JPS60260584A - Cephalosporin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R1 is (substituted) phenyl or lower alkyl; R2 is lower alkyl; R3 is H, halogen, OH, lower alkoxy or -CH2R5 [R5 is H, OH, halogen, azido, acyloxy, carbamoyloxy or (substituted) heterocyclic-thio]; COOR4 is (esterified) carboxyl}. EXAMPLE:7-( 4-p-toluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino )-3- methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester. USE:Antibacterial agent. PREPARATION:The alkoxyiminobutyric acid (or its reactive derivative) of formula II is made to react with the 7-aminocephalosporin derivative of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula [wherein B is an optionally substituted phenyl group or lower alkyl group, R2 is a lower alkyl group, R5 is a hydrogen atom, a halogen, a hydroxyl group, a lower alkoxy group, or expression −
〇H2R5 (in the formula, TL5 is a hydrogen atom, a hydroxyl group, a lower alkoxy group,], a rogene, an azide group, an acyloxy group,
Indicates a carbamoyloxy group and an optionally substituted heterocyclic thio group. ), 0OORA represent a carboxyl group which may be esterified. ] Cephalosporin derivatives represented by the above, synthetic intermediates thereof, methods for producing them, and formulas for reacting the above compound (I) with thiourea (syn type) [Symbols in the formulas have the same meanings as above. ] 7
-[2-(2-aminothiazol-4-yl)-2-(
Syn)-alkoxyiminoacetamide] cephalosporin derivatives.

Currently, some cephalosporins, along with penicillin, are widely used as excellent antibacterial agents for the treatment and prevention of infectious diseases, but there are also those with stronger antibacterial activity, those with a broader antibacterial spectrum, or those that can be administered orally. A lot of research is being carried out with the aim of finding out. As a result, among the compounds represented by the above formula (1), for example, oefotaxime
(R2 is a methyl group, town is an acetoxymethyl group, R4 is hydrogen or sodium), oefmenoxime (
R2 is a methyl group, R3 is (1-methyltetrazole-5
-yl)thiomethyl group, R4 is hydrogen or sodium)
, Oeftizoxime (where R2 is a methyl group, R3 is a hydrogen atom, and R4 is hydrogen or sodium) have been found to have strong antibacterial activity and a broad antibacterial spectrum, and are currently undergoing clinical trials.

Furthermore, the present inventors have discovered that a new compound in which R2 is a lower alkyl group, R3 is a lower alkoxymethyl group, and 000- represents an ester that is eliminated under physiological conditions is useful as an oral agent with strong antibacterial activity. (Japanese Patent Application No. 55-136449).

On the other hand, some methods for producing these materials are already known. For example, Tetrahedron, Volume 34, 2233
Pages 171-192 (1981), JP-A-52-102293, 53.
-34795, No. 54-98795, etc. Broadly speaking, these methods can be divided into 2-(2-aminothiazol-4-yl)-2
- a method of separately synthesizing an alkoxyiminoacetyl moiety and bonding it to 7-amitsefalosvorin;
Ru. In this case, the important thing is that it can be manufactured industrially, and
This is to suppress the by-product of anti-type compounds, which are unnecessary isomers in terms of antibacterial activity of the alkoxyimino moiety of the 1-position side chain.

According to the research conducted by the present inventors, the former method has a high production rate of anti-isomers, while the latter method has a high production rate in the literature (
According to The Journal of Antibiotics, Vol. 34, pp. 188-180), the yield is extremely poor.

Under these circumstances, the present inventors conducted research on an industrial method for producing the compound having the formula (I), and completed the present invention that allows the target compound to be obtained in high yield.
) [Symbols in the formula have the same meanings as above. A novel 4-sulfonyloxy-3-oxo-2-alkoxyiminobutyric acid (syn isomer) or a reactive derivative thereof represented by the formula (y) 00R4 [The symbols in the formula have the same meanings as above. ] 7
- When reacted with amitusephalosborin derivative, a novel compound (1) is obtained in high yield, and when this compound (I) is reacted with thiourea, the desired syn-type compound ( It has been found that I) can be produced.

That is, the present invention provides (1) 4-aryl (or alkyl) sulfonyloxy-3-oxo-2-alkoxyiminobutyric acid (m) (217-(4-aryl (or alkyl)) sulfonyloxy-3-oxo-2 -Alkoxyiminobutyrylamino)cephalosporin derivative (1) (3) Formula (I) where me is the reaction of the reactive derivative of compound (m) and the 7-aminocephalosporin derivative (■) Method for producing a compound represented by (4) a 7-[2-(2-aminothiazol-4-yl)-2-(syn)-alkoxyimino compound characterized by reacting compound (I) with thiourea. The present invention relates to a method for producing a cephalosporin derivative (1).

In formula CI), (lil), R1 is methyl, ethyl,
propyl, isopropyl, n-butyl, isobutyl, n
- It represents a lower alkyl group having 1 to 6 carbon atoms such as pentyl or n-hexyl group, or a phenyl group, and the phenyl group may have a substituent. That is, it may be substituted with a lower alkyl group such as methyl or ethyl group, a lower alkoxy group such as methoxy or ethoxy group, or a lower alkyl group such as chlorine or bromine, and the number of substituents is 1 to 5. , if there are multiple, they do not have to be of the same type. Generally preferred as R1 are phenyl, nokuramethylphenyl, methyl,
Ethyl group, etc.

In formulas (I) and (11), R2 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-
Pentyl and n-hexyl groups are lower alkyl groups having 1 to B carbon atoms, and methyl or ethyl groups are particularly preferred. TL5 represents a hydrogen atom, a chlorogen atom such as chloro or bromine, a hydroxyl group, a lower alkoxy group such as methoxy or ethoxy group, or an optionally substituted methyl group (formula -0H2R5), and as a substituent R5 is a substituted group such as a hydroxyl group, a lower alkoxy group such as methoxy, ethoxy, n-propoxy, or isopropoxy group, a halogen atom such as chloro or bromine, an azide group, acetyloxy, propionyloxy, or 3-oxobutyryloxy group. Examples include a lower aliphatic carboxylic acid acyloxy group having 2 to 4 carbon atoms, a carbamoyloxy group, and a heterocyclic thio group, which may have 2 to 4 carbon atoms. Herein, the term "petero ring" refers to a 5- to 4-carbon ring containing 1 to 4 heteroatoms selected from O, S, or N.
It is a 6-membered ring, and the N atom may be oxidized. Examples of these heterocyclic rings include pyridine, N-oxypyridine, pyrimidine, biricidazine, 1.2.4
= triacylone, thiazole, 1.2.3-thiadiazole, 1.3.4-thiadiazole, 1.34-oxadiazole, triazole, IH-tetrazole, and the like. Furthermore, on these heterocycles, lower alkyl groups such as methyl and ethyl, lower alkoxy groups such as hydroxyl, methoxy, and ethoxy, carboxyl groups, carbamoyl groups,
It may have a substituent such as a carboxymethyl group, a sulfomethyl group, or a dimethylaminoethyl group. It may be esterified as represented by 0OOR4 (Carboxyl group refers to carboxyl group or its inorganic or organic salts such as alkali or alkaline earth metals such as sodium, potassium, dicyclohexylamine, and salts, and means an esterified carboxyl group, such as esters forming protective groups in the process, such as methyl, ethyl, tertiary butyl, benzyl, phenacyl, trimethylsilyl, benzhydryl, phenyl or methoxymethyl esters; Ester or phthalidyl, alkanoyloxymethyl (e.g. acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl group, etc.) or lower alkoxycarbonyloxymethyl or ethyl (
For example, 1-ethoxycarbonyloxyethyl, 1-n
-propoxycarbonyloxyethyl, tertiary butyloxycarbonyloxymethyl, etc.), which are eliminated under physiological conditions, are used.

