JPS5920288A - Cephalosporin compound and its preparation - Google Patents

Abstract

NEW MATERIAL:A cephem compound shown by the formula I [R<1> is H, (substituted)(cyclo)alkyl, alkenyl, alkynyl, or O-containing heterocyclic; R<2> is H, (substituted)methyl; R<3> is H, or COOH-protecting group] and its salt. EXAMPLE:7-[2-(2-Aminooxazole-4-yl)-(Z)-2-methoxyiminoacetamido]-3-acet oxymethyl-3-cephem-4-carboxylic acid. USE:A strong antibiotic. An ester of it can be administered orally. PROCESS:For example, a compound shown by the formula II is reacted with a compound shown by the formula III (R<4> is H, or NH2-protecting group) or its reactive derivative at COOH(e.g., acid halide, acid anhydride, etc.) to give a compound shown by the formula IV, and, if necessary, the protecting groups of COOH and NH2 are eliminated, to give a compound shown by the formula I .

Description

Detailed Description of the Invention The present invention is based on the general formula [wherein R1 is a hydrogen atom, a linear or branched alkyl group that may have a substituent, an alkenyl group, or an alkynyl group that has a substituent] represents an optional cycloalkyl group or a heterocyclic group containing an oxygen atom, and R'1! Indicates a hydrogen atom or a methyl group which may have a substituent, and RSt-indicates a hydrogen atom or a protecting group for a carboxy group. ], pharmaceutically acceptable salts thereof, methods for producing them, and agents for preventing and treating bacterial infections containing them as active ingredients.

In general formula (1), R1 is preferably methyl, ethyl,
1 or more carbon atoms such as n-propyl or isopropyl
3 methylkyl groups, 2-propenyl, 2-butyl,
or 3 or more carbon atoms such as 2-methyl-2-propenyl
4 alknyl groups, 2-propynyl, 2-butynyl,
or an arunyl group having 3 to 4 carbon atoms such as 3-butynyl, cyclopropyl, cyclobutyl, cyclopentyl,
or a cycloalkyl group having 3 to 6 carbon atoms such as cyclohexyl, a heterocyclic group containing an oxygen atom such as 2-oxo-3-oxacyclopentyl or 2-oxo-3-oxacyclohexyl, 2-fluoroethyl, 2,2 ．．
2-1 lifluoro, loethyl, 2-fluoropropyl, 1
-Methyl-2-fluoroethyl, 1,3-difluoro-
2-7'-carbon atoms substituted with 1-3 halogen atoms such as 2-7', 2,2-cyfluorocyclopropyl, 2-chloroethyl, and 3-chloropropyl;
4 alkyl groups, cycloalkylargyl groups, hydroxyalkyl groups with 2 to 3 carbon atoms such as 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl, 2-methoxyethyl, 3 - a lower alkoxyalkyl group such as ethoxypropyl or 2-ethoxypropyl, carbamoylmethyl, 2-carbamoylethyl, 2-carbamoyl-2-methylethyl, 1m, N-dimethylcarbamoylmethyl, or N
.

1-3 carbon atoms such as N-diethylcarbamoylpropyl
carbamoylalkyl group, alkoxycarbonylalkyl having 1 to 3 carbon atoms, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-methoxycarbonyl-2-methylethyl, and 3-ethoxycarbonylpropyl. group, carboxyalkyl group having 1 to 3 carbon atoms such as carboxymethyl, 2-carboxyethyl, 1-methylcarboxymethyl, 111-dimethylcarboxymethyl or 3-carboxypropyl, cyanomethyl, 2-cyanoethyl,
A cyanoalkyl group having 1 to 3 carbon atoms such as 3-cyanopropyl or 1-cyano-1-methylmethyl, an acyloxy/alkyl group such as acetoxyethyl, 2-propionyloxyethyl, or 3-acetoxypropyl, or 1-carboxy Indicates a carboxy-substituted cycloalkyl group such as cyclopropyl, R1 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl or propyl, --4 Yugo 4 Tomoe-Une hydroxymethyl group, fluoromethyl, Halomethyl groups such as chloromethyl or bromomethyl, acyloxymethyl groups such as acetoxymethyl or propionyloxymethyl, lower alkoxymethyl groups such as methoxymethyl or ethoxymethyl, lower alkylthiomethyl groups such as methylthiomethyl or ethylthiomethyl, 1-methyl -1(5)-tetrazol-5-ylthiomethyl, 1-(2-N,N-dimethyl)ethyl-1(
5)-tetrazol-5-ylthiomethyl, 1-carboxymethyl-1-tetrazol-5-ylthiomethyl, 2-methyl-1,3,4-thiadiazol-5-ylthiomethyl, 2,5-dihydro-6-hydroxy -2
S which may have a substituent such as -methyl-5-oxo-as-)riazin-3-ylthiomethyl group.

A 1-pyridiniomethyl group which may have a substituent such as a heterocyclic thiomethyl group containing 1 to 4 heteroatoms selected from N and O, 1-pyridiniomethyl, 4-rubamoyl-1-pyridiniomethyl group, etc. and R% hydrogen atoms, alkali metals such as sodium and potassium, alkaline earth metals such as calcium, organic bases such as magnesium, ammonium, and dicyclohexylamine, tert-butyl, diphenylmethyl, and tert-butyldimethyl. Carboxy protecting groups that can be easily removed chemically such as silyl, 2,2゜2-trichloroethyl group, terjarifthylcarbonyloxymethyl, ethylcarbonyloxymethyl, 1-ethylcarbonyloxyethyl, 1-methylcycloethyl hexylcarbonyloxymethyl,
acyloxy/alkyl groups such as 1-(1-methylcyclohexylcarbonyloxy)ethyl, 1-[2,2,2)-bicyclooctylcarbonyloxymethyl groups,
Alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, 1-isopropyloxycarbonyloxyethyl, cyclopentyloxycarbonyloxymethyl,
1-cyclopentyloxycarbonyloxyethyl, 1
- Cycloalkoxycarbonyloxyalkyl groups such as methylcyclopentyloxycarbonyloxymethyl, 1-(1-methylcyclopentyloxycarbonyloxy)ethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-methylcyclohexyloxycarbonyloxymethyl groups, etc. shows a carboxy protecting group that forms a biologically active ester of

The present inventors have synthesized various cephalosporin derivatives having an oxazoleoxy/minoacetic acid group as the acyl group at the γ-position, and have demonstrated that these compounds exhibit strong antibacterial activity and have a broad spectrum. Examples of these cephalosporin M4 compounds represented by the general formula (r) obtained by the present invention include the compounds shown in Table 1 below.

Table 1 10H3HH 2//　　　OH,“ 3〃CHOAC// 4 tt OHF // 5〃0HCL　ri 6tt OHBr tt γ /, 0H200H3tt 8〃CH2SCH3〃 Oh.

2L; LJ2f1 Example R1u 2 R5is
ttC! H! 1OH20000 (C!
H,)320p 0H200H3C
H0000 (OH3) 3 cases RI
R2R5220H (!Hri OHH, H 2 23tt CH3" 〃24
pC! HOAc
tt25 tt
OHF tt28
// CHO4//27
tt 0H2Br〃 28〃CH2OCH3〃 2 g // -0H2()CONH2' example
R1R2R3 CH5 CH2C02H 34// 0H20CR30H20COC ((
”1(3)536 C!HC!:CHHH
37tt OHtt 38p 0HOAc
rt example R1R2R3 390Hc=cHCH2F H40p
0HOttt 41 tt C! HBr
〃42 〃0HOOHtt 3 Example RI R2u 54
80H method OT (OHCH0000(OH3)32
3 249
tt 0H200H5tt53
0HOHF HH2 54// OH3 55 /l OHF
//56 p.
CHCt p57
II CHBr t
r58 tt OH0C
)l tt3 59 0H20H2F OHSOHH2S 5Q tt OI(OA
cr rt) 2H5 CH2CO2H 67CH2CH2FCH3CH20COC(CH3)3
68 tt OHOO
H/73 71 -C) HH 72tt CH3N 73 p 0H2F
tt74 〃 0H
O4//75 〃0H2Br,
tt7@ // 0H
OOHtt3 77 tt C! H
OAc p example R'
R2R30H3 c'H2°)12NM82 92 # ' OHQC! HOH,,
0OCIO(OH3)33 84 // C of 0H30H20
(clap) 3135 0HOHOH0H2QC! H
3H2 86tt C! H2O0H5p67
0H20H20H0H2F H88p
0H20ttt fi9 p 0H2Br
tt9G, tt0H20
0H3tt91 tt OH2
(MattH3 96〃CH20CH3c!H20cDC(OIH3)3
97 0HCHON CH3H2 0HF // 98 “ 299
p CH20ttt10Q
tt CHBr
p101 tt CH20
0H3tr102pC
! HOAc p/#Il! λ 108 tt OH20Me
cH2000C! ((W,).

109 s CH3tt11
0 0H2ON p
Hllll 1 0
HF p112t
t CHOt tt1
13'/ (1:'H2B
r/1114p
0HOAc tt115
1/ OHOMe
//0 core 116 1 0HN CONH2
ttCHCo H 22 aH2CH2NMe2 121 p OHOMe 0
H20■0(OH3)5122〃CH3aH20COC
(CH5) 3123 0H0ONHOH, H 2 124 // 0H2F //
125 tt 0HOtt
tT26 tt 0HBr
〃127 tt
0HOAc tt example
RlR2R5 1280H0ONHOHOCRB 2 2 2 3 129 p 0HE3
CH//3 CH2C02H 135〃OHOCHCH0COC(C!H5)32
3 2 136 0HC0IJH' 0H3c! I(
26C(X:!(CH3)32 137 CHOONMθ HH2 138〃OH5〃 139 /l 01(F
tt140 tt
0HCA tt14T
tt CHBr tt14
2 tt CHOAc
tt143 tt
0HOCHtt3 144 tt 0H2-ND 1 listen 3 Example R1B2R3 cH2 open 2'KMe2 149 # OHOGHOH0OO
C! (OH3)32 3 2 150 1 CH3cH20000
(OH,).

1s t Q HH isz p 0H3p15
3tt OHF
/1154 n
CHOt〃155,F
0HBr〃15
6 # CHOAC/
/CH2 place-e2 162 tt 0H3cH20C
OC(CH3)si $3 # O
H,, OCH3 country, 0■C (country 5) 3164'-0
(CH5)2002HHH165tt 0
H5tt 166〃CH2F〃 16γ し(OH,)2Co,,HCH2C! f-H
2SON 0H2Br p169
#cHOAc
tt17G // 0H
2SOH3〃171 tt
0HOOHu3 CH3 0H2aH2NMe2 177 〃OH, part, 0000 (C!H3)
3178 tt C) (O
C+Hs3 11101/, CHOMe:, , O
H,,0OOC(OH mountain 1 R1//C!H
0OONH'H2 o 2H 1850H2 (3H200H3c praise H1H"
', 1"aHocHaHoaoc(aH
,)3〃 2 3 2 H3 1881/ CH200H30H20000(
C! H3) 3189 0H2Co2H"'OH", @
191 p 0H20CH3r
7192 tt p 0
H20(X)O(OH3)3194 tt
0H2QC! H3G! )T20000(OH3
).

Example RI R2R3195
”5 CjH0CjHH2S 196 p CH200ONH2t1 198 p 0HOAc
t7199 //
OHOCH/)5 200 1/ /7 0H2
0000(01(3).

201 p 0H3ttH3 204tt 0H2F #Example
H1R2R5 -111--1oo1--1-11-------
------4-111,--1,-1205CjH(O
H3) 20H2SOH3H206# 0H20
0H30H,,0000(OH3).

Enter °°2HΦ heart. ,,R2 2070H-N H2080H
,C! H20t horn 209
1F OHO/! , 0H2QC! 0
0 (OH3).

210/l
OHOMe H211//
OH20Me 0H20[X)O(OH3)3' 212 0H223 0HOOHH H3// 0HOAc ,
//214 1 0H%s //2
15〃CH2゜)CONH2,/ +m! H2O00H R9tt Cll0I
//220 //
0HOt C1□oCQO(cH3)3221
tt 0H200H3tt A method for producing a compound having the general formula (1) will be described below in accordance with the claims.

(A) General formula () [In the formula, R2 and 1% have the same meaning as described above. ] A compound having the general formula (2) [wherein R1 has the same meaning as described above, and represents an R-hydrogen atom and a protective group of 7 amino groups. ] Compound that has! Power,
Alternatively, a reactive derivative at the carboxy group is reacted to form the general formula (In the formula, n 1 'l R2, R5 and R 1 have the same meanings as above). ], and the protecting groups of carboxy and amine 7 groups are removed as necessary) General formula (1) [In the formula, R1, R2 and R% have the same meanings as above. A method for producing a cephem compound having the following.

