JPS63211286A - Beta-lactam derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I {R<1> is H or amino-protecting group; R<2> is H, salt-forming cation or carboxylic acid-protecting group; R<3> is H, (substituted) lower alkyl, (substituted) aralkyl, (substituted) phenyl, (substituted) heterocyclic or COR<4> [R<4> is (substituted) amino or OR<2>]} or a salt thereof. EXAMPLE:7-[ (Z)-2-Chloromethylene-2-( 2-aminothiazol-4-yl )acetamido]-3-vinyl-3- cephem-4-carboxylic acid.trifluoroacetate. USE:An antibacterial agent against Gram-positive and Gram-negative bacteria. PREPARATION:A compound shown by formula II or a reactive derivative at the amino group or a salt thereof is reacted with an acid shown by formula III or a reactive derivative at the carboxyl group or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [In the general formula, R1 is a hydrogen atom or a protecting group for an amino group, R2 is hydrogen, a salt-forming cation, or a protecting group for a carboxylic acid, and R3 is a protecting group for a carboxylic acid. a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent,
It represents a phenyl group which may have a substituent, a heterocyclic group which may have a substituent, or a group represented by COR'.

Here, R4 is an amino group which may have a substituent or O
Represents a group represented by R2. ] or its salts.

Conventionally, cephalosporin β-lactam drugs have shown broad antibacterial activity against Durum-positive and Durum-negative bacteria, and many semi-synthetic cephalosporin drugs have been commercially available and are used clinically as therapeutic agents for various infectious diseases. There is (W, E, Wic
k rCephalosporins and Peni
cilline, Chemistry and B
iology edited by J, E, H. F. 1ynn, A
Academic Press, New York,
N.Y.

1972: Chapter 11). In recent years, research to improve cephalosporin agents has progressed, and great progress has been made in terms of enhancement of anti-Daram-negative bacteria activity, but on the other hand, it cannot be said that the anti-Daram-positive bacteria activity has necessarily been improved.

(W, Dirkheimer, etal, A
ngew, Chem, Engineering nt.

Ea, Enyl, 24.180 (1985)
) The present inventors have discovered a novel β-
The present invention was completed by synthesizing lactam conductors and discovering that they have extremely broad-spectrum antibacterial activity and exhibit strong antibacterial activity not only against Durham-negative bacteria but also against Durham-positive bacteria.

The compound of the present invention represented by the general formula CI) will be described in more detail. The novel β-lactam derivative of the present invention is
It has a 2-(2-aminothiazol-4-yl)-3-chloro-2-7' amide group at the 7th position of the cephem nucleus. This substituent includes (E) and (Z
) There are isomers.

Furthermore, similar (E) and (Z) isomers exist in the ethynyl group substituted at the 3-position of the cephem nucleus, and the present invention also includes these (E) isomers, (Z) isomers, or mixtures thereof. do.

R1 in the formula is a hydrogen atom or a protecting group for an amino group,
Protecting groups for amino groups are usually protecting groups for amine groups that can be easily removed by acid hydrolysis or hydrogenolysis, such as tertiary butoxycarbonyl, benzyloxycarbonyl, formyl, chloroacetyl, trityl, and alkylsilyl groups. This is a group used as

R2 is hydrogen, a ring-forming cation, or a carboxylic acid protecting group. Suitable salts of the compound CI) of the present invention include:
Includes pharmaceutically acceptable salts, especially the customary non-toxic salts, salts with bases and acid addition salts, i.e. salts with inorganic bases, such as alkali metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts. alkaline earth metal salts such as ammonium salts, salts with organic bases such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts organic amine salts, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, tartrate, methanesulfonate, benzenesulfone M salt,
Included are organic carboxylic or sulfonic acid addition salts such as p-toluenesulfonate, salts with basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid. Protecting groups for carboxylic acids include alkyl groups, lower alkoxymethyl groups, lower alkylthiomethyl groups, lower alkanoyloxymethyl groups, aralkyl groups,
Examples include aryl groups and silyl groups that are conventionally used in penicillin and cephalosporin/based compounds. Furthermore, metabolically unstable protecting groups that can be hydrolyzed and removed in vivo are also included, and examples of such protecting groups include lower alkoxycarbonyloxyalkyl groups and substituents (2-oxo -1,3-dioxolen-4-yl)methyl ≠; Pilgrimage bh-61 where,
The term "lower" as used in the present invention means 1 to 6 carbon atoms, unless otherwise specified.

R3 is a hydrogen atom, a lower alkyl group which may have a substituent,
It represents an aralkyl group which may have a substituent, a phenyl group which may have a substituent, a heterocyclic group which may have a substituent, or a group represented by C0R4. Here, R4 represents an amine group which may have a substituent or a group represented by OR2.

Here, as a substituent, a lower alkyl group, a trihalo-di-substituted lower alkyl group, a hydroxy group, a lower alkoxy group, an acyloxy group, an allyloxy group, a carbamoyloxy group, a halogen atom, a nitro group, a mercapto group, an amino group, Examples include carboxyl group, carbamoyl group, di-lower alkylamino lower alkyl group, carboxyalkyl group, carbamoylalkyl group, hydroxyalkyl group, and the like.

The number of these substituents is usually 1 to 2.

When the group R3 represents a heterocyclic group which may have a substituent, examples of the heterocyclic group include pyridine, pyrrole, imbeer, furan, thiophene, imidazole, pyrazole, thiazole, inthiazole, triazole, thiadiazole, and tetrazole. etc. can be mentioned.

The compound of the present invention can be produced by the following method.

Method 1 General formula [In the formula, R2 and R3 have the same meanings as above. ] or a reactive derivative thereof at the amine group, or a salt thereof, [wherein R1 has the same meaning as above. ] The acid represented by the following formula or a reactive derivative of the carboxyl group of this acid or a salt thereof is reacted with the acid.

It can be easily produced from a l-4-yl acetic acid derivative (Japanese Patent Application Laid-Open No. 57-67581). In addition, the compound of general formula (II), which is the other raw material, can be prepared by a known method [for example,
H, Yamanaka, etal, J, Ant
ibiotics.

Week, 1739 (1985); Japanese Patent Publication No. 1983-1699
1] or by the method of Reference Example of the present invention.

Suitable examples of reactive derivatives at the amino group of compound [II) include thick base-type imino or its tautomer formed by the reaction of compound (n) with carbonyl compounds such as aldehydes, ketones, etc. enamine-type isomer; a silyl derivative obtained by the reaction of the compound [■] with a silyl compound such as bis(trimethylsilyl)acetamide; a silyl derivative produced by the reaction of the compound [ll] with phosphorus trichloride or phosgene; Examples include derivatives.

