JPS6089486A - 7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid derivative and production and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X is lower alkylene or lower alkenylene which may have hydroxyl; Y is lower alkyl, aryl or aralkyl, etc.; Y- SO2-X- forms formula II (l is an integer 0-3; m and n are integers 0-6; m+n is 2-6), etc. by bonding X to Y; R is substitutive hydrocarbon or 3--8-membered heterocyclic ring] and a salt thereof. EXAMPLE:Sodium 5,6-cis-3-( 2-acetamidoethylthio )-6-( 1-hydroxy-3-thiacyclopentyl- 3,3-dioxide)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate. USE:An antimicrobial agent and germicide effective against Gram-positive and Gram-negative bacteria. PREPARATION:A compound of formula III (Z is eliminative group; -COOR<1> is carboxyl which can be protected) or a salt thereof is reacted with a compound of the formula RSH or a salt thereof to give the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION 1-azabicyclo(3,2,0)but-2-ene-2
- Force μ Pon - Acid Rust Conductor (In this specification, the carbapenem compound represented by the following formula is 7-oxo-1-azabinclo(3,2,0) to but-2-ene-2- (named as ponic acid).

Regarding its manufacturing method and uses.

The compound of the present invention, 7-oxo-1-azabicyclo(3
,2,0) Hebut-2-ene-2-force μ-bonic acid derivative (
I) is an excellent antibacterial agent, p-lactamase inhibitor, and is used for the treatment and prevention of bacterial infections in large and domestic animals.

Prior art In recent years, various types of 7-oxo-1-azabicyclo (3,2,0
) Hebut-2-ene-2-carbon e derivatives have been prepared.

For example, 7-oxo-
1-azabinclo(3,2,0) to but-2-ene-2
Compounds having a 1-(lower acymuthio)ethyl group at the 6-position of the mu-bonic acid have been described and are known to exhibit antibacterial activity.

However, although these compounds exhibit effects in vitro, when administered in vivo, they are quickly degraded and inactivated by enzymes in the body (e.g., ghydrobebutidase, an I# enzyme). However, the compound has the disadvantage that the antibacterial and β-octamase inhibitory effects inherent in the compound cannot be sufficiently exhibited.

Problems to be Solved by the Invention The present inventors have been conducting extensive research with the aim of obtaining a compound that is stable against in vivo enzymes, has excellent antibacterial activity, and has an inhibitory effect on β-lactamase. However, the general formula [wherein, Group (3) lower γμ group (4) aryl group (5) aralkyl group or (6) 3- to 8-shell heterocyclic group r1 or the group represented by the formula ¥-802-X- is a group in which X and Y are R is a group represented by the formula (in the formula, t is an integer from 0 to 3, m and n are each an integer from 0 to 6, and the sum of m and n is 2 to 6). An optionally substituted hydrocarbon group or a 3- to 8-shell heterocyclic group] or a salt thereof meet the above objectives;
As a result of further research, the present invention was completed.

That is, the present invention provides: 1. a compound represented by general formula (I) or a salt thereof; 2. R is (1) a lower alkoxy group (2) a lower alkoxy carbonyl group (3) (a) an imino group; Lower alkyl μ group that may be substituted<b) 7-amino group that may be protected (c) Lower alkanoyl/l/ group or (d) 1 to 3 oxo groups may be substituted Heterocyclic group with 3 to 8 shells (4) Acyloxy group (5) Optionally substituted with imino group (6) Lower alkylthio group (7) Arylthio group (8) Optionally substituted with a lower Aμ group (9) A Phenyl group or a lower Aμ group optionally substituted with a Phenyl group or a lower Aμ group
Amino group QO Azide group (b) Optionally protected hydroxy V/l/group (2) Lower acetyl group (2) Carboxy μ group α which may be substituted with a μ group or protected (7 groups) → A compound or a salt thereof according to claim 1, which is a hydrocarbon group optionally substituted with a substituent of an ami7 group that may be protected by a halogen QG or a substituent of an acylami group (Qf); 3. General formula [ In the formula, Z represents a leaving group, -COOR1 may be protected, V/I/group iSX, Y represents the same meaning as above] or a salt thereof; A compound represented by the formula % formula % ([) [wherein -R represents an optionally substituted hydrocarbon group or a 3- to 8-membered heterocyclic group] or a salt thereof] is reacted with A method for producing a compound represented by general formula (1) or a salt thereof, characterized by subjecting it to a deprotection reaction, 4. A compound represented by general formula (1) or a salt thereof? 5. A β-lactamase inhibitory composition characterized in that it contains a compound represented by formula (1) or a salt thereof.

In the above general formula, X is, for example, methylene.

Hydroxymethylene, methylmethylene, dimethylmethylene, ethylmethylene, ethylene, propylene, butylene, hydroxyethylene, hydroxymethylethylene, 1
-Hydroxy-2-) lower alkylene group having a prime number of 1 to 4 which may have a hydroxyl group such as fμ ethylene, hydroxyethylethylene, 1-hydroxy-2-ethylethylene, or e.g., ethenylene, propenylene .

