JPS591465A - 4-cyano-2-azetidinone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is amino which may be acylated or protected; X is H, methoxy; W is H, sulfo). EXAMPLE:(3S-4R)-3-amino-4-cyano-2-azetidinone. USE:A useful intermediate in the synthesis of optically active 4-substituted-2-azetidinone with antibacterial and beta-lactamase-inhibiting activities. The compounds with sulfo group as W has both above activities and are used a remedy for infections caused by gram-positive and -negative bacteria in mammarian animals including men. PREPARATION:The reaction of a compound of formula II [R<2> is acylated or protected amino; Y is halogen, COOR<3> (R<3> is hydrocarbon), SCOR<3>] with a cyanide is carried out, preferably in the presence of a phase-transfer catalyst, when needed, deprotected to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to intermediates useful for the synthesis of optically active 4-substituted-2-azetidinone derivatives, which also have antibacterial activity and β-lactamase inhibitory activity. A new 4-
This invention relates to anor-2-azetidinone derivatives, their production methods, and their use as intermediates.

Background Art Recently, a new type of β-lactam antibiotic having a sulfo group at the 1st position has been discovered and reported (Nature + Vol. 289, p. 590 (198
1), vol. 291, p. 489 (1981)).

Synthesis of analogs has also been reported (for example, JP-A-55-164672, JP-A-56-125362, etc.). The latter report describes a method for synthesizing 2-azetidinone-1-sulfonic acids having a substituent at the 4-position.
The number of reaction steps is long and complicated, and a simple production method is not yet known.

DISCLOSURE OF THE INVENTION The present invention provides a novel formula [wherein R1 represents an optionally acylated or protected amino group, X represents hydrogen or a methoxy group, and W represents hydrogen or a sulfo group]. 4-￥Annault 2-
This invention relates to azetidinone derivatives, methods for producing them, and methods for using them as synthetic intermediates.

As a result of various studies, the present inventors reacted a compound represented by the formula [wherein R is acylated or protected and has the same meaning as described above] with a cyano compound, and optionally added a protective group. When removed, 4-cyano-
2-Azetidinone derivative CI) can be obtained, and the obtained compound CI) is an advantageous intermediate for the synthesis of 4-3-substituted-2-azetidinone derivatives, particularly for the synthesis of optically active substances. When subjected to the reaction and removing the protecting group as necessary, the formula [wherein R4 is an amino group which may be converted into a V/I/ or protected, and X and W have the same meanings as above] is obtained. vinegar〕
It was discovered that a 4-carbamoyl L/-2-azetidinone derivative represented by the following formula could be obtained, and the present invention was completed based on these findings.

That is, the present invention provides: (1) 4-cyano-2-azetidinone derivative
, (2) A method for producing a 4-cyano-2-azetidinone derivative CI), which is characterized by reacting the compound CII) with a cyano compound and removing a protecting group as necessary, (3) 4-cyano- 2-azetidinone ml conductor CI
) is subjected to a water-use reaction, and the protecting group is removed as necessary. A method for producing a 4-force μbamoyv-2-y zetidinone derivative [■], (4) Compound CIr) and This invention relates to the production method described in item (2) above, in which a cyano compound is reacted in the presence of a phase transfer catalyst.

In the above formula, the aryl group in the acylated amino group represented by R1, R2, and R4 is, for example, an acyl group substituted at the 6-position amino group of a conventionally known penicillin derivative, or a cephalyl group. An acyl group substituted at the amino group at the 7-position of a sporin derivative is used. Examples of such acyl groups include (1) formula % formula % () [wherein R5 is lower alkyl μ, phenyl which may have a substituent or phenyl which may have a substituent] heterocyclic group], a group represented by the formula (2) (where B6 is hydrogen, an optionally substituted amino acid residue, an amino group protecting group 1-(ca,)rn -co-C In the formula, R8 represents an amino group, a heterocyclic group which may have a substituent, a phenyl group which may have a substituent, a lower alkyl group which may have a substituent, m is an integer from 1 to 3, and represents an optional phenyl group, an optionally substituted heterocyclic group, or an optionally substituted cycloargunyl group, respectively; (3) Formula %) represents a heterocyclic group which may have a substituent or a phenyl group which may have a substituent, and B12 is hydrogen.

Phenyl, lower a(V)v which may have a substituent.

Lower alkyl/L' or formula -R13-R14 (wherein, B
13 is lower alkylene or lower γμkenylene, B1
4 represents a carboxy μ group or an ester thereof, respectively), R10 is a mere bond 1+ represents a heterocyclic group optionally having a formula substituent ), a group represented by ], [wherein R16 is hydroxylL
/l carboxyl, nurpho, formμoxy, halogen or azide group, R17 is hydrogen, lower alkylμ, lower alkoxy.

a halogen or hydroxyl group, respectively], a group represented by formula (5) (% formula %) [wherein R is cyano, phenyl which may have a substituent, or phenyl which may have a substituent B19 is a simple bond or -8 A group represented by -, respectively] is used.

In R5 to 'R19 in the above formulas CA) to CE),
Examples of lower alkyl μ include methyl and ethyl.

n-propyl, isopropyl, n-butyl, iso, butyl, wata-guchi/' + ter t-guchi ρ, pentyl.

1 carbon number such as isopentyl, hexyl, isohexyl
~6 alkyls are used.

Examples of lower alkoxy include methoxy.

Alkoxy having 1 to 6 carbon atoms such as ethoxy, n-propoxy, isopropoxy, n-gutoxy, imbutoxy, 5ee-butoxy+tert-gutoxy, pentoxy, isopentoxy, hexyloxy, and isohexyloxy is used. Examples of alkenyl include vinyl,
Allyl, isopropenyl.

2-methallyl, 2-guthynyl, 3-guthynyl, etc. are used. The cycloalkenyl is preferably a 5- to 6-membered ring, and examples of the cycloalkenyl include cyclohexenyl and cyclohexenyl=μ. The lower purkylene preferably has 1 to 3 carbon atoms, and examples thereof include methylene, dimethylmethylene, ethylene, methylethylene, and trimethylene. The lower alkenylene preferably has 1 to 3 carbon atoms, and examples thereof include vinylene and gropenylene.

Specific examples of halogen include chlorine, bromine, iodine, and fluorine. As a heterocyclic group, for example, a 5- to 8-membered ring containing one to several heteroatoms such as nitrogen atom (which may be oxidized), oxygen atom, sulfur atom, or a fused ring thereof, etc. Those having a bond are used, such as 2- or 3-pyrrolyl, 2-1 or 3-furyl, 2- or 3-chenyl, 2-4 or 3-pyrrolidiniμ, 2-. 3-1 or 4-pyridyl, N-oxide-2-13- or 4-pyridyl, 2-13- or 4
-piperidinyl, 2-. 3- or 4-bira 2μ, 2-
13- or 4-thiovirani, pifudinil, 2-94
- or 5-thiacylyμ, 2-14- or 5-oxasilyμ, 3-94- or 5-isothiazolyl, 3-.
4- or 5-inxazolyl, 2-. 4- or 5-
Imidazolyl, imidazolyl di/7,3-,4- or 5-pyrazoli μ, pyrazolidinyl, 3- or 4-pyridazinyl, N-oxide-3- or 4-pyridazinyl, 2-14- or 5-pyrimidinyl, N-oxide −
2-14- or 5-pyrimidinyl μ, piperidinyl, 4
-tti5-(+, 2.3-thiasiasili/l/),
3- or 5-(+, 2.4-thiasiasili/I/),
1.3.4-Thiasiasili/L', 1,2.5-Thiasiasily~, 4- or 5-(1,2,3-Oxasiasili μ), 3- or 5-(+, 2,4-Oxasiasily/ L/), 1.3.4-oxadiazolyl, 1.2.5
-oxadiazolyl, 1,2.3- or 1,2.4-
triazolyl, lH or 2H-tetrasiliμ, pyridoC2,3-d) pyrimidyl, benzopyranyl, 1.8-
．． 1.5-. 1.6-. 1.7-.

2.7- or 2.6-naphthyridyl, quinoriμ, Che/C2,3-b:)pyridyl, and the like are frequently used.

Examples of amino acid residues include glycyl, alanyl,
Paris A/, P Icil, Isoloil, Seri/L/.

threonyl, cysteinyl, cystyl, methionyl μ, α
- or β-asbalti〃, α- or γ-gutamiμ
, lysyl, arginyl, phenylglycyl, phenylglycyl, tyro\μ, histidiμ, tryptophy, prolyl, and the like are used.

As the protecting group for the amino group, those similar to the protecting groups for the amino group described below are used. The lower acyl μ group preferably has 2 to 4 carbon atoms, such as acetyl A/, propioni p, butyl lvl isobuty! J/L/ etc. are used. In addition, examples of lower alkyl which may have a substituent, and substituents for γμ which may have a substituent include fe2μ, forceμpamoi~, methylcapbamoyμ, forceμ Boxyl, cyano, halogen, hydroxy~
etc. are used. Substituents for phenyl which may have a substituent, phenoxy which may have a substituent, and cycloalkenyl which may have a substituent include, for example, lower alkyl having 1 to 3 carbon atoms, carbon Lower a[mu]koxy, halogen, amino of numbers 1 to 3.

Benzyloxy, hydroquine/I', acyloxy having 2 to 10 carbon atoms, aminomethy-, carbamoy-aminomethyl, 3-amino-3-oxypropoxy, etc. are used. As a substituent of a heterocyclic group which may have a substituent, for example, a heterocyclic group having a carbon number of 1 which may have a substituent,
~8 alkyl, lower alkoxy f having 1 to 3 carbon atoms, hydroxyVA/, carboxyl, oxo, monochloroacetamide, aldehyde, trifluoromethyl', amino, halogen, phenylene which may have a substituent such as the above. lv (e.g. 2,6-cyclopheniμ, etc.).

Coumarin-3-carbonyl, 4-formi/L'-1-pibewojiniμ, pyrroleaμtoimino, phonaμtoimino, thiophenealdimino, medi~.

MesS//L/amino, a protecting group for an amino group, acymu amino having 2 to 4 carbon atoms which may be substituted with halogen, and the like are used. As the protecting group for the amino group, those similar to the protecting groups for the amino group described below are used. As the substituent for the amino acid residue which may have a substituent, for example, amino, a body membrane group of an amino group, carbamoy/l/, methyl capamoy/L/, benzi μ, etc. are used. Preservation of the amino group! ! As the group, a group similar to the protecting group for the amino group described below can be used. Karuhoki V represented by R14
Examples of esters include methyl ester, ethyl ester, propyl ester and 1vlt-butyl ester.

Paranitrobenzyl ester lv*2-)limethylsilylethyl ester and the like are used.

An amino group among the substituents represented by R5 to R19.