Suitable salts of compounds (II) and 1] include those of the same kind as those exemplified for compound CI).

Examples of reactive derivatives at the carboxyl group of compound (III) include acid halides, acid azides, acid anhydrides, active amides 9, active esters, and more specifically, acid chlorides, acid bromides; Substituted phosphoric acids (e.g. dialkyl phosphates, phenyl phosphates, diphenyl phosphates, dibenzyl phosphates, halogenated phosphoric acids, etc.), dialkyl phosphorous/acids, sulfites, thiosulfates, sulfates, alkyl carbonates (e.g. methyl carbonate, ethyl carbonate, etc.) ), aliphatic carboxylic acids (e.g. pivalic acid, valeric acid, isovaleric acid, 2
- mixed acid anhydrides with acids such as (ethyl acetic acid, trichloroacetic acid, etc.) or aromatic carboxylic acids (e.g. benzoic acid, etc.); symmetric acid anhydrides: with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; activated amino acids or active esters (e.g. cyan methyl ester, methoxymethyl ester, dimethyliminomethyl (Mo2N == CH-) ester, hinyl ester, flonorgyl ester, p-nitrophenyl ester, 214-dinitrophenyl ester, 2+4- ') Nitrophenyl ester, trichlorophenyl ester, interchlorophenyl ester, mesyl phenyl ester, phenyl asophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, hyridyl ester, A') dile ester, 8-quinolyl thioester, etc.) or N-hydroxy compound (e.g., N, N
-dimethylhuman90xylamine, 1-hydroxy-2
-(IH)-pyridone, N-hydroxy-2-(IH)
-pyridonine, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hyProxy6-chloroIH-benzotriazole, etc.).

These reactive derivatives are appropriately selected depending on the type of compound CIII) used.

This reaction between compound (II) and (Ill) is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine. or in other organic solvents that do not adversely affect the reaction.

These solvents may be used in combination with water.

In this reaction, when compound (II) is used in free form or salt form, it is desirable to carry out the reaction in the presence of a condensing agent, and such condensing agents include, for example, N,
N'-dicyclohexylcarbodiimide 2N-cyclohexyl-N-morpholinoethylcarbosiimide 2N-cyclohexyl-N-(4-diethylaminocyclohexyl)carbodiimide 2N,N'-diethylcarbodiimide: N,N'-diisopropylcarbodiimide: N-
Ethyl-N'-(3-dimethylaminepropyl)carbodiimide": N,N-carbonylbis(2-methylimidazole): Intamethyleneketene-N-cyclohexylimine: Diphenylketene-N-cyclohexylimine: Ethoxyacetylene: 1- Alkoxy-1-chloroethylene: Trialkyl phosphite: Ethyl polyphosphate:
Isopropyl polyphosphate: Phosphorous oxychloride: Phosphorus trichloride: Thionyl chloride: Oxalyl chloride: Triphenylphosphine: 2-ethyl-7-hydroxy(zuinxazolium salt: 2-ethyl-5-(m-sulfophenyl)inxa Thulium hydroxide inner salt: 1-(p-chloro(benzenesulfonyloxy)-6-chloro-IH-benzotriazole): So-called Willsmeier obtained by reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc. Examples include reagents.

This reaction may also be carried out in the presence of an inorganic or organic base, examples of such bases include alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonates (e.g. sodium, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. calcium carbonate, etc.), tri(lower)alkylamines (e.g. trimethylamine, triethylamine, etc.), pyridine, N-(lower)alkylmorpholine, N,
Examples include N-di(lower)alkylbenzylamine.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Method 2 Step 2-1 ↓P(R5)3(V) Steps 2-3 ↓R3cHo (M
ll) [In the formula, R1, R2 and R3 have the same meanings as above, R5 is an aryl group, and xl and X2 each mean a halogen]. A detailed explanation of the steps in method 2 is as follows.

Method 2-1 Adding a compound of general formula (V) or a salt thereof to a compound of general formula (V
) to act on tri-substituted phosphine. Suitable salts of compound CI) include salts with the same bases as exemplified for compound CI).

This reaction is preferably carried out in the presence of a metal halide such as an alkali metal halide such as sodium iodide, potassium iodide, and sodium bromide. In this case, Xl of compound α] may be substituted with the halogen of the metal halide in the target compound (VI). The reaction is carried out in N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride, tetrahydropran, ethyl acetate or a mixed solvent thereof. The reaction temperature is not particularly limited, but room temperature is desirable.

Method 2-2 A compound represented by the general formula (2) or a salt thereof is reacted with a base. Suitable salts of compound CVI) include salts with the same bases as exemplified for compound CI).

The base used in this step includes those exemplified in Method 1. The reaction is usually carried out using acetone, tetrahedral 9
The reaction is carried out in 0 furan, methylene chloride, water, or a mixed solvent thereof. The reaction temperature is not particularly limited, but room temperature is desirable.

Method 2-3 A compound represented by general formula (5) or a salt thereof is reacted with an aldehyde represented by general formula (2). Suitable salts for compound CI) include those of the same type as those exemplified for compound CI). This reaction is usually carried out in tetrahydrofuran, dioxane, methylene chloride, or a mixed solvent thereof. The reaction temperature is not particularly limited, but is preferably around room temperature.

Method 3 j (R5)3P=C plate 3 [X] [In the formula, R1, R2, R3, and R5 have the same meanings as above].

Method 3 is a method in which a compound represented by the general formula [■] or a salt thereof is reacted with phosphorous iris 9 represented by the general formula (X). Suitable salts for compound [■] include those of the same type as those exemplified for compound CI). Among the raw material compounds (IX) is carboxylic acid (1) and 7-amino-3-hydroxymethyl-3-cephem-4
-Easily synthesized from carboxylic acid (see reference side below)
. On the other hand, phosphorus irito 9 [X] can be prepared by conventional organic synthesis techniques. Examples of the reaction solvent include those listed in Method 2-3. The reaction temperature is not particularly limited, but is preferably around 0°C to room temperature.

In addition, in the compound a of the present invention obtained by the above reaction, if necessary, the carboxyl protecting group and/or amino protecting group can be removed according to a conventional method, or the metabolically unstable non-toxic ester of the carboxyl group can be removed. Conversion to groups may also be performed. The method for removing the carboxyl protecting group and/or the amino protecting group is appropriately selected depending on the type of protective group to be removed. The elimination reaction of the amine protecting group involves hydrolysis and reduction.For compounds whose protecting group is an acyl group, a method of reacting with an iminohalogenating agent, then an iminoetherifying agent, and then hydrolyzing as necessary. Any commonly used method can be applied. The method of hydrolysis using an acid is applicable to the removal of groups such as alkoxycarbonyl groups, formyl groups, trityl groups, etc. as a general method. In addition, the acids used include formic acid, trifluoro Ff [, I)
-) organic and inorganic acids such as luenesulfonic acid, hydrochloric acid,
Preferably, formic acid, trifluoric acid, hydrochloric acid, etc., which can be easily post-treated, are appropriately selected depending on the type of amine protecting group. The reaction can be carried out in the absence of a solvent or in the presence of water, a hydrophilic organic solvent, or a mixed solvent thereof. Furthermore, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole.