Carbon i & 2 to 4 such as 1-butenylene, 2-butenylene, etc.
represents a lower aμkenylene group of (1), for example, methi μ
, ethyl, n-propyl lv, isopropyl μ.

n-buty/L/, isobuty μ, tert-buty IV, n
- Straight chain or branched lower ammonia groups of order prime numbers 1 to 6, such as pliers μ, n-hex VIV, isohexy μ, etc. (2)
For example, Kukuropropi! , Cyclobuchi μ, V Kurobench μ
, cycloalkyl μ group of order prime number 3 to 8 such as cyclohexyμ, cycloheptyμ, cyclooctyμ, etc. (3) Example, t
babini μ, probeni μ, 1-buteni μ, 2-buteni μ,
(4) An ary μ group (preferably a prime number of 6 to 10) such as phenyl or naphthiμ, (5) a lower γμ group having a prime number of 2 to 4, such as 3-gute diμ, (5) a benzene μ group, etc.
, fc is (6), for example, 1
- or 2-aziridini/I/, 2- or 3-pyrroliμ, 2- or 3-ph, su~, 2- or 3-thieneμ
, 2- or 3-pyrrolidini μ, 2-13- or 4-
Birigi! , N-oxide-2-13- or 4-viridiy + 2-1a- or 4-biberidini μ, 2-13- or 4-bivirani μ, 2-13- or 4-thiobirani μ
, pifudinil, 2-14- or 5-thiacyly! , 2-
14- or 5-oxasiliμ, 3-14- or 5-
Isothiasiliμ,.

3-14- or 5-isoxasiliμ, 2-14- or 5-imidazolyμ, 3-14- or 5-pyrazoly/l/j3- or 4-pyridaziniμ.

N-oxy7do-3- or 4-viridagini p, 2-14
- or 5-pyrimidinyl μ, N-oxide-2-14-
or 5-pyrimidinyl, biverazini μ, 4- or 5
-(1,2,3-thiasiasili〃), 3- or 5-(
1,2,4-Thiasiasili/lz), 1,3,4-Thiadiazolyl, 1,2゜5-Thiasiasiliμ, 4-F
i5-(1,2°3-oxacyacyly/l/), 3- or 5-(1.

2.4-oxacyacyly/L/)+134-oxacyacyly, &11+2,5-oxacyacylyμ.

1.2.3-or? , 2.4-) Reasiri/L/.

IH or 2H-tetofzolyl, benzothiasilyl! , indoliniμ, penzopikhni/' + 1 + 8- +
1.5-. 1.6-. 1.7-. 2.7- or 2.6
- Contains 1 to 5 heteroatoms such as optionally oxidized Arashi atoms such as naphthyridinyl, quinoli, etc., oxygen atoms, and sulfur atoms, and 3 to 8 members optionally fused with a benzene ring. Indicates a heterocyclic group or partial structural formula, Y
-8o2-X- is a combination of X and Y, for example, (3-thiacyclogutiμ-(3-thiacycloben3.3
-dioxide) methyl-3,3-dioxide) (3-thiacyclohexy/l/(3-thiacyclohexy, le-1 3,3-dioxide) 3,3-dioxide) methyμ(
3-thiacyclobench tv (3-thiacyclohexy,
-3,3-dioxide)guti/l/-a,3-dioxide)propyl formula (wherein, t is an integer from 0 to 3, m and n are each an integer from 0 to 6, and The sum of m and n is 2 to 6'lr: for example, a group represented by (1-hydroxy-3-(1-hydroxy-3-thiacyclobuty/L/-
3, thiacyclopentyl-3-dioxide) 3,3-
Dioxide) (1-hydroxy-4-(1-hydroxy-3-thiacyclohexy!-thiacyclohegishi ρ-4,
4-dioxide) 3,3-dioxide)(1-hydroxy-4-(1-hydroxy-3-thiacyclobenzi!)
-thiacyclohebuty, ru'-4,4-dioxytone 3
．． 3-dioxide)((1-hydroxy5/-3-((1
-Hydroxy-4-thiacyclobenchμ thiacyclohexyl-3,3-dioxide)methyρ) -4,4-dioxide)-cf/L/)((1-hydroxyV-3-thiacyclohexylμ m3,3 -dioxide)propy/L/) (the symbols in the formula have the same meanings as above), and R is an optionally substituted lower alkyl μ group having 1 to 6 carbon atoms. , a hydrocarbon group such as a cycloalkyl μ group having 1 and 3 to 8 atom atoms, a lower γμ 2 μ group having 2 to 6 carbon atoms, an ary μ group, or a nitrogen atom which may be oxidized.

A 3- to 8-membered heterocyclic group containing 5 heteroatoms such as oxygen atoms and sulfur atoms starting from t-1, and which may be fused with a benzene ring.

In the main group, examples of the lower 7μ group having 1 to 6 carbon atoms include methiμ, ethylρ, n-propyp, isopropyl, n-butyμ, and isobutyl.