If a carboxyl group or hydroxyl group is present, it may be protected. As the protecting group for the amino group, for example, the "protecting group for the amine 7 group" in R1 described later is used. As protective groups for carboxyl groups, all those that can be used as protective groups for β-octam and hydroxyl groups in the field of β-octam and organic chemistry can be used, such as methyl,
ethyl.

n-propyμ, isopropy/'+tert-butyl.

tert-ami~, benzyl, P-210 benzyl A/I
P-methoxybenzyl, benzhytril, phenasiμ
, phenyl, P-nitropheniμ, methoxyV methyl, ethoxymethy/L', benzyloxymethy77.7 setoxymethyl, pivaloyloxymethyμ.

β-Methylnuhoniμethyl, methylthiomethy 1vlt
Lythyl, β, β, β-trichloroethyl, β-iodoethyl/L/, 'l-'L-limethylsilylethy, TL
/,) Limethylsilyl, dimethylsilyl, acetylmethyl, P-nitrobenzoylmethyl, P-menlubenzoylmethy/L/I phthalimidomethyl, propionyloxymethyl lvl mesylmethyl, benzenesphonylmethy/
Ester groups such as L', phenylthiomethy/L/l dimethylaminoethyl, silicate groups, etc. are used. Among them, β, β, β-trichloroethyl μ, P-nitrobenzyl, tertiary butyl, 2-trimethylsilylethyl/l/,
P-methoxybenziμ is preferred. As a protecting group for a hydroxyl group, any group that can be used as a protecting group for a hydroxy S/A/ group in the field of β-octam and organic chemistry can be used, such as esters such as acetyl, chloroacetyl, V residues, etc. Esterified groups such as β, β, β-trichloroethoxycarbonyl/l/, 2-trimethylsilylethoxycarbonyl * ter
t-buty/L/, benzyl, P-nitrobendi/I/I
Ethe/L/lA groups such as trityl, methylthiomethyllv, β-methoxyethoxymethyl, trimethylsilyl"+
Silyl ether/L' residues such as je'rt-butyldimethylsilyl, aceters/L' such as 2-te[rahydropifni/%/+4-methoxy-4-tetrahydropyranyl
Residues etc. are used. In the present invention, the selection of the protecting group is not particularly limited, as is the case with the protecting groups for amino groups and phoxyl groups.

In the above Ashiμ group, specific examples of the Ashiμ group represented by 2R5-Co-[A) include, for example, 3-(2,
6-Cyclophenyl/)-5-methylisoxacy/L/-4-yl-carbony, etc. are used for μ, D-phenylalanyl, α-bendi/&-N-carbobenzoxy-γ-D-glutami 7-D-phenylglycyl/l', D-phenylglycyl V/L'-D-awoni/l/, N-carbobenzoki V-D-phenylglycyl/L/lD-awonyl-D-phenylglycyl, T-D- Glutamiμ-D-alanyl, N-carbobenzoxy&-D-1 phenyl-D-phenylglycyl.

D-Carpamoyltryptophyl A/-D-phenylglycyl 5ytv+x-02-amino-3-(N-methylcarbamoyl)propionyl)-D-phenylglycylμ, N-
Carbobenzoxy-D-phenyglycyl-D-phenyglycyl, D-alanyl-D-alanyl, 2-C2-
Amino-3-(N-methylcarpamoy/L/)propionamide]acetiμ.

D-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-methoxyphenyl)
AcetylV, D-2-C2-(4-ethyl/I/-2,3
-dioxo-1-piperazinocarboxamide)acetamidocy2-phenylacetyl,2-(2-aminothiazol-4-ifi/)-2-(4-ethyl-2,3-
dioxo-1-piperazinocarboxamide) acetyl A/
, D-2-(4-ethylv-2.3-dioxo-1-pipewodinocaboxamide)-2-chenylacetiμ, D
-2-(4-n-dobuyyv-2,3-dioxo-1-
piperazinocarboxamide)-2-phenylacetyl/u
, D-2-(4,6-die=yv-2,3-dioxo-
1-piperazinocarboxamide)-2-pheniNlsetiμ, D-2-(4-cyclohexy/L/-2,3-dioxo-1-piperazinocarboxamide)-2-chenylacetiv, D-2 -C4-n-amiA/-6(S)-
Methyl A/-2,D-3-dioxo-1-piperazinocarboxamide)-2-chenylacetyl, D-2-(4-
Ethyl-5-methy/I/-2+a-dioxo-1-piperazinocarboxamide)-2-chenylacety/L/,
D-2-(8-hydroxy-1,5-naphthyridine-7
-Caboxamide)-2-phenylacetyl, D-2-
(4-n-octyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetyl, 2-(4
-ethi'-2+ 3-dioxo-1-piperazinocarboxamide)-2-(4-chlorophenylv)acetyl, α-IJ-(4-di+/l'-2.3-dioxo-1
-piperazinylboni/l/)ri/lz/mini=#, D-
N-(4--r-chi/L'-2.

3-dioxo-1-piperazinocarbo=A/)phenylalanyl, D-2-(4-ethyl-2,3-dioxo-
1-Piperazinocarboxamide)-2-(4-hydroxypheny)L/)acetyl, 2-(4-ethyl/I/-2
,3-dioxo-1-piperazinocarboxamide)-2
-(1-cyclohexene-1-y/L/)acetate/$'
, D -2-(4-n-, t mouth 1v-2,3
-dioxo-1-piperazinocarboxamide)-2-chenylacety/9.2-(4-ethyfi/-2,3-dioxo-1-piperazinocarboxamide)-2-(2-
Methylthiazo-A/-4-i/L/)acety~,2-(
4-n-octμm2゜3-dioxo-1-piperazinocarboxamide)-2-(2-aminothiazo-A/-4
-Iμ) Acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-furyl acetyl, D-2-(4-ethyl-2,3-dioxo-
1-Piperazinocarboxamide')-2-(2-pyrroli/I/)acetyl, D-2-(4-ethyl-2゜3-dioxo-1-piperazinocarboxamide)-3-chloropropioni/ L,', D-2-C4-(2-hydroxyVethyl/l/)-2,3-dioxo-1-piperazinocarboxamide)-2-7enylacetyl, D-2-[4
-(2-chlorox f N ) 2 .

3-dioxo-1-piperazitsuka μboxamide]-2-
Phenylacetyl, D-2=C(3-)μ arylideneamino-2-oxoimidazolidine-1-ifi/) carboxamide-2-phenylacetyl, D-2-, C(
3-furfurylideneamino-2-oxoimidazolidine-1-iμ)carboxami l-2-(4-hydroxypheniμ)acetyl, D-2-CC2-oxo-3-(thiophene-2-aldoimino)imidazo Lysine-1-μ〃boxamide〃-2-phenylacetyl.

D-2-((3-Flupuriritinamino-2-oxoimidazolidin-1-I/I/)carboxamide 2-
3-methylsulfonyl
L/-2-oxoimidazolidin-1-i/L') carboxamide co-2-phenylacetiμ.

2-4 (3-furfuryritinamino-2-oxoimidazolidin-1-yl)carboxamide]-2-(2-
aminothiazo-A/-4-yl)acetyl, D-2-C
C2-oxo-3-(thiophene-2-aldoimino)
imidazolidin-1-yl]carboxamide]-2-thiediμacetyl/L/, D-2-(4-hydroxy-6-
Methylnicotinamide F)-2-(4-hydroxyphenylene/V) 7 cety~.

D-2-C5,8-dihydro-2-(4-formi/l/
-1-piperazinyl)-5-oxopyrido [2゜3-d
[pyrimidine-6-carboxamide]-2-phenylacetyfi/, n-2-(3,5-dioxo-1,2,4
-1-Ryazine-6-caboxamide)-2-(4-hydroxypheni/v)acetyl.

D-2-(Coumarin-3-carboxamide)-2-phenylacetyl, 2-(4-ethy, A/-2,3-dioxo-1-piperazinocarboxamide)-2-(2-chloro-1- cyclohexene-1-y/L/)acetyl, 2
-(4-Hydroquine-7-trifluoromethylquinoline-3-caboxamide)-2-phenylacetyl, N-
(2-(2-aminothiazo-A/-4-i1v)7(!
H/k)-D-7m nylglycyl, n-2-1: [3-
(2,6-cyclopheni1v)-5-methylisoxazole-4-y! [Carboxamide]-2-chenylacetyl μ, D-2-(carbamoyl)amino-2-chenylacetyl, N-carpamoy IL'-D-phenylglycyl μ, etc. are used. Formula R9-R10-CO-(C)
Specific examples of the acyl group represented by M-
C2-C2-aminothiazo-A/-4-yl)-2-methoxyiminoacety)-D-arani A/.

2-(2-chloroacetamidothiazo-1v-4-i/
L/)-2-methoxyiminoacetyl/L/, 2-(
2-aminothiazo-1v-4-i/L')-2-isopropoxyiminoaceti#, 2-(2-aminothiazo-A
/-4-i/I/)-2-methoxyiminoacetyl.

2-(2-aminothiazo-fi/-4-yl)-2-oxyiminoacetyl μ, 2-cheni/L'-2-methoxyiminoacetyl/L/12-furi/I/-2-methoxyiminoacetyl μ , 2-(4-hydroxypheny/I/)-
2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-cheni/L'-2-oxyiminoacety~, 2-cheniA/-2-dichloroacety!
Oxyiminoaceti μ, 2-[4-(3-amino-3-
carboxydipropoxy) Fe2μ]-2-oxiViminoacetyv, 2-(5-chloro-2-aminothiazo-/'v-4-i/l')-2-methoxyiminoacetiμ, 2-(2 -aminothiazo-/i/-4-ifi/)
-2-(1-carboxymethofrVimino)acetiμ,
2-(2-aminotinazolv-4-yl)-2-(+
-carboxyethoxyimino)acetyl/L/+ 2-
<2-aminothiazo-A/-4-iA/)-2-(1
-Carphoky-1-methylethoxyimino)acetyl, 2-(2-aminothiazo-1L/-4-fi/)-
2-(1-methoxycarbonyA/-1-methylethoxyimino)acetylv, 2-(2-7fi/flSoIV-4-i/L/)-2-(1-force7kyj(xy-1 -cyclopropy!methoxyimino)acetyl/I/,
2-(2-aminothiazol-4-i/L')-2-(
1-Carboxy-1-cyclothymomethoxyimino)acetyl, 2-(2-aminothiazol-4-i/I/)
-2-(1-carpamoy A/-1-methyμ ethoxyimino) acetyμ and the like are used. Specific examples of the acyl group represented by the formula include 9, for example, α-sulfophene-acetiμ, α-hydroxyphenylacetiμ, α
-Formyloxyphenylaceti! .

