hz, 13.85 Hz), 3.78 (dd, 1H, J=6.60 Hz, 12.21 Hz), 3.88 
(dd, 1H, J=4.95 Hz, 12.21 Hz), 4.38-4.47 (m, 1H) 
Example 3 
##STR83## 
A 25 ml suspension of tetrahydrofuran containing 1.28 g of 
2-chloromethylaziridine hydrochloride (3) obtained in the above Example 2 
was stirred in the atmosphere of nitrogen at -78.degree. C., and, to this 
solution, 21 mmol of n-butyllithium was added dropwise over a period of 
five minutes. After the addition was over, the solution was stirred at the 
same temperature for one hour, and, while left still so that it might have 
a room temperature, the solution was further stirred for 10 minutes. To 
the reaction liquid, there was added 2 ml of 50% aqueous solution of 
potassium hydroxide, and was stirred for 10 minutes. Thereafter, the 
reaction liquid was distilled under normal pressure, and, thus, there was 
obtained 1-azabicyclo1.1.0!butane (4) having a boiling point of about 
51.degree. C. The obtained distillate was dried with potassium hydroxide 
and potassium carbonate, and, then, was cooled to -40.degree. C., and, to 
the distillate, there was added dropwise a solution of 5 ml 
tetrahydrofuran containing 1.13 ml of formic acid. The resultant solution 
was left still until it had a room temperature, and, then, was further 
stirred for 18 hours, and, next, the solvent was condensed under reduced 
pressure, and, to this solution, there was added 16 .mu.l methanol 
solution containing 60 mmol of concentrated hydrochloric acid at 0.degree. 
C., and, subsequently, the solution was stirred for 20 hours. After the 
reaction was over, the solvent was evaporated in a vacuum, and, thus, 
there was obtained 570 mg (yield: 52.0%) of 3-hydroxyazetidine 
hydrochloride (5) in the form of colorless needle crystal. 
.sup.1 H-NMR (D.sub.2 O) .delta.: 4.0-4.3 (m, 2H), 4.1-4.3 (m, 2H), 4.6-4.8 
(m, 1H) 
Example 4 
##STR84## 
(i) To a 73 ml solution of methanol anhydride containing 7.95 g of 
3-hydroxyazetidine hydrochloride (5) obtained in the above Example 3, 
there was added 5.09 g of potassium hydrogencarbonate at a room 
temperature, and, then, there was added 9.67 g of 
2-(methylthio)-1,3-thiazoline dropwise, and, then, the resultant solution 
was subjected to heating and reflux for 20 hours. After the reaction 
liquid was left still until it had a room temperature, 3.63 g of potassium 
hydrogencarbonate was further added, and the liquid was stirred for one 
hour at the same temperature. After the reaction was over, precipitate was 
removed by filtration, and the solvent was evaporated in a vacuum, and, to 
the obtained residue, there was added 100 ml of tetrahydrofuran, and the 
resulting mixture was stirred for one hour at a room temperature. 
Insoluble matters were removed by filtration, and the solvent was 
evaporated in a vacuum, and, then, the residue was subjected to silica gel 
column chromatography (eluent: chloroform-methanol), and, thus, there was 
obtained 8.23 g (yield: 71.5%) of 
3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless 
crystal. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 3.356 (t, 2H, J=7.26 Hz), 
3.70.about.4.00 (m, 4H), 4.211 (t, 2H, J=8.21 Hz), 4.622.about.4.705 (m, 
1H), 4.971 (s, 1H) 
(ii) A 1.5 ml solution of acetonitrile anhydride containing 219 mg of 
3-hydroxyazetidine hydrochloride (5) was cooled to 0.degree. C. in the 
stream of nitrogen, and, to this solution, there were added 0.31 ml of 
triethylamine and subsequently a 0.3 ml solution of acetonitrile anhydride 
containing 250 mg of chloroethylisothiocyanate dissolved therein, and the 
resultant solution was stirred for 30 minutes at the same temperature, 
and, after left still until it had a room temperature, the solution was 
further stirred for two hours. Next, dichloromethane was added to the 
reaction liquid, and the resultant solution was washed with a saturated 
aqueous solution of potassium carbonate, and, thereafter, the 
dichloromethane layer was dried with magnesium sulfate, and then was 
condensed under reduced pressure, and, thus, there was obtained 300 mg 
(yield: 95%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form 
of colorless needle crystal. 