Linear or branched lower alkyl groups having 1 to 6 carbon atoms, such as Watari-petit #, tart-buti μ, n-pentyl, isobenchi/L/, n-hexyl, and isohexyl, are used; As the cycloalkyl group of 8,
For example, cyclopropyl ρ, V kurobuti μ, cyclobench μ, cyclohexy μ, cycloheptyl, cyclooctyl
Examples of the γμ 2μ group having 2 to 6 carbon atoms include vinylμ, ariμ, isoprobeniμ, and 2-metaliμ.

Linear or branched lower γμ groups having 2 to 6 carbon atoms such as 2-ptenylμ and 3-dateniμ are used, and examples of the aryμ group include phenyl, α-naphthylμ, β - Naphthyl, bife $kan, antrip, etc. are used, and
A heterocyclic group with 3 to 8 shells containing a total of 1 to 5 heteroatoms such as a nitrogen atom, an oxygen atom, a sulfur atom, which may be oxidized, and which may be fused with a benzene ring is defined in Y above. The same ones as those given above are used respectively.

Among the above, preferably, the group represented by 2Y-8o2-X- is a group in which X and Y are bonded to form the formula (where t is an integer from 0 to 3, m and n are each an integer from 0 to 6) and the sum of m and n is 2 to 6).

Most preferably, the group of formula Y-802-X- is
and Y bond to each other and represented by the formula (wherein m and n are each an integer from 0 to 6, and the sum of m and n represents 2 to 6).

Examples of substituents in the optionally substituted hydrogen ashing group represented by R include methoxy, ethoxy, n-propoxy, isopropoxy, n-butquine, isobutoxy, di-ethoxy, tert-gutoxy; , n-pentyloxy.

Lower acetoxy groups with numbers 1 to 6 such as isopentyloxy, n-hexVIvoxy, isohexyμoxy, ■
For example, methoxycarbonyl/I/, ethoxycarbonyl,
n-proboxycarbonyl, isopropoxycarbonyl, n-proboxycarbonyl.

Isobutoxycarbonyl, 5ec-butoxycarbonyl/
7. A lower atom with a broad prime number of 1 to 6, such as tert-gutoxycarboniμ, n-benchμoxycarboniμ, isopentyloxycarboniμ, n-hexyloxycarboniμ, isohexyloxycarboniμ, isohexyloxycarboniμ, μcoxycarbonyl group,
■(a) Iminomethylμ, 1-iminoethylμ, 2-iminoethyl, 1-iminopropyμ, 2-iminopropyμ, 3
-Iminopropyl μ, 1-Iminobuchi~, 2-Iminobuti μ, 3-Iminobuti p, 4-Iminobutyl H→Bangaku Kensen/Methi μ, ethyl, n-propy μ, isopropyl.

A lower alkyl group having a prime number of 1 to 6 which may be substituted with an imino group such as n-butyl, isobutyμs, tart-butyμ, n-benchiμ, n-hexyμ, etc. 7 groups of amino acids (-), such as acetyl, propioni, gucci, and isogly.

n-bentanoyμ, n-hexanoyμ, n-hep may also be -3- to 8-membered heterocyclic group (as the 3- to 8-membered heterocyclic group, the same one as defined in Y above is used ), ■0 homiμoxy group, ■eg acetoxy, propionyμoxy.

Acanoy μoxy groups having a prime number of 2 to 7, such as n-gutylyμoxy, isobutylyμoxy, n-pentanoyloxy, n-hexanoyloxy, 4-Methoxypencil μoxy group such as μoxy group;■
For example, phenylacetoxy, 4-hydroxyphenylacetoxy.

4-Methoxyphenylacetoxy and other afurkyl ρ carbonyl oxy groups; ■ For example, 2-cheni/recarpyloxy, 2-7lylcarponyloxy heterocyclic groups µ bonyl leoxy groups i (IJ, t ha 2 +, 4 - or 5-thiazolyl acetoxy, 2-tf'c is 3-thiediμ acetoxy, 2- or 3-furylacetoxy, 2-amino-
4tfc is a 7-syloxy group such as a heterocyclic acetoxy group such as 5-thiazolyl acetoxy, (2) for example butylamino, ethyl V7mino.

Propylamino, n-butylamino, isobutylamino, tert-butylamino, n-hebutylamino, n-
Hexylamino, dimethylamino, diethylamino, methylethyl p-amino, di(n-brohylv)amino, methyl/l/n-propylamino, di(n-buty/l/)amino, di( n-hebuti/I
/) Amino, di(n-hexy/l/)amino, iminomethylamino, 1-iminoethylamino 7.2-iminoethylamino, 1-iminoethylamino, 1-iminoethylamino, methiminomethylamino, Ethyliminomethylamino, n-propiiminomethylamino, 1-methyliminoethylamino, 1-ethyliminoethylamino, 1-n-propiiminoethylami //I/ (1 to 6 carbon atoms) amino 7 Groups (1) For example, methylthio, ethylthio, n-propylthio, isopropylthio, n-ethylthio, isobutylthio.