Any commonly used method such as hydrolysis or reduction can be applied to the elimination reaction of the carboxyl protecting group. Hydrolysis using an acid is one of the common methods and is applied, for example, to eliminate groups such as silyl groups and diphenylmethyl groups. The metabolically unstable esterification method is a commonly used method known per se, such as a method in which a metal salt of a carboxylic acid is reacted with a coexisting alkyl halide such as pino-20yloxymethyl halide in a solvent. .

All of the compounds of the present invention are new compounds, and the minimum inhibitory concentrations of some of them are shown in Table 1 (measured by the agar dilution method). As a result, all of the tested compounds had broad-spectrum and strong antibacterial activity, and the compounds of the present invention are useful as pharmaceuticals.

When administering the object compound (1) of the present invention or its pharmaceutically acceptable salt or ester for therapeutic purposes, an organic or inorganic compound containing the above compound as an active ingredient and suitable for oral administration, parenteral administration or external use, They can be administered in conventional formulations mixed with pharmaceutically acceptable carriers such as solid or liquid excipients. Such formulations include capsules, tablets, dragees, ointments, skewers, solutions, suspensions, emulsions, and the like.

Furthermore, as necessary, the preparation may contain adjuvants, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives.

Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples.

Reference example I PMB = CH260Me 7-7 minnow 3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl p-toluenesulfonate (10,89,0,02rIL0! ) (55xg) is suspended, then triethylamine/(2,09,0,02mal>
was added at 5°C and stirred until the reaction solution became homogeneous. Add (Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl) vinegar to this solution! (5,58L 0
．． 0241n01) t-Added. Next, the reaction temperature is 8
dicyclohexylcarbodiimide) so as not to exceed ℃
(DCC) (5,36 L O, 026 mol) was added little by little. After the addition, the mixture was stirred at 5° C. for 2.5 hours.

The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A small amount of THF was added to the concentrate, and it was reprecipitated in inpropyl ether. The precipitate was filtered, washed with isopropyl ether, and air-dried. 11.6 g of 7-( as a yellow powder
(Z)-2-chloromethylea2-C2-formylaminothiazol-4-yl)acetamide')-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl was obtained.

Yield 99 yen NMR (DMSO-a, , δ) 3.63 (q, B,
J=18Hz, 2H).

3.76 (θ, 3H), 4.53 (θ, 2H),
5.23(θ, 2H).

5.30 (d, J=6Hz, IH), 5.89 (a
d, J=6Hz, J=9Hz, IH).

6.92 (d, J=9Hz -2H) 17.07
(s, IH), 7.10('t IH).

7.40 ((1, J=9Hz, 2H), 6.53
(a, IH), 9.69 (d, J=9Hz,
IH% Engineering R (KBr) 1790,1720,1
660, 1620, 1550° 1520, 1390.1
360.1310.1250.1180.1100゜1
030.850,820-.

Reference Example 2 7-((Z)-2-chloromethylene-2 obtained in Reference Example 1)
-(2-formylaminothiazol-4-yl)acetamidocy3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl (4,0Of, 6.85
mmol) was dissolved in DMF (25rttt) and sodium iodide (1,029,6,85mm01) was dissolved in DMF (25rttt).
and triphenylphosphine (2,699,10,277
71 door oil) was added thereto, and the mixture was stirred at 25°C for 19 hours. The reaction solution was poured into Impro-Zonol (700m/). The precipitate was filtered and washed with isopropanol (70d). Air dry, (4-(4-methoxyvanzyloxycarbonyl)-7-((Z)-2-chloromethylene-2-(2
4.42 g of the product was obtained.

NMR (DllillS○-d6.δ) 3.53 (Q
AB, J = 18Hz, 2H).

3.76 (s, 3H), 5.13 (m, 4H), 5
．． 36 (m, IH).

5.76 (m, IH), 6.92 (d, J=9Hz
, 2H), 7.07 (g, lH+lH).

7.13((1, J=9Hz, 2H), 7.86(m,
15H), 8.53(s, IH).

9.66 (d, J=9Hz, IH).

Reference example 3 (4-(4-methoxyindyloxycarbonyl)-7
-((Z)-2-chloromethylene:/-2-(2-formylaminothiazol-4-yl)]]]acetamide 3
-Cephemu 3ylmethylcitriphenylphosphonium iodide l' (19,1,1 nol) was dissolved in methylene chloride (10 mA). Sodium hydroxide (0,18
9°4.4 mm01) was dissolved in distilled water (10°) and added. Stirred at room temperature for 15 minutes. The organic layer was washed with saturated aqueous sodium chloride solution. After drying the organic layer, the solvent was distilled off, and the residue was washed with ethyl acetate. -C(Z)-2
-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide)-3-)riphenylphosphoranyritenemethyl-3-cephem-4-carboxylic acid p
- Obtained methoxybenzyl (660).

NMR (DMSO-(1,)75 3.80(11,3
H), 5.07 (qAB.

J=16. sHz+2H)t 5.17(s, 2H),
5.20 (d, J=6Hz, IH).

5.36 (da, J=6Hz, J=9Hz, IH),
5.49 (d, J=19.5Hz.

IH), 6.93 (d, J=10Hz, 2H), 7
．． 03(s, IH).

7.10 (s, IH), 7.35 (d, J=10
Hz, 2H), 7.5~&0 (me 15H),
a54 (s, IH), 9.31 (a, J=9Hz
, IH).

Engineering R (KBr) 3450.3300.3100,3
050,2950,1760°1650.1610,1
520.1480, 1440, 1390, 1240゜1
180.1160,1100,1030,1010,1
000,940°880.820,740,720,6
90,520,500cm-1° Reference Example 4 CO2CHPh2 (Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid (11,0,o,osm
Oz) was dissolved in dry THF. Cool to 5°C, D
Add CC (6,29,0,03mat) and heat at the same temperature for 2
Stir for hours. Separately, 7-amino-3-human 90xymethyl-3-cephem-4-carboxylic acid was dissolved in distilled water (sodium chloride).
) and adjusted to pH 6 with saturated aqueous sodium bicarbonate solution.
5 and dissolved. Furthermore, add acetone (50d) and
Cooled to ℃. The above solution was added to the cooled and stirred reaction solution, and the mixture was stirred at the same temperature for 2 hours. The precipitate was filtered, and the pH of the furnace solution was adjusted to 2.5 using ethyl acetate and TH.
Extracted with a mixture of P (2:1). Immediately, diphenol diazometa (4,39,0,02rnol) was added. After the reaction was completed, the organic layer was dried and the solvent was distilled off.

