Process for the preparation of cephem derivatives

A process for preparing B-lactam derivatives of the formula (I): ##STR1## wherein R.sup.1 represents hydrogen or a metal salt; and R.sup.2 represents hydrogen, acetoxy methyl, (2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl or (1-methyl-1-H-tetrazol-5-yl)thiomethyl is disclosed. This process comprises the steps of (a) reacting triphenylphosphine and hexachloroethane or carbon tetrachloride with 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid in an organic solvent to give the corresponding acyloxyphosphonium chloride derivative of the formula: ##STR2## (b) acylating a previously silylated derivative of 7-ACA with this acyloxyphosphonium chloride derivative without its isolation.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a novel process for preparing 
.beta.-lactam derivatives, which are useful antibiotics, having the 
formula (I): 
##STR3## 
wherein R.sup.1 represents hydrogen or a metal salt; and R.sup.2 
represents hydrogen, acetoxy methyl, 
(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl or 
(1-methyl-1H-tetrazol-5-yl)thiomethyl. 
2. Description of the Prior Art 
Hitherto, a number of processes for the preparation of semi-synthesized 
.beta.-lactam antibiotic materials have been proposed. 
For instance, it is well known that an acylated compound of the formula (I) 
above can be prepared by converting an amino-protected organic acid of the 
formula (II): 
##STR4## 
wherein R.sup.3 is an amino-protecting group, into its activated 
derivatives, and then by acylating 7-ADCA 
(7-aminodesacetoxycephalosporanic acid), 7-ACA (7-aminocephalosporanic 
acid) or its derivatives with the activated derivatives. 
The activated derivatives of the compound of the formula (II) may include 
an acid chloride, an acid anhydride, an activated ester, an activated 
amide, an activated amide solvate, and so forth. 
In order to use an acid chloride as the activated derivative, the organic 
acid (II) is reacted with thionyl chloride (SOCl.sub.2), phosphorous 
trichloride (PCl.sub.3), phosphorous pentachloride (PCl.sub.5), or 
phosphorous oxychloride (POCl .sub.3). The resulting acid chloride is 
acylated with 7-ADCA, 7-ACA or its derivatives followed by removing the 
protecting R.sup.3 group to give a compound of the formula (I): see 
Japanese Laid-Open (Kokai) Patent Publication Nos. 52-102,096; 53-34,795; 
53-68,796; 54-52,096; and 54-157,596; as well as U.K. Patent No. 
2,025,933. 
However, the process mentioned above must be carried out under severe and 
complicated reaction conditions, because the process is subject to 
protection and deprotection of the amino group in the organic acid. This 
process further suffers from the defect that the acid chloride is 
unstable. 
In another method, 2-pyridinethioester, 2-benzothiazole ester, or 1-hydroxy 
benzotriazole ester is synthesized from an organic acid of the formula 
(III): 
##STR5## 
and then the resulting ester is acylated with 7-ADCA, 7-ACA or its 
derivatives to give a compound of the formula (I): see Japanese Laid-Open 
(Kokai) Patent Publication No. 52-102,293; 54-95,593; and 56-152,488. 
However, this process shows relatively low yields due to a side reaction 
accompanied when preparing the activated esters. Furthermore the process 
must be carried out at a high reaction temperature for a long period of 
reaction time during the acylation step, and requires a step of removing 
the by-products resulted from the process. 
It has also been reported that in order to resolve the problems encountered 
in utilizing the activated esters, an activated amide solvate of a 
compound of the formula (III) is isolated from an organic solvent, and 
then is acylated with 7-ACA or its derivatives to give a compound of the 
formula (I): see European Patent No. 175,814. However, this process has 
the disadvantages that it is difficult to isolate the activated amide 
solvate from the organic solvent used, and that it must be carried out 
under the substantially similar reaction conditions to those in the cases 
involving an activated ester or an activated amide, requiring a high 
reaction temperature and a long period of reaction time. 
