JPS5867697A - Aminoxazolyl compound and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention provides novel 7β-7-based oxazolyl acetyl-based compounds.
-3-77 emu 4-cal? All compounds and their production
Methods, pharmaceutical formulations containing the compounds and pharmaceutical manufacturing or pharmacy
The use of such compounds in the production of chemically active compounds, as well as new
This invention relates to a standard intermediate and a method for producing the same. The present invention relates to general formula (I);
9 is an amine group, protected ・A
() group, hydroxy group, protected hydroxy group, sulfur
group, protected sulfo group or mineral acid: % formula % (wherein R4 is hydrogen, lower alkyl group, substituted lower alkyl
group, cycloalkyl group, substituted cycloalkyl group, carba
(representing a moyl group or a substituted carbamoyl group)
Represents a substituted methylene group, R1h hydrogen, lower alkyl
group, lower alkoxy group, halodane or formula-Chi12 (
Shikinakamachi is a hydrocarbon group, a mercapto group, an esterification and a dopant group.
Tetoxy group or mercapto group, etherified hydroxy group
, represents an etherified mercazoto group or an 4-nio group.
), and Rs represents a kypw group or a protected
The 7β-amino group represents a xyl group]
Lylacetylaceno-3-cephem-4-caroon oxidation
Compounds, hydrates and salts of compounds of general formula (1)C), general formula
A method for producing the compound of (1), including a compound of general formula (I)
pharmaceutical formulations and pharmaceutical formulations or pharmaceutically active compounds;
Concerning the use of the compounds in the general formula for the preparation of. As used herein, groups such as lower alkyl groups, lower alkyl groups, etc.
1 group, lower 7 and koxy group, lower alkanoyl 1 group
The term "lower" used in
Contains up to 7, preferably up to 4 carbon atoms
It means tube. In the general formula (1), the index number first represents zero. When n is 1, the 1-oxide group is in the α-position or
May be present in the β-position, or 1-oxy in both positions.
It is a mixture of compounds with the general formula
Dihydroxalyl substituted with imino groups in isomeric form
exists as a group or as a mixture of both tautomers
It's okay. The position of equilibrium for both isomers is determined by temperature, solvent or μ
External (such as value) ・Depends on the meter. Honmei
In the specification, the adenoxazolisi group is simply the adenoxazolisi group.
It is based on sazori, but this is L nohydroidenoxolyl.
- Also includes tautomers. The general definitions above and below are used herein as follows:
It is preferable to represent something. The lower 7-kill group R1 contains 1 to 4 carbon atoms, e.g.
An ethyl group! p-pyl group, butyl group or especially methyl group
It is. The lower alkoxy group R1 contains 1 to 4 carbon atoms, e.g.
For example, ethoxy, globyl, and butoxy groups are particularly
It is a toxy group. Hallodan 8. is fluorine, bromine, iodine or preferably chlorine
It is. Esterified hydroxy or mercapto group8.
is an aliphatic carboxylic acid, an acyl group, e.g. an acetyl group.
aliphatic carnones substituted with lower alkanoyl groups such as
Hydrogenated with acid or phosphoric acid
xy or mercapto groups, such as lower alkanoyl groups.
oxy group, such as acetylated oxy group, lower alkanoyl group
alkanoyloxy groups, e.g.
or carbamoyloxy group or lower alkanoyl group.
Ilthio group, for example acetylthio group i9, is holζruthio
The group before is a carbamoyateo group. The esterified hydroxy group is converted into a Kusha mercarto group R2
is further esterified with N-pupil-converted carpatenic acid to form nine hydride.
The roxy group is a mercapto group. The N-substituent is, for example, a lower 7-kyl group, such as a methyl group or
or an ethyl group, or a radical, such as chlorine, or
Lower alkanoyloxy groups, e.g. alkoxy groups, substituted
A lower 7-hydroxy group, such as a 2-chloroethyl group or a Fi2
-acetoxyethyl group. Hydroxy group esterified with N-substituted carbamic acid
Or the mercapto group R2 is, for example, di-methidikasi/4%
4-yloxy group, N-ethylcarpamoisoxy group, N-
(2-Chloroethyl A/)-7 groups of pamoyloxy, N-
(2-ethoxyethyl)-carbamoyloxy group or t
iN-methylcarbamoylthio group. Etherified hydroxy group or mercapto group R2
is a hydroxy group etherified with an aliphatic hydrocarbon group or
or a mercapto group, e.g. a lower atom group having 1 to 4 carbon atoms.
alkoxy groups, such as methoxy or ethoxy groups, or
or a lower alkylthio group having 1 to 4 carbon atoms, e.g.
Methi is a thio group. The etherified mercapto group R2 is
HeteEllI, which binds to the sulfur atom of the mercapto group,
For example, 1 to 4 nitrogen atoms and possibly 1 p
Monocyclic Halt with additional oxygen and sulfur atoms
9 is a bicyclic heteroradical having 1 to 5 nitrogen heteroatoms
It becomes etherified. Etherified like this
The mercapto group is hereinafter referred to as [hete cyclylthio group l,]
write down heterocyclylthio group! The hetero radical in the middle is particularly aromatic.
The 5-membered monocyclic ring system has 6-membered Siade, Chiade, and Tet.
Laazo, Chiaday, Chiasiade, Chia, Oxaa
zo- or ox-diazocyclyl group, or tfI
- mineral aromatic or partially saturated, 11 to 5
or a bicyclic azo-, cyade, containing 6 31 atoms;
Triade, tetrazo- or
It is a ricy group. of the heterocyclic group in the heterosacrylthio group R□
Substituents include, for example, lower alkyl groups, such as ethyl groups, 1
-Globyl group, isotero I' group, 1-ethyl group, iso
Ethyl group is good for tart-butyl group, especially methyl group,
alkenyl groups, such as allyl or lower alkyl groups.
, for example, nine methyl groups or ethyl groups substituted with the following groups:
Is a group: hydroxy group, esterified and dotetraoxy
groups, such as lower arykyloxy groups, such as acetyloxy groups,
yloxy group, or 64dane, such as fluorine or salts
optionally in salt form, e.g. alkali metal salts, e.g.
Lower alkylphosphonyl group present in sodium salt form
, for example methylphosphonyl group or ethylphosphonyl group
group, di-lower alkylphosphonyl group, e.g.
Honyl group or diethylphosphonia group, optionally salt
forms, such as alkali metal salts or ammonium salts,
For example, the carfuxyl group present in the form of the sodium salt or
is a sulfo group, an esterified car? xyl groups, e.g.
Lower alkyl cycargenyl group, Hosomi ethoxycargenyl group
group, sulfamoyl group, amino group, lower alkylamine
a group such as a methylamino group or an ethylamino group,
di-lower alkylaelectrode] group, such as dimethylamino group or
For example, a diethyl group, an azyla group, etc.
An alkanoyl group, such as a d-7-V aryl group, and
is substituted with carmexyl group or hasidan, e.g. chlorine
lower alkanoyl groups, such as calxia
Amino group in cetidiamino group or chloroacetyl group. Such substituted lower alkyl groups include, for example, hydroxy lower
an alkyl group, such as a dimethyl group in hydro or a 2-hydroxy group;
Droxyethyl group, arythyloxy lower acyl group, e.g.
For example, a7tyloxymethy or 2-acetyloxy
ethyl group, halodane lower alkyl group, e.g.
thyl group, 2-chloroethyl a, 212.2- ) 9
p-roloethyl s or trifluoromethyl group, lower a
alkylphosphono groups on lower alkyl, e.g. ethylphosphono
Methyl group, di-lower alkylphosphono-lower alkyl group, e.g.
For example, diethylphosphonomethyl group,
Ki8/group, for example, carboxymethyl group
vl xyethylene group, sushiho lower acyl group, e.g.
Homeethyl group or 2-nulphethyl group, lower atomyl group
Cicalgenyl lower alkyl group, e.g. ethoxy lv&
2A/methyl group or 2-ethoxycar-nylethyl
Nulfamoyl lower alkyl group, e.g. sulfa
Moylmethyl group or 2-7-amoylethyl group,
Amino lower pulchyle group, such as aminoethyl group or
2-aminoethyl group, lower alkyl 72 lower alkyl
groups, such as methyl 72methyl group or 2-methyla
Minoethyl group, di-lower alkylamino lower alkya group,
For example, dimethylamino group or 2-zomethylamino group or
Noethyl group, lower alkanoylamino lower alkyl group
, for example, 2-acetyloxyethyl group, Cal? Kishi low grade
Based on the lower acronym of Alkanoi, e.g. 3-Kalge
oxypropionylaminoethyl group or 2-power group
Cyacetylaminoethyl group, or lower aura
Lucanoylua-based lower alkyl groups, such as 3-chlorote
Ropionylaminoethyl group or 2-chloroacetyl group
It is an aminoethyl group. Functional groups or modified, e.g. protected functional groups, e.g.
For example, halogens such as fluorine, chlorine or bromine, unoxidized
or a substituted amino group, such as an unsubstituted or lower amino group.
one or more alkyl groups, such as methyl or ethyl groups;
is replaced with two 9a () groups, such as d-amino group, methyla
mino group, or < is dimethylamino group, acylamino group
, for example, a lower alkakuyla 2no group, such as acetate,
or lower alkoxysulfonylamino group, e.g.
or halogen, such as chlorine or
a lower alkanoyl amino group substituted with a carboxy group,
For example, a 3-chloroglopionyl aino group or a 3-carboxylic group
Kingrobioni has amino groups, nitro groups, and hydroxyl groups.
groups, lower alkoxy groups, such as methoxy or ethoxy groups;
xy group, cal xy group, esterified cal xy group, e.g.
lower alkoxycarbonyl groups, such as methoxycarbonyl groups,
Nyl group or ethoxycargony group, optionally substituted
For example, 1 or 211 lower alkyl
Pamoyl group, such as methylcarpamoyl group or
or dimethyl casipamoishi group, or cyanogen group, and
A xo group or an oxide group can similarly be
It is a substituent of the heterocyclic group in the group R2. heterocyclic group represents a 5-membered aromatic monomer group
Icrylthio group 8. is especially an imidazolylthio group, e.g.
2-imidazolylthio group, triacylythio group, or
lower alkyl groups, such as methyl and/or phenyl groups;
A thio group on triacyly substituted with an R/ group, for example I H
-1,2,3-) lyazol-5-yl-thio group, 1-
Methyl-1) [-1,2,3-triazol-4-yl
Thio group, IH-1,2,4-)lyazol-3-ylthio group
O group, 5-methyA=-I H-1,2,4-) reary
, v-3-ylthio group or 4,5-dimethyl 4H
-1,2,4-) lyazole-3-y with thio group, tetra
Zolylthio group, e.g. IH-tetrazol-5-ylthio
or a lower alkyl group, such as a methyl group or
Ethyl group or substituted lower alkyl group, such as ethyl group
Sulfonomethyl group, diethylphosphonomethyl group, force pL/
To 1? xyethyl group, nulphomethyl group, 2-sulfoethyl group
group, 2-nomethyla-denoethyl group or cyanomethyl group
a tetrazolylthio group substituted with a radical, e.g. 1-methyl
Ru-IH-nato2zol-5-ylthio group, 1-ethyl
-iL<Ul-diethylphosphonylmethyl-IH-tet
Razol-5-ylthio group, l-carloxymethyl-I
H-tetrazol-5-ylthio group, 1-(2-car-
xyethyl)-1H-tetranol-5-y, a thio group,
1-Sulfomethyl-IH-tetrazo-5-ylthio
group, 1-(2-ethyl)-1H-tet2cu-
5-ylthio group, 1-(2-dimethylaminoethyl)-
1H-tetrazol-5-ylthio group or Fil-shi
anomethyl-IH-tetrazo-I&-5-ylthio group,
Thiazolylthio or lower alkyl groups, e.g. methyl
a thiazolylthio group substituted with a group, e.g. 2-thiazolyl
ruthio group or 4,5-dimethyl-2-thiazolyl group
o group, isothiazolylthio group, e.g. 3-inchazolyl group
ruthio group, 4-isothiazolyathio group or 5-iso
A thio group, a thiadiazolylthio group, or a lower atom
Thiadiazolyl substituted with an alkyl group, e.g. a methyl group
thio group, e.g. 1,2,3-thiadiazol-4-yl
Thio group, 1.2.3-thiadiazol-5-ylthio group
, 1,1゜4-thiazazol-2-ylthio group, 2-
Methyl-1,3,4-thiadiazol-5-ylthio group
, 1.2.4-thiadiazol-5-ylthio group or
is 1,2,5-thiadiazol-3-ylthio group, thia
triazolylthio group, e.g. 1,2.3.4-thiatri
Azol-5-ylthio group, oxazolylthio group or
Oxazo substituted with lower alkyl groups, e.g. methyl groups
a lylthio group, e.g. 2- or '5-oxazolyl
O group or 4-methyl-5-oxazolylthio group, low
Inoxa substituted with an alkyl group such as a methyl group
Zolylthio group, e.g. 3-methyl-5-isoxazoli
ruthio group, e.g. 3-methyl-5-isoxazolyl group
A thio group or a lower 7-group
Oxysiazolyl substituted with a kill group, e.g. methyl group
a thio group, e.g. 1,2,4-oxVdiazol-5-y
ruthio group or 2-methyl-1,3,4-oxadia
sol-5-ylthio, a group. Hetero all where the second group represents a 6-membered aromatic mononuclear group
Cyclylthio group R, al~3@ containing a nitrogen atom, e.g.
For example, 5,6-thioxatet2hydro-am-)riazini
Ruthio group or lower alkyl group, e.g., t if methyl group
, kal is a xyl lower a to a kill group, e.g. kashi is kishimethyl v
fI or sulfo-lower group, for example) tk home
5,6-thioxotetrahydro a substituted with thyl group
S-triazonylthio group, e.g. l- or 2-methyl
Ru-5,6-thioxo 1,2,5,6-thitrahydro
-1--triazin-3-ylthio group, 4-methyl-5
,6-thioxo 1,4,5,6-titrahydro a
--triazin-3-ylthio group, l- or 2-group
A/&Kishimechi I&-5,5-Le 1-Nakaso-1,2,5
,6-tet2hydro-aS-)riazin-3-ylthio
group, 4-cal is ximethypkf-5,6-thioxo 1
．． 4.5.6-Titrahydro-aS-triazine-3-
ylthio group, l-% or 2-sulfomethyl-5,6-
Thioxo 1,2゜5.6-titrahydro ag-)li
Azin-3-ylthio group Vi4-sulfomethyl-5
,6-diokidi-1,4,5,6-titrahydro a Hatake
-triazin-3-ylthio group. Bicyclic in which the heterocyclic group is aromatic or partially saturated
of,! Represents a group containing 5 or 6 nurenoko per unit
Heterocyclylthio! R, Fi, e.g. indolyl
substituted with thio group, lower alkoxy group, e.g. methyl group
indolylthio group, e.g. indol-2-ylthio group
or N-methylindol-2-ylthio group, iso
indolylthio group, e.g. isoindol-2-ylthio
a quinolylthio group, e.g. 2-14- or 8-
quinolylthio group, penzidendazolylthio group, lower alkylthio group,
Kyl group, e.g. methyl group or carxyl lower alkyl
penziyl group substituted with a carboxymethyl group, e.g.
Z mezolylthio group, e.g. 1-methyl-11-cal&-
? Dimethyl- or #1l- (2-carxyethyl)
-Penziken mesol-2-ylthio group, benzotria
Zolylthio group, lower alkyl group, such as methyl group i L
< $1 Carmexy lower alkyl group, e.g.
benzotriazolylthio group substituted with oxymethyl group,
For example 1-methyl- or ]-car-xymethyl-I
H-Payzo (:d]-)! J azole-51 ruthio group,
or especially the nato 2zo4pyridazinylthio group, lower alkyl
a group, such as a methyl group or an ethyl group, or an xyl group
, kal is a xy lower a-kyl group, e.g. kd xymethyl
groups, carbamoyl groups, lower alkyl carpamoyl groups, e.g.
Methyl carbamoyl group, di-lower alkyl carno
4-moyl group, e.g. dimethylcarbamoyl group, ami/
group, (ik It full * &7</ group, e.g.
) group, so-lower alkyl-ami7 group, e.g.
Substituted with a mino group or a noethyla group
lopyridazonylthio group, e.g. 8-methy to -18-ethyl
-18-car-xy-18-car-oxymethyl-13
-(2-cargaquicheti8)-18-carbamoyl-1
3-(N-methylcarbamoyl)-18-(N,N-di
Methylcarbamoyl)-18-amino, 8-dimethyl
Amino group or company 8-diethyl aonote 2zolo(1
, 5-b) pyridazon-6-ylthio group. The ammonio group R2 is a tertiary organic base, such as an aliphatic amino group.
or preferably from a heterocyclic nitrogen base;
Adding a nitrogen atom to the methylene group present at the 3rd position of the cephem skeleton
are connected through. For example, the positive charge of a quaternary phosphorus atom is
, a negatively charged hair located at the 4th position of the cephem skeleton.
neutralized by xylate groups. The ammonio group R1 derived from an aliphatic amine is e.g.
For example, tri-lower alkyl ammonio groups, e.g.
ammonio group or triethylammonio group. Derived from unsubstituted or substituted a3J1 nitrogen bases
The ammonio group R2 can be, for example, an unsubstituted or lower alkyl group.
groups, such as methyl or ethyl groups, lower alkenyl groups,
alyl groups, such as vinyl or allyl groups, calgexyl groups,
alkyl groups, such as carboxymethyl groups, lower alkyl groups,
Oxycargenyl lower alkyl group, e.g. methoxy k is
nylmethyl group, sulfo-lower alkyl group, e.g.
thyl group, amino lower alkyl group, e.g. 2-aminomethy
or di-lower alkyl to an amino-lower alkyl group, e.g.
For example, l substituted at the 2-position with a 2-dimethylaminoethyl group
-pyrazolio groups, such as 2-methyl- or 2-ethyl
Ru-1-virazolio group, 2-yv Ru or 2-vinyl
rub-1-bi-2zolio group, 2-calgexymethyl-l-pi
2zolio group, semethoxyka νginylmethyl-1-pyra
zolio group, 2-sulfomethyl-1-pyrazolio group, 2-
(2-aminoethyl)-1-virazolio group or 2-(
2-nomethylaminoethyl)-1-pyrazolio group
. The ammonio group R2 derived from the heterocyclic phonetic base is
, likewise for example 1-triazolio or lower alkyl
group, for example, methyl Go stone is based on methi, Cal is palm lower grade
Alkyl group, e.g.
alkyla lower alkyl group, such as 2-dimethylalkyl group,
a 1-triazolio group substituted at the 3-position with a noethyl group,
For example, 3-methyl-1-triazolio group, 3-kalgeki
Dimethyl-1-triazolio group or 3-(2-dimethyl
thylaminoethyl)-1-)riazolio group. A derivatives of unsubstituted or substituted heterocyclic nitrogen bases
The nmonio group R2 can likewise be, for example, a pyridinio group or a lower
alkyl groups, such as methyl groups, carbamoyl groups, lower
Alkylcarbamoyl group, e.g. methidicarbamoyl group
, hydroxy lower alkyl group, e.g. hydroxymethyl
group, lower akoxy lower alkoxy group, e.g.
thyl group, cyano lower alkyl group, e.g. cyanmethyl group
, carmexyl lower alkyl group, e.g. the force v is oxymethyl
group, sulfo-lower alkyl group, e.g. 2-sulfoethyl group
, kashiboxy lower aVkylene group, e.g. 2-cal-y-kylene group
sibini base, pvde xy lower alkylthio group, e.g.
Bakal is oxymethylthio group, thio group is pamoyl group, halo
Geno, e.g. bromine or chlorine, calgexyl group, sulfonate
Pyridine substituted with one or two groups or cyan groups
nio groups, e.g. lower alkyl birizonio groups, - e.g. 2
-13- or 3-methyl has a pyridinio group or 2-1
3-IL<H4-methylbilizonio group, carbamoylpi
lysinio group, e.g. 3- or 4-carbamoylpyry
dinio group, e.g. 3- or 4-methylcarbamoyl
Pyridinio group, di-lower alkyl force k / blue moylpyrizo
Nio group, N, t is 3-, XL< is 4-zomethycarbamo
ylpyridinio group, hydroxy lower alkylpyridinio group
groups, such as 3- or 4-hydroxymethylpyridiny
o group, lower alkoxy lower alkyl birizonio group, e.g.
4-methoxymethyl birizonio group, cyano lower alkyl
Rubirizonio group, e.g. 3-cyanomethylbilizonio group
, casyloxy lower alkylpyridinio group, e.g.
+dimethylpyridinio group, sulfo-lower alkylpyridinio group
Zonio group, e.g.
o group), Cal is xy-lower alkenylpyridinio group, e.g.
3-(2-car-xyvinyl)-pyridinio group, car
-xy lower alkylthiopyridinio group, e.g. 4-cal
l-xymethylthiopyridinio group, thiocayapamoyi
dinio group, e.g. 4-thiocarpamoy with pyridinio group,
A halo r nopyrinonio group, such as Id3-frho%- or
is a 4-promobirizonio group, a tvNxypyrizonio group
, e.g. 4-carboxyviridinio group, sulfopyridinio group
o group, such as 3-sulfopyridinio group, cyano 2 rizoni group
O group, for example 3-cyanobilizonio group, force V? Kishi low
alkyl-carbamoylpyridinio groups, e.g.
is a oxymethyl-4-carbamoylpyridinio group, an amino
nocarpamoylpyrinonio group, e.g. 2-71/-5-
Carbamoylpyridinio group, Cal? xycarbamoilpi
lysinio group, e.g. 3-car-xy-4-carbamoyl
Pyridinio group, cyanomethylpyridinio group,
For example, 3-cyano-4-trifluoromethylvirizonio
group or anocarboxypyridinio group, e.g. 2-
The anor-3-cal is now the sibirizonio group. The quaternary ammonio group R2 is preferably 2-lower alkyl
l-bi2zolio group, e.g. 2-methyA/-1-piz
zolio group, 2-cal is xy-lower a-kyl-1-birazoly
O group, e.g. 2-car-xymethyl-1-pisizolio group
, 3-lower alkyl-1-)riazolio group, e.g. tf3
-Methyl-1-) lyazolio group, pyridinio group or hydroxy group
droxy lower alkyl group, such as hydroxymethy group,
Carboxy group, carboxy lower alkyl group, e.g.
is a xymethyl group, a hydrogen group, such as a chlorine group or a bromine group,
or nine pyridinio groups substituted with carbamoyl groups, e.g.
For example, a 3- or 4-hydroxymethylpyridinio group,
4-car-oxypyridinio group, 3- or 4-car-
oxymethylpyridinio group, 3- or 4-chloropyri
Zinio group, 3- or 4-7” lomoviridinio group
is a 3- or 4-carnotylpyridinio group
. [R, #i, where the retained cal represents xyl group 1, below
Cal esterified with one of the carxyl anchor groups of
Xyl groups, especially those that can be decomposed under physiological conditions, are
is a group. Amino) group, hydroxymethyl, which exists in a preserved form is
In the methylene group A substituted with a sulfo group, the corresponding
Amine methylene group, hydroxymethylene group or sulfonate
The methylene group can be an amino group or a hydroxy group as described below.
It is supported by an S group or a sulfo group. The group of the formula -〇 -R4 is at the 5yn- (9 is z-) position and the 9th is
present at the anti-(t or E-) position, in which case the syn-
(or z-) position is preferred. -〇 -R4 is 5yn-
Directs toward the cephalosporin backbone in the anti-position and reverses in the anti-position.
Direction. The lower alkoxy group R4 has 1 to 4 carbon atoms.
Preferably, for example, the main methyl group, globyl group, methyl group or
Especially the methyl group. The cycloacyl group R4 has 3 to 8 ring members, especially 3 to 6 ring members.
For example, cycloalkyl, 7cyclo
pentyl group, cyclohexyl group or especially cycloglobin
It is a base. The substituents of the lower alkyl group and the cycloalkyl group R4 are
Especially Yu1llI! or etherified hydroxy groups, e.g.
For example, a lower alkoxy group, e.g. Jl lower alkoxy group, the first
class, secondary or tertiary electrogroups, such as amino groups or
Linear di-lower alkylamino group, radical lII! or with a blind functional group
modified, e.g. esterified, amidated or
l! and nine carboxy groups or sulfo groups, and optionally
ureidocar-nyl N-substituted with a cycloalkyl group
It is the basis. Distilled lower acyl group and Schiff-alkyl group R
4 is substituted with a carboxy group or a sulfo group
Preferably, in that case these groups replace the oxygen of the oxyino group.