Of the residue, 1.5 g was dissolved in acetone, and Jones reagent (1.5 t/) was added while cooling on ice. After stirring for 10 minutes, Improvil alcohol was added, and the mixture was further stirred for 10 minutes. Acetone was distilled off, saturated brine, ethyl acetate, and THF were added to the residue, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. After drying the organic layer, it was filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain 7-((Z)-2-chloromethylene-2
-(2-formylaminothiazol-4-yl)acetami)")-3-formyl-3-cephem-4-carboxylic acid diphenylmethyl was obtained.

NMR (DMSO-a, , δ) 3.75 (qAB
, J=21Hz, 2H).

5.45 (a, J=6Hz, IH), 6.13 (dd
, J=6Hz, J=8Hz, IH).

7.13 (51, 2H), 7.3-7.6 (m, IIH
), 8.55 (ha, IH).

9.50 (e, IH), 9.78 (d, J=8
Hz, IH).

Reference example 5 Formic acid (4,3L O,093rnol) and anhydrous vinegar I! !
! (9,49°0.093 mal) and heated to 50°C.
The mixture was stirred for 1 hour.

7-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester p-)luenesulfonate (10,ill, 0.019 no, J
) was suspended in dry THE' (30%), and triethylamine (1,87LO, 01977L6A) was added dropwise to dissolve it. After cooling on ice, the above formic acid-acetic anhydride mixture was cooled to room temperature and added dropwise. Stirred for 2 hours. The solvent was distilled off, and ethyl acetate (250 d) and a small amount of saturated sodium bicarbonate were added to the residue to dissolve it. The organic layer was separated. The aqueous layer was further extracted with ethyl acetate. Dry the layer,
Filter, concentrate, wash the residue with hexane, crystallize,
p-methoxybenzyl 3-chloromethyl-7-formylamino-3-cephem-4-carboxylate (7 g) was obtained.

NMR (DMSO-d, )δ 3.67 (qAB, J
=18Hz, 2H).

3.78(θp3H)+ 4.55(bs-2H)+
5.22 (d, J=2Hz, IH).

5.27 (s, 2H), 5.87 (ad +
J=4Hz, J=8Hz, IH).

6.97 ((1, J=9Hz, 2H), 7.40
(d, J=9Hz, 2H).

a16 (s, IH), 9.10 (dsJ=8Hzt
IH).

Upper 3-position chloromethyl compound (7S), 0.018 ma
l) was dissolved in DMF (20d). Sodium iodide (2,75, o, oxsmOl) and triphenylphosphine (7,19°0.027 m01) were added, dissolved, and stirred at room temperature for 2 days. Inpropyl ether (4
00 mJ) and inpropyl alcohol (400 W). The precipitate was separated from house to house, and (7-(2-formylaminothiazol-4-yl)acetamide-4-(4
7 (6.6 g) was obtained.

NMR (DMSO-d,) δ 3.64 ((IAB, J
= 18Hz, 2H).

3.80 (e = 3H) -4,76 (qAB,
J=16Hz, 2H), 5.14(s12H)-s
, 33 (a, J==4Hz, LH), 5.76 (aa,
, T=4Hz, ,T=sHz, IH).

6.94 (d, J=10Hz, 2H), 7.24 (
cl, J=10Hz, 2H).

7.87 (B, 5H), 8.18 (s, LH),
9.17 (d, J=8Hz, IH).

The above phosphonium salt (0.5g, 0.67rlLm0
1) was dissolved in methylene chloride (5d). A 1N aqueous sodium hydroxide solution (0.75me) was added, and the mixture was stirred at room temperature for 15 minutes. The organic layer was washed with an aqueous sodium chloride solution until the aqueous layer became neutral, then dried and concentrated. The remaining precipitate was washed with hexane, and 7-(2-polaminothiazol-4-yl)°acetamide )'-3-) Riphenylphosphoranylidenemethyl-3-cephem-4-carbo/
The acid p-methoxybenzyl (0,329) was obtained.

NMR (DMSO-a6) δ 3.2-3.6 (m,
2H), 3.77 (s, 3H).

5.07 (s, 2H), 5.13 (d, J=4
Hz, IH), 5.23 (dd, J=4Hz.

J=8Hz, IH), '5.48(d, J=22
．． 5Hz, IH), 6.92 ((1°J=10Hz
, 2H), 7.35(d, J=10Hz,
2H), 7.77 (s, 15H).

&13(s, II(), 8.81(d-J=8H
z, IH).

IR(KBr) 3250,3050.2950,1
760.1680, 1620°1510, 1480.1
440.1390.1300.1240.1220゜1
170, 1100.1036, 1010.1000, 8
90,820,750°720,690.520.50
0 strokes.

Reference example 6 (7-(2-formylaminothiazol-4-yl)acetami)'-4-(4-methoxybenzyloxycarbonyl)-3-cephem-3-ylmethylcitriphenylphosphonium yogate (4,i, 5.tamm
4 g of crude 7-(2-formylaminothiazol-4-yl)acetamy-3-triphenylphosphoranylidenemethyl- prepared from vI4g by the method of Reference Example 5 using al) as a raw material.
p-methoxybenzyl 3-cephem-4-carboxylate (
3 min) in methylene chloride (20 m7) and 4-formi/”-11213-thiadiazole (1 g, 8.8
rrL-'l) was added. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography to obtain (Z)-7-formylamino-3-C2-(1
,2,3-thiadiazol-4-yl)ethynyl)-3
-cephem-4-carboxylic acid p-methoxybenzyl (o
, sg) t-obtained as a yellow powder solid.

NMR (DMSO-a6) δ 3.68 (qAB, J=
IBH2, 2H).

3.78(s, 3H), 5.03(s, 2
H), 5.27((1, J=5Hz, IH).

5.86 (ads J=9Hz 1J=5Hz t
IH), 6-72 (d, J==12Hz #
IH), 6°92((1, J=91(Z, 2H)
, 6.97 ((L, J=12Hz, IH).

7.28 (d, J=9Hz, 2H), 8.18 (s, I
H), 9.04 (8, IH).

9.13 (d, J=9Hz, IH).

The above ester (0,69 p 1-3 ''''l) was dissolved in methanol (10 ml). Concentrated hydrochloric acid (o, xmt
) and stirred at room temperature for 2 hours. After distilling off the solvent, a small amount of water was added to the residue, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to ~9. Ethyl acetate was added to dissolve, and the organic layer was separated. The organic layer was dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography.
7-amino-3-(2-(1,2
,3-thiadiazol-4-yl)ethynyl-3-cephem-4-carvoneffp-methoxybenzyl(0,
219) was obtained.