Meanwhile, T. Fujisawa et al. have reported in Chem. Letters, 1267 (1983) 
that a lithium carboxylate derivative is reacted with dichlorophosphoran 
to give a corresponding acyloxyphosphonium salt derivative, and then the 
resulting acyloxyphosphonium salt is reacted with a Grignard reagent to 
give a corresponding diketone.

DETAILED DESCRIPTION OF THE INVENTION 
Based on the Fujisawa's report, the present inventors have studied a 
process for preparing .beta.-lactam derivatives of the formula (I), and 
discovered that an acyloxyphosphonium chloride derivative obtained from an 
aminothiazole derivative of the organic acid (III) makes it possible that 
the acylation of 7-ACA or its derivatives with organic acid can be 
proceeded without the isolation of the acyloxyphosphonium chloride to give 
the final product, .beta.-lactam derivative, in good purity and high 
yield. Based on the above discovery, the inventors have now completed the 
present invention. 
Therefore, an object of the present invention is to provide a new process 
for preparing .beta.-lactam derivative of the formula (I) above, by which 
the disadvantages of the prior art processes have been eliminated. 
Another object of the present invention is to provide a novel process for 
preparing more economically and simply a compound of the formula (I) above 
in higher yields and purity as compared with the prior art processes. 
According to the present invention, a novel process for preparing a cephem 
derivative of the formula (I) above, which comprises steps of: 
reacting a mixture of triphenylphosphine and hexachloroethane or carbon 
tetrachloride with an organic acid of the formula (III): 
##STR6## 
in an organic solvent to give an acyloxyphosphonium chloride derivative of 
the formula (IV): 
##STR7## 
acylating a derivative of 7-ACA of the formula (V): 
##STR8## 
wherein R.sup.2 is the same as defined above, which has been previously 
silylated with a silylating agent in an organic solvent in the presence or 
absence of a base, with the acyloxyphosphonium chloride derivative without 
its isolation. 
The process of the present invention can be represented by the following 
reaction scheme: 
##STR9## 
R.sup.1 and R.sup.2 are the same as defined above. 
The acyloxyphosphonium chloride derivative can be synthesized by first 
reacting triphenylphosphine with hexachloroethane or carbon tetrachloride 
in an organic solvent to give dichlorophosphoran, which is then reacted 
with an aminothiazole derivative of the formula (III). 
For identifying the acyloxyphosphonium chloride synthesized, a number of 
attempts to isolate it, such as flash column chromatography and 
crystallization in a nonpolar solvent, etc., have been made. However, 
since the acyloxyphosphonium chloride compound is unstable and easily 
decomposable, its isolation could not be achieved. Thus, the 
acyloxyphosphonium chloride derivative is synthesized using CDCl.sub.3 as 
a solvent, and then directly sampled followed by identification of its 
chemical structure by means of the .sup.1 H-NMR spectra. 
The organic solvents for the above reaction may preferably include 
tetrahydrofuran, dichloromethane, acetonitrile, etc., and most preferably 
dichloromethane. 
Triphenylphosphine and hexachloroethane or carbon tetrachloride are each 
preferably used in amounts of 1.0-1.3 equivalents to an organic acid of 
the formula (III). 
The reaction for preparing the acyloxyphosphonium chloride is carried out 
at 0.degree.-30.degree. C. After 0.5-3.0 hours, the acyloxyphosphonium 
chloride derivative of the formula (IV) is obtained. 
The organic solvent for silylation of the compound of the formula (V) may 
include preferably tetrahydrofuran, dichloromethane, acetonitrile, etc., 
.and most preferably dichloromethane. The silylate agent may include 
dichlorodimethylsilane, chlorotrimethylsilane, hexamethyldisilazane, and 
N,O-bis-trimethylsilylacetamide, etc. The silylating agent is used in 
amounts of 2.0-4.0 equivalents to the compound of the formula (V). 
As the base, triethylamine, pyridine and N,N-dimethylaniline, etc. may be 
preferably used. The silylation reaction is preferably carried out at 
10.degree.-45.degree. C. for 0.5-2.0 hours. 