α-carboxyphenylacetyl μ, 2-promo-2-phenylacetyl μ, 2-azido-2-phenylacetyl μ, etc. are used. Formula R18-Rl9-CH-CO-CE
Specific examples of the acyl group represented by ) are, for example, nanoacety~, pheniμacetyμ, phenoxyacety/l/, )rif polomethyμthioacetyμ, cyanomethyμthioacetyA/, lH-tetrazoyl-1-acenal. 2-cheniμ acetyl/L'l'2-(2-aminothiazo-fi/-4-yl)acetyl #, 2-(2-
Chloroacetamidothiazo-μm4-I/I/)acety/I/, 4-pyridipthioacetyμ, 3,5-dichloro-1,4-dihydro-4-oxopyridine-1-acetyμ, β-carboxyvinyl Thioacety~, 2-(2-N
-carbobenzoxyaminomethylphenyl)acetyl/L
/, 2-(2-ureidomethylphenyl)acetyl, etc. are used.

As protecting groups for the protected amino groups represented by R, R and R, those used for this purpose in the fields of β-octam and peptide synthesis are conveniently employed. For example, phthaloyl, P-nitrobency/l/, P-tar
Aromatic acyl groups such as t-butylpency/'*P tart-butylbenzenesphonyl, benzenesulfonyl, toluenesulfonyl, etc., such as homi/I/, acetyl/l/, glopionyl, monochloroacetyl, dichloroacetyl, Aliphatic acyl groups such as trichloroacetyl, methanesyl, ethanesulfonyl, trifluoroacetyl/I/, phenylpcetyl, maloyl, nuccinyl, such as benzyloxycarbonyl, P-nitrobenzyloxyVcarboni/l/, P Esterified groups such as -methoxybenzyloxycarbonyl, 2-trimethyl Vsuethoxycarbonyl/I/, methoxycarbonyl groups, as well as, for example, t)! J Chiμ
, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, di- or trialkylsilyl, t-butyldimethylsilylμ.

t-butyldiphenylsili/I/, benzyl/IP-
Protecting groups for amino groups other than acyl groups such as nitrobenzyl are used. In the present invention, the selection of the protecting group is not particularly limited as in the case of the carboxy protecting group, but
Especially monochloroacetyl, trityl, benzyloxycarboni~, P-methoxybenzyloxycarboniμ, 2
-trimethylsilylethoxycarbonyl A/, P-nitrobenzyloxycarbonyl Y is a halogen or the formula -〇〇〇R3, -SCOIi
3 or yos-R3 (P? is a hydrocarbon group, n is 1
or co)n2). Here, the halogens are chlorine and fluorine. Iodine and bromine are used.

Examples of the hydrocarbon group include lower alkyl which may have a substituent such as those mentioned in R5-B19, a # group such as Aμkenyl/I/l cycloaμkenyl, or a # group such as VchloropropyA/, cyclobuty/ 1/. Cyclopentyl, cyclohexyl, cycloheptyl μ. Cycloalkyl groups with 3 to 10 base primes such as adamantyl, e.g.
Trill, Kisiri μ, Bihueni/I/, Nafuchi μ, Ant
Lil. Arary μ groups such as phenanthryl, aralky μ groups such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, etc. are used. These cycloalkyl and ary-1vl aralkyl groups may have a substituent, and such substituents include nine, for example, R5.
~The same substituents as the phenyl or phenoxy substituents mentioned for B19 are used. Particularly, Y is, for example, lower acyloxy (eg, evaacetoxy, propionyloxy, etc.), lower alkylsulfony/L' (eg, methylsulfony/L/).

Good results can be obtained when showing ethylsulfonyl, etc.). X represents hydrogen or a methoxy group. W represents hydrogen or a sulfo group.

In the present invention, the cyano compound is obtained by reacting the compound CII) with the cyano compound and removing the protecting group as necessary.

Compound CIO) can be used as a raw material for this reaction as it is, or in the form of salts with various acids or bases, esters, silyl derivatives (in the case of W=)I), etc. In addition, since the compound (IF') has substituents at the 3- and 4-positions, cis-trans isomers exist, and since the carbons at the 3- and 4-positions are asymmetric carbons, theoretically at least the total There are four stereoisomers, and these stereoisomers can be used alone or in mixtures. The same applies to the case where the group represented by R2 has an asymmetric carbon, and the resulting stereoisomer can be used either singly or as a mixture.

As the salt of compound CII), when a sulfo group is present at the 1-position and a carboxyl group is present at R2, a non-toxic cation such as sodium or potassium is used.

Basic amino acids such as arginine, ornithine, lysine, and histidine. Salts with polyhydroxyfurkylamines such as N-methylglutamine, jetanolamine, triethanolamine, and trishydroxymethylaminomethane are used. Further, when R2 contains a basic group, for example, acetic acid. Salts with organic acids such as tartaric acid and methanesulfonic acid, such as hydrochloric acid, hydrobromic acid, and sulfuric acid.
Salts with inorganic acids such as phosphoric acid, for example salts with acidic amino acids such as arginine, aspartic acid, and glutamic acid are used. Furthermore, when R2 contains a carboxyl group, it can be converted into an ester derivative and used,
In that case, the ester groups are methoxymethyl and ethoxymethyl.

Alkoxymethy/I/. such as impropoxymethyl, α-methoxyethyl, α-ethoxyethyl μ, etc. α-alkoxy-α-substituted methyl groups such as α-alkoxyethyl, alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl lvl isopropylthiomethymu, and oxymethyl groups such as pivaloyloxymethyl and α-acetoxybutyl. Alternatively, an α-alkoxycarbonate-α-substituted methyl group such as α-acyluoquine-α-substituted methyl group 1-ethoxycarbonyloxymethy/I/, α-ethoxyV carbonyloxyethyl, etc. can be used. Compound CII) which has been converted into Vviv with a V-lylating agent is also used as a raw material.

For example, as a silicidating agent, the formula is -7・R3・Si
-Hal [wherein Pl, R2, R3 are each, for example, lower alkyl IVc having 1 to 4 carbon atoms, such as methyl, ethyl/L/In-propyl, 1-propyl + n-
butyl, etc.), ary-/1/ (e.g. phenylv, tolyl, etc.), Hal represents a halogen, preferably chloro, bromo, and pi, p2
, p3, one or two of which are halogens, preferably chromium μ, bromine, pl, and one of p2 and p3 may be a hydrogen atom. Furthermore, for example, hexaalky(C
1,)y clotricifuzan, octaalkyl (C1-4
) Cyclotetofushiwozan, Tria p key VCC-4)
Silyl acetamide.

Bis-trialkyl/l/(Cney4)silylacetamide and the like are also used as silylating agents. Preferred silylating agents include, for example, formulas [wherein yl and Y2 are each lower alkyl].

phenyl, benzylv or lower alkoxy group, Y3
represents a t-butyl or isopropyl group, and y4 represents a reactive group that leaves the silylating agent. Examples of lower alkyl groups represented by yl and y2 in the silylating agent represented by the above general formula include methyl/I/l chloromethyl, ethyl/L'+n-pbifi71 isopropyl, n-buty/L' +tert-butyp, etc., and as the lower alkoxy group, for example, methoxy, ethoxy, n-propoxy, isopropoxy+n-gutoxy, t-butoxy, etc. are used. In addition, as the reactive group Y4 that is eliminated from the silylating agent, in addition to halogen (for example, chloro/I/, bromine, etc.), examples of the reactive group Y4 include N-(trialkylsili/l')) rif~oacetimidoi μoxy group. +N-() Real Kill Siri/
I/) Acetimidoi μOx V group l formi-amino, acetylamino, propionylamino, butyrylamino,
Acylamino group such as trifluoroacetylamino; (tri-t-butyldimethylsilyl)amino, isoprobyldimethy~silylamimchloromethyldimethylsilylv)
(trialkylsili/I/) amino group such as amino; amino; alkylamino group such as methylamino, ethylamino, propylamino iN, N-dimethyp-amino, N-chloromethyA/-N-methylamino, N, Heterocyclic groups such as N-diethylamino, N,N-dipropylamino, N-methyl-yl and the like are used. The alkyl group in the reactive group represented by Y'' has 1 to 4 carbon atoms.
Preferably methyl, ethyl/l/, n-propyμ
, isopropy~, n-butyl.

T-glythyl and the like are used.

Specific examples of this stronger Syriac compound include N,
O-bis(t-dimethylsilylv) trifluoroacetamide, N, O-bis(isopropyldimethylsiliμ)acetamide, bis(dimethylisopropylsilyl/I/)acetamide, isoprohyldimethylsilylacetamide, bis( Dimethyl tert-butylsili IL/)
Acetamide, N-methy/k-N-t-butyldimethysilyl-acetamide, H-methyA/-N-isopropyldimethylsilyltrifluoroacetamide, N-t
-Butyldimethylsilyldiethylamine, 1,3-bis(chloromethyl)-1,1,3,3-tetra-t-butyldimethyldisilazane, N-isopropyldimethylsilylimidazo-Iv, t-butyldiphenylchlorosilane , isopropyldimethylchlorosilane, isopropylmethyldichlorosiphon + tart-butyldimethylchlorosilane, isopropyldimethylchlorosilane, t-butyldiethylchlorosilane, etc.
When rt-butyldimethylchlorosilane, isopropyldimethylchlorothalane, etc. are used, the silyl derivative can be stably isolated. The temperature of the silyl compound is between θ and 50 °C, preferably up to 38 °C, usually at room temperature (about 20 °C
), and the reaction time is from several minutes (about 10 minutes) to 24 hours. The reaction can be carried out using, for example, ethyl acetate, dioxane, tetrahydrofuran, IN-dimethylacetamide, N,N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, etc., or a mixed solvent thereof, or any other solvent suitable for this reaction. It is convenient to carry out the process in a non-participating solvent. This reaction, for example, involves sodium hydroxide, potassium hydroxide, and sodium hydrogen carbonate.

Inorganic bases such as sodium carbonate, potassium carbonate, or trialkylamines such as triethylamine, triethylamine, tribenzylamine, N-methylmorpholine, N-methylpiperidine, N,N-dialkylaniline, N,N - Dialkylbenzylamine, pyridine, picoline, organic tertiary amine of Iv pyridine, or 1,5-diazabiscif P C
4+3.

0] Non-5-ene, 1,4-diazabicycloC2,2
+2. ) octane, 1,8-diazabicycloC5,4,
4) It can be carried out in the presence of an organic base such as undecene-7, and a liquid base can be used also as a solvent. The silyl derivative of compound CI) thus obtained is used as a raw material for the reaction with a cyano compound either as a reaction mixture or after isolation and purification by known means as described below.

In the 1-silyl derivative of compound CI[, 11 obtained in this manner, when R2 is a protected amino group, the protecting group is removed and the 1-silyl derivative is further subjected to an acylation reaction to form the desired compound. A 1-silyl derivative of [■] can also be produced. This acyl conversion reaction at the 3-position proceeds with good yield and is easy to operate, making it extremely useful for the synthesis of various 2-oxoazetidine derivatives substituted with desired acyl groups. The reaction with the cyano compound can also be carried out continuously.

Further, as the cyano compound, for example, a compound represented by the formula [wherein Z represents an alkali metal or an alkaline earth metal] can be used.