Next, the reaction of the present invention will be explained. Compound (I[)
is a new substance, for example, the compound (I [[a) in which B1 is a 4-methylphenyl group and R2 is a methyl group] was synthesized by the following route.

Br(IT(2000H2000-i-Bu + Ts
OAg -> Compound (m) and (W) are reacted to form (I)
In the reaction to obtain (III), (III) is used in its free form or as a reactive derivative thereof. When used in its free form, a suitable condensing agent is used. N as a condensing agent
, N'-dicyclohexylcarbodiimide and other disubstituted carbodiimides;

Azolide compounds such as N'-carbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2
- Dehydrating agents such as dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene; Vilsmeier's reagent prepared from dimethylacetamide and phosphorus oxychloride; and the like. As the reactive derivative of the compound having formula (m), acid halides, acid anhydrides, mixed acid anhydrides, active esters, active amides, acid azides, etc. are used. Mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monomethyl ester and carbonic acid monoisobutyl ester, and mixed acid anhydrides with lower alkanoic acids which may be substituted with halogen such as pivalic acid and trichloroacetic acid. etc. are used,
Examples of active esters that can be used include p-nitrophenyl ester, pentachlorophenyl ester, N-hydroxyphthalimide ester, and N-hydroxybenztriazole ester. The reaction is generally carried out in a suitable solvent. The solvent is not limited as long as it does not affect the reaction, and examples of the solvent include acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, dichloromethane, dimethylformamide, acetonitrile, water, and mixtures thereof.

Depending on the type of reactive derivative used in this reaction, a base may be present as necessary. Examples of bases include alkali metal compounds such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, aliphatic, aromatic, or nitrogen-containing heterocyclic bases such as triethyla, mine, dimethylaniline, N-methylpiperidine, Examples include N-methylpyrrolidine, pyridine, collidine, and lutidine. There is no particular limitation on the reaction temperature, but the reaction is usually carried out at room temperature or under cooling. The time required for the reaction varies mainly depending on the type of acylation method, reaction temperature, etc., but is usually from ten hours to several tens of hours. After the reaction has ended, the compound having formula (I) is recovered from the reaction mixture by conventional methods. If necessary, it can be purified by recrystallization, chromatography, etc., but it can also be used as a raw material for the next step without being separated.

The reaction of producing compound (1) by reacting compound (1) with thiourea is usually carried out by bringing the two into contact in a suitable solvent. The solvent used is not limited as long as it does not adversely affect the reaction, but examples include water, methanol, ethanol, dimethylformamide,
Solvents such as dimethylacetamide, acetone, acetonitrile, tetrahydrofuran or mixtures thereof are used. In some cases, it may be better to add a base such as sodium acetate or sodium bicarbonate to accelerate and complete the reaction.

Although there is no particular limitation on the reaction temperature, it can usually be carried out at room temperature. The reaction time is usually several tens of minutes to several hours, although it depends on the reaction conditions. After the reaction is completed, the produced (11) is collected from the reaction mixture by a conventional method. For example, vacuum concentration,
Compound (I) produced by the method of the present invention, which can be isolated by extraction, reprecipitation, chromatography, etc., includes:
For example, (1) 7-(4-halatoluenesulfonyloxy-3
-oxo-2-methoxyiminoptyrylamine)-3-
Cephem-4-carboxylic acid +21 7-(4-halatoluenesulfonyloxy-3-oxo-2-methoxyiminobutyrylamino)-3-methyl-3-cephem-4-
Carboxylic acid +317-(4-paratoluenesulfonyloxy-3-
Oxo-2-methoxy, iminobutyrylamino)cephalosporanic acid +417-(4-paratoluenesulfonyloxy-3-
Oxo-2-methoxyiminobutyrylamino)-3-(
1-Methyl-1H-tetraso A/ -5-yl)thiomethyl-3-cephem-4-carboxylic acid <5) T-(4-paratoluenesulfonyloxy-3~
Oxy-2-methoxyiminobutyryl amino)-3-(
4-Methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid +6) 7-(4-halatoluenesulfonyl) Oxy-
3-oxo-2-methoxyiminobutyryl amino)-3
-Methoxymethyl-3-cephem-4-carboxylic acid (717-(4-methanesulfonyloxy-3-oxo-2-methoxyiminobutyrylamino)cephalosporanic acid +817-(4-benzenesulfonyloxy-3-oxo- 2-methoxyiminobutyrylamino)-3-(2-
Methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (917(4-paratoluenesulfonyloxy=3-oxy-2-methoxyiminozutyrylamino)-3-methyl- 3-cephem-4-carboxylic acid pivaloyloxymethyl ester nor-<4-paratoluenesulfonyloxy-3-oxo-2-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester +1117-(4-paratoluenesulfonyloxy-3
-oxo-2-methoxyiminobutyryl amino)-3-
Cephem-4-carboxylic acid pivaloyloxymethyl ester a2r-(4-paratoluenesulfonyloxy-3-oxo-2-methoxyiminobutyrylamino)-3-methoxymethyl-3-7-carboxylic acid benzhydryl ester (137-(4-paratoluenesulfonyloxy-3-
oxo-2-ethoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid methoxymethyl ester ti4T-(4-paratoluenesulfonyloxy-3-
Oxo-2-methoxyiminobutyrylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid benzyl ester a! 97-(4-ethanesulfonyloxy-3-oxo-2-methoxyiminobutyrylamino)-3-meth)oxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester any -(4-benzenesulfonyloxy -3-oxo-2-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 0nT-(4-methanesulfonyloxy-3-oxo-
2-ethoxyiminobutyrylamino)-3-methyl-3
-Cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester (all are syn-type).

Compound (1) produced by the method of the present invention includes:
For example (1)? -[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide] = 3-cephem-4-carboxylic acid +2+ 7- C2-(2-aminothiazol-4-yl)-2-methoxyimino Acetamide]=3-methyl-3-cephem-4-carboxylic acid+31 7- [2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]cephalosporanic acid (4) ? -[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-
Methyl-1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid + 51 7- (2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide) -3-methoxymethyl-3-cephem-4-carboxylic acid + 61 7- (2 -(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(4-
Methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-
3-cephem-4-carboxylic acid + 7) 7- [2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxy Methyl ester (817-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (917-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-S-methoxymethyl-3-cephem-4-carboxylic acid isobutyryloxymethyl ester aI? -(2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester aυ ?-(2-(2 -aminothiazol-4-yl)
-2-ethoxyiminoacetamide] -3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (13F -(2-(2-amiftycyazol-4-yl)-2-methoxyimino , acetamido]-3-ethoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester am?-(2-(2-aminothiazol-4-ib)-
2-Ethoxyiminoacetamide]-3-methyl-3-
Examples include cephem-4-carvone $1-ethoxycarbonyloxyethyl ester (both syn-type).