Preferably, it is present on a carbon atom that is bonded to an atom. Substituted lower alkyl group or cycloalkyl group R4 company example
2-achinoethyl group, 2-dimethylannnoethyl group,
car2xymethyl group, x-iL< is 2-car2xymethythyl
group, 1-12- or F1a-cal is xyglog-l
-yl group, 1-1n<ti2-cal is xyzolof-2-
Based on A, 2-Power Hair-Kishiki Shigurogu 2-A based on #
'il- or 2-cal is oxycyclobutol-yl
group, as well as the corresponding lower alkyl substituted with a sulfo group.
and cycloalkyl. Cal in group R4 is an xy group or a sulfo group, for example, a lower alkyl group.
kill group, such as methyl ethyl group, or physiological
chemically degradable groups, such as piparoyloxymethyl
whether it is esterified with a group, the next is 3, primary or
is a secondary amine, e.g. heptano or di-lower alkyl
Amines, e.g. methylane, ethylane, dimethyl
Amidated with amine or diethylamine,
M*U Furthermore, it is also preserved in the regular use of Hokoshiki in the iJ story.
The 10-substituted carbamoyl group R4 is, for example, d-formula -C(=O)-N
HR, in which R is a lower alkyl group, e.g.
Methyl group, ethyl V group or 1- or 2-globyl group
, carboxy lower alkyl group, e.g. carboxymethyl
group, l- or 2-calge diethyl group or 1-1
2-or
The carboxy group is present in free form or
The fins are protected by carmexyl a-groups.
lower alkyl groups, such as methyl group, ethyl group,
or isoglobil group, or n- or tart-
esterified with ethyl group), sulfo-lower alkyl
groups such as sulfomethyl, 1- or 2-sulfo
Ethyl group, also Fil-12- or 3-sulfoethyl
group (in these sulfo lower acid dP groups)
The group may be present in the free O form or may be a conventional sulfo-protecting group.
or for example a lower alkyl group, e.g.
For example, it is ester-coordinated with a methyl group or an ethyl group.
), hydroxy lower alkyl groups, e.g.
group, 2-hydroxyethyl group or Fl2-i or 3
-Hydroxymethyl group (this is lanohydroxy lower
Is the hydroxyl group present in free form?
or protected with a commonly used hydroxy protecting group, or
For example, Fl is acylated, e.g. acetylated.
), amine lower alkyl group, e.g. 2-aminoethyl group
, 2- or ti3-aminoglovir group-*9ti2-
13- or 4-aminoethyl group (amino)
In class alkyl groups, the amino group is present in free form.
or protected with a commonly used 7-mino protecting group, or
or for example acylated, e.g. acylated),
Aryl lower alkyl groups, e.g. phenyl lower alkyl
The group, for example the benzyl group t*til-L<, is 2-phenylene
ethyl group, halo-lower alkyl group, e.g. fluoro
-, chloro- or zomu-mo lower alkyl groups, e.g.
2-chloropropyl group, round wire 4-chlorozotyl group, ali
a phenyl group, or a lower alkoxy group, e.g.
For example, methyl group, lower alkoxy group, such as methoxy group,
Halogeno, e.g. 1 to 3 substituted with chlorine or nitro groups
Represents the basis of Fueni. Functional groups present in the compound of general formula (1), especially calf
xyl group and amino group, as well as hydroxyl group and sulfate group
In some cases, penicillin chemistry, cephalosporin phosphorus chemistry
and protected by a commonly used protective compound used in peptide chemistry.
It's okay to stay. Such protecting groups easily cause undesirable side reactions, i.e.
For example, by solvolysis, reduction, and photolysis! lt
or can be desorbed under physiological conditions. This kind of protection and its removal! For example, 1973
Plenum bracelet of 2000, p.
``Grotectig Fist'' published by lenum Pr*ss)
Lucis in Organic Chemistry (Pro
te@tlve Groups ii* Orgmml
@Chemistry Month, 1965 p Ndon and Nie
- 7 Kaditsuk Breath (Aead・ml@P)
r・■) Published by Shi Tame Radar (8@hroder) and
Written by Sutamepuke (Lubk*) [De-4F Tights (Th
@P@ptid@s) J Volume 1 and 1974 sheet
Guorg Thieme Huzsylag of Utgart (
G@orgThl@m@Ver1mg) Published, 7-page
Houb@n-%V*yl
f'7mf'Le Organirashan Hei - (Mst
h@d@r d@rorganlsch@n Cham
l@) Described in J 4th edition, volume 15/1. Cal is a xyl group, for example Cal is a xyl group R3, and further 8
The xyl group present in the compound is usually in the nystylated form.
and the ester group is easily removed under mild conditions.
Can be detached. Carbo protected in esterified form
The nyl group is first esterified with a lower alkyl group, and this
The alkyl group is branched at the 1st position of the lower alkyl group,
or a suitable substituent at the 1st or 2nd position of the lower alkyl group
has been replaced with A lower alkyl group branched at the 1st position of the lower alkyl group
The tracked cal that has been told is pv group ij
, for example t@rt-lower alkoxycarzenyl group, e.g.
For example, one or
aryl methoxycarbonyl with two aryl groups
(The aryl group is an unsubstituted phenyl group or a lower aryl group, for example.
a group, e.g. t@rt-lower alkyle group, e.g. t
@rt-buty V group, lower alkoxy group, e.g. methoxy
groups, hydroxy groups, halogens, such as chlorine, and/or
represents a phenyl group substituted with one or more nitro groups)
, e.g. unsubstituted or substituted as e.g.
-noroxycar is a nyl group, e.g.
4-methoxybenzyl group, or 4-methoxybenzyl group
Xical? Nyl group or unsubstituted or
-substituted diphenylmethoxycarbonyl groups, e.g.
Basophenic methoxyl? Nyl group also Fi mino-4-
methoxyphenyl)-methoxycar-nyl group. low
The 1st or #i2 position of the class alkyl group is substituted with an appropriate substituent.
A protective compound that is esterified with a dangling lower alkyl group.
The straight carboxyl group is, for example, l-lower akoxy
Lower alkoxy V-nyl group, e.g. methoxymethoxy
Cal I group, 1-methoxyethoxy7 Cal I group, or
or 1-ethoxymethoxycarbonyl group, l-lower alkyl group
kylthio lower alkoxyka syNyl group, e.g.
methylthiomethoxycar is a nyl group or l-ethylthioethyl group
Toxic? Nyl group, aroylmethoxycal is el group (
Aroyl groups are unsubstituted benzoyl groups or e.g. bromine.
represents a benzoyl group substituted with a halogen), e.g.
For example, phenacyloxycar-nyl group 1 and 2-halodane
lower alkoxyl group, e.g. 2.2.2-)
IJ lloloethoxylic, ydisy group, 2-bromo
Ethoxycar♂yl group or 2-s-doethoxycarbo
It is based on d. The carboxyl group is an organic silyloxycar-14/-nyl group.
You may be kept under custody. Silyloxycarzenyl group
For example, tri-lower alkylsilyloxycargenyl group,
For example, trimethylsilyloxycarnonyl group. S
The silicon atom of the lyloxycar-el group is simply two lower atom
alkyl group, such as a methyl group, and a second group of general formula (1).
Molecular force J4/? Substituted by xyl or amino groups
1 Compounds having such a protecting group, which may be
For example, using trimethyldichlorosilane as the silylating agent,
It can be manufactured when used. A preferred protected carboxyl group is, for example, t@rt-
lower alkoxycasidenyl group, e.g. t.rt-butyl
Oxycal? Nyl group, unsubstituted or substituted as above
benzyloxycarbyl & e++ e.g. 4-ni
Tropencyloxycar-el group, or Zophenyl group
It is a methoxyfulgenyl group. Esterified carboxyls that can be degraded under physiological conditions
The group R1 is especially an acyloxy lower acykoxycal group.
and the acyl group is, for example, an organic carb-7 acid, especially a
Acyl group of lower alkane carboxylic acid converted by combination
or the acyloxymethyl group of the lactone
form a group. Such groups include, for example, lower alkanoyloxy lower alkyl
Coxycarginyl group, e.g. lower alkanoyloxymethane
Toxic acid 1%/M oxy to lower alkanoyl group
Ethical? secondary groups, e.g. acetyloxymethoxy
car-nyl group, piparoyloxymethoxycar is 2Jk
fl also bride 2-(gropionyloxy)-ethoxylic
-Nyl group, lower alkoxycar♂ dioxy lower alkoxy
oxycarnyl group, for example 1-(ethoxycargenyl group)
Kishi) - based on ethoxycardani @rt-! Chill
Oxycar is a nyl group, oxymethoxycar is a nyl group, amino
Lower alkanoyloxymethoxycaryl groups, especially α
-amino-lower alkanoyl-dimethoxycarinyl
groups, such as the glycyloxymethoxycarbonyl group, L-
Valyloxymethoxycarl group or L-leucyl
Oxymethoxycar-nyl group, and also phthalinoloxycar-nyl group
lugenyl group, such as 2-phthalinoloxcarmenyl group
, or an indanyloxycargenyl group, e.g.
Nyloxycar is the nyl group. An example is an amino group, such as a 7-mino group at the 2-position of an oxacylyl group.
For example, acylamino groups that can be easily decomposed, arylmethyl
lyamino group, etherified mercaptoamino group, 2-acyl
-lower alkaline 1-enylamino group or silylamino group
It may be protected by a foundation. In the acylamino group that can be easily decomposed,
91'' is an organic carmine with up to 18 carbon atoms.
acids, especially unsubstituted alkanes or halides.
Gen group or aryl group-substituted ayara group? hmm
removed or unsubstituted benzoyl or e.g. halogen,
Benzoic acid substituted with lower alkoxy group or nitro group
l# or the acyl group of carbonic acid half ester. like this
An acyl group is, for example, a lower alkanoyl group, e.g.
group, acetyl group, detake propionyl group, halogenated
alkanoyl groups, such as 2-halogenoacetyls, especially
2-chloro-12-f lomo, 2-iodo-12,2
,2-trifluoro- or Fi2,2,2-trichloro
For example, halogen, lower alkyl
benzoyl group substituted with koxy group or nitro group,
For example, benzoyl group, 4-chloroyx4isoyl group, 4-
methoxybenzoyl group or 4-nitrobenzoyl group,
or lower alkyl branched at the 1-position of the lower alkyl group;
Cal? Nyl group, or appropriately substituted at the 1st or 2nd position
and the lower alkoxy group is replaced by a nyl group. Lower alkoxycarb branched at the 1st position of the lower alkyl group
Nyl group is, for example, tert- (jt-class alkoxylic
group, such as ijt@rt-butyloxycargenyl group,
Arylmethoxy with 1 or 2 aryl groups
car is a nyl group (aryl group is preferably unsubstituted phenyl group)
or for example a lower alkyl group, especially a tert-lower alkyl group.
alkyl group, e.g. tert-butyl group, lower alkoxy
groups, such as methoxy, hydroxy, halogeno, e.g.
For example, fluorine substituted with 1m or more of chlorine and/or nitrochloride.
phenyl group), e.g. unsubstituted or substituted diphenyl
Lumethoxical? 2A/groups, e.g. benzhydrodioxy
Shikal? 2/l/group or no (diphenyl in 4-meth)
)-Methoki7-rumenishi group. Lower alkoxylic group suitably substituted at the 1st or 2nd position
A bunyl group is, for example, a tri-lower alkylsilyloxycarboxylic group.
♂Nyl group, e.g. trimethylsilyloxy-rumenyl group
, aroylmethoxycar-nyl group (aroyl group is unmonosubstituted)
Or for example HaC! Guns, e.g. benz substituted with bromine
Represents a zoyl group -j-), for example, phenacyloxy7cal
Genyl group, 2-hero-lower J-rekoxy group is a nyl group.
, for example 2.2. Z −) ') Chloroethoxylic
♂Nyl group, 2-promoethoxycargoniX group t or 2~
iodoethoxy 7-power IV canyl group, 9 is 2-(tri-substituted
silicondensation) - ethoxycarbonyl group ([substituents are
erically unsubstituted or lower alkyl group, lower alkoxy group, etc.
Replaced with cy group, aryl group, halodane or branched nitro group
aliphatic, araliphatic, alicyclic having 15 or less carbon atoms
Formula 19 represents an aromatic hydrocarbon group, such as an unsubstituted or
Lower alkyl group substituted as, phenyl lower alkyl
group, cycloalkyl group, 9 represents a phenyl group),
For example, 2-) 17 low N alkylsilylethoxycargeni
group, such as 2-trimethylsilylethoxycar? Second
group or 2-(11-7" methyldimethylsiliJ%/)-
Ethoxycar is a nyl group, maku is 2-triarylsilyl
Ethoxycarbonyl group, NJLd 2-) IJ
6 is a phenylsilylethoxycar-el group. Furthermore, an acyl group #i organic phosphoric acid corresponding to the amino-binding N group
, acyl groups of phosphonic or phosphinic acids, e.g.
lower alkylphosphoryl, e.g. dimethylphosphoryl
group, soethylphosphoryl group, c-n-zorobylphosphoryl group
Ru group or Noiso! robylphosphoryl group, dicycloal
Kylphosphoryl group, e.g. dicyclohequinulfonuphoryl
group, zophenyl V phosphoryl group, unsubstituted or e.g.
Phosphoryl group substituted with a*zophenyl lower alkyl group
, for example nobenzylphosphoryl group or di-4-nitro
Penzolphosphoryl group, phenyloxyphenylphosphoryl group
Nyl group, di-lower alkylphosphinyl group, e.g.
cyphosphinyl group, and further -)7elphosphinyl group
be. Mo/-, especially triarylmethylamine
In the arylmethylamino group, which is the aryl
The group is especially a phenyl group. Such groups are, for example, ben
Zorua-kenno group, diphenyla-7 group and especially Flithia 2
It is a radical. In the etherified mercaptoamino group, the ether
mercazoto group ti especially arylthio group or arylthio group
is a lower alkylthio group, and the aryl group is particularly unsubstituted.
substituted phenyl groups or lower alkyl groups such as methyl
or tert-butyl group, lower alkoxy group,
For example, methoxy groups, halogens, such as chlorine and /l or
=) It is a phenyl group which is Ii# at the o group. like this
An example of an adenohyro group is a 4-nitropherthio group.
. Lower alkyl to 2-acyl which can be used as an amino anchoring group
The acyl group in the l-enyl group KtIP is, for example, a lower acyl group.
lukanol I phosphoric acid, unsubstituted benzoic acid, or lower e.g.
Alkyl groups, such as methyl or t-rt-butyl
groups, lower alkoxy groups such as amethyst group, halogen,
For example, nine benzoic acid substituted with chlorine and/or nitro groups
Based on the reeds of
It is an acyl group of an alkyl half ester. This is more like Ami
The nohokoshi group is especially 1-lower alkanoyl-glob-1-ni.
-2-yl group, such as 1-acetylglog-1-yl group
-2-yl group, before 1-lower alkoxylic group
Rob-1-ene-2-(x4, e.g. ttfl-ethoxy
It is a cargenylzologul-l-en-2-yl group. The silylua group is, for example, trilower alkylsilylamino
group, such as the trimethylsilydiamino group. Syria
The silicon atom of the mino group is simply two lower alkyl groups, e.g.
methyl group, and general formula (1) 12) amino of the second molecule
The group may also be substituted by a xyl group.
. Compounds with such film-retaining groups are, for example, silylating agents.
When using dimethyldichlorosilane as
can be done. The amine group may be protected in the form of 111m.
. Anions include particularly strong inorganic acids, such as halogens.
Hydrogen acid anions, such as chlorine and bromine anions,
is an organic sulfonic acid, such as p-toenesulfonic acid.
This also applies to ions. Preferred amino binding groups include, for example, carbonic acid semi-esteric hair noacyl.
groups, especially tart-glutyl π radicals, are nyl groups, unsubstituted
or a penzoloxycarbonate substituted as e.g.
lugenyl group, e.g., t-benzyloxycaru
Nyl group or diphenylmethoxycargenyl group, 2-ha
rogene lower alkoxylic is a nyl group, e.g. 2,2.2
-) Lichloroethoxyca8/kenyl group, further trityl
group or formyl group. Hydroxyimino group, e.g. hydroxyimino group -N-
For example, the hydrogen group in 0-R4 (R4-hydrogen) is
a lower acykyl group substituted with a halogen
, e.g. 2,2-dichloroacetyl group, or especially deep
The acyl of the carbonate half ester mentioned in relation to the amino group
It may be maintained by a group i. Preferred hydroxy wire retention
The group is, for example, 2,2,2-trichloroethoxycar-nyl
group, further the above-mentioned (organosilyl group having a DM substituent, furthermore a capacitor)
Etherizable groups that can be easily eliminated, e.g. t@rt-lower
Alkyl groups, such as t@rt-butyl, 2-ox-1
or 2-thia-aliphatic or monolipidated hydrogen radicals, e.g.
For example, 1-lower aR/koxy lower alkyl group or 1-lower
alkylthio lower alkyl group, e.g. methoxymethyl
group, 1-methoxyethyl group, l-ethoxyethyl group, 1
-methylthiomethidi group, 1-methylthioethyl group or
1-ethylthioethyl group, or having 5 to 7 ring atoms
2-oxa-mayu is based on 2-thia-cycloalkyl,
For example, 2-tetrahydrofuryl group or 2-tetrahydride
ropyranyl group or corresponding thia analog, as well as unsubstituted
or a substituted l-phenyl lower alkyl group, e.g. unsubstituted
The substituted or substituted benzyl group is a diphenylmethyl group (
Phenyl groups include, for example, chlorine, lower alkaline
Koxy groups, such as methoxy groups, and /'*takenitro groups
has been replaced with A sulfo group, for example a sulfo group present in R1, is an aliphatic
, aliphatic, cycloaliphatic, aromatic or araliphatic
For example, a lower alkanol, for example, t@rt-!
tanol, or silyl groups, e.g. tri-lower alkoxysilyl
Preferably, it is esterified with a lyl group to form a i0 sulfo group.
is preserved in the same way as, for example, the caldfdP group. Salts of the compounds according to the invention are in particular compounds of general formula (1)
It is a pharmaceutically usable non-toxic salt of Such salts may be present, for example, in the compound of general formula (1).
acidic groups, e.g. Formed from xyl or sulfo groups
especially metal or ammonium salts, e.g.
Potassium metal salts and alkaline earth metal salts #Rie is sodium
salt, potassium salt, magnesium salt, calcium salt and
and ammonia or a suitable amine.
Ammonium salts, in this case aliphatic, cycloaliphatic,
Primary, secondary or tertiary of formula aliphatic or araliphatic
mono-, di- or polyamines, and heteromonic bases
The area is ravaged due to salt production. Such bases are, for example, lower a
Rukylamines, e.g. triethylamine, hydroxylamine
For example, d2-hydroxyethylamine,
Bis-(2-hydroxyethyl)-amine or tris
-(2-hydroxyethyl)-amine, salt of carlinic acid
For example, 4-aminobenzoic acid $-2-
2-ethyldiaminoethyl ester, lower alkylene aza
For example, 1-ethylbi(lysine, cycloalkylamine)
amine, or benzylamine to dicyclohexyl.
amines, such as N,N'-zopenzylethylenediamine
, and also pyridine type bases, such as pyridine, collidine or
or quinoline. Basic groups present in the compound of general formula (1), such as a
The scion group is an inorganic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or
is a suitable organic carmonoacid or diphonic acid, e.g.
Lifluoroacetic acid, and amino acids such as arginine and
Acid addition salts can be formed with lysine. The compound of general formula (1) contains several acidic groups, for example two
Ryxf xyl group, also #i several basic groups, e.g.
When two anno groups are present, mono- or /su
Can form salts. The compound of general formula (1) is small.
At least one acidic group, e.g.
at least one free basic group, e.g.
When the compound has a free amino group in the general formula (1),
1 can exist in the form of an inner salt, the general formula (1
), one acidic group and one basic group
is present in the form of an inner salt, with an additional acidic group and /l or a salt
Basic groups can be used, for example, as acid addition salts and/or base addition salts.
May exist. Do not use pharmaceutically unsuitable salts for isolation or purification.
You can also Only pharmaceutically acceptable non-toxic salts are used to treat
These salts are therefore preferred.
stomach. The functional group is present in free form,
Generally exists in the form of a physiologically decomposable substance.
Formula (1) (D compound and pharmaceutically usable non-toxic
A is a useful antibiotic substance, especially an antibacterial antibiotic.
It can be used as The functional group is present in free form, with the carboxyl group optionally
The general formula exists in the form of a physiologically degradable ester.
The compound (1) and pharmaceutically usable non-toxic salts are
It is a useful antibiotic substance, especially used as an antibacterial antibiotic.
can be used. For example, these compounds are tested in test tubes.
Gram-positive bacteria, including β-lactamase-producing strains,
Gram-negative bacteria, e.g. Gram-positive cocci, e.g. aureus
5taphylocoeus aur
@ws ) % t or streptococci, such as Streptococcus vulgaris
(Sir・pto@o*+ems pyog@n*s)
. Pneumonia chain ball i (str@pt@@@@@til pu
@um@nla*) or Stregsycoccus feca
- Squirrel (8tr@pto-coa@ua fa@cal
1m) or Gram-negative bacteria, such as Neisseria gonorrhoeae (N@iss
@ria go11errho@ae) about 0
．． 001 μmi 1 no ~ approx. 32 μmi/1111C) @ Small degree
In addition, Durham-negative bacteria such as Pseudomonas aeruginosa
M. naga*ruglnoam), S. influenzae
(Ha*mophilusinflu@nza・)Also
are intestinal bacteria, such as Escherichia coli (Eseh@rlehla
coil), Proteus (Protonsspp, ),
Pneumonia l1l (K1@+5lalla pn@umo
nias). Seventhia marcescens (S. rratta mar
e@-sceng) or Enterobacter cloa
Crab (Enterabaetor alomea*)
At a minimum concentration of about 0.005-132 μg/ml for K
It is valid. In vivo, when injected subcutaneously into mice,
Systemic infections caused by Gram-positive bacteria, such as Staphylococcus aureus
in the dosage range of about 143 to 55 I9/kII, and
Total infection by intestinal bacteria, such as Gram-negative bacteria such as Escherichia coli.
In the dosage range of about 0.63 to 3019/yu for personal infection
It is valid. The test report below contains general formulas based on the selected compounds.
Indicates the activity of the compound (1): test report ■, test compound 1.3-(1-methyl-IH-tet2zol-5-yl
thiomethyl)-7β-(2-(Z-methoxyiminoacetate)
amino acid)]-]3-cephemu-4-carboxylic acid sodium
salt (Example 5a), 2,3-(1-car?xymethyl-IH-tetrazole)
-5-ylthiomethyl)-7β-[2-[2-amino-
4-oxacylyl)-2-Z-methoxyiminoacetyl
Akenno]-3-cephem-4-carganic acid sodium salt
(Example 6m) 3, 3-(1-(2-dimethylaminoethyl)
)-1H-tetrazol-5-ylthiomethyl]-7
β-(2-(2-annor-4-oxacylyl)-2-Z
-Methoxyiminoacetyl-3-cephem-4
-force n/canoate hydrochloride example 7) 4, 3-[1-(2
-zomethylaminoethyl)-1H-tetrazole-5-
ylthiomethidi]-7β-(2-(2-amino-4-o
xacylyl-2-1-methoxyii 2 noa dragon chi νa (])
-]3-cefe5-4-carunic acid dihydrochloride, Example 7')
5, 3-(4-carbamoylgiridiniummethyl)-
7β-[2-A-Treasure No 4-Oxacylyl]-2-2-Me
Toxiiminoacetylamino]-3-cephem-4-power
syz xylate (Example 8) 6.3-acetoxymethyl
7β-(2-(2-annor-4-oxacylyl)-2-
Z-hydroxyiminoacetyl-3-cephem
-4-Carboxylic acid sodium salt (Example 9) 7.3-acetoxymethyl-7β-(2-(2-amino
-4-oxacylyl)-2-Z-2-(2-calI3ξ
xyzolo-f-2-yloxyimino)-acetylamino
Co-3-cephem-4-forcejl//l/umium thenate salt (
Example 101) 8.3-acetoxymethyl-7β-(2-(2-amino
-4-oxanolyl)-2-Z -(2-t@rt-bu
Chiloxycar I-Nil! log-2-yloxyimino)
-acetyladeno]-3-cephem-4-carboxylic acid (
Example IQb) 9.3-pyrinoniomethy+-7β-(2-(2-anno
-4-Okienshiri arrangement)-2-Z-(2-Cal is Kishi!Ro
Zo2-yloxyden))-acetyl-acetyloxydenno]-3-
Cephem-4-cal is medium sylate sodium salt (example) 1
) 10.3-(4-carbathylpyridiniomethyl)-7
β-(2-(2-annor-4-oxacylyl)-2-Z
-(2-Cal material xypro!-2-yloxyinno)-
7 cetyl akenno]-2-cephem-4-cal is xylene
sodium salt (Example 12) 11.7β-[2-(2-a
mino-4-oxacylyl)-2-Z-(2-carboxy
Prog-2-Iruo diimino)-7+Chirua ζノ]-
3-cephem-4-carboxylic acid sodium salt (example) 3a
)】2,7β-[2-(2-amino-4-oxacylyl
) -2-Z -(2-t@rl-Putilo Imashikaruge
Nylprop-2-yloxyimino)-7cetylamino
]-3-cephem-4-carboxylic acid sodium salt (example)
3b) 13.3-acetoxymethyl-7β-[2-(2-ami
No-4-oxacylyl)-2-2-methoxyiminoacetate
Chiru7kenno]-3-cephem-4-carboxylic acid sodium
Mu salt 111 M) 14.7β-[2-(2-ainor4-oxyfsilik)
-2-z-methoxyiminoacetylamino]-3-ceph
em-4-carboxylic acid sodium salt (Example 2 Hatake), 15.7β-[2-(2-amino-4-oxacylyl)
-2-2-methoxyquinoacetyl 7ono]-3-ceph
em-4-carboxylic acid hivaloyloxymethyl ester
(Example 3), 16.3-(3-chloropyridiniomethyl-7β-(2
-(2-amino-4-oxacylyl)-2-2-methoxy
Shiiminoacetyl 7-)-3--b7-5-4-cal
-xylate (Example 15), 17.3-(4-caru)
ratepyridiniomethyl)-7β-(2-(2-aono
-4-oxacylyl)-2-z-methoxyiminoacetyl
-3-cephem-4-carxylate
Liumanawa (9Ii] 6), 18.3-carbamoyloxymethyl-7β-[2-(
2-amino-4-o-sazolyl)-2-z-methoxyi
Mino-7cetyl74-3-cephem-4-carboxylic acid
Sodium salt (Example 17 Hatake), ■, Experiment A, the antibiotic activity of the test compound in vitro was determined by Erickson (
Erl@asom, H,M, ) and Cialis (!