Lower 7 μm thio groups having 1 to 6 carbon atoms such as tert-butylthio, n-bentylthio, isobentylthio, n-hexy pthio, and inhexylthio, ■ ary-frethio groups such as phenylthio and naphthylthio, ■ for example,
Power μ bamoyl optionally substituted with a lower alkyl p group having 1 to 6 carbon atoms such as bamoy N carp, methyl μ bamoyl, ethyl p carbamoy μ, n-benzen carbamoy μ, isohexycarbamoy μ, etc. Base, ■For example, Fenip force! 1 to 2 lower alkyl groups having 1 to 6 carbon atoms such as bamoy μ-amino, methyl carbamoyamino, ethyl carbamoylamino, diethylcarbamoylamino urbamoylamino, n-hexylcarbamoy μ-amino, etc. Optionally substituted carbamoyamium amide 7
group, [phase] azide group, ■ optionally retained hydroxy μ group, @eg iminocapsular.

Methylimino, butylimino, n-propynodiimino,
Substituted with a lower alkyl group having 1 to 6 carbon atoms such as inpropylimino, n-butylimino, isobutylimino, sec-butylimino, tert-butylimino, n-pentylimino, isobentylimino, n-hexylimino, isobutylimino, etc. Good imino group, [phase]
Force μ boxy μ groups that may be protected, such as fluorine, chlorine, and bromine.

Halogen such as iodine, [Phase] optionally protected amino group, or [Phase] e.g. acetylamino, propionyl μ
A lower a[mu]karylamino group having 2 to 10 carbon atoms, such as amine 7; Heterocyclic group (as a 3 to 8-membered heterocyclic group,
Examples of the substituted carbonyl group (the same ones as defined in Y above are used) include a phenyx μhoni μoxy group.

p-toenes phonyloxy group, p-nitrophenylsulfonysulfonyloxy group, phenylsulfonyloxy group optionally substituted with p-iodophenylsulfony, such as methane μhoniμoxy group, ethanes μhonyloxy group A lower alphanumeric group having 1 to 6 carbon atoms such as a μoxy group, such as a halogen such as chlorine or bromine, or a diary μphosphorymuoxy group such as diethylphosphoryloxy, such as a diethylphosphoryloxy 6 (lower alkyl group) substituted oxy group, etc. are used. Further, a specific example of R is as follows.

As the protecting group for the amino group, those used for this purpose in the field of β-lactam and peptide synthesis are appropriately used, such as phthaloy μ, p-nitrobency μ, p-t
ert-butyμbencyμ etc. aromatic acid μ group i p-t
Aromatic nulphoni groups such as ert-guti, benzene μ, P-), 11/enesulfoni μ, benzenesulfoni μ; for example, formyl, acetyl/I/, propioni p
, aminoaceti/L/.

Aliphatic 7yμ groups 11J, such as methylμ aminoacetyl, monochloroacetyp, dichloroacetyl/l/, ) dichloroacetylv, )su7/I/oacetyl, mallei p, succiniμ, t hamethane μhoniμ, ethanes μfo aliphatic sulfonic groups such as 2p; for example, methoxycarbonyl ρ,
Ethoxycarboniμ, t-gutoxycarboniμ, isopropoxycarboniμ, 2-cyanoethoxycarboniμ,
2,2.2-trichloroethoxycarbonyμ, 2-)limethylsiliμ ethoxycarbonyμ, benzyμoxycarbonyμ
Bonyp, 2-methylsulfonymu ethoxycarbonyl.

p-Nitrobendi poxycarboni μ, p-methoxybendi! Oxycarbon μ Boni〃, Dipheni μ Methyl Oxica μ
Ponyμ, methoxymethoxyμoxycarboniμ, acetyp methyloxycarboniμ, isoboμ2μoxycarboniμ
, the esterified force ρ such as phenyloxycarboniμ
Boxy μ group; further, for example, trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene,
For example, tri-lower alkyl/I/(prime number 1 to 6) silyl such as triethylsiliμ, methyldiethylsiliμ, etc.

Protecting groups for amine 7 groups other than acyl &, such as benzi μ and p-nitrobendi μ, are used. The selection of the protecting group is not particularly limited in the present invention.

As the protecting group for the V/I group, all those that can be used as the protecting group for the Vlv group in the field of β-lactam and organic chemistry can be used, such as methylp, ethyl, n-propyμ, isopropyμ, tert-
Guchiμ, tart-amiμ, bengeμ, p-nitrobendi/L/, 0-nitrobendiμ.

p-methoxybenzi ρ, benzhytril, phenan μ
, pheni/L', p-nitropheniμ, methoxymethi!
, ethoxymethyl, benzyμoxymethy~, acetoxymethyμ, bivaloy poxymethyl.

2-Methyμsuμhoniμethyl, 2-trimethylsiliμethyl, methylthiomethy/l/,)richμ, 2゜2.2-
Trichloroethyl, 2-iodoethyl μ.

trimethyl siliμ, dimethyl siliμ, acetyl methoxyμ,
p-nitrobencyμmethyμ, p-mesylpencyμmethyl, phthalimidomethyl, propioniμoxymethyμ
, 1,1-dimethylpropyrho.