Specifically, for example, potassium V-anide, sodium cyanide, calcium cyanide, etc. can be used.

In this reaction, approximately 1 to 37 µm of the V ano compound is reacted, preferably 1 to 1.1 mol, per 17 µm of the compound [■]. Usually carried out in a solvent. The solvent used is water or ethers such as dioxane, detofhydrofuran, and diethyl ether.

Esters such as ethyl acetate and ethyl formate, dichloromethane, halogenated hydrogens such as chloroform and dichloromethane, hydrogen ash such as benzene, toluene and n-hexane, amides such as dimethylformamide and dimethylacetamide Alcohols such as methanol, ethanol, impropano-p, t-getano-p, etc., and common organic solvents such as dimethyl sulfoxide, sulfofane, and hexamethylphosphoramide are used alone or in combination. Among them, for example, water, dioxane, tetrahydrofuran, dichloromethane, and dichloroμmethane.

Chloroform, benzene, dimethylformamide.

Dimethylacetamide, methanol, impropano~
, dimethyl sulfoxide and the like are preferred. Also,
When this reaction is carried out in the presence of a phase transfer catalyst, the compound [
In [I], the production of a compound in which a CN group is introduced in the cis coordination with R1 is promoted, and more favorable results can be obtained. The phase transfer catalyst referred to here is a catalyst that promotes a reaction by solubilizing one of the reaction substrates, which exist separately in two liquid-liquid phases, into the other liquid phase in the form of an ion pair. means substance. Such phase transfer catalysts include, for example, an alkyl μ group on a nitrogen atom or a phosphorus atom.

A cation (ammonium ion or phosphonium ion) and an acid group (anion, such as C17+ Br-+ I-, F't010″4° BF''
4. BH;, aso;, OH-, u2po;, etc.), which can achieve the purpose of this reaction.

Specifically, for example, tetramethylammonium chloride,
Tetraethylammonium chloride, tetra-n-butylammonium chloride, jl-n-octylmethylammonium chloride, trimethylstearylammonium chloride,
Tetra-alkyl halides such as tetra-n-amylammonium bromide, n-pequin μ-trimethylammonium bromide/l/(i prime number total 4 to 50) ammonium, ary-μ-trialkyl halides such as phenyltrimethylammonium bromide lv (Total number of elements 9 to 50) Ammonium, benzychloride/L/dimethyldecylammonium.

Alkyl groups, aryl groups, aryl groups such as halogenated afurkyl triple K/L/(total of prime numbers 13 to 50) ammonium, such as benzyltriethylammonium chloride and seciμbenzyldimethylammonium chloride. Those consisting of an ammonium ion and a halogen ion substituted with the same or different four groups selected from the rμ group, such as tetraalkyl hydrogen sulfate such as tetra-n-butylammonium hydrogen sulfate and tetramethylammonium hydrogen sulfate. Synthesis ti4-50) Ammonium ion substituted with four same or different groups selected from alkyl groups such as ammonium, aryl groups, araμkyl groups and H8
consisting of 0-(hydrogen sulfate ion), tetra-hydroxide
Tetraalkyl hydroxides such as n-glylammonium (
Total number of return primes 16 to 50) Ammonium ions substituted with four same or different groups selected from alkyl groups, aryl groups, aralkyl groups such as ammonium ions and 0H-
(hydroxyl ion), such as tetra-bromide
Tetraalkyl halide (total number lft 4-50) phosphonium such as n-butylphosphonium, aralkyl triary halide such as benzyltriphenylphosphonium chloride /L/(total number 9-50) phosphonium bromide Buty-μ triphenylphosphonium and other alkyl-triary-μ (total number of return elements 19-5
0) Those consisting of a phosphonium ion and a halogen ion substituted with four identical or different groups selected from alkyl groups such as phosphonium, aryl groups, and aralkyl groups are used. Among others, for example trichloride
-Octylmethylammonium, W acid hydrogen tetra-n-
Glylammonium, tetra-n-7-myl ammonium bromide, benzyltriethylammonium chloride, tetra-n-1 tylphosphonium bromide, etc. are used. These phase transfer catalysts are about 0.0% per mole of compound [■].
01 to 17 μm, preferably 0.05 to 0.2 molar reaction. When a phase transfer catalyst is used, the solvent is preferably a mixture of water and an organic solvent such as those mentioned above, and the mixing ratio is 0.5 to 5 parts, preferably 0.5 to 1 part, of an organic solvent to 1 part of water. things are used. The reaction temperature is usually in the range of 0 to 2 liters, but the conditions are not particularly limited and heating and cooling may be performed as necessary.The reaction time also depends on the solvent used. , is determined appropriately depending on the temperature, etc., but usually ends in a short time.

After completion of the reaction, the produced compound CI) can be obtained in any purity by means of separation and purification known per se, such as solvent extraction, recrystallization, and chromatography, but it can be used as a raw material for the next reaction as a reaction mixture. May be used.

When the compound CI) thus obtained has a protecting group, the protecting group can be removed if necessary. Methods for removing protective groups include methods using acids, depending on the type of the protective group.

base method, reduction method, thiourea or N-
This can be carried out by appropriately selecting a commonly used method such as a method using thorium methyldithiocarbamate. In the case of a method using an acid, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, etc., depending on the type of protecting group and other conditions. In addition to organic acids such as P-)μenesulfonic acid, acidic ion exchange resins and the like are used. In the case of a method using a base, the base may be an inorganic base such as a hydroxide or carbonate of an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium or magnesium, although it depends on the type of protecting group and other conditions. In addition to organic bases such as , metal alkoxide-calcined organic amines, and quaternary ammonium salts, basic ion exchange resins and the like are used.

When a solvent is used in the above acid or base method, a hydrophilic organic solvent, water or a mixed solvent is often used. When using a reduction method, it varies depending on the type of protecting group and other conditions, but for example, soot,
Methods using metals such as zinc or metal compounds such as chromium dichloride and chromium acetate and acids such as organic and inorganic acids such as acetic acid, propionic acid and hydrochloric acid, methods of reduction in the presence of a metal catalyst for catalytic reduction, etc. Examples of catalysts used in the catalytic reduction method include platinum catalysts such as platinum wire, platinum sponge, platinum black, platinum oxide, and colloidal platinum;
Palladium sponge, palladium black.

Baodium oxide, Baodium barium sulfate, Palladium barium suboxide, Palladium selective element, Palladium silicage/
L/L, colloidal palladium, etc., reduced nickel/L/l nickel oxide/I/l Raney nickel, urushihara nickel, etc. are used. In the case of a reduction method using a metal and an acid, a metal compound such as iron or chromium, an inorganic acid such as hydrochloric acid, and an organic acid such as formic acid, acetic acid, or propionic acid are used. Reduction methods are usually carried out in a solvent; for example, in catalytic reduction methods, methanol, ethanol, etc.
/L/l Alcohols such as propyl alcohol, isopropyl alcohol, ethyl acetate, etc. are often used. Furthermore, in the method using a metal and an acid, water, acetone, etc. are often used, but when the acid is liquid, the acid itself can also be used as a solvent. The reaction temperature is usually cooled or heated. The obtained compound CI) can be isolated and purified by known means as described above, but it can also be used as a raw material for the next reaction as a reaction mixture.

In addition, in the obtained compound CI), when R2 is an amino group, a carboxylic acid represented by the formula % formula %) Alternatively, it can be converted into a V/I/ as appropriate by reacting with a reactive derivative thereof.

The compound CI) in which R2 is an amino group can be used in the free form or as a compound as described in the compound CM].

It may also be used in the form of an ester or silyl derivative.

Examples of reactive derivatives of organic acids (CIL) include acid halides, acid anhydrides, active amides, and active esters.Specifically, these reactive derivatives of organic acids are as follows. It is.

1) Acid anhydride: Examples of acid anhydrides include mixed acid anhydrides such as hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, etc.).

Heptanoalkylic acid mixed acid anhydride, aliphatic acid (e.g., acetic acid, pivalic acid, valeric acid, impentanoic acid, trichloroacetic acid, etc.) mixed acid anhydride, aromatic carboxylic acid (e.g., benzoic acid, etc.) mixed acid Anhydrous.

A symmetrical acid anhydride or the like is used.

2) Active amide: Examples of active amide include imidazo-y' +
4-substituted imidazo-/L/, dimethylpyrazole.

Amides with benzotriazole and the like are used.

3) Active ester: Here, the active ester includes, for example, methyl ester,
Ethyl ester, methoxymethyl ester, propargyl ester/l/, 4-diprophenyl ester, 2.4
-dinitrophenyl ester) vl In addition to esters such as trichlorophenyl ester, pentachlorophenyl ester, and menulfenyl ester, 1-hydroxy-IH-
2-Pyridone.

N-hydroxysuccinimide, N-hydroxy-5-
Esters of norbornene-2,3-dicarboximide, N-hydroxyphthalimide, etc. and acids such as the above-mentioned carboxylic acids are used.

Such reactive derivatives of organic acids are selected as appropriate depending on the type of acid used. Furthermore, when using a free acid as an acylizing agent, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of condensing agents include H, N'
-dicyclohexylcarbodiimide, N-cyclohexy/L'N'-morpholinoethylcarbodiimide, N-cyclohexyl-1f'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc. used.

The acylation reaction is usually carried out in a solvent.

As the solvent, water, acetone, dioxane, acetonitrile/L/l methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, or other general organic solvents that do not participate in the reaction are used. The solvent can also be used in combination with water.

In addition, the acylation reaction can be carried out using, for example, inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, trialkylamines such as trimethylamine, triethylamine, triethylamine, N-methypmophorine, N-methylpiperidine, etc. , N-sialkylaniline, N.

N-sialkylbenzylamine, pyridine, picoline,
Lutidine, organic tertiary amine, 1,5-diazabicycloC
4,3,0) non-5-ene, 1°4-diazabicycloC2,2,2) octane.

It can be carried out in the presence of a base such as 8-diazabicyclo[5,4,4)undecene-7, and the base or the liquid one of the above-mentioned condensing agents can be used also as a solvent. . Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature.

In addition, in the acylation reaction, compound CI) and
Stereoisomers can be used either singly or in mixtures, provided that they contain not % of the stereoisomers in the compounding agent CIV). Furthermore, if a mixture of these isomers is produced in this reaction, each can be isolated by conventional methods such as column chromatography and recrystallization, if necessary. When a protective group is added to the thus obtained compound (1'l 4NH3), it can be removed in the same manner as described above, if necessary. Furthermore, in the compound CI) obtained by the above method,
If W represents hydrogen, it is also possible to carry out sulfonation.

Sulfonation in this reaction refers to 1 of compound CI) (W=H).
This refers to the introduction of a sulfo group into the compound CI) (W
=H) with, for example, sulfuric anhydride or a reactive derivative of sulfuric anhydride. Compound〔
Engineering) (W=H) remains free or forms a compound (I
They are used in the form of salts, esters, and silyl derivatives as mentioned in connection with I), and can also be subjected to the reaction in the form of stereoisomers that may theoretically exist, either alone or as a mixture.