! h@rris+s, c,) (1971), A@t
a Path, Ml*rob. 8@and, S@@tion B58tspp1.
N@, D by agar dilution method according to Volume 217.1-90
The growth of the test organisms was measured at 1° in OT agar.
For each test, set the minimum concentration that suppresses the effect (MIC==minimum inhibitory concentration).
The test compounds are listed in Table 1 in Yu/d. B, #C)! iPF, total in MF2 mice
Zlk (Zlk) has demonstrated in vivo chemotherapeutic activity against human infections.
, O) et al. (1979) Drugs Ixptl,
C1t1. R@m, Volume 5 45-59 by negative method
I measured it. Measured ED5° values for some microorganisms (matrix)
Subcutaneously inject 1 volume of the substance (v/#) into the
Table 1: Antibiotic activity (in vitro) m0g--E*No Table 2: Chemotherapy activity (in vivo) n0g, e test The compound of general formula (1) whose functional group is preserved without any functional group is
The group is present in free form or 4-cardoxy
Calcium radicals can be decomposed under physiological conditions.
medium for producing a compound of general formula (1) existing in the form
Used as an intermediary. In particular, the present invention is applicable when n represents 0 and R is hydrogen or lower a
Kill groups, e.g. methyl groups, lower alkoxy groups, e.g.
Toxy group, halodane, e.g. chloride, has the formula -CH2-R
, 8. is a lower alkanoyloxy group, e.g.
For example, acetoxy group, carpamoyleoxy group, N-lower a
cypamoyloxy group, 5-membered or tia-membered aromatic
Aromatic monospecific thiade, triazo, tetraaza, thiaza
-, cyanoazor, thia-, oxazo- or oxazo-
Sazoaza-cyglyl groups, e.g. thiazolylthio groups, e.g.
For example 1) I-1,2,3-triacyofure 5-i
nithio group, nato2zolylthio group, e.g. l■-tetrazo
-5-ylthio group, thiazolylthio group, thiadiazole
Lylthio group, e.g. 1,3,4-thiadiazole-5-
Nithio group, oxazolylthio group, oxadiazolylthio group
o group or 5,6-thioxotet 2hydrorotri
azinikethio groups, such as unsubstituted or lower alkyl groups,
For example, methyl group, di-lower 7 and kylamino lower alkoxy group
, for example, a methyl group, < is a 2-S7 method.
Diaminoethyl group, sulfo lower alkyl group, e.g.
Sulfomethyl group, Cal/Co lower alkyl group, e.g.
w & xymethyl group, amino group, car xy lower alkyl
Amino group, such as 2-calkeya ethyl amino group or
5,6-dioxo-1 substituted with carnomoyl group
, 2,5,6-tetotsuhito"lowrotriazine-3-
Ilthio group or #i5.6-nooxo1.4,5
．． 6-tetrak)'a-as-)rianon-3-ylth
or ammonio group, e.g. 2-lower alkyl group
l-virazolio group, e.g. 2-methyl-1-virazolio
group, 2-carloxy lower alkaline group, l-virazolio group,
For example, 2-carmexymethyl-l-bi2zolio group, 3-
Lower alkyl-1-)riazolio groups, e.g. 3-methyl
-1-triazolio group, pyridinio group, hydroxy lower
Alkyl groups, such as hydroxymethyl groups, cal? xy group
, carn 2xy lower alkoxy group, e.g. carboxymethy
a halodane, such as chlorine or bromine, or carbon.
a bilinonio group substituted with a rubamoyl group, e.g.
or 4-hydroxymenalbilinonio group, 4-cal is
Xypyridinio group, 3- or 4-kaya? oxymethyl
pyridinio group, 3- or 4-chloropyridinio group,
3- or 4-bromopyridinio group or 3-it,
<Fi4-cal-domoylpyridinio group, R is
The carmexyl group ti has a decomposable force k under physiological conditions.
I xyl group, e.g. acyl Voxy lower alkoxyka A=
/2 groups, e.g. lower alkanoyloxy lower alkoxy
cycargenyl group, e.g. lower alkanoyl oxymethoxy
Cycarmenyl group or lower alkanoyloxyethoxy
Capvsle nyl group, e.g. p/40yloxymethoxy
7cal is a nyl group or Id2-Cf robionyloxy)-
Ethoxycar is a nyl group, or a lower alkoxycar- nyl group.
lower alkoxycargenyl group,
Toxicayabonyloxy)-ethoxycar-nyl group
ijt@rt-butyloxycar is nyloxymethoxy
When a group is represented by a group, a person is an amine group, an aminomethylene group.
group, hydroxymethyl group, sulfomethylene group or formula W
Represents a nine methylene group substituted with N-0-R4 group, R
4 is hydrogen, lower alkyl group, such as methyl group, hydroxyl group
lower alkyl group, such as 2-hydroxyethyl group,
mino-lower alkyl group, e.g. 2-aminoethyl group,
&de'ilower alkyl group, e.g. 2-carxy-2
-! Lopyl group, carbamoyl group, lower alkyl carbamo
yl group, such as a methylcarbamoyl group, or an amino group
represents a class alkoxy group, such as a 2-aminoethyl group, and has the formula
-0-84 group has -yn- (or 2-) position
A compound of general formula (1) having a salt-forming group and a compound of general formula (1)
), particularly pharmaceutically acceptable salts. The following margins The present invention mainly applies to the case where n is 0 and R1 is hydrogen or a lower atom.
alkyl groups, such as methyl groups, lower alkoxy groups, such as
A methoxy group, a halodane, such as [8, or the formula -CH2
-R2 represents a lower alkanoyloxy group, and R2 is a lower alkanoyloxy group.
, such as alkoxy groups, carbamoyloxy groups, thoria
Zolylthio group, e.g. IH-1,2,3-)lyazole
-5-ylthio group 1 tetrazolylthio group, e.g. IH-
Tetrazol-5-ylthio group t-+ is lower alkyl group
, e.g. methyl group, di-lower alkylamino lower alkyl
groups, such as 2-tmethylaminoethyl group, sulfo-lower atom
alkyl groups, such as sulfomethyl groups, carboxy lower alkyl groups,
A kill group, such as a calgeoxymethyl group, is
a tetrazolylthio group substituted with a yl group, e.g.
thyl-IH-tetrazol-5-ylthio group, 1-sul
Homethyl-IH-tetrazol-5-ylthio group, 1-
Calgeximethyl-IH-tetrazol-5-ylthio
The base is 1-(2-trimethylaminoethyl)-1H-te
torazol-5-ylthio group, thiazoazolylthio group,
For example, 1.3.4-thiazazol-5-ylthio group,
Thiadia substituted with lower alkyl groups, e.g. methyl groups
zolylthio group, e.g. 2-methyl-1,3,4-thiazidi
Azol-5-ylthio group, lower alkyl group, e.g.
5,6-dioxotetrahydrotri substituted with thyl group
Azin-3-ylthio group, e.g. 2-methyl-5,6-
Thioxo 1,2,5,6-titrahydro am-tri
Azin-3-ylthio group t+ is 4-methyl-5,6-di
Oxo-1,4,5,6-titrahydro-a-monotria
Din-3-ylthio group, pyridinio group and hydroxy
Lower alkyl groups, e.g. hydroxymethyl group, carboxylic acid
sil group, calgexi, cy lower alkyl group, e.g. calgexi
a methyl group, a halogeno such as chlorine or bromine, or
Pyridinio groups substituted with carmoyl groups, e.g.
3-L<H4-hydroxymethylpyridinio group, 4-
Carboxypyridinio group, '3- or 4-carboxypyridinio group
Dimethylpyridinio group, 3- or 4-roviridium
Nio group, 3- or 4-bromopyridinio group, manah
3-or 4-cal-gumoylpyridinio group
, R3 is Cal? Degradable under xyl groups or physiological conditions
functional calgexyl groups, such as acyloxy lower alkoxy
cicalbunyl, e.g. lower alkanoyloxy lower alkanoyl
Rukoxycarbunyl group, e.g. lower alkanoyloxy
The methoxycargenyl group te is a lower alkanoyloxyethyl group.
hydroxylgenyl group, e.g. p/40yloxymethoxy
2-(propionyloxy)-ethyl group
Toxy group, lower alkoxy group
Ruoxy lower alkoxylic? Nyl group, e.g. 1-(eth
(toxycarbyloxy)-ethoxylgenyl group or
is t@rt -butyloxymethoxy
represents a trigenyl group, and A is a group of the formula =N -0-R4;
Represents a substituted methylene group, % R4 is hydrogen, lower atom
alkyl groups, such as methyl groups, carboxy lower alkyl groups
, e.g. 2-calzexy-2-propyl group, force A/1
R% yl group or lower alkylcarbamoyl group, e.g.
represents a methylcarbamoyl group, and the group of formula -〇-R4 is s
) Compounds of general formula (I) having the t+-(4 or Z-) position
A salt of a compound of general formula (1) having a salt-forming group and a salt-forming group;
The invention relates to salts that can be used pharmaceutically. The present invention particularly applies to n is O, R1 is hydrogen, lower alkyl
methyl groups, lower alkoxy groups such as meth
Oxy group, halogeno, e.g. chlorine-free formula -CH2-R2
represents a group in which R2 is a lower alkanoyloxy group, e.g.
acetoxy group, carbamoyloxy group, tetrazolyl
a thio group, such as an IH-tetrazol-5-ylthio group,
Mana is a lower alkyl group, such as a methyl group, a di-lower alkyl group,
lyamino lower alkyl group, such as 2-dimethylaminoethyl
thyl group, sulfo-lower alkyl group, e.g. sulfomethyl group
or cal is a xyl lower alkyl group, e.g.
A tetrazolylthio group substituted with a methyl group, e.g. 1-
Methyl-1-tetrazol-5-ylthio group, 1-(2
-dimethylaminoethyl)-tH-tetrazole-5-
ylthio group, ■-Calkakidimethyl-IH-tetrazo
l-5-ylthio group, l-sulfomekyl-IH-tetra
Is the sol-5-ylthio group 1-cal? oxymethyl
-IT(-tetrazol-5-ylthio group, thiadiazo
alkio group, e.g. 1,3,4-thianoanol-5-
ylthio group, lower alkyl group, e.g. methyl group
Substituted thiadiazolylthio groups, e.g. 2-methyl-
1=5*4-thiazazol-5-ylthio group, lower a
5,6-dioxyl substituted with alkyl group, e.g. methyl group
sotetrahydrolorotriazinylthio group, e.g. 2-
Methyl-5,6-thioxo 1,2,5,6-thitrahy
Draw ag ~ triazin-3-ylthio group or 4-mer
Chill-5,6--/oxo-1,4゜5.6-thitrahy
Draw a--triacin-3-ylthio group, pyridinio
group or hydroxy lower alkyl group, e.g. hydroxy
Methyl group, carboxy group, carboxy lower alkyl group,
For example, Cal is a oxymethyl group, halogeno, such as chlorine or
Pyridine not substituted with bromine or carbamoyl group
nio groups, e.g. 3- or 4-hydroxymethylpyri
dinio group, 4-carboxypyridinio group, 3- or
4-carboxymethylviridinio group, 3- or 4-
Chloropyridinio group, 3- or 4-bromopyridiny
Fi4-carbamoylpyridinio
represents a group, and R3 is car? xy group, lower alkanoyl group
xy-lower alkoxycargenyl group, e.g. lower alkano
yloxymethoxycar is a nyl group t-+ lower alkano
yloxyethoxycar♂yl group, e.g.
Oxymethoxyrudenyl group t or 2-(f lopioel
oxy)-ethoxycar is a nyl group or lower alkoxy
cargenyloxy lower alkoxy carzenyl S, e.g.
1-(ethoxylgenyloxy)-ethoxycal? D
group or t@rt-butyloxycar♂yloxymethane
represents a toxiccargenyl group, and A is the formula =N -0-R4
represents a methylene group substituted with a group, and R4 is a lower alkyl group.
Kyl groups, such as methyl groups, carboxy lower alkyl groups,
For example, 2-carboxy-2-propyl group, carboxy-2-propyl group,
712: is a lower alkylcarbamoyl group, e.g.
For example, it represents a methylcarbamoyl group, and a group of the formula -〇-R4
of the general formula (1) in which has the 5yn- (or Z-) position
A salt of a compound of general formula (1) having a compound and a salt-forming group,
In particular, it relates to vine salts for pharmaceutical use. The present invention particularly relates to compounds of general formula (1) and
This invention relates to its salts, especially its pharmaceutically used salts. Compounds of general formula (1) and salts of compounds having a salt-forming group
is produced, for example, by the following method: a) General formula (If
) : 5 [In the formula, n% R and R3 are those listed in general formula (1).
Is the 7β-amino group present in free form?
Protected by a group that allows acylation reaction and present in R1
[the functional group in the compound or its salt is preserved]
7β-amino group is represented by the general formula ():
The amino group at the 2-position of the silyl group and the functional group present in A are
The acyl group of calgenic acid (which is preserved in some cases)
By reacting with the acylating agent Natakeso salt to be introduced,
b) Produce a compound of general formula (1) where n is 0
Name, general formula (■): [In the formula, R,, R3 and person are those listed in general formula (1)
represented by the amino group at the 2-position of the oxacylyl group and R1 and
The functional groups present in A and A are optionally preserved.
-Cephem- Compounds are prepared by isomerizing their salts.
3-cephem compound, or C) General formula (V): "(V). [In the formula, n5R1, R3 and A represent the above, and X
represents a halogeno, and the functional groups present in R1 and A are
optionally protected] or its salts in the urine.
d) A is hydroxyimide.
Formula (I) representing a methylene group substituted with a group
In order to produce a compound of the general formula (■):
represents the amino group at the 2-position of the oxacylyl group and in R1
The functional groups present in the compound are optionally protected.
Treat monomanakeso salt with an etorophizing agent, and if necessary,
The obtained compound of general formula (1) is converted into another compound of general formula (1).
A compound in which n is O, obtained by changing to a compound and/or obtained
to the compound #i2 where n is 11, and /l'
The unobtainable compound where feken is 1 or 2 is given as n is 0.
and/or in the resulting compound.
converting functional groups present in protected form into free radicals, and/or
The salt obtained can be converted into the free compound Mana or other salts, and
and/or converting the resulting free compound into a salt, and/or
resolves the resulting isomer mixture into individual isomers. In addition to the starting materials of general formula (U), the functional groups present in R1
functional groups, such as carboxyl groups, amino groups or hydroxyl groups;
The syl group is protected with the above-mentioned protecting group. The 7β-amino group in the starting material of general formula (U) may
This is protected by a group that allows more acylation reaction.
Such groups include, for example, organic silyl groups, and also silyl groups together with amino groups.
It is a ylidene group that forms the base of FF. organic silyl group
For example, in the case of carboxyl group R3, the protected carbon
It is a vine group that forms a carboxyl group. This type of base is particularly
tri-lower alkylsilyl group, especially trimethylsilyl
It is the basis. 4-carboxy in the starting material of general formula (II)
When silylating to protect sil groups, use a silylating agent.
Can be used in excess to similarly silylate amino groups.
Wear. The ylidene group is particularly 1-aryl lower alkyl
lyso-y group, especially °1-arylmethylene group, whose
In particular, aryl groups are carbon homocyclic, especially monocyclic aryl groups.
groups, such as optionally lower alkyl groups, hydroxy groups
, substituted with a lower alkoxy group and/or a nitro group
represents a phenyl group. The acyl group of the carboxylic acid of general formula (nl) is introduced.
The cargenic acid itself of the general formula (fir) is
It is a reactive functional derivative of Manakeso salt. General formula (II
In the starting material of I), the acylation present in R4
Functional groups that should not participate in the reaction, such as carboxyl groups
, the amino group is reduced to the human lloxyl group, which has a 1IfJ configuration.
Protect with a protective group. Amino groups present in the starting material of general formula (III)
is in ionic form, e.g. acid addition salts, e.g. strong inorganic acids, e.g.
Hydrogen acids such as hydrochloric acid or sulfuric acid are
formed by organic acids such as p-)luenesulfonic acid
It may also be protected in the form of an acid addition salt. When using the free acid of general formula (III) for acylation,
The reaction is carried out in a conventional manner using a suitable condensing agent, e.g. calgediimide, e.g.
For example, N, N'-jetylrugezimide, N,
N/-dizolopylcarposiimide, N,N'-dicyclo
Hexylcar over diimide N-ethyl-N'-3-
, y methylaminoderopylcargediimide, suitable
Luzenyl compounds, such as car-nyldiimidazole, or
1.2-oxacillium compounds, such as 2-ethyl
-5-7enyl-1,2-oxacillium-3'-sul
Honate manaha 2-t@rt-f-thyl-5-methyl-
1,2-oxasiri f) Mut'? -ri01/-to, 4
A suitable acylamino compound, fllf, 2-ethoxy
C-1-ethoxylic? Nilu 1.2-Nopito 90 keno
Performed in the presence of phosphorus. The condensation reaction is carried out in an anhydrous reaction medium, preferably in a solvent or diluted
diluents such as methylene chloride, dimethylformamide,
In the presence of setonitrile or tetrahydrofuran, the required
Depending on the temperature, for example, about -40℃ to approx.
+100°C, preferably about -20°C to about +500°C
range and/or inert gas, e.g. in a phonetic atmosphere.
It is advantageous to implement. The reactivity of the carboxylic acid of general formula (III), i.e., the carboxylic acid
Cyamide-forming, functional derivatives are particularly suitable for the general formula (III
) is an anhydride of carnic acid, preferably a mixed anhydride.
. Mixed anhydrides can be used, for example, with other acids, such as inorganic acids such as hydrogen.
Formed by combination with chlorohydrogen acid, e.g. the corresponding
Cal-acid herronide, e.g. Cal? acid chloride also
is a promid. The mixed anhydride is further formed by condensation with hydronitridic acid,
For example, carbic azide. Suitable for forming mixed anhydrides
Suitable inorganic acids also include phosphorus-containing acids, such as phosphoric acid and diethyl phosphoric acid.
or phosphorous acid, sulfur-containing acids such as sulfuric acid, or cyanide
It is hydrohydric acid. Reaction of carbic acid of general formula (III)
The functional derivative may further include an organic carbic acid, e.g.
Substituted lower alkanecarbic acids or halogens, e.g. fluorine
Lower alkanecarbic acids substituted with chlorine, e.g.
For example, piparic acid or trifluoroacetic acid, the lower atom of carbonic acid.
lukyl half esters, such as ethyl half esters of carbonic acid or
or isobutyl half ester, or organic, e.g. aliphatic
or aromatic sulfonic acids such as methanesulfonic acid or
or formed by combining with p-toluenesulfonic acid.
Ru. The reactive functional derivatives of carbic acid of general formula (III) are
Similarly, for example vinyl alcohols, i.e. enols, e.g.
For example, it is formed by condensation with vinyl lower alkenol.
active ester of carbic acid of general formula (Ill),
Carbic acids of general formula (III) and, for example, carbic acids of formula ((CI(j
) ρ=C(C4)CH3]Cf) dimethyl-(1
-chloroethylideneiminium chloride (e.g. N, N
-dimethylacetamide and phosdanamide chloride oxa
iminomethyl esters produced from
Halonide, side light dimethyliminomethyl ester
LoliF1 aryl esters, such as salts, e.g.
phenyl groups substituted with elementary and/or nitro groups, e.g.
(4-nitrophenyl ester, 4-nitrophenyl ester)
Ester t-1'? is 2,3-dinito tetraphenyl ester
N-heteroaromatic esters, such as N-pensito,
Riazole ester or N-diacyl imino ester
such as N-su-winter cinyliminoester or N
- a reactive functional derivative of carnic acid of general formula (1) which is a phthalyl imino ester, e.g.
to the corresponding anhydride, especially the acid.
In the presence of a suitable acid binder, e.g. a suitable organic base,
It is preferable to carry out. Suitable organic bases include, for example, amines.
, e.g. tertiary amines, e.g. tri-lower alkyl amines
, for example, trimethylamine, triethylamine 41
Ethyl-diiso! Lopilua knowledge, Matake N, N-ji low grade
Alkylanilines, such as N,N-dimethylaniline,
or cyclic tertiary amines, such as N-lower alkylated moieties.
luforin, such as N-methylmorpholine, or
is, for example, a pyridine type base, such as pyridine. suitable
The acid binder may also contain an inorganic base, such as an alkali metal or
Alkaline earth metal hydroxide, carbonate 1+ is bicarbonate,
For example, hydroxylation of sodium, potassium or calcium
substance, carbonate or bicarbonate, or oxirane
, e.g. 1°2-lower alkylene oxide, e.g. ethyl
Ren oxide or deropyrene oxide. By reactive functional derivatives of carbic acid of general formula (In)
The acylation is preferably carried out in an anhydrous inert solvent or solvent.
mixtures, e.g. carbic azides, e.g. formamide
, e.g. dimethylformamide, halodanized hydrocarbons
, e.g. methylene chloride, tetralayered carbon or chlorobenze
ions, ketones, e.g. a7tones, cyclic ethers, e.g.
trahydrofuran, esters such as ethyl acetate ester
mana is a nitrile, e.g. acetonitrile, or
in these mixtures, reduce the temperature or
is elevated, for example from about -40°C to about +100°C, preferably 1-
<in the temperature range of about -10°C to about +50°C and/or
It is best to carry out the process in an inert gas atmosphere, such as a nitrogen atmosphere.
preferable. In the presence of a suitable acylase, the acid of general formula (Ill) can be
Compounds of general formula (U) using reactive functional derivatives
can also be acylated. Ashiras like this
It is known that some bacterial organisms, such as Acetobacter o.
-Lantium (Ae@tobaet@raurat+
t1um), more Acetobacter, Achromobacter
-・Neeris (Aehromobaet@r a@ri
Achromobacter such as M), Aeromonas hid
Aeromonas hydrophila
) like Aeromonas, Bacillus megateri
CBmaillus megat@rium)
Produced by z4 tyrus such as 400. This way
In the case of enzymatic acylation, reactive functional derivatives
In particular, amides and esters of cardanic acid of general formula (III)
or thioesters, such as lower alkyl esters,
For example, using methyl ester or ethyl ester
. Such acylation occurs in media containing the corresponding microorganisms.
, in the filtrate of the culture medium or, in some cases, including adsorption to the carrier.
After first isolating the acylase, optionally containing a buffer.
in an aqueous medium, e.g. in a temperature range of about +20°C to about +40°C.
The stone is normally carried out at ambient temperature, preferably at about +37°C. Reactive group of acid of general formula (II) used in acylation reaction
Functional conductors can be formed in situ as needed.
Ru. For example, general formulas where functional groups are optionally protected
Cl1l) in a suitable pot, e.g. ammonium
salts such as pyridine or 4-methylmorpholine
Ammonium salts formed with organic bases such as
is a metal salt, such as an alkali metal salt, such as a sodium salt.
with suitable derivatives of other acids, such as unsubstituted lower alkanes.
Lower acid salts are substituted with chlorine, e.g.