3-methyv-3-guteniμ, succinimidomethiμ,
3,5-di-tert-buty/l'-4-hydroxybendi/L/, mediμmethyl, benzenesulfonyμmethyl
, que diμ thiomethi/L/, iminomethyμ aminoethyl, 1-iminoethylaminoethyl μ, dimethy p aminoethyl p, pyridine-1-oxide-2-methyl, methy μ sulfini μ meth/I/, bis(p- Methoxypheny/I
/) Methyl, ester μ residues such as 2-cyano-1°1-dimethylethyl p, siliμ groups, etc. are used.

Further, as a protecting group for a hydroxyl group, any group that can be used as a protecting group for a hydroxyl group in the field of β-lactam and organic chemistry can be used, such as ester μ residues such as aceti μ and chloroaceti μ; for example, 2,2 .2-) Esterified force μboxy μ residues such as dichloroethoxycarbonyl, 2-trimethoxycarbonyl;
For example, tert-guchi μ, benzi μ, p-nitrobendi μ.

trityl, methoxymethiμ, methiμthiomethip.

β-Me1xyethoxymethyl which ether residue; e.g. trimethyμsiliμ, tert-pdimethylsily/
siliate μ residues such as L'; e.g. 2-tetofhydrobirani μ, 4-methoxy-4-tetofhydropirani μ
acetal residues such as; sulfonic acid groups, etc. are used. In the present invention, the selection of the protective group may be an amino group,
As with the protecting group for the S/lv group, it is not particularly limited.

Compound (I) may be used in its free form if the 2-position μ boxy μ group or R contains a μ boxy μ group, but it may be pharmacologically determined by a method known per se. It can also be used in the form of acceptable salts. Amicable cations such as sodium and potassium, basic amino acids such as aginine, onithine, lysine, and histidine, such as N-methylglucamine, jetanolamine, triethanolamine, trishydroxymethylamino It may be used by forming a salt with a polyhydroxyamine such as methane. Further, when a RIC basic group (for example, amine 7 group) is contained, for example, a salt with an organic acid such as acetic acid, tartaric acid, or methanesulfonic acid, such as hydrochloric acid or hydrobromic acid.

Salts with inorganic acids such as sulfuric acid and phosphoric acid, such as salts with acidic amino acids such as aginine, aspartic acid, and glutamic acid? It may be formed and used.

Compound (I) or a salt thereof of the present invention is obtained from the starting compound (1
) may exist in a racemic form, but this racemic form can be used as a medicine as it is or as an optically active form (d-form, 4-form, etc.) by optical resolution.

The compound (1) of the present invention or a salt thereof has antibacterial activity against various Guhumu-positive and Guhumu-negative bacteria, and is used as a medicine for humans and livestock, and is particularly effective against Gram-positive bacteria (e.g. Staphylococcus aureus), or Gram-negative bacteria (may be added to animal feed as a disinfectant to preserve engineered feed, and can also be used as a disinfectant on medical and dental equipment.

Compound (I) of the present invention or a salt thereof may be used alone or in combination with other active ingredients in any of a variety of pharmaceutical preparations.
For example, in combination with Cef 10 (penicillin antibiotic), tablets, Kabu 7, powder, etc.
The solution, suspension or 71c is used as an elixir.

These preparations can be administered orally or parenterally (eg, intravenously/intramuscularly).

Preparations for oral administration include pharmaceutically acceptable excipients known per se (e.g., starch, lactose, psium carbonate, psium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, etc.). , hydroxyprovir cellulose, bound A cellulose, etc.), lubricants (e.g.
(magnesium stearate, tart, etc.) and disintegrants (e.g., boxymethylcalcium, tart, etc.) to form tablets, capsules, powders, fine granules, and granules using a conventional method. be able to.

Oral liquid preparations include solutions, aqueous or oily suspensions.1. It may be used as a milk concentrate, syrup, elixir, or as a dry product to be dissolved in water or other suitable solvent before use.

Such liquid formulations may be prepared by suspending agents (e.g.
Preservatives (e.g. methy/l/l)-hydroxybenzoate, propy/l/p-hydroxybenzoate, etc.) may also be included. The herbal medicine can use common herbal substrates, such as cocoa patter or other glycerides.

Injectable preparations are solutions in oily or aqueous solvents.

Suspensions, emulsions, or emulsions may be in powder form and may contain appropriate auxiliary agents such as suspending agents, stabilizing agents, and/or dispersing agents. When the injectable preparation is in powder form, it is dissolved in an appropriate solvent, such as distilled water from which pyrogens have been removed, before use.

Furthermore, this injection J@ preparation contains other active ingredients (e.g., penicillin antibiotics, Cef10sporin antibiotics, etc.)
- It is also possible to exhibit antibacterial activity with a wider spectrum μ by including it.

The compound CI) of the present invention or a salt thereof can be used as a therapeutic agent for bacterial infections, for example, for mammalian respiratory tract infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections, It can be used to treat surgical infections, etc. The daily dosage is about 10 to about 200j as compound (1).
Iy/# (body weight), and it is appropriate to administer the drug by intravenous injection, for example, in an amount of about 5 to about 100 M1/# (body weight) divided into 2 to 4 doses per day.