Examples of reactive derivatives of sulfuric anhydride include sulfuric anhydride-
Addition of base complexes (e.g. sulfuric anhydride-pyridine, sulfuric anhydride-trimethylamine, sulfuric anhydride-picoline, sulfuric anhydride-lutidine, sulfuric anhydride-N,N-dimethylformamide, etc.), sulfuric anhydride-dioxane, sulfuric anhydride-chlorosulfonic acid, etc. The body is used.

In the above sulfonation reaction, about 1 to 10 sulfuric anhydride or its reactive derivative is added to 1 mole of compound (I) (W-H).
mol to about 5 mol, preferably about 1 to 5 mol. The reaction temperature is
The temperature is about -78 to about 80°C, preferably about -20 to about 60°C. In some cases, a solvent may be used in the above reaction,
Examples of the solvent include water, ethers such as dioxane, tetrahydrofuran, and diethyl ether, and ethyl acetate.

Esters such as ethyl formate, halogenated hydrocarbons such as chloroform and dichloromethane, and recycled hydrogen such as benzene, toluene and n-hexane.

Common organic solvents such as amides such as N,N-dimethylformamide and N,N-dimethylacetamide can be used alone or in combination. Raw material CI used) (W=H
), the sulfonating agent, the reaction temperature, and the type of solvent, but the reaction usually completes in several tens of minutes to several tens of hours, but it may sometimes take several tens of days. After completion of the reaction, the reaction mixture is subjected to purification and separation means known per se such as solvent extraction, recrystallization, and chromatography to obtain compound CII).
(W=SO3H) can be obtained in any purity. Furthermore, if a protecting group is present, it can also be removed by the method described above.

When the compound CI) obtained in this way is in free form, it may be converted into a salt or ester as described for the compound CII) by a conventional method; conversely, when it is obtained in the form of a salt or an ester, , may be converted into a free form by conventional methods.

The 4-v ano-2-azetidinone derivative [technique] obtained in this way is a novel compound, and has various 4-substituted
In addition to its wide range of uses as an advantageous synthetic intermediate for 2-azetidinone derivatives, those with W=5o3H have antibacterial and β-lactamase inhibitory effects.

For example, the compound CM,l is produced by subjecting the compound CI')l to a water utilization reaction and removing the protecting group as necessary. In this reaction, the cyano group of compound [■] is converted to a carbamoyl group.

Compound CI) used as a raw material may be in free form or may be converted into a salt, ester or silyl derivative as mentioned for compound CII). Also, compound CI)
has substituents at the 3- and 4-positions, so cis-trans isomers exist, and the carbons at the 3- and 4-positions are asymmetric elements: theoretically, there are at least four types of stereoisomers. Although isomers exist, these stereoisomers can be used alone or in mixtures. The same applies to cases where the group represented by Pl has an asymmetric structure, and the resulting stereoisomers can be used either singly or as a mixture.

This water utilization reaction may be carried out by any method as long as it converts the cyano group at the 4-position of compound CI) into a carbamoyi μ group, such as a method in which an acid or a base is reacted on the compound, , ) and hydrogen peroxide in the presence of a base. Such bases include, for example, hydroxides of alkali metals such as lithium, potassium, and sodium, or alkaline earth metals such as psium and magnesium (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, hydroxide, etc.). inorganic bases such as carunium oxide, magnesium hydroxide, etc.) or carbonates (e.g., sodium selectate, potassium sulfate, calcium carbonate, etc.), metal alkoxides (e.g., sodium methite, sodium ethift, etc.), and organic amines. (e.g., triethylamine, N-dimethylaniline, diisopropylamine, etc.), quaternary ammonium salts (e.g., organic bases such as tetra-n-ammonium hydroxide, basic ion exchange resins, etc. are used. Among them, Preferred bases are often used, for example, alkali metal hydroxides (such as sodium hydroxide).As acids, for example, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, ferric chloride, zinc chloride, etc. , inorganic acids or their salts such as manganese dioxide, boron trifluoride, bafdium chloride, titanium tetrachloride, formic acid, acetic acid, organic acids such as 1) -) / l / en sulfonic acid, trifluoroacetic acid, Acidic ion exchange resin etc. are used. Particularly preferred are acids such as hydrochloric acid, sulfuric acid, manganese dioxide, palladium chloride, and titanium tetrachloride. The amount of such base or acid used is usually 0.1 to 131 moles of the compound [131 moles].
The amount is 4.0 mol, preferably 0.1 to 1.0 mol. In addition, when hydrogen peroxide is used, 0.05-4. Qmo/Lz1 preferably 0.
05-1.0 mo/l' is used. The amount of hydrogen peroxide used is usually 1.0 to 10 mol, preferably 1.0 to 4 mol, per 1 mol of compound CI). This reaction is usually carried out in a solvent, such as water, ether (for example, tetrahydrofone, dioxane, etc.).
, acid amides (e.g. H,M-dimethylformamide,
N, M-dimethymu acetamide, etc.), hydrocarbons (e.g. benzene, etc.), ketones (e.g. acetone, etc.), alcohols/L/(e.g. methanol/L/l ethanol, propano-p, getanol, etc.), halogens Hydrocarbons (e.g. chloroform, dichloromethane, etc.)
, fatty acids (e.g. formic acid, acetic acid, etc.), esters (e.g. ethyl acetate, etc.), dimethyl sulfoxide, sulfolane.

Hexamethylphosphoramide or a mixture thereof is used, among which water, isopropano-/L/,
Tetrahydrofuran, dichloromethane.

Dimethyl sulfoxide etc. are often used. Further, when a mixture of water and an organic solvent is used as a solvent, the reaction can also be carried out in the presence of a phase transfer catalyst. As the phase transfer catalyst, the same one as used in the reaction of the compound CID and the cyano compound described above is used. These phase transfer catalysts are used in the reaction in an amount of about 0.1 to 27 μm, preferably 0.5 to 1 mol, per 1 mol of compound CI). The reaction temperature is usually in the range of 0 to 80'C, but is not particularly limited to these conditions, and heating and cooling may be carried out as necessary. The reaction time is usually completed in a short time.

After the reaction is complete, the reaction mixture is extracted with a solvent, for example.

By subjecting it to purification and separation means known per se, such as recrystallization and chromatography, the compound [■] can be made to any purity, but the reaction mixture can also be used as a raw material for the next reaction. In addition, if a mixture of isomers is produced in this reaction, they may be isolated by known means as necessary, and if a protecting group exists in the substituent of compound CI[), they may be isolated as necessary. It can also be removed in the same manner as above.

When W in the compound Cm) obtained in this way is hydrogen, it is necessary to sulfonate it in the same manner as the sulfonation of the compound [Cm) (W=H), and the compound [ 111) is obvious.

When the compound CI[I] thus obtained is in free form,
The above salts and esters may be substituted by conventional methods.
If the compound Cm) is obtained as a salt or ester, it may be converted into the free form by conventional methods.

Among the obtained compounds Cm), the compound with w = 803 H is a new compound and has excellent antibacterial activity and β-lactamase inhibitory activity (German application P314802).
1, 7).

Furthermore, when compound CI) is reacted with hydrogen sulfide, a compound having -C8NH2 in place of the cyano group at the 4-position of compound [C] is produced. In this reaction, it is preferable to react about 1.0 to 3 moles of hydrogen sulfide with respect to 1 mole of compound CI) or its salt or ester Vyl derivative. Advantageously, the reaction proceeds at room temperature or below. The reaction can be carried out using, for example, chloroform, dichloromethane, benzene, ethyl acetate, tetrahydrofuran, dioxane, H,
Preferably, the reaction is carried out in a solvent such as N-dimethylformamide, M,N-dimethylacetamide, dimethylsulfoxide, acetic acid, or water. The reaction usually completes in a short time.

In addition, when the compound [technique] is reacted with a μcop group such as methanol or ethanol, the compound CI) 4
A compound having an a-koxycaponymo group instead of a cyano group at the position is produced. The reaction is carried out by reacting the compound [technique] with an equimolar or more amount of alcohol-μ, but the alcohol-μ itself is often used as a solvent. When a solvent is used, it is preferably carried out in a solvent such as chloroform, dichloromethane, benzene, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, or the like. The reaction temperature is usually in the range of 0 to 80°C, but the conditions are not particularly limited, and heating and cooling may be performed as necessary. The reaction time and other conditions are appropriately determined depending on the solvent used, temperature, etc., but for example, inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid
The reaction time can be shortened by coexisting an organic acid such as P-t/reninsulfonic acid, for example, a Lewis acid such as aluminum chloride, zinc chloride, or boron trifluoride.

Note that the raw material compound (It) of the present invention can be produced, for example, by the method shown below.

The raw material compound CI[)(WH) of the present invention is such that Y is
In the case of an oxy group, for example, tetrahedrol letters (
Tetrahedron Letters) +
405'9 (1978), Wariwa JP-A-54-765
70, or a method analogous thereto, or, for example, by the method described in Annalen der Hemie (A
19
It can be synthesized by the following routes 1) and 2) according to the method described in 74+ 539.

1) [V] 2) [■] [■] In each of the above steps, R2, Y, and X have the same meanings as above,
B20 represents a protected amino group, and B21 represents an atomized amino group.

Further, the starting compound [■] in which W=SO3H can be synthesized by sulfonating the compound [II] in which W=H obtained as described above. This sulfonation can be carried out in the same manner as the sulfonation of the compound (W=H).

Next, the present invention will be specifically explained with reference to Examples and Reference Examples. Note that the IME spectrum was measured using Parian HA100 (100 MHz), and the δ value is expressed in ppm using tetramethylsilane as a reference. Also, 8 is singlet + br, s is wide singlet, d is doublet)
, dd is Doug μ doublet.

t is a triplet, q is a cultite, m is a μ triplet, ABqFiAB type force ρt, J is a coupling constant,'
I"HF is tetrahydrofuran, DM1i' is dimethylformamide, DMSO is dimethylsulfoxide +
br or broad means broad, and arom means aromatic.

In the following Reference Examples and Examples, unless otherwise specified, V Likage μ-cam chromatography is Art.

9185.230-400 Metschyu, Kiesel Ge IW
(Kiesel Gel) 60 (manufactured by Muri Co., Ltd.) was used to perform TLC analysis of the crude product before chromatographic purification, and a fraction showing the same Rf value as the main spot newly appearing on the TLC plate was collected. collect.

TLC is Art unless otherwise specified.

564-2, HPTLC Kiesel Ge/L' (K
ieselGel)"F254 (manufactured by Merck & Co., Ltd.) plate and the same developing solvent as the solvent used in chromatography, and detected with a UV detector.
D-II (100 to 200 mV) column chromatography uses water to 20% ethanol water as a developing solvent, and absorbs at 254 nm (LKB UV technology C0R).
D 2 , (made in Sweden) used) are collected respectively. The collected fractions are freeze-dried to produce purified products.