Acid halides of alkanedic acids, e.g. trichloro
Acetyl chloride, half ester of carbonic half halonide, e.g.
For example, chloroformic acid ethyl ester, or isobutyl ester
Stell, Mana is helognide of di-lower alkyl phosphate, e.g.
Diethyl phosphorobromidate (triethyl phospha)
When reacted with
A mixed anhydride can be produced in situ by The mixed anhydride obtained in this way is
It can be used without taking it apart. Process b) (isomerization) In the 2-cephem starting compound of general formula (IV),
The optionally protected 4-carboxyl group has an α-configuration.
It is preferable to have The 2-cephem compound of general formula (IV) is used as a weakly basic reagent.
to isomerize the corresponding 3-cephem compound.
Can be isolated. Suitable isomerizing agents include, for example, organic
nitrogenous bases, especially aromatic tertiary heterocyclic bases,
First, pyridine-type bases, such as pyridine itself, and pico
Phosphorus, collidine or lutidine, and also quinoline, tertiary
aromatic bases, such as aniline type bases, such as N, N
- di-lower alkyl phosphorus, such as N,N-dimethylalcohol
Nirin Wakasuke N, N-diethyl ayurin, 4-take third
aliphatic, azocycloaliphatic or aromatic aliphatic bases, e.g.
Tri-lower alkylamines, such as trimethylamine or
or N,N-diisoglobylethylamine, N-lower
Rukyladecycloalkanes, such as N-methylpiperid
N, ttakeN, N-di-lower alkylphenyl lower alkyl
amines, such as N,N-dimethylbenzylamine, and
mixtures of basic reagents such as pyridine-type salts
mixtures of groups and tri-lower alkyl amines, e.g.
It is a mixture of triethylamine and triethylamine. Furthermore, bases, especially medium to strong bases, and inorganic or
is an organic salt, for example, an alkali of a lower alkane caldic acid.
Metal #1 spanning ammonium salts, e.g. sodium acetate
, triethylammonium acetate or N-methyl
biperidi/acetate, and other similar bases or this
It is also possible to use mixtures of basic reagents such as. A 2-cefuyum compound of the general formula (F/) is mixed with a basic reagent.
For isomerization in an anhydrous medium, a solvent, e.g.
Optionally chlorinated, e.g. non-chlorinated aliphatic, fatty
Presence of cyclic or aromatic hydrocarbons or solvent mixtures
or in the absence (then used as reactant, reaction conditions)
A liquid base can also be used as a solvent at the same time.
), preferably while cooling or heating.
Inertness is activated within the reaction temperature range of approximately -30°C to approximately +100°C.
in an atmosphere, such as a nitrogen atmosphere and/or in a closed container
It is preferable to operate with The obtained 3-cephem compound of general formula (1) is
By known methods, e.g. by adsorption and/or crystallization,
The 2-cephem still present is separated from the starting material by
can be done. Oxidation of the 2-7-femu compound of general formula (1'/) at the 1st position
and, if necessary, an isomer mixture of the produced 1-oxide.
and the corresponding 3-cephem compound thus obtained.
By reducing 1-oxyP of the general formula (1'i
l') 2-7phemu compound to the corresponding 3-cepheme
- isomerization to the compound is preferred. Hierarchize the 1st position of the 2-7-femu compound of general formula (■)
Therefore, a suitable oxidizing agent is at least tun + 1.5 & rut.
It has a reduction potential of
from peracids or hydrogen peroxide and acids, especially organic carmenic acids
, and the mixture has a dissociation constant of at least 10.
I guess. Suitable inorganic peracids are, for example, periodic acid and persulfuric acid.
be. Organic peracids include, for example, percarlage/acids and persulfonic acids.
and these should be added as is or at least
in situ using equivalent amounts of hydrogen peroxide and calgenic acid.
can be formed. In this case, for example acetic acid or
When using carb/acid, avoid using a large excess of carb/acid.
is advantageous. Suitable peracids include, for example, performic acid, peracetic acid,
Refluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloride
Loroperbenzoic acid, monoperphthalate, also FiP=)
It is ene persulfonic acid. Similarly, an acid catalyst with a dissociation constant of at least 10-5
Oxidation can also be carried out using hydrogen peroxide along with the amount of solvent.
In that case, a small amount or a low concentration of acid, e.g.
can be used in relatively large amounts. In this case the mixture
Activity primarily depends on the strength of the acid. Examples of suitable mixtures
For example hydrogen peroxide and acetic acid, perchloric acid or trifluoro vinegar
It is an acid. Said oxidation can be carried out in the presence of a suitable catalyst.
. For example, oxidation with percaldic acid of at least 10-
can be catalyzed by the presence of an acid with a dissociation constant of 5
The activity of an acid as a catalyst depends on the strength of the acid.
It is right. Acids suitable as catalysts include, for example, acetic acid and perchloric acid.
and trifluoroacetic acid. Usually at least equimolar
amount of oxidizing agent, preferably a small excess of about 10 to about 204
Use an oxidizing agent, but in large excess, i.e. up to 10 times the amount
agents or more can be used. Oxidation is carried out under mild conditions, e.g. from about -50°C to about +100°C.
, preferably at a temperature of about -10°C to about +40°C.
. Reduction of 1-oxide of 3-cephem compounds is known per se.
treatment with a reducing agent, optionally in the presence of an activator.
It can be implemented by Example as reducing agent
For example, catalytically activated hydrogen (tucladium, platinum or
Uses precious metal catalysts containing bamboo rhodium, and in some cases
with a suitable carrier material, e.g. carbon or tetralium sulfate.
(used for
Inorganic cations (inorganic cations are organic compounds or complex forms)
For example, chloride, fluoride, acetate or
do not eat formate, iron(II) chloride, sulfate, or oxalate.
Succinate, copper(1) chloride, benzoate or oxidation
or manganese(II) chloride, sulfate, acetate
or oxides, or e.g. ethylenediaminetetraacetic acid or
or as a complex with nitrosotriacetic acid;
Nithionite anion, iodine anion or
Iron cyanide (It) anion (corresponding inorganic
salts, e.g. alkali metal salts of dithionite, e.g.
Rium Hanawa 41-nen is potassium salt, sodium iodide or iodine.
Potassium chloride, or iron ([) sodium cyanide]
in the form of potassium iron(II) cyanide or the corresponding acid
, used for example in the form of hydriodic acid); has a reducing action
The trivalent inorganic-1 is an organic phosphorus compound, such as phosphine.
, esters, amides and halide of phosphonic acid or phosphorous acid
rhodanides and their corresponding phosphorus-oxygen compounds
compounds (in these compounds, the organic groups are especially
, aromatic or araliphatic groups, e.g. optionally substituted
lower alkyl group, phenyl group means phenyl lower
(representing an alkyl group), e.g. triphenylphosphine
, trilobylphosphine, diphenylphosphine
acid methyl ester, diphenylchlorophosphine,
Nyldichlorotetraphosphine, benzene dimethyphosphonite
ester, butane phosphonite methyl ester, phosphoric acid
triphenyl ester, phosphorous S trimethyl ester,
Phosphorus trichloride 1. Phosphorus tribromide; halogen that has a radical effect
la/compounds (at least hydrogen atoms bonded to silicon atoms)
1 ft of chlorine and bromine is equivalent to iodine.
Additionally, organic groups, such as aliphatic or aromatic groups, such as
optionally substituted lower alkyl group or phenyl group
), e.g. chlorotetrasilane, bromosilane, no
or triflurosilla/, sea or kake tribromoshi
Ran, diphenylchlorosilane, or diphenylchlorosilane
silane, and halogens in which all hydrogens are replaced with organic groups.
Logenosilane compounds, such as tri-lower alkyl halo
Silanes, such as trimethylchlorosilane or trimethyl
Ruiodosilane or sulfur-containing cyclic silane, such as 1.
3-cythia2,4-zosilacyclozotane t or l. 3.5-trithia-2,4,6-)lysilacyclohexa
, the silicon atom is a hydrocarbon group, for example @ is a lower alkyl group.
Said compound substituted with, for example 2.2.4.4-
Tetramethyl-1,3-dithia-2,4-nosilacyclo
Butane 2,2゜4.4,6,6--S hexamethyl
-1,3,5-') Lithia-2,4,6-drisilasic
Lohexane, etc.: Quaternary chloromethylene with reducing action
Iminium salts, especially chloride or promide (iminium salts)
A mu group is one diorganic group or two monoorganic groups, e.g.
For example, an optionally substituted lower alkylene group refers to a lower alkyl group.
(substituted with alkyl group), e.g. N-chloromethyl
N-N, N-noethyliminium chloride or N-k
Loromethylene pytetradinium chloride r; t is reducing action
complex metal hydrides, such as cobalt(n) chloride, having
borohydride in the presence of a suitable activator such as)
, and I range dichloride. said reduction with or without weak Lewis brewing properties
activator used with the agent, i.e. especially dithionite
Reducing agent, iodine reducing agent or iron(II) cyanide 8-element agent
and a haridan-free trivalent phosphorus reducing agent.
As the activator used during catalytic reduction, especially organic
Cargenic acids and sulfonic acids, and also benchloride
2-digit divine tree resolution equal to or larger than Zoil
sulfur, #t is a halide of silicon, e.g.
Phosdane, oxalyl chloride, and acetic acid chloride t+ are pro-
Mido, chloroacetic acid chloride; pino-tetraphosphate tetralide, 4
-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride
lido, p-)luenesulfonic acid chloride, methanesulfonate
phosphoric acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride
, phosphorus tribromide, phenyldichlorophosphine, benzene
Phosphonic acid dichloride, dimethylchlorosilane or
Lichlotetrasilane, as well as acid anhydrides such as trifluorotetravinegar
Acid anhydride, meaning is cyclic sultone, example t is ethane sultone
,! b, f sultone% 1.3-7” tansultone also
Examples include 1-3-hexane sultone. Preferably, the reduction is carried out in a solvent or a mixture thereof.
The selection depends on the solubility of the starting materials and the selection of the primary agent.
For example, in the case of catalytic reduction, the lower alkane
Carcinic acid or its esters, such as acetic acid and ethyl acetate
ester, and optionally together with a chemical reducing agent.
For example, halogenated or nitrated fat
group, 'alicyclic, aromatic or araliphatic hydrocarbon, e.g.
Benzene, methylene chloride, chloroform and nitro
Methane, suitable acid derivatives, e.g. lower alkane caldenes
Acid ester 4 or nitrile, e.g. acetic acid ethyl ester
or acetonitrile, as well as inorganic or organic acids.
For example, trimethylformamide or hexamethylformamide
Sphoramide, ether 1 e.g. diethyl ether, ether
Trahydrofuran and nooxane, ketones, e.g.
Setone, or sulfone, II? to aliphatic sulfones, e.g.
For example, dimethylsulfone or tetramethylenesulfone, etc.
and these solvents preferably do not contain water. General
Usually operated at temperatures of about -20°C to about 100°C, extremely reactive.
If a specific activator is used, the reaction may be carried out at a lower temperature.
It can also be implemented. In the starting material of general formula (v), X is halogeno, preferably
stands for chlorine, bromine stands for bromine, and stands for fluorine. salt formation
General formula with R5 representing a group, e.g. car-xyl group
Compound (V) may be a salt, such as an alkali metal salt or an alkali metal salt.
Monium salts, such as lithium salts, sodium salts, potassium
salts, tri-lower alkyl ammonium salts, e.g.
Tylammonium salt or triethylammonium salt
Then you can use the stone. Urea is added in an equivalent amount, but in excess. The reaction is generally carried out in a solvent such as water, an organic inert solvent or
is carried out in the mixture. As an organic solvent, alco
alcohol, such as methanol, ethanol or isoglo
9nors, ketones such as a7tones, ethers such as
dioxane or tetrahydrofuran, nitrile, e.g.
For example, acetonitrile, halodanated hydrocarbons, e.g.
tyrene, chloroform or carbon tetrachloride, esters, e.g.
e.g. ethyl acetate, or amides, e.g. dimethylform
Amide or dimethylamide, etc. are suitable. one
When using the free compound of general formula (V), the reaction is carried out with a base.
It can be carried out in the presence of A suitable base is alkali gold
hydroxides such as sodium hydroxide or potassium hydroxide
um, alkali metal carbonates such as sodium carbonate or
is potassium carbonate, or an organic tertiary nitrogen base, e.g.)
I3 lower alkyl amines, such as trimethylamine,
Triethylamine, ethyl-diisopropylamine, pi
Ami with lysine etc. The reaction temperature is above room temperature, preferably 60°C.
°C to the boiling temperature of the reaction mixture. First, for example, the partial formula NH2-C(=NH)-0-CH2
A ring-opening intermediate of -Co-A is produced and then heated in a second step.
It is also possible to carry out the reaction in stages by dehydration.
Wear. The functional group in the starting material of general formula (■) is protected. suitable
Suitable nitrosating agents include nitrous acid and its derivatives, e.g.
Nitrosyl chloride, such as nitrosyl chloride
Disilosyl bromide, salts of nitrous acid, e.g. alkali metal salts,
For example, sodium nitrite or potassium nitrite, manaha
Especially esters of nitrous acid, such as lower alkyl esters,
For example, nitrous butyl, hentyl t or especially isoal
be. When using nitrous acid salts as nitrosating agents
, the reaction is stimulated with a strong inorganic or organic acid, such as hydrochloric acid, sulfuric acid, etc.
It is preferable to carry out in the presence of acid, formic acid or acetic acid.
When using esters of nitric acid, start the reaction with a strong base, e.g.
It is preferably carried out in the presence of an alkali metal alkanol.
Delicious. The nitrosation is carried out in a suitable solvent such as water, carboxylic acid, etc.
For example, acetic acid, lower alkanols such as methanol or alcohol.
Tanol, ether, e.g.
Dorofuran, or hydrocarbons such as hexane or benzene
or a mixture of these, if necessary.
or while heating, especially in the temperature range of about -15°C to about room temperature.
and/l or an inert gas atmosphere, such as a nitrogen atmosphere.
Conducted inside. Subsequent operations Conversion of R4 Obtaining general formula (1) in which the functional group is optionally protected
In such compounds, the group R1 can be replaced with another group by a method known per se.
These seven angles can be replaced by R1 or replaced by other groups R4.
Ru. For example, R1 represents a group of formula -C)I2-82,
R2 represents a group substituted with a nucleophilic substituent, for example;
In the compound Mana of general formula (1) or its salt, such
The group R2 can be replaced with a mercaptan compound, e.g. heterocyclyl
Mercaptan compound, mana is a thiocarboxylic acid compound
By treatment, etherified mercagut groups, e.g.
Terocyclyl mercapto group or esterified mercapto group
can be changed to a group R2. Substituted with a nucleophilic substituent, e.g. an etherified mercagut group
Suitable groups that can be used include, for example, lower aliphatic carbogenic acids.
It is a doroxy group when it is telated. Such esterified hydroxy groups are particularly suitable for acetyl hydroxy groups.
cy group and acedo-heptoxy group. Such a compound of general formula (1) and a suitable mercaptan
compounds, such as heterocyclyl mercaptan compounds and
The reaction is carried out under acidic, neutral or weakly basic conditions.
be able to. In acidic conditions, operate in the presence of concentrated sulfuric acid,
Concentrated sulfuric acid may be diluted with an inorganic solvent, e.g. polyphosphoric acid.
stone. Under neutral or weakly basic conditions, the reaction can be carried out with water and
The method is carried out in the presence of an organic solvent that is miscible with water. Basic conditions include, for example, inorganic bases, such as alkali metals or
is an alkaline earth metal hydroxide, carbonate or bicarbonate
addition of, e.g. sodium, potassium or calcium
hydroxide, carbonate or bicarbonate.
can be done. As an organic solvent, e.g.
Alcohols such as lower alkanols, such as methano
Examples include ethanol, ketones, lower alkanones, etc.
, e.g. acetone, amides 1, e.g. lower alkanes
Genic acid amides, such as dimethylformamide, 4 are
Using a class alkanoic acid nitrile, e.g. acetonitrile
can be done. R4 is of the formula -0H2-R2 (wherein R2 is a free hydroxy group)
In the compound of general formula (1) representing a group of
, the free hydroxy group is optionally N-substituted carboxylic acid
Can be esterified with the acyl group of minic acid. free
The hydroxy group is converted into an isocyanate compound, e.g.
Sulfonylisocyanates, such as chlorosulfonyl isocyanates
a socyanate, or a carbamate halide, e.g.
When esterified with CalI4 minor chloride, the general formula (
■) N-unR-substituted 3-carbamoyloxymethyl
Pharoszolin is obtained. Free hydroxy group in N-position
inocyanate compound or N-mono- or N,N
-disubstituted carbamic acid compounds, e.g.
Carbamic acid halides, such as N-mono-manahan
, when esterified with N-disubstituted car/tetraminic acid, the general
N-mono- or N,N-disubstituted 3-cal/ of formula (1)
Gumoyloxymethyl-cephaloszolin is produced. General
Always in the presence of a solvent or diluent, with cooling if necessary.
In a closed container while heating, sometimes in an inert atmosphere.
The operation is carried out in an atmosphere of gas, such as nitrogen. R1 is formula-0
M2-R2 group (wherein R2 represents a free hydroxy group)
) is an acetyloxy group.
By removing the acetyl group from R7, for example
Weakly basic medium, e.g. hydroxide (pH 9-10) IJ
Hydrolyze it in an aqueous solution or use a suitable ester.
for example, Rhizobium tritori 4 (Rhlzob
lum tritolii), Rhizobium rubinii
(Rhlzobium 1uplnli), Rhizobium
A-Rhlzoblum japonle
um) Bacillus subtilis
llsm) is an extract obtained from the peel of an orange, for example.
Manufactured by treatment with appropriate citrus esterase
be able to. Furthermore, R1 is a group of -CT(, -R2 (wherein R2 is, for example,
The general formula (
1) with a tertiary organic base, especially an optionally substituted
under neutral or slightly acidic conditions, preferably with
Possibly miscible with water in the presence of water with a value of about 6.5
The reaction is carried out in an organic solvent, and R1 has a group of the formula -CH, -R2.
represented by the general formula (1) in which R2 represents an ammonio group
compound can be obtained. Weakly acidic conditions include suitable organic or inorganic acids, such as acetic acid,
Can be adjusted by adding hydrochloric acid, phosphoric acid or sulfuric acid.
I can do that. As an organic solvent, for example, the above-mentioned water-miscible
Vine solvents can be used. To increase yield,
Certain salts, such as inorganic acids, such as halodane, are present in the reaction mixture.
Hydrohydric acids, such as chloric acid and especially hydriodic acid,
and thiocyanic acid, or organic acids such as lower alkanoic acids
(alkali metal salts of acetic acid, e.g.)
Can be added to IJum salts and especially potassium salts
stone. Suitable salts include, for example, sodium iodide, potassium iodide and
Potassium dithiocyanate. Acids such as acetic acid and suitable
liquid ion exchangers in the form of salts, e.g.
Transmutation, e.g. Amber Light (Amb@rlibe)
LA-1 (liquid secondary amine with molecules [351-393
; oil-soluble and water-insoluble; m k@g/l = 2.5
~2.7, e.g. a7tate form) is used for this purpose
be able to. R2 is substituted, especially aromatic substituted car♂ylthio group and especially
Using an intermediate of general formula (1) representing a benzoylthio group
The ammonio group R2 can be advantageously produced in this manner. For example, when R2 in group R4 is esterified and doxy group,
fixed lower alkanoyloxy group, e.g. acetyloxy group
The compound of general formula (■) representing
A suitable list of aromatic thiocarginic acids, e.g. thiobenzoic acid.
Reacts with salts, e.g. alkali metal salts, e.g. sodium salts
The intermediate as described above obtained by
In cases where tertiary amines, special tertiary heterocyclic bases, e.g.
By reacting with more substituted pyridine,
The corresponding compounds are obtained. The reaction is usually followed by suitable desorption.
Sulfurizing agents, especially mercury salts, such as mercury perchlorate (■), and suitable
In the presence of suitable solvents or diluents or mixtures thereof,
in a container and/or in an inert gas atmosphere, e.g. nitrogen atmosphere.
It is carried out in air, with cooling or heating as necessary. In the obtained compound of general formula (1), hydroxymethane
Thyrene group A can be oxidized to oxymethylene group
. Oxidation optionally removes free amino groups and cargexyl groups.
, and convert the hydroxy group into an oxo group.
The oxidation can be carried out by a known method. acid
Examples of oxidizing agents include manganese, chromium, nitrogen, and sulfur.
Yellow oxidizing oxides, such as manganese dioxide, chlorotrioxide
such as Jones reagent or acetic acid,
Sulfuric acid or t? Chromium trioxide in the presence of IJ amine,
Dinitrogen tetroxide, optionally dicyclohexylcardii
dimethyl sulfoxide in the presence of hydrogen or oxygen, and
Peroxides, e.g. hydrogen peroxide, oxygen-containing acids, e.g.
nganiic acid, chromic acid or hypochlorous acid or its salts,
For example, potassium permanganate, sodium dichromate,
Potassium dichromate and potassium hypochlorite are mentioned.
Ru. The hydroxymethylene group is
enauer) converted into oxomethylene group by oxidation
Ketones, such as acetone,
The presence of lohexanone or fluorenone reduces steric hindrance.
Salts of alcohols such as aluminum-t+ with carbon
Lium-tart-butoxide, -isozolo 4oxide
By treatment with bamboo phenoxide, hydroxyl
Simethylene group can be changed to oxomethylene group
. Furthermore, by dehydrogenation, e.g. with Raney nickel,
So, change the hydroxymethylene group to oxomethylene group
You can also Oxidation is in water or possibly with water depending on the oxidizing agent
It is carried out in an organic solvent at a temperature of about 100°C to about 100°C. Reaction: Unobtainable compound of general formula (1) where A represents a carbunyl group
hydroxylamine, optionally preserving functional groups.
Also treated with tfo-,1-methylhydroxylamine
The carbunyl group is converted to hydroxyiminomethylene by
Can be converted to lene group or methoxyiminomethylene group
can. The reaction between carbunyl group and hydroxylamine compound is
In the conventional method, for example, both reaction components are mixed in a solvent, for example, water is mixed with an organic solvent.
temperature in a solvent, e.g. an alcohol, e.g. methanol.
Slightly higher or lower, possibly inert, e.g.
It is carried out by reacting in a nitrogen gas atmosphere.
. Hydroxylamine compounds can be converted in situ to their salts, e.g.
From hydrohalides, e.g. hydrochloride', to inorganic salts, e.g.
For example, alkali metal hydroxides, such as sodium hydroxide,
- additional organic bases, e.g. tertiary amines, e.g.
lower alkyl amines, such as tri-lower alkyl amines, e.g.
For example, triethylamine and ethyl-diisopropyla
or a heterocyclic-tertiary base, e.g. pyridine.
It can be liberated by treatment. Conversion to d: The compound of general formula (1) in which 1 represents 0 is converted into
The corresponding 1-oxygen to represent our 1 using the following oxidizing agent
Can be changed to Sid. The compound of general formula (1) where n is O or 1 is
Fido group is a test to convert sulfoxide group into sulfone group.
By reacting with a drug, the corresponding l-
It can be converted into NO oxide. Such reagents are particularly suitable for hydrogen peroxide, organic peracids, and fats.
Group percarzenic acids, such as peracetic acid, perbenzoic acid, chloroperoxylic acid,
Benzoic acid, such as m-chloroperbenzoic acid and monoperfusate
Talic acid, an oxidizing inorganic acid or its salt, e.g.
Nitric acid, tetramic acid, potassium permanganate or alkali
Metal hypochlorite (e.g. hypochlorous acid) 13um,
and anodic oxidation. A suitable active solvent, such as Hero
Hydrocarbon water 1 For example, methylene chloride, chloroform
Carbon chloride, alcohols such as methanol or ethano
alcohols, ketones such as acetone, ethers such as noe
thyl ether, dioxane or tetrahydrofuran,
Amide, e.g. dimethylformamide, sulfone, e.g.
Dimethyl sulfone, liquid organic carbon? acids such as acetic acid
, or in water, or mixtures of these solvents, especially water
at room temperature or cooled in aqueous acetic acid, e.g.
′! ! or slightly heated and heated from the front, i.e. from about -20℃ to about 90℃.
℃, preferably from about +18°C to about +30°C.
It is preferable to First, at a low temperature, that is, about -20℃ to about 0℃.
Oxidize to the sulfoxide stage by adding an equivalent amount of oxidizing agent.
, which is optionally isolated and preferably placed in a greenhouse in a second step.
sulfoxide by adding the oxidizing agent.
to sulfone, i.e., 1,1-dioxide of general formula (1)
Oxidation can also be carried out in stages by
After-treatment, remove any excess oxidant that may still be present.
Reduction, especially reducing agents such as thiosulfates, e.g. thiosulfate
Can be destroyed by treatment with sodium
Ru. 1-oxide of general formula (1) where n represents 1 and my 2
1-dioxide representing the reducing agent described in method b)
to the corresponding 1-sulfide where n represents 0.