When R in the compounds of general formulas (2) and (I) is a protecting group for an amine/group, the protecting group for the amine 7 group is preferably one that can be easily removed and converted into an amino group, for example, by acid treatment. Trityl group, formyl group, t-butoxycarbonyl group, 2-ethoxy/carbonyl-1-methyl-ruvinyl group, 2,2,2-trichloroethoxycarbonyl group that can be removed reductively, by alkali treatment 2- that can be removed
A methylsulfonylethyloxycarbonyl group, a chloroacetyl group that can be removed by thiourea treatment, and the like are used.

This method consists of two steps: an acylation step and, if necessary, an unbinding C.k step.

In the acylation step, the compound having the formula (I) is used in its free form or as a reactive derivative thereof, and when used in its free form, a suitable condensing agent is used. As the condensing agent, disubstituted carbodiimides such as dicyclohexylcarbodiimide, imidazolides such as carbonyldiimidazole and thionyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, or dimethylformamide and oxy Examples include Vilsmeier reagent prepared from phosphorus chloride, thionyl chloride, etc.

Examples of reactive derivatives of the compound having the formula (g) include acid halides, acid anhydrides, mixed acid anhydrides, active esters, active amides, acid azides, and the like.

As mixed acid anhydrides, mixed anhydrides with carbonic acid mono-lower alkyl esters such as carbonic monomethyl ester and carbonic acid monoisobutyl ester, and mixed acid anhydrides with lower alkanoic acids such as pivalic acid and trichloroacetic acid are used. Examples of active esters include p-nitrophenyl ester, pentachlorophenyl ester, N-hydroxyphthalimide ester, and N-hydroxybenztriazole ester (L).

This step is usually preferably carried out in a solvent solution, and the solvent used is not limited as long as it does not adversely affect this reaction, such as acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, dichloromethane, acetonitrile, dimethylpolamide,
An inert organic solvent such as dimethyl sulfoxide or a mixed solvent with water is used. Depending on the type of reactive derivative used, 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, nitrogen-containing heterocyclic bases such as triethylamine, dimethylaniline, diethylaniline, N-methyl Examples include piperidine, N-methylpiperidine, pyridine, collidine, and lutidine. Reaction temperature &: 1, although there is no particular limitation, the reaction is usually carried out at room temperature or under cooling. The time required for the reaction varies mainly depending on the Type 1 reaction temperature of the acylation method, but is usually from several tens of minutes to several tens of hours. After the reaction is completed, the compound having the formula (property) is recovered from the reaction mixture by a conventional method.

For example, if the reaction solvent is water-miscible, first distill it off under reduced pressure and replace it with a water-miscible solvent; if the solvent is water-immiscible, wash it with an acid and a base, dry it, and then remove the solvent. Obtained by distillation. If necessary, purification can be carried out by conventional methods such as various chromatography methods.

In the deprotection step, the protective groups are removed by a conventional method based on the characteristics of each protective Xi group, and the crude product is purified to obtain the formula (1).
■ The desired compound can be obtained.

Note that the raw material compound of general formula m is synthesized as follows.

(a) (C') (e) (e) (IID) A compound having the general formula (a) [in the formula, represents a protecting group for the Rt carboxy group] is converted into an alkyl hashide (RX) in the presence of a base. Reacted with the compound (2) [in the formula, R1 is the same as above 4, Re is a carboxy group-retaining compound (JSi)
Indicates the group. ] and reacted with sulfuryl chloride or bromine to form the general formula [wherein R1 and RM have the same meanings as above or represent a halogen atom such as chlorine or bromine. ) is obtained. Compound r-
t is reacted with urea to form an oxazole compound) [in the formula, R
1> and R8 have the same meanings as described above. 〕year,
By removing the 2-amino Z group of oxazole, the compound (e)
[In the formula, R", R' and R8 have the same meanings as defined above.] When the carboxy protecting group of compound C→ is removed, the general formula GID C is obtained. In the formula, R1 and R4 are as defined above. The same meaning is shown.] A compound having (Rirari, Ru.) The specific synthesis method for the compound will be described using Part 1 as an example.

CF3) general formula ([in the formula, R1, 'FC5 and Rst have the same meanings as above, R is substituted with chlorine, bromine, iodine, acetoxy, carbamoyloxy, N,N-dimethylcarbamoyloxy group, etc. represents a methyl group] to a compound having the general formula () [wherein Het is a hetero atom containing 1 to 4 heteroatoms selected from sulfur atoms, nitrogen atoms, and oxygen atoms that may have substituents. pyridine (which may have a substituent), such as pyridine, 4-
Carnocumoylpyridine, 2-carboxypyridine, etc. are reacted to form a compound of the general formula [wherein, R1, R3 and R4 have the same meanings as described above and are shown below. ], and remove the protecting groups for the amino and carboxy groups as necessary to obtain the general formula () [wherein R1 and R] have the same meanings as above and are shown below]. A method for synthesizing cephem compounds with

Het in formula (b) is 1-methyl-T (H)-
Tetrazol-5-yl, 1-(2-N,N-dimethyl)ethyl-1(6)-tetrazol-5-yl, 1-carboxymethyl-1(ro)-tetrazol-5-yl,
2-methyl-1,3,4-thiadiazol-5-yl,
2,5-dihydro-6-hydroxy-2-methyl-5-
It represents a heterocyclic group such as oxo-R8-triazin-3-yl group.

R in formula ■, (■) 1-methyl-ICE) −
Tetrazol-5-ylthiomethyl, 1-(2-N,N
-dimethyl)ethyl-1(ro)-tetrazol-5-ylthiomethyl, 1-carboxymethyl-1(ro)-tetrazol-5-ylthiomethyl, 2-methyl-1,3,
4-thiadiazol-5-ylthiomethyl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-a
s -) A heterocyclic thiomethyl group such as a riazin-3-ylthiomethyl group, a 1-pyridiniomethyl group such as 1-pyridiniomethyl, 1-(4-carbamoylpyridinio)methyl, 1-(2-carboxypyridinio)methyl, show. □ The present invention is a method for obtaining a compound of general formula (I) by a substitution reaction step at the 3-position of a cephalosporin ring and, if necessary, a protective group removal step.

This substitution reaction step is carried out in the presence or absence of a base. Preferred salts include bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and N,N-dialkyl aromatic amines such as diethyl ether.

Preferably, the reaction is carried out in a solvent. The solvent used is not particularly limited as long as it does not participate in this reaction, but
Suitable examples include water, ethers such as diethyl ether, THF, and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, dimethylformamide (DMF), dimethylacetamide (DMA),
A non-aqueous polar solvent such as dimethyl sulfoxide (DMSO) is used. The reaction is usually carried out at a temperature of θ°C to 100°C. It is preferably carried out at room temperature to 50°C. The time required for the reaction varies mainly depending on the type of compound (1) or (2), the presence or absence of a base, and the type of solvent used, but is usually several tens of minutes to several tens of hours. After the reaction is complete, the formula (to)
The compound having the compound is collected from the reaction mixture by conventional methods.

For example, if the reaction solvent is water-miscible, it is first distilled off under reduced pressure and then replaced with an immiscible solvent; if the solvent is water-immiscible, it is washed directly with water or phosphate buffer, dried, and then the solvent is removed. Obtained by distilling off. If necessary, it can be purified by conventional methods such as various chromatography methods.

As mentioned above, in the disengagement step, the protecting groups are removed by a conventional method based on the thn of each protecting group, and the crude product is purified to obtain the target compound having the formula (■). can.

((J method general formula () [wherein R1, R2 and Rst have the same meanings as above]) is added to a compound having the general formula [wherein R7 is an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, or It represents a cycloalkoxycarbonyloxyalkyl group, and Y represents a leaving group.]
A general formula () characterized by reacting a compound having the following and removing it when R is a protecting group for an A1no group [In the formula, R1, R2 and R7 have the same meanings as described above] ] A method for producing a compound having

In formulas ① and (g), R7 is a group that forms a so-called biologically active ester that can be easily hydrolyzed in living organisms and targets, such as tertiarybutylcarbonyloxyethyl, ethylcarbonyloxyethyl, and 1-ethylcarbonyl. Oxyethyl, 1-methylcyclohexyl, carbonyloxy/methyl, ? -(1-methylcyclohexyl, carbonyloxy)ethyl, 1-[2,2,2) -
Acylokynealkyl groups such as bicyclooctylcarbonyloxymethyl group, alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxy7ethyl, 1-isoprobyloxycarbonyloxymethyl group, cyclopentyloxycarbonyloxy7methyl group, etc. , 1-cyclopentyloxycarbonyloxyethyl, 1-methylcyclopentyloxycarbonyloxymethyl, ? It represents a cycloalkoxycarbonyloxyalkyl group such as (1-methylcyclopentyloxycarbonyloxy)ethyl, 1-cyclohexyloxycarbonyloxyethyl, and 1-methylcyclohexyloxinecarbonyloxymethyl group.

Y in formula (g) represents a leaving group selected from halogen atoms such as chlorine, bromine, and iodine.

In this reaction, compounds having the formula (1) may be used as reactive derivatives advantageous in the condensation.

Examples of the reactive derivative of the carboxylic acid moiety of the compound having formula (1) include salts with metals such as sodium and potassium, salts with organic amines such as triethylamine, and the like. The reaction is preferably carried out in a suitable solvent,
Examples of such a solvent include those that do not adversely affect this reaction, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethyltriamide phosphate, acetonitrile, etc., or mixed solvents with other inert organic solvents. The reaction is usually preferably carried out at room temperature or under cooling. The time required for the reaction is usually several minutes to several hours. After completion of the reaction, the reaction mixture is diluted with a water-immiscible solvent, washed with an aqueous potassium bisulfate solution and an aqueous base solution, dried, and then the solvent is distilled off to obtain the target compound of the reaction. This product can be further purified by conventional methods such as various chromatography methods.

When the amino group is protected, 1c is converted to an amine 7 group in the same manner as the removal of the compound having the above formula.

It has been revealed that the compound of general formula (1) obtained by the present invention exhibits excellent antibacterial activity by the agar plate dilution method. (Table 2). It was also revealed that the ester type compound of general formula (1) showed a high urinary recovery rate when administered orally to mice (Table 3).

o2H [Table 3] Recovery rate (Ia) of the parent compound when compound (Ia) is orally administered to mice Compounds represented by the general formula (IJ) according to the present invention include Staphylococcus aureus, Bacillus subtilis, etc. It is an antibiotic substance that has extremely remarkable effects on the treatment of bacterial infections caused by Durham-positive bacteria and Gram-negative bacterial pathogens such as Escherichia coli, Shigella, Klebsiella pneumoniae, M. aeruginosa, etc. On the other hand, general When the ester compound represented by formula CI) is orally administered, it is well absorbed from the gastrointestinal tract, and the ester moiety is rapidly decomposed in vivo to form a carboxylic acid compound.

Therefore, these ester compounds are excellent compounds that can be used as orally administered agents for the treatment of bacterial infections.

The compound represented by the general formula (1) obtained by the present invention and pharmaceutically acceptable carboxylic acid salts and acid addition salts (for example, mineral acid salts such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, citric acid) , malic acid, maleic acid, and other organic acid salts)
A composition containing as an active ingredient can be administered orally or parenterally, intramuscularly, cutaneously, or locally. The composition according to the invention may be solid or liquid and in the form of pharmaceutical forms commonly used in human medicine, such as tablets or dragees, gelatin capsules, granules, herbal medicines, injectable preparations, ointments, creams. Can be provided. They are manufactured by conventional methods. The active ingredients may include excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, an aqueous or non-aqueous vehicle, fats of animal or vegetable origin. It can be incorporated into substances, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

These compositions may also be provided in the form of a powder intended for immediate dissolution in a suitable vehicle, such as pyrogen-free, voluminous water.

The dosage may vary depending on the symptoms to be treated, the patient, the route of administration, etc., but the dosage is 0.259-420% per day when administered orally.
between 0.5f and 1f, and also by intramuscular route three times a day.

<Reference example 1. Urea 301 was dissolved in 250 m7 of dimethylformamide, heated to 100-105°C and stirred, and then methyl 4-bromo-3-oxo-(Z)-2-methoxyiminobutyrate 151 was added. After 20 minutes, add 200 mJ of ice water to the reaction solution.
After adjusting the pH to 1 to 8 with saturated sodium bicarbonate solution, ethyl acetate BOO+++/ was added and extracted. The aqueous layer was extracted once with a small amount of ethyl acetate, and the ethyl acetate layers were combined and washed five times with brine. This was dehydrated over anhydrous magnesium sulfate, concentrated under reduced pressure, dissolved in 70 ml of carbon tetrachloride, and left overnight in a trap at room temperature. The precipitated crystals were collected in a furnace to obtain 5.4f of methyl 2-(2-aminoxazol-4-yl)-(Z)-2-methoxyiminoacetate.

NMR spectrum (ODOI-, δppm) 3.88
(3” n e p OHs ) 3-97 (3-Hx
e a Ods ) 5, Jl (2H, brs, NH
2) 2-(2-ami/oxazol-4-yl)-(6)-
Methyl 2-methoxyiminoacetate 52 was suspended in 10 ml of dimethylacetamide, and chloroacetylchloride 2.
2d was added at room temperature with stirring.