The NMR spectrum of this product was utterly identical with that of the 
product obtained in the above (i). 
Example 5 
##STR85## 
(i) To 2 ml suspension of tetrahydrofuran anhydride containing 790 mg of 
3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) obtained in the above 
Example 4, there was added 6 mg of N,N-dimethylaminopyridine while the 
suspension was cooled with ice, and, subsequently, there were added 
dropwise 557 mg of triethylamine and 575 mg of mesyl chloride while the 
suspension was cooled with ice, and the resulting mixture was stirred for 
40 minutes at the same temperature. After the reaction was over, the 
solvent was evaporated in a vacuum, and, to the resultant residue, there 
was added ethyl acetate, and the resultant mixture was washed with a 
saturated aqueous solution of sodium hydrogencarbonate. Then, the 
resultant aqueous layer was further extracted with ethyl acetate. After 
the obtained organic layer was dried with magnesium sulfate, the solvent 
was evaporated in a vacuum, and the residue was subjected to silica gel 
column chromatography (eluent: chloroform-methanol), and, thus, there was 
obtained 995 mg (yield: 84.3%) of 
3-mesyloxy-1-(1,3-thiazolin-2-yl)azetidine in the form of colorless 
crystal. 
.sup.1 H-NMR (CDCl.sub.3, 270 MHz, ppm) .delta.: 3.07 (s, 3H), 3.39 (t, 2H, 
J=7.6 Hz), 4.03 (t, 2H, J=7.6 Hz), 4.14-4.19 (m, 2H), 4.37-4.31 (m, 2H), 
5.28-5.33 (m, 1H) 
Next, to a 1 ml solution of dimethylformamide anhydride containing 118 mg 
of 3-mesyloxy-1-(1,3-thiazolin-2-yl)azetidine obtained from the above 
reaction, there was added 228 mg of potassium thioacetate at a room 
temperature, and the mixture was stirred at 80.degree. C. for four hours. 
After the reaction was over, the solvent was evaporated in a vacuum, and, 
then, after ethyl acetate was added, the solution was washed with a 
saturated aqueous solution of potassium hydrogencarbonate, and, then, the 
aqueous layer was subjected to back extraction with ethyl acetate. The 
obtained organic layer was dried with magnesium sulfate, and the residue 
was subjected to silica gel column chromatography (eluent: chloroform), 
and, thus, there was obtained 88 mg (yield: 81.2%) of 
3-acetylthio-1-(1,3-thiazolin-2-yl)-azetidine (7) in the form of 
light-yellowish oily matter. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.333 (s, 3H), 3.352 (t, 2H, J=7.26 Hz), 
3.885 (dd, 2H, J=8.24, 5.28 Hz), 4.012 (t, 2H, J=7.26 Hz), 
4.250.about.4.374 (m, 1H), 4.426 (t, 2H, J=8.25 Hz) 
(ii) There were added 119 mg of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine 
(6) and two molar equivalents of thioacetic acid, while cooled with ice, 
to 10 ml of tetrahydrofuran solution containing two molar equivalents of 
triphenylphosphine and two molar equivalents of diethylazodicarboxylate, 
and the resultant solution was stirred for one hour at the same 
temperature, and for further one hour at a room temperature. The solvent 
of the reaction liquid was evaporated in a vacuum, and the obtained 
residue was subjected to silica gel column chromatography (eluent: 
chloroform-ethanol), and, thus, there was obtained 107 mg (yield: 65%) of 
3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine (7). 
The NMR spectrum of this product was utterly identical with that of the 
product obtained in the above (i). 