NMR (DMSO-a6) δ 3.56 (qAB,,T
=18H2,2H).

3.77 (s = :3H), 5.03 (B -2
H) s 5.16 (d, J==5Hz, l H)
.

ci, 6s (a, J=12Hz, IH), 6.93
(d, J=9Hz, 2H).

6.96 (d, J=12Hz, IH), 7.2
8 (d, J=9Hz, 2H).

9.03 (s, IH).

Reference example 7 [7-phenylacetamide"-4-(4-methoxybenzyloxycarbonyl)-3-cephem-3-ylmethylcitriphenylphosphonium yogui)' (4,
09.5mm01) was dissolved in methylene chloride (30a*J).

36 thiformaldehyde (20g, 0.25m01)
and sodium carbonate (1 L 25 mmt) were dissolved in water (10 m) and added, followed by stirring at room temperature for 1 hour and 30 minutes.

Neutralized with 20 sulfuric acid. The organic layer was separated and washed three times with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography.
NHL, 3-ethynyl-7-phenylacetamide-3
-cephem-4-carboxylic acid p-methoxybenzyl (1
, 24g) was obtained.

NMR (DMSO-a6) δ 3.60 (8,2H),
3.76 (qAB.

J==18Hz, 2H), 3.79(s, 3H), 5.
20(d,, J=4Hz, IH).

5.37 (d, J=12Hz, IH), 5.66 (
d, J=16.5Hz, IH).

5, 74 (dd, J=4klz, J=3Hz,
IH), 6.87 (dd, J=12Hz.

J=16.5Hz, IH), 6.97(d, J=9H
z, 2H), 7.31 (s, 5H).

7.42 (d, J=9Hz, 2H), 9.14 ((1
,, T=8Hz, 1B).

Example 1 (Z) -2-chloromethylene-2-(2-formylaminothiazol-4-yl) vinegar @ (0.11 g, 0
．． (H,
Yamanaka, 5ta1. , J.

Antibiotics, 38.1738 (198
5)) was dissolved in THF' (10m7). DCC(
0.12 L O, 57 mm 0)) was added, and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7-((Z)-
2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide 9]-3-vinyl-3-
Cephem-4-carboxylic acid diphenylmethyl (0,26
59) was obtained as a pale yellow powder.

Yield: 95 cm.

NMR (DMSO-a, δ) 3-80 (qAB,
J=16.5H2,2H).

5.33 (d, J=10.5Hz, IH), 5.3
6(d, J=4.5Hz, 11().

5.66 ((L, J=18Hz, IH), 5
．． 92 (dd, J=4.5Hz, J=7.5Hz
, IH).

6.76 (dcl, J=10.5&, l-48Hz,
IH), 6.96 (s, IH).

7.08 (a, IH), 7.12 (s, IH),
7.40 (m, 10H).

8.50 (s, IH), 9.70 (d, J=7.5
Hz, IH).

Engineering R (KBr, cm) 3350, 2950, 2
880, 1780, 1720° 1665, 1630.1
540.1380.1220.1160.1010゜1
000.860,740,700°The ester (0,265, 0,43m) obtained above was dissolved in methanol-THF (x:x) (12m), and concentrated hydrochloric acid (o, 189) was added. and stirred at room temperature for 1.5 hours.

After the reaction solution was concentrated under reduced pressure, the residue was dissolved in THF. After washing with an aqueous sodium hydrogen carbonate solution, the organic layer ILl)
was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was poured into diethyl ether. The precipitate was filtered and washed with diethyl ether.

Dry and give 7-((Z)-2-chloromethylene-2-(2
-aminothiazol-4-yl)acetamiK)-3-
Vinyl-3-cephem-4-carboxylic acid trifluoroacetate (0,0749) was obtained as a white powder.

NMR (DMSO-a, δ) 3.73 (qAB,
J=18H1,2H).

5.23 ((1,, T=4.5Hz, IH), 5
．． 44 ((1, J=9Hz, IH).

5.80 (d, J=16.5Hz, IH),
5.80 (aa,, r=4.5Hz, J=9Hz,
IH).

6.43 (s, IH), 6.86 (s,
IH), 6.96 (da, J=gHz, T=16
．． 5H.

IH), 9.58 (d, J=-9Hz, IH).

IR (KBr, m) 3350, 2950, 28
60,1770,1670°1530,1430.13
50.1240.1200.1180.1140°10
60.1030,990,820,800,710゜Example 2 7-((Z)-2-tertetramethylene-2-(2-formylaminothiazol-4-yl)acetamide")-3
-Triphenylphosphoranylidenemethyl-3-cephem-4-carboxylic acid p-methoxybenzyl (0,669
) was dissolved in methylene chloride (0,479,3,4mF!Li
1) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off to obtain a crude product (1,39). Purified by silica gel column chromatography, 7-((Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl)
] p-Methoxybenzyl acetamide 9-3-((Z)-2-(2-chenyl)ethynyl-3-cephem-4-carboxylate (90 µ) was obtained.

NMR (DMSO-a,) δ 3.76 (a, 3H)
, 5.07 (s, 2H).

5.37 (d, J=4Hz, LH), 5.94 (
Ad, J=4Hz, J=9Hz, IH).

6.21 (d, J=15Hz, IH), 6.90
(d, J=10Hz, 2H).

7.10(s, 2H), 7.25(a, J
=10.5Hz, 2H), 6.6~7.5(m
, 4H).

8.53 (B, IH), 9.72 (a, J=9H
z, IH).

The above ester (90μ, 0.15 mmol) was dissolved in methanol (8d). Concentrated hydrochloric acid (0,06'ij
, L5 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, trifluoroacetic acid (1d) was added, stirred for 1 hour, and then concentrated under reduced pressure. A small amount of THF was added to the residue to dissolve it. The mixture was poured into n-hexane and the precipitate was filtered. 7-(2-(2-aminothiazole-4
-yl)-(Z)-9-chloromethylene)-1? Torimido-3-((Z)-2-(2-thenyl)ethynyl-3-cephem-4-carboxylic acid trifluoroacetate (80 μm) was obtained.

NMR (DMSO-a6) δ 2.8-3.6 (m
-2H) p 5.45 ((L e J = 4Hz.

IH), 5.93 (dd, J=4Hz, 8Hz,
IH), 6.45 (t3, IH).

6.13-7.60 (m, 8H), 9.62 ((
L, J=8Hz, IH).

