JPS6013787A - Novel azetidinone derivative and its salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is tetrazolyl; R<1> is azido, acylamino, substituted alkylideneamino, (protected) amino, etc.; R<2> and R<3> are H, halogen azido, carboxyl, amino, alkyl, alkenyl, cycloalkyl, alkyloxy, etc.; X is H or alkyloxy] or its salt. EXAMPLE:(3S,4S)-3-t-Butoxycarbonylamino-1-( 1-diphenylmethyl-1H-tetrazol-5-yl )- 4-methyl-2-azetidinone. USE:Antibacterial agent effective to Gram-positive and Gramnegative bacteria. PREPARATION:The compound of formula I can be prepared e.g. by cyclizing the compound of formula II (Y is hydroxyl, halogen, etc.) in the presence of triphenylphosphine, etc., and if necessary, alkoxylating the resultant compound of formula III.

Description

[Detailed description of the invention]

The present invention relates to novel azetidinone derivatives and salts thereof.
do. More specifically, the new general expression
This invention relates to azetidinone derivatives and salts thereof. Therefore, the aim is to provide a wide range of antibacterial spectra.
against Gram 1 and Gram-negative bacteria.
shows excellent antibacterial activity, especially against conventional penicillins and
Excellent antibacterial activity against bacteria resistant to cephalosporins
and β-lactamase produced by bacteria.
It has the property of inhibiting humans and has low toxicity.
New products useful as pharmaceuticals for animals and intermediates thereof
The objective of the present invention is to provide a compound of interest. In order to achieve this purpose, the present inventors have conducted extensive research.
As a result, the 1st position of azetidinone may be substituted.
Found that compounds with a tetrazolyl group are useful
However, the present invention was completed. In this specification, unless otherwise specified, cy, alkyl
means straight-chain or branched C1-14 alkyl, e.g.
, methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isobutyl, 5ec-butyl, tert-butyl
Pentyl, Hexyl, Heptyl, Octyl, Dotesyl
i alkenyl and ld: C2-1o alkenyl, etc.
For example, vinyl, allyl, impropenyl, 2-pente
Nyl, phthynyl, etc. i alkynyl (!: (d, C2
-+1o alkynyl, e.g. ethynyl, 2-propyl
Nil fz doj Arcagenilt is C4, grave. Arcage
Nil, Tatoei iJ:, 1,3-butadienyl, 2,4-
Alkylene f'i such as hexagenyl: Cs-,
. Alkylene, such as methylene, ethylene, propylene
[Ren, trimethylene, etc.] Alkenylene is C2-10
alkenylene, fc, 't-vinylene, propenylene
What is cycloalkyl? cycloalkyl,
For example, cyclopropyl, cyclobutyl, cyclopene
icycloa, such as chill, cyclohexyl, cycloheptyl, etc.
Lukenyl is C5-7 cycloalkenyl, fct'tt
d, cyclopentenyl, cyclohexenyl, etc.; cyclo
Alkadienyl is 05-7 cycloalkadienyl.
For example, cyclopentadienyl, cyclohexadienyl
etc.j cycloalkyl trienyl and ha07~. cycloal
Cal-IJ enyl, e.g. cyclohebutatrienyl
Aryl is, for example, phenyl, tolyl, na
Phthyl, indanylnatosialalkyl is benzyl,
Phenethyl, 4-methylbenzyl, naphthylmethyl, etc.
jAcyl means C5-12 acyl, such as acetyl,
propionyl, butyryl, pivaloyl, benzoyl, sodium
Phthoyl, pentanecarbonyl, cyclohexanecarbo
i Phosphoryl, such as nil, furoyl, thenoyl, etc.
For example, phosphoryl, methylmethylphosphonyl, dimorpho
Linophosphoryl, methylphosphoryl, dimethylphosphoryl
Heterocyclic groups include oxygen, nitrogen, diethylphosphoryl, etc.
At least one or more atoms selected from elementary and sulfur atoms
Heterocyclic groups containing heteroatoms, e.g. furyl, chenille
pyrrolyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl
, inthiazolyl, oxazinol, isoxasilyl,
Oxadiazolyl, triazolyl, tetrazolyl, thia
Diazolyl, imidazolidinyl, imidazolinyl, pyro
Lysinyl, pyrazolidinyl, pyrazolinyl, pyrrolinyl
, thiatriazolyl, oxatriazolyl, tetrahydride
loimidazolyl, indolyl, pyridyl, pyrimidinyl
, pyridazinyl, pyridonyl, pyrazinyl, pyranyl,
piperazinyl, piperidinyl, hexamethyleneimino,
Morpholinyl, triazinyl, 2,3-dihydrotria
Zinyl, benzochenyl, benzofuryl, pendiogiza
Zolyl, benzothiazolyl, inbenzofuryl, isoi
ndryl, benzofuryl, purinyl, quinarinyl, quino
Lyle, isoquinolyl, phthalazinyl, 1,3-benzodi
Oxolanil, phthalazinyl, quinazolinyl, quinazoli
nil, indolinyl, isoindolinyl, coumarinyl,
Chromenyl, naphthyridinyl, pyrido C2,3-d]
Pyrimidinyl, Cheno[:2,3-d]pyrimidinyl or
or the formula R6#4Σ (wherein R6 may be substituted
Indicates a methylene group. ) and the group J and noroge represented by
An atom is a fluorine, chlorine, bromine or iodine atom, etc.
each meaning. For example, alkyl, alkyl,
Kenyl, aryl, acyl, heterocyclic groups (heterocyclic groups are also
There is no special exception when the term has the same meaning as
Indicates the meaning given above. The compound represented by the general formula [I] will be explained in detail below.
Ru. R represents an optionally substituted tetrazolyl group;
The torazolyl group can be obtained from the following tetrazole isomers:
However, the present invention includes any of them.
. 1 In addition, a substituent of a tetrazolyl group that may be substituted
For example, hydroxyl groups, amino groups, sulfonate groups, etc.
group, sulfoxy group, alkyl group, alkenyl group, alkali
Jenyl group, cycloalkyl group, cycloalkenyl group,
cycloalkagenyl J, ji, aryl group, aral
Kyl group, acyl group, alkylthio group, arylthio group
group, alkylamino group, dialkylamine group, aryl
Amino group, aralkylamino group, acylamino, i3
; , alkylsulfonyl group, arylsulfonyl group,
Carbamoyl group, N-alkylcarbamoyl group, N, N
-dialkylcarbamoyl group, N-arylcarbamoy
group, N,N-diarylcarbamoyl group, sulfamoyl group, N,N-diarylcarbamoyl group,
yl group, N-alkylsulfamoyl group, N,N-dia
Rukylsulfamoyl group, N-arylsulfamoyl group
group, N, N-diarylsulfamoyl group, N-alkyl
-N-arylcarbamoyl group, N-alkyl-N-
Arylsulfamoyl group, ureido group, 6 imino groups
, trialkylsilyl group, trialkyloxysilyl group
, heterocyclic groups and the like. These 1P1 substituents may further include, for example, nitro groups,
Hydroxyl group, alkyl group, aryl group, alkyl group
cylindrical group, acyloxy group, carbamoyl group, protected
141i or more groups such as carboxyl groups which may be present]
1rt may be substituted with a group. R1 is an azide group, acylamino group % substituted alkyl
The amino group, which may be substituted, has the same meaning as mentioned above.
Has taste. ) and ranks 6th among conventional penicillin fat conductors.
, cephalosporin conductor 7 or azetidinone derivative
The substitute in the 3rd position of the jintai is added. Examples of this acylamino group include, for example. Examples include an acylamino group represented by the formula %. In addition, as the above-mentioned substituted algylidene amino group,
For example, a group represented by is added. alkyl of l74 in the formula, R'5O2NH-;
As the lyal or the cyclic group, the specific examples are as explained above.
The following groups are mentioned. T5 As a cyclic group, for example, a nitrogen atom, an oxygen atom in the ring
and at least one complex atom selected from sulfur atoms
A nitrogen-containing heterocyclic group having a
Azolyl, oxacylyl, isothiazolyl, isoxa
Silyl, imidazolyl, pyridyl, pyrimidinyl, kino
Lyle, benzothiazolyl, benzoxacylyl groups, etc.
Can be mentioned. Also, alkyl or alkenyl of R5 in the formula
, aryl, aralkyl, heterocycloalkyl or hetero
Specifically, the ring alkenyl group includes the groups described above.
Can be mentioned. In the above formula, amino in R11 and R12
Acid residues include glycyl, alanyl, valyl, and a
Le, isoleucyl, seryl, threonine, cysteil,
cystyl, methionyl, α- or β-aspartyl,
α- or β-asparaginyl, α-2β-straddling γ-
glutamyl, lysyl, arginyl, phenylalanyl,
Phenylglycyl, tyrosyl, histidyl, tryptophyl
Examples include amino acid residues such as yl, prolyl, and the like.゛Also, 几13 and HM and R22 and 1ζn are in instant contact.
It may also be believed that the nitrogen atom is
When forming a heterocyclic group, the heterocyclic group should be
Among the heterocyclic groups described, complexes containing 1 or more nitrogen atoms
Examples include elementary cyclic groups. Specifically, as the alkyloxy group in X,
Mention may be made of the groups described. Alkyl, alkenyl, alkali in R2 and R3
Genyl, cycloalkyl, cycloalkagenyl, a
alkyl, alkyloxy, alkylthio, aryl
Thio, alkylsulfonyl, 71J-lsulfonyl, a
Lucylamino, arylamino, arylsulfonylamino
mino, arylsulfonylamino, acyloxy or
Specifically, the acylamino group is the group explained above.
yJ'1 is given. In addition, as a substituted group for R1-furnace and 6, for example,
, halogen atom, hydroxyl group, cyano group, amino group
, acylamino group, alkylamino group, dialkylamino group
group, arylamino group, aralkylamino group,
Boxyl group, oxo group, thioxo group, carbamoyl group,
Mercapto group, nitro group, imino group, ureido group,
Ruho group, alkyl group, alkenyl group, aralkyl group,
Aryl group, cycloalkyl group, alkylthio group, alkyl group
Kyloxy group, alkagenyl group, cycloalkagenyl group
group, aralkyloxy group. Aralkylthio group, alkenyloxy group, alkenyl
Thio group, acyl group, phosphoryl group, sulfamoyl group,
Argylcarbamoyl group, alkylsulfonyl group, urethane
Idoalkyl group heptafurfrideneamino, benzylideneamino
Substituted alkylidene amino such as mino, alkyl
Silyl group, aralgyloxycarbonyl a, 71J-
aryloxycarbonyl group, aryloxycarbonyl group
group, aralkyloxycarbonylaminoalkyl group
jAminomethyl, aminoethyl, hydroxyethyl,
Substituted alkyl groups such as loloethyl and carboxyethyl;
2-oxoimidazolidin-1-ylcarbonylamino
Methyl, 3-benzylideneamino-2-oxoimidazo
Lysin-1-ylcarbonylaminomethyl, 3-chenylated
Lydenamino-2-oxoimidazolidine-1-dolphin
rubonylaminomethyl, 3-furfrideneamino-2-
Oxoimidazolidin-1-ylcarbonylaminomethy
Imidazolidine-1- which may be converted into
ylcarbonylaminoalkyl group j4-ethyl-2,3
Substitutions such as -dioxy-1-piperazinecarboxamide
1-piperazinecarboxamide group which may be
Rukyloxycarbonylalkylcarbamoyl group 4-
Optionally substituted amines such as sulfamoylanilino
lylamino group j In addition to the heterocyclic group defined above, 4
-Heterocyclic groups such as formylpiperazino are praised.
Ru. And R'~lN24 and pi are one or more of these
One substituent may be substituted. Specific examples of the acyl group of the acylamino group of R1 include
For example, phenylacetyl, phenoxyacetyl, sia
Noacetyl, trifluoromethylthioacetyl, cyano
Methylthioacetyl, IH-tetrazol-1-ylua
Cetyl, (4-hydroxy-5-methylpyridine-3-
yl) carbonyl, 2-(thiophen-2-yl)acetyl
Chil, 2-(2-aminothiazol-4-yl)acetyl
2-(pyridin-4-yl)thioacetyl, 2-(
Thiophen-2-yl)thioacetyl, [3-(2,6
-dichlorophenyl)-5-methylisoxazole-4
-yl]carbonyl, 2-(2-chloroacetylamino
thiazol-4-yl)acetyl, 2-(3,5-di
Chloro-1,4-dihydro-4-oxopyridine-1-
yl)acetyl, 2-(2-aminomethylphenyl)a
Cetyl, 2-'(β-carboxyvinyl)thioacetyl
, 2-(2-N-benzyloxycarbonylaminomethy)
ruphenyl)acetyl, 2-(succinimide)acetyl
2 (3-acetyl-2,5-dioxoimidazoli
din-1-yl)acetyl, 2-(2-ureidomethyl)
phenyl)acetyl, 2-(2,5-dioxopyrrolidi)
(2-3-yl)acetyl, 2-C2-(2-oxoimi
dazolidin-1-yl) carbonylaminomethylphenylene
Lecoacetyl, 2-(5,6-sihydro-4-oxa
tin-2-yl)acetyl, C4-C carbamoyl](
carboxy)methylene-1,3-dicetan-2-yl
]Carbonyl, 2-C2-(2-oxo-3-benzyly
thiaminoimidazolidin-1-yl) carbonyl amide
nomethylphenylcoacetyl, D-phenylcrisyl,
D-alanyl, α-amino-4-hydroxyphenyla
Cetyl, α-hydroxyphenylacetyl, α-carbo
Xyphenylacetyl, α-carboxy-4-. Hydroxyphenylacetyl, α-sulfophenylacetyl
Chil, α-sulfogycyphenylacetyl, α-formyl
Oxyphenylacetyl, α-sulfamoylphenyl
Acetyl, α-benzyloxycarbonylphenyl acetate
Chil, α-carboxy-(thiophen-3-yl)acetate
Chil, α-phenoquine carbonylphenylacetyl, α
-Azidophenylacetyl, 2-(N,N-dimethyls)
rufamoyl)-2-phenylacetyl, 2-(4-)
Ryloxycarbonyl)-2-phenylacetyl, N-
Benzyloxycarbonyl-α-aminophenyl acetate
α-tert-butoxycarbonylamino-4-hydroxy
Droxyphenylacetyl, 2-(4-ethyl-1-pi)
perazinecarboxamide)-2-phenylacetyl, 2
-(4-ethyl-2-oxo-1-piperazinecarboxy
samido)-2-phenylacetyl, 2-(4-ethyl-
2-oxo-1-piperazinecarboxamide)-2-(
2-aminothiazol-4-yl)acetyl, 2-(4
-ethyl-2-oxo-1-piperazinecarboxamide
)-2-(4-hydroxyphenyl)acetyl, 2-(
4-ethyl-3-oxo-1-piperazinecarboxami
)-2-phenylacetyl, 2-(4-ethyl-3-
Oxo-1-piperazinecarboxamide)-2-(4-
hydroxyphenyl)acetyl%2-(4-ethyl-3
-oxo-1-piperazinecarboxamide)-2-(2
-aminothiazol-4-yl)acetyl, 2-(4-
Ethyl-2,3-dioxo-1-piperazinecarboxa
(mido)-2-phenylacetyl%2-(4-ethyl-2
,3-dioxo-1-piperazinecarboxamide)-2
-(4-hydroxyphenyl)acetyl, 2-(4-ethyl)
Chil-2,3-dioxo-1-piperazinecarboxamide
de)-2-(thiophen-2-yl)acetyl, 2-(
4-ethyl-2,3-dioxo-1-piperazinecarbo
xamido)-2-(furan-2-yl)acetyl, 2-
(4-ethyl-2,3-dioxo-1-piperazinecal)
boxamide)-2-(2-aminothiazol-4-yl
) Acetyl, N-(4-ethyl-2,3-dioxo-1
-piperazinocarbonyl)-D-alanyl, N-(4-
Ethyl-2,3-dioxo-1-piperazinocarbonyl
)-D-phenylalanyl, N-(4-ethyl-2,3
-dioxo-1-piperazinocarbonyl)-D-methio
Nyl, N-(4-ethyl-2,3-dioxo-1-pipe
radinocarbonyl)-D-)leonyl, 2-(4-ethyl
-2,3-dioxo-1-piperazinecarboxamide
)-2-(4-sulfoxyphenyl)acetyl, 2-(
4-ethyl-2,3-dioxo-l-piperazinecarbo
Kisami)”)-2-(4-10lophenyl)acetyl,
2-(4-ethyl-2,3-dioxo-1-piperazine
carboxamide)-2-(4-methoxyphenyl)acetate
thyl, 2-(4-ethyl-2,3-dioxo-1-pipe
Radinecarboxamide)-2-(4-benzyloxif)
phenyl)acetyl, 2-(4-ethyl-2,3-dioxyl)
so-1-piperazinecarboxamide)-2-(3-chloro
rho-4-methoxyphenyl)acetyl, 2-(4-ethyl)
-2,3-diogyso]-piperazinecarboxamide
)-2-(4-trimethylsilyloxyphenyl)acetate
thyl, 2-(4-ethyl-2,3-dioxo-1-pipe
radine carboxami)”)2(3-chloro-4-sulfo