After 30 minutes, 150 ml of ethyl acetate and 50 ml of water were added, and the aqueous layer was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate and stirred. Count the precipitated crystals.1. After washing with water and a small amount of ethyl acetate, the residue was dried to obtain 4.8f of methyl 2-(2-chloroacetylaminoxazol-4-yl)-(Z)-2-methoxyiminoacetate.

The ethyl acetate layer of the slurry was separated, washed with brine, dehydrated over anhydrous magnesium sulfate, concentrated under reduced pressure, and the precipitated crystals were washed with a small amount of ethyl acetate, resulting in an additional 0.5? The above compound was obtained.

NMR spectrum (DMSO-46δppm) 389
(e, 3H, 01(3)3.99(s, 3H,
-0H3) 4.38 (s, 2H, C Tomoe, at) The above 2-(2-chloroacetylaminoxazole-
Methyl 4-yl)-(Z)-2-methoxyiminoacetate 1
．． Suspend 27 F in 12 ml of ethanol and have a caustic strength of 85 cm! 1.27 g of J was dissolved in 12 ml of water and added thereto under ice-cooling and stirring. After 30 minutes, add 50 ml of ethyl acetate and 5 ml of water.
0ml was added to separate the liquids, and the aqueous layer was separated. This was converted into 11)182 using hydrochloric acid and extracted twice with 50 ml of ethyl acetate. These were combined, washed with brine, dehydrated over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was washed with isopropyl ether to obtain the title compound 1.12.

NMR spectrum (DMSO-46δppm) 3,93
(3H, θjOC month,) 8.5-10.5 (I H, br, NH) 11.85
(I H, brs・, 0OOH) <Reference example 2. Process for producing 4-bromo-3-oxo-(2-2-ethoxyiminobutyrate 20 t1 urea 50 t1 dimethylformamide 50 ml) in the same manner as in Reference Example 1 to produce 2-(2
-aminooxazol-4-yl)-(Z)-2-ethoxyiminoacetate methyl 52 was obtained as yellow crystals.

This was dissolved in 25 ml of dimethylacetamide, 2.23 mlJ of chloroacetyl chloride was added, and the mixture was stirred at room temperature for 30 minutes, water and aqueous sodium bicarbonate were added, and the mixture was further stirred for 10 minutes. The precipitated crystals were collected and washed with water and ethyl acetate. Suspend this in 60ml of ethanol and add 85% caustic potassium6.
? A solution of 6 Gml of water was added under water cooling and stirred for 30 minutes.

Add 100ml of ethyl acetate to the reaction solution, and adjust the pH to 2~ with hydrochloric acid.
It was extracted as 3. The aqueous layer was further extracted once with a small amount of ethyl acetate, and the extracts were combined, washed twice with brine, dehydrated and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was washed with ether and dried to obtain the title compound 3.2F.

NMR spectroscopy (DMSO-d6 δppm) 1.2
2 (3H, t, 0OH2C!H, 3, J=7Hz)4.
14 (2H, q, 0-0H2CH,,,J,,-
7Hz) 4.30 (2H, s, Oμ20A) 8.1 (IH mountain'fOI/ya) 9-11 (IH, br, NH) 11.1g (IH, bs, 0OOH) <Reference example 3
〉 3-oxo-(phrase-2-hydroxyiminobutyric acid t-buf
24.5 ff of 24.5 ff was dissolved in 200 mJ of dimethylformamide, 9.122 ml of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature. This is α-bromoisobutyric Pp-nitrobenzyl 40?
was added and stirred at the same temperature for 24 hours, then 1 t of acetic acid was added and water, water,
Wash twice with saturated aqueous sodium bicarbonate solution, saturated aqueous potassium bisulfate solution, and brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to give 3-oxo-(Z)-2-(2-1-nitrobenzyloxy). Carbonylpropyl-2-yl)oxyiminoacetic acid t-butyl 602 was obtained as an oil. This compound 30f was dissolved in 200mgK of methylene chloride, and 7.4% of bromine was added.
A solution of 50 ml of methylene chloride and 2 t3 mA of a 30% hydrogen bromide vinegar solution were simultaneously added dropwise to the mixture under heating under reflux.

The dropwise addition was completed in 3 hours, and after further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add this to 500 pr/! of ethyl acetate! The solution was dissolved in water and washed five times with brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Add this again to 250ml of ethyl acetate.
While stirring, 157 ml of diphenyldiazomethane was dissolved in 250 ml of ethyl acetate and added dropwise. This was concentrated under reduced pressure to obtain an oil containing diphenylmethyl 4-promo-3-oxo-(but-2-(2-1)-nitrobenzyloxycarbonylpropyl-2-yl)oxyiminoacetate. This was dissolved in 50 ml of dimethylformamide, and 105
℃ and added dropwise while stirring. Completed dropping in 30 minutes and added 1 more
After stirring for 5 minutes, pour into ice water and adjust pH using saturated sodium bicarbonate solution.
7-B and extracted with 1 t of ethyl acetate. After the aqueous layer was further extracted once with a small amount of ethyl acetate, the extracts were combined, washed five times with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oil obtained in this way was added to 1k of silica gel.
Solvent system n-hexane, ethyl acetate-(1:1) using p
The fraction containing the target product was concentrated under reduced pressure to obtain 2-(2-aminoxazole>-<z>-2
-(2-p-nitrobenzyloxycarbonylpropyl-2-yl)oxyiminoacetate diphenylmethyl 14.
8S' was obtained as a yellow foamy powder. .

NMR spectrum (CDC43δppm) 1-51 (
6Hjs, 0HsX2) 5.19 (2H, S,
OH bill No. 2) 16.30 (2H, bs, NH
2) 6.89 (IH, s, eel (@) 2) U The above compound 14.6 F in dimethylformamide 10
4.5 ml of triethylamine and 92 ml of trityl chloride were added to the solution, and the mixture was stirred at room temperature for 24 hours. Add 500 ml of ethyl acetate to the reaction solution, wash sequentially with brine and saturated potassium bisulfate aqueous solution, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and chromatograph using silica gel 5002 with a solvent system of n-hexane and ethyl acetate (2:1). Processed.

The fraction containing the target product was concentrated under reduced pressure to obtain 2-(2-tritylaminoxazole)-(Z)-2-(2-p-nitrobenzyloxycarbonylpropyl-2-yl).
Oximinoacetic acid 12.6 F was obtained.

This was dissolved in 150 ml of methylene chloride, 15 ml of trifluoroacetic acid was added under water cooling, and the mixture was stirred for 30 minutes at room temperature.

This was concentrated under reduced pressure, dissolved in 300 d of ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution, saturated aqueous potassium bisulfate solution, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Dissolve this in a small amount of ethyl acetate, add isopropyl ether to solidify, and calculate the number of units to obtain the indicated compound: 4°5? I got it.

NMR spectrum (cDct3δppm) 1.49 (6
H, θ, OH%)-) 7, 5~! '(l H, br, OOOH) <Reference example 4
> To a solution of 2-hydroxyimino-3-oxobutyric acid methyl ester 29.2.9 in 300 mt of dimethylformamide, potassium carbonate 41.59 and Ta-doamotoamide 40. After adding 9 ml of fluorine, the mixture was stirred at room temperature for 1.5 hours.

After adding 5QQmJi of ethyl acetate and filtration, concentrate under reduced pressure and chromatize the residue on a silica gel column (developing agent: ethyl acetate).
After purification with , crystallization with benzene, m, p114-115
25.9p of 2-carbamolylmethyloxyimino-3-oxobutyric acid methyl ester'i was obtained.

NMR spectrum CDMSO-d6δppm)2.
35 (3H,s,CshiC!O-)3.81(3H,
s.

-CooCH3) 4.65 (2H, e, 0O
H2CONH2)6.82~7-50 (br, 2
H, -0ONg2) Ester obtained above 10.1.
Acetic acid was added to the mixture, and 4.45 ml of sulfuryl chloride was added under ice cooling, and the mixture was allowed to stand at room temperature for 11 hours. After concentrating the reaction product under reduced pressure, silica gel column chromatography (developing agent: ethyl acetate) was performed. l, 4-10 low 2-
Carbamoylmethyloxyimino-3-oxobutyric acid methyl ester11. ll+j9' was obtained.

NMR spectrum (CDC13δppm)3,90
(3H, θ, -0000H3), 4.55 (2H
.

El, -0CH2CONH2), 4.
75 (2H, e, 0ICH2CO) 61-69
(br,2HI-coNH2) 3.0 g of urea and 5 mb'1 g of di,methylpolamide) 100°C to 110°
The solution of chloride 2.379 and methylformamide rmt obtained above was added dropwise over 71 hours while heating and stirring at C.C.

After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, cooled, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing agent ethyl acetate cyclohexane 9:1 to ethyl acetate methanol 95:5) and precipitated with ethyl acetate.
2-(2-aminothiazole-4-(ru)-(2)-2
-800 mg2 of carbamoylmethyloquiniminoacetic acid methyl ester was obtained.

NMR spectrum (DMSO-46δppm)3.
83 (3) (, day, -0000H3) 4.44 (2
H,s.

-0OH2CONH2) 6.40~Otsu45 (br
, 4 H, -NH2゜-cH2coNH2) 7.59
(t H, 8 Yomi) The above mixture was dissolved in 10 mt of the oxazole ester dimethylformamide prepared above, and 3.06 g of trityl chloride, 1.1 t of triethylamine, and !i'Y were added and stirred for 22 hours. Ethyl acetate was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate.
Concentrate under reduced pressure and chromatograph the residue on silica gel column chromatography (acetic acid,
Cyclohexane 3:T to 9:1) 19t Small 7L, 2-(2-)ditylaminoxazole-4-
yl)-(Zl-2 carbamoylmethyloxyiminoacetic acid methyl ester 2.77.9'Y was obtained.

NMR spectrum (cDcz, δppm)
3.82 (3H1s, -COOCHs) 4.6
1 (2H9s.

-ocH2coN6) 6.0~6.66 (br
, 3H, TrNfi--COη Rico2) 7.20
(Japanese, 1e HPl'+50-4JJ 2 ingredients) To 2.179% of the above 14% oxazole carboxylic acid ester, 2TrrttY of ethanol was added and stirred under ice cooling. To this stirred solution, water-cooled potassium hydroxide'i,
A solution of rr9 and 77 ml of water was added, and the mixture was stirred for 30 minutes under water cooling. The reaction solution was made acidic with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, concentrated, and then acetic acid ethane was added to precipitate 2-(2-1 literaminooxazol-4-yl)-(2)-2-carbamoylmethyloxyiminoacetic acid. . The precipitate P was collected and washed with a small amount of ethyl acetate to obtain the desired product 2.0.9.

NMR spectrum (DMSO-d6 δppm)
4.38 (2H, B, -QC!H2C0NH2)
4.60-545 (2H, br, -0ONH2)
6.68(T)T,br,TrNp-)7.22(15
H, day, ph5C-) 745 (+H, a, )
〒'zg)〈Reference Example 5〉 (1) Potassium carbonate r, 1sj and 6.159% prohargyl bromide were added to a solution of 2-hydroxyimino-3-oxobutyric acid methyl ester 509 dissolved in dimethylformamide 50ml t/C. After heating and stirring at room temperature for 3 hours, ethyl acetate was added, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.

After drying and condensation, it was purified by silica gel column chromatography (developer: n-hexane: ethyl acetate 95:5-8:2) to obtain 3-oxo-2-(2-propyn-1-yl)oxyiminobutyric acid s, s g Obtained.

NMR spectrum k (0DO13δppm)2.4
0 (3H, white, 0H3Co) 2y5? (IH,t
J Ushi 2-5 I(7,-CFT=CH)' 3.86
(3H, s, C00CHs)'L T 9 (2
H, d, J" 2.5 H7, -0H20miO')
i) (2) The above ester 509 was dissolved in 5 ml of acetic acid, 2.2 mA) of sulfuryl chloride was added under ice cooling, and ethyl acetate was added to reaction product 11, which was left at room temperature for 11 hours. In addition,
Washing with water, washing with a 7Kf sodium carbonate aqueous solution, drying with anhydrous sodium sulfate after washing with water, and condensation to obtain 4-chloro-3-oquin-2-(2-propyn-1-yl)oxyiminobutyric p 4.869't.

+31 4.86 g of this chlorester Y solution dissolved in 5 mi of dimethylformamide 105-11
Heat to 0°G and stir. 6.0g of urea and 6IIL7 of dimethylformamide! was added dropwise to the solution over 50 minutes. After the dropwise addition, react for 30 minutes at the same temperature, cool, add 7 ethyl acetate, wash with an aqueous sodium bicarbonate solution, wash with water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and remove the residue by silica gel column chromatography (developing agent: cyclohexane: ethyl acetate: 1:
1-2:8) to give 2-(2-aminoxazol-4-yl)-(2)-2-(2-propyn-1-yl)oxyiminoacetic acid methyl ester 1. Got to Oi'.