Example 6 
##STR86## 
There was dissolved 12.98 g of 3-acetylthio-1-(1,3-thiazolin-2-yl 
)azetidine (7) obtained in the above Example 5 into 58.3 ml of 
isopropylalcohol, and to the resultant solution which was being cooled 
with ice, there was added 37.3 ml solution (1.69N) of potassium hydroxide 
dissolved in methanol, and the resultant solution was stirred for 10 
minutes. Then, at the same temperature, 66 ml solution (2N) of 
hydrochloric acid in methanol was added to the above solution so that it 
might be quenched, and, after the resultant mixture was stirred for 15 
minutes at a room temperature, insoluble matters were removed by 
filtration. The residue obtained by condensing the filtrate was dissolved 
in 39 ml of isopropylalcohol, and, after insoluble matters were removed by 
filtration, the filtrate was condensed. To the obtained residue, there was 
added 58.5 ml of n-butanol so that the residue might be condensed, and, 
thus, there was obtained 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine 
hydrochloride (8) in the form of yellowish white solid. 
To this solid, there was added 22.8 ml of acetonitrile, and the resulting 
mixture was stirred at a room temperature for 15 minutes so that the 
mixture might be dissolved, and, then, 113.4 ml of acetone was added 
dropwise over a period of 30 minutes. Then, further 113.4 ml of acetone 
was added dropwise over a period of 15 minutes, and, then, the resultant 
solution was stirred for 30 minutes while cooled with ice. The solid which 
was deposited was taken by filtration, and then was washed with 150 ml of 
acetone, and next was dried for a day under reduced pressure, and, thus, 
there was obtained 10.419 (purity: 97.5%; yield: 80.3%) of 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8) in the form 
of colorless needle crystal. 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.57 (d, 1H, J=8.2 Hz), 3.59 (t, 2H, 
J=7.4Hz), 4.02-4.18 (m, 4H), 4.63 (t, 2H, J=7.4 Hz), 5.19-5.26 (m, 1H), 
12.19 (s, 1H) 
This product was confirmed as a crystal by means of polarizing-microscopic 
observation. Besides, in powder X-ray diffraction pattern, there was shown 
a characteristic Peak at each of the following lattice spacing (d) (unit: 
A) 
7.32, 5.96, 5.04, 5.00, 4.90, 4.44, 4.23, 4.08, 3.79, 3.71, 3.66, 3.29, 
3.14, 3.10, 2.98, 2.91, 2.82, 2.55, 2.50 
Incidentally, both the above crystal filtrate and the acetone washings were 
condensed, and the resulting residue was dissolved in 10 ml of n-butanol 
and then was re-condensed, and, next, was dried under reduced pressure for 
one day. To the obtained 1.7 g of orange solid, there was added 1.7 ml of 
acetonitrile, and the resulting mixture was stirred for 15 minutes at a 
room temperature so that it might be dissolved, and, to the resulting 
solution, there was added 17 ml of acetone dropwise over a period of 15 
minutes, and the solution was stirred for 30 minutes while cooled with 
ice, and, thus, there was obtained 1.2 g (purity: 89.3%; yield: 8.5%) of 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8) in the form 
of colorless needle crystal. 
Example 7 
##STR87## 
To a 12 ml suspension of dried tetrahydrofuran containing 1.009 of 
2-bromomethylaziridine hydrobromide (2) obtained in the above Example 1, 
there was added dropwise 5.94 ml (1.63M) of of n-butyllithium at 
-78.degree. C., and the resulting mixture was stirred for one hour. The 
reaction liquid was distilled under normal pressure in a water bath 
(90.degree. C.), and each of the evaporated fraction was taken out, and, 
thus, there was obtained a solution of 1-azabicyclo1.1.0!butane (4) 
dissolved in tetrahydrofuran. 
To a 5 ml solution of dried tetrahydrofuran containing 550 mg (4.61 mmol) 
of 1,3-thiazoline-2-thione which was being cooled with ice, on the other 
hand, there was added 181 mg (55%) of sodium hydride, and the resulting 
mixture was stirred for one hour. To the obtained solution, there was 
added dropwise the above solution of 1-azabicyclo1.1.0!butane dissolved 
in tetrahydrofuran at -78.degree. C., and the resulting solution was 
stirred at a room temperature for 20 hours, and, then, the reaction liquid 
was subjected to high performance liquid chromatography, and, thus, there 
was obtained 2-(azetidin-3-ylthio)-1,3-thiazolidine (9). 