I can do it. General formulas in which one or more functional groups are protected
In these compounds, e.g.
xyl group, amino group, hydroxy group and /l sulfonate
The group can be solvolysed, in particular hydrolyzed, alkalized in a manner known per se.
colysis mana acidolysis or reduction, especially hydrogenation
Depending on the case, step by step one! ! Thoughts are free at the same time
can be done. The type of protecting group that is known per se for the protected carboxyl group
Depending on the
released by the source. t@rt-Lower alkoxy force
Nyl group is a lower alkali whose 2-position is substituted with an organic silyl group.
Coxylugenyl group 4! The first position is a lower alkoxy group.
Lower alkoxy substituted with lower alkylthio group
Cal is a nyl group, and optionally substituted fe diphenyl
Methoxylic/nyl groups optionally with nucleophilic compounds, e.g.
Looks like phenol, anisole or ethylene thioglyco
For example, a suitable acid such as formic acid or toric acid may be added.
Free carboxylic acid by treatment with refluoroacetic acid
can be changed to a base. Pens that may not be replaced
For example, by hydrogenolysis of the dioxycargenyl group,
i.e. the presence of a metal hydrogenation catalyst, e.g. a mother radium catalyst.
can be liberated by treatment with hydrogen at
. Furthermore, an appropriately substituted pendyloxycargenyl group
, for example, 4-nitropenzyloxyrudenyl group conversion
By chemical reduction, for example, alkali metal salts of dithionite,
For example, dithionite) or treated with IJium or -!
, Bamboo hydrogen release agent (generates nascent hydrogen together with metal)
acids, especially suitable calgenic acids, e.g.
Lower alkanes which are not substituted with e.g. hydroxy groups by
Caldic acids, such as acetic acid, formic acid, glyfuric acid, diphenic acid
Nylglycolic acid, lactic acid, mandelic acid, 4-chloroman
Delate or tartrate are reducing metals due to the presence of thiols.
, such as zinc or metal salts, such as tetra(II) salts,
For example, by treatment with chromium (It) chloride (this
(preferably adding water) to the free force of the lugexyl group
It can be changed. Optionally 2-bromo lower alpha
Sul-2-iodo lower alkoxy corresponding to xycargenyl group
carbonyl group, nahaloylmethoxy group, and rugenyl group.
After that, it can be pre-treated by treatment with reducing metals or metal salts.
2-halogeno lower alkoxycarbunyl group as shown below.
can be converted to free cargexyl group, in which case allocargexyl group
The ylmethoxyl group is similarly nucleophilic, preferably
Salt-forming reagents, such as sodium thioferrate
It can be decomposed by treatment with Fi sodium iodide.
I'm self-sufficient. Macrocyclic priether (“crown ether”)
”) in the presence of fluoride ion-forming salts of hydrofluoric acid, e.g.
Alkali metal fluorides, such as sodium fluoride, are
treated with or mixed with non-detetratonic polar solvents, e.g.
For example, dimethyl sulfoxide or N,N-dimethyl acetate
The presence of toamide 9 inhibits the fluoride of organic quaternary bases, e.g.
lower alkylnanmonium fluoride is silica
Lower alkylaryl ammonium fluorides, e.g.
Tetraethylammonium fluoride or tetrabutylene
Replaced by treatment with ammonium fluoride
2-silyl ethoxylic? Nyl group to free car-xyl group
(can be varied with organosyl groups, e.g. tri-lower
Esthetics with alkylsilyl groups, e.g. trimethylsilyl groups
The converted carfoxyl group is usually solvolyzed, e.g. with water.
, released by treatment with alcohol or acid
be able to. Protect the bound amino group using a method known per se.
Depending on the
Release the original. In some cases, 2-7' lomo low grade a
Lucoxical? nylamino group to 2-iodo lower alkoxy
Shikal? nylamino group, aroylmethoxycarbunyl group
4-Nitropenzyloxyrudenylamine with amino group
After converting the group, a suitable chemical primary agent, e.g.
In the presence of a suitable calgenic acid, e.g. hydrated acetic acid, 2-halogen
(r) Decomposition of lower alkoxy groups and rdenylamino groups.
I can do that. aroylmethoxycarbnylamino group,
Nucleophilic, preferably salt-forming reagents such as sodium thio
It can be decomposed by treatment with ferrate.
4-nitrobenzoloxycargenylamino group
alkali metal dithionite, e.g. sodium dithionite
to be treated with

[Therefore, it can be decomposed. Optionally substituted diphenyl amicyl? nylamino group, tart-lower alkoxycarbnylamino group t
or 2-trisubstituted silylethoxycargenylamino groups are liberated by treatment with a suitable acid, e.g. an optionally substituted triarylmethylamino group, formylamino group or 2-acyl lower alk-1-ene-1- The ylamino group, optionally in the presence of water, is treated with an acid, e.g. a mineral acid,
For example, hydrocyclized acids or organic acids such as formic acid and acetic acid are liberated by treatment with trifluoroacetic acid,
The amino group protected by an organosilyl group can be liberated, for example, by hydrolysis or alcoholysis. An amino group protected with a 2-halogenoacetyl group, for example a 2-chloroa7tyl group, is treated with thiourea in the presence of a base.
Thiolate salts of ureas, such as those mentioned above, can be liberated by treatment with alkali metal thiolates and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product. By treating the amino group protected with the 2-fl-substituted silylethoxycardenyl group with a fluoride ion-forming salt of hydrofluoric acid, 1! It is also possible to convert to a free amine group as described above in connection with the release of the calgexyl group. A phosphoric acid amide group, a phosphonic acid amide group or a phosphinic acid amide group can be used, for example, with a phosphorus-containing acid, such as phosphoric acid,
Freed by treatment with phosphonic or phosphinic acids, such as orthophosphoric acid or prephosphoric acid, acidic esters such as monomethyl-, monoethyl-, dimethyl- or diethyl-phosphate 1 or monomethylphosphonic acid or its anhydride, such as phosphorus pentoxide. It can be converted to an amino group. Hydroxy groups protected with suitable acyl groups, organosilyl groups or unsubstituted or substituted 1-phenyl lower alkyl groups are liberated in the same manner as correspondingly protected amino groups. 2. The hydroxyl group protected by the 2-nochloroa7tyl group is liberated, for example, by basic hydrolysis, and the tar
Acidolysis of the unetherified droxy group with a t-lower alkyl group or a 2-oxa- or 2-thialiphatic or cycloaliphatic hydrocarbon group, such as a mineral acid or a strong carboxylic acid, e.g. trifluoro It is liberated by treatment with acetic acid. Protected, especially esterified, 9-sulfo groups are liberated in the same manner as protected carboxylic groups. The decomposition reaction is carried out under conditions known per se in a closed container and/or in an inert gas atmosphere, for example a nitrogen atmosphere, with cooling or heating as required. If several functional groups are present, more than one protecting group can be treated with acidolysis, e.g. trifluoroacetic acid or formic acid, or reduction, e.g. with subsalt and acetic acid, or hydrogen and hydrogenation catalyst,
For example, it can be desorbed at the same time by treatment with a black catalyst. It is preferable to select as follows. Esterification of a free redexy group as follows: The reaction in which a free redexy group, e.g. This is carried out by a known esterification method. For example, a compound of general formula (1) in which the carb to be esterified has a xyl group in a free form and another functional group, such as an amino group or a hydroxyl group, in a protected form, or Compounds of the general formula (1) or salts of the compounds of the general formula CI) in which the groups are present in the form of reactive functional derivatives are combined with the corresponding alcohol or with the reactive functionality of this alcohol.
React with a conductor. When esterifying compounds of general formula (1) in which the carboxyl group to be esterified is present in free form with the desired alcohol, the same condensing agent, e.g. calgezoimide, the same solvent as for the acylation according to method a) is used. , keeping the same reaction conditions. Compounds of the general formula (D) in which the carboxy group to be esterified is present in the form of a reactive functional derivative are, for example, mixed anhydrides or activated esters, which can be prepared by the method described in method a) (acylation). It can be obtained by condensing calgenic acid of the general formula (I) with an inorganic acid, cardanic acid, with a half ester of carbonic acid, or with a sulfonic acid, or more preferably with a vinyl alcohol. The reactive functional derivatives of the alcohols to be esterified are in particular the esters formed by condensation with strong inorganic or organic acids, such as the corresponding octa-nides, e.g. chlorides, bromides or iodides, or the corresponding esters. The lower alkyl compound is an aryl-sulfonyloxy compound, such as a methylsulfonyloxy or 4-methylsulfonyloxy compound. When esterifying a compound of general formula (1) in which the carboxyl group to be esterified is present in the form of a reactive functional derivative with the corresponding sulfur-4-yl, it is possible to When a compound of general formula (1) is esterified with the corresponding reactive functional derivative of an alcohol, when acylated by method a) K using an exhaustive functional derivative of caldicic acid of general formula (III). Use the same solvent and keep the same reaction conditions. Compounds of general formula (1) in which the carboxyl group to be esterified is present in the form of a reactive functional derivative are prepared and isolated in situ similarly to Method 6, as described in the section Method @) (Acylation). (It can also be reacted with a corresponding alcohol.) Formation of salt The salt of the compound of general formula (1) can be produced by a method known per se. of the general formula (I), for example by reacting the acid group with a metal compound, such as a suitable alkali metal salt of a calgenic acid, such as the sodium salt of α-ethylcaffanoic acid or sodium carbonate or ammonia or a suitable organic amine. Salts of the compounds can be formed, in which case it is preferred to use stoichiometric amounts or small excesses of salt-forming agents. Acid addition salts of compounds of general formula (1) can be obtained in conventional manner, for example by treatment with acids or suitable anion exchange reagents. The inner salt of the compound of general formula (1) can be prepared, for example, by neutralizing a salt such as an acid addition salt to the isoelectric point with a weak base, or 4! can be produced by treatment with a liquid ion exchanger. Salts can be converted into the free compounds in the usual manner, metal salts and ammonium salts, for example by treatment with a suitable acid, and acid addition salts, for example by treatment with a suitable basic reagent. I can do it. In all the above reactions carried out under basic conditions, 3-
Cephem compounds can optionally be more or less isomerized to 2-cephem compounds. The obtained 2-cephem compound or a mixture of 2- and 3-cephem compounds can be isomerized to a desired 3-cephem compound by a method known per se. The mixture of isomers is prepared in a manner known per se, for example by fractional crystallization,
It can be resolved into the individual isomers by chromatography. The process of the invention includes embodiments in which the compounds formed as intermediates are used as starting materials and the remaining operational steps are carried out or the operation is interrupted at any stage. Furthermore, the starting materials can also be used in the form of derivatives or formed during the reaction. It is preferred to use such starting materials and to select the reaction conditions so as to obtain the compounds described as particularly preferred. Pharmaceutical formulations The pharmaceutically used compound of general formula (■), its hydrate or salt, is used in the production of pharmaceutical formulations. The pharmaceutical preparations contain an effective amount of the pure active ingredient of general formula (1) alone or an effective amount of the active ingredient of general formula (1) in an inorganic or organic solid form suitable for oral administration. or as a mixture with liquid pharmaceutically acceptable excipients. Injecting the active ingredient of general formula (I) of the present invention 1,',
Preference is given to use, for example, in the form of intravenous preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions and can be prepared before use, for example from lyophilized formulations containing the pure active ingredient or the active ingredient together with excipients, such as mannitol. can. The pharmaceutical formulation is preferably sterile and contains auxiliary agents such as preservatives, stabilizers, wetting agents and/or emulsifying agents, solubilizing agents,
Osmotic pressure adjusting salts and/or buffers may be included. The pharmaceutical formulations of the invention may optionally contain other pharmaceutically useful substances, and may contain from about 0.14 to 100 m, especially from about 1 mo to about 504 m, of the lyophilizate to up to 100 m of the active ingredient. Contains Pharmaceutical preparations are prepared in a manner known per se, for example, by a conventional dissolution method or freeze-drying method. Uses Compounds of general formula (I), aquariums or pharmaceutically used salts can be used in the form of pharmaceutical preparations as antibiotic agents for the treatment of humans or animals, such as Gram-positive or Gram-negative bacteria and cocci. can be used for the treatment of infections based on Enterobacteriaceae, such as Escherichia coli, Klebsiella pneumoniae, and B. britella. Depending on the type of infection and the condition of the infected organism, the weight of
It can be used subcutaneously, intravenously or intramuscularly at a dosage of about 0.51 to about 51 licks for the treatment of 0 kg of mixed-breed animals (humans and animals). Starting materials: The starting materials used in the method for producing the compounds of the present invention are known, or if they are new, they can be produced by methods known per se. - The starting materials of general formula (II) and the corresponding compounds with respect to functional groups are known or can be produced by methods known per se. The starting materials of the general formula CIII) and their esters and reactive derivatives are new and likewise 1c objects of the present invention. The cargenic acid of the general formula ([l) used to introduce the acyl group of the cargenic acid of the general formula (DI) or its reactive functional derivative can be produced by a method known per se. These compounds, for example, have the following general formula (■): O 1 X-CH2-C-A-COOH (■) [wherein X represents halor the carboxyl group is present in an esterified form or the mana is protected with a conventional carboxyl protecting group] is reacted with urea and, if necessary,
removing the carxyl protecting group in the obtained compound, and/or protecting the amino group present at the 2-position of the oxacylyl group, and/or protecting the functional group present in the compound A,
and/or obtained by changing the group A to another group A. In the compound of general formula (to), X is chlorine or bromine,
More preferably, it is iodine or fluorine. The carboxyl group is present in esterified form, for example as a methyl ester or ethyl ester, or is protected with the customary protecting groups mentioned above, for example the t@rt-butyl group. The reaction of compounds of the general formula (-) with urea can primarily be carried out under the same conditions as mentioned in process C), dimethylformamide being preferred as solvent. It is preferred to operate at temperatures from about 80°C to the boiling point of the reaction mixture. It is considered that a compound of the general formula (to) in which A represents, for example, a carbunyl group, an unsubstituted methylene group, or a group of the formula =N-0-R4 - a methylene group substituted with, for example, a methoxyimine group, is reacted with urea. . The amino group present in the 2-position of the oxacylyl group in the obtained compound of general formula (II) can subsequently be converted into an amino group protected, for example with a t@rt-butyloxycargenyl group. If free cargenic acid of general formula (III) is to be used in the acylation reaction according to method a),
The protected carboxylic group is converted into a free carboxylic radical beforehand. In the compound of general formula (III), the carbunyl group A is replaced with a hydroxylamine compound of 202N-0-R4 in the same manner as described in the section of subsequent operations.
It can later be changed to a methylene group A substituted with a group of the formula =N-0-R4. For compounds of general formula (Ill), the unsubstituted methylene group A is converted into hydroxyimino group = N This can be done by changing to a methylene group which is not substituted with -0-H. The compounds of general formulas (IV) to (4) are known or, if new, can be produced by methods known per se. New starting compounds as well as intermediates and processes for their preparation are likewise the subject of the invention. Next, the present invention will be explained in detail based on examples. In the examples, temperatures are given in degrees Celsius and BOC stands for t@rt-butyloxycar/nyl group. Below is a blank example 1 a) Dimethyl-7β-[2-(2-amino-4-oxacylyl)-2-Z-meth in 3-acetate is noco-3-ceph, 5-4-cal is sodium salt dimethyl-7β in 3-acetate in methylene chloride 1.1-
-(2-(2-BOC-7-4-okinazolyl)-
2-Z-methodakashiizunoacetyladenno]-3-ceph,
Knee 4-power k dln gl Schiff, x k methyl ester 0.2611-) 17 fluoro l:f vinegar i11.
Stir for 1 hour at room temperature with 1 and 0.2 of anisole, add 50 sd of water-cooled toluene and subsequently evaporate in vacuo. After aging the residue in ether and drying, the corresponding trifluorot'he salt is obtained as a yellowish powder. The salt is taken up in methanol 5-, followed by -3 mol + lI [11? Nanothousand solution 0.
Add 2-. To precipitate the sodium salt, diethyl ether is added and the resulting precipitate t-F is separated, washed with ether and dried. The title compound was obtained in the form of a pale yellow & colored powder.
Rf ~0.23 (Siri* l” At: *-
Butano-V acetic acid/water = 67: 1 G: 2 m
) ; UV (H2O) :λmaw = 21
3mm (17200) and 261+am (1210G)
-b) s-acetoxymethyl-7β-(2-(2-
BOC-A#/-4-O (tezolyl) -2-Z-meth or siiminoacetylamino) -3-- to 7 *Mu4-Carousi H Schiff,! methyl ester 0.1 mK-10C'e in methylene chloride 4sg
Add 0.09 ml of zomethylformamide and stir for 30 minutes, then add 2-(2-110C-amino-4-odtzolyl)-2-1-methodP cycloelectroacetic acid and 0.14-ml of N-methylmorpholine. Add. After further stirring for 30 minutes at about -5 DEG C. to -100 DEG C., the reaction mixture was dissolved in methylene chloride 5-03-aceto-dimethyl-7/-adenno-3-cephhem-4-carun, nylmethyl ester 526 da and N -Methylmorpholine 0.14
- and react for 2 hours at about OC. For work-up, the reaction mixture was concentrated, the residue was taken up in ethyl acetate, and the mixture was shaken out successively with about 0.5 f hydrochloric acid, saturated hydrogen carbonate solution, and saturated sodium chloride solution. After drying the organic phase over sodium sulfate and evaporating, the title compound is obtained as crude product. This product is purified by preparative thick-layer atomography (silica dal, acetic acid ethyl ester). Rf approximately 0.53 (silica glu;
acetic acid ethyl ester); IR (tJI methylene); 3
400% 1785.1785k. 1740sk, 1680 and 163i'lL, the starting materials are produced as follows: 2-(2-BOC-Aj/-4-, resazolyl)
-2-(2-BOC-amino-4
-Zolyl)-2-Z-Methyl chloride acetic acid methyl ester 11 to 1.29 potassium hydroxide in 105 g of water
Add a solution of and stir at room temperature for 50 minutes. Subsequently, the reaction mixture is concentrated in vacuo, diluted with acetic acid ester and adjusted to 1-2 with IN hydrochloric acid. Evaporate. Residue tWP acid ethyl ester and heli? After ripening in a mixture with ten, the title compound is obtained as a yellowish powder. Ceramics approx. 0.38 (silical; m: butanol/acetic acid/
Water” 67: 1O: 23); Z R (JE
$'W-ru) s3400b%1735, 171
0 and 1640cIL-'. d) 2-(z-noc-amino-4-oj?tzolyl)
-2-Z-methoxyiminoacetic acid methyl ester sheet @rt-notylzocarne) 3.05 JI
PK2 (2-7</-4-oI?tzolyl)l! -Z-
Suspending 2.01 liters of ionic acetic acid methyl ester in meth,
Heat to 100°C and add 4-dimethylaminopyridine 0.1
ft-Add 6 React at 100°C for 7 minutes, cool,
The reaction mixture is diluted with ethyl acetate, extracted twice with saturated sodium chloride solution, the organic phase is dried over sodium tiiiate and evaporated in vacuo. The crude product was treated with 100 I of silica glu, 1 Matodara 74, with toluene and ethyl acetate 1! The title compound is separated using $16vK and subsequently crystallized from ether. Melting point =
142-146C; IR (CH, C4,): 341
5.1740%1715mb% 163g, 1515C
ML-”: U V (ietOH): λmaz =
227nm (16000) and 261℃m (7900
). @) 2-(2-amino-4-ocypnolyl)-2-Z-
Methoxyionoacetic acid methyl ester zomethylformamide 480-4-f3%-2-methoxy 2-noacetoacetic acid methyl ester 47.61 and urine 1 gtzoyti
ooc for 1 hour, then add urea 301, then add 1
React at 00C for 1 hour. Pour the dark reaction mixture onto ice water, thoroughly extract with acetic acid ethyl ester, and! The phase is loaded three times with water and twice with saturated saline solution and dried over sodium sulfate. After evaporation in vacuo, the title compound is crystallized from a mixture of acetic acid diethyl ester and diethyl ether. Melting point 142-147°C; IR (Nujol) especially 3438.3181.1701,1680,1
5B to 5, x. Example 2 a) 7β-[2-(2-amino-4-osazolyl)-2-Z-methoxyi? Noacetyladeno'-3-ceph, mu-4-carganic acid sodium salt Methylene chloride2.
05-Medium 07β-E2-C2-BOC-a is no 4-oxacylyl)-1-Z-(Methoya shii? Noacetyluaden)) -3-* 7 s Mu 4-Karoon lIP Schiff,
Nyl methyl ester 0.43 #t trifluoro t'hl1
2. It is stirred for 1 hour at room temperature with O5- and anisole α37-, mixed with water-cooled toluene 50- and subsequently evaporated in vacuo. After maturation of the residue with ether and drying, the corresponding trifluoroacetate is obtained as a yellowish powder. The salt was taken up in methanol (lO) and then dissolved in 113 molar methanolic sodium ethyl dPt (110.4 molar).
Add -. Diethyl ether is added to precipitate the sodium salt, and the resulting precipitate is separated off from P, washed with ether, and dried. The title compound is obtained as a page-colored powder. af approximately 0.24 (silica dal: 1-f tanol/acetic acid/water = 67:10:28kUV (in water): λw
ax = 205 mm (17600) and 26011
a(8400), b) 7/-(3-(2-BOC-7denno 4-
oxacylyl)-2-Z-Metho Life Shii Den Noah Ryu Chiru 72
0.2 ml of oxalyl chloride in chloroform 8-3-ceph 8mu 4-carvone #ll diphenyl methyl ester 0.18 mt''-10C of dimethylformamide was added at 30
12-(2-BOC-amino-4-oI?fuzolyl)-2-Z-methoxyimino vinegar @570Q
and 0.28 tf of N-methylmorpholine. Approximately -5
7β-amino-3-ceph, 0.845 μl of 4-carboxylic acid Schiff deuterium methyl ester and N-3-amino-3-ceph in 10 d of methylene chloride were added to the reaction solution with further stirring for 30 min at −10° C.
A solution consisting of 0.28% of methylmorpholine is added and the reaction is then continued for a further 45 minutes at 0-5°C. For work-up, the reaction mixture was concentrated, the residue was taken up in ethyl acetate, diluted with about 0.5N hydrochloric acid, and saturated diluted with hydrogen).
Shake out sequentially with IJum solution and saturated saline solution. After drying the organic phase 1 over sodium sulfate and evaporation, the title compound is obtained as a crude product. This compound is purified by thick-layer chromatography (silica dal, ethyl acetate). R4 approx. 0.3 (silica dal; ethyl acetate/toluene = 1:1): IR (in methylene chloride)
: 3402.1788.1755.1730.16
80.1628 and 1512 (Eel""i(/
f / )'; [J V (:'-/ /-le)
:λgH-260mm (7000sk): 215m
m(ah) Example 3 a) 7/-[2-(2-acylO4-oxacylyl)-2
-2-Methoxyacetyl-3-Cef, Mu4-
Calzyg4 dimethyl ester acetone in biparoyl 1.5 sg aa methyl bipa V-) 0.
11- and sodium iodide Q, 45J14D mixture is stirred at room temperature for 3 hours.Subsequently, suspension t11. 7β-[2-(2-72 no 4-
oxacylyl)-2-Z-methoxycynoacetate]-3-cefomi 4-callinic acid sodium salt 0.1
Add 0 #t- and further stir at room temperature for 1 w #0. Dilute the reaction mixture with ethyl acetate and saturated chloride) +3 um water S
The residue was talomatographically treated with silica dal using a 1:1 mixture of toluene and ethyl acetate and ethyl acetate to give 7β-( 2-:2-amino-4-o11?sazolyl)-2-methoxyiminoacetamide]-3-ceph2-4-carmenic acid bipayl-dimethyl ester is obtained. b) 7β-[2-(2-ami]-4-oxacylyl)-2-Z-meth-24221-24221-24221-3--I
c78 Mu 4-carunic acid pi/yaroyloxymethyl ester hydrochloride The piparoyloxymethyl ester is converted to the hydrochloride salt by treatment with a saturated HCl solution in methylene chloride and precipitation with ether. R4-Q, 25 (ethyl acetate')
: IR(CH,CL,'): 3490.33
80. 1780, 1751.1677.1620 Band on knee 1. Example 4 a) 7β-[2-(2-amino-4-okinazolyl)-2-Z-methoxycynoacetyl acetate-1-(ethyloxycarboxylate) 2-(2-BOC)-ethyl ester 7β-(2-(2-BOC
-1denno4-Ji"??zolyl)-2-Z-methoxyionoacetylamino]-3-ceph, 5-4-fJk-
A mixture of 0.75 # of ethyl ester, 3.9 # of ethyl ester, 3.9 # of ethyl ester, and 3.9 # of methylene chloride was stirred at room temperature for 1 hour, and added to a cold toluene tube. Evaporate under reduced pressure. To the residue, add hot metal containing toluene and atx-form, evaporate, add a mixture of toluene and ether, and evaporate again. The residue is crystallized from ether. The title compound, trifluoroacetate-a, melts at 14°C to 150°C with decomposition. ! R-svetator (mesol): 1790.