The acylation reaction to prepare .beta.-lactam derivatives of the formula 
(I) is appropriately carried out at between -5.degree. C. to 40.degree. C. 
for 1-3 hours. This reaction is carried out stoichiometrically. When the 
reaction is completed, a base such as triethylamine and sodium 
bicarbonate, and water are added to the reaction mixture, and two layers 
are then separated. Then, a mixture of organic solvents is added to the 
aqueous layer, and then the pH of the aqueous layer is adjusted to an 
isoelectric point to give the final product, .beta.-lactam derivatives of 
the formula (I), in precipitate form. 
PREFERRED EMBODIMENT OF THE INVENTION 
The present invention will be described in greater detail by way of the 
following examples. It should be, however, noted that the examples are 
presented for illustration purpose only and should not be construed as 
limiting the invention which is properly delineated in the claims. 
EXAMPLE 1 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]CEPHALOSPORANIC 
ACID 
Step A 
Into a 3-neck flask, 12.14 g of triphenylphosphine, 10.96 g of 
hexachloroethane and 150.0 ml of dichloromethane were placed. The 
resulting mixture was stirred for 1 hour at about 20.degree. C. Then, to 
the mixture, 8.88 g of 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic 
acid was added. The resulting mixture was further stirred for 1.5 hours at 
20.degree. C. to give a reaction mixture. 
Step B 
Into a 3-neck flask, 10.0 g of 7-aminocephalosporanic acid, 150.0 ml of 
dichloromethane and 12.32 g of N,O-bis-trimethylsilylacetamide were added. 
The resulting mixture was stirred for 1 hour at about 30.degree. C. To the 
mixture, the reaction mixture obtained from Step A was added dropwise at 
20.degree. C. The resulting mixture was stirred for 1 hour. Upon 
completion of the reaction, 14.0 g of sodium bicarbonate and 180.0 ml of 
water were added to the reaction mixture which was then stirred to 
separate a water layer. 90.0 Ml of a mixture solvent of ethyl acetate and 
n-butanol (8:2) was added to the water layer, which was then adjusted to a 
pH of about 2.6 to precipitate white crystals. The resulting crystals were 
filtered out and dried to give 15.02 g (90.0%) of the title compound. 
.sup.1 HNMR (DMSO-d.sub.6, .delta.ppm): 2.0(s,3H); 3.5(AB,2H); 3.8(s,3H); 
4.7(q,2H); 4.8(d,2H); 5.8(dd,1H); 6.8(s,1H); 7.2(s,2H); 9.5(d,1H). 
EXAMPLE 2 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]CEPHALOSPORANIC 
ACID 
Step A 
The same procedure as in Example 1, Step A was repeated to give a reaction 
mixture. 
Step B 
Into a 3-neck flask, 10.0 g of 7-aminocephalosporanic acid, 150.0 ml of 
dichloromethane and 9.28 g of triethylamine were placed. To the mixture, 
9.97 g of chlorotrimethylsilane was added dropwise at 15.degree. C. The 
resulting mixture was stirred for 1.5 hours, to which the reaction mixture 
obtained from Step A was then added. After stirring for 1 hour at 
20.degree. C., 16.0 g of sodium bicarbonate and 200.0 ml of water were 
added to the mixture which was then stirred again to separate the water 
layer. 100.0 Ml of a mixture solvent of ethyl acetate and n-butanol (8:2) 
was added to the water layer, which was then adjusted to a pH of about 2.6 
to precipitate white crystals. The resulting crystals were filtered and 
dried to give 14.55 g (87.2%) of the title compound. 
EXAMPLE 3 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]CEPHALOSPORANIC 
ACID 
The same procedure as in Example 1 was repeated, except that 
tetrahydrofuran in the same amount was used in place of dichloromethane. 