NMR spectrum (DMSO-d6 δppm)
3.0 (1H1tJ=2.5H2,0CH2C34)3
．． 83 (3H, Sun, -Coo Misaki 3) 4.78 (2H, d
.

(4) Oxazole acetate 800■ obtained above
593 μl of triethylamine and 1.59 μl of trityl chloride were dissolved in 5 mA of dimethylformamide.
After adding Y and stirring at room temperature for 11 hours, ethyl acetate was added, followed by washing with water, dilute hydrochloric acid pickling, water washing, and hydrogen carbonate solution. After washing with water, the mixture was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the 2-(2-
tritylaminooxazol-4-yl)-(katana-2-
(2-propyn-1-yl)oxyiminoacetic acid methyl ester 1.279'Y was obtained.

(5) 1.25 g of the above ester and 12.
A solution dissolved in 5+ILl was cooled on ice, and added to a solution of 1.2595 potassium hydroxide dissolved in 12.5 m of water.
The mixture was stirred for 40 minutes under water cooling. Make the reaction solution acidic with dilute hydrochloric acid,
It was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. After concentrating under reduced pressure, acetic acid ethane was added to make a powder, and P was collected.
．． 1 g of 2-(2-)literaminoxazole-4-
yl)-(Zl-2-(2-propyn-1-yl)oxyiminoacetic acid was obtained.

<Reference Example 6> Production of monoyl)-(2)-2-cyanmethyloxyiminoacetic acid 2-hydroxyimino-3-oxo-butyric acid methyl ester 8.31i, chloroacetonitrile 5.8g, potassium carbonate 10.3g The reaction, treatment, and purification were carried out in the same manner as in Reference Example 5 +11 to obtain 8.39 ton of 2-cyanmethyloxyimino-3-oxobutyric acid.

NMR spectrum/' (ODO/, δppm)
2-38 (3Hs lit,, CH39-) 3
82 (3H-e lC!0OOH,) 4.83 (2
H,s,OC! H2ON) The above ester t5.79Y
501 nt of carbon tetrachloride and 10 m of 1゜2-dichloroethane
The solution dissolved in A was heated and stirred at 85°C, and a solution of 5.1 ml of bromine and 5 ml of carbon tetrachloride was added dropwise over 730 minutes. The reaction mixture was cooled, added with ethyl acetate, washed with water, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. Concentrate silica gel column chromatography (developing agent cyclohexane:
Purified with ethyl acetate 2.1) to give 4-bromo-2-cyanomethyloxyimino-3-oxobutyric acid 15.4. pi'
I got it.

NMR spectrum (CDC7, δppm) 3.99
(3H, e+-Cooc) (3) 4.33 (2HI
s.

Br0JC-) 490 (2H-s, C+cH2
C! N) The above bromobutyric acid ester 15.4. After reaction and treatment in the same manner as in Reference Example 5 (3) using 2462 pieces of li+ and urea, purification with silica gel column chromatography (developing agent: cyclohexane × ethyl acetate = 25 nia 5), and ethyl acetate.
Recrystallized with a mixed solvent of benzene (1:2), m9149
1.909 g of 2-(2-aminoxazol-4-yl)-(Zl-2 cyanomethyloxyiminoacetic acid methyl ester at ~150°C) was obtained.

NMR spectrum (DMSO-d6δpp
m ) 3.86 (3H,e, -coocH5) -50
8 (2H1θ.

00H2CN) 7.00 (2H9e, H2N
) 7.89 (IHIIIll. Ding-) 1.136 g of the above obtained oxazole acetate,
Trityl chloride 2,835 and triethylamine 1.02 Jify' were treated and purified under counter pressure 1 in the same manner as in Reference Example 5 (4) to give 1.89 g of 2-(2-1 lythylaminoxazol-4-yl). -(2-cyanomethyloximinoacetic acid methyl ester) was obtained.

1.89 fl of the above ester and potassium hydroxide J-1,89
After reaction and treatment in the same manner as in (5) of Reference Example 5 using 9, FF [2-(2-tritylaminoxazole- 4-yl) -(Zl -' 2
-1159 pieces of cyanomethyloquiniminoacetic acid were obtained.

<Illusionary example γ> (1) 6.57 yen of 4-chloro-(sword-2-cyclopentyloxyimino-3-oxobutyric acid methyl ester) was added to a solution of 4.75 g of urea in dimethylformamide (20 ml) at 100 to 110°. Then, slowly drip it.

After stirring for 60 minutes, pour into ice water and extract twice with ethyl acetate. The extraction liquid is washed with saline, a 5% carbonate solution, and saline in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Remaining a Y, Wakogel c-10
Purify by column chromatography using 0 ml of silica gel. Ethyl acetate-cyclohexane (1:2), yield 3
1.73.9. m, pH 6-118°N MR spectrum (CDCl3 δppm)
t3~z, + (8H9m, CH2X4) 3.9
0(3H1θ.

eOCH,) 4.7~5.0 (1)(, m, H
) CI'7 ) 5.66 (2H, Sun, NF2)
7,35 (1H, 6, ~rOUCH) (2+2-
(2-aminoxazol-4-yl)-(katana-2-cyclopentyloxyiminoacetic acid methyl ester 1.71
g'k, suspended in dimethylacetamide C4ml) and filtered with water cooling. Add chloroacetyl chloroacetide (IJ) dropwise, stir at room temperature for 15 minutes, and add hydrogen carbonate to the reaction solution.
Pour into ice water containing umun. After extraction with ethyl acetate, the extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Yield 1.909 m, p 165-167O
NMR spectrum (yL acetone, δppm) 14~
L9 (8H1m, 4XC!H2) 3.84 (
3H# 8゜C02CH,) 4.40 (2H,e
, 0lOH200-)+312-(2-chloroacetylaminoxazol-4-yl)-(Zl-2-cyclopentyloxyiminoacetic acid methyl ester 1.90
1. Suspend in ethanol (1 sml) and cool on ice. 1.90 g of potassium hydroxide is dissolved in 19 ml of water, cooled on ice, and stirred for 40 minutes. Add ethyl acetate, The pH was adjusted to 1 with 10 dihydrochloric acid, and the organic layer was separated.The aqueous layer was extracted once with ethyl acetate, and all the extracts were combined, washed with brine, dried over anhydrous magnesium nitrate, and concentrated under reduced pressure to obtain the title compound. Yield 1.6G, !i1.m
p 158° (resolved) N M R spectrum x (DM
so-a6 δppm )1.3~2-0 (8H9
m 14 X OH2) 4.3 G (2H.

s #002)() Reference Example 8> 2-(2-chloroacetylaminooxazo-(1)2-
Hydroxyimino-3-oxobutyric acid methyl ester (8
7,! 9) and 2-fluoroether methanesulfonate (87 g) were dissolved in 7al'DMF (ioOrnt), and a small amount of K2co3 (1279) and crown-18 ether were added, and the mixture was stirred vigorously for 6 hours.
React at °C. The reaction solution was poured into cold dilute hydrochloric acid and extracted with ethyl acetate.

The extract is sequentially washed with water and saturated brine, dried over Glauber's salt, the solvent is distilled off, and the residue is distilled under reduced pressure.

2 of 9λ4g with bp81-83°C/H, Hg Y
-(2-fluoroethoxyimino)-3-oxobutyric acid methyl esterne was obtained.

(2) The 2-(2-fluoroethoxyimino)-3-oxobutyric acid methyl ester (sz, 4g) obtained above was dissolved in chemethylene chloride (SOOmJ) and dissolved in bromine (91,L9)' under heating under reflux. Methylene chloride (50
ml) is added dropwise while making sure that the color of bromine disappears in the reaction solution. After completion of the dropwise addition, the reaction solution was further refluxed for 30 minutes. Cool the reaction solution and add ether (
21) In addition, wash with water, then with saline, and dry with Glauber's salt. The bath medium was distilled off under reduced pressure to give 2-(2-fluoroethoxyimino)-3-oxo-4-bromobutyric acid methyl ester 13G! It was 9'24.

(3) Dissolve the 2-(2-fluoroethoxyimino)-3-oxo-4-bromobutyric acid methyl ester (5.6 g) obtained above in DMF (10 mA),
Urea (6,2 g) was dissolved in yr:oMy (z 5 mA) and slowly added to the solution heated in an oil bath at 105 °C for 45 min.
Drip over minutes. The reaction solution was cooled, poured into a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extracted solution is washed with saturated saline and dried with Glauber's salt. The solvent was distilled off, a small amount of benzene and isobrobyl ether were added to the residue, and the crystals precipitated. 3.2 fl Y of 2-fluoroethoxyimino)acetic acid methyl ester was obtained.

NMR spectrum/u (ODO/, Jusho ia'-DM
SO, δppm) 3.9 (3H, s, -CoocH3)
4-2 (2H, s.

OcH2) 46 (I H9m 9.-0-F',
) 5.0 (IH, m, -9-F) 6.2
．． (2fl, br, e, NH2) 7.3 (iH, s, H of oxazole) (4) 2-(2-
aminooxazol-4-yl)-(Zl-2-(2-
fluoroethoxyimino)acetic acid methyl ester (3,2
9) Dissolve in DMA (10 mA) and slowly add a solution of α-chloroacetyl chloride (1.88 g) in DMA (2 mA) dropwise under cooling without water. Stir vigorously for 20 minutes at room temperature. The reaction solution was poured into saturated sodium chloride water and extracted with ethyl acetate. The extract is sequentially washed with water and brine, and dried with Glauber's salt. The solution was distilled off under reduced pressure, and the residue contained a small amount of benzene and cyclohexane.
-yl)-C7J-2-(2-fluoroethoxyimino)acetic acid methyl ester was obtained.

NMR spectrum (0DO13 + small jic16-DM
EIO, δppm) 3-9 (3HIe, C!00C)i
s) 4-2 (2HI days.

C1-0H2CO-) 4.22 (2H, B,
-0-OH2-)S4.6(11(+m,O-F)5.0(I
H-m, -OF) meeting r, r (ia * s I oxazole 1■)
(5) 2-(2-chloroacetaminoxazol-4-yl)-(katana-2-(2-fluoroethoxyimino)acetic acid methyl ester (,2,13,9) obtained above
xo to an ethanol (25 ml) suspension of
Add an aqueous solution of HCl (20 rub) and react for 1 hour. Add 10 volumes of HCl to the reaction mixture to make it acidic and extract with ethyl acetate.

The extract was washed with saturated brine, dried over sodium sulfate, the solvent was distilled off, Sakura's chloroform was added to the residue, and the precipitated crystals were collected to give 2-(2-chloroacetylaminoxazole-4- yl)-(katana-2 (2-fluoroethoxyimino) vinegar [2,1,ji' missing.

NMR spectrum δppm (cncl, →-low 1i
a, -nMso )4-33(,4He br s 1
OIOH2CO+ OC! H2) 4.6 (IHlml
-6-F) 5.01(1)1. m.

-0-F) 7.71 (IH, s, H of oxazole) <Example 1> +112-(2-chloroacetylaminoxazole-
4-yl)-(Zl-2-methoxyiminoacetic acid 200
mq, was suspended in 2 ml of methylene chloride, and triethylamine 'I 7.2 TnLi '7 was added and dissolved under ice-cooling and stirring.

Add 107 m2 of oxalyl chloride to this, add 1 drop of dimethylformamide, and stir for 15 minutes L fv. - strength, diphenylmethyl 7-amino-3-acetoxymethyl-3-cephem-4-carboxylate 378 mI/
y<3 methylene chloride with 0.1 me of diethylaniline
mt and stirred under water cooling. The above reaction solution was added to this, stirred for 30 minutes, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate.
The solution was dissolved in Omx, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was chromatographed using 10I silica gel with chloroform and ethyl acetate (1:1) to obtain diphenylmethyl r-[2-(2-chloroacetylaminoxazol-4-yl)-(Z)-2-methoxy. 260 m9 of iminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate were obtained.

NMR spectrum (0DO13δppm)2.00
(3H, day, C dico) 3.47 (2H; b day, CH22 position) 4.00 (3H, θ, 0H50) 416 (2H, e, CH201) 4.90 (2H, ABq, 0H2-OAO , J=14
H2) 5.03 (II(, d, 6th position, J=5H7)5.
93 (IH, dd, 7th place, J: 5) (p(, 9I(z)
6.97 (I H, El, CH(@)2)7.3
1 (10H, s, Phenyl) 7.90 (IH, s
,'f(:Jr= )N~8.27(II(,d, NH7 position, J=9H2)10.
20 (IH+br, , NH) (21 The aforementioned diethylaniline r-[2-(2-chloroacetylaminoxazol-4-yl)-(Zl-2
-Methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate 2609 was dissolved in 2d of methylene chloride, added to 0.5 mAl of anisole 051 trifluoroacetic acid under water cooling, and removed from the cooling bath for 30 minutes.
The mixture was stirred at room temperature for several minutes.