Engineering R (KBr) 3300.320 sail 2950.17
60.1660.1610゜1530, 1500, 14
60.1430.1360.1300.1240゜11
70.1100, 1030.810-720CIFi
.

Example 3 In the same manner as in the previous example, acetaldehyde was reacted in place of 2-chenylaldehyde to produce 7-(2-(2
-Aminothiazol-4-yl)-(Z)-2-chloromethylenetacetamibi-3-((Z)-1-prohen-1-ylcy3-cephem-4-carboxylic acid trifluoroacetate (all Yield: 3.3%).

NMR (DMSO-d, )δ 1.64 (dd, J
=6.7Hz, J=1.7Hz, 3H).

3.56 (QAB-J=17.5Hz, IH)
, 5.23 (d, J=4Hz, IH).

5.60-5.69 (BS, IH), 5.76
(dcL, J=BHz, J=4Hz, IH)
.

6.16 ((1, J=11.5H2, LH), 6.4
3 (s, IB), 6.86 (s, IH).

7.1-7.4 (m, 2H) - 9,59 (d, J = 8H
zslH).

Engineering R (KBr) 3300.3100,3000,17
70.1660, 1530°1440, 1360.13
00.1250.1200.1190.1140°84
0.800,720 reserves.

Example 4 7-phenylacetamido-3-to IJ phenylphosphoranylidenemethyl-3-cephem-4-carboxylic acid p-
Methoxydi7 (3,79,5,3mWLO1) was dissolved in benzene (100d). Dehydrated acetaldehyde (114 g, 26 mm01) was added and stirred at room temperature for 5 hours. The solvent was distilled off, and the precipitate was purified by silica gel column chromatography to obtain 7-phenylacetamido-3-((Z)-1-propen-1-ylcy3).
-cephem-4-carboxylic acid p-methoxyindyl (0
, 829) was obtained.

NMR/DMSO-a6) δ 1.56 (dd, J=7
．． 5Hz, aT=2Hz, 3H).

3.61 (s, 2H), 3°8 (s, 3H), 5.
17(8,2H)-5,23(d, J=4Hz, IH
), 5.5-5.8 (m, IH) t5.74 (dd
, J=8Hz, J=4Hz, IH), 6.1
3 (d, J=7.5Hz, IH).

6, '97 (d, J=10.5Hz, 2H), 7.
32(a, 5H).

7.37 (d, J=10.5Hz, 2H), 9.13
(d, J=9Hz, IH).

Phosphorus pentachloride (151), 4.5 mm01) was suspended in dry methylene chloride (10d) and cooled to 5°C.

Pyridi 7 (0.36 g, 4.5 mm01) was added and stirred at the same temperature for 1 hour. 7-phenylacetamido-3-((Z)-1-prono-1-yl]-3-
p-methoxybenzyl cefem-4-carboxylate (0,
729,1,5mm01) was added and stirred at 5-10°C. After 2 hours, it was cooled to -35°C and diluted with dehydrated methanol (6
, 2d, 0.151n01) were added. -10~-2
The mixture was stirred at 0°C for 1 hour and 30 minutes.

Once the temperature was at -20°C, water (1.25 d) was added. The temperature was raised to 5°C and stirred for 1 hour. The solvent was distilled off, the - of the reaction mixture was adjusted to 7, and then extracted with ethyl acetate.

Dry, filter, and concentrate to give 7-amino-3-((Z)-1-
[propen-1-yl]-3-cephem-4-carboxylic acid p-methoxy gave undil.

NMR (DMSO-a,) δ 1.54 (da, J=7
Hz, J=2Hz, 3H).

3.76 (s, 3H), 5.14 (s, 2H), 5
．． 18 (d, J=4Hz, IH).

5.5-5.9 (m-2H) -6,12(d,
J==11.5Hz e1)1).

6.96 (d, J=10.5Hz, 2H), 7.30
(bs, 2H).

7.36 (a, J=10.5Hz, 2H).

(Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid (0,29,0,83m
7716J) was dissolved in dry 'I'HF (7 mA) and cooled to 5°C.

DCC (0.17'i, 0.83 mmol) was added little by little and stirred at 5°C for 2 hours. 7-amino-3-(
(Z)-1-Pro is no 1-il]-3-Cefem-4
-p-methoxybenzyl carboxylate (0,25L O,
7mt rib) was dissolved in dry TRI' (3d).

The mixture was stirred at room temperature for 5 hours. After filtration, concentrate F solution under reduced pressure,
The residue was purified by silica gel column chromatography to give 7-((Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl))]acetamido-3-(Z)-1-propylene. -1-4x)-3-cefzmu-4-carboxylic acid p-methoxybenzyl (80 .mu.) was obtained.

NMR (DMSO-a6) δ 1.56 (ad, J=7
Hz, J=2Hz, 3H).

3.60 (bs, IH), 5.17 (s, 2H),
5.33 (d, J=4Hz, IH).

5.5-5.8 (m, IH), 5゜90 (da,, T
=gHz, J=4Hz, LH).

6.16 (d, J=11.5Hz, IH), 6.
96 ((1, J=10.5Hz, 2H).

7.37 (d, J=10.5Hz, 2H), 13.
54 (8, l) ri.

9.67 (d, J=9Hz, IH).

7-((Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamit'-3-
((Z)-1-Pro is no 1-il]-3-Sefuem-
p-methoxyindyl 4-carboxylate (SO■, 0.
14mm01) was dissolved in methanol (10%) and concentrated hydrochloric acid (0.05mJ).

1,4 rnmol) was added. After stirring at room temperature for 2 hours, the solvent was distilled off. Triple oroacetic acid (1d) was added and stirred at room temperature for 1 hour. The solvent was distilled off, and a small amount of THF was added to the residue to dissolve it. Pour into n-hexane and filter the precipitate to give 7-(2-(2-7minothiazo-4-yl)-(Z)-2-chloromethylenetuacetamide-3.
-((Z)-1-Prono-1-yl)-3-cephem-4-carboxylic acid trifluorohfR salt (51) was obtained. Agreed.

Example 5 7-((Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide]-3-formyl-3-cephem-4 in 1 Ph2 Yin-Yin (10 m/) on CO2C
-diphenyl carboxylate (n, 7 <), 1.2 m
After dissolving the mo/), benzyloxycarbonylmethylene phosphor 7 (0.48L 1.2 mm01) was added. After stirring at room temperature for a while, the mixture was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography to obtain 7-((Z)-2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetamide").
Diphenylmethyl-3-((E,)-2-,?endyloxycarbonylvinyl)-3-cephem-4-carboxylate (0.18 g) was obtained.

NMR (DMSO-a6.δ) 3.88 (qAE,
J=18Hz, IH).

5.24(s, 2H), 5.40((1, J=6H
z, IH), 6.04 (dd.