The compound (1) of the present invention or a salt thereof may be as described above. Examples of these stronger β-lactam antibiotics include, for example, benzylbeni/phosphorus, phenoxymethylpenicillin, penicillin, ampicillin, amoxicillin,
Penicillin antibiotics, such as cephaloridine, 7770tin, cefazolin, cefurxin, cefoxitin, and cefacedryl.

Cephalosporin antibiotics such as cef7mandoμ, cefmetuxime, cefsulodin, cefotiam, cefotaxime, cef1virin, ceftizoxime, ceffudine, and cephaloglycine are used, and injections and dry V
Drops, 2 granules, 7 turnips! Prepare the drug according to the conventional method.

Preferably, it is used in the form of a salt or hydrate as an injection. In the case of such monthly payment, the compound of the present invention (
1), 1/10 for 1 β-lactam antibiotic
~10 times the amount (weight) can be used, but 1~178
A ratio of, for example, 115 or 1/6 of
lq/# (body weight), for example, 1 to 6 times, more usually 2
Administered in ~4 doses.

The compound CI) of the present invention or a salt thereof can be produced into a container by a method known per se. That is, it can be produced by completely reacting the compound (1) or a salt thereof with the compound (1) or a salt thereof, and subjecting the compound (1) or a salt thereof to a deprotection reaction if necessary.

In this reaction, compound (1) and compound (if) may be used in their free form, but they may also be used as alkali metal salts such as lithium, sodium, potassium, etc.
It may be subjected to the reaction as an alkaline earth metal salt such as vVum or magnesium, or a silver salt. In this reaction, about 1 to 10 moμ of compound (1) or its salt per 17μ of compound (1) or its salt is preferably about 1 to 5 mo/I.
/ is used. The reaction is usually carried out in a solvent. Suitable solvents include, for example, hydrogen halides such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulphoxide, Hexamethylphosphoramide and the like are used. Furthermore, a base may be added to advantageously advance the reaction. Such bases include, for example, sodium hydrogen carbonate,
Potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide,
Sodium metkind, triethyl ρamine.

Diisopropyl ethylamine, pyridine and the like are preferred. The amount of base added is usually about 1 to 107 μ, preferably about 1 to 57 μ, per 1 mo μ of compound (II). The reaction temperature is about -50' to 40'O.

Preferably, this is carried out within a range of -30° to about 20°C. The reaction time is about 1 to 72 hours, preferably about 1 to 24 hours.

When the compound (1) obtained in this way or a salt thereof has a protecting group, the protecting group can be removed by a method known per se, if necessary.

More specifically, regarding the protective group removal reaction, if the protective group for the phoxyl group in compound (1) or its salt is a halogenoyl group, an arap group, a benzhydryl group, etc., a reducing agent may be used. This is accomplished by making contact. The reducing agent used in this reaction is a protecting group for the phoxyl group, such as 2,2-dibromoethyl, 2
Zinc and acetic acid are preferred when the protecting group is a halognoyl group such as , 2, 2-trichloroethyl, an araμ group such as p-nitrobenzyl, p-nitrobene diμ, or a benzhydryl group. hydrogen and, for example, platinum oxide, platinum black.

Platinum sponge, palladium-fuso, palladium-black,
Palladium-barium sulfate, palladium-barium carbonate, reduced nickel! , ONE 12 TSKE〃.

Catalytic reduction catalysts such as Urushibara nickel or alkali metal sulfides such as sodium sulfide and potassium sulfide are suitable. Further, in the case of an 0-nitrobenzene μ group, removal can be performed by light irradiation, and in the case of a p-methoxybenzi μ group, removal can be performed by electrolytic reduction. The reaction is carried out in the presence of a solvent. Examples of solvents used include alcohols such as methanol and ethanol, ethers/L's such as tetofhydrofuran and dioxane, and acetic acid.

Lower (prime numbers 2 to 7) fatty acids such as propionic acid and mixed solvents of these and water are preferred. The reaction temperature is usually around 0° to 40°C. The reaction time is usually about 5 minutes to 12 hours.

The protecting group for the amine 7 group in compound (1) or its salt is, for example, p-nitrobenzyloxy! Bonyl group, 0-nitrobenzyloxycarbonyl vMs, o-・
In the case of a nitrobendiμoxycarponiμ group, p-methoxybendiμoxycarponyμ group, bendiμoxycarponiμ group, etc., it can be removed in the same manner as the above-mentioned protecting group removal reaction for the forceμpoquinμ group. be done.

In compound (1)t or a salt thereof, the hydroxyl group-carrying group is a lower acanoid such as acetoxy, II/(carbon number 2 to 7).
) When it is an oxy group, it can be removed by treatment with a base in an aqueous solvent. Examples used are methanol-μ,
Akol lv such as nitano μ or tetrahydro 7
Mixed solvents with organic solvents such as ethane, dioxane, and the like are suitable. The base used is not particularly limited as long as it does not affect the β-lactam ring, and the temperature is about 0°C to room temperature. The reaction time varies depending on the type of raw material compound, reaction temperature, etc., but is usually about 1 to 6 hours. tyc.

tert-buty! as a protecting group for hydroxyl groups! Dimethylsiliμ
When a tri-lower (carbon number 1 or c) 6) a[mu]ki silyl p group is used, it may be treated with a fluoride compound such as tetrafluoride IV ammonium fluoride or potassium fluoride. removed. As the solvent used, ethers of tetrahydrofuran and Sy dioxane are suitable. The reaction is completed in about 10 to 188 hours at around room temperature.