Next, the method for producing the compound of the present invention will be specifically explained with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 4-promo-3-oxobutyric acid tert-butyl ester 7.1f and silver para-toluenesulfonate 945F were combined into 5
Add to 0 s/dry acetonitrile and stir at room temperature for 3 days in the absence of light. The reaction solution is filtered and the P solution is concentrated under reduced pressure.

The obtained crystals containing an oily substance are dissolved in ethyl acetate and insoluble materials are removed by filtration. Concentration of Ffi under reduced pressure yields a brown oil. The oily substance was separated and purified by silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent. The resulting colorless oily substance was recrystallized from ether-n-hekasan to yield 4-paratoluenesulfonyloxy-3-oxobutyric acid. Targer's stil ester was obtained as colorless columnar crystals at 4.5F. Melting point 67-69°C NMR (ODOI13) δppm: 1.43 (9H,s, tert-Butyl)2
．． 43 (3H,s, oiiμφ−)3゜43 (2
H, S, 0H20021Bu )4-80 (2H*
S# 80200H200) 1.20~7.90 (4
H, benzene ring) elemental analysis value 015H2oO6S Calculated value: o, 54.92; H, 6,15; s,
9.78 Actual value: 0,55.03: H, 6,07
; 8,9.86 Reference Example 2 4-paratoluenesulfonyloxy-3-oxobutyric acid tert-butyl ester 4,5f was dissolved in 40s/i acid and heated to 1.42F nitrous acid at room temperature for 10ν minutes. ) Add IJum. After further stirring at room temperature for 50 minutes, 200 s/ethyl acetate was added to the reaction solution, and the ethyl acetate solution was washed with brine.

The ethyl acetate solution is dried over magnesium sulfate and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, 1.66 f of 4-paratoluenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester was obtained as colorless crystals. Ta.

Melting point: 106-108°C (decomposition), (recrystallization solvent, ether-petroleum ether) NMR (onoJ5) δppm: 1.52 (9H, s, tert-Butyl)2.
43 (3H,s, OH3+) 5.04 (2H,S, -8020CfH200-)
Otsu 2G -7,112 (4H, benzene fM>10.2
3 (1H,s, -00-0-00)゛・.

Analysis value 015H,9NO7B Calculation value: o, 50.48; H, 5,36; N,
3.92; 8,8.98 Actual value: O+50.62
; H, 5,08; N, 3.83; 8,8.9
7 Reference Example 3 4-paratoluenesulfonyloxy-3-oxo-2-
Hydroxyiminobutyric acid tert-butyl ester 1.66 F was dissolved in 20 vtl of dry acetone and cooled with water with 960 wg of anhydrous potassium carbonate and 0466 g/! of dimethyl sulfate and stirred at room temperature for 3 hours. The reaction solution was poured into 200-ml ice water and extracted with methylene chloride. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, a pale yellow oil was obtained. Te4-halatoluenesulfonyloxy-3-oxo-2-(syn)
-Methoxyiminobutyric acid tert-methyl ester is S
SO* was obtained.

NMR (ODc/13) δppm: 1.50 (9
H,s, tert-Butyl) 2.4g (3H
, s, Shixka).

4.07 (3H, S, 1j-oji) 5.05 (2
H, S, -5o2ooH2oo-)1.20~7.9
0 (41(, benzene ring') Reference example 4 4-paratoluenesulfonyloxy-3-oxo-2-
Dissolve 418 q of (syn)-methoxyiminobutyric acid tert-butyl ester in 1-methylene chloride and 2
Add trifluoroacetic acid (d) and stir at room temperature for 4 hours.

Methylene chloride and excess trifluoroacetic acid were distilled off under reduced pressure, and the resulting brown oil was dissolved in isopropyl ether and left to stand.
-Oxo-2-(syn)-methoxyiminobutyric acid was isolated as colorless crystals as 1yswIgA.

Melting point 131-132°C (decomposition) Elemental analysis value o, 2H, 3No7s Calculated value: 045.72; H3, B4; N4.
45; 810.1B actual value: 045.50;
H3,92: N4.32; 89.98NMB (
d-6acetone) δppm: 2.47 (3
H,s, OHM @-)4.10 (3H,s, N
-0ji) 5.20 (2H,S, -80200H200)7.
25-7.95 (4H, benzene ring) 9, aO (IH
, b, s, -002H) Reference example 5゜4-bromo-3-oxobutyric acid tert-butyl ester 8.25 f,! : Ethanesulfonic acid 11.3!
was added to 50 ml of dry acetonitrile and stirred and refluxed for 30 minutes. The reaction solution is filtered and the r solution is concentrated under reduced pressure. The obtained oil is dissolved in benzene, washed with water, washed with heavy sodium chloride, washed with brine, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure to obtain a brown oil. The oil was separated by silica gel column chromatography using cyclohexane-tyl acetate as a developing solvent to obtain 4-ethanesulfonyloxy-3-oxobutyric acid tert-butyl ester at 7.7 F as a yellow oil.

NMR (obaJ3) δppm: 1.32 to 1.62 (9H+3H, s + t, tert
-Butyl-1-oH,oH2so5- ) 3.30 (2H,q, J=7.0.OH,0H2
803-)3.47 (2H,s,0H2002tBu
) 4.87 (2H,S, 80200H200) Reference Example 6 4-ethanesulfonyloxy-3-oxybutyric acid tert-butyl ester 7.7F was dissolved in 50ml of acetic acid, and 2.21ml of sodium nitrite and 0.0ml of sodium nitrite were dissolved under water cooling. Add 1 dew t of concentrated waxy acid. After stirring the reaction solution at room temperature for 40 minutes,
m of ethyl acetate is added and the ethyl acetate solution is washed with brine. When the ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated, golden yellow crystals are obtained. The crystals were recrystallized from ether-petroleum ether to give 5.9F of 4-nitanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester as colorless crystals. Melting point 85-87℃ (decomposition) NMR (opa13) Jppm l, 47 (3H,t, J=7.Q, 0H50H2
8020) 1.57 (9H,s, t-Butyl
)3.33 (2H+ q+ J”7.(Jp 0H3
0H28020)5.23 (2H,8,-80□oo
n2oo-) Elemental analysis value 01oH17N07S Calculation [: 0,40.71; H,5,81; N,
4.75; 8,10.87 Actual value: 0.4G, 2
9; H, 5,73; N, 4.6i; 8,11
．． 17 Reference Example 7 4-ethanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester 5.9
f in 50 ml of dry acetone, and while cooling with water, 4.14 N anhydrous potassium carbonate and 1.86 g/dimethyl sulfate were added, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was poured into 500 d of ice water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated to give a discolored oil. When this was separated and purified using silica gel column chromatography using benzene-ethyl acetate as a developing solvent, 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester was obtained as a pale yellow oil with λ13f. It was done.