.sup.1 H-NMR (CO.sub.3 OD) .delta.: 3.32 (t, 2H, J=8 Hz), 3.46 (dd, 2H, J=6 
Hz, 10 Hz), 3.90 (dd, 2H, J=8 Hz, 10 Hz). 4.06 (t, 2H, J=8 Hz) 4.3-4.5 (m, 
1H) 
Example 8 
##STR88## 
To a solution of tetrahydrofuran anhydride containing 
2-(azetidin-3-ylthio)-1,3-thiazolidine (9) obtained in the above Example 
7, there was added 0.329 ml of methylsulfonic acid, and, then, the solvent 
was condensed under reduced pressure, and, to the obtained solution, there 
was added methanol, and the resulting solution was subjected to heating 
and reflux for three hours. After the reaction was over, the solvent was 
distilled off, and the residue was separated and purified by high 
performance liquid chromatography, and, thus, there was obtained 186 mg 
(yield: 23.2%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (10) of the 
present invention. 
The NMR spectrum of the hydrochloride obtained by treating the above 
compound (10) with hydrochloric acid was utterly identical with that of 
the compound (8) obtained in the above Example 6. 
Example 9 
##STR89## 
With use of 2.00 g of 2-bromomethylaziridine hydrobromide (2) obtained in 
the above Example 1, there was produced a solution of 
1-azabicyclo1.1.0!butane (4) dissolved in tetrahydrofuran by the same 
method as in the above Example 7. Next, to a 5 ml solution of dried 
tetrahydrofuran containing 1.32 ml of thioacetic acid, there was added 
dropwise a solution of compound (4) dissolved in tetrahydrofuran at a 
temperature of -40.degree. C. or lower, and the resulting mixture was 
stirred at a room temperature for 18 hours. After the reaction was over, 
the solvent was distilled off, and the residue was separated and purified 
by silica gel column chromatography (eluent: chloroform-acetone), and, 
thus, there was obtained 828 mg (yield: 51.8%) of 
1-acetyl-3-acetylthioazetidine (11). 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.87 (s, 3H), 2.35 (s, 3H), 3.89 (dd, 
1/2.times.2H, J=5 Hz, 10 Hz), 4.01 (dd, 1/2.times.2H, J=5 Hz, 9 Hz), 
4.1-4.2 (m, 1H), 4.42 (t, 1/2.times.2H, J=10 Hz), 4.61 (t, 1/2.times.2H, 
J=10 Hz) 
Example 10 
##STR90## 
To 104 mg of 1-acetyl-3-acetylthioazetidine (11) obtained in the above 
Example 9, there was added 1.0 ml of 2.6N hydrochloric acid, and the 
resulting solution was subjected to heating and reflux for one hour. After 
the reaction was over, water was added, and the solution was washed with 
ethylacetate, and, then, the aqueous layer was evaporated in a vacuum. The 
obtained residue was dried in a vacuum, and, thus, there was obtained 71 
mg (yield: 94.4%) of 3-mercaptoazetidine hydrochloride (12). 
.sup.1 H-NMR (D.sub.2 O) .delta.: 4.0-4.3 (m, 3H), 4.5-4.7 (m, 2H) 
Example 11 
##STR91## 
With use of 1.28 g of 2-chloromethylaziridine hydrochloride (3) obtained in 
the above Example 2, there was produced a solution of tetrahydrofuran 
containing 1-azabicyclo1.1.0!butane (4). After this solution was dried 
with potassium hydroxide and potassium carbonate, there was added dropwise 
0.85 ml of thioacetic acid at a room temperature. After the resulting 
solution was stirred for one hour at the same temperature, the reaction 
liquid was condensed under reduced pressure, and, then, 3.33 ml of 3 N 
hydrochloric acid was added, and the resulting solution was subjected to 
heating and reflux for one hour. After the reaction liquid was left still 
until it had a room temperature, 30 ml of water was added thereto, and the 
resulting solution was washed with ethylacetate. The aqueous layer which 
was obtained by separation was put together with the aqueous layer which 
had been extracted from organic layer, and, then, the solvent was 
evaporated in a vacuum, and, thus, there was obtained 913 mg (yield: 
72.7%) of 3-mercaptoazetidine hydrochloride (12) in the form of colorless 
oily matter. 
The NMR spectrum of the compound (12) was utterly identical with that of 
the compound obtained in the above Example 10. 