natoxyphenyl)acetyl, 2-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)-2-
(3-10rho-4-hydroxyphenyl)acetyl, 2
-(4-ethyl-2,3-dioxy-1-piperazinka
ruboxamide)-2-(2-chloroacetamidothiazo
(4-yl)acetyl, 2-(4-ethyl-2,3
-dioxo-1-piperazinecarboxamide)-2-(
2-acetamidothiazol-4-yl)acetyl, 2
-(4-ethyl-2,3-dioxo-1-piperazine
ruboxamide)-2-(4-benzoyloxyphenyl
) Acetyl, 2-(4-ethyl-2,3-dioxo-1
-piperazinecarboxamide)acetyl, 2-(4-ethyl)
Chil-2,3-dioxy-1-piperazinecarboxamide
(d)-2-(in-tetrazol-1-yl)acetyl
, 2,2-bis(4-ethyl-2,3-dioxo-1-
piperazinecarboxamide)acetyl, 2-(4-ethyl
-2,3-dioxo-1-piperazinecarboxamide
) -2-(1,4-cyclohexagenyl)acetyl
, 2-(4-ethyl-2,3-dioxo-1-piperazi
-2-(1-cyclohexane-1)
-yl)acetyl, 2-(4-ethyl-2,3-dioxyl)
(so-1-piperazinecarboxamide)-2-(2-methy
ruthiazol-4-yl)acetyl, 2-(4-ethyl)
-2,3-dioxo-1-piperazinecarboxamide)
-1m(pyrrol-2-yl)acetyl, 2-C4-(
2-phenylethyl)-2,3-dioxo-1-pipera
Zincarboxamide Cou 2-phenylacetyl, 2-C
4-(2-hydroxyethyl)-2,3-dioxo-1
-piperazinecarboxamide-2-phenylacetyl
, 2-C4-(2-chloroethyl)-2,3-dioxo
-1-piperazinecarboxamide-2-phenylacetate
Chil, 2-(4-methyl-2)3-dioxo-1-pipe
Radinecarboxamide)-2-phenylacetyl, 2-
(4-sulfurylideneamino-2,3-dioxo-1-
piperazinecarboxamide)-2-phenylacetyl,
2-(4-methyl-2,3-dioxo-1-piperazine
carboxamide)-2-(4-hydroxyphenyl)a
Cetyl, 2-(4-n-octyl-2,3-dioxo-
1-Piperazinecarboxamide)-2-phenylacetyl
2-(4-n-octyl-2,3-dioxo-1-
piperazinecarboxamide)-2-(4-hydroxyph)
phenyl)acetyl, 2-(4-n-octyl-2,3-
dioxo-1-piperazinecarboxamide)-2-(4
-sulfonatoxyphenyl)acetyl, 2-(4-n-
Octyl-2,3-dioxo-1-piperazinecarboxy
samido)-2-(thiophen-2-yl)acetyl, 2
-(4-n-octyl-2,3-dioxo-1-pipera
Zinecarboxamide)-2-(2-aminothiazole-
4-yl)acetyl, 2-(4-n-octyl-223
-dioxo-1-piperazinecarboxamide)-2-(
2-Chloroacetamidothiazol-4-yl)acetyl
N-(4-ethyl-2,3-dioxo-1-pipera)
dinecarbonyl)-D-/rutamyl, 2,5-bis(4
-ethyl-2,3-dioxo-1-piperazinecarboxy
samido)pentanoyl, 2,3-bis(4-ethyl-2
,3-dioxo-1-piperazinecarboxamide)pro
Pioni/L;, 2-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide)-: 1-chloropropyl
onyl, 2-(4-ethyl-2,3-dioxo-1-pi
perazinecarboxamide)-3-sulfamoylgropi
onyl, 2-(4-ethyl-2,3-dioxo-1-pi
perazinecarboxamide)-3-[(1-methyl-i
H-tetrazol-5-yl)thio]prohionyl, 2
-(4-ethyl-2,3-dioxo-1-piperazine
ruboxamide)-3-(ethoxycarbonylmethylcarboxylic acid)
bamoyl)propionyl, 2-(4-ethyl-2,3-
dioxy-1-piperazinecarboxamide)-3-[2
-(1,H-tetrazol-1-yl)acetamide]
Gropionyl, 2-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide)-3-(thiophene-
2-yla-7doamido)propionyl, 2-(4-ethyl)
-2,3-dioxo-1-piperazinecarboxamide
)-2-(4-1-octanoyloxyphenyl)acetate
chill, N-(2-(2-F7minothiazol-4-yl)
)-2-methoxyiminoacetyl)-p-alanyl, 2
-[2-(2-aminothiazol-4-yl)-2-methane
Toxiiminoacetamidocoacetyl, N-[2-(2
-aminothiazol-4-yl)-2-methoxyimino
Acetyl]-〇-phenylglycyl, 2-(2-chloro
acetamidothiazol-4-yl)-2-(2-(2
-chloroacetamidothiazol-4-yl)-2-methane
Toxiiminoacetamide] acetyl, 2-CC2-o
xoimidazolidin-1-yl) carboxamide sea 2
-phenylacetyl, 2-C(3-fluorylideneamino)
(2-oxoimidazolidin-1-yl)carboxa
midocy 2-phenylacetyl, 2-([2-oxo-
3-(thiophene-2-ylaldoimino)imidazoli
Zin-1-yl]carboxamide)-2-phenylacetate
Chil, 2-+: (3-methylsulfonyl-2-oxoyl
midazolidin-1-yl)carfoxamide]-2-phe
Nylacetyl, 2-[(3-sulfurylideneamino-2
-oxoimidazolidin-1-yl)carboxamide]
-2-(4-hydroxyphenyl)acetyl, 2-[(
3-furfurylideneamino-2-oxoimidazolidine
-1-yl)carboxamide]-2-(thiophene-2
-yl)acetyl, 2-([2-oxo-3-(thiophyl)
hen-2-ylaldoimino)imidazolidin-1-y
]carboxamide)-2-(thiophen-2-yl)
Acetyl, 2-CC3-sulfurylideneamino-2-o
xoimidazolidin-1-yl)carboxamide:]-
2-(2-aminothiazol-4-yl)acetyl, 2
-CC3-sulfurylideneamino-2-oxoimidazo
lysin-1-yl)carboxamide)-2-(2-chloro
loacetamidothiazol-4-yl)acetyl, 2-
C(3-methyl-2-oxoimidazolidin-1-yl
) carboxamide'J-2-(thio7en-2-yl)
Acetyl, 2-[(3-sulfurylideneamino-2-o
xoimidazolidin-1-yl)carboxamide]-2
-C4-sulfonatokey/phenyl)acetyl, 2-4
(3-sulfurylideneamino-2-oxoimidazolidi
(n-1-yl)carboxamide]gropionyl, 2-(
4-Hydroxy-6-methylnicotinamide)-2-ph
Phenylacetyl, 2-[(4-hydroxy-1,5-carboxylic acid)
thyridin-3-yl) carboxamide cy-2-phenylene
Ruacetyl, 2-((4-hydroxy-1,5-catch)
lysin-3-yl)carboxamide)-2-(4-hydro)
roxyphenyl)acetyl, 2-(4-hydroxy-6
-methylnicotinamide)-2-(4-hydroxyphene)
acetyl), 2-C(6-hydroxy-1,5-na)
phthyridin-3-yl)carboxamide]-2~phenylene
Ruacetyl, z-C (6-hydroxy-1,5-naphthi
lysin-3-yl)carboxamide)-2-(4-hydro)
roxyphenyl)acetyl, 2([5,8-dihydro-
2-(4-formyl-1-piperazinyl)-5-oxo
Pyrido[2,3-d)pyrimidin-6-yl]carboxy
samide)-2-phenylacetyl, 2-([5,8-
dihydro-2-(4-formyl-1-piperazinyl)-
5-oxopyrido(2,3-d)pyrimidin-6-yl
]Carboxamide)-2-(4-hydroxyphenyl)
acetyl, 2-C(4-hydroxy-7-methyl-1,
8-naphthyridin-3-yl)carboxamide]-2-
Phenylacetyl%2-[(4-hydroxy-7-methy
(1,8-naphthyridin-3-yl)carboxamide
]-2-(4-hydroxyphenyl)acetyl, 2-C
(3,5-dioxo-1,2,4-)riazine-6-y
carboxamide]-2-(4-hydroxyphenyl)
) acetyl, 2-((4-hydroxy-7-dryfluoro)
lomethylquinolin-3-yl)carboxamide]-2-
Phenylacetyl, 2-C(4-hydroxy-7-tri
Fluoromethylquinolin-3-yl)carboxamide]
-2=(4-hydroxyphenyl)acetyl, 2-[(
coumarin-3-yl) carboxamide cy-2-phenyl
Acetyl, 2-C(coumarin-3-yl)carboxa
mido)-2-(4-hydroxyphenyl)acetyl, 2
-C(6-promo-1-ethyl-1,4-dihydro-4
-oxocheno[2,3-1]pyridin-3-yl)ka
ruboxamide-2-phenyla-7tyl, 2-[(4-
Carboximidazol-5-yl)carbogisamide]
-2-phenylacetyl, 2-[C4-(4-10 lov
enyl)imidasol-2-yl]carboxamide)-
2-phenylacetyl, 2-[(benzimidazole-
2-yl) carboxamide cy-2-phenylacetyl,
2-C(3,5-dioxo-1,2,4-)riazine-
6-yl)carboxamide]-2-(thiophene-2-
yl) acetyl, 2-[:(2,4-dioxypyrimidine)
-5-yl)carboxamide]-2-(thiophene-
2-yl)acetyl, 2-(N-penzyloxycarbo
Nylprolylamino)-2-(furan-2-yl)acetate
Chil, N-benzylcarbonyl-D-alanyl, N-(
4-hydroxybenzoyl)-D-alanyl, 2-(4
-chlorobenzamido) clopionyl, 2-(4-amido)
Novenzamido)acetyl, N-[2-(2-aminothi
azol-4-yl)acetyl]-D-phenylglycyl
2-[2-(2-chloroacetamidothiazole-
4-yl)acetamido]-2-phenylacetyl, 2
-[2-(4-ethyl-2,3-dioxo-1-pipera
Zinecarboxamide)-2-(thiophen-2-yl)
acetamide)”]-]2-phenylacetyl α-[(thi
Offen-2-yl]methylcarbonyl]-D-alani
2-(4-chlorobenzoylureido)-2-(thiyl)
(offhen-2-yl)acetyl, 2-C2-ureido-
2-(thiophen-2-yl)acetamide:]-]2
-phenylacetyl 2-[2-luido 2-(thiophene
l-2-yl)acetamide, l-2-(4-hydroxy
Cyphenyl)acetyl, 2-C2-(thiophene-2-
yl)acetamido]acetyl, 2-[2-ureido-
2-(thiophen-2-yl)acetamide]-2-(
4-sulfonatoxyphenyl)acetyl, N-mesyl-
D-phenylcrisyl, N-carbamoyl-D-phenylene
Luglycyl, 2-ureido-2-(thiophene-2-y)
) Acetyl, 2-(2-aminothiazol-4-yl)
)-2-u1/idoacetyl, 2-4:2-(2,6-
cyclophenylthio)acetamido]-2-phenyl
Acetyl, 2-(3-methylcarbamoyl-3-methyl
-1-ureido)-2-phenylacetyl, 2-(3-
Methylcarbamoyl-3-methyl-1-ureido)-2
-(4-hydroxyphenyl)acetyl, 2-(3-methyl)
Tylcarbamoyl-3-methyl-1-ureido)-2-
(Thiophere-2-yl)acetyl, 2-(: 3-(
2-hydroxybenzoyl)-1-ureido) -2-
(4-hydroxyphenyl)acetyl, 2-(3-(2
-hydroxybenzoyl)-1-ureido]-2-fe
Nilaceti#, 2-C3-(2-benzyloxybenzo
yl)-1-ureidocy 2-phenylacetyl, 2-
C3-(2-benzyloxybenzoyl)-i-urei
)-2-(4-hydroxyphenyl)acetyl, 2-
[3-(2-benzyloxybenzoyl)-1-ure-
()”]-2-(4-sulfonatoxyphenyl)acetyl
2-[2-[benzyloxycarboxamide)-2
-(benzyloxycarbonyl)ethanesulfonamide
C2-phenylacetyl, 2-(2-phenylaceto
amido) clopionyl, 4-ethyl 1,3-dioxo-
1-piperazinocarbonyl, 2-benzyloxycarbo
Xamido-2-phenylacetyl, N-benzyloxy
Carbonyl-D-alanyl, 2-benzyloxycarbo
Xamido-3-(N-methylcalcimoyl)propio
Nyl, 2-[2-amino-3-(N-methylcarbamoy)
) Glopionamide] acetyl, 2-[2-amino-
3-(N-methylcarbamoyl)gropionamide]-
2-phenylacetyl, 2-(2-amino-3-sulfur)
amoylpropionamide)-2-phenylacetyl,
2-112-(4-ethyl-2,:3-dioxo-1-
piperazinecarboxamide)acetamide]-2-phe
Nylacetyl, 2-C2-(4-ethyl-2,3-dio
xy-1-piperazinecarboxy-1-mido)-3-(N
-methylcarbamoyl)globionamide]-2-phene
Nylacetyl, 2-C2-benzyloxycarboxami
Do-3-(N-methylcarbamoyl)gropionamide
]Acetyl, 2-(N-penzyloxycarphonylph)
(phenylglycylamino)-3-(N-methylcarbamoy)
) clopionyl, 2-(3-sulfamoyl-2-
(benzyloxycarboxamide)globionamide]
-2-phenyla7glu, 2-C2-penzyloxy
Ruboxamide-3-(4-methoxyphenyloxycarboxylate)
ruboxamide) glopionamide]-2-phenylacetate
Chil, N-D-alanyl-D-phenylglycyl, N-
D-phenylglycyl-D-alanyl, N-D-7rani
RuD-7 ranyl, 2- (2,3-diaminogropio
(Amido)-2-phenylacetyl, N-γ-D-glue
Tamyl-D-alanyl, N-(N-benzyloxycal
Bonyl-D-phenylcrisyl)-D-phenylcrisyl
N-(N-benzyloxycarbonyl-D-arani)
)-D-phenylcrysyl, N-(N-penzyloxy
cyclocarbonylmethylamide (asbaragyl)-D-phenylene
Lucrisil, N-(N-methylamidoasparagyl)-
D-phenylglycyl, N-(N-carbamoyl-D
-t'J7') phanyl)-D-phenylglycyl
, 2-(2-aminothiazol-4-yl)-2-meth
xyiminoacetyl, 2-(2-chloroacetamidothi)
azol-4-yl)-2-methoxyiminoacetyl,
2-(2-7minothiazol-4-yl)-2-ethoxy
Shiiminoacetyl +2-(2-aminothiazole-4-
yl)-2-ingloboxyiminoacetyl, 2-(2
-aminothiazol-4-yl)-2-tcrt-buto
xyiminoacetyl, 2-(thiophen-2-yl)-
2-methoxyiminoacetyl, 2-phenyl-2-meth
xyiminoacetyl, 2-(4-hydroxyphenyl)
-2-methoxyiminoacetyl, 2-(furan-2-y)
)-2-methoxyiminoacetyl, 2-(2-amino
oxazol-4-yl)-2-methoxyiminoacetyl
2-(2-aminothiazol-4-yl)-2-hydroxy
Droxyiminoacetyl, 2-(2-aminothiazole)
-4-yl)-2-cyanomethoxyiminoacetyl, 2
-(2-aminothiazol-4-yl)-2-(2-a
Mineethoxyimino)acetyl, 2-(2-aminothia)
sol-4-ylk-2-sulfoximinoacetyl,
2-(2-aminothiazol-4-yl)-2-benzi
2-(2-aminothiazole)
-4-yl)-2-phenoxyiminoacetyl, 2-(
Thiophen-2-yl)-2-hydroxyiminoacetyl
2-(thiophen-2-yl)-2-hydroxyyl
Minoacetyl, 2-(4-hydroxyphenyl)-2-
Hydroxyiminoacetyl, 2-(furan-2-yl)
-2-hydroxyiminoacetyl, 2-(2-aminoacetyl)
xazol-4-yl)-2-hydroxyiminoacetyl
2-(2-aminothiazol-4-yl)-2-4
(1-carboxy-1-methylethoxy)iminocoacetate
Chil, 2-(thiophen-2-yl)-2-C(1-ka
ruboxy-1-methylethoxy)iminocoacetyl, 2
-phenyl-2-((1-carboxy-1-methyleth)
xy)iminocoacetyl, 2-(4-hydroxyphenylphenyl)
)-2-[(t-carboxy-1-methylethoxy)
iminocoacetyl. 2-[furan-2-yl)-2-4(1-carboxy-
1-methylethoxy)iminocoacetyl, 2-(2-a
Minoogizazol-4-yl)-2-C(1-carboxy
C-1-methylethoxy)iminocoacetyl, 2-(2
-aminothiazol-4-yl)-2-carboxymeth
xyiminoacetyl, 2-(thiophen-2-yl)-
2-carboxymethoxyiminoacetyl, 2-phenyl
-2-carboxymethoxyiminoacetyl, 2-(4-
Hydroxyphenyl)-2-carboxymethoxyimino
Acetyl, 2-(furan-2-yl)-2-carboxy
Methoxyiminoacetyl, 2-42-aminooxazole
(4-yl)-2-carboxymethoxyiminoacetyl
2-(5-amino-1,2,4-thiadiazole-
3-yl)-2-methoxyiminoacetyl, 2-(5-
Amino-1,2,4-thiadiazol-3-yl)-2
-Hydroxyiminoacetyl, 2-(5-amino-1,
2,4-thiadiazol-4-yl)-2-C(1-ka
ruboxy-1-methylethoxy)iminocoacetyl, 2
-(5-amino-1,2,4-thiadiazole-4-y
)-2-carboxymethoxyiminoacetyl, 2-(
2-aminothiazol-4-yl)-2-(IH-tet
Lazol-5-ylmethoxyimino)acetyl, 2-(
Thiophen-2-yl)-2-(IH-tetrazole-
5-ylmethoxyimino)acetyl, 2-phenyl-2
-(lH-tetrazol-5-ylmethoxyimino)a
cetyl, 2-44-hydroxyphenyl)-2-(I
H-tetrazol-5-ylmethoxyimino)acetyl
2-furyl-2-(IH-tetrazol-5-yl
methoxyimino)acetyl, 2-(2-aminooxazo)
(IH-tetrazol-5-yl)-2-(IH-tetrazol-5-yl)
methoxyimino)acetyl, 2-(5-amino-1,
2,4-thiadiazol-3-yl)-27(IH-te
Torazol-5-ylmethoxyimino)acetyl, 2-
(2-aminothiazol-4-yl)-2-benzylide
acetyl, 2-(2-aminothiazol-4-yl)
-2-(2,6-dichlorobenzylidene)acetyl, 2
-(2-aminothiazol-4-yl)-2-(2-ph)
rufurylidene) acetyl, 2-(2-aminothiazole)
-4-yl)-2-(4-chlorobenzylidene)acetylene
2-(2-aminothiazol-4-yl)-2-(
3-chenylmethylene)acetyl, 2-(2-aminothi
azol-4-yl)-3-(2,,4,6-trimethane)
methylbenzylidene)acetyl, 2-(2-aminethiazo)
(4-yl)-2-(2-)lifluoromethylben
zylidene) acetinope 2-(2-aminothiazole-4)
-yl) -2-(2,3,゛6-drichlorobenzyl)
den)acetyl, 2-dichloromethylene-2-(furan)
-2-yl)acetyl, 2-(2-aminothiazole-
4-yl)-2-dichloromethyleneacetyl, 2-(2
-aminothiazol-4-yl]-2-chloromethylene
Acetyl, 2-(2-aminothiazol-4-yl)-
Examples include 2-butenoyl. Also, a substituted alkylidene group of a substituted alkylidene amino group
As a specific example, for example, hexamethylene iminomer
tyrene, carboxy-hexamethyleneiminomethylene,
Diethylaminomethylene, [4-(3-amino-1-propylene)
(ropyru) piperidin-1-ylmethoxy, 1-hexame
Tylenimino-1-propylidene, hexamethyleneimine
Examples of non-aminomethylene and aminomethylene include
For example, l-methylpyridinium-4-yl, 1-methyl
Quinolinium-4-yl, 1-(2-methylphenyl)
Pyridinium-4-yl, 1-methylpyridinium-2
-yl, 1-benzylbididinium-4-yl, 1-(
4-methoxybenzyl)pyridinium-4-yl, 1-
(2-furylmethyl)pyridi-tum-4-yl, 1-methyl
Chylpyrimidinium-2-yl, 1-benzylbyly<
1', = pmu-4-yl, 1,3-dimethylbenz
imidazolium-2-yl, 2-ethylthiazolium-
3-yl group, etc. Further, the formula R4S of the group represented by the formula R4562NII-
For example, the sulfo group methane
sulfonyl, trifluoromethanesulfonyl, ekunsul
Optionally substituted alkylsulfonyl group such as fonyl group
group nobenzenesulfonyl, tosyl, mesitylenesulfonyl
Substituted compounds such as %2-naphculenesulfonyl group
optional arylsulfonyl group; 3-pyridinesulfony
Even if Jt is substituted with quinaldine sulfonyl group,
Examples include good heterocyclic sulfonyl groups. However, the compound of general formula (I) and its salts are
Syl group, hydroxyl group, amino group and/or imitation group
If it has a group of
It's okay to be considerate. Here, the hydroxyl group is usually
All glues that can be used as storage groups for droxyl groups, 1
; For example, benzyloxycarbonyl, 4-
two!・Lobenzyloxycarbonyl, 4-bromobendi
oxycarbonyl, 4-methoxybenzyloxycar
Bonyl, 3,4-dimethoxybenzyloxycarbonyl
, 4-(phenyl, azo)benzyloxycarbonyl,
4-44-methoxyphenylazo)benzyloxycal
Bonyl, tert-butoxycarbonyl, 1, age
Methylgloboxycarbonyl, isopropoxycarbonyl
diphenylmethoxycarbonyl, 2,2,2-
)! j dichlorotoxycarbonyl, 2,2,2-
) Lipromoethoxycarbonyl, 2-furfuryloxycarbonyl
Cycarbonyl, 1-adamantyloxycarbonyl, 1
-cyclopropylethoxycarbonyl, 8-ginolyl
Elimination blocker for xycarbonyl, trifluoroacetyl, etc.