When this is concentrated under reduced pressure and solidified by adding 2 ether, r-
[2-(2-chloroacetylaminothiazol-4-yl)-(Zl-2-methoxyiminoacetamide]-3-
Acetoxymethyl-3-cephem-4-carboxylic acid 20
0m9 was obtained.

This was dissolved in 2 ml of water along with 97.5 m9 of sodium bicarbonate, and 58.8 m9 of thiourea was added thereto, and the mixture was kept at room temperature overnight. This reaction solution was concentrated under reduced pressure and placed on a 10 g silica gel column using the solvent system.
Chromatography was performed using ethyl acetate, ethanol, and water (5:21), and the eluate was concentrated under reduced pressure to obtain the title compound 11.
3ml17 pieces were obtained as a solid.

NMR spectrum (Acetorie a6+D20
δppm) 2.10 (3H, 8, 0H4co) 3.57 (2H, ABq, (:!) T22nd place, J==
18H7) 4-00 (3H=s, OOHx)5
-06 (2H*ABq, CH20A(!, J
= 15 Hz) 5.30 (IH, d, 6th place, J = 5H
z) 5.92 (IH, d, 7th place, J=5Hz) 7.60
(IH, Japan, Tsu A) 4 <Example 2> Production method [112-(2-chloroacetylaminoxazole-
4-yl)-(Zl-2-methoxyiminoacetic acid 113■
and triethylamine 47.6 ml 9'l methylene chloride 1
1 drop of oxalyl chloride 54.3 my dimethylformamide. Diphenylmethyl 1-amino-3-methyl-3-cephem-4-carboxylate 160 myin, dietheraniline 0.1
The product was acylated and post-treated in the same manner as in Example 1 in 2 mg of methylene chloride.

Using silica gel 10,9Y and solvent system chloroform,
Chromatography with ethyl acetate (1:1),
The eluate was concentrated and diphenylmethyl r=[2-(2-
Chloracetylaminooxazol-4-yl)-(Z
)-2-methoxyiminoacetamide]-3-methyl-3
-Cephem-4-carboxylate 115Q? I got Y.

NMR spectrum (CDC136ppm)2.10
(3H+ s, C1(5)3, 28 (2H, bs
-C! H22 position) 3.98 (3H+ s -00H
4) 4.11 (2H, Japan, CH2C1) 5.03 (IH, d, 6th place Kei J: 5 H2) 5.81
(IH, dd, 7th place * J” 5 Hzs 9 Hz
)6-93 (I H= s -(!)((@ )2
)7.37(10H,e,Phenyl)7.
88 (IH, e, deshi) 8, 30 (I Hh a17th position NH,, l'=9Hx
)121 Diphenylmethyl r-[2-(
2-chloroacetylaminooxazol-4-yl)-
(Zl-2-methoxyiminoacetamide]-/3-methyl-3-cephem-4-carpoxyle-)11
0.25 m of anisole in 1 rnb of methylene chloride
A.) Treated with 0.25IrLt lifluoroacetic acid in the same manner as in Example 1, and ? -[2-(2-chloroacetylaminooxazol-4-yl)-3-methyl-3-cephem-4-carboxylic acid 74~ was obtained. This is kesa baking soda 40.6
II, thiourea 24.5 50% with Tn9
After stirring overnight in THF-water and concentrating the reaction solution, 10 g of silica gel was used, solvent system: ethyl acetate, ethanol, water =
(512:1) and the eluate was concentrated under reduced pressure to obtain the title compound 5B as a colorless solid.

NMR spectrum (Acetone-a4+D20δ
ppm ) 2.11 (3H, θ* aH) 3.53 (2H, ABq, 2nd position e 'J = 18 H2
) 4.02 (3H, θ, ○0H3) 5.21 (IH, a, 6th position, J = 5-Hz) 5.89 (
IH, d, 7th position, T = 5H2) <Example 3> (1) In 0.19-dimethylformamide under ice-cooling and stirring.

Add 0.23ml 1'i of phosphorous oxychloride and
The mixture was stirred for a minute. This was depressurized to remove excess oxygen, and 6 portions of ethyl acetate and 9 portions of 2-(2-chloroacetylaminoxazol-4-yl)-(Z)-2-methoxyiminoacetic acid 6541n were added at room temperature and stirred for 5 minutes. On the other hand, diphenylmethyl T=niamino-3-methoxymethyl-3
-Cephem-4-carboxylate hydrochloride 1. tzy and diethylaniline 0.93gY methylene chloride 10
The solution was dissolved in mA, cooled to -30°C, and stirred. The above-mentioned reaction solution was added to this, stirred for 1 s, and then concentrated under reduced pressure. The residue was dissolved in 150% ethyl acetate, washed successively with water, IN-hydrochloric acid, and 1M neutral phosphate buffer, dried over anhydrous magnesium sulfate, and then removed and concentrated under reduced pressure. The residue thus obtained was dissolved in 14 ru of dimethylacetamide,
Add 7'83 ml of N'-dibutylthiourea and stir at 55°C for 4 hours and 30 minutes. Ether acetate (150%) was added to the reaction solution, washed twice each with 1M neutral phosphate buffer and saline, and dehydrated over anhydrous magnesium sulfate. F was removed and the mixture was concentrated under reduced pressure. This was subjected to chromatography using chloroform and ethyl acetate (1:4) using silica gel Ragy7, and the eluate containing the target compound was concentrated under reduced pressure. )
-(Zl-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylate 60
I got 0■.

N M R,;<vector(cDc13 δT'T'
m) 3.18 (3H, e, 3rd place QC!H!l) 3,5
3 (2H, bs, CH22 position) 4.02 (3H
, s, OCH3 oxime) 4.25 (2)1,
S, cq, ocH5) 5.05 (IH, d, 6th position, J = 5H2) 5.50' (2H, be, NH2) 5,94 (l H, dd, 7th position + J = 5
Hz 19 Hz) 6.92 (IH・θ・Plastic 0) 2) 7.32 (11H, m, Phenyl, 'V"7CM
) 8.58 (IH, d, NH7 position, J = 9) (z) (
2) Diphenylmethyl 7-[2-(2-aminoxazol-4-yl L-(Zl-2-methquiniminoacetamide)-3-methoxymethyl-3-cephem-4
-carboxylate was dissolved in 6 ml of filled methylene, 3 ml of aniso-x was added to 3 ml of trifluoroacetic acid with ice-cooling and stirring, and the mixture was removed from the cooling bath and stirred at room temperature for 1 hour. Reaction liquid? The mixture was concentrated under reduced pressure, and the solidified Naze P was further dried by adding isobrobyl ether to obtain the title compound Y370.

NMR spectrum (Acetone-d4+D20δ
ppm ) 3.30 (3H, e, 3rd place QC!H5) 3,
60 (2H, bs 1CHZ 2nd place) 39.9 (3H
-e, 0CHz, oxime) 4.31 (2H,
8, aH2-c+cH3) 5.18 (IH, d, 6th position,
J = 5.5H7) 5.87 (IH, 6th, 7th place, J”
5.5 Hz) 7.59 (IH, 6, sound) <Example 4> Milk 2- (2--Chloracetylaminoxazole-4
-yl)-(Zl-2-methoxyiminoacetic acid 2QOm9
'll methylene chloride 2m/! Triethylamine 01 inside
Add 2 ml of chloride, dissolve, and prepare the acid chloride in the same manner as in Example 1 using 0.0 T ml of oxalyl chloride and dimethylformamitone.

This was concentrated under reduced pressure and dried, dissolved again in 5 ml of methylene chloride, and acylated in the same manner as in Example 1 using 228 μm of pivaloyloxymethyl 1-amino-3-methoxine phosphorus at -30°C, followed by post-treatment. A crude product of 4γa rruq was obtained as a brown solid.

To this was added 5 ml of 7 ml of VC, 294 ~ of dipylthiourea dissolved therein, and the mixture was stirred at 50°C for 3 hours and 20 minutes. Add 100ml of ethyl acetate to the reaction solution and add IM-
Wash three times with neutral phosphate buffer, dehydrate over anhydrous magnesium sulfate, and vacuum J8! Shrunk. Add this to 15 m of ethyl acetate.
The resulting precipitate was dissolved in YrQ and dried to obtain the compound 1941n17.

NMR spectrum/l-(CD(J, δppm)1
, 23 (9H, e, tBu) 333 (3H, day, ○OH3' 3rd position) 3.55 (2H, be, CH
22nd place) 4.03 (3H, Japan, OCR, oxime) 4.
33 (2H, 8, 0H20CH5) 5.05 (1H,
d, 6th place, J = 5.5H2) 5.62 (2H, be, N
H2) 5.7-6.2 (3H,m, -OCHO-, 7th position)
7.41 (IH, day, = )〈Example 5
(1) 2-(2-chloroacetylaminoxazol-4-yl)-(Z)- using Vilsmeier reagent prepared from dimethylformamide o,31- and phosphorus oxychloride 037- in the same manner as in Example 3. 2-Methoxyiminoacetic acid 1.06 p and diphenylmethyl 7-ami/-3-(1-#thi-1(H)-tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylate 19 was condensed in the presence of 0.61 ml' of diethylaniline and treated similarly to give diphenylmethyl 7-[2
-(2-chloroacetylaminooxazol-4-yl) -(Z) -2-methoxyiminoacetamide] -3
-(1-methyl-1(H)-tetrazol-5-yl)
1.65 g of a crude product containing thiomethyl-3-7-methyl-4-carboxylate was obtained as a brown solid. This was dissolved in 20-dimethylacemide, 1.5 g of N,Nl-dipylthiourea was added, and the mixture was allowed to stand overnight at room temperature. Ethyl acetate 200- was added to the reaction solution, washed twice each with 1M neutral phosphate buffer and saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. : 1). The fraction containing the target product was concentrated, and diphenylmethyl 7-[2-(2-aminooxazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3
-(1-methyl-1(H)-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylate 78
I got 0■.

NMR spectrum (ODOt5δppm) ~3.7
(2H, 0H 22nd position) 3J2 ('3H,s, N OH5) 3.90 (3
H, s, 00H3) 4~4.5 (2H, -0H
2-8-) 4.98 (I H, d, , '6th place,
J = 5.5 Hz) 5.59 (2H, bs
INH2) 5.88 (IH, dd, 7th place,
J = 5.5 Hz, 9 Hz) (2) Diphenylmethyl 7-[2-(2-aminoxazol-4-yl)-(Z)-2-methoxyiminoacetamide] obtained as described above -3-(1-methyl-1(H)-
Tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylate 360 rag anisole 3
1 ml of trifluoroacetic acid was added under water cooling, and the mixture was stirred at room temperature for 1 hour without cooling. This was concentrated under reduced pressure, solidified by adding isopropyl ether, P was removed, washed and dried to obtain the title compound 210i+g as a colorless amorphous isomer.

NMR spectrum (DMSO-(16δppm)3.
6G (2H, bs, 2nd CH2-3, all
(3H, s, NCH3)3.93 (3,H
2s'*0OH5)4.30 (2H,bg
, 0H2-8-)5, (Ill (I H, d
, 6th place, J = 5.5 Hg5) 5.70 (I H
, dd, γ position, J = 5.5, 9 H2) 6
．． 6-8.0 (4H, br, Hg2, -C
OOH, 0F5000H) <Example 6> 5195 g of 2-(2-chloroacetylaminooxazol-4-yl) -(Z) -2-ethoxyiminoacetic acid
To the mixture was added 50 mL of methylene chloride, 1 mL of methylene chloride, 28 BllIg of N-hydroxybenzotriazole monohydrate and 38811 i of dicyclohexylcarbodiimide at room temperature, and the mixture was stirred for 1 hour. Pivaloyloxymethyl 7
-Amino-3-methoxymethyl-3-cephem-4-carboxylate) p-) 1 g of luenesulfonate and 2 aom9 of diethylaniline were dissolved in 20-methylene chloride, and this was added to the above reaction solution at room temperature for 2 hours. After stirring, the mixture was concentrated under reduced pressure. Add 50-ethyl acetate to this and remove the insoluble matter.
After removal, 1% with 1N hydrochloric acid 3 times and 1% with 1M neutral phosphate buffer.
The mixture was washed twice, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.

This was dissolved into dimethylacemide 10-/g to give N, d-
Diptylthiourea 710'M9 was added and allowed to stand at room temperature for 15 hours. 100 ml of ethyl acetate was added to the reaction solution, washed successively with 1M neutral phosphate buffer and saline, dehydrated and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was chromatographed on a silica gel column using chloroform and ethyl acetate (1:4), and fractions containing the target product were collected and condensed under reduced pressure. This was dissolved in 5-ethyl acetate and dropped into 50 d of Ω-pentane with stirring to remove the resulting P precipitate, washed with rhopentane and dried to obtain 542 ml of the title compound as a colorless amorphous powder.