Then, 14.0 g of sodium bicarbonate and 180.0 ml of water were added to the 
resulting mixture. After the mixture was saturated with NaCl while 
stirring, the water layer was separated. 90.0 Ml of a mixture solvent of 
ethyl acetate and n-butanol (8:2) was added to the water layer, which was 
then adjusted to a pH of about 2.6 to precipitate white crystals. The 
resulting crystals were filtered out and dried to give 13.97 g (83.7%) of 
the title compound. 
EXAMPLE 4 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]-ACETAMIDO]CEPHALOSPORANIC 
ACID 
The same procedure as in Example 1 was repeated, except that acetonitrile 
in the same amount was used in place of dichloromethane. Then, the 
resulting mixture were treated in the same manner as described in Example 
3 to give 14.10 g (84.5%) of the title compound. 
EXAMPLE 5 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]CEPHALOSPORANIC 
ACID 
The procedure similar to that described in Example 1 was carried out using 
9.77 g of hexamethyldisilazane in place of N,O-bis-trimethylsilyl 
acetamide. Then, the resulting mixture was treated in the same manner as 
described in Example 3 to give 14.49 g (86.8%) of the title compound. 
EXAMPLE 6 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]CEPHALOSPORANIC 
ACID 
Step A 
The same procedure as in Example 1 was repeated to give a reaction mixture. 
Step B 
Into a 3-neck flask, 10.0 g of 7-aminocephalosporanic acid, 150.0 ml of 
dichloromethane and 9.56 g of N,N-dimethylaniline were placed. To the 
mixture, 9.47 g of dichlorodimethylsilane was then added dropwise at 
15.degree. C. The resulting mixture was stirred for 1.5 hours. To this 
mixture, the reaction mixture obtained from Step A was added. After 
stirring at 20.degree. C. for 1 hour, 17.0 g of sodium bicarbonate and 
200.0 ml of water were added to the reaction mixture. The mixture was 
stirred again, and a water layer was separated therefrom. 100.0 Ml of 
mixture solvent of ethyl acetate and n-butanol (8:2) was added to the 
water layer, which was then adjusted to a pH of about 2.6 to precipitate 
white crystals. The resulting crystals were filtered and dried to give 
14.35 g (86.0%) of the title compound. 
EXAMPLE 7 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDOl-3-](1-METHYL-1H-T 
ETRAZOL - 5-YL)THIOMETHYL]-3-CEPHEM-4-CARBOXYLIC ACID 
Step A 
Into a 3-neck flask, 12.14 g of triphenylphosphine, 10.96 g of 
hexachloroethane and 180.0 ml of dichloromethane were placed. The mixture 
was stirred for 1 hour at 20.degree. C., to which 8.88 of 
2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid was added. The 
resulting mixture was stirred for 1.5 hours at 20.degree. C. to give a 
reaction mixture. 
Step B 
Into a 3-neck flask, 12.05 g of 7-amino-[3-(1methyl-1H-tetrazol-5-yl) 
thiomethyl]-3-cephem-4-carboxylic acid, 180.0 ml of dichloromethane and 
12.32 g of N,O-bis-trimethylsilyl acetamide were placed. The mixture was 
stirred for 1 hour at 30.degree. C. To the mixture, was added dropwise the 
reaction mixture obtained from Step A at 20.degree. C. The resulting 
mixture was then stirred for 1.5 hours. After completion of the reaction, 
13.0 g of sodium bicarbonate and 180.0 ml of water were added to the 
reaction mixture. After the mixture was stirred, the water layer was 
separated. 95.0 Ml of a mixture solvent of ethyl acetate and n-butanol 
(8:2) was added to the water layer, which was then adjusted to a pH of 
about 2.8 to precipitate crystals. The resulting crystals were filtered 
out and dried to give 16.60 g (88.4%) of the title compound. 
.sup.1 HNMR (D.sub.2 O/NaHCO.sub.3,.delta.ppm): 3.84(d,2H); 4.01(s,3H); 
4.05(s,3H); 5.18(d,1H); 5.76(d,1H); 7.00(s,1H). 