acyl group mebenzyl group trityl group methoxymethy
The group j2-nitrophenylsulfeny has a 52,4-di
Examples include nitrophenylsulfenyl group. In addition, as a protecting group for amino groups and imino groups,
Contains all groups that can be used as amino groups, and
For example % 2.2.2-trichloroethoxycarbonyl
, 2.2.2-1-ribromoethoxycarbonyl, ben
Zyloxycarbonyl, methanesulfonyl, benzene
Ruhoni 7tz, p-toluenesulfonyl, 4-nitrobe
2-bromobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl
rubonyl, (mono-, di-, tri)chloroacetyl,
trifluoroacetyl, phenylacetyl, acetyl,
Formyl, tert-amyloxycarbonyl, methoxycarbonyl
Cycarbonyl, ethoxycarbonyl, 2-cyanoethoxy
cycarbonyl, tar t-butoxycarbonyl, meth
Ki7 methyloxycarbonyl, acetyl methyloxycarbonyl
carbonyl, 4-methoxybenzyloxi7carponyl,
phenoxycarbonyl%3,4-dimethoxybenzyloxy
Cycarbonyl, 4-(phenylazo)benzyloxyca
rubonyl, 4-(4-methoxyphenylazo)benzyl
Oxycarbonyl, pyridine-nioxide-2-yl
-methoxycarbonyl, 2-7lyloxycarbonyl,
diphenylmethoxycarbonyl, 1,1-dimethylpoxycarbonyl
Ropoxycarbonyl, isopromo mixicarpa? Nil,
1-cyclopropylethoxycarbonyl, phthaloyl,
Succinyl, l-adamantyloxycarbonyl, 8-
Quinolyloxycarnitroyl, benzoyl, 4-nitro
Deletion of penzoinope 4-tert-butylbenzoyl etc.
Acyl hacitrityl, diphenylmethyl, and base that are easy to comb.
3,5-di-tert~butyl-4-hydroxy
Shibenzyl, 4-nitrobenzyl, 4-methoxybenzyl
2,4-dimethoxybenzyl, 2-nitrophenyl
sulfeni/l/, 2.4-shi'-)rofeni
Rusulfenyl, hinochloroyloxymethyl, benzyl
Chin, 4-nitrobenzilitin, 2-hydroxybe/di
lidene, 2-hydroxy-5-chlorobenzylidene, 2
-Hydroxy-1-naphthylmethylene, 3-hydroxy
-4-pyridylmethylene, 2-(1-ethoxycarbonylene)
(1-propenyl), 2-(1-(1-morpholino)
carbonyl-1-propenyl], 2-(1-propenyl)
ruaminocarbonyl-1-propenyl) + 1-methoxy
Carbonyl-2-propylidene, 1-ethoxycarbonyl
-2-propyritine, 3-ethoxycarbonyl-2-
Butylidene, 1-acetel-2-propylidene, 1-beylidene
Nzoyl-2-propylidene, 1-[:N-(2-meth
xyphenyl)carbamoyl]-2-propyritine, 1
-[N-(4-methoxyphenyl)carbamoyl]-2
-prohyritene, 2-ethoxycarbonylcyclohexy
Lyden, 2-functional toxycarbonyl cyclopentylene %
2-acetylcyclohexylidene, 3,3-dimethyl-
Detachable threads such as 5-oxycyclohexyritene
of amino groups such as di- or tri-alkylsilyl groups.
Protecting groups are honored. Furthermore, as a protecting group for carboxyl group, 11'I ordinary
All of the carboxyl groups used as alcohol-retaining groups are
groups, such as methyl, ethyl, n-propyl,
Inculpil, tert-butyl, n-butyl, phenyl
ru, indanyl, benzyl, diphenylmethyl,)! ,
I-thyl, 4-nitrobenzyl, 4-methoxybenzyl,
Benzylmethyl, acetylmethyl, 4-nitrobene
Zoylmethyl, 4-bromobenzylmethyl, 4-meta
sulfonylbenzoylmethyl, phthalimidomethyl,
Trichloroethyl, 1,1-dimef-2-Frobe
Nyl, 1,1-dimethylglobil, acetoxymethyl
, propionyloxymethyl, pivaloyloxymethyl
, 1-acetylethyl, 1-pivaloyloxyethyl,
1-pivaloyloxy-n-propyl, acetylthiome
Chil, pivaloylthiomethyl, 1-acetylthioethyl
, 1-pivaloylthioethyl, methoxymethyl, ethoxy
dimethyl, propoxymethyl, impropoxymethyl,
n-butoxymethyl, methoxycarbonyloxymethyl
, ethoxycarbonyloxymethyl, tCrt-butoxy
Cycarbonylmethyl, 1-methoxycarbonyloxyethyl
thyl, 1-ethoxycarbonyloxyethyl, 1-iso
Probogicicarbonyloxyethyl, 7talidyl, 2-
Phthalinyldenethyl, 2-(5-fluorophthalinyl)
ethyl, 2-(6-chlorophthalidylidene)ethyl
2-(6-medoxy7clydylidene)ethyl, 5-
Methyl-2-oxo-1,3-dioxo-4-yl
, 5-ethyl-2-oxo-1,3-dioxy-4
-yl, 5-propyl-2-oxo-1,;3-diox
Thor-4-yl, 1,1-dimethyl-2-propenyl
, 3-methyl-3-butenyl, succinimidomethyl,
”-cyclopropylethyl, methylthiomethyl, phenyl
ruthiomenal, dimethylaminomethyl, quinoline-1-
Oxide-2-yl-methyl, pyridine-1-oxide
-2-yl-methyl, bis(4-methoxyphenyl)methyl
Groups such as titanium are removed, and non-groups such as titanium tetrachloride are added to the formula.
If the carboxyl thread is protected by a gold-plated compound,
and Japanese Patent Application Publication No. prJJ46 7073 and
As described in Japanese Patent Publication No. 7105259,
For example, a silyl compound such as dimethylchlorosilane can be used to
Examples include cases where the xyl group is protected. Then, in R/R' p R2 and R3, the
Carboxyl group that may be protected, even if protected
Good as a protective group in amino and imino protecting groups
is the carboxyl group mentioned above. The groups exemplified as the protective groups for amino and imino groups are
Can be mentioned. In addition, as salts of the compound of general formula [I], basic groups
Alternatively, salts of acidic groups can be mentioned. basic
Examples of salts in groups include hydrogen chloride and hydrogen bromide.
, salts with mineral acids such as sulfuric acid, oxalic acid, succinic acid, formic acid2
Organic carbs such as trichloroacetic acid and trifluoroacetic acid
Acid! oJJ Methanesulfone t'J % Benzene Sulfone
Fonic acid, toluene-4-sulfone LI2. Mesitylens
Sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-
Salts with sulfonic acids such as t,5-disulfonic acid, or
Examples of salts with acidic groups include sodium,
Potassium and other alkali metals such as Calcium, Mag
Ammonium salts with alkaline earth metals such as nesium
Salt i Procaine, dibenzylamine, N-benzyl-β
-Phenethylamine, 1-ephenamine, NN-diben
Dillethylenediamine, trimethylamine, triethyl
Amine, triethylamine, pyridine, N, N-dime
Tylaniline, N-methylpiperidine, N-methylmol
Holin, diethylamine, synchhexylamine, etc.
Nitrogen-containing '7.7 jb'4% 1 ton, salt with IH
can be given. In the compound of general formula CI) or its salts,
Optical isomers (D, L, DL form, S or R
configuration Iζi゛), geometric isomers (cis, trans or
mixtures thereof or syn, anti or mixtures thereof
stereoisomers such as tautomers) and/or tautomers exist
However, the present invention does not include any of them.
Reeds, as well as compounds of general formula [■] or their salts.
It also includes hydrates as well as various crystalline forms. The compound of general formula [11] or its salts of the present invention may be
It can be administered orally or parenterally to humans and animals.
When applying membrane pressure to animals, penicillin and cephalograms are usually used.
Dosage forms applied in the case of sporin drugs, e.g.
, tablets, capsules, lozenges, injections, suppositories, etc.
It is prepared in a form h1 and is suitable for oral or parenteral administration.
used. The administration needle should be selected appropriately according to the patient's symptoms.
Generally, adults have an IQ of 1 to 200 IQ/day.
(preferably about 2W to 100W/m/1=l)
It may be administered in divided doses. The compound of general formula [I] or a salt thereof of the present invention may be
In addition to its uses, it also has a β-lactamase inhibitory effect.
It can be used in combination with β-lactam antibiotics. Examples of such mu-lactam antibiotics include
, penicillin and cephalosporin antibiotics
Substances etc. can be used. Next, the pharmacological effects of representative compounds in the present invention will be explained.
. ■ Antibacterial activity against typical Gram-positive and Gram-negative bacteria
Regarding the minimum nephrogenic inhibition level (MIC+mcg/d),
This chemotherapy society marking method [CI+emoil+crapy vol. 23, jjT 1
-2 pages (1975)]. II
cart Infusionbrolh (Eiken Kagakusha)
11 cells containing the drug were cultured at 37°C for 20 hours at
Heart Infusion agar medium (513
After inoculating the cells (manufactured by Kenkagaku Co., Ltd.) and culturing them at 37°C for 20 hours,
The presence or absence of bacterial growth was observed, and the growth of bacteria was stopped in 1)11.
The minimum concentration was defined as the MIC (mcg/me). However, the amount of bacteria in contact is 104/plate (106/plate)
ml). The results are shown in Table-1. (Left below) Table 1 *Test compound was dissolved in hydrogen carbonate (IJum) water bath solution.
Let's use it. Compound A 2(3S,4R)-3-(2-(2-aminothiazo
(Z)-2-hydroxyiminoacetate
toamide]-4-methyl-1-(IH-tetrazole-
5-yl)-2-azetidinone B' (3S,4R)-3(, 2(2-aminothia
sol-4-yl)-(Z)-2-C(1-carboxy
-1-methylethoxy)imino]acetamide)-4-
Methyl-1-(I II-tetrazol-5-yl)-
2-Azetidinone c: (38,4R)-3-[:2-(2-aminothi
azol-4-yl) (Z) 2-tert-buto
xyiminoacetamide]-4-methyl-1-(II
I-tetrazol-5-yl)-2-7 zetidinone o s (38,4R)-3-C2-(2-7 minothia
sol-4-yl) -(Z) -2-isopropoxy
iminoacetamide]-4-methyl-1-(in-tet
Razol-5-yl)-2-azetidinone E: (3s)-3-(2-(2-aminothiazole)
(4-yl)-(Z)-2-C(1-carboxy-1
-methylethoxy)imino]acetamide)-1-(1
4-tetrazol-5-yl)-2-azetidinone F: (3S,4S)-3-(2-(2-aminothia
sol-4-yl) (z) 2-tert-butoki
shiiminoacetamide]-4-methyl-1-(i n-
(tetrazol-5-yl)-2-ar7'1tidinone 2, β-lactamase inhibitory effect Enterobacter as a representative example of cephalosporinase
・Produced β-lactamase of cloaca H-27 and appropriate
A concentration of inhibitor at 1/15 Mp, a7.0 phosphate
After incubation at 30°C for 5 minutes in buffer, the final humidity was 100°C.
Perform an enzymatic reaction by adding micro or molar amounts of cephaloridine.
It was. β-lactamase activity was determined by spectrophotometric method
[Biocl+ernicaJ Jourr+aJ 1
Volume 39. 780-789 (1974)]
Ta. Required to inhibit β-lactamase activity by 50%
Inhibitor concentration was taken as ID 5Q. The results are shown below-2. Table-2 Compound a: (3s)-3-[2- to 2-aminothiazole-
4-yl) (z) -2-tcrt-butoxyimino
acetamido)-1-(IH-tetrazol-5-yl
)-2-azetidinone H: (3s) -3-C2-(2-aminothiazole
-4-yl) (Z) -2-tert-butoxyimide
noacetamide)-1-(1-carboxymethyl-IH
-tetrazol-5-yl)-2-azetidinone CH2COOH I: (3S)-3-(2-(2-aminothiazole)
-4-yl) -(Z) -2-tert-butoxy
Minoacetamide)-1-(2-carboxymethyl-2
H-tetrazol-5-yl)-2-azetidinone J: (3S)-3-(2-(2-aminothiazole)
-4-yl) (Z)-2-[(i -tert-but
oxycarbonyl-1-methylethoxy)imino]aceto
amido)-1-(IH-tetrazol-5-yl)-2
-Azetidinone 8, acute co]j (LDso value) LD shown in A-J by intravenous injection of ζ compound in mice
All 5Q values were 1oooπy/Ky or more. According to the above test results, the compound of the present invention is effective against Durum-positive bacteria and
It has a broad antibacterial spectrum against Gram-negative bacteria and Gram-negative bacteria.
, exhibits excellent antibacterial activity and also has excellent β-lactam
It is clear that it has a tamase inhibitory effect, and two people and
It has been shown to be extremely useful in the treatment of bacterial infections in animals and animals.
I can understand it. Next, a method for producing a compound of general formula [I] or a salt thereof
I'm thinking about it. The compound of the present invention can be prepared by a method known per se or by a method similar thereto.
For example, the following
It can be manufactured by the method. (Left below) Manufacturing method (1) Manufacturing method (2) or its salts or its salts manufacturing method (4) In the formulas for each of the above manufacturing methods, R, R1, R2, R'', R
5゜Hu, R23, +124, X and before sinking
R25 has the meaning described in 121.
Acyl group of mino group or formula n' of 2R'5O2NIL-
5o2- (in the formula, 14 has the meaning described above)
, R21+ is the acylamino group described above, formula 11'SO, NH- or
1B is a group, Y and Q are groups that can be used as legs, and 2 is an anion.
It shows that. As the removal group of Y, if L, hydroxy
group. A halogen atom or an optionally substituted acyl atom
cy, alkylsulfonyloxy or alkylsulfonyloxy
Nyloxy groups etc. are included. The 91 reactors this month include a 1-ton reactor and an O.
The following substituents are listed below. Examples of groups that can be eliminated from Q include no-rogen atoms, etc.
It will be done. An anion of - is one proton from an inorganic acid or an organic acid.
This inorganic acid or organic
Hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.
Hydrogen chloride; sulfuric acid, perchloric acid, tetrafluoroboric acid
, inorganic acids such as hexafluorophosphoric acid or benzene
Sulfonic acids such as sulfonic acid, p-)luenesulfonic acid
; Organic acids such as alkyl sulfuric acid such as methyl sulfuric acid, etc.
can be lost. As the acyl group of the acylamino group of R25, the acyl group of R1 is
Acyl group of acylamino group exemplified as cylamino group
But also, the formula R45O,- of the formula R' S 02Nu-
Then, 2R exemplified as the formula R'5o2NH- of R1
The formula R'5O2- of '5O2NH- is lowered, and R27's
Acylamino group, formula R'SO□Ni1- and ter6N
As n-, the corresponding groups explained for R1 are each
The alkyloxy group of Xl is the group explained for X.
single gla fl,ru. General formula [:IJ'), [river], [VD~Dll]
As the salts of the compound, jj'' compound of formula [I]
The salts of basic groups or acidic groups explained with salts are the same.
It is mentioned as follows. As a reactive derivative of the compound of general formula [■], for example,
i'+', (CHs)3Si-, (CIIs)+S
iri) CC11s)2[(CHs)zCII)S+-
, (CIT30)3S1 / CH3(CH30)2S
Organic silyl groups such as I-, (CH3MCH30)Si-
, or ((jI30)zP pgeratL. As a reactive derivative of the compound of the general formula [river], R3 is
In the case of the acyl group of the acylamino group specified by 6Iλ in R1 (
-1: For example, chloride, acid anhydride, mixture
Acid anhydrides, active acid amides, active esters, acid azides,
Reaction of compound of general formula [:IID with Vilsmeier reagent
4t derivatives, and more specifically acid halogens.
Examples of acid salts include acid chloride and acid bromide.
However, as the mixed acid anhydride, for example, charcoal 1"d mono
Charcoal such as ethyl ester, carbonate monoisobutyl ester
Mixture with acid monoalkyl esters - hydrothermal acetic acid, piva
Phosphoric acid, valeric acid, trichloroacetic acid, etc.) and rogens I
Ft, 49! with aliphatic carboxylic acid which may be
mixed molten hydrothermal fluid j methanesulfonic acid, ethanesulfone deep
Which alkylsulfone dianhydride; phenylsulfone
f! :9. p − ) ary such as luenesulfone order
Mixed acid anhydrides with sulfonic acid, etc. have active t'Ii2
Amides include, for example, N-acylsaccharin, N
-acylimidazole, N-acylpyrazole, N-a
Silbenzoylamide, N-acylbenzotriazole
, N,N'-dicyclohexyl-N-acylurine'JA,
N-acylsulfonamide etc. as active esters
For example, cyan methyl ester, 4-nitrophe
ester, 2,4-dinitrophenyl ester,
Lichlorophenyl ester, pentachlorophenyl ester
[Nisdel] 1-Hydroxybenzotriazole
N-Hydroxysuccinimide% N-Hydroxyfyl
Esters with cluimid, etc., are still available.