NMR spectrum (ODol-5δppm) 1.23
(9H,s,tBu)1.30(3H1tlO
CH2CH5, J=TH2] 3.30 (3H, s,
0OH5) 3.54 (2k king, bs, OH2
2nd place) 4.27 (2H, (L, 0OH20J,
J = 7 Hz ) 430 (2H + a *
an2-oca, )5.03(i I(,a, 6
J = 5.5 H2) 5.63 (2H, t'
s, Nl2) <Example 7> Il) -(Z) -2-Ethoxyiminoacetamide 2
-(2-chloroacetylaminoxazol-4-yl) -(Z) -2-ethoxyiminoacetic acid 260 mg
, N-hydroxybenzotriazole monohydrate 144r
sg and dicyclohexylcarbodiimide 24Qmg
was prepared in the same manner as in Example 6 using diphenylmethyl 1-amino-3-methoxymethyl-3.
-Cephem-4-carboxylate hydrochloride 420t1g
and similarly condensed in the presence of diethylaniline 14Qxg,
Processing gave a brown solid containing condensate. Add this to 20ml 1 IC of dimethylacetamide! 710 flll of N, W-diptylthiourea? After stirring at 50° C. for 2 hours, ethyl acetate was added and the mixture was treated in the same manner as in Example 6, and purified by silica gel chromatography. This was dissolved in 10-methylene chloride, 1 ml of trifluoroacetic acid was added under water cooling, and the mixture was stirred for 30 minutes at room temperature. Reaction t was reduced under reduced pressure, and inpropyl ether was added to solidify it.
Obtained.

NMR spectrum A/ (Acotone-d6 δp
pm ) 1.38 (3H, t, O(,!H20H
,, J == 7 H2) 3.211 (3H, s ,
OOH, ) 3.60 (2, H, bs, OH22
) 441 (2H, s, C1 (20085) 43
4 (7H, q, 0OH20H5, J” 7H
2) 5.19 (I H, d, 6th place, J = 5
5Hz) 53-6.9 (4H, br, Nl2.
0OOHX 2 ) 5.89 (I H, d-a,
7th place, J=5.5, 9 Hz) <Example 8> Production method of phosphoric acid trifluoroacetate (1) Dimethylpolamide 0.15d, phosphorus oxychloride 018-12-(2-1 lytylaminooxaso) -ru-4-yln-(Z) -2-(2-p-nitrobenzyloxycarbonylpropyl-2-yl)oxyiminoacetic acid 19 in the presence of diethylaniline 032-, diphenylmethyl 1-amino-3 -acetoxymethyl-3-cephem-4-carboxyle) 700 j
The mixture obtained by treating the reaction solution was subjected to chromatography on a silica gel column in the solvent system n-hexane, ethyl acetate = (1: 1>''Q), and diphenylmethyl 7- [2-(2-tritylaminoxazol-4-yl) -(Z+-2-(2-p
-nitrobenzyloxycarbonylpropyl-2-yl)oxyiminoacetamide]-3-acetoxymethyl-
3-cephem-4-carboxylate 11 was obtained.

NMR spectrum # (CDOL, δppm)1.
64 (3H, s, OR5) 1.67 (
3H,,,L)H3) 1!8 (3)i,s, 0J(300)3.
37 (2H, ABq, 2nd place 082, J-18
Hz)485 (2H-AB(L, CH20A
c, J = 14 H2) 4.87 (I H, a
, 6th place, J = 5.5 H2) 5.12 (2H
, s , L3H2@NO2)5.78 (I H,
a-d, 7th place, J = 5.5, 9 Hz)
6.37 (IH, bs, NIP-Tr
) “9 (IH, s” plate t@)z ) □, 9
゜7.61 (I H, d, NH7 position, J=9H2)
(2) Dissolve 1 g of the compound obtained as described above in vinegar M1G, add 10% palladium on carbon, and dissolve at room temperature and normal pressure for 30 minutes.
Time contact/! l! ll reduced. The catalyst was removed, 100 tnt of ethyl acetate was added, the mixture was washed three times with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

This was dissolved in ethyl acetate again, and diphenyldiazomethane was added until it became colored, and the mixture was concentrated under reduced pressure. Add this to silica gel 5
Diphenylmethyl 7-[2
-(2-)lytylaminoxazol-4-yl)-(
Phrase-2-(2-diphenylmethoxylponylglobyl-2-yl)oxyiminoacetamide]-3-acetoxymethyl-3-7-methyl-4-carboxylate 380
It's m9'14.

NMR spectrum k (UDC4δppm)168 (
6H, S, CH3X2 1.98 (3H, s,
(,H,Co)3.29 (2H,AB(L,
1st place, J=18H2) 4.89 (I H, d, 6
J = 5.5 Hz) 4.92 (2H, A
Bq, 0H20Ac, J == 14 H2)
5.89 (I H, dd, 7th place, J = 5
．． 5,9 H2) (3) The above compound 3801117 was dissolved in 3 ml of methanol, and formic acid 3- was added thereto at 50°C for 30 min.
The mixture was stirred for a minute. The reaction solution was concentrated, dissolved in 50% ethyl acetate, washed with ice-cooled aqueous N carbon dioxide, washed twice with brine, dried over anhydrous magnesium chloride, and concentrated under reduced pressure. This was carried out using silica gel 20F as the solvent system ethyl acetate, chloroform = (3
: 1) and chromatographically treated with diphenylmethyl 7-[2-(2-amitsuoxazol-4-yl)
-(Z) -2-(2-diphenylmethoxycarbonylpropyl-2-yl)oxyiminoacetamide" -3-
Acetoxymethyl-3-cephem-4-carboxylate 237 was obtained.

Dissolve this in methylene chloride 2-trifluoro: vinegar @
0.5- was added and stirred at room temperature for 1 hour. The reaction solution was concentrated and isopropyl ether was added to precipitate it, which was washed with ether and dried to give the title compound 120m+17.
I got it.

NMR spectrum pv (Acetone-d6δI)l
) m ) 1.64 (3H, s, OJ)
1.70 (3H, S, OH,)2.02
(3H, s, 0H400) 3.59 (2H
, b8.2 position 0H2) 494 (2H, ABq,
0H20Ac, J = 14 H2)5.13
(I H, d, 6th place, J = 5.5 Hz)
5.4-6.3 (5H, m, 7th place, Nl2, 0
OOHX2, 0F5Cool) <Example 9> (1) 2-(2-Chloracetylaminoxazole-
4-yl) -(Z) -2-cyclopentyloxyimino vinegar 6't316Q, 1-hydroxybenzotriazole 153+1111, methylene chloride 3m/! and dimethylformamide 1rn1. Add 206 μl of dicyclohexylcarbodiimide and stir for 45 minutes.

diphenylmethyl 1-amino-3-methoxymethyl-
3-cephem-4-carboxylate hydrochloride 4A7'm
Add to the above reaction mixture 149 mg of N,N-diethylaniline (dissolved in 3rn1. of methylene chloride. After stirring for 1.5 hours, set aside overnight. After concentrating under reduced pressure, add ethyl acetate to remove the insoluble The materials were separated and the P solution was concentrated under reduced pressure.The residue was purified by column chromatography using silica gel.Ethyl acetate-cyclohexane (1:1) Yield: 5
46■ NMR spectrum/l/ (ODOt3, δppm >
1.5-2.0 (,8H, m, 0H2XJ)3
°20 (3Hz 8 + ), 10CR,) 3.53
(2H, s, ""\0H2) - 4,20 (2H, s, 0tOH200) 4.26
(2H, s, person 0H2-0) 4-99 (I H
, dt J-5HZ, 6 H) Yu5.89 (IH, d-i, J=5H2,9H2,7
-H) 7.30 (10H, s, 0HPhz
)(2) Diphenylmethyl 7-[2-(2-chloroacetylaminooxazol-4-yl)-(Z)
-2-cyclopentyloxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylate 546 mg and NIN'-di-0-butylthiourea 29019'l dimethylacetamide smti dissolved,
After stirring at 40° C. for 8 hours, the mixture was left at room temperature overnight. Add ethyl acetate, then wash with brine, 5% hydrogen carbonate, IJum aqueous solution, and brine in this order, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was purified by column chromatography using silica gel. Ethyl acetate-cyclohexane (3:1). Situation 300 m, p, 150° (resolved) NMR spectrum (ODO4δppm) 1.4-2.
1 (8H#m, 0H2X4)3.21 (
3H, ts, input OCR,) 4.28 (2H, s
, person0H2-0-)4.8~5.1 (I H, m
, X)) 亙5.02 (IH, a, J=5H2,6-H)5.
35 (2H, br 8 , Nl2 )5.93 (
I H, dd, J = 5H2,9Hz, 7-
H) s9o (I H+ a * 'j020
Hg) 7.31 (10H, s, 0HPhz)8
．． 10 (I H, a, J = 9 H2,0ON
H) (3) Diphenylmethyl 7- obtained in the above reaction
[2-(2-aminoxazole-4-i#) -(
Z) 300 m9 of -2-cyclopentyloxyiminoacetamidoco-3-methoxy, methyl-3-cephem-4-carboxylene), 1 ml of anisole and 1
．． Dissolve 1 part of 2-dichloroethane, 17 parts of trifluoroacetic acid! Add and stir for 30 minutes. After reducing EE and concentrating, ether was added to collect P.

Collection 1219 Translation 9 NMR, z, vector CDMSO-46, δppm)
1.4~2-El (8H1m t 0H2X4)3
．． 23 (3H, 8,)VOCl2)4.5-4.8
(1)(,Ill, ,'lQ)513(ノH,
d, J=SH2, [1-H)5.73 (IH, d, -
d, J=SHz, 8H2,? -H)9.4
7 (I H, d, J == 8nz, UONH
2) Elemental analysis value: 21H24N5098F5, calculated value in °C: 043.52, H4,17, N 12.0
9 analysis value; f,! 43.62, H4,30,N
12.12 Example 10> 2-(2-chloroacetylamitumexazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetic acid 316jIg and 1-hydroxybenzotriazole 1
53117'4 Dissolve 4 ml of methylene chloride and dimethylformamide 1-, add dicyclohexylcarbodiimide 206Q'Y, and stir for 50 minutes. Piparoyloxymethyl 7-amino-3-medoxymethyl-3-cephem-4-carboxylate p-1, luenesulfonate S
13 jIg and N,N-diethylaniline 141g'
a? Dissolve in 3 ml of methylene chloride, add to the above reaction mixture, and stir for 2.5 hours. After concentration with EE, ethyl acetate was added, insoluble materials were separated from C1, and the C1 solution was diluted with saline, diluted hydrochloric acid,
After washing with brine in that order, drying with anhydrous magnesium 4A acid and concentrating under reduced pressure.

This crude product was dissolved in dimethylacetamide 6-
, 7-diΩ-butylthiourea'477m9 was added, 4
After stirring for 2.5 hours at 0 C, leave overnight at room temperature. Ethyl acetate is added, and the mixture is washed with brine, a 5% aqueous sodium bicarbonate solution, and brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel. Ethyl acetate-cyclohexane (3:1) Yield: 344rs9 Elemental analysis: Expressed as U25H, weak N509S.
2.0B, 8 5.53 analysis value; C52
, 17, H6, 14, N 11.81, B 5.5
9NMR spectrum/L/ (ODO23, δppm)
1.23 (9H, s, t-Bu) 1.4-2.
1 (8H, m, 0H2X4)3.32 (3H
, 13, 0M9)"' (2n, 6, /"
\0H2)4-30 (2H, s, person0H2-)4.
99 (IH, tl, J-5Htr, 6-H)5.
37 (2HIbr-8*IH2)5.115
(2H, s, 0020H2-) <Example 11> Production method (112-(2-chloroacetylaminoxazole-
4-yl) -(Z) -2-Cyclopentyloxyimino vinegar (ill 15g mg) and 1-hydroxybenzotriazole 77f1g'l were dissolved in methylene chloride 2- and dimethylformamide 0.51nt, and dicyclohexylcarbodiimide 103cm was added to the solution. Stir for 1 minute.Diphenylmethyl 7-amino-3-(1-methyl-IR-
Tetrazol-5-yl)thiomethyl-3-cephem-
Add 247++1 g of 4-carboxylate to the above reaction mixture and stir for 70 minutes. After concentration under reduced pressure, ethyl acetate is added and insoluble matter wP is determined. The first solution is washed with brine, diluted hydrochloric acid, and brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The crude product was dissolved in dimethylacetamide 3dK, N,I
Add 18111 g of -di-n-butylthiourea and leave at room temperature overnight. After further stirring at 50° C. for 4.5 hours, ethyl acetate was added, and the mixture was washed with brine, 5% hydrogen carbonate solution, and brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by column chromatography using silica gel. Ethyl acetate-cyclohexane (3:1)
Yield 2QAmg NMR, l', hectA/(('DOj5, δp
pm) 1.4~2.1 (8H1m + 4XOH
2) 3.75 (2H+s+””ゝcH2)4
．． 8-5.1 (I H, m, 'l:)3) above 5.01 (I H, d, J = S Hz, 6
-H) 5.19 (2H, br-s, NH2) 5.9
4 (1H1d-d, J-5H2,9H2,1-H)6.
89 (I H, s, Co20Hgu)7
．． 30 (10H, s, 0HP)1. )(2)
diphenylmethyl 7-[2-(2-aminooxazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetamide]-3-(1-methyl-1H-
Tetrazol-5-yl)thiomethyl-3-cephem-
200 ml of 4-carboxylate was suspended in 1 ml of anisole and 1,2-dichloroethane, and 1 ml of trifluoroacetic acid was added. Add and stir for 40 minutes. After concentration under reduced pressure, isopropyl ether was added to powder and P was collected. Yield 68
mg NMR spectrum CDMSO-06, δppm >1-
2-2-0 (8H, m, 0H2X4) 5.09
(I H, d9. J = 5Hz * 6-H)9.
39 (I H, d, J = 8H2,0ONH)
<Example 12> (1) 2- (2-tritylaminoxazole-
4-yl) -(Z) -2-carbamoylmethyloxyiminoacetic acid 2351. 92 mg of 1-hydroxybenzotriazole was dissolved in 5 rrL of methylene chloride and 0,5L of dimethylformamide, and 123.5 FFLL of dicyclohexylcarbodiimide was dissolved. 'f Add at room temperature, same temperature 1
．． Stirred for 5 hours. 7-amino-3-(1-methyl-1H-tetrazol-5-l)thiomethyl-3 in the reactant
-Cephem-4-carraboxylic acid bemphydryl ester (248 mg'l) was added and stirred at room temperature for 2 hours. After 1 filtration, the reaction product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (developing agent: benzene: ethyl acetate 1:1-ethyl acetate) to obtain 7-[2-(2-)
lythylaminoxazol-4-yl) -(Z) -
2-Carbamoylmethyloxyiminoacetamide]-
43 omg of 3-11-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester was obtained.