NMR (oDoly, )δppm: 1.43 (3
H, t, J=7. Q, 0H50H28020-)1.5
0 (9H,s, t-Butyl) & 27 (2H
p (1+ J”7-0.(l) (30H28020)
4.07 (3H,s, -oo,t;ao-)300shi5.18 (2H,S, -80200H200-)Reference Example 8 4-Promo-3-oxobutyric acid tert- Butyl ester 5. Of and iron benzenesulfonate 6.5F to 4-benzenesulfonyloxy-3-oxobutyric acid tert-butyl ester as colorless needle crystals 3.49? It was done. Melting temperature 494-96℃ Elemental analysis value 014H18068 Calculated value: 0,53.50; H, 5,78; 8,
10.20 Actual value: 0,5B,49; H,5,'
rQ; 8. IQ, 16.

NMR (ODOJ3) δppm: 1.43 (9H,8,t-nutyl) 3.43
(2H,S, -000H200-)4.63 (2H
,8,-80200H200-')7.40~8.03
(5H, m, benzene ring-H) Reference Example 9 4-benzenesulfonyloxy-
3-Oxobutyric acid tert-butyl ester 3,4F and sodium nitrite 900μ to 4-benzenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester as colorless needle crystals 2.95
f was obtained. Melting point 93-95°C (decomposition) Elemental analysis value o14H17No7s Calculated value: 0,49.02; H, 5,00; N,
4.08; 8,9.35 Actual value: 0.4B, 93
; H, 5,06; N, 4.01; 8,9.4
1FMB (oDoJ3) δppm: 1.57 (
9H,S,t-Butyl)5.07 (2H,S,
-80200H200-)1.40~8.03 (5
H, m, benzene ring-H) 10.1-7 (IH, b,
s, 1lj-OH) Reference Example 10 4-benzenesulfonyloxy-
3-oxo-2-hydroxyiminobutyric acid tert-butyl ester 2.95f anhydrous potassium carbonate 1.8
Of and dimethyl sulfate 0.8-4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester as a colorless oil.
009 was obtained.

NMR (ODO15) δppm: 1.50 (9H, s, t-Butyl) 4.05
(3H,8,N-00H,)5.07 (2H,8,
80200H200) 7.30~'It, 00 (5H
, m, benzene ring-H) Reference Example 11 4-promo 3-oxobutyric acid tert-butyl ester s, o y silver tomethanesulfonate r, yf for 40s
Add to +1 dry acetonitrile and stir and reflux for 30 minutes. The reaction solution is thoroughly filtered, and the r solution is concentrated under reduced pressure. The obtained oil is dissolved in benzene, washed with water, sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure to obtain a brown oil. When the oil was separated and purified by silica gel column chromatography using benzene-ethyl acetate as a developing solvent, 4-methanesulfonyloxy-3-oxobutyric acid tert-butyl ester was obtained as a pale yellow oil with 5.5F. ) δppm: 1.47 (9H, 11) 3.14 (3H, s) 3.47 (2H, s) 4.89 (2H, 8) Reference Example 12 4-Methanesulfonyloxy-3-oxobutyric acid tertiary Butyl ester 1. Dissolve Og in 10 ml of glacial acetic acid, add 386 nitrous acid and 1 drop of concentrated sulfuric acid under water cooling. After stirring the reaction solution at 10°C for 20 minutes, 50g+
Add ethyl acetate and wash with brine. When the ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated, yellow crystals are obtained.

When the crystals are recrystallized from ether-petroleum ether, 4-methanesulfonyloxy-3-oxo-
2-hydroxyiminobutyric acid tert-butyl ester was obtained. Melting point 103-104'c
(Decomposition) NMR (0DOJ 5 + 0D3000D3
) δppm: 1.56 (9H,s) &20 (3H,s) 5.23 (2H,S) 11.93 (IH,S) Elemental analysis f direct 09H15NO78 Calculated value: 0,38.47: H,5 ,311; N
, 4.99; Lll, 41 actual value: 0,3B, 4
1; H, 5,37: N, 4.117; 8,1
1.32 Reference Example 13 4-methanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester 2.8
Dissolve f in 30 g/dry acetone and add 2.07 g under water cooling.
Add F (anhydrous potassium carbonate) and 1.6 d of diethyl sulfate, and stir at room temperature for 1 hour.

The reaction solution was poured into 300 d of ice water and extracted with ethyl acetate. The extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified by silica gel column chromatography using benzene-ethyl acetate as a developing solvent, 4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyric acid tert-butyl ester was obtained as a colorless oil with a concentration of 1.31% I got it.

NMR (onoj5) δppm: 1.27 (3H, t, J=7.Q) 1.54 (
9H,s ) 3.19 (3H,s ) 4.20 C2H,q; J=7.0 >5.23 (
2H,S') Example 1 4-paratoluenesulfonyloxy-3-oxo-2-
(Syn)-methoxyiminobutyric acid 464 is suspended in 20% methylene chloride, cooled to -5°C, added with 0.204st of triethylamine, and stirred for 5 minutes to form a solution. To this solution were added 0.17 gd of oxalyl chloride and 1 drop of dimethylformamide, and the mixture was stirred at -5°C for 20 minutes. When the solvent is distilled off, 4-paratoluenesulfonyloxy-
3-oxo-2-(syn)-methoxyiminobutyric acid chloride is obtained. On the other hand, T-amino-3-methoxymethyl-3-
Cephem-4-carboxylic acid hivaloyloxymethyl ester paratoluenesul, phonate 530119 20
0394- diethylaniline was dissolved in 5 g of methylene chloride at -5°C, and then a solution of the above acid oxide dissolved in 10 liters of methylene chloride was added. After stirring for 5 minutes at −5° C., the solvent is concentrated. Dissolve the resulting residue in ethyl acetate and wash with dilute hydrochloric acid. Dry over magnesium sulfate and concentrate to give a brown oil. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as a developing solvent, 7-(4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutrylamino)-3-methoxymethyl -3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained as a colorless foam at 51 (IP).

NMR (ODOJ5) δppm: 1.22 (9H, s, tert-Butyl) 1
43 (3H, S, G (58) 3.30 (3H, 8, 3rd position - 00H3) 3.51 (
211,s, 2nd position -0H2-)4.10 (SR,8
,ft-00M, )427 (2H,s, 3rd place-0
n2-) 4.97 (IH, d, J=5.0.6th place-
I()5-Or (2H, Se 80200H200-
) 5.53 to 5.97 (3H, m, 1st position - H and ester 100H202) 7.2 (1 to 7.93 (5H, m, 7th position - book 1 and benzene ring) Example 2 A solution of 4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid chloride prepared by the method of Example 1 dissolved in 10 parts of methylene chloride was
450 q of T-amino-3-methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride and 40 q of diethylaniline were dissolved in 20 ml of methylene chloride and added to the solution cooled to -5°C. After stirring at room temperature for 15 minutes, the reaction solution was washed with dilute hydrochloric acid, dried over magnesium sulfate, concentrated, and the residue was purified using silica gel column chromatography.
T-(4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3
-Methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained as a pale yellow powder.
Yield 430 N NMR (ODOj3) δppm: 1.23 (9H,B) 2.18 (3H,8') 2.44 (3H,s) 3.46 (2H,br) 4.09 (3H,s) 4.97 (IH, d) 5.07 (2H, s) 5.5-6.0 (3H, m) 7.2-7.9 (5H, m) Example 3 Adjusted by the method of Example 1 A 10-methylene chloride solution of the prepared 4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid chloride, 7-amitusephalosboranic acid asosp, and bistrimethylsilylacetamide 1f were added to 5d of ethyl acetate. The solution was heated to -5°C.
Add dropwise. After further stirring for 1 hour under water cooling, 50 ml of ethyl acetate was added to the reaction mixture, and the mixture was concentrated to about half its volume under reduced pressure. The residual liquid is washed with water, further washed with brine, dried over magnesium sulfate, and concentrated. When ether is added to the precipitate and collected,
T-(4-paratoluenesulfonyloxy-3-o=￥
-/-2-(syn)-methoxyiminobutyryl amino)
420q of cephalosporanic acid was obtained.