As a derivative reactive with the Yer reagent, N,N-dimethyl
Acids such as formamide and N,N-dimethylacetamide
Phosgene to amide,” electrified thionyl, Sanno, +. lization
Phosphorus, phosphorus tribromide, phosphorus oxyj-sH, phosphorus pentachloride
, trichloromethyl-chloroformate, oxarylk
Pills obtained by reacting halogenating agents such as loride
Myers 71: ≦ reactive derivatives, etc.
悉geraii, also, R”kaR”teiisha was revealed.
In the case of 2R'SO2- of the formula R'S 02 NH-,
For example, polyamides or acid anhydrides are listed.
Jl, more specifically, as the acid halide,
For example, sulfonyl chloride, sulfonyl bromide, etc.
but. 18!2 Anhydrides include, for example, sulfonic acid anhydrides.
There are so many things that can be mentioned. Anti-kl 111 of the compound of general formula [IV]? , 17 bodies
Examples include acid amide chloride, acid amide bromide, etc.
Acid amide halide j Acid amide acetal, Acid amide dia
Examples include rukylsulfate complex. As reactive derivatives of the compound of general formula [lX], general
The organic compound described in the reactive derivative of the compound of formula [■]
A silyl group or a phosphorus group is the reactive site〉NH
Examples include bonded compounds. Next, each manufacturing method will be explained in detail. Production method (1) Compound of general formula CIO, use thereof or induction of reactivity thereof
and the compound of general formula [m], its salts or its reactivity
The reaction with the derivative (acylation reaction) is carried out in the presence of a solvent or
It cannot be done in its absence. The molten base used in this reaction must have a negative impact on the reaction.
Any solvent can be used without particular limitation as long as it is
For example, water i tetrahydrofuran diethyl ether
, dimethoxyethyl ether, 2-dimethoxyethyl ether
Ethers such as dioxane, dioxane, etc. Methylene trichloride
, chloroform, carbon tetrachloride, 1.2-cip O/l
/Halogenated hydrocarbons such as ethane, methanol,
Tanol, Impropatool, tert-phthanol,
tcrt-amyl alcohol, ethylene glycol,
Alcohols such as tyrene glycol monomethyl ether
Class; N, N-dimethylformamide, N, N-dimethyl
Amides such as acetamidej Acetonitrile. Nitriles such as propionitrile, benzene, toluene
Aromatic hydrocarbons such as carbon, xylene, pN, '1:i;
Nitromethane 1 and 210 alkanes such as nitroethane
] Tertiary amines such as pyridine and quinoline
Sulfoxides such as methyl sulfoxide, ethyl acetate,
Esters such as butyl acetate, acetone, methylimbu
Examples include ketones such as tilketone. mentioned above
A mixture of two or more solvents can also be used. Also,
This reaction can be carried out in the presence of a base. used here
Examples of bases that can be present include sodium hydroxide.
Alkaline hydroxides such as potassium hydroxide and potassium hydroxide; charcoal 1 character
Aluminum hydrogen carbonates such as sodium hydrogen and potassium hydrogen carbonate
Potassium; alkali carbonates such as sodium carbonate and potassium carbonate
alkali acetates such as lye, sodium acetate, potassium acetate, etc.
Inorganic bases such as triethylamine, tributylamine
, N, N-diethylaniline, pyridine, N-methylpyridine
Peridine, N-methylmorpholine, lutidine, collidine
, 1,5-diazabicyclo(4,a,o]methane 5-e
1,4-diazabicycloC2,2,2”J octane
, 1.8-diazabicyclo(rs, 4.4]undecene
Tertiary amines such as
Polymeric t [nit Ba5e]
can be mentioned. Furthermore, this reaction
Presence of alkylene oxides such as butylene oxide, butylene oxide, etc.
You can also do it below. Compounds of the general formula [river] are used in the form of free acids or salts.
If so, an appropriate ffli mixture can be used. As the condensing agent, for example, N N'-dicyclohexy
carbodiimide, N-nocyclohexyl-N'-morpholinoethylcarbodiimide
Mido, N-cyclohexyl-N/ (4-diethylamide
(nocyclohexyl)carbodiimide, N-ethyl-N'
-(3'-dimethylaminopropyl)carbodiimide
Which N,N''-di-converted carbodiimide j N,N'-
Azolide compounds such as thionyldiimidazole
Ethoxycarbonyl-2-ethoxy-1,2-dihydro
Quinoline, oxychloride, alkoxyacetylene j2-
Chloropyridinium methyliosito, 2-fluoropyri
2-logenoviridine, such as dinium methyliosito
polytriphenylphosphine-2,2'-dipyridi
Rusulfide etc. are popular. In addition, the reaction temperature and reaction time are not particularly limited, but
It is preferable to carry out the reaction at -50 to 80°C, and the reaction usually takes 5 minutes.
Completed in ~30 hours. Then, the general formula [I11] is
The compound, its salts or its reactive derivatives have the general formula [I
Compound D. 0.00% per mole of its salt or its reactive ηλ form.
9 mol or more, preferably 0.9 to 1.5 mol is used.
. Reactive derivatives of the compound of general formula [1v] and general formula [TI
), its salts or its reactive derivatives.
is carried out in the presence of a solvent inert to the reaction. The inert (naive) solvent used in this reaction is diethyl
ethers, tetrahydrofuran, dioxane, etc.
ter Mj methylene chloride, dichloroethane, chlorobor
Munato's halogenated hydrocarbons j benzene, toluenna
aromatic hydrocarbons, ketones such as acetone, etc.
Can be mentioned. These solvents are used in combination of two or more
You can also do that. Furthermore, the reaction must be carried out in the presence of a base.
As a base, for example, trimethylamine,
Triethylamine, N-methylmorpholine, pyridine, etc.
Which tertiary amines may be mentioned. Reaction 18 nr'L
The temperature and reaction time are not particularly limited, but at -50 to 30°C.
It is preferred to carry out the reaction, and the reaction is usually JJ L? complete in between
Ru. In addition, as an alternative method, the reaction of the compound of general formula [■]
1-(benzyloxycarbonyl-ethyl derivative)
methylthiomethylene) hexamethylene immonium tetra
1-(Hotan carboxyalkyl) such as fluoroborate
ruthiomethylene) alkylene immonium tetrafluoro
Roborate is reacted by a method known per se.
Ruike, R at the 3-position amino group of the compound of the general formula [TI,]
(R241' may be substituted with ■ζ24)
Alkyl. Aralkyl and aryl represent heterocyclic groups. ) basis
is substituted with acylamino derivative by a method known per se.
The iminohalogen derivative is reacted by a known method.
There are several methods. Furthermore, the compound of general formula [V] and the compound of general formula [■]
, its salts may react with its reactive derivatives in a soluble manner.
Performed in the presence or absence. The solvent used in this reaction must be
Any solvent can be used without any particular restrictions as long as it is
However, specifically, as exemplified in the above-mentioned acylation reaction,
These solvents can be used by mixing two or more of them.
You can also be there. However, this reaction cannot be performed in the presence of a base.
I can. The bases that can be used here are
Specifically, in the acylation reaction mentioned above,
Examples include inorganic bases and tertiary amines. In addition, the reaction temperature and reaction time are not particularly limited, but
It is preferable to carry out the reaction at a temperature of 0 to 50°C, and the reaction is usually carried out for 30 minutes to
Completed in 25 hours. And the compound of general formula [V] is
, the compound of the general formula [■], its salts are still
1 mol or more per 1 mol of conductor, preferably 1.0-2
．． 0 mol used. Stinging Act (2) Alkoxylation of the compound of general formula 1 or its salts
By doing so, a compound of the general formula [VII[:] or its
salts can be prepared. This reaction first begins with a compound of the general formula [~TD or its J
fX and 1 mol J per 1 mol of this compound fio
υ, the above chlorine size or the ingredients, etc.),
−j; Donated potassium, sodium hypochlorite or hypochlorite
2nd grade calcium and other hypochlorite 3: ii
Chronucunnimide or N-promosuccinimide
N-haloimidono-N-chloroacetamide such as
or N-broamides such as N-bromoacetamide.
jN-chlorobenzenesulfonamidomata is N-chloro
-p-Toluenesulfonamitonatono N-halosulpone
Amides;
Halogenating agents such as pochlorides j are mixed with dichloromethane.
Norogenized hydrocarbons such as purple hydroxide, methanol and other alkaline
Hydrogenation of coal water-water such as dichloromethane
Two-phase solvent for hydrocarbons N,N-dimethylformamide
The reaction is carried out in a polar solvent such as amides such as hydrogen. this
/・Logenation reaction is carried out using sodium borate decahydrate etc.
Which base, tetrabutylammonium bromide or sulfur
Phase transfer of tetra-n-butylammonium oxyhydrogen, etc.
It may be carried out in the presence of a catalyst or the like. Reaction temperature and reaction
The time is not particularly limited, but it is carried out at about -50 to 50℃
Preferably, one reaction is usually completed in 10 minutes to 5 hours.
. The intermediate nologenide thus obtained is a simple
The next alkoxylation reaction can be carried out, for example in the solvent mentioned above.
It may be added to the reaction system, or the next alcohol
It can be subjected to oxygenation reaction. The alkoxylation reaction is performed on the above-obtained
, methanol, ethanol or propatool, etc.
Alkali metals (lithium or sodium) in alcohols
salts or alkaline earth metals (such as magnesium) or alkaline earth metals (such as magnesium).
) is carried out by reacting salts. alkaline earth gold
The genus salt is a compound of general formula 〇'[0 or a salt thereof, 1 mol.
(about 1 to 20 mol is used) 1 is sufficient. reaction temperature
And reaction time! IJ4 is not specified for '+'j, but -
It is preferable to carry out the reaction at 80 to 30'C, and the reaction time is usually 5 minutes.
It will be completed in ~2 hours. This alkoxylation reaction is carried out as needed.
By the way. The reaction can be stopped by making the reaction system acidic.
It as a suitable acid to stop the reaction, e.g.
Acetic acid, acetic acid, trichloroacetic acid, etc. are used. In addition, excessive halogenating agents such as sodium thiosulfate
Thorium Ota Arin Gi, '2) Real Kill Enute
It is removed by treatment with a standard reducing agent. Production method (3) Compound of general formula [IX], salts thereof or reactivity thereof,
i'; 2! By ring-closing the 'b body, the general formula (X
] or its salts can be produced. This reaction is generally carried out in the presence of molten Ik, and
The solvent to be used is a solvent that does not have an adverse effect on the reaction.
If there is, it can be used without any particular restrictions, but please be specific.
include the solvents exemplified in production method (1), and these solvents
A mixture of two or more types of media can also be used. This reaction is
, sodium hydroxide, potassium hydroxide, etc. as necessary
alkaline hydroxide, sodium hydrogen carbonate, hydrogen carbonate
Alkali bicarbonate such as lithium anhydride. Alkali carbonates such as sodium carbonate and potassium carbonate, or
is an acetate alkali such as sodium acetate or potassium acetate.
Which inorganic bases are triethylamine, tributylamine,
N,N-diethylaniline, pyridine, N-methylpipe
Lysine + N-methylmorpholine, lutidine, collidine,
1,5-diazabicyclo[4,3,0)non-5-ene
, 1,4-diazabicyclo[: 2.2゜2]octane
or 1,8-diazabicyclo(5,4,4)undece
Organic bases such as
Lomide or aqueous bulk tetran-butylammonium sulfate
etc. is carried out in the presence of
It will be done. Also, compounds of general formula [IX], salts thereof, ll7
1t Takeso's reactive inducer i;・In one body, Y is hydroxyl
If it is a syl group, it, diethyl azodicarboxylate or
In the presence of carbon tetrachloride, triphenylphosphine is commonly
Compound of formula [IX], salt thereof or reactivity thereof 692
It is preferable to add 1 mol or more per mol of the 3-body.
. The reaction temperature and reaction time are not limited to J[,:r
However, it is preferable to carry out the reaction at -20 to 100°C.
It can be completed in 5 minutes to 5 hours. Production method (4) Azidation of the compound of general formula CXI) or its salts
In particular, compounds of the general formula [X+1) or their J'A
;, I'i can be produced. This reaction is generally carried out in the presence of a solvent, and such solvent
As long as the solvent does not have a negative effect on the reaction, it is particularly limited.
For example, tetrahydrofura
diethyl ether, dimethoxyethyl ether, 1
, 2-dimethoxyethane, dioxane, etc.
Aromatic hydrocarbons such as benzene, toluene, xylene @
1TjN, N-dimethylformamide, N,N-dimethy
Examples include amides such as ruacetamide, and these
Two or more kinds of solvents can also be used as a mixture. Azidation is carried out on the compound of general formula [XI] or its salts.
, lithium diisopropylamine or n-butylamine at low temperature.
Using commonly known strong organic bases such as chilllithium
and then methanesulfonyl azide, trifluoromethane
Even with halogen substitution such as tansulfonyl azide
Good alkylsulfonyl azides; toluenesulfonyl
Aryls such as azide, mesitylenesulfonyl azide
Commonly known azidating agents such as sulfonyl azides
and then add an organic compound such as trimethylsilyl chloride.
can be obtained by reacting silyl halides.
can. Reaction σ, 1 (anal and reaction time i'; I: 'f, "to
Although not limited to
Actually, reaction &:j:i・, 1 always 30 minutes to 511. '
? It will be completed in 11fl. General formula [■] created by each of the above-mentioned construction methods
(-j,'? expression cvo / [1iff]t CX'3
Oj D D! D Compound of (name) also U: that J
For example, iQ Ii
i? , solvent extraction, crystallization, recrystallization or chromatography
11 r! It can be made of cats. ,
In addition, if stereoisomers are mixed, respond to
Column chromatography and ion pairing of each sushi
Conventional methods such as chromatography, optical resolution or recrystallization
It can be heated using the following method. The compound of general formula [I] thus obtained or its
The classes include protected amine groups and preserved imino groups.
, preserved hydroxyl group and/Gotake ILJ
When it has 6 groups such as a carboxyl group, it has 8 groups, such as a carboxyl group.
The maintenance group can be removed according to the requirements. The retention group
Depending on the type of hoki group, there are two ways to remove it:
Methods using acids, methods using reduction,
, an iminohalogenating agent, and then an iminoetherifying agent.
A method of hydrolyzing as necessary after use, using a base
Conventional desorption methods such as the method or hydrazine method
can be selected as appropriate. In addition, in each production method, the target compound
For example, conversion of acyl groups or amine, imino, hydro
Preservation of xyl and/or carboxyl groups)
Compounds of the present invention can be prepared by conventional methods such as addition or elimination.
It can also lead to things. In addition, to obtain salts of the compound of general formula CI), the reaction system
produced in the form of salt within
If it is produced in free form, it can be isolated.
Salts are formed using conventional methods using polybasic or acids;
Then, it can be isolated and purified by conventional methods. Next, the general formula [II) of each production method, 1:■], [
IX) and CX1] compound, salt thereof or reaction thereof
Sexual visit, body in a known method or a method related to it
Therefore, j:l, j4 can be used, but for example,
, the 2A manufacturing method of the compound of the present invention explained above or the method of
It can be manufactured by the method. [λ11.1] [DO [In the formula, R, R', R2, R3 and Y&'i
It has a meaning. ] This eyebrow jf method is based on the general formula CXfl
A compound of l'J, its salt 8a or its reactivity,
l(4' and the compound of the general formula [λ■], its salts)
By reacting reactive derivatives of the general formula CIX
) compound, its salt ζ is one reactive B9♂
can be manufactured. As salts of compounds of general formula [XJJI) and α■]
is a basic group as explained in the salts of the compound of general formula (I) or
or J, a in acidic groups are likewise honored. As a reactive α conductor of the compound of the general formula [■], the general formula
Same as exemplified in the reactive derivative of the compound in [■1]
acid halides, acid anhydrides, mixed acid anhydrides, active acids
Amides, active esters, acid azides or Vilsmeier
Examples include reactive derivatives with Shi-Raku. As a reactive derivative of the compound of the general formula [)ffV),
As exemplified in the reactive α conductor of the compound of general formula [■]
Similar to silyldi 1 (, or organic phosphorus group etc.
Examples include compounds that bond to the reactive site H2N-.
Ru. This reaction is generally carried out in the presence of a solvent, and such solvent
As long as the solvent does not adversely affect the reaction,
Although it can be used without any specification, specifically, the above-mentioned
The same solvent as exemplified in production method (1) is added, and these
Two or more types of the /8 medium can also be used in combination. It's a sword
, this reaction can be carried out in the presence of a base. here
Examples of bases that can be used include the above-mentioned -
・I・: Base similar to that exemplified in Iji'-j method (1)
can be mentioned. Ma7'ko, anti1. r; submergence and anti-L[; 11','
There is no particular limitation on the time between i, but it should be carried out at -50 to 50°C.
is preferred. Reaction pregnancy usually takes 5 minutes to 30 hours to complete. And general
A compound of the formula ``l'', its ixJ class or its reactivity j
l'/23 body is a compound of general formula [X1'V], its
Salt 9++4 sweet/辷d [zono reaction bone attraction 2J7. 1 mole of rest
0.9 mol or more, preferably 0.9 to 1.5 mol
used. Compounds of the general formula OX) which are thus prepared,
The reactive derivative of JM 2a1i Takeso is known per se.
Means, 7'C and eg, l', #fif, in? ,'＋
': m (13, crystallization, recrystallization size/koha chromatog
Raffy etc. can be prepared by the government. Also, if stereoisomers are mixed, it can be prepared as necessary.
Column chromatography, ion pair chromatography
tography, optical resolution still normal, such as tr4rz crystals
It can be isolated by the following method. In this reaction, the general formula [XIII) and [XJv
) has a reaction-active group, such as an amino group or an ionic group.
Mino group, hydroxyl group and/or zecarboxy
When equating groups such as
It is best to pre-preserve the color with a group of 8 and then subject it to the reaction.
After that, it may be removed if necessary. Furthermore, the general formula fJ
If the compound X] is obtained in a free state, use the usual method.
may lead to its salts or its reactive conductors.
can. Also, the compound of [XD or its salts] is
The general formula [j
Production of Fl compounds, their salts or their reactive α-conductors
Then, conduct the same reaction as in the production method (3) above.