Compound CI) has carboxy Vfi/group, so
In general, salts can be formed by interaction with bases. therefore,
Compound (1) may be collected as a salt, or may be obtained as a free form of the salt, or may be used as other salts. Furthermore, compound (1) obtained in free form
It may also be used as k salt. As a method for converting the compound (1)' obtained as a salt into a free form, for example, a method using acid r can be used. The acid to be used varies depending on the type of protecting group and other conditions, but examples include non-alpha acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid-acetic acid-p-to-z-reens μ-phonic acid. used. In addition, acidic ion exchange resins and the like are used. Further, as the solvent, for example, a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol-μ, dioxane, water, or a mixed solvent thereof is often used. The method is usually carried out at room temperature; it may be carried out under cooling or heating. The reaction time is generally about several tens of minutes to one hour.

Compound (1) or a salt thereof obtained in this way is
MonotS can be purified by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, crystallization, recrystallization, fractional distillation, and chromatography.

When a free amide group exists in the substituent represented by R in compound (1), this amino group t and an amide group (e.g.
ace[amide group, propionamide group, etc.), ureido group, imino group-substituted lower apkyl A/(C1 to 6 amino group, R prime number 1 to 6 lower apkyl /L/ (1 to 6 carbon atoms) can be converted to an amino group, a guanidi7 group, etc.

Imino group-substituted lower alkyl/l/(carbon 9 & 1 to 6) amino group, and lower akylimino group-substituted lower alkyl having 1 to 6 carbon atoms IL'cR prime number 1 to 6) Amino group is the same as above are used.

When a hydroxyl group is present in the substituent represented by R in compound (1), this hydroxyl group ? Furthermore, acyloxy groups (e.g. acetoxy, propionyloxy 4).

It can also be converted into a halogen or azide group.

Lower alkyl μ (carbon number 1 to 6) substituted with amide group, V ide group, imino group, lower γ μ μ imine with secondary prime number 1 to 6, lower alkyl lv (carbon number 1 to 6) The reaction of converting into amide 7 group and guanidi 7 group is achieved by various known methods. The reaction of converting the amide group into an amide group can be carried out by bringing it into contact with an acylating agent in the presence of a solvent. The solvent to be used is not particularly limited, but halogenated hydrogen compounds such as chloroform and dichloromethane, and ether/L/s such as tetrahydrofuran and dioxane are suitable.

The acylating agent to be used is not particularly limited as long as it converts ordinary amino compounds into acylates, but for example, lower acylating agents (having 2 to 7 carbon atoms) such as acetic anhydride and propionic anhydride are used.
Fatty acid anhydrides 9 For example, lower (carbon a2 to 7
) Can open fatty acid halide derivatives. This reaction is suitably carried out in the presence of a base, and the bases used include, for example, triethyl amine, an organic base exclusively for pyridine, or fatty acid alkali metals such as sodium m-acid and potassium acetate. Salt is preferred. The reaction temperature is not particularly limited, but is preferably from 0° to 40°C. The time required for the reaction varies depending on the type of annulating agent, reaction temperature, etc., but is usually about 30 minutes to 5 hours.

The conversion reaction of an amino group into a ureido group is carried out by reacting a substituted isocyanate in the presence of a solvent. Suitable substituted isocyanates include, for example, methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p-glomophenyl isocyanate, and the like.

The reaction temperature is around 0° to 40°C, and the reaction time is usually 30°C.
It takes about 5 minutes to 5 hours.

Imino group-substituted lower Apki/I/(1 to 6 carbon atoms) Amino 7 group, lower Apki μ imino group having 1 to 6 carbon atoms 7
The conversion reaction to group-substituted lower aμ * (degree prime number 1 to 6) ami 7 group is performed using dioxane, tetofhydrofufun, dimethyρ
Formamide, chloroform, acetone, acetonitrile! , for example, by reacting with imidoester/L/s in a solvent such as water. Suitable imidoesters/L's include, for example, methi-ρ-formimidate, ethitsuno-V-homimidate, and benzi-μ-formimidate.

Methylacetimidate, methylacetimidate, methylphenylacetimidate, ethyl N-methylhop
Muimidate, mechi/L/N-ethylho! Muimidate, methiIL'H-isopropylformimidate, and the like are used. The reaction temperature is around 0° to 25°C, and the reaction time is usually about 1 to 6 hours. The conversion reaction of an amino group to a guanidino group can be carried out in a solvent such as water, dimethylphosphoramide, hexamethylphosphoramide, etc.
1μ Kiμ or 0-aryl pseudourea, or
This is carried out by reacting with S-akyl or S-ary μ pseudothioureas. The above pseudoureas include 0-methylpseudourea, S-methylpseudourea, o-2°4-dichloropheny! Pseud R
element, o, -x l N-trimethyl pseudourea, etc.
The pseudothioureas mentioned above include 5-p-nitropheni! Pseudothiourea and the like are used. The reaction temperature is 0
The reaction time is usually about 1 to 24 hours.