NMR (DM80-d6) δppm: 2.00 (3
H,s ) 2.49 (3H,s ) 3.55 (2H,brs') 4.15 (3H,s ) 4.85 (2H,q ) 5.05 (IH,d ) 5.10 (2H ,s) 5.82 (1)1. d, d) 7.2-7.8 (4)i, brs) Example 4 Following the method of Example 3, 7-amitscephalosboranic acid 380 instead of 1-a and no 3-cephem-4 -Carbonl! Certo, reacted with 350 mg? −
(4-halatoluenesulfonyloxy-3-oxy-2
-(Syn)-methoxyiminobutyrylamino)-3-cephem-4-carboxylic acid was obtained. Yield aso Wg
NM几(DM80-d6) δppm: 2.42 (
3H, s ) 3.51 (2H, d ) 4.12 (3H, s ) 4.99 (IH, d ) 5.10 (2H, s ) 5.60 (IH, d, d ) 6.51 ( IH,s) 7.1-8.0 (4H,brs) Example 5 1-amino-3-methoxymethyl-3-cephem-4-
Carboxylic acid benzhydryl ester 360 # and diethylaniline 300 j If methylene chloride 5 Ill
4-balatoluenesulfonyloxy-3-oxo-2-(syn)- prepared by the method of Example 1 was added to the dissolved solution.
A 10 m methylene chloride solution of methoxyiminobutyric acid chloride is added dropwise at -5°C. After stirring for 30 minutes under water cooling, the reaction solution was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography. −
Oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester was obtained as a slightly yellow powder. Yield 42011g NMR (oDo15) δppm: , 2.43 (
3H,S ) 3.30 (3H,s ) 3.53 (2H,s ) 4.08 (3H,s ) 4.29 (2H,q ) 5.00 (IH,d ) 5.0S (21( , s ) 5.65 (IH, d, d ) 6.90 (IH, s ) 7.2-7.8 (14H, brs ) Example 6 ?-(4-balatoluenesulfonyloxy-3-oxo- 2-(syn)-methoxyiminobutyryl amino)-3
-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (510 μm) was dissolved in 51 μg of ethanol, 76 μg of thiourea and 841 Ig of sodium acetate were added, 3 d of water was added little by little, and the mixture was heated at room temperature. 3
Stir for 30 minutes. Ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with brine. Dry over magnesium sulfate and concentrate to give a pale brown foam. When this is separated and purified using silica gel column chromatography, y-+:2-<2-
392 ml of aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester were obtained as a colorless foam.

NMR (oDo15) δppm: 122 (9H,s, tert-Batyl)3.
30 (3H,s, 3rd place-00H5) 3.53 (2
H, s, 2nd-0H2) 4.00 (3H, s, N
0OH3) 4.30 (2H,s, 3rd position-〇H2-)
s, os (IH, d, J=5.0.6-H)5.
70-6.30 (5H, m, 1-position-2 and side chain-1 and 100H,2O- of the ester) 6.63 (IH, s, aminothiazole ring 5-H)
8.27 (IH, d, J = 9.0.7 position -NH) Example 7 7-(4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyi) according to the method of Example 6 7-[2-(2-aminothiazole-4
-yl)-2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid propionyloxymethyl ester 370 ml was obtained.

NMR (onojtS) δppm: 1.17 (3H, t) 2.41 (2H, Q) 3.28 (3H, S) 3.51 (2H, Q) 4.02 (3H, s) 4.27 (2H, S) 5.08 (IH, d) 5.6~6.2 (5H, m) 6.67 (IH,s) 8.10 (IH, d) Example 8 The following compound was obtained by the same reaction as in Example 6.

A) 7-[2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester NMIIL (anol,) δppm: 1.30
(3H,t) 1.61 (3H,d) 3.32 (3H,s) 3.57 (2H,S) 4.03 (314,S) 4.30 (2H,s) 4.21 (2H , (] ) 5.10 (IH, d) 5.6-6.2 (3H, m) 6.70 (IH, s) 6.92" (IH, q) 8.20 (IH, d) B )7-[2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid inbutyryloxymethyl ester NMR (oDoJ3) δppm: 1.20 (6H, d) 2.66 (IH, 5eptep ) 3.21 (3H,s) 3.40 (2H,q) 4.01 (3H,s) 4.16 (2H,s) 5.05 (IH,d) 5.6~6.2 ( 5H,m) 6.65 (IH,s) 8.06 (1H,d) 0)7-[2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide]-3-ethoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester NMII, (0DOJ5) δppm: 1.19
(3H,t) 1.24 (9H,S') 3.49 (2H,q) 3.58 (2H,s) 4.06 (3H,s) 4.37 (2H,S) 5.07 ( IH, d ) 5.57 (2H, s ) 5.88 (2H, s ) 6.04 (IH, d, d ) 6.76 (IH, s ) 7.90 (IH, d ) D) ? -[2-(2-aminothiazol-4-yl)-2-(syn)-ethoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester NMR (opOJ5) δppm: 1.22 (9H,s) 1.31 (3H,t) 3.30 (3H,S) 3. 53 (2H,s) 4.28 (2H,Q) 430 (2H,S) 5.01 (IH,d) 5.7-6.2 (5H,m) 6.76 (IH,S) 7, TO(IH,d) Example 9 7-(4-haF)luenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3
-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (35011 g) was dissolved in dimethylacetamide 5-, and 100 η of thiourea was added.
and stirred at room temperature for 4 hours. Add 50% ether to the reaction solution.
d was added, the precipitated insoluble material was separated, dissolved in a small amount of 5% aqueous sodium bicarbonate solution, and purified by column chromatography using Amberlite XAD-2.
Sodium 2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate is obtained as a colorless powder. Yield 160111F nuclear magnetic resonance spectrum (D
20) δppm: 3.59 (2H,q) a,sa (3H,8) λ99 (3H,s) 410 (2H,q) 5.11 (IH,d) 5.72 (IH,d) 6. 95 (IH,s) Example 10 In the same manner as in Example 9, T-(4-paratoluenesulfonyloxy-3-oxo-2-methoxyiminobutyrylamino?)cephalosporanic acid 300 q to 7-
C2-(,2-aminothiazol-4-yl)-2-(
140 wg of sodium cephalosporanate (methoxyiminoacetamide) was obtained.