Example 12 
##STR92## 
To a solution of 22.7 mg of 3-mercaptoazetidine hydrochloride (12) obtained 
in the above Example 11 dissolved in 95% methanol (including 1 ml of 
water), there were added 26.6 mg of 2-(methylthio)-1,3-thiazoline and 5.2 
mg of triphenylphosphine, and the resulting solution was subjected to 
heating and reflux for six hours. After the reaction was over, the solvent 
was evaporated in a vacuum, and the obtained residue was dissolved in a 
0.1N hydrochloric acid, and the resulting mixture was washed with 
ethylacetate. The solvent in the obtained aqueous layer was evaporated in 
a vacuum, and the obtained residue was separated and purified by high 
performance liquid chromatography, and, thus, there was produced 29.1 mg 
(yield: 73.4%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride 
(8) in the form of colorless needle crystal. 
The NMR spectrum of this product was utterly identical with that of the 
product obtained in the above Example 6. 
Example 13 
##STR93## 
To a solution of 63.3 mg of 3-mercaptoazetidine hydrochloride (12) obtained 
in the above Example 10 dissolved in 1.0 ml of dried tetrahydrofuran, 
there was added 0.07 ml of triethylamine in the stream of nitrogen at a 
room temperature, and the resulting solution was stirred for 30 minutes. 
To this solution, there was added dropwise a solution of 70.3 mg of 
2-chloroethylisothiocyanate dissolved in dried tetrahydrofuran, and the 
resulting solution was further stirred for one hour. After the reaction 
liquid was cooled to 0.degree. C., 0.04 ml of methanesulfonic acid was 
added dropwise, and the resulting solution was stirred for 30 minutes, 
and, then, the solvent was evaporated in a vacuum. To the obtained 
residue, there was added 1.0 ml of dried methanol, and the resulting 
solution was subjected to heating and reflux for one hour, and, then, the 
solvent was evaporated in a vacuum. The obtained residue was separated and 
purified by thin-layer chromatography, and, thus, there was obtained 53.4 
mg (yield: 39.2%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine 
methanesulfonate (13) in the form of colorless oily matter. 
Example 14 
##STR94## 
(i) There was dissolved 700 mg of 
3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8), which was 
obtained in the above Example 6, in 15 ml of a mixed solvent composed of 
water, acetonitrile and chloroform, and, to the resulting solution, there 
was added 1668 mg of p-nitrobenzyl (1R, 5R, 
6S)-2-(diphenylphosphoryloxy)-6-(R)-1-hydroxyethyl!-1-methyl-carbapen-2-e 
m-3-carboxylate (14). To the obtained solution which was being cooled with 
ice, there was added 2.8 ml of diisopropylethylamine in the stream of 
nitrogen, and the resulting mixture was stirred at the same temperature 
for two hours. To the reaction liquid, there was added ethylacetate, and 
the resulting solution was washed with a saturated aqueous solution of 
sodium hydrogencarbonate and with a saturated aqueous solution of sodium 
chloride, and, then, the solvent was evaporated in a vacuum, and the 
obtained residue was subjected to silica gel column chromatography 
(eluent: chloroform-acetone), and, thus, there was produced 1339 mg 
(yield: 92%) of p-nitrobenzyl (1R, 5S, 
6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyethyl!-1-m 
ethyl-carbapen-2-em-3-carboxylate (15). 
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.235 (d, 3H, J=7.26 Hz), 1.349 (d, 3H, 
J=6.27 Hz), 3.160 (quintet, 1H, J=7.26 Hz), 3.265 (dd, 1H, J=2.3, 6.26 
Hz), 3.367 (t, 2H, J=7.26 Hz), 3.898.about.4.038 (m, 4H), 
4.071.about.4.147 (m, 1H), 4.212.about.4.278 (m, 2H), 4.372 (2H, J=7.92 
Hz), 5.255 and 5.517 (d(AB), 2H, J=13.85 Hz), 7.665 (d, 2H, J=8.58 Hz), 
8.226 (d, 2H, J=8.58 Hz) 
(ii) To a solution of 1339 mg of the compound (15) obtained from the above 
reaction (i) which was dissolved in 20 ml of tetrahydrofuran, there were 
added 60 ml of 0.38M phosphate buffer solution (pH 6.0) and 11.2 g of zinc 
powder, and the mixture was stirred vigorously for two hours. The reaction 
liquid was filtrated by Celite.RTM. so that insoluble matters might be 
removed, and, then, the filtrate was adjusted to pH 5.5 after washed with 
ethylacetate. Then, the obtained solution was condensed under reduced 
pressure, and this condensed solution was subjected to column 
chromatography Diaion HP-4.RTM. (made by Mitsubishi Chemical Corporation) 
(eluent: 5% aqueous solution of isopropyl-alcohol), and, thus, there was 
produced 861 mg (yield: 87%) of the desired (1R, 5S, 
6S)-2-1-(1,3-thiazolin-2-yl)azetidin-3-yl!thio-6-(R)-1-hydroxyethyl!-1-m 
ethylcarbapen-2-em-3-carboxylate (16). 