(2) Add methanol 5TRt and 3-formic acid to 430 mg of the obtained benzhydryl ester at 50-60℃ for 30 minutes.
The mixture was stirred for a minute. After concentrating the reaction solution under reduced pressure, it was made into a powder using ethyl acetate 9, and washed with a small amount of ethyl acetate.
I got 0■. 5-methylene chloride and 0.3-trifluoroacetic acid were added to 150 mg of the obtained amino acid, stirred at room temperature for 1 hour, concentrated under reduced pressure, and powdered with ethyl acetate. The powder was washed with a small amount of ethyl acetate and 7-[2-(2-
aminooxazol-4-yl) -(Z) -2-carbamoylmethyloxyiminoacetamidoco3-(
5sxipv of 1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid trifluoroacetate was obtained.

4.45 (2H*br8, -00H2-UONH
2) 5.09 (H* d-J = 5-OH2, 6th position)
5.75 (I H, (L(1, J = 5.0.8.
0 Hz, 7th place) 695-7.60 (4H, br
, 2'Tk, 0ONH,)7.47 (I H
+'s, ', >'') <Example 13> Chil-3-cephem-4-carboxylic acid triphium 2-42-
) lythylaminooxazol-4-yl-(Z)-2
-(2-propyn-1-yl)oxyiminoacetic acid 220
mg% 1-hydroxybenzotriazole 92w,y
Dicyclohexylcarbodiimide 123.5+iy
, and 7-amino-3-(1-methyl-11!-tetrazol-5-yl)thiomethy/L-3-cephemu 4
-Carboxylic acid benzhydryl ester 2ts*gw was used to react, treat and purify the same root as in Example 12 (1), and 7-
[2-(2-) I+ thylaminoxazol-4-yl) -(,z) -2-(2-propyn-1-yl)
Oxyiminoacetamitoco-3-(1-methyl-IH
-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 312Q was obtained.

The top is benzhydryl ester 312119. After reaction, treatment and purification in the same manner as in Example 12 (2) using methanol 5- and formic acid 3-, treatment with trifluoroic acid MO13me gave 7-[2-(2-aminooxazol-4-yl)
-(Z) -2-(2-propyn-1-yl)oxyiminoacetamide]-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid trifluoroacetate 13Qmy was obtained.

NMR spectrum CDMSO-d6 δppm)3
．． 43 (I H, t, J = 2.5 H2,-
0-;OH) 3.69 (2H, ABq, J: 1
2 H2, 2nd place 0H2) sudden 4.33 (2H, AB (L, J: 13 H2)
, 3' position (,!H2) 4.70 (2H, d, J
= 2.5 H2,O-(,!H20:(3H)5.1
2 (I H, d, J = 5.0 H2, 6th position)
5.75 (I H, d, a, J = 5.0, 8
．． 0 H2, 7th position) 9.68 L I H, (1, J
= 8.0 H2,-0ONH) (Example IA) Method 2-12-tritylaminoxazol-4-yl)
-(Z) -2-cyanmethyloxyiminotriacid 4
51 wag.
-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 4451j7
For conversion (・, reaction and treatment in the same manner as in Example 12 (1), 4
7-[2-12-tritylaminooxazol-4-yl)-(Z)-2-cyanomethyloxy 1-minoacetamide"-3-(1-methyl-1H-tetrazol-5-yl) ) Thiomethyl-3-cephem-4
-Carboxylic acid benzhydrylnisdel 184ra9f
I got 7.

The above ester IB4'M9, methanol 5-, formic acid I
After reaction, treatment, and purification in the same manner as in Example 12 (2), treatment was performed with 0.3 rag of trifluoroacetic acid, and 1-[2
-(2-aminoxazol-4-yl)-(Z) -
2-cyanomethyloxyiminoacetamide]-3-(
1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid trifluoroacetate.

NMR spectrum (DMSO-d-6δI)pm)3
．． 68 (2H, ABq, J = 18 H2, 2
position CH2) 3.93 (3H, s, NOH Otsu) 4.
32 (2H, 8Bq, J = 13 H7, 3
' position aH2) 4.68 (2H, s, -00H2
UN ) 5.13 (I H, 6,, J = 5.0
Hz, 6th place (jH) 5.17 (1h lda #
J = 5.0.9.0H2, 7th position OH) 9.54 (I
H, d, J”' 9.0 Hz, (3ONH
) <Example 15> 2- (2-tritylaminooxazol-4-yl)
-(Z) -2-cyanmethyloxyimino vinegar CI/
452 yng, 1-hydroxybenzotriazole 184 mg, dicyclohexylcarbodiimide 247
W1g, and 7-amino-3-methoxymethyl-3-
Using 415+I1 g of cephem-4-carboxylic acid benzhydryl ester hydrochloride and 150'I1 g of diethylaniline, the reaction was carried out in the same manner as in Example 12 (1), and the treatment was carried out,
? -[2-(2-tritylaminooxazol-4-yl) -(Z) -2-cyanmethyloxyiminoacetamide" -3-methoxymethyl-3-cephem-4-
Carboxylic acid benzhydryl ester 20Cmg'l;A
@is.

205m9 of the ester obtained above, 5me of methanol,
After reacting, treating and purifying 2 ml of formic acid in the same manner as in Example 12 (2), it was treated with 0.3-trifluoroacetic acid to form 7-[
2-(2-aminoxazol-4-yl) -(Z)
-2-cyanomethyloxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate 300,0009' was obtained.

NMR spectrum (CD30D δppm) 3.5
5 (2H, s, 2nd place 0H2) 4.30 (2H,
s, 3' position 0H2)5.09 (I H, (1, J
= 5.0 Hz, 6th position OH) 5.78 (1)
1, d, J = 5. OHz, 7th aH)
Example 16> (1) 2-chloroacetylaminooxazol-4-yl)-(z)-2-(2-fluoroethoxyimino)acetic acid (2SOmg) ff, dimethylformamide (0
, 5 ml) and methylene chloride (15 m/), and dissolved % N-hydroxybenzotriazole (14 ml) under stirring at room temperature.
Add 3iin and stir for 30 minutes. Next, dicyclohexylcarposiimide (DOO) (193,6) was added at room temperature and stirred for 1 hour. This reaction solution was added with diphenylmethyl 1-amino-3-methoxymeglu 3-cephem-4-carboxylate hydrochloride (380H&) and diethylaniline (127,5Q).
f > (4 ml) K dissolved solution was added at room temperature, stirred for 1.5 hours, and the precipitated insoluble matter was filtered,
Solution e was concentrated under reduced pressure.

Ethyl acetate was added to this residue, the precipitated insoluble matter was collected, and the P solution was concentrated under reduced pressure. Using 509 silica gel, the solvent system cyclohexane-ethyl acetate (2:3
), and diphenylmethyl 1-[2-(2-chloroacetylaminoxazol-4-yl)-(Z)-2-(2-fluoroethoxy)iminoacetamitoco-3-methoxymethyl- 3
-cephem-4-carboxylate 3331117 was obtained.

NMR spectrum A/ (ODO7,, δppm)3.
18 (3H, B, 0OH3)3.41 (
2H, s, 2nd position CH2) 4.12 (2H, 8,
01CH200-) 4°9B (I H・°・Blue) 4.98 (I H, d, 6th position H,, T = 4.
6 Hz) 5.82 (I H, q, 7th position H, J
= 4.6, 9.2 Hz) 6.85 (I
H, s, 9jipHλ)7.1~7.4 (15
H, diphenyl H) a, os (I H* d,
J = 9.2 Hz, NH) (2) The above diphenyl methyl ester (3331Ag) and di-Ω-butylthiourea (1501117) were dissolved in dimethylacetamide (1
, 5mA) and bath temperature 60°.

Stir for 10 hours. Ethyl acetate (60-) was added to the reaction solution, washed with phosphate buffer, then saturated saline, and dried over Glauber's salt. After concentrating the solvent, the remaining mass was treated with 50.9 silica gel in the solvent system cyclohexane:ethyl acetate (
Diphenylmethyl 7-[2-(2-aminooxazol-4-yl)-(Z)-2-(2-fluoroethoxy)iminoacetamide]-3-methoxymethyl- 306 ml of 3-cephem-4-carboxylate was obtained.

NMR, (Pect# (CD02g, δppm)3
．． 20 (3H, s, 0OH5)3.52 (2H
, s, 2nd place 0H2) 4.25 (4H, s,
/)-UH2-0 and 5=o-cu2-)1 4.70 (I H, rn, -o, )0-F 5.04 (I H, m + 1) 5.03
(I H, d, , J = -4, 4H2, 6th position H) 5
．． 22 (2)1, s, NJn5.92 (I
H, q, J = 4.4, 8.5 H2IT position H) 6.91 (I H, 3, -0HPhz) 7.2
-7.4 (10H, diphenyl H) 7.52 (IH
,s,,'oxazole H)0.13 (I H,
a, J = 8.5 Hz, -0ON
H-) (3) The above diphenylmethyl 7-[2-(2-
Aminoxazol-4-yln-(Z)-2-'
(2-fluoroethoxy)iminoacetamide]-3-
Methoxymethyl-3-cephem-4-carboxylate (306 my) was suspended in 1,2-dicylethane (1-) and anisole (1 ml) to 11%, and trifluoroacetic acid (1,2 m) was added under stirring under ice cooling. and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and diluted with ether (50 m
) 'Add Y to precipitate the target product. The resulting solid fiP
The sample was washed with ether and dried to give 1431 g of the title compound.
Obtained.

NMR spectrum (CD, 0OOD, , δI)I)m
)3-30 (3H'+ 8 # -00H5)3.
44 (I H, d, J = 18 Hz, 2
Position H) 4.46 (2H, m, =N-0-
OH2-)￥4.70 (1h, n]*”)5.
06 (I H, m, -tj-
F ) 5.22 (I H, d, J = 5 H
2nd, 6th position H) 5.94 (IH, q, J=5 +
10H2+ 7th position H) 7.84 (l H, 6,,
Oxazole H) 7.7-8.3 (3H, -or
s, -NH2, Coon)8.67 (I
R, d, J = 111 H2,0ONH-) <Example 17> +112 (chloroacetylaminoxazol-4-yl) -(Z) -2-(2-fluoroethoquinoid) vinegar 1fi (250Q) ftrni The mixture was dissolved in dimethylacetamide (0.75 mA) and methylene chloride (20 mA), and while stirring at room temperature, N-hydroxybenzotriazole (1ts 9) was added and stirred for 30 minutes.

Dicyclohexylcarposiimide (194s+y)
) at room temperature and stirred for 1 hour. A solution of diphenylmethyl 1-amino-3-methyl-3-cephem-4-carboxylate in methylene chloride (5 ml) was added to this reaction solution at room temperature and stirred for 5 hours. Below, Example 16 (
The residue obtained in the same manner as in 1) was treated with column chromatography using 65 g of silica gel in the solvent system cyclohexane-acetic acid (j/z), and diphenylmethyl 1-
[2-4z-chloroacetylaminooxazole-4-
yl) -(Z) -2-(2-fluoroethoxy)iminoacetamide]-3-methyl-3-cephem-4-
Carboxylate 422■ was obtained.