Nuclear magnetic resonance spectrum (I)2o) δppm: 2.
10 (3H,s) 3.53 (2H,q) 3.118 (3H,S) 4.75 (2H,q) 5, old (IH,d) 5.81 (IH,d) 7.00 ( IHIs) Example 11? -(4-paratoluenesulfonyloxy-3-oxy-2-(syn)-methoxyiminobutyrylamino)-3
-cephem-4-carboxylic acid 5ooq, thiourea 200
A mixture of Misaki, sodium acetate tSO*, and methanol 5 hours is stirred at room temperature for 5 hours. Add 20-diisopropyl ether to the reaction solution, collect the precipitate, and wash with ether.
T-(2-(2-aminothiazol-4-yl)-2-
400 ml of (syn)-methoxyiminoacetamide]-3-cephem-4-carboxylic acid was obtained.

Nuclear magnetic resonance spectrum (I)2o) δppm: 3.
60 (2H,m) 3.98 (3H,s) 5.16 (IH,d) 5.80 (IH,d) 8.30 (1B,t) 6.98 (IH,s) Example 12 Implementation React in the same manner as Example 11 and 1-(4-para)
Luenesulfonyloxy-3-oxo-2-(syn)-
methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid 650 cape to 7-[2
-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid 36 (bl'P) was obtained.

Add 3 dK of methanol to the crystals and add 1 d of a 2M solution of sodium 2-ethylhexanoate in ethyl acetate to form a solution. Part of the solvent was distilled off under reduced pressure, and the precipitated crystals were removed with ethyl acetate and washed with ethyl acetate to obtain the sodium salt of the carboxylic acid. yield sso sv
NMRδ (DM80 D20) pI)m: 3.18
(3H,s) 134 (2H,br) 187 (3H,S) 4.25 (2H,s) 5.00 (IH,d) 5.5il (IH,d,d) 6-74 (IH+s) 7.26 (2H,br)! L52 (IH, d) Example 13 The following compound was obtained from the corresponding compound (I) and thiourea in the same manner as in Example-11.

A) 7-C2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide)-3-(
4-Methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4=triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid NMR (DM80-66) δppm: 34O( 3H,
s ) 3.63 (2H,s) 3.93 (3H,s) 4.12 (2H,Q) 5.13 (1M, d) 5.711 (IH,q) 841m (IH,IB) 7. 21 (2H,S) 9.5s (IH,d) B) 7-C2-(2-aminothiazol-4-yl)-
2-(syn)-methoxyiminoacetamide)-3-(
2-Methyl-5-oxo-6-hydroxy-2,5-dihyde C1-1,2,4-)I77cin-3-yl)thiono2thyl-3-cephemu-4-carboxylic acid NMR (DM80-d6) δppm: 3.51 (
2H,br) 3.61 (3H,s) 181 (3H,s) 4.18 (2H,q) 5.12 (IH,d) SJ? (IH, d, d) 6.811 (IH, s) 7.21 (2H, 8) 153 (IH, d) Example 14 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyimino 1.56 f of butyric acid tertiary/methyl ester was dissolved in 51 of trifluoroacetic acid and stirred at room temperature for 7 hours. Concentrating the reaction solution gives a brown oil. If the oil is left overnight, it will crystallize. The crystals were dissolved in acetone, treated with decolorizing charcoal, concentrated, and the resulting crystals were recrystallized from methylene chloride-petroleum ether to give 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxy as pale pink needles. Iminobutyric acid was obtained sss sv. Melting point 85.5-89℃ NMB (heavy acetone) δppm: 1.40 (3H, t, J"7.0.0H30H28
020) 134 (2H, q, J=7.0.0H50
H28020-)5.33 (2)1. s, 8020
0H200) 11.10 (IH, b, s, -002
H) Elemental analysis value c, HuOqNS calculated value: 0,3 &28; H, 4, $8; N,
5.54; 8. f2.6F actual value: 0,38.1
8; H, 4,29; Nl2.49; 8,12
．． 67 Example 15 480μ of 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid was dissolved in 20m of methylene chloride.
1 and cooled to 51Z' with 0.263ml of triethylamine and 0.22g1! oxalyl chloride and 1
Add a drop of dimethylformamide and stir at 5'C for 120 minutes. By distilling off the solvent, 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid chloride is obtained. On the other hand, 690 mg of T-amino-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester paratoluenesulfonate
was dissolved in 20 g/methylene chloride at -5°C, 0.51 g/l of diethylaniline was added, and then 10 g/l of the above acid chloride was added.
Add a solution dissolved in 1 liter of methylene chloride to the solution. 1 at -5℃
After stirring for 0 minutes, the solvent is concentrated. The resulting residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid and water. Dry over magnesium sulfate and concentrate to give a brown foam. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, a colorless foam was formed.
632 ml of (4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester were obtained.

NMR (onOj13) δppm: 1.22 (!IH,s, t-Butyl) 1.4
3 (3H, t, J=7.0.di0H28020-)
3.27 (2H, q, J=7.0.0H3CII(
28020-)3.30 (3H,s, 3rd place-00H
3) 3.54 (2H, b, s, 2nd position-〇H2-)4
．． 13 (3H,s,N 00H3)4.26 (2H
,s, 3rd position-ol(2-)5.00 (IH,d,
J=5.0.6-H)5.27 (2H,S,-8
0200H200-)5.60~5.97 (3H, m
, 7th position -H and ester 100H20-) 7.55 (IH, d, J = 9.0.7th position -NH-)
Example 16 7-(4-ethanesulfonyloxy-3-oxo-2-
(Syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (632 ml) was dissolved in 8 d of ethanol and 91111 I of thiourea and 146 ml of thiourea. 1.Add sodium acetate, add 3 portions of water little by little, and add 1. Stir at room temperature for 5 hours and 30 minutes. Ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with brine. After drying with magnesium sulfate and concentrating, a brown foamy substance ζ is obtained. When this was separated and purified using silica gel column chromatography, 7-C2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-, which is the same as the compound obtained in Example 6, was obtained. 440 ml of methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained as a colorless foam.

Example 17 In the same manner as in Example 14, 4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester 800η and trifluoroacetic acid 5
Bakara, 4-benzenesulfonyloxy-3-oxo-
2-(syn)-methoxyiminobutyric acid as crystals
mg was obtained.

NMR (heavy acetone) δppm: 4.06 (3H,S, N-00H3) 5.17 (
2H,s, -5o2-0-OH2Co-)7.3T
~8.03 (5H, m, benzene ring-H) 10.33
(IH,s, -00) Example 18 4-benzenesulfonyloxy-
3-oxo-2-(syn)-methoxyiminobutyric acid 350
■ and 7-amino-3-methoxymethyl-3-cephem-
4-Carboxylic acid pivaloyloxymethyl ester electro-paratoluenesulfonate 530 ■ or II), 7-(4-
Benzenesulfonyloxy-3-oxo-2-(syn)
510Q was obtained as a pale yellow foam.

NMR (oDo13) δppm: 1.22 (9H,s, t-Butyl) 3.30
(3H,S, 3rd position-〇-)3.52 (2H,b,
s, 2nd position -0H2-) 11 = 4.10 (3H, s, N-0 di).