J=8Hz, IH), 7.03(s, IH), 7
．． 10(s, IH), 7.13(s, IH),
7.42 (bs, 15H), 7.72 (a, J=1
5Hz, tH).

8.53(s, IH)-9,76(cl,, T=8H
z, IH).

The above ester (0.18 g) was mixed with methanol (10 ml).
) dissolved in Add hydrochloric acid (0,089) to 1 at room temperature.
．． Stirred for 5 hours. Methanol was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried, the solvent was distilled off, and 7-(
(Z)-2-chloromethylene-2-(2-amifthiazol-4-yl)acetamide)-3-((E)-2+
+ “ndiloxycarbonylvinyl)-3-cephem-
4-carbo/diphenylmethyl acid (0.13 g) kA.

NMR (DMSO-d6) 3.86 (qAB-J=
18Hz, LH), 5.20 (s, 2H), 5.3
7(d, J==6Hz, IH), 6.05(da,,
T=6&.

J = 8Hz, IH) e 6-42 ((1* J
=15hz -IH) e 6.45 (8-IH)
+6.9 (s, IH), 7.03 (s, IH)
, 7.18 (ba, 2H), 7.30-7.55 (
m, 15H), 7.70 (tl, J=15Hz,
IH), 9.66 (d.

J=3Hz, IH).

The above amino compound (0,139) was added to anisole (1.5 g)
dissolved in. Cool to 0°C and add aluminum chloride (0,2
1 g) was added. The mixture was stirred at the same temperature for 4 hours. The reaction system was adjusted to pH 2 with a dilute aqueous sodium hydrogen carbonate solution, water was then added, and the precipitate was collected. The precipitate is washed with water, water and RP-
Purified with 3 columns and lyophilized to give 7-((Z)-2-chloromethylene-2-(2-aminothiazol-4-yl)
Acetamide)-3-((E)-2-carboxyvinyl)-3-cephem-4-carboxylic acid disodium salt (0,0239) was obtained.

NMR (DMSO-a6) 3.36 (QA8.J=
18H2, 2H).

5.10 (d, J=6Hz, IH), 5.63 (d
d, J==6&, J=9&, IH).

5.76 (d, J=18Hz, IH), 6.47
(s, IH), 6.86 (s, IH).

7, 17 (bs, 2H), 7.46 (d, J=18
Hz+IH), 9.55 (d.

J=9Hz, IH).

Engineering R (KBr, cm) 3400,1750.1
650, 1600, 1520° 1360, 1300.1
230.1160.770.710.650.610°550.480°Example 6 (Z) -2-chloromethylene-2-(2-formylaminothiazol-4-yl)acetic acid (0.39g, 1.
68 mmol) was dissolved in THF (20 mJ), and 5
Cooled to ℃. DCC (0,349,1,53mm0l
) and stirred at the same temperature for 1 hour. 7-amino-3-
(2-(1,2,3-Thiadiazol-4-yl)ethynylcou 3-cefxmu 4-carboxylic acid p-methoxybenzyl (o-sg*L 4 mmol) was dissolved in THI' and added. Overnight at room temperature. The solvent was distilled off and purified by silica gel column chromatography to obtain (Z)-7.
-(2-chloromethylene-2-(2-formylaminothiazol-4-i)acetamido-3-(2-(1,
2,3-thiadiazol-4-yl)ethynyl-3-
p-methoxybenzyl cephem-4-carboxylate (0,
289) Got it.

NMR (DMSO-a6) δ 3.67 (qAB-J=
18Hz, 2H).

3.86 (s, 3H), 5.09 (s, 2H)
, 5.43 (d, J=5Hz, IH).

6-02 (dip J=8 Hz e J=5Hz
+ IH), 6-78 (6,!=12Hz, IH
) +6.98 (d,, T=9Hz, 2H), 7.0
6(d,, T=12Hz, IH), 7.16(a,
IH), 7.35 (d, J==gHz, 2H), 8
．． 63(s, IH).

9.10 (s, IH), 9.77 (d,, T=8H
z, IH).

IR (KBr) 3250, 3050, 2950, 2
850,1780.1720゜1670.1610.1
550.1510, 1440, 1390, 1360゜1
300.1240, 1220.1170.1120.1
090,1030°820.720,690,540t
:m.

The above ester (0.28g) was mixed with methanol (20d).
Concentrated hydrochloric acid (0.2 m) was added and stirred. After evaporating the solvent, a small amount of water was added to the residue, the mixture was neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate.

After drying the organic layer, the solvent was distilled off to obtain crude (Z)-7-(2-(2-aminothiazol-4-yl)-2-chloromethylene)acetamide 9-3-(2 −
(1,2,3-thiadiazol-4-yl)ethynyl-3-cephem-4-carboxylic acid p-methoxy (o, 14 g) was obtained.

NMR (DMSO-clg) δ 3.57 (qAB-J
=18H2,2H).

3.76 (E+, 3H), 5.02 (8, 2H),
5.34 (d, J=5z, IH).

5.88 (dd, J=8Hz 1J=5Hz -I
H) + 6-70 (d 1J=12Hz, IH)
-6,89 (s, IH), 6.96 (s, IH),
6.97 (cl, J=9Hz, 2H).

7.02 (d, J==12Hz, 1a), 7.18
(bs, 2H), 7.40(d, J=9Hz,
2H), 9.03(s, IH), 9.62(d,
, T=8Hz, IH).

The above ester (0.14g) was mixed with trifluoroacetic acid (ld
) and stirred for 1 hour. The solvent was distilled off and a small amount of TH
F and poured into n-hexane. The precipitate was separated, washed with ether, and dried under reduced pressure to obtain bonic acid/trifluoroacetate (90 aF).

NMR (DMSO-a,) δ 3.2-3.8 (m-2
H) e 5.87 (ddeJ=8Hz, J=5H2,I
H), 6.47 (s, IH), 6.80 (d, J=
12Hz.

IH), 6.92 (s, tH), 7.17 (d,
J=12Hz, LH), 9.07(s.

IH), 9.63 (d, J=8Hz, IH).

Engineering R (KBr) 3300.3100,2950,1
780, 1660, 1620° 1510, 1440.1
360.1300.1250.1200.1180゜1
140.1030,840,800,720.540c
tn.

The above trifluoroacetate was dissolved in water and neutralized with a saturated aqueous sodium bicarbonate solution. Insoluble materials were filtered and the tear fluid was purified using an HP-20 column.

The distillate was concentrated and lyophilized to give (Z)-7-(2-(2
Thorium (15~) was obtained.

NMR (DMSO-a6) δ 3” (qAB, J=18
Hz, 2H).

5.17 (d, J=5 & , IH), 5.68
(aa, J=8Hz, J=5)fz, IH).