EXAMPLE 8 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]-3-[(1-METHYL-1H-T 
ETRAZOL-5-YL)THIOMETHYL]3-CEPHEM-4-CARBOXYLIC ACID 
The same procedure as in Example 7 was repeated, except that acetonitrile 
in the same amount was used in place of dichloromethane. Then, 13.0 g of 
sodium bicarbonate and 170.0 ml of water were added to the resulting 
reaction mixture. After the reaction mixture was saturated with NaCl while 
stirring, a water layer was separated by extracting with 150 ml of 
dichloromethane. 80.0 Ml of a mixture solvent of ethyl acetate and 
n-butanol (8:2) was added to the water layer which was then adjusted to a 
pH of about 2.8 to precipitate crystals. The resulting crystals were 
filtered out and dried to give 15.90 g(84.7%) of the title compound. 
EXAMPLE 9 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]-3-CEPHEM-4-CARBOX 
YLIC ACID 
Step A 
Into a 3-neck flask, 12.14 g of triphenylphosphine, 10.96 g of 
hexachloroethane and 170 0 ml of dichloromethane were placed. The mixture 
was stirred for 1 hour at about 20.degree. C., to which 8.88 g of 
2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid was added. The 
mixture was stirred for 1.5 hours at 20.degree. C. to give a reaction 
mixture. 
Step B 
Into a 3-neck flask, 7.35 g of 7-amino-3-cephem-4carboxylic acid, 170.0 ml 
of dichloromethane and 7.84 g of pyridine were placed. To the mixture, 
11.84 g of dichlorodimethylsilane was added dropwise at 10.degree. C. The 
resulting mixture was stirred for 1.5 hours at 20.degree. C. To this 
mixture, the reaction mixture obtained from Step A was added, and then the 
resulting mixture was stirred for 1.5 hours at 10.degree. C. After 
completion of the reaction, 16.5 g of sodium bicarbonate and 210.0 ml of 
water were added to the mixture. The mixture was stirred, and then a water 
layer was separated. 100.0 Ml of mixture solvent of ethyl acetate and 
n-butanol (8:2) was added to the water layer, which was then adjusted to a 
pH of about 2.9 to precipitate crystals. The resulting crystals were 
filtered out and dried to give 12.61 g (89.6%) of the title compound. 
.sup.1 HNMR (DMSO-d.sub.6,.delta.ppm): 3.58(bs,2H); 3.84(s,3H); 5.12(d,1H); 
5.84(d,1H); 6.51(s,1H); 6.77(s,1H); 7.26(bs,2H); 9.65(d,1H). 
EXAMPLE 10 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]OXO-AS-TRIAZIN-3YL) 
THIOMETHYL]-3-CEPHEM-4-CARBOXYLIC ACID 
Step A 
Into a 3-neck flask, 12.14 g of triphenylphosphine, 10.96 g of 
hexachloroethane and 150.0 ml of dichloromethane were placed. The mixture 
was stirred for hour at about 20.degree. C., to which 8.88 g of 
2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid was added. The 
mixture was stirred for 1.5 hours at 20.degree. C. to give a reaction 
mixture. 
Step B 
Into a 3-neck flask, 13.62 g of 7-[amino-3-(2,5- 
dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl]-3-cephem-4-ca 
rboxylic acid, 200 ml of dichloromethane and 26.13 g of 
N,O-bis-trimethylsilylacetamide were placed. The mixture was stirred for 
hour at about 30.degree. C. To the resulting mixture, was added dropwise 
the reaction mixture obtained from Step A at 10.degree. C. The resulting 
mixture was then stirred for 1 hour. After completion of the reaction, 
16.0 g of sodium bicarbonate and 180.0 ml of water were added to the 
reaction mixture. After the mixture was stirred, the water layer was 
separated. 50.0 Ml of a mixture solvent of ethyl acetate and n-butanol 
(8:2) was added to the water layer adjusted to a pH of about 3.1 to 
precipitate crystals. The resulting crystals were filtered out and dried 
to give 18.45 g (90.6%) of the title compound. 