4.27 (2H,s, 3rd position-0H2-)4.98
(IH, d, J = 5.0.6th place - 5) 5.08 (2
H,8,-80200300-)5.6(1~5.90
(3H, m, once the 7th position and -oOH2o- of the ester
) 7.40-8.03 (5H, m, benzene Ejg-A
) Example 19 7-(4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4 was prepared in the same manner as in Example 6.
- From carboxylic acid pivaloyloxymethyl ester 510 and thiourea 76T#g, 7-[2-(2-aminothiazol-4-yl)-2-(syn)methoxyiminoacetamide]-3-methoxymethyl- 3-Cephem-4
-Carboxylic acid pivaloyloxymethyl ester is 360
III? Obtained.

Example 20 In the same manner as in Example 14, 4-methanesulfonyloxy-
From 1.31 f of 3-oxo-2-(syn)-ethoxyiminobutyric acid tert-butyl ester and 10 g of trifluoroacetic acid, 4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyric acid is produced. 980η was obtained as a pale brown oil.

8 parts (heavy acetone) δppm: 5.20 (2H,S, so2arrogant0O-)IQ, 2B
(IH, s, 002H) Example 21 4-methanesulfonyloxy-3 was prepared in the same manner as in Example 1.
-Oxo-2-(syn)-ethoxyiminobutyric acid 480■
and 7-amino-3-desacetoxycephalosporanic acid pivaloyloxymethyl ester hydrochloride 474 and 7=(4-methanesulfonyloxy-3-oxy-2-
520 μl of (syn)-ethoxyiminobutyrylamino)-3=methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester were obtained as a pale yellow foam.

NMR (0DOA5) δppm: L21 (9H, s, t-Butyl) 1.30
<3H,t, J=7. Q, Y-00H2 town) 2.
12 (3H,s, 3rd position-0H3)3.16 (3H
,s, OH! , 8020 ) 3.43 (2H, AB
q, J=18.0.2nd-0H2-)4.21 (2
H, q, J=7.0. N-00H20H5) 4.9
9 (IH, d, J = 5.0.6 position - H) 5.24
(2H,8,-5o2oao2oo-)5.60~5.
93 (aH, m, 7-H and 10OH2 of the ester
0-) 7.56 (IH, d, J=9.Q, between 7th position and -)
Example 22 T-(4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyrylamino)-3-methyl-3-cephem-4-carboxylic acid pivalo was prepared in the same manner as in Example 6. 7-[2-(2-aminothiazole-
380 μ of pivaloyloxymethyl 4-yl)-2-(syn)-ethoxyiminoacetamide]-3-methyl-3-cephem-4-carboxylic acid were obtained.

NMR (onoj3) δppm: 121 (9H, s, t-Butyl) 1.27
(3H, t, J=7.Q, N-0CH2di)2.1
2 (3H,s, 3rd place-〇H,)5.02 (IH,
d, J = 5.0.6 position - H) 5.60 ~ 6.40 (
5H,m, -0OH20- of the ester at the γ position and -NHX on the thiazole ring on the side chain at the 7th position)8.67 (IH,s
, aminothiazole ring 5th position) 7.93 (IH, d
, J = = 9.0.7 position - trace) Example 23 4-methanesulfonyloxy-3 in the same manner as in Example 1
-oxo-2-(syn)-ethoxyiminobutyric acid 3809
and T-amino-3-desacetoxycephalosporanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride 367 Lylamino)-3-methyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester was obtained as a pale yellow foam.

2.13 (3H,s, 3rd position-0H5)3.16 (
3H, S, cH, 8020-) 'ru no 10-g-0
0H2 (3H3) 4.98 (11 (, d, J = 5.0.6 position - H) 5
．． 22 (2H, S, 80200H200) 5.80
(IH, d, d, J=5.0. J=9.0.7th place-
2) 6.83 (IH, q, J=5.Q, ester 10-Tsu (OH5) 0-) 7.58 (IH, b, d, 7th position -NH-) Example 24 Fire example In the same manner as in 6, T-(4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyrylamino)-3-methyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester 39
4■ and thiourea 76■, 7-42-(2-aminothiazol-4-yl)-2-(syn)-ethoxyiminoacetamide]-3-methyl-3-cephem-4-carboxylic acid 1- Ethoxycarbonyloxyethyl ester can be used.

Chill's 10・CO・o>2o; ) 1.57 (3H, d, J=5.0. Ester's -o
on(OH5)O-) 2.12- (3H,s, 3rd position -cIH5) ===
Acyl 10・00・00H2ON(3)5.02 (I
H, d, J = 5.0.6th place) 5.83 (IH,
dd, J=5. (1, J = 9.0.7th place - H) 6.1
8 (2H, b, s, -NH2 on side chain thiazole ring)
6.70 (IH, s, 5-position on side chain thiazole ring) 6.83 (IH, b, q, J = 5.0. 10.0H(OH3)O- of ester) 7.90 (IH, b, d, 7-position-) Example 25 In the same manner as in Example 1, 4-methanesulfonyloxy-
3-oxo-2-(syn)-ethoxyiminobutyric acid 380
From ■ and 7-amino-3-desacetoxycephalosporanic acid 1-n-propyloxycarbonyloxyethyl ester hydrochloride 5lit wIg, T-(4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxy (iminobutyrylamino)-3-methyl-3-cephem-4-carboxylic acid 1-n-propyloxycarbonyloxyethyl ester as a pale yellow foam at 460 #
Obtained.

NIJR (ODOj3) δppm: o, ys~1. ss (11H, m, N 0OH20
H5 and ester 100H(OH3)O- and -0φω・
00H2 stuttering) 2.13 (3H,! 1.3rd place - Hit 5
)3.16 (3H,S,OH;8020-)-
O-■・0di0H20H3) 4.99 (IH, d, J=5.0.6 position-see)5.
20 (2H,S, -8020CsH200-)5.8
2 (IH, d, d, J=5.0. J=11.0.
1st place-H) 6.83 (IH, b, q, J=5.0.
-o-OH (side,)O-) of ester 7.56 (11(, b, d, J=9.0.7 position -N
! ! 7) Example 26 In the same manner as in Example 6, 7-(4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyrylamino,)-3-methyl-3-cephem-4- From carboxylic acid 1-n-propyloxycarbonyloxyethyl ester 460~ and thiourea yesw, '? −
(2-(2-aminothiazol-4-yl)-2-(syn)-ethoxyiminoacetamide]-3-methyl-3
320 η of -cephem-4-carboxylic acid 1-n-propyloxycarboxylic ethyl ester were obtained.