1745.1730.1670,1640 and 1540
Band trifluoro awPys salt to α4*n in acetate and wash twice with cold saturated sodium bicarbonate solution. The organic phase t** After drying over sodium, it is concentrated under reduced pressure on 1lII liquid gold. The residue was chromatographed (silica dal 60; methylene chloride/ethanol) and 0.6
The title compound is obtained with a 1 g value of 2 (silica dal 60; methylene chloride/ethanol-9=l). b) 7β-[2-< 2- BOC-A1)-4-
7β-(2-(2-BOC -7
t/-4-oxacylyl)-2-Z-/tokinimi/-
Acetyl adeno]-3-ceph, 5-4-calcyic acid-(
i-ethoxycar-nyloxyethyl)-ester is
Can be manufactured as below self. 1-aa minityl dithyl carbonate in 10-10% acetone) 0.45. Sodium iodide 1.8 It-
Add. Stir for 2 hours at room temperature, add 70% of the total
β-C2-(2-BOC-amino-4-oxacylyl)
-2-Z-methoxyimino-acetylamino]-3-cephem-4-karoon 91.161! and 1,5-zoazobisic E115.4°
Add a solution of sIi, stir the reaction mixture for 4 hours at room temperature, dilute with acetate and saturated salt) 17,
Wash with a damp solution. The V phase is dried over sodium sulfate and evaporated under reduced pressure. Purify by N minute column chromatography (Silical 60: methylene chloride/ethanol). Example 5 a) 3(1-Methyl-IH-tetrazol-5-ylthio, methyl)-7β-[2-(2-AZno4-oxacylyl)-2-Z-methoxyiminoacetylamino]-
3-Cef8mu4-carnoic acid sodium salt 3-(1-methyl=IH-tetrazol-5-ylthiomethyl)-7β-[2-(2-
BOC-azuno 4-oxasilyl)-2-Z-methoxyionoacetylaminoco-3-77 z A -4-
Force k wW y@Schiff 8nyl methyl ester 5.5It
- trifluoroacetic acid 1I22- and anisole 3. at room temperature.
9-, add 200 s# of water-cooled toluene and evaporate in Xg. After aging the residue and drying in ether, the corresponding trifluoroacetate is obtained as a yellowish powder. Suspend in 50ml of this salt water and
Add NaOH solution tube to adjust - to 7.0. Cloudy solution tAnno4-rai(Amb@rllt*)
AD-2 @ 4cII diameter filled with adsorbent resin 400 resistant
Coomadography is carried out on a column of L. After 12 elution with an aqueous solution of inglobalanol, the homogeneous product-containing fractions are combined by thin layer chromatography, and lyophilized, the title compound is obtained. Rf~0.2
(Silica gel; n-butanol/ice vinegar #/water = 67:1
0:23) iIR (nuzoyol): especially 3330.17
70.1667.1606c, z, U V(H,
O): J,, x= 270 ysm (15000
) @b) 3-(1-methyl-IH-tetrazole-5
-ylthiomethyl) -77-[2-(2-BOC-amino-4-oxacylyl)-2-Z-methoxyionoacetylamino]-3-ceph, nee 4-carunic acid Schiff~
Nyl methyl ester methylene chloride 14d glue methylformazole 1.26
- 1.40d of hydrogen chloride in methylene chloride 42-
-(2-BOC-Amino-4-Ozolyl)-2-Z-MeF Add 3.99 # of 2-noacetic acid and 1.96 d￥r of N-methylmorpholine. -5℃～
The reaction mixture was then mixed with 3-(1-methyl-IH-tetrazol-5-ylthiomethyl)-7β-amino-3 in methylene chloride 70-.
A solution consisting of 7.311 phenyl methyl ester and 1.96 N-methylmorpholine is added and reacted at 0-5° C. for 45 minutes. For work-up, the reaction mixture was concentrated, taken up in acetate and
Shake out sequentially with 0.5N hydrochloric acid, saturated NaHCO3 solution and saturated saline solution. After drying over IJ sulfuric acid and evaporation, the crude product obtained was
Escape from madography. Elute with toluene solutions of increasing concentrations of toluene and acetate (10-25);
After evaporation, the title compound is obtained as a yellow foam. Rf-o, ssc acetate; silica dal);! 8
(CH,C6,): especially 341O11793,1758
, 173 to 1684.1632cIL”; U V (
ItOH) :λ1□:261 am (16200). Example 6 3-(1-car-xymethyl-IM-tetrazol-5-ylthiomethyl)-77-[2-(2-amino-
4-oxitezolyl)-2-8-methomodiiminoacetyl-2noco-3-ceph8-4-carmenic acid disodium salt 3-(1-cal?xymethyl-IH-tetrazole-5
-ylthiomethyl)-7β-C2-<2-BOC-7<
/-4-r#? 3.5F
'i methylene chloride 18.6 mg and trifluoroacetic acid 1
Stir in &6- for 1 hour at room temperature.1. water-cooled toluene 10
Add 0100III and subsequently evaporate and the residue is aged at 2111, separated from P and dried. The trifluoroacetate salt is suspended in water, brought to a pH of 7, and the solution is evaporated onto an An/Multi-XAD-2 adsorbent resin. After elution with water, homogeneous nephraction in thin layer atomography and freeze-drying, the neat title compound is obtained e Rf ~ 0.55 (V lylated silica ff
A/UPct*; water/acetonitrile = 95:5); l
1l (streak): 41K 3325b %17$8.166
5-1628 (31-'; UV (Hlo): λm,,
= 2681m (1400G) *b) 3-(1-cal-dimethyl-IH-tetrazol-5-ylthiomethyl)-7β-[2-(2-11Oc-amino-4-o a
? Sazori #) -3-2-Methochudennoacetylatno)-3-77 Tsuta Mu4-Cal? di-sodium chloride salt zomethylformamide 2 in methylene chloride 13-0.92
- to -25C within 10 min dropwise addition of r-r chloride #1.115s[)lI solution in methylene chloride 13-
Stir for 30 minutes at 5C, followed by dilution of
-(2-BOC-af/-4-,1xazolyl)-g
- Add a solution of 112.85 I of methacrylate vinegar and 1.34 I of N-methylmorpholine. Another 30 minutes -2
Stir at 5C (11 liquids). A suspension of 4.48N of 3-(1-cal-xymethyl-IH-tetrazol-5-ylthiomethyl)-7β-amino-3-ceph,mu-4-carunic acid in 40-methylene chloride was diluted with bis-carunate at room temperature. Stir with (trimethylsilyl)-acetamide (BSA) 11.70- for 1.5 hours,
Add 1.60 - of N-methylmorpholine and cool to -25°C (solution 1). Solution Bt is added dropwise to solution A and the mixture is subsequently allowed to react for 113 hours at room temperature. For work-up, the reaction mixture is poured onto ice water, adjusted to a value of -7 with t-IN caustic soda solution, and the aqueous phase is shaken out three times with total acetate.After the phases have been separated, the aqueous phase is mixed with acetate. Extract two more times with a (4:l) mixture with acetone. The organic phases are combined, the saturated saline solution is shaken off, dried over sodium sulfate and evaporated. The title compound is obtained as a brown powder. For purification, the crude product was mixed with 1 ml of silica dal, previously inactivated by the addition of 5 ml of water.
y deri cii thornfish treatment. Loli wings. After washing with acetic ester containing 251t-, pure acetate and acetic ester containing 101% of acetone, mark 1
1 (compound D is obtained. Rt~o, 2 (silica dal;
Example 7 3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl"-7β-[2-(2-
Amino-4-Onosazolyl)-2-2-methodakasi? Noacetylua Denno] -3-Seph 8 Mu 4-Cal? Sodium iodide 29.961 and 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylmercapmene 2 in brine 15 and rice vinegar 11[0,93]
．． 251 heated to 700 °C, add 3-acetyldimethyl-7β-(2-(2-amino-4-ozolyl)-
2-Z-Metho-Nacetyl-3-Cef,
Mu-4-carganic acid sodium salt (ljl 1 m)
4.621 was added to ILb, and compound a was stirred at 700 for 75 minutes under an atmosphere of tfijl. Pour the brown reaction solution over 200ml of ice water and adjust to pH 5 with IN caustic water.
, 5 and subjected to a column packed with Amberlite XAD-2@adsorbent resin. Elution with a water bath with increasing water and isopropanol content (5-154) and combination of homogeneous fractions by thin layer chromatography/roughy yields the compound 1ljl#I and the corresponding 2-E-compound after death. Silylated silica l”k (
After rechromatography and elution with a 9:1 mixture of water and acetonitrile, thin layer chromatography gives the homogeneous title compound and the corresponding 2-E-compound. These compounds are each taken up in methylene chloride, treated with HCl-containing methylene chloride, and added dropwise into ether. The resulting sediment #
Separate ItF and dry it. 2-Z4. Compound: R4-0.
33
20, l782.1718.1680.1635 ($1
-'; UV (R20); -, x=270 am (1
4500): NMR (d-0M80); Oxacylyru Hδ = 7.75, N-OCH, δ = 3.95
．． 2-E-compound; Rf ~0.25 (Silicadal oP
TI tJpc-12; H2Q/acetonitrile 4
:1);IR()IRdi,-ru);especially 330.178
4.1718.1682.1632cga. UV (H*O): 2705k (6500):
NMR (d-0M80);tdFtf-LouHJ=&
35, CH, O-N J-4, 15° Example 8 3-(4-carbamoylpyridiniomethyl) = 7β-[
2-(2-7N/-4-1dP?!')k>-2-Z-
Meto Middle School Den Noacetera Denno J-3-Seph, Mu 4-
11.25 of sylate water in Cal df and 22.51 of sodium iodide and isonicotine aj) in rice vinegar IIQ, 43- and 3-acetyl dimethyl-7!
[2-(2-72-4-oxacylyl)-2-Z-Metho-3-Cef, Mu4-Calgenic acid sodium salt (Example 1m) Add 3.46jl' to the reaction mixture Stir at 70° C. for 1 hour under nitrogen atmosphere. After cooling, condition the brown reaction solution with 5.2 Kl of tIN caustic Soumet solution.Amberlite XAD-2@
After the meeting, there are 9 columns a! Treat thornfish*12
After elution with 46 isonoropanol solution and combining the product-containing fractions, homogeneous by thin layer chromatography and lyophilization, the title compound is obtained as a yellowish lyophilizate. R(:0.6(silylated silica gel UPC,
2; water/acetonitrile = 4:1); IR (replacement alcohol); especially 3340b% 17F 6.1655.1615
cl! ! , UV (R20): 212nrn(
22300), 261mm (15400). Example 9 &) Dimethyl-7β-(2-(2-amino-4-oxacylyl)-2-Z-hydroxyiminoacetylamino)-3-cef, mu 4-cal dy in 3-acetyl salt methylene chloride 3-acetate dimethyl-7β- in 16-
[2-(2-BOC-aki]-4-oxasilyl)-2
-Z-(2-tetrahydrobilanilo-diimino)-acetyl 72noco-3-77gourd 4-carlinic acid nophenyl methyl ester 4.2#trifluorovinegar@16.
5 wt and anisole for 1 hour at room temperature, the brown reaction mixture was mixed with water-cooled toluene 10 G,
Evaporate in vacuum. After drying and aging the residue in ether, the corresponding trifluoroacetate is obtained as a yellowish powder. This salt is suspended in water SO- and the sea value is adjusted to 7.4 by addition of 2N soda. Diameter 3.5 c filled with Amberlite XAD-20 with turbid solution
Perform a mudgraphy treatment on the aO column. After elution with 124 isoglopanol solution and combining the homogeneous product-containing fractions by thin layer atomography and lyophilization, the title compound is obtained. Rt~0,45(
Silylated silica R0PTI-UPC,; water/acetonitrile: 4:1) GrR (nuzo, -R); especially 332
5b% 1770.1665.1608cs”; U
V (H, 0'): 209 (20000); 26
0 (12200). b) 3-acetomethyl-7β-(2-(2-B
OC-at/-4-oxitezolyl) -2-Z -(2
-tetrahydryl ycI bilanyl chloride)-acetylamino''-3-7-7-4-carN 7 @ Schiff, dimethylformide 2 in methylene chloride 40- 0,9
1.011 tt of oxalyl chloride in 30 wt of methylene chloride was added at 15C to m/, stirred for 20 minutes at -5°C to -100, followed by 2-(2-BOC-amino-4-oxasilyl)-2-Z- Add 13.551 m'i of (2-tetrahydropyranyloxyimino)-acetic acid and 1.4 m'i of N-methylmorpholine. Stir further for 30 minutes at -10C. The reaction mixture was then mixed with 3-acetoxymethyl-7β-amino-3-ceph in 44-methylene chloride. Ni 4-carmen 4.39
Mixed with a solution of NN-methylmorpholine 1.4- and -5
React at 0°C for 30 minutes and at 0°C for 75 minutes. After work-up, the reaction mixture is concentrated, taken up in acetic acid ester and shaken out with 0.5N hydrochloric acid, saturated NaHCOs solution and saturated sodium chloride bath. After drying over 61 Cal sodium and evaporation, the crude product obtained is 25
0Ii and perform a mudgraphy treatment. After dissolution in a toluene bath with increasing toluene and acetate content (10-50), combining the homogeneous product-containing fractions by thin layer atomography and evaporation, the title compound is obtained. a R4~0.5 (silica glu; acetate ester); I R (CH, C10): Special K 3410.17
96.1748.1683.1631clL-':
UV (ItOH): λ ” 258 nmma wing (15100). The starting material is prepared as follows; e) 2-(2-
noc-ami)-4-oxacylyl)-Z-Z-(2-
Tetrahydropyranyloxy1)-2-(2-BOC-A1)- in acetic acid ethanol 158-
To a solution of 15.8 N of methyl 4-oxacyl)-2-Z-(2-tetrahydropyranyloxygino)-acetate was added a solution of 11.66 N of potassium hydroxide in 100 of water and 158 sdtlk of ethanol, approx. Stir for 15 minutes at 15C. At the ninth step of the work-up, the aqueous phase was evaporated in ^9, the aqueous phase was extracted with 2 g of acetic ester, adjusted to -λ4 with 2N@@, and the aqueous phase was diluted with vinegar ester, acetone, and O (4:1). )8
The combined organic phases are shaken out with water and saturated aqueous sodium chloride solution, dried over 6[mu]m and evaporated.The residue is aged with hexane, separated from P and dried. 41m compound K122-125C (obtained in the form of a pale yellow fine powder with a D melting range of 8'. d) 2-(2-BOC-Aξ)-4-O11? sazolyl)-2-Z-(2-tetrahydropyranyloxy 1)
)-acetic acid methyl ester 2-(2-amino-4-oxacylyl)-2-2-(2
-tetrahydropyranyloxyz))-Acetate methyl ester 18.4.9 and di-tart-butyl sulfate 44.7F to zomethylanoviridine 1. Add OI violet one by one. The mixture is stirred at room temperature for 4 hours. For post-treatment, the cloth was diluted with acetic acid ester, water, saturated hydrogen carbonate (IJum water bath solution) and saturated saline bath solution were used to loosen the cloth,
(ik acid) Dry over IJum and evaporate. After elution with toluene and increasing (5-10) toluene solutions of ethyl acetate and combining the homogeneous product-containing fractions by thin layer atomography and evaporation, the title compound is obtained. af~0.58 (silica r; toluene/acetate=, l:l). *) 2-(2-A-Sai)-4-oxacylyl)-2-Z-
(2-Tetrahydropyranyloxyimino)-acetic acid methyl ester 181.8 g of 4-promo 2-Z-(2-tetrahydropyranyloxyimino)-acetic acid methyl ester in 900 W It of dimethylformamide and 354.411 W It of urea for 1 hour at 100° C. The reaction mixture heated to 0°C was then poured onto ice water, salted out with common salt and extracted four times with acetic acid ester.The combined Ariiso extracts were shaken out with a saturated aqueous solution of common salt and diluted with sulfuric acid). ,Evaporate. The crude title compound was obtained as a dark oil, which was purified opo on silica gel.
Purify by mudgraphy treatment. After 8$11 with a mixture of toluene and acetate (2:1 to 1:1),
The resulting compound 41111 is crystallized from ether. During melting 1fi145-149C (decomposition) f) 4-Zo-a-Mo 2-Z-(2-tetrahydropyranyloxyimino)-acetoacetic acid methyl ester Example 1 g) Nine crude 4-fcl Mo 2-Z-
Hydroxyionoacetoacetic acid methyl ester tert dioxane 1°65/dissolved in 3,4-dihydro-2H-bilane 20.1 wt and p-)luenesulfone #R1 hydrate 0.69N for 15 hours at room temperature. Stir. For better work-up, the reaction mixture was concentrated and the residue was taken up in acetic acid ester.
, shaken out with water, saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over sodium sulfate and evaporated. The title compound is obtained as a dark red oil. Rf~0,6
and 0.54 (silica gel, toluene/acetic acid flN ester = 1:1). g) 4-promo 2-Z-hydroxyiginoacetoacetic acid methyl ester in 2-Z-human a in 5505 g of chloroform.
The noacetoacetic acid methyl ester is mixed with a solution of bromine 50.9 in Oaform 200 at 40 DEG C. within 1 hour and subsequently stirred for a further 1.5 hours at room temperature. For work-up, the reaction mixture was shaken out three times with a fully saturated saline solution, and the organic phase was
- Dry over sodium and evaporate in a vacuum. The resulting crude title compound is further processed without purification (Example 9f) aR (~0.29 (silica);
Toluene/acetic acid ester = 11). Example 1O a) 3-acetoxymethyl-7β-(2-(2-amino-4-oxacylyl)-2-Z-(2-carxygulog-2-yl-oxyimino)-acetyla2no]
-3-Cef, mu4-car2phosphate sodium salt 3-acetoxymethyl-7β- in methylene chloride 10-
(2-(2-amino-4-osazolyl)-2-Z −
(2-BOC-glogu-2-yl#*diimino)-acetyla2no3-s-cephsmu4-cals:/acid 9.3
1 to trifluoro#+@34- and anisole 5.8-
Stir for 75 minutes at room temperature and add 200 sd of water-cooled toluene.
Add t and evaporate in vacuo. The residue is aged in ether and after drying, a colored powder is obtained. This powder is suspended in 50ml of water. I
After adjusting the μ value to t-7.5 with N caustic soda, the solution was transferred to a column of diameter 3 cx packed with Amberly) XAD-20 adsorbent resin 200 cF! Treat thornfish. Elute with water and combine the homogeneous product-containing fractions by thin layer atomography. After ILki has dried,
The title compound is obtained. R (~0.23: (silica gel; n-butanol/rice vinegar/water ==67:10:23); IR (nuzo, -ru)
; 3350b, 1770.1668.1600*t
-'HUV (H2O); λ, , = 264 nm (127
00):210nm(sh)*b) 3-acetoxymethyl-7β-[2-(2-amino-4-oxacylyl)-2-Z-(2-t@rt-butyloxycal is nylproa'-2- yloxyimino)-acetylaminoco-3-cefmu4-carmenic acid 3-acetoxymethyl-7β-[2-(2-BOC-ami/-4-yF'P sazolyl)-2-Z-(2 -B.O.C.
-prog-2-yl-iono) = 7cetylamino]
-3-Cepham-4-calcinic acid Schiff, nylmethyl ester 2.5#, methylene chloride 25-, trifluoro afi
A mixture I#IJ consisting of 4.5 p-acid and 0.48 g 1t anisole is stirred at room temperature for 75 minutes, diluted with water-cooled toluene and evaporated in vacuo. The residue is aged with ether, separated and dried to give the corresponding trifluoroacetate as a page one color powder. Suspend the powder in 10ml of water-cooled methanol and add 2 dl of a 3M methanolic sodium α-ethylhexyl 1/ate solution.The resulting oil is decanted and the residue is ether and diluted with ether (1'). : 1'') mixture, separated by F and dried.
pe, developing agent; water/acetonitrile = 3:1
), the product-containing zone was washed with acetonitrile/water (1:1)
Remove from bath with 50 mg of the mixture and filter through Milliball filter.
After heating and evaporation, the pure title compound obtained is reprecipitated from an acetone/ether mixture. af ~ 0.4 (silica rol; n-tutanol/rice vinegar/water = 67:10:
23): IR (nuji, -ru); 3320b% 1770
sh% 1730.1674.1598fi. UV (H, O): 210 nm (sh); 263 am (1
0900) @@) 3-acetoxymethyl-7/-(2
-(2-BOC-amino-4-omosazolyl)-2-Z
8
Nyl methyl ester oxalyl chloride 40-Nakagori methyl formamide Z 0.9
1.0 m'i of oxalyl chloride in 30 methylene chloride was added to - at about -5°C, stirred for 20 minutes at -5°C to -100°C, and then 2-(2-BOC-7j/-4-oxacyl) Add 3.55 JI of -2-Z-(2-BOC-glob-2-yloxycon)-acetic acid and 1.4 s/ of N-methylmorpholine. Stir for 30 minutes at about -100 °C and then add 4.39 L of 3-acetoxymethyl-7β-amino-3-cef, mu-4-carmenic acid Schiff, nylmethyl ester in methylene chloride 44 to the reaction mixture. - Add a solution of 1.4 yd of methylmorpholine and
0 minutes, and react for 75 minutes at OC. For work-up, the reaction mixture was condensed and taken up in acetic acid ester, fi, 5 Nmg.
ll. Shake out sequentially with saturated NaHCOsm solution and saturated saline bath solution. After drying over sodium sulfate and evaporation, the crude product is obtained as a brown foam. This product was added to silica gel 2
Chromatograph on 50 g. Elution with toluene solution with increasing toluene and acetate content (10-50 s) and homogeneous thin layer chromatography containing the product-containing fraxin carbonate are combined and after evaporation the title compound is obtained.Rf ~0.52 (silica gel; toluene/#
Acid xytte&=1:1); IRCCH,C
1,): especially 3420°1800.1745.169
0.16334. 0V(ItO)I) knee a x =
The 258 nm (15400) starting material is prepared as follows. d) 2-(2-BOC-amino-4-oxacylyl)
-2-Z-(2-BOC-grog-2-kt-2))-acetic acid! //-2-(2-bi”-(IIOC) in −kVswl
)-amino-4-oxasilyl)-2-Z-(2-BO
C-fel 2-ylol-drcyf/)-Acetate methyl ester 10.55 JI in water 50-KOH 7,08
Add goH solution and ethanol 75-. The S compound is stirred at room temperature for 1 hour, then concentrated in vacuo, adjusted to a value of approximately 1.6 with 14N hydrochloric acid, and extracted several times with acetic acid ester.
After shaking out the combined organic phases with water and saturated aqueous sodium chloride solution, drying over sodium sulphate and crystallizing the evaporated crude product, the title compound 41 is obtained in the form of a pale yellow powder. Melting range: 14° to 144C (decomposed). @) 2-(2-ni's-(Roe)-7(/-4-
#xazolyl) -2-Z -(2-BOC-faf-
2-yl-o-o-o-si-z))-acetic acid methyl ester di-t@
rt-Butylcica-I nate 60.5111C11 cloudy 2-(2-amino-4-oxacylyl)-2-Z-
(2-BOC-guaf-2-ih#decspii2))
- Add 0.91 t of 4-dimethylanobilisone to 30.2 liters of methyl acetate and stir at room temperature for 1 hour. It is then diluted with acetate, shaken out with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Oily residue t silica gel 600jl a Matodarafui treatment,
Toluene and acetate content increases (2.5 to 5
rs)h 111III11 in toluene solution, evaporated, and then thin layer chromatography yielded the homogeneous title compound @uv<czn@oH):λ,,x=211nm
(10500) and 2 series theory (9200); IR (OH
, CA, ): 1812.1783.1748.1600
゜1587m-'. f) 2-(2-aki)-4-oxacylyl)-2-Z
-(2-!10(1'-gmf-2-iht*94i)
)-Methylnystyl dimethylsulfonate acetate 45-Medium OfQ Moiso Vinegar @t@r
t-methyl ester 11.25jl and potassium carbonate A
2-(2-at)-4-oxacylyl)- in dimethyl sulfoxide 45- under ice cooling at 6.21OffrH.