Reference Example 1 of the best form for carrying out the invention (38,48)-4-cyano-3-CD-2-(4-ethylv-2.3-dioxo-1-pibefudinecarboxamide)-2 -(thiophene-2-y/l/)acetamido-2-azetidinone 0.488f was dissolved in dimethylformamide 2d, and dimethylformamide 3.5 ml t-70 containing 0.536F of sulfuric anhydride-dimethylformamide complex was added. The mixture was added at 0.degree. C. and reacted at OC for 2 days. After adding 0.5 ml of pyridine to the reaction solution, it was concentrated under reduced pressure. Water was added to the residue to remove insoluble matter, and the furnace solution was passed through a sodium-type comb made of Dowex 50 W resin (manufactured by Dow Chemical Company), and then treated with Amberlite xhD-TI resin (BNc manufactured by Rohm & Haas Company). When purified by column, (38,4B)-4-cyano-
3-CD-2-C4-xttv-2,3-dioxo-1
-piperazinecarboxamide)-2-(thiophene-2
0.35Of sodium acetamido-2-azetidinone-1-sulfonate was obtained.

IRvKBrcm-': 1780. 1710.
1675゜ax +510.1280, 1260.10105ON (D
MSO-d6. ppm): 1.10 (t, J=5H2
゜CH3), 3.41 (CL r J -5Hz
l-CH2-), a, 60(m, -CHa)
, 3.93 (m, -an2-), 4.90 (d+
J-4Hz+04-H), 5.30(ddlJ-4
゜8Hz, C3-H), 5.83 (d, J=4
Hz, -CL).

6.90-7.60 (m, aromH), 9.76 (
d, J=4Hz, MH) 19.83(a, J=8
H2, NH) Reference Example 2 1) (38,48)-3-C2-(2-Cryloacetamidothiazole--4-ip)-2-methoxyimino]acetamido-4-cyano-2-azetidinone 0. 220
f was dissolved in DMt'2d, and sulfuric anhydride-DMli was added to this.
'nMFl containing complex 0.2751, 8m?
The m solution was added at -TO°C and reacted at 0°C for 3 days. When 0.5 ml of pyridine was added to the reaction solution and treated in the same manner as in Reference Example 1, +(38,48)-3-C2-(2-chloroacetamidothiazo-μm4-iA/)-2-methoxyimino ] 0.170 f of sodium acetamido-4-cyano-2-azetidinone-1-sulfonate was obtained.

IRJ/KBrcIr1:17B0. 1670.15
40+aX 1260.1055 NMI1055N, external standard, ppm)' 4.04
(s + ocu3), 4.44(s, -Cn2-
), 5.26 (a,, T=5Hz + C-H)
, 5.46 (d, J=5H2lC3-H), 7.
50 (a, 8YH) 2) Dissolve the chloroacetamide derivative 0, 1501/ obtained in 1) above in water 6IId,
Sodium monomethyldithiocarbamate 0.05 (l
was added under water cooling, and stirred at room temperature (approximately 25°C) for 3 hours. When the reaction solution was purified using an XAD-I column, (38,
48) Sodium -3-C2-(2-7mi/thiazo-1v-4-ylcy-2-methoxyimino)acetamido-4-cyano-2-azetidinone-1-sulfonate 0.0
I hope I can get 67f.

IRvKBrax-': 17B0, 1665, 161
0゜m&X 1520.1260.105O NM105ON, external standard + ppm): 4.00
(s + Reference Example 3 1) (38,4B)-3-[2-(2-chloroacetamidothiazol-4-y1v)-2-methoxyimino]
Acetamide-4-￥ano-2-azetidinone 0.48
2f was dissolved in 2 ml of DMF, and DMF containing 0.597f of sulfuric anhydride-DMF complex was added.
3.9 ml of the solution was added at -70°C and reacted for 2 days under OC. When 0.5 ml of pyridine was added to the reaction solution and treated in the same manner as in Reference Example 1, (38,4'B)-3-C2
-(2-chloroacetamidothiazo-μm4-i1v)
-2-methoxyimino]acetamido-4-cyano-2
-Sodium azetidinone-1-sulfonate 0.39 (
l was obtained.

IRvKBrW': 17B5.16HT, 1550°ax 1260, 1055 NM1055N, external standard, ppm): 4,06
(s +0CH3), 4.44 (s, -0M2-)
, 5.14 (d.

J=2Hz, C-H), 5.40(d, J=2Hz.

. 3-H), 7.43(s, 8YH)2) 1) above
The chloroacetamide derivative 0,190 f obtained in 6-
(38,4R)-342-(2-aminothiazo-
/l/-4-i/L/)-2-methoxyimino]acetamido-2-azetidinone-1-sodium sulfonate 0.074F was obtained.

KBr-4ErvmaXc11:1780. 1660. 16
15°+520.1280.1250.105ONM1
05ON, external reference, ppm): 4.02 (s.

(d, J=6Mz, U3-M)+tj, 9ti(1
3+T) Reference Example 4 D-2-(4-ethy/L'-2,3-dioxo-1-biverazinecasboxamide)-2-(thiophen-2-yl)acetic acid 1.196 f, methylene chloride 20 l/ ,) 0.775F of pulverized phosphorus pentachloride was added to the mixture of 0.530F of ethylamine while stirring under water cooling. After stirring for 1 hour under water cooling, the mixture was concentrated under reduced pressure f, n-hexane was added to the residue, and the mixture was washed by decantation several times. Dry tetrahydrofuran was added to the residue, and insoluble materials were removed in an oven.

On the other hand, (38,48)-3-amino-4-cyano-2-
Azetidinone p-toluenesulfonate 0.992F
was dissolved in 15ml of dry tetrahydrofuran, and 1.06011 of triethylamine was added thereto under ice-cooling.
The tetrahydrofuran solution of acid chloride prepared above was added. 40 minutes at room temperature (about 25℃) or 1! After mixing, the mixture was concentrated under reduced pressure, and the residue was chromatographed on a silicage μ column chromatograph [ethyl acetate/I/:chloroform 2 methanol/
l/(313:1)] gives (38,4S) -
4-V7/-3CD-2-(4-work f)v-2+ 3-
0.56([ of dioxo-1-pibewodinecarboxamide)-2-(thiophen-2-yl)]]acetamido-2-azetidino was obtained.

KBr-1 1Rvmaxcm: 1785, 1710.167
0°50O NMR (DM80-da Ippm): 1.
09 (t, J = 5 Hz +CH3), 3.
40 (q lJ =5Hz, -CH2-) 13.
56(m, -CH2-)+3.90(m+-CH,()
, 4.76 (a.

J"'4Hz, C, -H), 5.30 (dd, J=8.
4Hz.

C3-H), 5.83 (d1J=4Hz, -C
H-) 16.90-160 (nzaromH)+9
．． 03 (br,s+NH)+9.70(d+
J = 4Hz, NH), 9.80 (d lJ
=8H7,,NH) Reference Example 5 (38,48)-3-Amino-4-cyano-2-azetidinone p-)/l/Ensulfonate 0.96 O
f Dry m Tetrahydrofuran 15g+/%% cloudy,
Triethylamine 1.40Of under water cooling, then 2-(
2-chloroacetamidothiazol-4-yl)-2-
A solution of methoxyiminoacetic acid chloride salt am1.04Of in 10 liters of dry tetrahydroflough was added.

Stir for 30 minutes at room temperature (approximately 25°C), then concentrate under reduced pressure, and subject the residue to silica gel column chromatography [acetic acid
Expanded by (3: 3:1)], we get (38,48)-3
-[2-(2-chloroacetamidothiazo-μm4-iA/)-2-methoxyimino]acetamido-4-cyano-2-azetidinone, 0°910f, was obtained.

■Rv"ror': 1790.tars, 1540
゜aX05O NMR (DMSO+D20, ppm): 3
．． 93 (s + 0CH3).

4.33 (s, -CH2-), 4.83 (d,
J = 4 Hz, C4-H).

H 5,40 (d, J=4Hz, C3-H), 7.46 (8
, Y) Reference Example 6 (38,4B) p-)/l/enesulfonate of (38,4B)-3-amino-4-cyano-2-azetidinone 0.54Of
was suspended in 10 ml of dry tetrahydrofuran, and 0.787 F of triethylamine was added to the suspension while cooling with water.

Then 2-(2-chloroacetamidothiazole-4-
A solution of 0.600 g of -2-methoxyiminoacetic acid chloride hydrochloride dissolved in 5 liters of dry tetrahydrofuran was added. After stirring at room temperature (approximately 25° C.) for 30 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [developed with ethyl acetate/L/:chloroform:methanol (3:3:l)] to give (38°4B)-3-[2-(2-chloroacetamidothiazo-μm4) -1v)-2-methoxyimino]acetamido-2-azetidinone, 0.52!
M was obtained.

Engineering Rshi copy tym': 1780. 1670. 15
40°04O NMR (DMSO-d6.ppm); 3.92
<s, ocH3+.

4.36 (s, -CH2-), 4.5j (d,
J=2Hz, C4-H).

Old reference example 7 (38,4R8)-3-amino-4-cyano-2-azetidinone (P-) Added 3F. Room temperature (25
℃) for 10 minutes, then shaken with water, and the organic layer was separated and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and purify the residue with a silica gel column [ethyl acetate/l
/ : n-hexane (2:l)) Then, (3S, 4
B) -4-cyano-3-phenylacetamido-2-azetidinone (Shu 1. l 6 f, then the corresponding (3
B, 4) 1)-Rust conductor (B) 0.84 f was obtained.

(Shu IRIJKBrWl: 2250, 1770, 1665
゜aX 1530.135O NMR (DMSO-d6.ppm): 3.60
(a, -CH2-).

4.20 (d, J=4Hz, C4-H), 4.
86 (dd + J=4.

8Hz, C3H), 6.56 (d, J-3Hz+NH)
+″r, 26 (8+ arom H) (Bl erνfnaX3 :2250'+ 17801
tsso.

1520. 135O N MR (DMSO-d6.ppm): 3.60 (
s, -CH2-).

4-10 (d, J = 2 Hz, C4-H)
, 4.80 (d d , J =2+8Hz, C3-H
) +6.60 (d, J””8Hz, NH) +7.20
(s*arom H) Reference Example 8 (38,4R)-3-amino-4-cyano-2-azetidinone (P-)/&enesulfonate 1.66f, pyridine 0.5f, methylene chloride 5s1! The mixture was stirred at room temperature (approximately 25 Yc) for 15 minutes.

To this was added 10 d of propylene oxide and 1.1 f of 2-trimena/L/V μ-ethoxycarbonyp chloride while stirring under water cooling. After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure, and the residue was subjected to silicage μ column chromatography [developed with ethyl acetate/I/:n-hexane (1:1-)] to give (38,4B). -4
-cyano-3-(2-trimethylsili/I/)ethoxycarboxamide 2-azetidinone 1. Of was obtained.