It can be manufactured in various ways. Next, the present invention will be explained by citing reference examples and the mouth side of the fruit.
However, the number of trees is limited to this example.Example 1 (2875B) -2tert-butoxycarbonyl
Amino-5-hydroxybutyric acid 28 Methylene chloride 28
14.71Lt of N-methylmorboline dissolved in 0g
and cooled to -20°C. Add 13.4 #lt of thalol ethyl carbonate to this stone powder at -2
Add dropwise while maintaining the temperature at 0 to -10°C. Then, at the same temperature
After reacting for 60 minutes, 5-amino-1H-tetra
Sol 1 aqueous phase product 15. IW to N,N-dimethylphos
Dissolve in Lumamide 50IIL and add dropwise. After the dropwise addition was completed, the reaction solution was raised to 20°C and heated at 6 o'clock.
After U reaction, 600 Me water and 10 ethyl ethyl
Pour into 0 ml of the mixture. t, q, press this solution to pH' with sodium bicarbonate.
After adjusting to 7.0, separate the aqueous layer. Then, under stirring
After adjusting the aqueous layer to pl (2.0) with 6N-hydrochloric acid,
Two crystals were taken and dried, showing a melting point of 189°C (decomposition).
White crystalline (2S,3B)-2-tart 7' toxica
rubonylamino-6-hydroxy-N-(IH-tetra
sol-5-yl)butyric acid amide 302 (yield 82.1%
). I Jl (KB r ) cm' t 'c=o 1
725+ 168 ONME (ds-DMSO) δ value 1 1.18 (d, J=6.5Hz 3H), 1.4
4(II, 9H). 5.90-4.39 (m, 2H), 5.06 (bs
, IH). 6.69(d, J=8HE, II(), 12.0
In the same manner as 9(a, IH), the compounds shown in Table 3 were obtained.
Ta. Reference'4 Example 2 (11(2S)-2-benzyloxycarbonylamino
-6-hydroxy-N-(IH-tetrazol-5-y
) Globionic acid amide 109 is anhydrous, N-dimethyl
Borumamide 50at (dissolved in sodium hydride at room temperature)
Lium (50% purity) 1,56 f! Add hydrogen gas
Allow the reaction to occur until the generation stops. Then, iodide the reaction solution.
Sodium 495I and 4-methoxybenzylchloride
Add 4.9d of chlorine and allow to react at room temperature for 1.5 hours. unintentionally
Then, the reaction solution was mixed with 20ON of water and 150a of ethyl acetate.
Pour into the mixture and adjust the pH to 7.0 with 2N hydrochloric acid. Separate the organic layer and add 100 ml of water. IN-thiosulfur
1001 g of sodium acid solution and 100 g of saturated saline solution
After sequentially washing with water and drying with anhydrous magnesium sulfate,
The hot medium is distilled off under pressure. Inglovir the resulting residue
Heating the stone chips in alcohol 10011/, the crystals precipitated when cold
When removed and dried, it is white with a melting point of 122-123℃.
Crystalline (28)-2-benzyloxycarbonylamino-
R-HydroxyN-42-(4-methoxybenzyl
)-28-tetrazol-5-yl]globionic acid amide
5.2 pieces (yield 57.4%) were obtained. 1 (f value; 04 (developing solution; chloroform: acetone-2
=1゜The plate Kiego1gaj60 Fts
a. Art. 5715-Merck) IH (KBr) car-';I'C=0 171
5.1675NMII (+L DMSO) δ value i 3
69-3.78 (11,511), 439 (m, 1H
), 5. IQ (m. 2H), 5.1H (s, 2H), 6.99 (d,
J='9HE, 2H). 7, 30-Z50 (mt 811) (11) (
Concentrate the P solution obtained in 1) to half the volume and leave it at room temperature for 1 day.
After standing, the precipitated crystals are removed and dried for 2 tons, the melting point is 172 ~
17! A white crystal of (2S)-2-benzylo exhibiting l'c
oxycarbonylamino-6-hydroxy-N-(1-(
4-methoxybenzyl)-1II-tetrazole-5
-yl] Globion tS amide 411 (yield 28.8%
) to meet. RJψ; 0.5 (expansion T ori roloborum: acetone
=2:1゜TLC Gray) Kieselgol 60
F! Ilt., Art. 5715-Merck) I II (KBr) rv' 3 I'C-0168
ONMR (d@-DMSU) δ value] 67o ~ 3.78 (rn,, 5H), '4.37
(m, IH), 5.07 (1°2H), 5, Ro6 (
8,2n), 69o(d, J=8.541Z, 2
H). 722-Z41 (In, 8II) Compounds shown in Tables 4 and 5 were obtained in the same manner. Material 1-116 (283R) 2 tert-butoxycarbononylamino-6-hydroxy-N-(1H-tetrazo
50 tons of methanol
Stone) θ1. Let me, this
Add 8 parts of diphenyldiazomethane to it and add 2 parts in the chamber.
4:00j1) [Reaction is made. Then, the resisting medium was distilled off under reduced pressure.
The resulting residue was diluted with ethyl acetate 200IIe 6 and
Add hydrogen carbonate to a mixture of 100 parts of water and add hydrogen carbonate to it.
Adjust the pH to 7.0 using a vacuum cleaner. Yes (:, separate the upper layer and
Wash with Sagara Hanawa water i o o #It, and anhydrous sulfuric acid magne.
After drying in a vacuum, the solvent was distilled off under pressure.
Ru. The resulting constant residue was subjected to column talomadography (phase
Genrin Rikagel C-2oo, r# Rikan] Benzene: Acid-resistant E
Chill = 50: If you make Ait with 1), the amorphous (2
8,3R) 2-tert-butoxycarbonylamino
-to-(1-diphenylmethyl-IH-tetrazo-#-
5-yl)-6-hydroxybutyric acid amide 12.6y (yield
79.7%). I n (KB r ) am y C-0, 1720
7170ONMII (dg 1) M, SO) δ value 3t
18 (% J = 7 HZ73 H) / 1-35
(a, 9 H)) 4.20-4.60 (tri, 2
11), 5.95 (d, J=7Hz, , IH). 7.00 (o, In), 7.5N n, 10H)
, 10.52(bs, Similarly to 11(), Table-6
The compound shown in was obtained. Table-6 Implementation Izuj11 (2S, 3R) 2-tert-ptoxyluponylua
dNoN-(1-diphenylmethyl-1H-7-thoraso
(5-yl)-3-hydroxybutyric acid amide 167
Dissolve 4 oomtvc of anhydrous tetrahydro 7ran and
Add 12 g of triphenylphosphine to the mixture and cool on ice. Add 7.2 m of diethyl azodicarboxylate to this bath solution.
was dropped at 5 to 10°C over a period of 15 hours, and after the dropping was completed,
React for 6111 minutes at room temperature. Then, the heating medium is introduced under reduced pressure.
dt removed, 2"t remaining! 50 tiles of water and 1 tori
Mix 4 g of ethyl acid 100#+t and dissolve 6. organic layer
was collected, washed with 5 Q of saturated water, and diluted with acetic anhydride.
After drying with magnesium, the bath medium is distilled off under reduced pressure.
. Added 80% of benzene to the residue left over from the factory.
and remove the solvent under reduced pressure. Unearned residuals
Column talomadography of objects (Wako silica gel C-
200, m trit; Benzene: Ethyl acetate = 50
: 1), it becomes amorphous (3S 4 S)
-5-tert-butoxycarbonylamino-1-(
1-diphenylmethyl-I H-tetrazole-5-y
)-4-methyl-2-azetidinone BY (yield 52%)
) get it. TR(KBr) cn” 7’C-01780,17
10ゝNMn(coCls) δ value j 1.38-1.45 (m, 12H), 4.08-4
．． 68 (m, 2H), IIK5.76 (d, J=7
Hz, IH), 7.08-7.58 (m, 10H). 7.69 (s, IH) Compounds shown in Tables 7 and 8 were obtained in the same manner. Example 2 (II (28)-2-tart-butoxycarbo=
Ruamino-he-(1-diphenylmethyl-I H-tet)
Lasol-5-yl)-6-hydroxyglobionic acid a
Add a bath solution containing 4.5 ml of Mido 152 and pyridine.
Cool HI L to 60℃, add methanesulfonyl taro
Dim 0.32 m and cool with water for 1 hour at 20°C.
11. The reaction is carried out under stirring for 419 minutes. Next,) intimidation
Under the water, the bath W was distilled off, and the resulting residue was washed with acid.
Add a mixture of 3 Q ml of ethyl and 30 ml of water.
After stirring, adjust the pH to 2.0 by intoxicating to 2. organic layer
Separate water 3 Q #It and saturated saline 6071
1, and dry-brined with anhydrous magnesium 6 perseate.
After that, if the myth is distilled off under reduced pressure, the amorphous (2S)
-2-tert-butoxycarboniamino-~-(1-
diphenylmethyl-IH-tetrazol-5-yl)-
3-Menyloxyglobionic acid amide t7v (yield
96%). I 11 (KRr) ”” t C”0 1720
t 170 ONMntcpcts) δ value i 1.40 (8,9H), 2.99 (8,3H), 4.4
0-5.05 (m, 5H), 6.22Cd, J=7H2
, IH). 7.08 (B, IH), Z45 (s, 1oiI). 1 tto (bs, I H) (( 2 S ) 2- t obtained in III +11
art-butoxycarbonylamino-N-(1-dife
Nylmethyl-1H-tetrazol-5-yl)-6-methyl
Siloxy 10 pionic acid amide 052g and hydrogen sulfate
Tetra-n-butylammony 17Ap04 12
-Dichloroethane? 1 liquid 5” to potassium carbonate 0.559
, water 10111 and 12-dichloroethane 15#I
Add to the mixture of
React to pregnancy. Then, the reaction solution was cooled and diluted with 10#lt of methylene chloride.
After dilution, separate the organic layer. Water 1Qaj and saturated food
Wash with 1.3s+l of salt water, and then wash with anhydrous sulfuric acid magnesia.
After drying with a vacuum for 1 hour, the solvent was distilled off under reduced pressure. obtained
Residue column chromatography (Wako silica gel)
C-200, bath separation benzene:ethyl acetate = 15:1
), the amorphous (6S)-6-tart-butyl
Toxicarbonylamino-1-(1-diphenylmethyl
-I Ff-tetrazol-5-i/L/)-2-aze
0.25 g of tidinone (yield 591%) is obtained. 111 (KD r') LsJ (-01780t
1710 ■ Length MR (CDC1j) δ value; 1.40 (s, '?) ■), 3.90 = 4.15 (m
, 2H). 4.80 ('m, IH), 5.80 (d, J='811
z, IH). 135 (at 10 H)y Z8' (lIp
I H) Real fit (2s)-2-benzyloxycarbonyl
-3-hydroxy-N-(IH-tetrazole-5-
yl) propionic acid amide 0.31 g and triphenyl
Ruphosphine 0.39 y om water tetrahydro 7 run
10 #l K bath W) and cooled to -10℃ (1
. Add 0.2 (noethyl azodicarboxylate) to this bath solution.
4 Anhydrous tetrahydrofuran m 3 III
was added at the same temperature for 10 minutes, then cooled with water for 60 minutes.
, react at room temperature for 60 minutes with stirring. Then under reduced pressure
The solvent was distilled off, and the resulting residue was subjected to column chromatography.
Graphy (Wako silica gel c-2oo, iW syneresis)
10% ethyl acetate: ethyl acetate I = 10 = 1)
White product (3S)-3-ben with a temperature of 153-156°C
Zyloxycarbonylamino-1-(IH-tetrazo
(5-yl)-2-azetidinone 0.077 (yield
4%). IR(KBr)f, cmo 1800, 1780. L
70ONMB (d@-DMSO) δ value me 380~4-30 (my 2 H) 7 5.00~5
．． 51 (my 3 H)77.56CB, 5H), 8
．． 40(d, J=8Hz, IH)(Ill (28)-
2-benzyloxycarbonylamino-3-hydroxy
-N-(IH-tetrazol-5-yl)globionic acid
Example 2 using amide CI+, (same as III
(3s)-5-benzyl
Oxycarbonylamino-1-(i H-tetrazole
-5-yl)-2-azetidinone is obtained. of this compound
Physical properties (III and NMII) are those obtained in (1)
1. :. Pumino r = Example 4 (s S 4 II ) -5-benzyloxycarbo
Nonylamino-1-(2-(4-methoxybenzyl)-
2II-tetrazol-5-yl2-4-methyl-2-
Azetidinone 0.75 Li in 90% acetonitrile water
mrL15 #It was dissolved in M at room temperature (ifljf
fi47 heptalium (IV) alliumum 4.3y once
and react for 1 hour at the same temperature. Then, ethyl acetate
Le 205+7 and ('& market price salt water 2011j plus
, organic j ~ was fractionated and treated twice with 2011 g of saturated co-salt water each time.
Washing (add 10μ of water to the bales and add hydrogen carbonate) II
ili,j to pH 7.5. Separate the aqueous layer and add vinegar
Add ethyl acid 15@f- and adjust the pH to 2.0 with 2N-hydrochloric acid.
After preparing the mold, separate the organic layer. The collected organic hega
, f8, washed with 10M Japanese saline, and anhydrous magnesium sulfate.
After drying with a vacuum, the solvent is distilled off under reduced pressure. I got it
Add 15 d of diethyl ether to the residue and remove the precipitated crystals with a needle.
If the plate is removed, it will be a white product (3S) with a melting point of 147-149°C.
, 4n)-s = benzyloxycarbonylamino-4
-Methyl-1-(111-tetrazol-5-yl)-
0.399% of 2-azetidinone (yield 73%) is obtained. I R(THF) cm t C=o 1770t
172 ONMII (comiC0CDI) δ value 1t5
o(a, , r=iz, 3H), 4.64(IYI,
IH). 5.15 (B, 211), 5.35 (nl, 1B)
, z40 (a. 5H), 7.60 (d, J=71TZ, IH) same
The following compound was obtained. 0(38,4S)-4-methyl-6-phenylacetoa
Mido-1-(1n-tetrazol-5-yl)-2-a
Zetidine y Melting point 382-85℃ (decomposition) II ((KI3r) ” y C-01770p
165 ONMII (CDCill) δ value 1 1.67 (d, J=7Hz, 3H), 5.66 (@
, 2H). 4.37-4.80 (m, 2K), 7.40 (s, 5H
). 8.62 (d7J =8 it II/I H) Real
Example 5 (38)-3-benzyloxycarbonylamino-1-
(1-(4-methoxybenzyl)-1H-tetrazole
-5-yl2-azetinone 39 to anine-/l/
Dissolve 6omtlc trifluoro-111-acid at room temperature.
Add 901It and react at the same temperature for 5 hours. Then
, the solvent was distilled off under reduced pressure, and diethyl was added to the obtained IA distillate.
Add 20M of ether and 20ml of water ice, and add carbonated water.
jj to pl-I 7.5 with sodium ii solution! 'l
1st. Separate the aqueous layer and add 2Q ethyl butyrate to the colander.
Add pnl and adjust the pH to 2.0 with 2N-hydrochloric acid gQ7
Observe L. and separate the 41st layer. Add 1Qs6 of ethyl 11ate to the aqueous layer to separate the organic
Remove and combine with the previous organic layer. Add this organic layer to 2016 ml of water.
Rinse with 20 m of water and wash with anhydrous It acid mug.
After drying with nesium, the solvent is distilled off under reduced pressure. Obtained 2
'L TThe residue was washed with ethyl l'+l' acid in 5 mounds and diluted
Treated with a mixed solution of 10 ml of ethyl ether to remove 2 precipitated crystals.
After removing F, wash with diethyl ether 3 red and dry.
(3s)-3 is a white crystal of phosphor with a melting point of 156-157°C.
-benzyloxycarbonylamino-1-(1u-tet)
Razol-5-yl)-2-azetidinone 1.5 y
(yield 70.8%). Physical properties of Motoichi (rr+ and
NMR) was obtained in Example 5 by Kutsu et al.'j1. It matched what was written. Example 6 (3S)-3-penzyloxy; lylphonylamino-1
-(2-(ro, 5-di-tart-butyl-4-hydro
xybenzyl) -2J(-tetrasol-5-ylc)
-2-Azetidinone 0.27 F to 2 m of methylene chloride
1 and methanol 2tri, and this
triethylamine 0.074a and 2,6-cyclo
Ru 5,6-dishya2p-penzoquinone 0.157
In addition, the mixture was allowed to react at room temperature for 60 minutes. Then, let it stand still under reduced pressure.
The residue was distilled off and 10d of methylene chloride and
Add 1QaJ of water and dissolve in saturated sodium hydrogen carbonate water.
Adjust the pH to 7.5. Separate the organic layer and add 10 parts of water
and twice with 10 μl of saturated brine;
[After drying with magnesium sulfate, dry under reduced pressure.
To leave. The resulting residue was diluted with 10 d of methanol.
Add p-toluenesulfonic acid monohydrate 1ogy to this.
Add and incubate for 5° at room temperature. Then, decrease
The m1s was distilled off under pressure, and the resulting residue was added with water ioag and
and ethyl acetate and clarified with hydrogen carbonate)
Adjust to p) J Z5 with IJum water bath. Separate the aqueous layer
To this, add 10α of ethyl/11ate, and add 2N-hydrochloric acid.
After adjusting the pH to 20 for 1 hour, separate the organic layer. organic
The layers were sequentially divided into 10 liters of water and 10 liters of saline.
After washing and drying with anhydrous magnesium sulfate, under reduced pressure
Distill the fuken. The obtained residue was subjected to column chromatography.
Graphy (Wako silica gel C=200'Rj IMI
I Y&; Benzea: rr+rself')x-1-r
= 4: 1) The melting point is 155-15
(3S)-'l-benzyloxy 7ka of white crystals showing 7c
Luponylamino-1- (I Jl-Tellazol-5-
i/l/) -2-acetidinone 08y (yield 52%)
get. The physical properties (Il+ and NMR) of Motoichi were obtained in Example 3.
ty, - matched. Example 7 (3B,4S)-3-tert-butoxycarbonyl
Amino-1-(1-diphenylmethyl-1H-tetrazo
(5-yl)-4-methyl-2-azetidinone 4y
Anisole 10#It and trifluoro 50#It
mt mixture and reacted at room temperature for 5 minutes. One
Then, the bath medium was distilled off under reduced pressure, and the resulting residue was diluted with 2 ml of water.
0m and 20IIIt of ethyl acetate in a bath iQ!
f= and separate the aqueous layer. Furthermore, in the aqueous layer, ethyl facetate
After washing 10 times with 101j each, the seiza was distilled off under reduced pressure.
do. The resulting residue contains I! I'1' acid enal 1017
After stirring for 30 minutes, the precipitated crystals were collected and
Drying 2t is a white crystal with a cutting point of 190-193°C.