.sup.1 HNMR (DMSO-d.sub.6,.delta.ppm): 3.2(d,2H); 3.61(s,3H); 3.95(s,3H); 
4.21(d,2H); 5.18(d,1H); 5.72(d,1H); 6.95(s,1H); 7.2(bs,2H); 9.45(d,1H). 
EXAMPLE 11 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]3-[(2,5-DIHYDRO-6- 
HYDROXY -2-METHYL-5-OXO-AS-TRIAZIN-3-YL)THIOMETHYL]-3-CEPHEM-4-CARBOXYLIC 
ACID 
The same procedure as in Example 10 was repeated, except that acetonitrile 
in the same amount was used in place of dichloromethane. Then, the 
resulting reaction mixture was treated in the same manner as described in 
Example 3 and adjusted to a pH of about 3.1 to precipitate crystals. The 
resulting crystals were filtered out and dried to give 17.53 g (86.1%) of 
the title compound. 
EXAMPLE 12 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]3-](2,5-DIHYDRO-6- 
HYDROXY -2-METHYL-5-OXO-AS-TRIAZIN-3-YL)THIOMETHYL]-3-CEPHEM-4-CARBOXYLIC 
ACID 
Step A 
The same procedure as in Example 10 was repeated to give a reaction 
mixture. 
Step B 
Into a 3-neck flask, 13.62 g of 7-[amino-3-(2,5- 
dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3yl)thiomethyl]3-cephem-4-carb 
oxylic acid, 200.0 ml of dichloromethane and 14.84 g of triethylamine were 
placed. To the mixture, 16.58 g of dichlorodimethylsilane was added 
dropwise at 15.degree. C. The resulting mixture was stirred for hour, to 
which the reaction mixture obtained from Step A was then added, and the 
resulting mixture was stirred for 1 hour at 10.degree. C. After completion 
of the reaction, 17.0 g of sodium bicarbonate and 210.0 ml of water were 
added to the reaction mixture. After the mixture was stirred, the water 
layer was separated. 100.0 Ml of a mixture solvent of ethyl acetate and 
n-butanol (8:2) was added to the water layer, which was then adjusted to a 
pH of about 3.I to precipitate crystals. The resulting crystals were 
filtered out and dried to give 17.30 g (85.0%) of the title compound. 
EXAMPLE 13 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]CEPHALOSPORANIC 
ACID 
The same procedure as in Example 1 was repeated, except that carbon 
tetrachloride in the same equivalent was used in place of 
hexachloroethane. Then, the resulting reaction mixture was treated in the 
same manner as described in Example 1 to give 14.67 g (87.9%) of the title 
compound. 
EXAMPLE 14 
7-[[2-(2-AMINOTHIAZOL-4-YL)-2-SYN-METHOXYIMINO]ACETAMIDO]3-](2,5-DIHYDRO-6- 
HYDROXY -2-METHYL-5-OXO-AS-TRIAZIN-3-YL)THIOMETHYL]-3-CEPHEM-4-CARBOXYLIC 
ACID 
The same procedure as in Example 10 was repeated, except that carbon 
tetrachloride in the same equivalent was used in place of 
hexachloroethane. Then, the resulting reaction mixture was treated in the 
same manner as described in Example 10 to give 17.8 g (87.4%) of the title 
compound. 
As described above, the present invention is featured by removing the steps 
of protecting and deprotecting the amino group in the aminothiazole 
derivative (III). Also, the subsequent acylation step can be carried out 
without isolation of the acyloxyphosphonium chloride of the formula (IV). 
Furthermore, the reactions involved may be carried out at near room 
temperature in a relatively short reaction time. 
In addition to the advantages mentioned above, after the completion of the 
reactions involved, the separation of the desired product can be easily 
achieved by adding a mixture of organic solvents to the aqueous layer. 
Thus, according to the present invention .beta.-lactam derivatives, which 
are a useful antibiotic, of the formula (I) above and prepared more 
economically and simply in high yields and purity.