-00H(OH3)O- and -〇-00-00H20
H20H,) ===== 2.13 (3H, S, 3rd place - 0H5) 3.33 (
2H, ABq, J=18.0.2nd-C)'3.9
0 to 4.50 (4H, m, N-00H20H!, and ester ・0・00・0OH20H20H5) 5.0
1 (IH, d, J = 5.0.6 once) 5.70 ~
6.20 (3H, m, -H at the 7th position and -NH2 on the side chain thiazole ring) 6.70 (IH, s, once at the 5th position on the side chain thiazole ring)
6J3 (IH, b, q, J=5.Q, Esther's 10th oath,)O-) 7.80 (IH, d, J=9.9.7th place - Estimated) Example 2T Example In the same manner as in 1, 4-methanesulfonyloxy-
3-oxo-2-(syn)-ethoxyiminobutyric acid 380
■ and T-amino-3-desacetoxycephalosporanic acid tert-butyloxycarbonyloxymethyl ester hydrochloride 381η and 1-(4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyryl amino )-3-Methyl-3-cephem-4-carboxylic acid tert-butyloxycarbonyloxymethyl ester 4204i.

149 (9H,s, ester 10.00.oo(o
H3)3)3.16 (3H,S, oHSso2o
) 3.41 (2H, ABq, J = 18.0.2nd - G) 4.9B" (1) 1. d, J = = 5.0.
8th place Ryomi) 5.24 (2H, S, -80200H2
00-,) 5.60-5.93 (3H, m, 7th place-
Mito Ester's 10OH20-) 7.56 (IH, d, J=9.0.7th place-Kariichi) Example 28 In the same manner as Example 6, ? -(4-Methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyrylamino)-3-methyl-3-cephem-4-carboxylic acid tert-butyloxycarbonyloxymethyl ester 420 Wg and thiourea 719 and 7-(2
-(2-aminothiazol-4-yl)-2-(syn)
-Ethoxyiminoacetamide]-3-methyl-3-cephem-4-carboxylic acid tert-butyloxycarbonyloxymethyl ester was obtained in an amount of 293Q.

1.49 (9H,s, ester -o-oo-oo(
oH3)3)5.01 (IH, d, J=5.0.6
position) 5.63~6.40 (5H, m, 7th position -H
and s, ss of the ester (1He s, 5-M on the side chain thiazole ring) 7.90 (IH, d, J = 9.0.
7th position - 1) Example 29 In the same manner as in Example 1, 4-methanesulfonyloxy-
3-oxo-2-(syn)-methoxyiminobutyric acid 440
# and 1-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1-isopropyloxycarbonyloxyethyl ester 370 WIg, T-
Methanesulfonyloxy-3-oxo-2-(syn)-
480Q of methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid 1-isopropyloxycarbonyloxyethyl ester was obtained as a pale yellow powder.

NMR (ODOI3) δppm: 1.28 (6H, d, J=6, o, -o of ester
8-o-o1 ((di)2) 1.55 (3H, d, J=6.0. Varnish f Renault
002-OH(OH5)o8- ) 3.11 (3H,S, 0H58020) 3.30 (
3H,s, 3rd position -o di)4.24 (2H,s,
3rd position --〇-) 4.60~5.1O (2H, m, 6th position -H and ester 5.23 (2H, S, 80200H
200) 5.77 (IH, d, d, J=: 5.0.
J=9.0.7 position -H)6.83 (IH,m, -oo2oz(cH,)o-)7.58 (II
(,d, J=9.0.7-position-open-) Example 30 In the same manner as in Example 6, 7-(4-methanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyryl Amino)-3-methoxymethyl-3-cephem-4
- From 480 μl of carboxylic acid 1-l sopropyloxycarbonyloxyethyl ester and 152 m”+? of thiourea, T-[:2-(2-aminothiazol-4-yl)
=2-(syn)-methoxyiminoacetamide]-3-
Methoxymethyl-3-cephem-4-carboxylic acid 1-
390 kg of isopropyloxycarbonyloxyethyl ester was obtained as a colorless powder.

NMR (oDo15) δppm: 1.28 (6H, d, J=6.0.
OOOOH(OH3)2) 1.55 (3H, d, J=6.0.100□〇H of ester (C)0-) 3.27 (3H,s, 3-position-00H5)4. 30
(2H,s, 3rd place-on2o-)4.60~5.15
(2H, m, 6th position 1 and ester 5.70-6.40
(3H, m, 7th position -H and side chain thiazole roof)
-NH2) 6.61 (IH,s, 1 of the side chain thiazole ring) 6.8
0 (IH, m, -oo2oz(on3) of ester
O-)8.23 (IH, d, J=9.0.7 position-M
7) ~ Patent applicant Sankyo Co., Ltd. Agent Patent attorney Shoji Kashi Continued from page 1 ■InJCj' Identification code Office reference number // A 6
1 K 311545 ADZ 6664-4C@ Departure
Author: Makoto Kanhara - Inside Hiromachi, Tokyo Parts Office 0 Author: Isamu Arashi, Inside Hiromachi, Tokyo Parts Office

Claims (4)

[Claims] (1) Formula (syn type) [In the formula, R1 is a phenyl group or a lower alkyl group that may have a substituent, R2 is a lower alkyl group, R5
is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, or the formula -0H2R5 (wherein R5 is a hydrogen atom, a hydroxyl group, a halogen atom, an azide group, an acyloxy group, a carbamoyloxy group, an optionally substituted heterocyclic thio 000fL represents a carboxyl group which may be esterified. ] A cephalosporin derivative represented by (2) Formula (Shin type) [In the formula, B represents a phenyl group or a lower alkyl group which may have a substituent, and TL2 represents a lower alkyl group. ] Alkoxyiminobutyric acid or its reactive derivative in a carboxyl group and the formula [wherein R5 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, or the formula -0H2R5 (wherein R5 is a hydrogen atom, a hydroxyl group, 000B represents a carboxyl group which may be esterified. ] 7
Formula characterized by reacting with -7 minosephalosporin derivative (syn type) [In the formula, R1, R2, R3 and 000R4 have the same meanings as described above. ] A method for producing cephalosporin derivatives. (3) Formula [In the formula, R1 is a phenyl group or a lower alkyl group that may have a substituent, R2 is a lower alkyl group, R3
is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, or a formula -0H2R5 (wherein R5 is a hydrogen atom, a hydroxyl group, a halogen atom, an azide group, an acyloxy group, a carbamoyloxy group, an optionally substituted heterocyclic thio group) ), and 0OOR4 represents a carboxyl group which may be esterified. A formula (syn type) characterized by reacting a compound represented by the following with thiourea: [In the formula, R2=TL3 and 0OOR, 4 have the same meanings as described above. ] A method for producing a cephalosporin derivative represented by (4) Formula % Formula % (Syn type) [In the formula, R1 represents a phenyl group or a lower alkyl group which may have a substituent, and R2 represents a lower alkyl group. ] Alkoxyiminobutyric acid or its reactive derivative in a carboxyl group and the formula [wherein R55 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group or the formula -cH2R5 (wherein R.5
represents a hydrogen atom, a hydroxyl group, a halogen atom, an -azido group, an acyloxy group, a carbamoyloxy group, or an optionally substituted heterocyclic thio group. ), 0OORA represents a carboxyl group which may be esterified. ] is reacted with a T-aminocephalosporin visiting conductor represented by the formula [wherein R1, R2, R, and 0OOR4 have the same meanings as described above. ] to produce a compound represented by
A formula characterized by reacting the compound with thiourea [wherein R2, R3 and 0OOR,l have the same meanings as described above]. ] A method for producing a cephalosporin derivative represented by