6.45 (s, IH), 6.65 (d, J=12H
z, IH), 6.87 (s, IH).

7.16 (d, J==12Hz, IH), 7.17 (
bs, 2H), 9.02 (g, IH).

9.54 (d, J=8Hz, IH).

Engineering R (KBr) 3300, 3200.3100, 17
60,1660,1600°1530,1380.13
50.1230, 1170.1050.1020°79
0.750,700 mouths.

Example 7 A method similar to Reference Example 6 and Example 6 was adopted, 7enethylaldehyde was used as a raw material, and (Z) -7-(
2-(2-aminothiazol-4-yl)-2-chloromethylene]acetami)-''-3-((Z)-3-phenyl-1-proyn-1-yl2-3-cephem-4-
Carboxylic acid trifluoroacetate was obtained.

NMR (DMSO-d6) δ 3.47 (m, 2H),
3.60 (m, 2H).

5.30 (d, J=4.5Hz, IH), &72
(m, IH), 5.82 (Ad.

J=9Hz, J=4.5Hz, IH), 6.30(a
, J=12Hz, IH).

6.43 (s, IH), 6.87 (s, IH),
7.26 (m, 5H), 9.57 (a = J =
9Hz + IH).

Engineering R (KBr) 3350.1770, 1670.16
40,1530,1360°1200.1140,10
30,840,800,740,710,700cWL
.

Example 8 A method similar to Reference Example 6 and Example 6 was adopted, 1,2-diacetoxy-4-formylbenzene was used as one of the raw materials, and (Z)-7-(2-(2-7 (minothiazol-4-yl)-2-chloromethylene]acetamide)
Sodium -'-3-((Z)-2-(3,4-dihydroxyphenyl)ethynyl]-3-cephemu-4-carboxylate was obtained.

NMR (DMSO-a6) δ 3.3-3.6 (m,
2H), 5.13 (d.

J=5Hz, IH), 5.84((L(L,
J=JHz, J=5Hz, xH).

6.56 (s, LH), 6.91 (s, IH),
7.18 (bit, 2H), 6.2~7.4 (m
, 5H), 8.9-9.3 (m, 2H),
9.57 (d, J=8Hz, IH).

Engineering R (KBr) 3350, 3200, 2950, 1
760,1610,1510゜1370.12B0,1
240.1180, 1110.1060, 1030°8
70.830,760-700c1rL.

Example 9 The same method as in Reference Example 6 and Example 6 was adopted, and 1-7cetoxy-4-formylbenzene was used as one of the raw materials to produce (Z)-7-C2-(2-aminothiazole-
4-yl)-2-chloromethylene]acetamido-3-
Sodium ((Z)-2-(4-hydroxyphenyl)ethynylcy-3-cephem-4-carboxylate was obtained.

NMR (DMSO-d, )δ 3.2-3.6 (m,
2H), 5.13((1, J=5Hz, IH)
, 5.43 (aa, J=3HztJ=5Hz IH
), 6.43((1°J=12Hz, IH), 6
．． 58((1, J=12Hz, tH)*6.69(
s, IH).

6.84 (d, J=7.5Hz, 2H), 6.86 (
s, IH), 7.19 (d, J=7.5Hz, 2
H), 7.21 (be, 2H), 9.53 (
a, J=8Hz, IH).

IP-(KBr) 3350, 2950, 1740,
1640, 1600, 1520° 1500, 1430.
1360.1300.1260.1220.1160°830, 790.700 side.

Example 10 Using the same method as in Reference Example 6 and Example 6, using 5-formyl-3-methylthiazole as one of the raw materials, (Z)-7-(2-(2-7minothiazole- 4
-yl)-2-chloromethylene]acetamide"-3-
Sodium ((Z)-2-(3-methylthiazol-5-yl)ethynyl)-3-cephem-4-carboxylate was obtained.

NMR (DMSO-a, )δ Z34(s, 3H
), 3.00 ((L, J=18Hz, IH)
, 3.35 (d, J=18Hz, IH), 5.1
6((L, J=-5Hz=1'') e5.
67 (da* J=9Hz 1J=5Hz t I
H) -6-37 (cl, J=12Hz, IH), 6.
41 (s, IH), 6.81 (d, J=12Hz.

IH), 6.85 (s, IH), 7.14 (bs, 2H
), 8.92 (s, IH).

9.53 ((1, J=9Hz, IH).

IR (KBr) 3350, 3200, 1760.
1670,1600゜1530.1390,1350,
1280, 1240, 790, 760.710 m-”.

Application Example 1 Representative examples of the β-lactam derivatives and nontoxic salts thereof of the present invention were tested for antibacterial activity.

Antibacterial activity is determined by the minimum inhibitory concentration (MC) (unit: μ9/d).
), and the measurement was performed using the method specified by the Japanese Society of Chemotherapy, Minimum Inhibitory Concentration Measurement Revision Committee [Chemotherapy (Che
29, No. 1, pp. 76-79 (1981)).

The results of the antibacterial activity measurements were as shown in Table 1 below, and the compounds were indicated by example numbers.

Procedural amendment (voluntary) March 30, 1988 Kunio Ogawa, Commissioner of the Patent Office, 1, Indication of the case, ``Detailed description of the invention'' column 5 of the specification of Patent Application No. 43099 of 1988, Amendment. Content +11 rll, OJ on page 26, line 1 of the specification of the present application'
Corrected to ``11.0g''.

(2) On page 26, line 11, "mixed liquid" is corrected to "r mixed liquid."

(3) On page 28, lines 12 to 14, “3-chloromethyl...methoxybenzyl” is replaced with “7-formylamino-
3-chloromethyl-3-cephem-4-carboxylic acid p-
Corrected to ``Methoxybenzyl.''

(4) p. 29, lines 6 to 9 and p. 31, lines 1 to 4. )-3-cephem-3-ylmethyl]
Corrected to "triphenylphosphonium iodite."

(5) "r7-(2-formylaminothiazol-4-yl)acetamide" on page 30, lines 1 to 2 is corrected to 17-formylaminoj.

(6) On page 31, lines 5 to 7, r7-(2-formylamino...acetamide) is corrected to "7-formylamino."

(7) Structural formula on page 34, line 6

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the general formula, R^1 is a hydrogen atom or a protecting group for an amino group, and R^2 is hydrogen, a salt-forming cation, or a carboxyl group. It is an acid protecting group, and R^3 is a hydrogen atom, a lower alkyl group that may have a substituent, an aralkyl group that may have a substituent, a phenyl group that may have a substituent, a substituent represents a heterocyclic group which may have , or a group represented by COR^4. Here, R^4 represents an optionally substituted amino group or a group represented by OR^2. ] A β-lactam derivative or a salt thereof.