1 shark fth1” 31:2950,1885.171
0°ax +510. 1250. 860. 84ONMR(C
DCl2. ppm): 0.03 (s, CH3), 1
．． 00(t, J=8Hz, -CH2), 4.20(
t, J = 8Hz.

-CH2-), +, 5o(a,,T=2)(Z+04-
H), 5.33 (dd, J-2+8Hz, C3-H),
5.70 (d, J=8Hz.

NH), 6.80 (br, s, NH) Reference Example 9 P-)A/enesulfonate 11.2f of (38,4R8)-3-amino-4-cyano-2-azetidinone
Suspend in Q ml of tetrahydrofuran and cool with water for 5 minutes.
After adding triethylamine from step 1 and stirring for 30 minutes,
Concentrate under reduced pressure. Add 20 ml of methylene chloride to the residue. Propylene oxide 8 (1+7) was added and dissolved, and 6.81 carbobenzoxy chloride was added to this solution under water cooling. After stirring at 25°C for 30 minutes, it was concentrated under reduced pressure. The residue was diluted with ethyl acetate. Water was added and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified with a column using 15 of silica gel [ethyl acetate: n-hexane (1: 1)] Then, 2.1f of (38,4R)-3-benzyloxycarboxamide-4-cyano-2-azetidinone is converted into an oily substance, and further (3B,48)-4-3/ano-3-benzyl Oxycarboxamide-2-azetidinone 3.21f was obtained as crystals.

(38, 4B ”) Integral mp 167-170℃ (dec,) +805.17
65.1675.1525NMR(DMSO-d6
．． ppm): 4.50 (d, J=5)Iz
.

C4-H), 5. lo(8,-CH2-), 5.16(
dd.

J=5 + 8Hz + 03-H) + 7.26
(s + arOIIIK) + 8.16 (d, J=
8Hz, NH), 8.56 (broad s.

NH) Reference Example 10 +) (3R,4B)-3-benzyloxycarboxamide-4-methylsulfony/L'-2-azetidino: zo
, 298ft-Tur15mK was dissolved, palladium black 0.25F was added thereto, and the mixture was stirred for 2 hours in a hydrogen stream.

The catalyst was removed and the furnace liquid was concentrated under reduced pressure to about 3 d.

On the other hand, 2-(2-chloroacetamidothiazo-/L'-
4-I1v)-2-methoxyiminoacetic acid (syn isomer)
0.555 F was added to 10 dO methylene chloride, and to this was added 0.25 y of triethylamine and then 0.42 F of phosphorus pentachloride under ice cooling, and the mixture was stirred for 5 minutes. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure, the residue was washed with n-hexane, 5d of THF was added thereto, and the insoluble matter was removed in the oven. This furnace solution was added to a mixed solution of the previously prepared solution and 1 ml of propylene oxide under water cooling. After evaporating the solvent under reduced pressure, the residual ethyl acetate solution was washed with water and concentrated under reduced pressure. The residue was subjected to a silica gel column (lFIMcn-hexane-ethyl acetate (1:l')) to give (3R14R)-
3-[2-(2-chloroacetamidothiazo-A/-4
-yl)-2-methoxyiminoacetamide]-4-methylnulfony A/-2-azetidinone 0.13F was obtained.

ERJ'cIl:3370. 3270.
1790°max 1680, 154O NMR (DMSO-da+ppm): '3. oo
<s, CH3).

3.93 (s, CH3), 4.33 (e, CH2-)
, 4.93 (d * J -5Hz + C4-H)
, 5.57 (d d , J = 5.

9 Hz, C3-H), I5'j-(s, >
H) +8-30(d, J=9Hz, NH),
9.40 (s, NH), 12.73 (s, NH) 2) (3R,,4R)-3-C2- obtained in 1) above
(2-ri p-roacetamidothiazo-A/-4-i/L'
)-2-methoxyiminoacetamide]-4-methylsulfonyA/-2-azetidinone 0.46ftDMF3d
and add sulfuric anhydride-pyridine complex 0 to this.
．． 36f was added and allowed to react for 12 days. Ether was added and the oil that separated was washed with ether. The oil was dissolved in water, 10ml of Dowex 50W resin (manufactured by Dow Chemical Co., sodium form) was added, and the mixture was stirred for 30 minutes. When the resin is removed and the r liquid is purified using a column filled with XAD-n resin (manufactured by Rohm and Haas), the result is 3R14R.
-3-[2-(2-chloroacetamidothiazole-4
-yl)-2-methoxyiminoacetamide]-4-methylsulfony/l/-2-azetidinone-1-sodium sulfonate 0.023F was obtained.

KBr-1 1R&, aXff: 3450-3400.1785
゜16B5.1672.1280,1260,1052
NMR (DMSO-d6.ppm): 3.84
(s, CH3)+4.33(s, -CH2-)
, 5.15 (a, J-5Hz.

C4-H), 5.71(ddlJ-5,9H2,C3-
H) 17.53 (s, 〉-H), 9.45 (d, J
-9Hz.

NIII), 12.88 (s, NH) Reference Example 11 (31'l, 4R)-3-amino-4-cyano-2
-Azetidinone P-) Luens μ phonate 0.3Of
was dissolved in 12#t of tetrahydrofuran, and 0.12N triethylamine was added to the solution under water cooling, followed by 2-(2-chloroacetamidothiazo-A/-4-i/I/)-2-'
(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetic acid chloride hydrochloride 0.60 f
added. The mixture was stirred at room temperature for 40 minutes, concentrated under reduced pressure, and the residue was purified with a silica gel column [ethyl acetate m chloroform-methanol (3:3:1)] to give (38,4
8) -3-C2-(2-chloroacetamidothiazo-1
0.271 of V-4-1/%/)-2-(+-p-nitropenzyloxycarbonyl-1-methylethquinimino)acetamido)-4-cyano-2-azetidinone was obtained.

IRvKBrcml: 1785.1740,1675
+aX 530 Reference Example 12 Dissolve (38,48)-3-amino-4-cyano-2-azetidinone (P-) to enesulfonic acid 41001 in 850 ml of a tetrahydro-7-water <1:1) solution and stir. , Sodium hydrogen chloride 7 below 10℃
4.1 f was added gradually.

Then, at 3-5°C, add 40 μbopenzoxy chloride.
The mixture was added for 30 minutes and stirred for an additional 30 minutes at the same temperature. 300 ml of ethyl acetate was added to the reaction solution and the mixture was shaken, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. When concentrated under reduced pressure and the precipitated crystals were collected (38,4
8) -4-cyano-3-benzyloxycarboxamide-2-azetidinone 34F was obtained.

The engineering R and NMR vector of this compound matched those of the compound obtained in Reference Example 9.

Example 1 1) (3R,4R)-4-Methylsulfony A/-3-tritylamino-2-azetidinone 12.3f in DMF1
Potassium cyanide 1.6f in a solution dissolved in 50gt
A solution prepared by dissolving . Ice water and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column [developed with ethyl acetate:n-hexane (1:1)] to give (3S,4BS)-4-
Cyano-3-tritylamino-2-azetidinone (4R
:48=1:'1) of 6.7F was obtained.

KBr-1 1RvrnaXcII:2230. 17702) The (38.4R8)-4-cyano-3-tritylamino-2-azetidinone + 0.6F obtained in 1) above was dissolved in acetone 2
After adding 6.3 F of p-toluenesulfonic acid heptubiderate to the solution dissolved in the solution to obtain a homogeneous solution, the precipitated crystals were collected in a furnace and washed with a small amount of acetone and then ether. The F3 liquid was concentrated under reduced pressure, acetone was added to the residue, and the precipitated crystals were collected in a furnace. Concentrate the furnace liquid and perform the same operation as above to obtain a total of 3.4 f (38
゜4F)-3-Amino-4-cyano-2-azetidinone p-)luenes μphonate c~ was obtained. After concentrating the furnace liquid under reduced pressure, ether is added to the residue, and the resulting insoluble matter is taken out and washed with ether (3S).

48)-3-Amino-4-cyano-2-azetidinone
p-)/7enesulfonate (B) 4. lf was obtained. This product contained about 10% of C3B, 4B>integrity.

(Input KBr = 1 engineering ην 3: 1770. 1200aX NMR (DM80-d6.ppm): 2.30
(s, CH3).

4.55(a, J=2Hz, C4-H), 4.95(
d, J-2Hz.

C3-H) + 7.03 (d + J = 8Hz
+ aroma H) +7.46 (d, J-8H
z+aromH)+8.30-9.00(broa
d+ NH2L 9.46-(broad 81
NH) (B) Example 2 1) (38,4R8)-4-cyano-3-tritylamino-2-azetidinone 1.10f, to! To a mixture of 0.50 F of J ethylamine and 20 ml of methylene chloride was added 0.56 F of tert-butyldimethylsilyl chloride while stirring under water cooling. After stirring at room temperature (approximately 25°C) for 30 minutes, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [ethyl acetate lN/:n
-Developed with hexane (1:3)] (3B, 4R8
) 1-tert-butyldimethylsilylv-4-cyano-3-tritylamino-2-azetidinone, 0.6
4F was obtained.

IRtiKBraii"' :2950,2240.1
760°ax 26O NM'B (CDCI, ppm): 0.13(s,
CH3), 0.80(s + t-B u ), 3
-03 (d, J Mi2 Hz, C4-H) +3
,'l0(d, J=8Hz, NH) ,3.43(d,
J=5Hz.

C-H), 4.46 (dd, J=2.8Hz, C-H)
.

4
34.50 (cid +, r=5.8H
z, c3-](),]7.0Q-7.50 m r
aromH) 2) 4-S/ano compound obtained in 1) above 0.469
V, methanol 5 liters, 30% hydrogen peroxide solution 0.33-
A mixture of 1 d of IN-sodium hydroxide solution was stirred at room temperature (approx. 25 ml) for 4 hours. After concentrating the reaction surface under reduced pressure, ethyl acetate and saturated brine were added to the residue.
The organic layer was separated and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developed with ethyl acetate) to obtain (38,4R8)-
4-carpamoy/l/-3-) dithylamino-2-azetidinone (4R:48-1: to mixture) 0.557
F was obtained.

KBr -1 pv cm: 1750,1670maχ NMR (DM80-d, +D20.ppm):
3.46 (d, J-4'Hz+C4-H), 3
．． 56 (d, J=2Hz.