2-Z-hydroxyiminoacetic acid methyl ester 8.31
Add 10 solutions. Grind and stir the reaction mixture at room temperature for 18 hours. Work-up rounding, pouring onto ice water, extracting with acetic acid ester, shaking out the organic phase with water and saturated saline bath solution,
Dry over sodium sulfate and evaporate. After crystallization of the residue from ether, the title compound is obtained in the form of yellowish crystals. Melting range; 156-160C*g)L! −
(2-amino-4-oI?dezolyl)-2-Z-hydroxyiminoacetic acid methyl ester 2-(2-amino-4-oxacylyl)-2-Z-( in methylene chloride 300-
2-tetrahydropyranyloxyimino)-acetic acid methyl ester 26,9.9 t-)lifluoroacetic acid 9300 m
Stir for 2 hours at room temperature, then add cold toluene,
^ Evaporate in the air. The residue is taken up in acetic acid ester, extracted successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The oily residue is crystallized from ether and after death the compound II@ is obtained. Melting range; 151-155C (decomposition) Example 11 3-pyridiniomethyl-7/-[2-(2-a2no4
-oxacylyl)-2-Z-(2-cal-glogu-2-
Iloxii 2)) -acetyl adeno] -3-ceph, mu 4-cal♂ palmate - A bath solution of 30 I sodium iodide in 16 m of sodium brine heated to 70°C, wood vinegar @ 1.2 m, pyridine 1.15 sd and 3-acetate and dimethyl-7/~[2-(2-amino-4
Add 5.55 jlt of -2-Z-(2-cal-2-yloxy-2))-acetyladeno]-3-ceph, 4-carunic acid sodium salt. This mixture 1-* Stir in an elementary atmosphere for 1.5 hours. After cooling, add IN caustic soda to adjust the temperature to 5.1, and fill the mixture with XAD-2 adsorbent resin about 75i01. A column with a diameter of 4.5 cllL was treated with a column of 4.5 cllL, and the mixture was separated with a 10 m aqueous isoglopanol solution. After nine months, the compound of am is obtained in the form of a yellow powder m Rf ~ 0.47 (silylated silica l' lk
UPC12: Water/A7tonitrile = -6:1); IR (
Nuzo, -ru): especially 3345.1770.1665.1
600bca-'; UV(H,O):λ-,! ==2
55 mm (1200G) 6 examples 12 3-(4-carbamoylpyridiniomethyl)-7β-[
2-(2-amino-4-oxasilyl-2-Z-(2-
Caluxig C1f-2-yloxyimino)-acetylaminoco-3-7F, Mu4-cal is added to a solution of sodium iodide 2111 heated to 70C in xylate sodium brine 11-. 16j', ice vinegar ell
O,8- and 3-acetyl dimethyl-7β-(2-(
2-Anno-4-Oxacylyl)-2-Z-(2-Carme, 2-Iluo, 1))-Acetylamino'-3-Cef, 5-4-Cal? Sodium salt 3.
88jlvI-Add. The mixture was heated under nitrogen atmosphere for 1.5
Stir for an hour. After cooling, the temperature was adjusted to 5.3 by adding IN′fI soda, and the mixture was
A column with a diameter of 4.51 mm filled with D-2 @ absorbent resin 650- is subjected to a mudgraphy treatment. After stripping with water and homogeneous thin-layer chromatography, the product-containing 7-lactones were combined, evaporated, and rounded to remove any remaining isonicotinamide.After several ripening in acetone, the title compound was obtained. is obtained. Rf-0,6 (silylated silica 1"
k UPo 12 a water/acetonitrile” (s:
i) #IR (J di-ru): especially 3320b%17
7G. 1665, i 600b cm-': UV (Hl
o): 4yB@
2-Z-(2-caru, 2-yloxyimino)-acetyloxyimino]-3-cef, mu 4-calanoic acid disodium salt 7β-[2-(2-BOC-amino) −
4-oxacylyl) -2-Z -(2-BOC-gC
1f-2-(ruoxyi2)-acetylaminoco-3
-cephem-4-calcinic acid Schiff, nyl methyl ester 3.041) Lifluoroacetic acid 15 mg, anisole 2,
- and 3.0 sgt of methylene chloride - stirred at room temperature for 1.5 hours, then added 100-7 gt of ice-cold toluene to the mixture,
After evaporation and ripening in vacuo, drying and post-mortem, the corresponding silifluoroacetate is obtained. This is methanol! Ssd
Add 3 dt of the medium sanoate solution to 3 m methanolic sodium α-ethyl, precipitate, add ether'ft to make it complete, filter and wash with ether. The resulting precipitate was dissolved in water, the temperature was adjusted to t-7.5 with IN caustic soda, and the solution was mixed with Amberlite XAD.
-2・250sd! Filled and chromatographed on a nine column with a diameter of 3.5 mm. Elution with an aqueous solution of 10-isoglobanol and a homogeneous product by WIN chromatography were combined and lyophilized to give the title compound R45-cL25.
Pru: n-sitanol/rice vinegar #/water = 67:10:23
); IR(X y, -b): assob%1
77G, 1668b. 15953, UV(H,O);λ-,:264n
Im (9700) -b) 7β-[2-(2-amino-4-oI?sazolyl”) -2-Z -(2-BO
C-Glogu-2-yloxyimino)-acetylakinoco-3-cephem-4-carmine sodium salt 7β-(2-(2-BOC-7) in methylene chloride 50-
i/-4-oxasilyl)-2-1-: . (2-1100-grogu-2-i h-j medium t/)-
acetylamide]-3-cef, mu-4-cal I phosphoric acid Schiff 8-el methyl ester 5.0jk7 Nisole 1.051
The mixture was stirred for 3 hours at room temperature with 1It and 96.25ml of Tritruff vinegar, added with 200mt of water-cooled toluene, and evaporated in vacuo. After aging and evaporation of the residue, the corresponding trifluoroacetate is obtained. This is water 5
〇 - KJI was turbid in medium, adjusted to pH 7.3 with 1N NaOH, and treated with a column filled with Amberlite XAD-28 adsorbent resin 500 mm. After separation with increasing (5-50°) aqueous solutions of water and inglopanol and thin-layer chromatography to obtain a homogeneous product-containing flux, the title compound was obtained after evaporation and drying. can get. No. 84-0.4 (silical; n-butanol/rice vinegar al/water = 67:10:23); IR (nuji, -l): especially 3340b, 1764.1737.1
668.1600(:IIL, UV(H,0): 2
05mm (20800): 262nm (10000)
. e) 7β-(2-(2-BOC-A2NO4-O-Scorpion #) -2-Z -(2-BOC-faf-2-
3-ceph, 1.35 m of nylmethyl ester dimethylformamide and 1 oxalyl chloride.
．． 5- was reacted in 100% methylene chloride at about -1C for 30 minutes to give 2-(2-BOC-7f/-4-oxasilyl") -2-Z -(2-BOC-glogu-2-yloxy Add 6.2N (imino)-acetic acid and 2.1 dl of N-methylmorpholine and react for an additional 30 minutes at -5°C to -10°C.Subsequently, the reaction mixture totals 555g of methylene chloride.
A solution of 7β-amino-3-setemul-4-calcinic acid Schiff, nylmethyl ester 5.511 and N-methylmorpholine 2.1- in the solution was added, and the mixture was allowed to react at -5C for 30 minutes. For work-up, the reaction mixture was concentrated and taken up in acetic acid ester at 9.0%. Shake out sequentially with IN hydrochloric acid, saturated NaHCO3 bath solution and saturated saline solution. After drying on silica gel, the resulting crude product was purified with silica gel 2501.
Treat with madography. Increasing toluene and acetate content (104~20)) @l in toluene solution
The homogeneous product-containing fractions obtained by IL and thin layer chromatography are combined and evaporated to give the labeled compound. ;IR(CM,C42);341
8.180G, 1758.1733.1686.16
32C1l″″’; trv(gtog):λmax
=260mm (sh) (6700). Example 14 a) 7/-[2-(2-ami]-4-oxacylyl)
-2-Z -(2-BOC-gC1f-2-Iruo-meishiden))-A7-7-Yomu-4-Carunic acid bipalyloxymethyl ester dimethyl formamide 8 -Naka07β-(2-(2-Amino-4-O-Nazolyl)-2-Z-(2-BOC-Glogu-2-yloxyden))-Acetyl-2-Noko-3-
Ceph-4-karoon sodium salt o, 5IIt■
-Domethyl bi/f rate 0.4- and reacted at 0 °C for 30 min, stirred while adding pi (g) of phosphate buffer, and extracted with acetic acid ester.
s f# Shake out with saturated salt solution and sulfuric acid) IJ
Dry on a plate and let it dry. The crude product vIJ1 is chromatographed on silica 4fkl'll. Increase in toluene and vinegar rice ester content (10'll~s
Q) fiIrlIi with toluene solution containing! b) 7/-(2-(2-amino-4-oxasilyh)
Example 14a ) obtained by dissolving the 40yloxymethyl ester in ether 5-O in methylene chloride.
Add 1.6 hours of O,5Nm acid and precipitate with helium. filtered and reprecipitated from ether V hexane (1:l);
After drying, the title compound is obtained. Bf~0.39
(/Rikadal, acetate). Example 15 3-(3-glolopyridiniomethyl)-7β-(2-(
2-ami]-4-osazolyl)-2-2-methonaka? Noacetylua Denno]-3-Seph 2 Mu 4-Cal IdF
3-acetoxymethyl-7β-(2-(2-amino-4-okinazolyl)- 2-Z-Method Meeting ζ Noah Seven Chill 12)
-3--nifu, mu-4-sodium carmenate 1.71
and 0.21 mt of acetic acid. -70℃ under nitrogen atmosphere
After stirring for 1 hour at
．． 2 and treated with Glomatodalafy on a Tuberite ER-1800. Rf value 0.69 (upc
B-Grate: Water/acetonitrile =: 4: 1'
) to obtain the title compound of 41 u v (water): λ
-@, = 215mm (sh) and 265+am (1
4000). Example 16 3-(4-cal?xylatepyridiniomethyl)-7β
-(2-(2-akino4-o11?nazolyl)-2~
2-Methodium-neutral electric noacetyl-a-electro-3-Seph 3-mu-
A solution of 5.6 g of sodium iodide ILZ and 610 da of isonicotinic acid in 5.6 sg of 4-cal reactor sodium brine was heated to 70°C to form a solution of 3-acetyl-7β-.
[2-(2-amino-4-oxacylyl)-2-Z-methoxyidenoacetylat-3-ceph8mu4-cal I acid sodium salt 1.7I and vinegar 110.21sf
Add t. After stirring for 1 hour at 700 m atmosphere,
Adjust the bath solution to 147.2 with IN caustic soda and chromatograph on Amberlite ER-1dO@a
nf value 0.75 (UPC, -grate, water/acetonitrile = 4:1): UV (water): λmax = 216 m
+ (21200) and 260 nm (18300) *Example 17 a) 3-carnomoyloxymethyl-7β-[2-(
2-Amino-4-oxacylyl)-2-2-methodacyl
7/-[2-(2-amino-4
-3-carpamoyl methyl-3-ceph,
Mu4-Karoon IIl Schiff. Nyl methyl ester 45 Ios*t trifluoro vinegar 11
Stir with 219.7- and anisole & 3- for 1 hour, add 2505 g of water-cooled toluene and evaporate. The residue was aged with ether, filtered with suction, dried, and after death.
The triflic monoacetate of the title compound is obtained as a beige-crystalline powder. This powder is suspended in 20 ml of water. IN
Solution t was used on the caustic solution. −7,2 at °C, Amberlite ER-1800
The top is treated with a mudgraphy. Rf value 0.77 (silica/le 60; n-butanol/vinegar all/water = 6
7:10:23); ■V (Wed): λmH221211m
(18000) and 260! II! I (12400)
-b) 3-carbamoyloxymethyl-7/-(2-(
Oxalyl chloride under nitrogen atmosphere -, dimethylformamide 0.9-, and methylene chloride 405g
-t・rt-Puchilo no Shikaru? Nilua 1)-4-Ozolyl)-2-Z-methoxy2 vinegar @2.85jl
and N-methylmorpholine 1.4-7. After stirring for another 30 minutes at this temperature, 3- in methylene chloride 45-
Dimethyl-7β-amino-3-cefemu-4-cal? Schiff 2 Nyl Methyl Ester 4.3
Add 1.4 sdl of 91 and rJN-methylmorpholine. Incubate at about -5°C for 30 minutes and OC for 1 hour. The reaction mixture was concentrated and the residue was taken up in acetic acid ethyl ester. Shake out sequentially with IN hydrochloric acid, saturated hydrogen carbonate solution and saturated salt bath solution. The organic phase is dried over 9 ml of sodium t-sulfate. P) Mt, After evaporation and post-mortem, the crude title compound is obtained. This compound t column chromatography (
Purified by silica glu 60 (toluene/ethyl acetate) and melted at 70°C. Example 18 3-Carbamoyloxymethyl-7β-[2-(2-amino-4-oxacylyl)-2-Z-metho-dimethyl]-3-7-dimethyl-5-4-carunate biparoyl Iodomethyl biverley in ester dimethylformamide 15-
2-Z-methodium chloride noacetylaminoco-3-ceph,
Ni-4-carunic acid sodium salt 2.6Alt-0'C
and stir at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and added with water 25-1
It is successively shaken with 10 - liters of saturated aqueous sodium bicarbonate solution and 10 - liters of saturated aqueous saline solution, dried over sodium sulfate and evaporated in vacuo. lI & ni ichikarak a! 11 g of the compound has an Rf value of 0.75 (Silical 60; methylene chloride/ethanol = 9:1).
*IR (methylene chloride): 1790.17
40.1685.1600 and 1525 (m s Example 19 3-pyridiniomethyl-7β-[2-(2-amino-4
-oxacylyl)-2-Z-methquiniminoacetylamino”-3-ceph8mu4-cal&=? Add dimethyl-7β-[2-(2-a2-4-o-sazolyl) in 3-acetate to a preheated bath solution of 11.25 jl of sodium iodide in 5.6-Jl of sylate water and 0.4 JI of pyridine. )-2-Z-Methokai Electric Noacetyl Akino”-
3-ceph, mu 4-cal I7M) +7um salt 1.7
Add I and 0.21- of acetic acid. Stir at 70c for 1 hour and dilute the solution with IN caustic soda by -5.
2 and perform Kukumatography on Amberlight MZJ111@. 0.25 ORflil (UP
Cll-f rate, water/acetonitrile = 4:1
) t- is obtained; Uv-spectrum (water); λm@z ” 2571111 (1a
ooo) m Example 20 a) 7/-[2-(2-a2-4-o-sazolyl)-
2-Z-metho middle school? Noacetyl 1zuno'-3-ceph wing mu 4-cal I phosphoric acid-t@rt-butyloxybutylene methyl ester 7β-[2-(2-BOC-amino-4-oxanolyl)-2-Z- Meto middle school 2 Noacetylua Kenno]-3-Sefu Tomi 4-Karun single-t@rt-Puchilo middle Shikaru? Nyl methyl ester 0.751 trifluoro vinegar @3.
A mixture of 9-1 and methylene chloride 3.9-1 is stirred at room temperature for 1 hour, then a mixture of cold toluene is added and evaporated under reduced pressure. KoO
Step 1-) Repeat using a mixture of toluene and oo-form and a mixture of toluene and nitrate, and the residue is crystallized from ether. The trifluoroacetate salt of the 11 title compound melts at 145-14 g'C with decomposition. ! R-spectrum (nuzo, -ru): 1785.17
40.1660.1630.1540csa e'c
band. The trifluoroacetate salt is taken up in acetic acid ester and washed with cold saturated sodium chloride carbonate solution for 2 wA. After drying the organic phase over +7 μm, the solution is condensed under reduced pressure. The title compound is obtained, having a fraction of σ matodalaphytin (methylene chloride/ethanol), 0.21 ORf111 (60 in silyl tJl'; methylene chloride/ethanol 9:1). b) 7β-(2-(2-BOC-7/-4-oxyzolyl)-2-Z-methoxyiminoacetylaminoco-3
-Sef, Mu4-'Cal? N-shun-t@rt-butyloxycarbonylmethyl ester 7β-[2-(2-BOC
-7mi/-4-#+? zolyl)-2-Z-methoxyiminoacetyl 12-3-ceph, A-4-force k de
7 Acid-t@rt-butyloxybutylmethyl ester 7β-[2-(2-BOC-7mi/-4-oxyzolyl)-2-z-methoxyiminoacetelamino]-3-cephem- Potassium phthalimide 1.4-calXll/acid 2.3I and N,N-dimenalacetoacide 18- were added to a mixture of 18 and 20° C. at 20°C. Add 1.33j"i of iodoacetic acid-4art-butyl ester cooled to OC. After stirring for 30 minutes, add 50% of acetate and 50% of water.
11 gt-J, t, INW soda to 7 ml to separate the ester phase. Extract again with ester, wash the combined ester phases with saturated sodium chloride solution, dry and evaporate under reduced pressure.
, methylene chloride/ethanol). Example 21 3-Carpamoyluoquinemethyl-7β-[2-(2-oxychloride-4-oxolyl)-2-Z-methodanoacetyladenoco-3-ryu78mu-4-carganyl #-1-
(Cyl in ethyl)-ethyl ester 1-(1-chloroethyl)-ethyl ester M4-) 1.7
6jl, sodium iodide 1.99N and anhydrous acetone 1
5-Heat the mixture under reflux for 135 minutes. The acetone is distilled off under reduced pressure. The residue is partitioned between 25*t of water and 25*t of ether, the ether phase is separated and washed with water and a sodium chloride water bath. The ether solution is dried and evaporated under reduced pressure. The remaining 1-(1-n-doethyl)-ethyl carnate was dissolved in dimethylformide 5- and this solution was dissolved in 3-carbamoylmethyl-7β-[
Add to solution IIi 2-(2-amino-4-acetyl)-2-Z-methoxy 2-noacetylamino-3-cephem-4-carboxylic acid sodium JA salt 1.15JF. 1 compound, stirred at room temperature for 1 hour, and then acetic acid ester 5
Add o-. Wash the JW phase sequentially with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution; dry over 1 m magnesium;
F,! do. The solvent is distilled off under reduced pressure. The residue is purified by column chromatography (Silica Dal 6O; methylene chloride/ethanol). The title compound has a Bf concentration of 0.47 (Silica Dal 6O: methylene chloride/ethanol = 9:1); xR-spectrum (methylene chloride): 1790. 1765.1740.1675.
Band on 1655.1586 儂-1. Example 22 Dimethyl-7β-[2-(2-7
1/-4-oh? 3-carbamoyl-7β-[2-(2 -2
-Z-Methoxyideno]-3-cephem-4-carunate sodium sodium salt 2.31 Globion 11ii-tomethyl ester 1.25 #tOC is added to the Ofli solution. After stirring at 410 C for 2 hours, the reaction mixture is is diluted with 100% acetate and washed with water and a saturated sodium bicarbonate bath and a saturated sodium chloride bath. After drying over sodium sulfate, the bath liquid is distilled under reduced pressure and the remaining residue is chromatographed (silica 6
0; methylene chloride/ethanol) *0.47OR1 value (
Silica gel 60; methylene chloride/ethanol = 9:l)
;IR-spectrum (KBr): 1785.1735.
Band at 1660.1600ca+-'. Example 23 Example 4ms Analogously to Example 20m and Example 21, the following ester can be prepared: dimethyl-7β-[2-(2-amino-4-oxacylyl)-2-Z- in 3-carpamoyl] Methoxyiminoacetylamino〕-3
-Cefromu 4-cardanic acid-1-(glohionyl)-ethyl ester: IR(CH,0L2): 17
90% 1760.1740 y 1675, 1655
, 1520cg* -Rf: approximately 0.44 (silica gel, cH, ct, βton = 9:1), 7β-[2-
(2-12-4-oxacylyl)-2-2-methoxyiminoacetylamino-3-ceph, 4-cardan-1-(gukubionyloxy)-ethyl ester-I
R(CH2CA,): 1792, 1760. 174
0. 1660% 1640. 1520 me. Rf: Approximately 0.61 (Syryl, CH2Ct2/T:
tOH:9:1), 3-(l-methyl-1-H-tetrazol-5-ylthiomethyl)-77-[2-(2-1
2-4-oxacylyl)-2-Z-meth-2-noacetylamino]-3-ceph, 4-karoon all-
(,;Scypionyloxy)-ethyl ester-IR
(CH, Ct2) :1790.1765.1742.
1678.1655.17sscILIRf: Approx. 0.2
3 (silica gel, CH2Ct2/ItOH9: 1'
), 3-(l-methyl-IH-tetrazol-5-ylthiomethyl)-7/-(,!-(2-anno-4-o or nazolyl>-2-2-methano-7/-)
-3-Cef8mu-4-cardanylpipalyloxymethyl ester-IR(cH,Ct,); 1785.174
0%1670.1620%1520m-'#J:
Approximately 0.38 (Silica Dal, CHzCLs/'EtOH9
: l), 7β-[2-(2-7i)-4-1dtt
zolyl)-2-hydroxynoacetylamino”-3
-Cepham-4-Cal? Dimethyl dimethyl ester of divinic acid! a(cH, ct2); ryso, 1745
．． 1675.1625, xsnsaILI R,: about 0
．． 42(/Liquor, CH, Ct,/1itOH9:
1) 3-(1-Methyl-IH-tetrazol-5-ylthiomethyl)-7β-[2-(2-akino-4-oxacylyl)-2-Z-methoxyiminoacetylamino]
-3-Seph+a Mu4-Cal? :/#1l-1-(ethyl ester)-IR(C)
I2C2,):1785.1745.1673.162
0.1545cm, R,: approx. 0.28 (Silica 4
Full, CH, Ct2/EtO) [9: 1), 7β-
(2-(2-amino-4-oxacylyl)-2-hydroxyiminoacetylamino)-3-ceph,ni-4-carne1ll-1-(ethoxycarlnilo-kai)-ethyl ester-IR(CH, Ct2): 1788.176
2.1740% 1672.1640%1555caa
. Rf: about 0.38 (silica gel, Cki2CL2/)C
tOH9:1χ Example 24 The following compounds are obtained in a similar manner to Examples 1 to 3 and Examples 5 to 19 using appropriate starting materials: 3-(1,3,4
-thiadiazol-5-ylthiomethyl)-7β-[2
-(2-amino-4-o?funolyl)-2-Z-methominoacetylaminoco-3-ceph, mu-4-calgenic acid sodium salt -Uv("maw); 215nm(
16800), 257am (13200); Rt: Approx. 0
．． 78 (UPC, □-Great, H, O/CH, CN
), 3-(2-methyl-5,6-thioxo 1.2°5.6
-tetrahydro-11-triazin-3-ylthiomethyl)-7β-[2-(2-annor-4-oxasilyl)
-2-Z-diiminoacetyla2no]-3-cef,ni-4-carunate sodium salt -UV (J,B,)
:21Hmm(17400), 265(14200)a
m; town; approximately 0.68 (UPC, - Great, R20
/cHsCN), 3-(dimethylpyridiniomethyl in 4-hydro)-7β
-[2-(2-annor-4-oxacylyl)-2-2-
Meto Chuiden Noacetylua Denno] -3-Seph, Knee 4-
xylene) -UV (λ, ri; 216 nm (s)
, 262 nm (13800); Rf: approximately α72 (UP
C,,-great, H,O/CHsCN), dimethyl-7/-[2-(2-aono4-
O*1zolyl)-2-z-hiTfoxyiminoacetylamino)-3-ryufu, mu4-cal? sodium salt - UV (λwax): 211 (18100), 260 (
13400) am; R(: about 0.68 (UPC, -
Great, R2VCHs CN), 7β-[2-amino-4-oxazolyl-2-hydro-acetyl acetyl az)]-]3-ceph3-4-carmen sodium salt UV (λ, ri=207 (17400), 261 (128
00) nm; Rf: about 0.72 (tJPc, 2-grate, H2O10H, CN), 3-(l-methyl-IH
-tetrazol-5-ylthiomethyl-)-7β-(2
216 (■),
264 (14400) ntr+; R1: about 0.63
(UPC,,-great, R20/CH,CN), 3-acetoxymethyl-7/-[2-(2-azu]-4
-oxacylyl), -2-Z-(2-12noethodiimino)-acetylaminoco-3-ceph, ni-4-cal♂
Sodium salt -〇V (-0): 213 (15800
), 262 (13600) cotton; R1 approximately 0.65 (UPC
-Grate, )1,0/CH,CN),2 3-acetoxymethyl-7β-[2-(2-1 electron no 4
-Oxacylyl)-2-Z-(2-tdocll?shed diimino)-acetylaminoco-3-cephem-4-
Carmen saline sodium salt-Uv (λ□x): 212 (1
620G), 280 (1350G) am: Rf: Approx. 0
．． 68 (UPC, 2-great, R20/C1, CN)
. Example 25 0.51C)'4g active ingredient, e.g. 3-acetoxymethyl-7β-[2-(2-7f/-4-1-?1M'lJ
)-2-Z-methoxyζnoacetyl-3-
Cef 8 Mu 4-Cal? A vial of dry angle ma9 containing *1 can be manufactured as follows: Composition (angle or vial 1@as above); Active ingredient
0.5I Mannitol 0.05N Sterile water bath solution consisting of the active ingredient and mannitol [Filled in a 5-angle or 5-size vial without any constriction,
It is then closed and tested. 1 or less margin

Claims (1)

[Claims] [The middle part of the formula is θ~2! I# represents I#, and M is a nyl group, a methylene group, an amino group, a 9-electron) group,
Hydroxy group, protected hydroxy group, sulfo group, protected sulfo group or formula:% formula% (in the formula, 84 is hydrogen, lower alkyl group, substituted lower furkyl group, cycloalkyl group, substituted 9 an alkyl group, a carbamoyl group (Mara represents a substituted carboxylic group), R1 is hydrogen, a lower furkyl group, a lower alkyl group, /%gf y or the formula -CH
rR2 (in the formula, R, dkPl- group, mercazoto group, esterified human-oxy group represents meencapto group, etherified hydroxy group, etherified mercazoto group or ammonio group); 7 represented by car-xyl group or 4M-car represents xyl group]
β-7onooquinazolyl 7cetera-containing 3-em-4-carboxylic acid compounds, hydrates and salts of compounds of general formula (1). 2.11 represents an integer from θ to 2, M is a nyl group, M is an amino group, a protected 7R group, a human oxygen group, a protected hydroxy group, a sulfo group, a protected 9 sulfo group or formula -N-0-14 (in the formula, R4 is hydrogen, lower alkyl group, substituted lower 1a furkyl group, cycloalkyl &, t
hcTh dichlorofurkyl group, carbamoyl group represents a methylene group substituted with a group (9 represents a substituted carbamoyl group);
Claim 1 which is a 7β-7ξno-dP sazolyl 7cetylamino-3-cephem-4-carmenic acid compound of the general formula (1) having nine definitions listed in Section 1, and hydrates and salts of the compound. Compounds described in 3. n represents an integer of O to 2, m is a carunyl group, i9 is an amino group, a preserved amino group, a hydroxy group,
Protected hydroxy group, sulfo group, retained sulfo group or formula -II N -0-R. (In the formula, R4 represents hydrogen, a lower furkyl group, a substituted lower alkyl group, a Schiff-alkyl group, a substituted Schift-alkyl group, and a carbamoyl group represents a Kuhiro-substituted carΔmoyl group). and 81% R1 and the town have the general formula (1
) of 7! -7-denoxazolyl acetylamino-3-77emu-4-carboxylic acid compound, hydrates and salts of the compound, and the compound according to item 1 above. 4. m represents 0, aRl is hydrogen, a lower alkyl group, such as a methyl group, a lower alkoxy group, he is a methoxy group, a halogen, such as a salt l/A or the formula -cH, -12
represents a group, where the group is a lower fulcaryloxy group, such as an acetoxy group, a carboxylic group, an N-lower alkylcarbamoyloxy group, a 4- or 6-membered aromatic monocyclic Schiffde, tri7de, tetrazo-, Cheers
, Thiazo 7 Day, Cheer, Ochusu Ade or Okit
Schifdacyclyl groups, e.g. thiazolylthio groups, e.g. FilH-1,2,3-)lyazol-5-ylthio groups, tetrazolylthio groups, e.g. 11-tetrazol-5
-ylthio group, thiazolylthio group, thiadiazolylthio group, e.g. am-) riazinylthio group, such as an unsubstituted or lower alkyl group,
For example, a methyl group, a di-lower alkyl group, an electro-lower alkyl group, a dimethyl-alkyl group or a 2-zomethelazanoethyl group, a sulfo-lower alkyl group, such as a sulfomethyl group, a lower furkyl group, an example of a -xymethyl group, amino group, 5,6-thio-1.