(ss,4s)-ro-amino-4-methyl-1-(1
n-tetrazol-5-yl)-2-azetidinone 06
2 (yield a<sa, a%). IR(KI3r) tv, C-(+1775I)
koMl (1) tO-D C1) δIb, pt74
(a, J=7Hz, 5H), 452-4.92 (m
z 2H) [α] +3 = +40.7° (e = t, nt
o (Equivalent molar salt@)] Example 8 (38)-3-benzyloxycarbonylamino-1-
(I H-tetrazol-5-yl)-2-acetidino
0.7 g of methanol and 2.0 g of methanol. Q #/nirir month'
r';j'-tj-, 5-paradigm carbon 005-
Add and hydrogenate at 6 o'clock IL1' at normal pressure.
. Next, touch v, v, )°'', and add 11 liquids under pressure.
Concentrate to dryness. -10,000, -21 Separated catalyst is 0.25 thorium packed with ice carbonate
This was treated with RFL R-Ki, which was treated with water (10 times more severe).
Nowa'self d+I/i! L is one more concentration +'i (i
Residue of T1 liquid and machine 1
. This heavy solution was adjusted to pH 4.5 with 2N-hydrochloric acid.
, stir at room temperature for 60 minutes under ice (90 minutes).Precipitated product
Take n pieces of soot, wash with 2 parts of water, and after 1 part dry soot.
For example, a white crystal (s
s)-3-amino-1-(1H-tetrazol-5-y
)-2-azetidinone 0.27P (yield 76%) was obtained.
Ru. In(KBr) cm, C=0 1785.1765
NMn(DgO-DCI) δ value i 4.23-4.68 (m, 2H), 5.24 (m,
IH) Example 9 (38,4S)-4-(2-(4-methoxybenzyl)
2H-te)hiso-5-yl]-4-methyl-ro-
Chloride of phenylacetamido-2-azetidinone 191
Dissolve in 20m methylene and cool to -45°C. this
Add 1 ml of dimethylaniline to the bath solution, then add 1 ml of phosphorus penta-JA.
06 was added and reacted at -25°C for 60 minutes, and then
Cool to 60°C and add anhydrous methanol 7,11I1
Add 1 and react at -20 to -60℃ for 30/A-
. Add 20 tons of water to this reaction and cool for 60 minutes at ℃ water.
Stir for a while. Separate the water layer, diethyl ether 1011
1j! After washing twice with
In addition, add saturated carbonated water to the purple sodium water bath to pH 7,'5.
Both are balanced. Separate the organic layer and dilute with anhydrous magnesium sulfate.
After drying, the bath medium was distilled off under reduced pressure to obtain a constant residue.
Add diethyl ether and wash until the melting point is 8.
(38,4S)-3-amino, a white product exhibiting a temperature of 5 to 88°C
-1-C2-(4-methquinbenzyl)-2H-tetra
sol-5-yl]-4-methyl-2-aceticiff
1.2'i (yield 825%) was obtained. IR (KT3r) Cl1l 7 C=0 175
ONM r+ (CDCII+) δ value j161 (d,
J=6Hz, 3H), 1.88 (8,2H). 368-4.20 (m, 5H), 5.59 (8,2H
). 6, a6 (d, J=9Hz, 2H), z, 52 (d
, J=9Hz. 211) Example 10 (11(58,4R)-3-benzyloxycarbonyl
Amino-4-methyl-1-(IH-tetraso /L/
-,5-i/l/) -2-azetidi/729t
zr: Dissolve in 5 Q ml of methanol and add 5% paradi
Add 0.59 um-carbon and hydrogenate at room temperature and pressure for 15 hours.
Add. Next, separate the catalyst and add sodium hydrogen carbonate.
Wash 0869 with water 1' line solution 2011j, and use this washing.
A'+ Combine the slurry with the slurry 1-. Add 6N-salt to this M solution.
After adding #2, the hot medium is distilled off under reduced pressure. obtained
Dissolve the residue in 50 ml of ethanol while heating.
, remove the unbathables, leave to cool, and then collect the precipitated product.
When removed, it has a melting point of 196°C (decomposition) (3s,
4u)-5-amino-4-methyl-1-(I H-tet
Lazol-5-yl)-2-azetidinone mound 1
(yield 74.1%). 9 I R (KB r ) cm p cmo 1 B 0
07 1780 (lNMR (DIO) δ value i 1.72 (d, J=7Hz, 311), 4.64~
5.09 (m. 2H) [α] 1. -110,0° (cm1.'H:O)C
Ill (obtained in 11 (3S,4N()-3-amino)
-4-methyl-1-, (IH-tetrazol-5-y)
)-2-azetidinone hydrochloride 0.5! 'f tetra
Sol Q me, Saze Noyama, Pyridine Q, 3 l1
Add Iy and stir at room temperature for 5 hours. Akira Hidede J: 3 points
When dried, it shows a melting point of 192°C (decomposition) (3S,
4R)-ro-amino-4-methyl-1-(IH-tetra
sol-5-yl)-2-azetidinone 0.649 (yield)
82.9%). 111 (KI3r) cm ) C=0 1810 1
775NMII (D, O”DCl) δ value i1.72
(d, J=7Hz, 3H), 4.64-5.09(
m, 2H) Example 11) (S y 4 It ) 5-amino-4-methy
Ru-1-(I II-tetrazol-5-yl)-2-
034g of azetidinone was added to N,N-dimethylform under water cooling.
lumamide 6Wlt and triethylamine 0,28
Mixture of mt'rLFCRj 111'j 'a Se, mo
L/cue) - Add Sheeps 4 A O,59,
Then 1-hydroxybenzotriazole/1 aqueous phase substance o
277, (Z)2 (1tert-butquine carbonyl
-1-methylethoxy)imino-2-(2-toIJphe)
Nylmethylaminothiazol-4-yl)acetic acid 1,1
and N,Nl-dicyclohexylcarbodiimide
Add 0.467 and react at the lowest temperature for 2 hours. Precipitates? The solvent was distilled off under reduced pressure to remove the resulting residue.
Add the substance to a mixture of water 15#It and acid resistant ethyl 1517.
After dissolving and adjusting the pH to 2.0 with 2N acid,
Separate the machine layer. Wash the organic layer with 10μ of saturated saline
, Sumisui 1 After drying with magnesium phosphate, under reduced pressure;
Distill the medium. Flowered Residue Shikajim Shiromadograph
i (Wako silica gel C°200) 7W i beat 1'
Purified with lll mechloroform:methanol=50:1)
Then, a white crystal with a melting point of 104-108°C (decomposition) will be produced.
(3St 4R)-4-methyl-1-(IH-tetrazo
-5-yl)-3-(2-(2-)liphenylmethy
-2-(
(1-to+t-butoxycarbonyl-1-methyleth
xy)imino]acetamido)-2-azetidinone 0.
/) 7y (yield 48%) is increased by 4. xt+(+Br) cm, C=0 1770.
1750. 167ONFJI ro (CLICl++
) δi14j; 1.1U~1.67(m, '18
11), 4.80 (m, 1ft). 56L] (m* 11(), 7.09(II, ut)
, Zi (m. 15 H)t 960 (d, J = 8 Hz, 111)
/100 (b my I H) Compounds shown in Table 9 were obtained in the same manner. (Ill (+1) gives f(38,411)-4-
Methyl-1-(I II-detrazol-5-yl)-
5(2-(2-) IJ phenylmethylaminothiazole
Zl 2 L (1-tart-yl) (Zl 2 L
Toquincarbonyl-1-methylethoxy)imino]acetate
toamide)-2-azetidinone 0.589 to tetrahydride
Mixture of Ro7ran 2#ll- and 50% formic acid 4d, 'color
and react at 40 to 50°C for 1 hour. under reduced pressure
(a) IN was distilled off, and the resulting residue was diluted with ethyl acetate.
10a+1 and water 10a,
Soak your skin to pi+7.5 with saturated ash intoxication sodium water bath solution
Ru. Separate the aqueous layer, add 10ml of ethyl acetate, and add 2N-
After adjusting the pH to 2.5 with an acid and removing the amorphous layer. water layer
Add saturated salt to the mixture, and add 1 []m each of 1) edyl 1 acid.
2 times, and combine this number of extractions with the organic layer separated earlier.
Ru. Wash with this nice saturated Ahanawa water IDd, then anhydrous 1
After incubating with magnesium formate, the 1d solvent was distilled off under reduced pressure.
do. The resulting Jt residue was treated with diethyl ether,
When removing insoluble matter, the melting point is io~120°C (min Wi
(684R)-3-(2-(2-
aminothiazo-al-4-yl)-(z+ 2C(1-tart-but-
(oxycarbony)v-1-methylethoxy)imino]acetate
toamide)-4-nonal-1-(IH-tetrasol-
5-yl)-2-azetidinone o16y (yield 64%)
get. IR(KBr) Ls, C=0176Ll, 172
0.16iNMII (d6-DMSO) δ value i 1.25 (d, J=7Hz, 6H), 1.45 (,
m, 15H). 4.75 (m, IH), 5.60 (m, IH). 6.90 (a, IH,), 7.18 (bR, IH). 8.95 (d, J=9Hz, IH) Similarly,
The compounds shown in Table 10 below were prepared as follows:
thiazol-4-yl) -(Zl 2- [(1
tert-]I.gincarbonyl-1-methylethquine
)imino'acetamide)-4-methyl-1-(1kT
-tetrazol-5-yl)-2-azetidinone 016
0.3 m of JM-modified methylene, heated under water cooling.
Refluoro 1 → 11, +a 1 m wo) III H
,;, ? Incubate at iA°C for 1 hour. Then under reduced pressure
I stayed in the bathroom W1f, and left the rest of my belongings.
Treated with diethyl ether (deviation, melting point 120-14
(RoS, 4R) -6-(2-(2
-aminoguazol-4-yl) unitary no 2-((1
'-carbooxy-1-methino

[Etchin)imino]acetamido)-4-methyl-1-(II I(-tetrazol-5-yl)-2-azetidinone trifluorocarbon F
Unehanawa 0.11! @(Yield: 61.1%). l1l(KBr) am , C=0 1760.166
ONMII (do-DMSO) δ value; 1.52 (a, 6H), 1.6'4 (d, J=7H
z, 3H). 4.71 (m, 11), 5.61 (m, IH), 7
．． 00 (8, IH). 9.62 (d, J=8Hz, IH) Example 13 (3S)-5-(2-(2-aminothiazo-fiv-
4-i/l/ ) -(Zl -2-(1-tart-
butoxycarbonyl-1-methylethoxy)imino]acetamide) -1-(1rr-tetrazol-5-yl)-2-azetidinone 105 times methylene 2.1
Trifluoroboric acid 6.3 N was dissolved in 1 m and cooled with water.
and incubate at the lowest temperature for 15 hours. Then, the i6 sister was distilled off under reduced pressure, and the resulting residue was diluted with ethyl m-acid 5Q.
ml and 5 Qal of water to dissolve, adjust the pH to 4.0 with sodium bicarbonate, and then separate the aqueous layer. Add 5Qml of ethyl acetate to the aqueous layer, and add 2N-W
After adjusting the PL (2.0) with Nr&, separate the organic layer. Saturate the aqueous layer with salt, add 7ffl of a mixture of 40M ethyl acetate and 10% tetrahydrofuran twice, and pour this extraction first. The separated organic layers are combined. This organic layer is washed with 20 ml of saturated brine and dried over anhydrous magnesium sulfate for +it'L, then the drunken medium is distilled off under reduced pressure, and the resulting residue is evaporated into diethyl ether. If treated with
(ss)-s-(2-
(2-aminothiazol-4-yl)-(Zl-2-4
(1-carboxy-1-methylnidoquin)imino]acetamido)-1-('IH-tetrazol-5-yl)
-2-acetidinone 0.55'i (yield 598%)
I 40 ro, I H (KB r) Kushi 7 C=0 17707 16
6 ONMII (d8-DMSO) δ value] 1.48CB, 6■1), 3.80-4.30 (m,
2H). 5.55 (mz 1rr), 6.90 (s, IH'). 92o(d, J=Bur,, Hr) Example 14 (1) 2-(2-tart-amyloxycarbonylaminothiazol-4-yl)IZ+-2-methoxydiiminoic acid U 0.24 F and (ss) -s-amino-1-
When 0.089 (IH-tetrazol-5-yl)-2-azetidinone was treated in the same manner as in Example 11-(υ), a white product (3S) with a melting point of 97-100°C (decomposition) )-3-[2(2tarhyamyloxycarbonyl°aminothiazol-4-yl)-(Zl-2-methoxyiminoacetamide]-1-(I K-tetrazol-5-yl)-2-azetidinone 0.22 S'
(yield 71%). IR (KBr) m 5 C=0 1780. 172
0. 1665NMII (d@DMSO) δ value i 0.89 (t, J=6.511z, 3H), 1.4
7 (++, 6H). 1.8? +(m, 2H), 3.80-71.50(r
n, 5H). 5.32 (m, 1ll), 6.50 (bs, IH)
, 766 (a. In), 9.50 (d, J=7I (Z, IH) (I
II (to n obtained in II (3s) -3-[2-ta
rt-Amylox 7carponylinothiazole-4-
yl)-(Zl-2-7toxyiminoacetamide]-
1-(IH-tetrazol-5-yl)-2-azetidinone 0137 is dissolved in stratified methylene 1N at 61M, trifluorocarboxylic acid 2R1 is added under water cooling, and the mixture is reacted at the same temperature for 1 hour. Next, 5 ml of chloroform was added to the resulting λtf residue under reduced pressure (by evaporation), and after stirring for 30 minutes, the precipitated crystals were dried with an ILL12 oven.
I;+','U point 120-130°C (minute 19'1.
)-1-(2-(2-aminothiazol-4-yl)-(zl-2-methoxyiminoacetamide)-1-(1n-tetrazol-5-yl)-2
-Azetidinone trifluoro15I salt o, o7s+
(yield 568 times). =1. ν I It (KII r ) ri m t C-(J 1
7 7 07 1 6 6 0Nll D+(d @
-DMSO) δ i direct; 382 ~ 4.69 (IT) 21
■), 691 (8, 3H). 5j8 (m, l11), 6.92 (s, 111). 9 us (a, J=711 111) Example 15 (11<58.4B)-3-amino-4-methyl-1-
(I I(-tetrazol-5-yl)-2-azetidinone flJJp 0.21-9 was suspended in N,N-dimethylformamide 4a, and triethylamine 0.29 rat was added at room temperature. After dissolving, cool on ice. Add 2-(2-tart-amyloxycarbonylaminothiazol-4-yl)- to this FSg at the same temperature.
(0.319 g of Zl-2-monochloromethylene oxalic acid and 0.259 g of NN'-synchronhexylcarbodiimide were sequentially added and allowed to react at room temperature for 3 hours. Example 1
l-If processed in the same way as (1), the pyroelectric type (3S 4
n) -sl [2(2-tert-amylox7carponylinothiazol-4-yl)-(Zl-2-monochloromethyleneacetamide)-4-methyl-1-(ox-tetrazol-5-yl)-2-azetidinone 0.25 F (
A yield of 540% was obtained. In(KIJr) cm; C=0 1770.17
20.1655NMR (da 0M80) δ value] 0.8 (t, J"7Hz, 511), 1.30~1
．． 85 (m, 11H). 44-61 (, IH), s, sl (m, IH), 7.
48 (1, IH). 7.65 (m, 111), 9.30 (m, 2H) f
Ill fll obtained by (38,4Tl) -x-
[2-(2-tert-amyloxycarbonylaminothiazol-4-yl)-(Zl-2-monochloromethylenea+doamide]-4-methyl-1-(IH-tetonzol-5-yl)-2-azetidinone 0159 When reacted and treated in the same manner as Example 14-(111), (38°4n)-3-'(2(2-
aminothiazole-4-(2)-2-monochloromethyleneacetamide]-4-methyl-1-(I
The trifluorocarbon 1'* salt of H-tetrazol-5-yl)-2-azetidinone 0.12F (yield: 8o%) was obtained. 117(KEr)z; I:=0 1765.166
0'NMH(ds-DMSO) δf direct,;;t4
s(d, J=6H1,!III), 455(m, IH
). 5.55 (m>IH), 7.11 (1, IH). 7.48 (8, IH), q, 52 (a, J=811Z
, IH) Example 16 (38)-3-(D(-)-2tert-butoxycarbonylamino-(4-hydroxyphenyl)acetamide]-1-(IH-tetrazol-5-yl)-
2-azetidinone 0.27 to 1,2-dichloroethane 2
Let Rt solve the mystery, pick up trifluorobacterium acid 3at at room temperature, and stir it at the same temperature for 1.5 hours. Then, the solvent is distilled off under reduced pressure, and the obtained residue is added with xylene 5a and dried under reduced pressure (M preparation is carried out twice. The obtained residue is dissolved in 2 suK of inpropanol, and the obtained residue is dissolved in 2 suK of inpropanol, Add 0.08 m of pyridine, stir overnight at the same temperature, remove the precipitated crystals, and dry -I'' to obtain a melting point of 218°C (decomposition).
White crystals of (38)-3-[D (-) -2-amino-(4-hydroxyphenyl)acetamide]-1
-(IH-tetrazol-5-yl)-2-azetidinone 0.092 (yield 60%) is obtained. I R(KB'r) crn 1p C-=0 1
765.1685 NMR (da-DMSO) δ value 3 150-4.06' (m, 2H), 4.80-5.3
0(m, 2H). 6.5o(a, J=10Hz 2H), y, 32(
a, J=1DH! . 2H), 9.34 (d,, T=9flZ, IH) Example 17 (II (3S) -3-tert-butoxycarbonylamino-1-[2-(4-nitrobenzyloxycarbonylmethyl)-2H- Tetrazol-5-ylk-2-azetidinone 3322 was dissolved in methanol 150#I/lla+', 5% palladium on charcoal) g70,
Add 7y and hydrogenate at room temperature and pressure for 15 hours. Next, the catalyst was separated and washed with 15 liters of methanol, and this cleaning solution was combined with the previous f' number to reduce r42 and I? Shrink. Obtained'rLr:, the residue was diluted with 50 #ll of ethyl acetate.
:T6 and water 50Kt (1) RF to mixed liquid, 4M8
Adjust the pH to 7.5 with aqueous sodium carbonate. Separate the aqueous layer, fill with 50.11j of ethyl acetate, adjust the pH to 2.0 with 2N-carboxylic acid, and then separate the organic layer. The amorphous layer was sequentially washed with 6011 t of water and 30 d of Lusangian water, dried over anhydrous magnesium chloride, and then the solvent was distilled off under reduced pressure.