.sup.1 H-NMR (D.sub.2 O) .delta.: 1.093 (d, 3H, J=6.93 Hz), 1.207 (d, 3H, 
J=6.27 Hz), 3.05.about.3.20 (m, 1H), 3.357 (dd, 1H, J=2.3, 5.94 Hz), 3.558 
(t, 2H, J=7.26 Hz), 3.920 (t, 2H, J=7.26 Hz), 4.00.about.4.20 (m, 5H), 
4.20.about.4.30 (m, 1H). 4.60.about.4.70 (m, 1H) 
IR (KBr): 1740, 1640, 1590 cm.sup.-1 
Experimental Example 1 
The 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8) in the 
form of crystal obtained in the above Example 6 was left still in 
dehumidified state at a room temperature for one month. Resultantly, it 
was confirmed that the purity of this compound did not change at all, and 
that it had good storage stability. 
Experimental Example 2 
There was measured, by the following method, the antibacterial activity of 
the compound (16) which had been produced in Example 14 with use of the 
compound (I) of the present invention as a synthesis intermediate. 
(1) Test method 
There was employed the agar plate dilution method in accordance with the 
standard method of the Japanese Chemotherapy Society Chemotherapy, vol. 
29, 76-79 (1981)!. Concretely, a Mueller-Hinton (MH) agar liquid medium 
containing the test microorganism was cultured overnight at 37.degree. C., 
and the resultant culture medium was diluted with a buffered saline 
gelatin (BSG) solution so that the concentration of the test microorganism 
might be about 10 cells/ml. Then, with use of a microplanter, this diluted 
solution was inoculated each about 5 .mu.l on MH agar media containing the 
test compounds. Thus, the minimum concentration of the test compound in 
which no growth of the test microorganism was observed after the 
incubation at 37.degree. C. for 18 hours was regarded as Minimum 
Inhibitory Concentration (MIC). Incidentally, all of the test organisms 
used here were standard strains. 
(2) Results 
The results of the above experiment are shown in the following Table 1. 
TABLE 1 
______________________________________ 
MIC (.mu.g/ml) 
Test organisms Test compound (16) 
______________________________________ 
S. aureus FDA209P JC-1 
0.013 
S. aureus Terajima 
.ltoreq.0.006 
S. aureus MS353 .ltoreq.0.006 
S. pyogenes Cook .ltoreq.0.006 
B. subtilis ATCC 6633 
0.025 
M. luteus ATCC 9341 
0.2 
E. coli NIHJ JC-2 
0.013 
E. coli K-12 C600 
0.1 
E. cloacae 963 0.05 
E. aerogenes ATCC 13048 
0.1 
K. pneumoniae PCI-602 
0.013 
S. typhimurium 11D971 
0.025 
S. typhi 901 .ltoreq.0.006 
S. paratyphi 1015 
0.05 
S. schottmuelleri 8006 
0.025 
S. enteritidis G14 
0.39 
S. marcescens IAM 1184 
0.05 
M. morganii IFO 3848 
0.39 
P. mirabilis IFO 3849 
0.39 
P. vulgaris OX-19 
0.1 
P. vulgaris HX-19 
0.1 
P. rettgeri IFO 3850 
0.39 
______________________________________ 
It is known from the above results that the compounds of formula (I) 
provided by the present invention are useful as intermediates of 
carbapenem compounds having excellent antibacterial activity.