2.5.6-thitrahydro as-)7din-3-ylthio or 5,6-thio 1.4.5.6-
Tetotsuhi PEI-as-)su7son-3-ylthio group,
or an ammonio group, such as a 2-lower alkyl-1-virazolio group, such as a d2-methyl-1-virazolio group, 2
- Cal is lower alkyl, 1-pyrazolio group, for example t
f2-cal is a dimethyl-1-virazolio group, a 3-lower alkyl-1-)riasili group, e.g. 3-methyl-1
- triazolio group, pyridinio group, hydroxy lower alkyl group, e.g. and do-4oxymethyl group, car is xy group, cal is xy lower alkyl group 1 e.g. cal-oxymethyl group,
For example, a pyridinio group substituted with tzm or bromine, or a carbamoyl group, for example, a tf3- or 4-hydroxymethylpyridinio group, a 4-cal xypyridinio group, a 3- or 4-cal group. simetelvirizonio group, 3- or 4-talolopyridinio group, 3
- Preferably, the 4th position represents a 4♂rizonio group or a 3-or 4-carpamoylpyrizonio group, and R5 is a carpamoylpyrizonio group.
xyl group or carxyl group decomposable under physiological conditions, for example acyloxy lower alkoxy car I nyl group 1 example lower alkanoyloxy lower alkoxy car?
A nyl group, such as a lower alkanoyloxymethoxycar-nyl group or a lower alkanoyloxyethoxycar-nyl group, such as a piparoyloxymethoxycar-nyl group or a 2-(propionyloxy)-ethoxycal group, or A lower alkoxyl is a nyl group, for example a 1-(ethoxycar is a nyloxy)-ethoxycar-nyl group, ijt@r't-
butyloxycar represents a nyl group, and m represents a methylene group substituted with an amino group, an adenomethelene group, a hydroxymethyl group, a sulfomethylene group, or a group of the formula -N-0-R4, R4 is hydrogen, a lower alkyl group such as a methyl group, a human tetraxy lower alkyl group, such as a 2-hydroxyethyl group, an a-based lower alkyl group, e.g. -car-xy-2-f lobyl group, carbamoyl group, lower alkyl group Jk p4 moyl group, for example methylcarba(yl group), also represents a diamino lower alkyl group, for example 2-a-denoether group, and has the formula -〇- R4
General formula (1) having 0 groups and 1-(ma9#1Z-) positions
The compound according to claim 1, which is a generally pharmaceutically acceptable salt of a compound of general formula (1)0 having a salt-forming group. 5, n%A%R1, R1 and R4 are in claim 111
[Represents the one described in item 4, and R1 is a syl group or a car-xyl group decomposable under physiological conditions, such as a cycargonyl group in acyloxymeth, e.g., a lower alkanoyloxymethoxycar group is a nyl group, e.g. a cicalzenyl group in bipa-tetrayl, or a lower alkoxycar-nyloxy lower alkoxycar is a nyl group, Example JJ
fl-(ethoxycal is nyloxy)-ethoxycal-
Compounds of the general formula (1) representing a nyl group, salts of these compounds, particularly pharmaceutically acceptable salts, according to claim #g2. 6, ms AI, R1, R2 and R4 are patent fiX
s RH is a car-xyl group, dimethoxycar in the piparoyl is a nyl group t7'
Is j 1-(ethoxycal is nyloxy)-ethoxycal? Compounds of general formula (1) representing a nyl group and salts of these compounds, particularly pharmaceutically acceptable salts, according to item 3. 7, - is 0, R1 represents hydrogen, a lower alkyl group, such as a methyl group, a lower alkoxy group, such as a methoxy group, a halogen, such as chlorine, or a group of the formula -CH, -R2, and R2 is a lower Alkanoyloxy groups, such as acetoxy groups, CalΔ% (ruoxy groups, triazolylthio groups,
For example, IH-1,2,3-triazol-5-ylthio group, tetrazolylthio group, e.g. IH-tetrazol-5-ylthio group is lower alkyl group, e.g. methyl group, di-lower alkyl group) lower alkyl group , for example 2-
A dimethylaminoethyl group, a sulfo-lower 8-furkyl group, such as a sulfomethyl group, a carmexyl-lower furkyl group, such as a tetrazolylthio bird in which cal is replaced with a oxymethyl group or a hacarpamoyl group, such as 1-methyl-IH-tetrasol- 5-ylthio group, 1-sulfomethyl-IH-
tetrazol-5-ylthio group, l-cal is xymethyl-IH-tetrazol-5-ylthio group or 1-(2
-Zometeratnoethyl)-1H-tetrazole-5-
ylthio group, thiadiazolylthio group, e.g. 1, 3.4
-thiadiazol-5-ylthio group, lower thylkyl group 1
For example, a thiadiazolylthio group substituted with a methyl group, such as tf2-methyl-1,3,4-thiazoazole-5-
5,6-thioxotetrahyPH) substituted with a ylthio group, a lower alkyl group, such as a methyl group;
2.5.6-titrahydro-a-triazin-3-ylthio group or 4-methyl-5,6-thio group 1.4
．． 5.6-titrahydro a-triazin-3-ylthio group, pyridinio group or human E1dP lower alkyl group, hydroxymethyl group, cal? xyjk%cal is xy lower alkyl group, for example, carboxymethyl group. Pyridinio groups 12 substituted with halogens, such as chlorine or bromine, or with carbamoyl groups, such as 3- or 4-hydroxymethylpyridinio groups. 4-cal is a xypyridinio group, 3-cal is a 4-car-
represents a oxymethylpyridinio group, a 3- or 4-chloropyridinio group, a 3- or 4-bromopyridinio group, or a 3- or 4-carmonoylhyridinio group, and R5 is a car-xyl group or under physiological conditions Is the decomposable car a xyl group, such as an acyloxy lower alkoxy car? Nyl group, for example, lower alkanoyloxy lower alkoxycar is a nyl group, Hosomi is lower alkanoyl, dimethoxycar? Nyl group M9 is a lower alkanoyloxyethoxycar is a nyl group, for example, in pinoyloyloxymeth, the cylyl group 1* is 2-(f ropionyloxy)-
An ethoxycar-nyl group, or a lower alkoxycarmenyl group in which the lower alkoxyl is niluo, such as tfl-(
ethoxycarbonyloxy)-ethoxycar represents a nyl group, tart-butyloxycar-nyloxymeth, and ^ represents a methylene group substituted with a group of the formula -N-0-R4C), and % R4 represents a water group. , a lower alkyl group, such as a methyl group, car represents a xy-lower alkyl group, such as 2-car represents a xy-2-propyl group, a carbamoyl group or a lower alkylcarbamoyl group, such as a methyl car/4 moyl group, and the formula -〇-14 The base of is my
Claims for the preparation of compounds of general formula (1) having a tortoise-(or 2-) position and salts of compounds of general formula (1) having a salt-forming group, in particular pharmaceutically usable salts The compound described in I8 Iris item 4. 8, 11% AI, R1, - and R4 represent those listed in claim 7, R1 is a xyl group, lower alkanoyloxymethoxycar is a nyl group, for example, piparoyloxymethoxycar- Nyl group refers to a compound of the general formula (1) in which the lower alkoxy group is niluo, and the ethoxycar represents a nyl group, such as tjl-(ethoxycar is nyloxy)-ethoxycarb is a nyl group, and salts of the compound, particularly pharmaceutically acceptable Salt Oa+Synthetic O*g
'rb Compounds listed in 5 terms of the O range collection. 9;
A compound of the general formula (1) in which (ethoxycarbyl represents a nyloxy)-ethoxycar-nyl group and a salt of the compound, which is a pharmaceutically acceptable salt! ! 6
Compounds described in Section. 10, n is 0, R1 represents hydrogen, a lower alkyl group, such as a methyl group, a lower alkyl group, such as a methoxy group, a halodane, such as chlorine, or a group of the formula -CI2-R, and %R2 is Lower alkanoyloxy M, 11 is an acetoxy group, a carbamoyl group, a tetrazolylthio group, such as an IH-tetrazol-5-ylthio group,
or a lower alkyl group, such as a methyl group, a lower alkyl group, such as a 2-dimethylazanoether group, a sulfo-lower furkyl group, such as a sulfomethyl group or a xyl-lower alkyl group, such as CalMdP
A tetrazolylthio group substituted with a dimethyl group, e.g.
-methyl-1-tetrazol-5=ylthio group, 1-(
2-dimethane7minoethyl)-IH-tetrazole-5
-ylthio group, 1-cal I xymethyl-IH-tetrazol-5-ylthio group, 1-sulfomethyl-IH-tetrazol-5-ylthio group, or 1-cal? oxymethyl-IH-tetrazol-5-ylthio group, theacyazolylthio group, e.g. 1. &4-Thiazoazol-5-ylthio group, or thiadiazolylthio group substituted with a lower alkyl group, e.g. d-methyl group, e.g. 2-methyl-1
,3,4-thiadiazol-5-ylthio group, 5,6-/o-sotetrahydro aS-triazinylthio group substituted with lower alkyl group, e.g. methyl group, e.g. 2-
Methyl-5,6-thioxo 1.2.5.6-thitrahydro-a-triazin-3-ylthio group or 4-methyl-5,6-thioxo 1.4.5.6-thitrahydro&- - triazin-3-ylthio group, pyridinio group, 9 is a human-oxy lower alkyl group, for example a dimethyl group, car is an xy group, car is an xy lower alkyl group, such as a car-oxymethyl group, a halodane, e.g. chlorine or a pyridinio group substituted with bromine or a carbamoyl group, such as a 3- or 4-hydroxymethylpyridinio group, a 4-car-xypyridinio group, a 3- or 4
-Cal? 9 represents a 3- or 4-carbamoylpyridinio group; is a nyl group, Hosomi is a lower alkanoyloxymethoxycar is a nyl group, or a lower alkanoyloxyethoxycar is a nyl group, for example a piparoyloxymethoxycar-nyl group or a 2-(fνbioeroxy)-ethoxycar-nyl group or a lower alkoxycarp. is a nyloxy lower alkoxycar is a nyl group, e.g. 1-(
Ethoxycal is nyloxy) - Ethoxycal is nyl group 1
ft.rt-butyloxycal represents a diloxymethoxycargonyl group, M represents a methylene group substituted with a group of the formula -N-0-R4, and tR4 is a lower alkyl group, such as a methyl group, Cal represents a xy-lower alkyl group, such as a 2-car-xy-2-propyl group, a carbamoyl group or a lower alkylcarbamoyl group, such as a methylcarbamoyl group, and the formula -〇-R40 group is in the aym- (or 2-) position. 8. The compound according to claim 7, which is a salt, in particular a pharmaceutically usable salt, of a compound of the general formula (1) having a salt-forming group and a compound of the general formula (1) O having a salt-forming group. 11, r*, AlR,, R1 and R4 are defined in Claim 8 No. 10. Represents the one listed in lii, and R5 is Cal?
In the syl group, in the alkanoyl group, in the alkanoyl group, the cyl group in the middle group is a nyl group, for example, if Id is 40yloxymethoxycal? = group *a Low M sicalunyloxy lower alkoxycar-nyl group, N, tlfl-(ethoxycarunyloxy)-ethoxycaryl group f: General formula (1) represented by
and salts thereof, particularly pharmaceutically acceptable salts. 12, m, ^, R1, R1 and R4 represent those listed in claim 1O, and R5 is Cal? xyl group,
When pipapyl-Φ dimethoxycal is a compound of the general formula (1) in which l-(ethoxy-rumenyl)-ethoxycar represents a nyl group, and a salt of the compound, particularly a pharmaceutically acceptable salt; A compound according to item 9 of the FfllyX scope. 13.3-acetoxymethyl-7β-(2-(2-amino-4-oxacyl)-2-Z-methoxyiminoacetylamino]-3-cephem-4-carmenic acid as described in claim 1O) The compound 14.7β-(2-(2-72no-4-oxacylyl)
-2-Z-Methoxyiminoacetylamino]-3-cephem-4-carboxylic acid, the compound according to item 10, wherein the desired range of % M is desired. 15. Claim lI# which is a sodium salt of the compound
! Item 13 or #! A compound according to item 14. 16.3=-(1-methyl-IH-tesilazole-5-
12. The compound according to claim 11, which is ethylthiomethyl)-7β-(2-(2-amino-4-oxacylyl)-2-Z-methoxyiminoacetylamino-3-cephem-4-calcinoic acid. 17.3-(1-car?xymethyl-IH-tetrazol-5-ylthiomethyl)-7β-[2-(2-amino-4-oxacylyl)-2-Z-methoxyiminoacetylamino]-3-cephem-4- The compound according to claim 10, which is carnic acid. 18.3-(1-(2-nometheranoethyl)-IH
-tetrazol-5-ylthiomethyl]-7β-(2-
1112. The compound according to claim 1111, which is (2-amino-4-oxolyl)-2-Z-methoxyiminoacetylamino]-3-77emu-4-carboxylic acid. 19.3-(1-(2-dimetelanoethyl)-IH
-tetrazol-5-ylthiomethyl]-7/-(2-
The compound according to claim 11, which is (2-amino-4-odP4rzolyl)-2-methoxyiminoacetylamino]-3-7femu-4-carboxylic acid. -carpamoylbilizoniomethyl)-7β
-[2-(2-amino-4-oxacylyl)-2-2-
Methoxyiminoacetylamino]-3-cephem-4-
11. A compound according to claim 10, wherein cal is xylate. 21. Claim 11, which is 3-7cetoxymethyl-7β-[2-(2-anno-4-oxacylyl)-2-Z-hydroxyiminoacetyl]-3-7femu-4-carmenic acid compound. υ, 3-7cetoxymethyl-7β-(2-(2-anno-4-oxacylyl)-2-Z-2-(2-cal is xyzoloxy-2-yloxy))-7cetylamino]-
Claim 1 which is 3-cephem-4-calanoic acid
A compound according to item 111. 23, 3-acetoxymethyl-β-(2-(2-7
4-oxacylyl)=-2-Z-(2-t@rt
12. The compound according to claim 11, which is -butyloxycarinylfa-diimino-7cetyl-3-cephem-4-carunic acid. fi, 3-(3-chloropyridiniomethyl)-7β-(
2-(2-7-ken no 4-o*-!l″zolyl)-2-2
-MethoxyiZnoacetylaZノ]-3-cephem-4
12. The compound according to claim 11, which is a -carxylate. 21i3-(4-calMdP sylate viridiniometel)-7! -(2-(2-72no-4-oxacylyl)-
1112. The compound of claim 1111, which is 2-Z-methoxyZnoacetelato]-3-cephem-4-calctdF sylate sodium salt. Elephant 3-carbamoylodimethyl-7β-(2-(2
-4-oxacylyl)-2-2-methoxyt
The compound according to claim 5IIjL11, which is noacetyl heptadeno]-3-cephem-4-calanoic acid sodium salt. Claim 16, which is a sodium salt of compound O'
Section, Section 17, Section 21 to Section 23, Section 2 or @
A compound according to item 26. η Compound monolithic or zohydrochloride special #”F#
*The compound described in item 18 or item 19 in desired range 1. Claim #12 which is 3-pyridiniomethyl-7β-(2-(2-amino-4-oxacylyl)-2-Z-methoxyiono-acetyl 7zno]-3-cephem-4-car-oxylate) Compound described in Section 307β-(2-(2-amino-4-oxacylyl)-
2-Z-Methoxyinoaceteraono]-3-cephem-4-carboxylic acid-t@rt-butyloxycarboxylic acid is a nylmethyl ester, a compound described in Section JI 112. 31.3-carbamoyloxymethyl-7β-(2-(
2-Aino4-suimasazolyl)-2-2-methoxyiminoaceterazno]-3-cephem-4-cargane
! 13. The compound according to claim 12, which is -1-oxycarbonyloxy)-ether ester. (transformation), general formula (■): [in the formula, n represents an integer of O to 2, A is a carbonyl group, a methylene group, or a Z) group, a protected amino group,
Hydroxy group, 9-hydroxy group, sulfo group, protected sulfo group or formula: % formula % (wherein R4 is hydrogen, lower alkyl group, substituted lower alkyl group, cylindrical alkyl group, substituted cycloalkyl methylene group substituted with a group (representing a group, a carbamoyl group or a substituted carbamoyl group) f: Representation, B1 company water ligation, lower alkyl group, lower fluoroxy group, ha or: yi or formula -C
HrR2 (in the formula, R2 represents a hydroxy group, a mercapto group, an esterified hydrocarbon group, a mercapto group, an etherified hydrocarbon group, an etherified mercapto group, or an ammonio group), and Rs represents a carbohydrogen group. 7β representing a syl group or a protected carboxyl group
-7 Minoxazolyl acetyl 7 Minnow 3-77 Engineering 5-
In order to create hydrates and salts of 4-carganic acid compounds, compounds of general formula (1) general formula (U): i [in the formula, n5R1 and R3 represent the above, and 7β-
The 7β-72 group is present in free form or is protected by a group that allows acylation, and the functional group present in R4 is protected. Formula @: [In the formula, ^ represents the above, the 7-mino group at the 2-position of the oxacylyl group and the functional group present in A are optionally protected] Introducing the acyl group of carnic acid Acylated by reacting with an acylating agent or a salt thereof, or b),! In order to produce a compound of the general formula (■), which is 1 or 0, the general formula (■) is: and KR, and the functional baselines present in A and W! Slaughter 2 - Cephem -
The compound or its salt may be isomerized to the corresponding 3-cephem compound, or may be expressed by the general formula (V), where n, R1, u, and M represent the above,
X represents Hapgun, the functional group present in R4 and A is optionally protected] or a salt thereof is condensed with urea, or d) A is substituted with a hydroxyl group In order to synthesize a compound of the general formula (1) representing a methylene group, [in the formula, n5R1 and R5 represent those of the previous We, and the amino group at the 2-position of the oxacylyl group and R
The functional group present in 1 is optionally protected] or a salt thereof is treated with a nidotetratizing agent, and if necessary, the obtained compound of general formula (1) is converted into a compound of general formula (1). and/or change the obtained compound in which IN is 0 to a compound in which n is 2, and/
Also, the obtained compound where #i1K is nio or 2 is n
is 0, and/or a functional group present in a protected and good form in the obtained compound is freed from 2I! and/or convert the obtained salt into the free compound or other O salt, and/or convert the obtained free compound into a salt, and/or convert the resulting nine isomer mixture into the individual O14-mers. 1. A method for producing a 7β-7-denoxazolyl acetelamine-3-77 emu-4-ol phosphoric acid compound. 3! l, General formula (■): [In the formula, n represents an integer of θ ~ 2, A is a nyl group,
Methylene group, or i) group, retained 972 group, hydroxy group, retained hydroxy group, sulfo group, protected sulfo group or formula:% formula% (in the formula, R4 is hydrogen, lower alkyl R1 is hydrogen,
A lower alkyl group, a lower alkoxy group, a group of the formula -〇HzRz (wherein R1 is a hydroxy group, a mercapto group, an esterified hydroxyl group or a mercapto group, an etherified human tetraxyl group, an etherified mercapto group or an ammonio group) ), and R1 represents carxyl IIs or a protected carxyl group]
7β-aminooxacylylacetyl acetyl acetate compound, an aquarium and a pharmaceutically usable salt of the compound of general formula (1). 〆The pharmaceutical preparation according to paragraph 33 for use in the treatment of single-stage infections in humans or animals. 3. General formula (2): [In the formula, M is a nyl group, a methylene group or an ano group,
Protected heptadyl group, hydroxy group, protected hydroxy group, sulfo group, protected sulfo group or formula -N
-0-R40 group represents a methylene group, R4
represents a hydrophobic group, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a carbamoyl group, or a substituted carbamoyl group, and the anno group and the functional groups present in A are protected by a single rζ.] Calcium acid, its reactivity, functional conductors and salts. 2-(2-
The compound according to claim 3, which is amino-4-o or sazolyl-2-Z-methoxyiminoacetic acid. 3'1. 2-(2-7minor-4-oxacylyl)-2-human 12dP cyielectronoacetic acid in which the hydroxyl group and/or the atom) 1 is protected by combination; Compound. 39, 2-(2-amino-4-oxasilyl) in which car is an xyl group and/or an amino group is optionally omitted
36. The compound according to claim 35, wherein -2-Z-(2-cal is diglogu-2-yloxyimino)-acetic acid. c? 9. General formula (to): [In the formula, A is a nyl group, a methylene group, or a 72) group,
Protected amino group, hydroxy group, protected hydroxy group, sulfo group, protected sulfo group or formula -N
-0-R represents a methylene group substituted with a group, R
4 represents a water bulk, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a carbamoyl group, or a tah-substituted carbamoyl group, and the amino group and the functional group present in A are optionally reserved. In order to create carnic acid, its reactivity, functional conductor barrier and salt with the general formula (■): Reacting a compound with urea, where M is as defined above and Cal is present in an esterified form or a conventional Cal is "protected" with a syl protecting group; If necessary, Cal in the obtained compound removes the xyl protecting group, and/or protects the amine group present at the 2-position of the oxacylyl group, and/or protects the functional group present in A. A method for producing a carbic acid compound in which protecting a group and/or changing a group to another group is used as fF mold.Left below -