When the precipitated crystals are collected by P, they are (3.5)-3-tart-butquinecarbonylamino-1-(2-carboxymethyl-211-tetrazole-5-), which has a melting point of 165°C (decomposition). yl)-2-azetidinone 1.839
(yield 78.9%). 111 (THF) cm'; C=0 1775 17
40 1715 horn N MH (ds DMSO) δ value 1 1.38 (s>9n), 3.9o (m, 2H), 4
-97(4-97(, 5, t53(lI, 2I(),
Z40 (bsz IH″). 7.72 (d, J=8Hz, IH) In the same manner, the following compound was obtained. -carboxymethyl-1H-tetrazo-)L/-5-yl)-2-azetidinone anatomical form I B (KB r ) C; 1p 'C=0 171
30 1720 1700J No NMI ((CDCIm) δ value; 5.50 (1,2'lI), 6.40 (d, J=8H
z, IH). 947 (b st I H) CIll Obtained with CI+ (58) 5 tert-
Butoxycarbonylamino-1-(2-carboxymethyl-2H-tetrazol-5-yl)-2-azetidinone (1.77 g) was diluted with 1.7 ml of anisole, 917 ml of Triful No. Allow time to react. Next, ω-g was distilled off under reduced pressure, xylene 20#Ii was added to the resulting 1 residue, and ρ- was distilled off under reduced pressure. This operation was repeated twice. The obtained residue was dissolved in 1511 tlC of ethanol and 0.8 tl of pyridine.
After stirring at room temperature for 2 hours and under water cooling for 60 minutes, the precipitated crystals were converted to (3S)-3-amino-1-(2-carboxylic acid) with a melting point of 195°C (decomposition). Methyl-2H-tetrazol-5-yl)-2-azetidinone t I S+ (yield i 94.8%) is obtained. I IT (KW r ) =” p c = o 178
5p 1635N M n (Da O) δ value; Similarly, the following compound can be prepared. 0(38)-5-amino-1-(1-carboxymethyl-1H-tetrazol-5-yl)-2-azetidinone Melting point] 172-174°C (decomposition) IR(KBr)L;'°'c=o 1780 1610
No No NMR (D, O) δ value i 420 (my 2 H) p 5.10 (my I
H)7 540 (m. 21■) 0111 fZl-2tert-butoxyimino-2
-(2-triphenylmethylaminothiazol-4-yl)acetic acid 0.979 to N,N-dimethylacetamide 5
Ferment to Rt and cool to -10'C. A 1Rt solution of methylene chloride containing 0.19 IIt of phosphorus oxychloride was added dropwise to the solution, and the reaction was carried out for 60 minutes at the same γ, 1j (degrees). Amino-1-(2-carboxymethyl-2H-tetrazole-5
-yl)-2-acetidinone (0.42W) to N-dimethylacetamide (5"Ke) was mixed with 0.28It of triethylamine, stirred at room temperature for 60 minutes, and fermented. was cooled to -20°C, added dropwise to the previously prepared reaction solution, and allowed to react for 1 hour in room 6. Then, 20 mA of ethyl acetate and 201 I of water
Add the mixture of t and separate the organic layer. The aqueous layer was washed successively with 10 parts of water and 10 parts of saturated brine, dried over anhydrous magnesium sulfate, and then the hot medium was distilled off under reduced pressure. When the obtained residue was purified by column chromatography (Wabu silica gel C-200.I14 surgical solution; chloroform:methanol=50:1), peak points 168-175 were obtained.
(5S)-1-(2-carboxymethyl-2H-tetrazol-5-yl)-3-[2-(2
-1 rifhenylmethylaminothiazol-4-yl)-
(Zl 2-tert-butoxyiminoacetamide)-2-azetidinone 07v (yield 522%) is obtained. In(Kllr) cm'; c=o 17B5.
1740. 167ONMR (da DMSO) δ value; 1.25 (s, 9H), 3.9! +(y 2H), 4.
70 (n52H). 5.13 (m, IH), 5. +D(s,,2H). 475 (8, IH), 735 (s, 15H). Similarly, 900 (a, J-a51 (Z, 1) 1),
The following compound was obtained. 0(3S)'-1-(1-carboxymethyl-1H-tetrazol-5-·fl)-6-(2-(2-triphenylmethylaminethiazol-4-yl) -(Zl
2-tart-butoxyiminoacetate]-2-
Acetidinone amorphous 11+ (KBr)+a++; C=o 1780,1
725,166ONhlL+ (CDCIg) δ1 Direct] 1.28 (8,91(), 40B(m, +211),
4. q8(m, ul'). 5.36. (a, 2H), 6.58 (m, 211)
. 12 B (@, 15 'kl)7 8.73 (
my 2 H) 4vl (obtained by lj r, f, -(3!
3) -1-(2-boxymethyl-2M-tetrazol-5-yl)-5-[2-('2-triphenylmethylaminothiazol-4-yl) -(Zl 2-t
When 0.5 g of art-butoxyiminoacetamide]-2-azetidinone was reacted and treated in the same manner as in Example 1l-(IN), the result was (3S)-1-[2- ('2-aminothiazol-4-yl)e+2-tert-ptoxyiminoacetabad]-1-(2-carboxymethyl-2H-tetrazol-5-yl)-2-azetidinone 0.17 g (expropriated 561 %) is obtained. I n (+< +3 r ) U'C; 0 177
5y 1650t 1620! NILRI II (dn −DMfi υ) δXFr'
l-J152 (s, 911), 4.02 (m, 2H
), 4.82-5.92 (II+, 5H), 6.83
(It, iH), 7i2 (bs, IH). 912 (' b B, i H) The same compound was obtained. 6s) -5-(2-(2-aminothiazol-4-ino') (Zl 2-tert-butoxyiminoacetamide)-1-(1-carboxymethyl-
1) 1-tetrazol-5-yl)-2-azetidinone amorphous I 11 (KB r ) Cm s C=o 1 7
7 5t 1 6507 1 62 ONMB(as
-pMso) δ value] 1.35 (s, 9H), 4.10 (nl, 2H), 5
．． 05-6.00 (m, 5H), 6.65 (8,1
11), 7.40 (BS, IH). 920 (b s, IH) Example 18 (1) Sodium borate/10 aqueous phase 959.5% sodium hypochlorite water bath release 67a, hydrogen sulfate tetra-n
- A mixture of 0.089 g of butylammonium and 180 g of water was cooled to 0 to 5'C, and the bath was cooled to 7 mL (3
S)-3-penzyloxysoJluponylamino-1-(
2-(4-methoxybenzyl)-2H-tetrasol-
5-yl]-2-azetidinone 2.0/l' to R-'r
Add the filtered methylene chloride bath solution 180#It to 0-5
React for 165 hours at °C. Then, 0.5 M −I
After adjusting the pH to 117.0 with a potassium dihydrogen phosphate water bath solution, the organic layer was separated. The organic layer was washed successively with 100 d of water and 100 liters of saturated brine, dried over anhydrous magne sulfate, and after 1 hour, the liquid was distilled off under pressure. The obtained residue was dissolved in 28N of N,N-dimethylformamide, and the solution was heated to -75°C, and then a methanol bath solution of lithium methoxide (1,75N) was added.
．． 6 m and reacted for 60 minutes at the same temperature when pressing ()L. Then, the reaction solution was poured into a 0.5 M potassium phosphate dihydrate water bath and further extracted with methylene chloride iso*. This extraction 11jj'<y
The mixture was washed successively with 10,117 ml of water and 100 ml of saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to column talomadography (Wako silica gel C-200, τul'; II
6-benzyloxycarbonyl 7i purified with benzene:11-ethyl acid-20:1)
No 1-[2-(4-methquinbenzyl)-2H-tetrazol-5-f]-ro-methoxy-2-azetidinone 04 (yield 183%) is obtained. I 11 (NEET) Confucianism; c=o 1780,17
1ONMn(coCts) δ value i 5.60 (@, 5H), 3.85 (s, 3H), 4
．． 25(d. J =8 IIz t I H)7 44ro(dp J
-a az71 a) 75.25 (s, 2H),
5.75 (s, 2H), 6.30 (a. IH), Zoo (d, J=8Hz, 2H). 730-7.60 (my 7 H) (previously obtained in (1)) 6-benzyloxycarbonyl 7i no 1-[2-(4-methoxybenzyl)-2H
-tetrazol-5-yl]-3-methoxy-2-azetidinone was treated in the same manner as in Example 4 to give 6-benzyloxydicarbonylamino-ro-methoxy-1-( IH-tetrazole-5
-yl)-2-azetidinone 0159 (yield 517%)
Have a meal. Eva (ICl1r) Y C-01780,171
ONMn (as-DMSO) δ value; 35+(s, 3H), 4.2o(a, J=6Hz,
IH). 4.62(a, J=67(Z, IH), 5.20(
8,2H). 7.50 (S, 5H), 9.20 (11, IH) (i
ni+ Ill 'J rat'L rcro-pencyloxycarbonylaminoro-methoxy-1-(I H-
Tetrazol-5-yl)-2-azetidinone 015g
To 5 ml of methanol, add 5% palladium-charcoal hydrogen to 5 ml of methanol and hydrogenate for 6 hours at room temperature. Then, after removing the catalyst with iF, it was distilled off under reduced pressure.
(1rx-tetrazol-5-yl)-2-azetidinone o, n 6 y (yield 69%) was obtained. I n(KT3r) cn+ 7 C-01770(I
v+ (in+ multiplied by 6-amino-ro-methoxy1-(I n-tetrazol-5-yl)-2-
Example 1 Azetidinone 0069 and (Zl-2-tert-butoxyimino-2-(2-)liphenylmethylaminothiazol-4-yl)r-1 acid o,i sg
l-(If reacted and treated in the same manner as II, the melting point is 145
6-Medoxy 1- as white crystals exhibiting ~150°C (decomposition)
(IH-tetrazol-5-yl)-3-(2-(2-
) liphenylmethylaminothiazol-4-yl) (
Zl 2-tert-butoxyiminoacetate
-2-Azetidinone o, o1s' (yield 5 LIJ) is obtained. III(KBr) cm';'c=o 1770.
1660 Example 19 (3s)-x-(o(-)-2-(4-ethyl-2,3
-dioxy-1-piperazi7carboxamide)phenylacetamide]-1-(IH-tetrazol-5-yl)-2-azetidinone 016y was dissolved in anhydrous N,N-dimethylborumamide, and tart-butoxypotassium 0 Add .047. Further, 0.0941 ml of bivaloyloxymethyl iodide was added to the bath surface, and the mixture was incubated at the same temperature for 1 hour. Next, the myth was distilled off under reduced pressure, and the resulting residue was dissolved in a mixture of 1ON ethyl chloride acid and 1Qml of water, and 1Qml of sodium thiosenate was added.
After adding 0.0 ml, adjust the pH to 7.0 with sodium bicarbonate.
Yu. The organic layer was separated, washed with 10μ of t'lL Japanese saline solution, and dried with 5 seric acid anhydride.The solvent was distilled off under the pressure of a washer to obtain (?1S)-3-(1
-1-2-(4-ethyl-2,ro-dioxy-1-piperazi7carboxamide)phenylacetamide]-1-
(1-pivaloyloxymethyl-1H-tetrazole-
5-yl)-2-azetidinone and (3S)-6-[
D←)-2-(4-ethyl-2,3-dioxo-1-piperazinecarbogizamide)phenylacetamide]-1
-(2-Bivaloyloximetal-2H-tetrazol-5-yl)-2-azetidinone combination′i7η01
Get 4 no. This was subjected to column chromatography (Wakoon Likagel C-200.% I1K; Benzene: +:
n1 diethyl chloride 1.1), each minute ν, 1", then 9 tomephthalomadography (development 711
;Chloroform:acetone-2:1,'l''LC grade Kleselge160Ftm4. Art, 571
5-melta tl-defect) and upper bar 111 spot (nt value;
0.4) is 0.05 (yield 25%), lower spot (Ill value; o, +7) is also +7) 0.049 (
Yield: 20%). Melting point of Q upper spot: 120-160℃ (decomposition) -1, ν IR(1(Br) a++, C=0 1780.17
40°1710.167O N MR (CDCIll) δ value: 1.05-1.27 (m, 12H), 3.30-3.7
5 (m. 4H), 3.75-4.30 (m, 411), 5.2
5 (m. IH), 5.55 (d, J=611z, IH). 6.40CB, 2H), 7.36(s, 5H), 8
．． 15(d, 'J=6Hz, III), 9.83(
d, J=7Hz. IH) 0 lower spot melting point: 160-140℃ (decomposition) I) + (KBr) cm; C=0 1780.17
40゜1710.167O NMII (CDC1g) δ value: 1.02-1.27 (m, 1211), 3.27-3
;77 (m. 4H), 3.77-4.37 (m. 4.11), 5.
18 (m. 1) I), 5.55 (d, J=7Hz, I H
). 6.52 (d, J=11Hz, l11), 6.67
Cd. J=1'IHz, IH), 7.59CB, 5H). 8.27 (d, J=71TZ, l11), 9.78
d.
5-yl)-2-azetidinone (02) to sodium bicarbonate (1)
, 006 g of 1 ram was added to 2 ml of water in a bath, mixed with Thai-1' ion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd., M syneresis; 10 thiacetone water), and added to a bath F'fi under reduced pressure.
Dry the filtrate and fill the resulting residue.
'+-ethyl 111t and diethyl ether 5 ml
: After treating with 11 cups of water, and collecting 1 part of the precipitated crystals, dry under reduced pressure.
, 4n)-3-(DL-2-azidophenylacedore;
)-4-methyl-1-(I H-tetrazole-5-
yl)-2-azetidinone sodium IB o, 1
6 g (yield 76.2%) is obtained. I n (KT3 r ) clRy (-=0 17
50r 1660 Example 21 (38p4S) Dissolve 65 5-tart-butoxycarbonylamino-1-(1-)phenylmethyl-1H-tetrazol-5-yl)-4-methyl-2-azetidinone in 6oIlt of methanol Then, 10% palladium-carbon 27 was added and hydrogenated at room temperature and pressure for 4 hours. Then, the catalyst was separated and the td was heated under reduced pressure to J1.
7i leave. The resulting residue was 20 ml of ethyl acetate.
and 2 oz of water were added, and the pH was adjusted to 70 with a saturated sodium bicarbonate water bath. Separate the aqueous layer, 1)1
．． Add 30ILt of ethyl acid, and add 2N114 (pi at Jh).
(Adjust to 2.0 and separate the organic layer.The aqueous layer is further extracted with 20M ethyl acetate, and the organic layer is I+2!Japanese salt solution 3
After washing with 0M, the anhydrous solution is dried with magnesium acid and the solvent is distilled off under reduced pressure. If point 134~1
? White product (58,4S)-3- exhibiting 15C (decomposition)
tart 7') oxycarbonylamino-4-methyl-
1-(IH-tetrazol-5-yl)-2-acetidino/2-(yield lcA 92.6%) is obtained. 1B(KBr) any C=0 1770.17
0 ONM direct da-DMSO) δ value t 1.41 (s, 9H), 162 (d, J=711z
, 5H). 4.16-4.76 (m, 2H), 7.85 (d,
J=7Hz, IH) Example 22 (,liS,4B)-5-amino-1-(In-tetrazol-5-yl)-4-methyl-2-azetidinone hydrochloride 0.29% N, N- Dimethyl i-trumamide 1
Plow and muddy 01Il, add triethylamine Q under ice cooling,
Add 41ml and mix well. At the same temperature, 1-benzyl-4-fluoropyridinium bromide (purity 65
%) and stirred at room temperature.Then, insoluble materials were separated from l'-I, and the solvent was distilled off under reduced pressure using r. Add 5 otn of taloloform to the residue.
Mix with a knife and stir for 15 minutes. No? I'm sorry for the inconvenience.
Rice 1. l Rohm and Haas, water: tetrahydrofuran - 95:5). (3s. 4 R)'-3-((1-benzylpyridinium-4-
yl)amino]-1-(IH-tetrazol-5-yl)-4-methyl-2-azetidinone o1a 9 (yield 5
4.5%). I II(KBr) ('I''';'C=0 1
77 ONMR (dg DMSO) δ value] 1.30 (d, J=71 (z, 3H), 4.01 (
m, 1) f). 5-30~5;'50 (my RoH), 7.18~
7.42 (m, 7 H). 8.55(m, 2J(), 9.70(d, J=8Hz,
IH) Example 23 (38,411)-3-amino-1-(IH-tetrazol-5-yl)-4-methyl-2-azetidinone 0.
34 was suspended in methylene chloride (5d), triethylamine 056N was added at room temperature, and the mixture was molded at the same temperature for 15 minutes. Then, the mixture was cooled to -70°C, 0.34 m of trifluoromethanesulfonic anhydride was added at once, and the temperature was gradually raised to aC over 45 minutes. The reaction solution was ice-cooled with 30 parts of ethyl acetate and 20 parts of water! The mixture was poured into a mixed solution of 300 ml of water, and the mixture was brought to a temperature of 2.0 pm with 2N hydrochloric acid. Separate the organic layer and add water 2
Q 1st and 2nd row, washed in sequence at 20m of Kazunaga water,
After drying over magnesium hydroxide sulfate, the residue is distilled off under reduced pressure. The resulting good residue was subjected to column talomagography (wa) °C on silica gel, elution filtered with chloroform:
Acetone = 20:1) to prepare amorphous (5S, 4n)-4-7'thyl-6-trifluoromethanesulfonylamino-1-(1is-tetrazole-
5-yl)-2-acetidinone 04g (656%)
get. I It (I<rm) an ; c=Oi 77O
NMII (do-oA(so) δ value) 158 (d, J=7Hz, 3J(), 4.74(m,
IJi). ! :)Roy(d, J=6Hz, 1n), 7.04(b
s, IH) Real ht! i Example 24 (11p-glolophenanylamine hydrochloride 20.6)
, 2-methylthioiminollV'l limit j 6.29,
Sodium chloride 92 and 1 (l 200 at
The mixture was stirred at 90 to 100 C for 45 t), then 4.59 g of 2-methylthioiminoacetic acid was added, and the mixture was reacted at the same temperature for 60 minutes with stirring. Then, the total amount of 5Q under reduced pressure
The solvent is distilled off to m. Add 2 ethyl acetate to the obtained concentrate.
Add 00 crocodile ε and 200 d of water, collect a lot of phase crystals, wash sequentially with 301 of water and 30 M of ethyl acetate, and then dry.71
．． For example, 4-(4-
Chlorophenyl)-2-ethoxycarbonylimidazo-
2.1 y (yield 48.4%) was obtained. Furthermore, F'i is hydrogen carbonate) IJum to pH' 6.0
and leave it at room temperature overnight. Take 1 part of the precipitated crystals and add 5 parts of water.