NIAR spectrum (fJDC4s rδppm)2
．． 10 (3H, s, 3rd place C!H5) 3.23 (
2H, s, 2nd place tJH2) 4.11 (2H, s
*0tOH200)4.17 (2H,s
, =N-00H2-)4.65 (I H,
m, -0-F)4.96 (IH,
m, -0-F)4.97 (IH, 6+
J = 4.3 H2, 6th position H) 5.80 (I H
, q, J = 4.3, 9.2 Hz, 7th position H) 6.86 (I H, s, -U Phz
)7.1-7.6 (10H, diphenyl H)7.8
2 (I H,s, oxazole H)8.14 (
I H, d, J = 9.2 Hz,
-0ONH-) (21 above diphenyl methyl ester (442■) and di-n-butylthiourea (2541)
1' was dissolved in dimethylacetamide (3-) and stirred at room temperature for 2 days. Thereafter, post-treatment and silica gel column chromatography were carried out in the same manner as in Example 16 (2), and diphenylmethyl ? -[2-(2-aminooxazol-4-yl) -(Z) -2-(2-fluoroethoxy)iminoacetamitoco-3-methyl-3-cephem-4-carboxylate 216 mF/ was obtained.

NMR spectrum (ODOt5.δppm) 2.12
(3H, s, 3rd place 0H5) 3.31 (2H,
s, 2nd place 0H2) 4.22 (2H, a, miN
-0-0H2-) ■ 4.66 (I H, m, -0-F) 5.01
(IH,m, -C-F)5.05(IHld,
J = 50H2, 6th position H) 5.42 (2H, br s
, -NH2) 5.91 (I H, q, J =
5.0, 9. OH2, 7th position H) 6.94 (I H,
s, caPhz) 7.15-7.6 (10H, diphenyl H) 7.49 (I H, B, oxazole H) 8.42 (I H, d, J = 9.0 H
2,-0ONH-) (3) Diphenylmethyl obtained above 7-[2-(2-aminooxazol-4-yl)-(z) -2-(2-fluoroethoxy)iminoacetamide]-3- Methyl-3-cephem-4-carboxylate (276 mg) was dissolved in 1,2-dichloroethane (
2-) and anisole (1 m7!), trifluoroacetic acid (1-) was added while stirring under water cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ether (SOm
g) to precipitate the target product. One portion of the resulting solid was washed with ether and dried to obtain the title compound 140t+9.

NMR spectrum/l/(OD5COCD5, δpp
m ) 2.17 (3H, s, 3-position OH,) 3.3
5 (I H, d, J = 18 H2, 2nd H
)3.66 (I H, d, J = 18 H2,
2nd place H) 431 and 4.55 (2H, 2X m * RONO0J-) 4JO (I Ham r 'j-F
)5.10 (I H, rn, -U -F)■
(5,20(I H, d, J = 5.0 Hz,
6th place H)S, 4~6.4 (3Ha br s *
NH2*CooH)5.86 (I H, q,
J = 5.0, 9.0 H,, 7th place H) 7.83
(2H* s-oxazole H)”5 (” *
d, J"' 9.0 H2, -CONI(-) <Example 18> 1(1) 2-(chloroacetylaminoxazole-4-
dimethylformamide (Z) -2-(2-fluoroethoxy)imino acid fp(25029)'
0.5m/ ) and methylene chloride (1sme>),
N-Hydroxybenzotriazole (1
43■) and stirred for 30 minutes.

Then dicyclohexylcarposiimide (194v+y
) at room temperature and stirred for 1 hour. Add diphenylmethyl T-amino-3-(1-methyl-1H
-Tetrazoyl)thiomethyl-3-cephem-4-carboxylic acid (420 shots) in methylene chloride (3-) was added at room temperature and stirred for 4 hours. Hereinafter, the residue obtained by the same treatment as in Example IB (1) was treated with 15 g of silica gel.
, column chromatography with the solvent system cyclohexane-ethyl acetate (1:4), and diphenylmethyl ? −
[2-(2-chloroacetylaminooxazole-4-
yl) -(Z) -2-(2-fluoroethquin)iminoacetamide]-3-(1-methyl-IH-tetrazoyl)-3-cephem-4-carboxyle) 483
I got i+9.

NMR spectrum (aDczS-δppm) 3.73
(2H, s, 2nd position OH,)3.79 (3H, a
, -N-CHs, )40~4.45 (6H, m
, J CH2-8-,-toQC! H2-, C1-(
4,70 (IH, m, -C-F) 4.85-5
．． 13 (2H, m, -0-F, 6th position H) warm 5.6 to 6.1 (I H, rn, γ position H) 6.89
(I H, s, Pkz4-)7.1-7.8(1
0,1 (, diphenyl H) 7.84 (I H, oxazole H) 8.111 (I H, (1, J = 9.
0 Hz, T position NH-) (2) Diphenylmethyl ? -[2-(2-/loloacetylaminoxazol-4-yl) -(Z) -2-(
2-Fluoroethoxy)iminoacetamito(1-methyl-IH-tetrazoyl)thiomethyl-3-cephem-4-carboxylate) (480 molecules) and di-0-dipylthiourine (1F5111?) were dissolved in dimethylacetamide (2 , 5 mZ), stirred at room temperature for 30 hours, and then heated to 40° C. for 3 hours. Example 1 below
After post-treatment and silica gel column chromatography in the same manner as in 6-(2), diphenylmethyl 7
-[2-(2-aminooxazol-4-yl) -(
Z) -2-(2-fluoroethoxy)iminoacetamitoco-3-(1-methyl-IH-tetrazoyl)thiomethyl-3-cephem-4-carboxylate 140m
I got g.

(3) Diphenylmethyl 1-[2-(
2-aminoxazol-4-yl)-(Z)-2-
(2-fluoroethoxy)iminoacetamide]-3-
(1-methyl-1H-tetrazoyl)thiomethyl-3-
Cephem-4-carboxylate (140 g) 1,
2-dichloroethane (1 ml) and anisole (1 ml)
), trifluoroacetic acid (17) is added while stirring under water cooling, and the mixture is stirred at room temperature for 15 hours. Concentrate the reaction solution under reduced pressure and add needles (50 m/h) to precipitate the target product. The resulting solid yP was collected, washed with ether and dried to obtain the title compound 113mQ.

NMR7, acetone rδpp
m) 3.75 (2H, 2-position OH2) 3.98 (3H, s, N-Cs5) 4.1-4.
4 (2H, m, /”0H2-8-)4.4 (
2H,s, =N-0-OH2-)4.67 (I
H, m, -C-F)5.14 (I H, m
, -〇 -F )5.16 (I H, d,
J = 5. OHz, 6th position H) 5.0 - 5.
55 (3H, br s, NH2, -0ON
H-)5.89 (I H, (1, J = 5.OH2
, 7-position H) 7.64 (I H, oxazole H) <Example 19 (1) 2-(2-chloroacetylaminoxazole-
4-yl)-(Z)-2-(2-fluoroethoxy)iminoacetic acid (250 μl) was dissolved in dimethylformamide (0
, 5m7 was bathed in methylene chloride (15m), and while stirring at room temperature, N-hydroxybenzotriazole (143
n9) and stir for 30 minutes. Next, dicyclohexylcarposiimide (193.1 g) was added at room temperature,
Stir for 1 hour.

Add pivaloyloxymethyl 1-amino-3 to this reaction solution.
-Methoxymethyl-3-cephem-4-carboxylate) p-) Luenesulfonate (450 mg) was mixed with diethylaniline (12 rmg) in methylene chloride (4
ml) was added at room temperature and stirred for 3 hours. The following results were obtained by processing in the same manner as in Example 16 (1).
Column chromatography treatment using silica gel of t751/ with solvent system cyclohexane-ethyl acetate (4:6). )
-2-(2-fluoroethoxy)iminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylate 33o+lIg was obtained.

NMR spectrum (ODOt5*δppm) 1.20
(9H, s, -6-〇(OH5)5)3.30
(3Hjs, -00H4)3・53 (2H,
s, 2nd position 0H2) 1-4.23 (4H, s, OH2-0, O2
0,H2O0-)4.27 (2H,s, =
N-0-OH2-)4.70 (I H, m, -1
j −F ) 4.9B (I H, m, −
0-F)5.00 (I H+ dr J =44
H2, 6th position H) 5.7-6.02 (3H, m,
7th position H, 0-0H2-0-)7.90 (I H, s
, oxazole H) 8.06 (I H,a,
J = 9.0 H7,7-NH-) (2) Pivaloyloxymethyl 7-[2-(
2-chloroacetylaminooxazol-4-yl)
-(Z) -2-(2-fluoroethoxy)iminoacetamide]-3-methoxymethyl-3-cephem-4-
(330■) and di-n-butylthiourea (140Q) were dissolved in dimethylacetamide (1.5m
l) and stirred at room temperature for 24 hours. Ethyl acetate (60 ml) was added to the reaction solution, washed with phosphate buffer, then saturated saline, and dried over Glauber's salt. After concentrating the solvent, the residue was subjected to column chromatography using 50.9 silica gel and ethyl acetate as a solvent to obtain the title compound 1.
I got 40Q.

NMR spectrum (ODO45, δppm) 1.22
(9HI S l −0CO”s)s >3.28
(3H, S, -00J)3.50 (2
H, s, 2nd place CH2) person

Claims (1)

[Scope of Claims] (1) General formula (1) [In the formula, R1 is a hydrogen atom, a linear or branched alkyl group which may have a substituent, an alkenyl group or an alkynyl group, a substituted represents a cycloalkyl group which may have a group or a heterocyclic group containing an oxygen atom, R2 represents a hydrogen atom or a methyl group which may have a substituent, and R5 & represents a hydrogen atom or a protecting group for a carboxy group. show. ] and pharmaceutically acceptable salts thereof. (2) General Formula - (1) [In the formula, R%-z represents a hydrogen atom or a methyl group which may have a substituent, and R) represents one hydrogen atom or a carboxy protecting group. ] to a compound having the general formula () [wherein R1 is a hydrogen atom, a linear or branched alkyl group that may have a substituent, an alkenyl group, or an alkynyl group that has a substituent] Rt represents a cycloalkyl group or a heterocyclic group containing an oxygen atom, and represents a protecting group for a hydrogen atom or an amyl group. ] or a reactive derivative thereof at the carboxy group is reacted to form a compound having the general formula [wherein R1, R2, R5 and Rs-z have the same meanings as above. [In the formula, R1, R2 and R% have the same meanings as above. show. ] A method for producing a cephem compound having (3) General formula () [In the formula, nl is a hydrogen atom, a linear or branched alkyl group that may have a substituent, an alkenyl group or an alkynyl group, or a cycloalkyl group that may have a substituent. R represents an alkyl group or a heterocyclic group containing an oxygen atom, R represents a hydrogen atom or a carboxy protecting group, R represents a hydrogen atom or a @ group holding an amino group, and R represents a methyl group having a substituent. A compound having the general formula [where Het represents a heterocycle containing 1 to 4 heteroatoms selected from a sulfur atom, a nitrogen atom, and an oxygen atom which may have a substituent. ] or pyridine which may have a substituent is reacted to form a compound having the general formula [wherein n 1 , R3 and R4 have the same meanings as above, and R% or pyridine may have a substituent. good sulfur atom,
1 to f4 fil selected from nitrogen atoms and O oxygen atoms
a heterocyclic thiomethyl group containing 1 heteroatoms or a group λ
Indicates a 1-pyridiniomethyl group which may have k. A cephem compound having the general formula [wherein R1, R3 and RSv - the same meanings as above], characterized by removing the protecting groups of the amino group and carboxine group as necessary. manufacturing method. (4) General formula [wherein R1 is a hydrogen atom, a linear or branched alkyl group which may have a substituent, an alkenyl group or an alkynyl group, a cycloalkyl group which may have a substituent R'1 represents a hydrogen atom or a methyl group which may have a substituent; RS represents a hydrogen atom or a protecting group for an amino group. ] or a salt thereof having the general formula [wherein R7 represents an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, or a cycloalkoxycarbonyloxyalkyl group, and Y represents a leaving group. ]
A general formula () characterized in that a compound represented by Show meaning. ] A method for producing a cephem compound having (5) General formula) [In the formula, R1 is a hydrogen atom, a linear or branched alkyl group which may have a substituent, an alkenyl group or an alkynyl group, a cyclo which may have a substituent. It represents an alkyl group or a heterocyclic group containing an oxygen atom, R2 represents a hydrogen atom or a methyl group which may have a substituent, and R%t represents a hydrogen atom or a protecting group for a carboxy group. ] and a pharmaceutically acceptable salt thereof as an active ingredient.