C4-H), 4.03 (d, J=2Hz, C3
-H) + 4.26 (d + J = 4 Hz +
03-H) + 72~7-7 (m + ar
om H) Example 3 1) (38,48)-4-acetoxy-3-benzyloxycarboxamide-2-azetidinone 6V dissolved in dimethylformamide 30 resistant and potassium cyanide 1.5f dissolved in water 511. was added under water cooling, and stirred at room temperature (approximately 25°C) for 30 minutes. The mixture was poured into ice water and extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 30°C of methylene chloride and 2.21°C of triethylamine was added.
and tert-butylsilyl chloride 3. under water cooling.
Added 2g. After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography [ethyl acetate/L/; developed with 11-hexane (1+1)] to give (38,4R)-3-benzyloxy. Carboxamide-1-tert-butyldimethylsilyl-
4-cyano-2-azetidinone, 0.300f was obtained.

EngineeringRν”Ill 41: 29501 2920.21
40゜aX 1γ45.1720.125O NMR (CDCl2.ppm): 0.06 (s
, CH, , ), 0.90(s,t-Bu)+4.3
6(a, J=2Hz, C4-H)+4.70(dd, J
-2,8H2,C3-■), 5.02(8゜-CH2-
), 5.46 (d, J-3Hz, NH), 7.23
(s, arom H) 2) 4-cyano compound o, ao obtained in 1) above.

Dissolve f in 5 ml of ethanol, add 0.3 g of 30% hydrogen peroxide solution and 0.0 g of iN-sodium hydroxide aqueous solution while cooling with water.
．． 15 ml was added and stirred at room temperature (approximately 25°C) for 1 hour. After concentration under reduced pressure, ethyl acetate was added to the residue.

Water was added and the mixture was shaken, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. When concentrated under reduced pressure and subjected to silica gel column chromatography (developed with ethyl acetate), (
38,41'? )-3-benzyloxycarboxamide-4-carbamoy IV-2-azetidinone 0.041 was obtained.

mp153-155″O(dec,) KBr-1 1RLIrlIELXcI11:1770.1705
．． 169011665.1520.125O NMR (DMSO-d6, ppm): 3.9
1 (d, J −2Hz.

c, -H), 4.42 (aa, J=2.8Hz, C3-
H).

5.06 (8, -CH2-), 7.1 B, 7.
60 (each brs.

C0NH2) + 7.36 (s, aromH) + 8
．． 04(a, J+8Hz, NH), 8.3
0(br, s, NH) Example 4 (38,4S)-3-benzyloxycarboxamide-
4-cyano-2-azetidinone 12211v was dissolved in dimethyl sulfoxide 111%, and while stirring at 20°C, 0.1 ml of 30% hydrogen peroxide solution and then 0.1 g of IN-sodium hydroxide solution were added.

After 10 minutes, the precipitated crystals were collected, washed with a small amount of 99% ethanol, and dried to obtain (38,48)-3-benzyloxycarboxamide-4-carbamoyl-2-azetidinone 4211v. p solution 1 Azetidinone 37
I got ~.

mp236-240℃(dec,) [α]M”IO,43<DMSo, 8=1)RJ/KBrax-1: 3400.3310,177
5°aX 1740.1675.1545 NMR (DMSO, ppm): 4.14 (d,, T=
5Hz.

C4-H) + 5.06 (s, -CH2-), 5
．． 08 (dd+J=5.8Hz+03-H),
7.30 (broad 81 NH2) + 7.35 (
s * arom H) + 752 (d + J
= 8 Tl z +NH), 8.33 (broad
s, NU) Example 5 (38-74R,S)-4-cyano-3-triphenylmethylamino-2-azetidinone 1. Dissolve Oi in 12 liters of dichloromethane, add 1.02 f of tetra-n-butylammonium hydrogen sulfate, and stir while cooling with water.
Add 0.68 ml of 0% hydrogen peroxide solution and 4.5 ml of 1N sodium hydroxide solution, and heat vigorously for 5 minutes.
I mixed it up. The reaction solution was poured into ice water containing 1.3 ml of 1N hydrochloric acid, and after separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with an aqueous solution of sodium thiosulfate and common salt, and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was purified using a silica gel column column (eluting with chloroform:ethyl acetate A/:methanol 1 L/(50:50:5)) and (3S, 4S).
)-4-carbamoyl-3-triphenylmethylamino-2-azetidinone 0.2239 was obtained.

KBr-1 Engineering Rvmax3: 3370. +750.1675°05 NMR (DMSO-d6.ppm): 3.44 (
a+J-5Hz.

C4-H), 3-55 (d, J = l OHz
, NH).

4.10 ((id, J-5, 10Hz, C3-H)
, 6.90 (broad IIL NH2L 7.0-
7.6 (m + aromHL7.89 (s, NH) Example 6 (38,48)-3-[2-(2-ri p-roacetamidothiazole/l/-4-i/L-)-2m Dissolve 0.38 f of (1-p-nitrobenzyloxycarbonylv-1-methylethoxyimino)acetamidocy4-cyano-2-azetidinone in 2 ml of dimethyl sulfoxide, and add 30% hydrogen peroxide solution to this solution. Add .1yzl and 0.1d of IN-sodium hydroxide aqueous solution and stir at about 25°C for 30 minutes.The reaction solution is added to the XAD-■ cuff and purified [eluted with 30% ethanol] to give (3B, 48)-
4-Carbamoyl-3-C2-(2-chloroacetamidothiazo-μm4-iA/)-2-(1-p-nitrobenzyloxy-μboni7-1-methylethoxyimino)acetamidocou 2-azetidinone 0 .12 f!
is obtained.

1520, 135O NMR (DM80-d6.ppm): i, 52
(8,aa3)+4.27(d,J=6H2,C4-
H), 4.34 (s, c1cH2-).

5.32 (s, CH2), 5.46 (dd 1
J=6.9Hz.

C3-H), 7.41 (a, 8>H), 7.60°8.08 (d + J = 9 Hz + aro
m H) + 8.47 (slNH), 8.86 (d,
J=9Hz, NH) Example 7 (38,48)-4-cyano-3-triphenylmethylamino-2-azetidinone (160 da
154 q of tetra-n-glylammonium hydrogen sulfate was added to the solution, and while stirring under cooling with water, 0.103 ml of 30% hydrogen peroxide solution and 0.68 II l of 1N aqueous sodium hydroxide solution were added, followed by vigorous stirring for 30 minutes.

The reaction solution was poured into ice water containing 0.22 ml of 1N hydrochloric acid, and the separated aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue is purified by silica gel column chromatography [chloroform:ethyl acetate/I/
: methanol/L/(50:50:5)] and (3
75 wv of 8,48)-4-carbamoy)V-3-7triphenylmethylamino-2-azetidinone were obtained.

The engineering R and NMR spectrum/L' of this compound matched those of the compound obtained in Example 5.

Example 8 (3F,4R)-4-Methylsulfonyl-3-tritylamino-2-azetidinone 12.2f, tri-n-
2.441 octylmethylammonium to 1 carbon tetrachloride
While stirring, a solution of potassium cyanide 2.15F in 30 ml of water was added under water cooling. After stirring vigorously for 15 minutes at the same temperature, separate the organic layer and extract the aqueous layer with chloroform. The organic layers were combined, washed with water, and treated in the same manner as in Example 1, 1) to obtain (38,
4R8)-4-cyano-3-tritylamino-2-azetidinone 7,66f was obtained.

This compound is (38,4B):(38,48)-1:5
It was a mixture of

0(38,4F) NMR (CDCl2.ppm); 2.94 (d,,
T=I IHz, Tr(trichyμ)NH-), 3.0
0 (d, J=2H2, C4-H) 1 4.64 (aa + J=2, l lHz.

C3-H) 16.40 (slNH).

7゜l-7,7(m+aromH) o(38,48) body NMR (CDCI31ppm): 3.17(d, 7J
=llHz.

TrNdan-), 3.56 (a, J- 51 (Z I C4-a), 4.64 (aa.

J" 5.11 Hz + C3-H).

6.30 (s, NH), 7.1-7.7 (m + ar
om H) Example 9 (3R,4R8)-4-cyano- obtained in Example 8
Dissolve 3-tritylamino-2-azetidinone 3,54F in 40 ytt of chloroform and add
- Processed 3.4v of glylammonium, added 2.3f of 30% hydrogen peroxide and 1N aqueous sodium hydroxide solution i5*J while stirring under water cooling, and stirred vigorously for 30 minutes. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with water, and treated in the same manner as in Example 7 to obtain 0.76 f of 38°48)-4-carpamoy1V-3-)ditylamino-2-azetidinone. The R and NMR spectra μ of this compound were consistent with those of the compound obtained in Example 5.

Example 10 (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone 0.5 mmol.

Tetra-n-amylammonium bromide 0. l m1n
ol was dissolved in 2 ml of benzene, and a solution of 55 mmol of potassium cyanide Q dissolved in 0.55 s of water was added thereto at 15°C. After stirring vigorously for 15 minutes, the same treatment as in Example 8 yielded (38,4R8)-
A (38,4R):(3S,4S)=1:4 mixture of 4-cyano-3-tritylamino-2-azetidinone was obtained.

Example 11 In Example 10, when the reaction was carried out using benzyltriethylammonium chloride in place of tetra-n-amylammonium bromide, (38,4R8)-4-cyano-
3-tritylamino-2-azetidinone (4R:4S=
1:3.5) was obtained.

Example 12 In Example 10, when the reaction is carried out using tetra-n-butylphosphonium bromide instead of tetra-n-amylammonium bromide, (38,4)? 5) -4-cyano-3-tritylamino-2-azetidinone (4R:3S
=1:3.5) was obtained.

Industrial applicability 4-cyano-2-azetidinone derivative CI) is used to synthesize optically active forms of 4-substituted-2-azetidinone derivatives that have excellent antibacterial activity and β-lactamase inhibitory activity. CI), which is used as an advantageous synthetic intermediate and in which W is a sulfo group, has itself antibacterial activity and β
-Has a lactamase inhibitory effect on humans, dogs, cats, and cattle.

β- When used in combination with lactam antibiotics, it is used as a decomposition inhibitor for the antibiotics.

Claims (1)

[Claims] Formula (1) [In the formula, R1 represents an amino group which may be acylated/I/ or protected, X represents hydrogen or a methoxy group, and W represents hydrogen or a sulfo group] A 4-cyano-2-azetidinone derivative represented by: (2) Formula [wherein, R2 is an acylated or protected amino group, X is hydrogen or a methoxy group, W is hydrogen or a sulfo group, Y is a halogen or a hydrogen group, and n is 1 or 2) is reacted with a cyano compound, and if necessary, the protecting group is removed. A method for producing a 4-cyano-2-azetidinone derivative, wherein X and W have the same meanings as above. A 4-cyano-2-azetidinone derivative represented by [wherein R represents an amino group that may be acylated or protected, X represents hydrogen or a methoxy group, and W represents hydrogen or a sulfo group]. [In the formula, R4 is an optionally acylated or protected amino group, and X and W are the same as above. A method for producing a 4-carbamoy tv-2-azetidinone derivative represented by: (4) The production method according to claim 2, wherein the reaction is carried out in the presence of a phase transfer catalyst.