After successively washing with 0 ml and 1 Qx+l of ethyl acetate and drying, 575 pieces of 4-(4-chlorophenyl)-2-ethoxycarbonylimidazole having a melting point of 197-204° C. (yield 26%) are obtained. Recrystallization of this from methanol yields 4,952 white crystals having a melting point of 209-210°C. I R(KIlr) eta-'° l'L:=017
10 NMn (da DMSO) δ value; 1.35 (t, , T=7Hz, 3H), 4.54 (
q, J-711t,. 2H), 7.37 (d, J=9uz, 2H), 7.
27-7.90(m, 3f(), 136(bs, +IH
) (li) 4-(4-chlorophenyl)-2-ethoxycarbonylimidazole 177 was suspended in 34 m7 of 10% sodium hydroxide hydrochloric solution, and ? d Press the stirring button and apply heating for 0 minutes. After cooling, leave at room temperature overnight, collect a lot of phased crystals, and wash with 3 ml of water. Ko'L, water 3 Q
After adjusting the pH to 1.0 with IN l1fb acid and stirring at room temperature for 10 minutes, remove the precipitated crystals, which are white with a melting point of 172-176°C (decomposition). 1.39 (yield: 86.5%) of 2-carboxy-4-(4-glofuconinyl)imidazole was obtained. I IT (K11r) Cm / C-Oj 630
(iii) The mixture of 2-carboquine-4-(4-chlorophenyl)imidazole 50y≠ and NN-dimethylformamide 005 is heated under reflux for 1 hour. After cooling, the solvent is distilled off under reduced pressure, and the resulting residue is i, H6 water supporting methylene 100a
After stirring at room temperature for 15 minutes, remove the precipitated crystals and dry them.
7-bis(4-chlorophenyl)-s,1o-dihydro-5,10-dioxydiimidazo[1,2-a:
1', 2'-d] pyrazine 4, 49 (yield 95
%). -1ν IR(KBr) ai; Cm0 17.4 million, D
Add 3.8 g of (-)-phenylculine diphenylmethyl ester/p-)luenesulfonate to 40 g of ethyl acetate.
Sodium bicarbonate was suspended in a mixture of IIe and water for 7 hours at room temperature. l! 'Add and stir for 15 minutes. The organic layer is separated, washed twice with 30μ of water and 601μ of water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue obtained is dissolved in N,N-dimethylbormamide 5Qxrl and cooled to -60°C. To this, triethylamine/1.2#Ig and the previously obtained 2,7-bis(4-chlorophenyl)-5 were added at the same temperature.
,10-dihydro-5,10-dioxydiimidazo[
1,2-a:1'2'-d] Pyrazine 1.759 was added all at once, the temperature was raised oc't for 50 minutes, and 41 was pressed for 50 minutes under water cooling and at room temperature for 2 hours. Make it react. Then, the solvent was distilled off under reduced pressure, and 5 Q ml of ethyl acetate and 5 Q tag of water were added to the resulting 7" L residue, stirred for 10 minutes, and the precipitate was collected. The melting point was 180.
White product diphenylmethyl = D(-) exhibiting ~182°C
-2-t[4-(4-chlorophenyl)imidazole-
2-yl]carbonylamino)phenylacedeh2y
(yield: 49.5%). Furthermore, the pH of the P solution was adjusted to 2.0 with 2N hydrochloric acid, the organic layer was separated, and the water
After sequentially washing with 1 ml and saturated brine 301, drying over anhydrous magnesium acid. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate iQa+t.
Recrystallized from a mixture of Jt and ethanol 1011Z
is diphenylmethyl=0(-)-2-((4-(4-ylorophenyl)imidazol-2-yl)carbonylamino)phenylacetate 0.951 (yield IR(KB r ) ” 7 C=U 1735y
16'5 ONMR (da-DMSO) δ value] 6.01 (d, J=811+1+), 7.03(
8, IH). 12D-177(In, 17H')y8. [)
2~B17 (m, 3H) 78.99 (% J
-8II Z/ 11()(1v) diphenylmethyl-IC(-) -2-(C4-(4-ylorophenyl)
Imidazol-2-yl]carbonylamino)phenylacetate 29 is dissolved in a mixture of 33 ml of tetrahydrofuran and 30 M of water, and 1 g of 10% palladium-barium sulfate is added thereto, followed by hydrogenation at room temperature and pressure for 15 hours. The pFI of the reaction mixture was adjusted to 7.0 with a 1ζ4-phase hydrogen carbonate solution, and the non-('a) was removed. The organic layer was further extracted with 1Qt+l of water.The aqueous layers were combined and washed with 30Int of ethyl acetate.
New γ Koni t'l'[&f ethyl 20m6 addition, 2N-
5 Kai 6 and ethyl acetate 3, 1llt at mA! Next, after washing, dry the tin a&'J,,i:41i! point 240'C
White crystal (1) DC)-2-((4-(4)
-talolophenyl)imitazol-2-yl)carbonylamino)phenyl yields 12 (yield <765%). I n (KB3 r ) side y L=0 1715
16501DMn(ds-DMso)δI+u;5.
81 (d, J=811Z, l11), 7.50-
7.80 (m, 7H). 8.03-8.25(m, 31D, 8.80(d,
J=8Hz, + IH) (V+ (3S, 4R) -3-
7mi/-4-methyl-1-(I H-tetrazole-5
-il)-2-7sage/70.345IKD(
-)-2-f L 4-(4-OA phenyl) imidazo/L/-2-yl]
f1'"Mermaid 9i with acid 0.759) 11-(9 reactions and treatments as in II) (ss, 4n)-3-(D(-)) -2-
L[:4-(4-talolophenyl)imidazole-2-
yl]carbonylamino]phenylacetamide)-4
-Methyl-1'-(I H-tetrazol-5-yl)
-2-Azetidinone 067 (Yu'RL 5 fJ, 8
%). I n (KB r ) 傂t C=0 177071
65 ONMR (da-DMSO) d value; 1.31 (m, 3H), 4.64 (m, IH), 5
．． 58 (rr>IH), 5.89 (d, J=8Hz,
HI), 7.28-8.15 (m, 10H), 86
6 (d, J = 8H3, 1H). 9.60 (d, J=8Hz, IH) Example 25 (3S,4B) -5-amino-4-methyl-1-
(I H-tetrazol-5-yl)-2-azetidinone 0.29′N,N-dimethylformamit” 24
After adding and dissolving triethylamine 058d at room temperature, -
Cool to 10°C. Then, 062 pieces of 4-pyridylthioacetyltalolide hydrochloride were added at once, and the mixture was heated at 0 to 5°C.
Time: 1 hour at room temperature 4't7: Allow to react to the press. Then, the reaction solution was poured into 5 atm of ice water, and the pH was adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was separated, washed with 5N methylene chloride, and then adjusted to pH 3 with 2N acidic acid.
, 5, and stirred at room temperature for 1 hour and then 60 minutes under water cooling, and the precipitated product was collected in 1 ml of water and 1 ml of acetone.
After sequentially washing with l, dry at 241-243℃
White crystals of (3S,4)1)-4-methyl-3-C2-(4-pyridylthio)acetamide showing (decomposition):]-
1-(IH-tetrazol-5-yl)-2-azetidinone 02y (yield 526%) is obtained. I n (KB r ) CIl+' / c-o 1
755 1650 NMR (Dx o-N, , cQ, ) 6-value j1.29
(d, J=71rZ, 3H), 4.12 (b8.2
H). 461 (m, IH), 5.45 (d, J=6H1,
IH). 7.42 (m, 2H), 8.52 (m, 2H) Patent applicant Toyama Chemical Industry Co., Ltd. Continuation of page 1 ■Int, C1,' Identification code Office serial number (C0
7D 417/14 205:00 241:00 257:00 ) 0 Inventor Kiyoshi Tanaka 232 Kitatakagi, Oshima-cho, Imizu-gun, Toyama 0 Inventor Yutaka Ochiai - 8-51 Shimoshinkoku-cho, Toyama City Inventor Joji Nakano Toyama 1-6-1-4 Ichishimo-Okui 0 Inventor Yoshikazu Fukuoka Toyama Car-mounted Kawahara 1-10 Prefectural Housing 4 204 0 Inventor Ken Tai 3-17-30 Awashima-cho, Toyama City 0 Inventor Yoshikazu Saiyo Oizumi, Toyama City Nakamachi 7-52 Hand a Amendment Book II? (+1159th June 14th, Mr. Commissioner of the Japan Patent Office 1 Indication of the case 1988 Patent p, G1 No. 121236 2 Title of the invention Novel azetidinone 15 fathoms and its salt knowledge 3 Person making amendment Monocrop and Relationship ・1'r permission - = i1 person Address 〒160
IE 2-5-3, Shinjuku-ku, Tokyo 4, Date of amendment order 5, Details subject to amendment 1°) Column 6 of “Detailed description of the invention” 1 of the abstracts
At the end of Table 9 of 1274T, page 164, line 16 says, ``Similarly, the following compound proboscis was obtained. (38,4R)-s-(2-( 2-aminothiazole-
4-yl)-(dog-2-((2-carboxy-2-methylpropoxy)imino]acetamido)-4-methyl-
1-(1H-tetrazol-5-yl)-2-azetidinone Yield 50.0% 1d (point 240°C or higher (thickness?) Engineering R (KBr) cm-1; Soc=o 1765,171
0゜655 NMR (H-DMSO) δ value; t 1 o (m, 6H), t 4s (d, J-=
sHz. 5H), 4.35 (S, 2) (), 4.62 (m, 1
H). 5.55 (m, IH), 6.96 (S, IH), 774
Insert (bs, 1H), y, 59 (d, J=sHz, IH). After page 135, line 16 of the same page, "1u119.' K site, a clear compound: igy was obtained. (J Sr 4 R) 3
(Ro-2-(ethoxyimino)acetamide]-4-methyl-1-(1fEjtrazol-5-yl)-2-
Azetidinone 111tei 500% Point 220°C or higher (minutes M) I Ei (KBr ) cm'; νC=0 177
5,1720°655 IJmu(f((d, -Dmu4SO) δ 1bif;0.
90-2.00 (m, 17H), 4.24 (m, 2H)
4.68 (m, IH), 5.68 (m, IH), 7.4
5 (S, IH), 9.72 (d, J,,,jo Hz
, IH). Insert 11.8o(bs, 1H) J. (5) After page 166, line 15, Example 2
Add 6-60. [Example 26 3g of fruit was suspended in 60° of water, and sodium hydrogen carbonate 083
Add 9 and dissolve. Next, Iil pressed down zinc 0
．． Add 77 ri and press gently at room temperature for 30 minutes. i before precipitation
Take fJ, wash with water 10-1; wash and dry.
,, /j & point 240°C or higher f Show f (2S, 3
S ) -2-hey siloxyluponia ζ no 6
-Hydroxy-N-(IH-tetrazol-5-yl)
327% of butyric acid amide + sailboat jΣK + hydrate (yield 973%) was obtained. IR(KBr)cm'; VC-01700167
0(2S,3S)-2-benzyloxycarbonylamino-6-hydroxy-N-(1H-tetrazole-5-
il) acetic acid amide +rH! e platform JM-+o (Japanese product 2.
Dissolve 8Q in tetrahedral O75770fnl and acetone 7Qtnl and dilute with anhydrous sulfuric acid) IJum 5.0
Add the mixture and stir at room temperature for 30 minutes to dissolve. The solvent is distilled off under reduced pressure. The resulting residue was added with anhydrous Latrahydro 7ran 12 omK solution M, 2.699 g of triphenylphosphine, and mixed at 20-25°C with a combined solution of 1.62 tnt of diethyl azodicarboxylate and 0 tnl of anhydrous tetrahydrofuran. The total solution solution was reduced to η5;1 over a period of minutes, and then reacted at the same temperature for 12 hours. 1: Remove 11 liters of the solvent under pressure, add 0 ml of 1 ic ja minityl and 20 ml of diethyl ether to the filtrated residue, and take 1 liter of the solvent before precipitation. Add this to a mixture of 6y rj; ethyl 30- and water 30-
j, 'Ei NJ Sase, 6N-41'@TEpH1,5K
mml, molten F; Separate the organic j moth and add 5Q of water.
Add td and adjust the pH to 7 with saturated carbonated water Wg sodium.
After 1 'F'G L, separate the aqueous layer and add 3Q ethyl acetate.
ml and make T)H2,o Kθ,W with 2N-acetic acid. Separate the organic layer, wash with 10 liters of water and 10 liters of Japanese salt solution (then wash with 10 liters of water, dry over anhydrous magnesium sulfate, and evaporate the solvent in a vacuum. .Add 20 ml of diethyl ether (I-) to the resulting residual 10,000, and take 14 ml of precipitated IJ to give a melting point of 147-149°.
C58,4B)-5-benzylox7carponylamino-4-methyl-1-(IH-tetrazole-5
-yl)-2-azetidinone 1.479 (yield 627
%). The 4iU properties (IR and NMR) of this product were consistent with those obtained in Example 4. Example 27 (2S)-2-be/zyloxycarbonylamino-3-
Hydroxy-N-(1-diphenylmethyl-I H-7
”) rag-ru-5-yl) propion 1 sand amide 0.
59
Let it react for 03 minutes. Next, anti-J heart rf'r: Button 1-
4ii t'iQ Ethi/L/ 20 ml and water 5
Pour into a mixed nt of Qml, and separate out VS +;;t. 50ml of water and 1□+! 4R saline 5Qm
After sequentially washing with J and drying with anhydrous magnesium dioxide, the solvent was removed in a vacuum chamber. The obtained residue was subjected to column chromatography (Wako silica gel C-2OO, solution 1: L solution; toluene: ethyl acetate #=-2U: i
) f+1 ``!'J Thread, t, unspecified Jb(r)
(5S)-3-benzyloxycarbonylamino-1
-(1-diphenylmethyl-IH-tetrazole-5-
yl)-2-azetidine 7o, 25 g (yield 522
%). The properties (IR and NMR) of this product are actually 1K[5
I admired him for getting 1st place in 1st row. Real+I+It C'125 (3S, 4R)-5-[2-(2-tert-amyl-aminothiazol-4-yl)-(l-ethoxyiminoacetabado]-4-methyl-1- (
IH-tetrazol-5-yl)-2-azetidinone 0
249 was dissolved in 2.4 ml of trifluoroacetic acid in a K bath of mono'nisole 24IIJk and allowed to react at room temperature for 2 hours. Then, the solvent was distilled off under pressure, and the resulting 5 distillates were 1111% white, 1Qag ethyl, and 1Qag water.
Add 011 and let it dissolve. Adjust the pH to 7.0 with 11 ml of saturated sodium bicarbonate solution in 1:1: Roast and separate the aqueous layer. Ethyl acetate iQ in the separated aqueous layer? After adding ff and adjusting the pH to 0 with 2N-hydrochloric acid, the crystals formed by I Jr were collected and dried to give a melting point of 240.
'C or higher (3S, 4R) -3-(2-(
2-Aminothiazol-4-yl) = (le-ethoxyiminoacetamido]-4-methyl-1-(IH-tetrazol-5-yl)-2-azetidinone o, o q
g (II ratio 49., '1%) is obtained. IR (KBr) cm'; V, /C=0 1770
, 1655N M R (d 1l-Dl, (So)
δ I direct; 105-1.50 (m. 6H), 4.16 (q, J=7H2,2H). 4.61 (m, IH), 5.61 (m, 3H). 6.80(S, IH), 7.26(t)S, IH). 9.50 (d, J = 10i (Z, IH) Example 29 (3S41'()-3'-(2-(2-aminothi!azol-4-yl)-(Zl-2-(diphenylmethoxycarbonyl) methoxyimino)acetamide]-4-
Methyl-1-(IH-tetrazol-5-yl)-2-
Dissolve 0.509 ml of azetidinone in 5 tnl of anisole, add 5 ml of water-cooled F trifluoroacetic acid, and react for 20 minutes at a diversion rate. The solvent is distilled off under reduced pressure, and the resulting residue is treated with a mixture of 10 parts of ethyl acetate and 10 parts of ethyl ether, and the precipitate is evaporated for 1 time.
(38,4R)-5-( exhibiting a melting point of 140°C (decomposition)
2-(2-aminothiazol-4-yl)-(Z)-2
-(carboxymethoxyimino)acetamide]-4-
Methyl-1-(IH-tetrazol-5-yl)-2-
Trifluoroacetate of azetidinone o279 (113?
600%), IR(KBr)cm';:,'O-01770,
1670°64O NMFI (d6-DMSO) δ value; t49(d, J
=6Hz. 3H), 4.75 (m, 3H), 5.70 (m, IH)
. 7.08 (S, IH), 720 (In, 3H), 9.7
0(d, J=1oHz, 1H) Example 60 (38,4S)-3-C2-(2-aminothiazole-
4-yl)-(Z)-2-(diphenylmethoxycarbonylmethoxyimino)acetamidocy4-methyl-1
-(iH-tetrazol-5-yl)-2-azetidinone is reacted in the same manner as in Jitsugaku i Example 29, (3
S,4S)-3-[2-(2-aminothiazole-4
-yl)-(Z)-2-(carboxymethoxyimino)
Acetamido2-4-methyl-1-(1f-etetrazol-4-yl)-2-azetidinone is obtained. This was suspended in water (1-1), stirred with f6J, carbonated water, and 7jζ sodium water, adjusted to pH 7.0, and melted. Add this aqueous solution to Amberlite
If acetone=9(]:1) and 1"fi+'4,
1itj point 22 D 'C or higher (3S 48) -
3-[2-(2-aminothiazol-4-yl) -(
2',)-2-C carboquinnodoximino)acetamide]-4-Meboulu-1-(IH-tetrazole-5
-yl)-2-azetidinone dinatrium A +;
Obtain f O, 12 (+1 skewer 38.3%). etho ((KBr) (m'; V G-0176
0t 1665. 63O NMR (d, -DMSO) 64 (d/
J = 6 Hz / 3H), +, 2s (bs, 2H)
,4. so(m, 1H). 4.90 (m, IH), 6.91 (S, IH). 9,50 (,d, J=8H2,IL()" or more

Claims (1)

[Claims] Azetidinone derivatives and salts thereof represented by: (2) Tetrazole- in which R may be (+2 m)
5-yl azetidinone derivative according to claim (1) and its ff1i (3) azetidinone according to claim (1) or (2), where X is a hydrogen atom Derivatives and their salts. (4) Claim No. + where X is an alkyloxy group
Azetidinone derivatives and salts thereof according to item 1) or item 2). (5) Azetidinone derivatives and salts thereof according to any one of claims (1) to (4), wherein R'' is an acylamino group or an optionally retained amine group. (6) R2 and R3 are an alkyl group optionally substituted with 1 or 15 hydrogen atoms;
1) The azetidinone derivative and its salts according to any one of item (5).