The reaction of converting a hydroxyl group into an acyl ρoxy group, a halogen, or an azide group is coupled by various known methods. The reaction for converting a hydroxyl group into an acyloxy group can be carried out in the same manner as the reaction for converting an amino group into an amide group. Conversion to a halogen atom is achieved by halogenation according to a conventional method. Examples of the halogenating agent used include thiodiμ chloride and thiodiμ bromide.

Oxalyl chloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine, etc. are used. Suitable examples of the ig used include ethers such as tetrahydrofuran and dioxane, and aromatic subhydrogenides such as benzene and toene. The reaction temperature is preferably about 0° to room temperature, and the reaction time is usually about 15 minutes to 5 hours. The conversion reaction of a hydroxyl group to an and group is achieved by reacting with hydrogen azide or dipheny/l'phosphorus 11112 azide in the presence of a phosphine derivative and an azosica μponic acid diester. The phosphine derivatives used include, for example, triphenylphosphine, trin
-butylphosphine is preferable, and as the azodicarboxylic acid diester, for example, azosica phosphoric acid dimethyl ester, azosica phosphoric acid diethylnisder, etc. are used. The solvent used is, for example, dichloromethane.

Preferred are halogenated hydrogenated hydrogen compounds such as chloroform, ethers such as tethohydrofuran and dioxane, and the like.

The reaction temperature is preferably about 06 to 60°C, and the reaction time is preferably about 5 minutes to 5 hours. Compound (1,) or a salt thereof obtained in this way is purified by a method known per se, such as concentration, liquid conversion, dissolution, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography, etc. be able to.

The raw material compound (1) used in the present invention can be produced by a method known per se or a method analogous thereto. For example, it can be manufactured by the method shown in Scheme 1 or a method similar thereto.

[In the formula, R1, X, Y and 2 have the same meanings as above, t, X'
is a lower alkylene group or a lower γμkenylene group which may have a protected hydroxyl group, R2 is a hydrogen atom or a protecting group for an amide group, R'' is a hydrogen atom or a protecting group for a hydroxyl group, or R2 is a hydrogen atom or a protecting group for an amide group, or R3's are bonded to each other to represent a hydrogen ashing group or a heterocyclic group, and R4 represents a hydrogen ashing group or a heterocyclic group].

In the above, the lower alkylene group or lower γμkenylene group in the lower alkylene group or lower alkenylene group which may have a protected hydroxyl group represented by X' is as defined in X. Similar ones are used.

A protecting group for the hydroxyl group in the lower alkylene group which may have a protected hydroxyl group represented by X' and R3
As the protecting group for the hydroxyl group represented by, the same ones as in 4 above can be used. The protecting group for the amide group represented by R includes, for example, a tri(lower axyl group having a prime number of 1 to 6) substituted silyl group such as trimethy/L/S/suμ, t-buty p-dimethylμ, etc. A 5- to 6-shell cyclic ether group such as -tetrahydropyran is used. The hydrogen ashing group or heterocyclic group represented by R and R bonding to each other, and the hydrogen ashing group or heterocyclic group represented by R, are the same as those defined for R above.

According to the above scheme, starting materials include, for example, 4-(2-hydroxyethyl/I/)azetidin-2-one (B.G. Kristen et al., Journal of Organic Chemistry).
al of Organic Chemistry L
45, p. 1130 (1980), the compound (IV) obtained by subjecting an amide group and a hydroxyl group to a cyprotection reaction by a known method is used.

There are no restrictions on the selection of the amide group-protecting group R2 and the hydroxyl group-protecting group R3' as long as they do not interfere with the following reaction. μ group etc. are used.

Furthermore, R2 and R3 combine to form a compound of compound 1) represented by the formula [in the formula, R5 and R6 each represent a hydrocarbon group]. You can. Here R
The hydrocarbon group represented by R is the same as that defined for R above, and includes, for example, lower alkyl groups having an ash number of 1 to 3 such as methi, ethyl, iso, and propyl groups. , and those in which R5 and R6 are bonded through an alkylene group of 3 to 6 prime numbers are often used.

In compound (XVI), both R5 and So are methyμ
Compounds of the group have already been described in the literature (B.G. Christensen et al., J.A./l/II Op.
Ni, Ri Chemistry (Journal of Org
anic chemistry) + vol. 45, 11
30 pages (1980)). This compound is 4-(2-hydroxyethyl/L/)azetidin-2-one,! -2, 2
-dimethoxyfuropane in the presence of an acid catalyst such as boron trifluoride etherate*p-)p-ensulphonic acid. The compound (XVI) in which R5゜R6 is a group other than a methoxyμ group is ``2,2-dimethoxypropane used in the above reaction
Ketones (e.g. diethyl ketone).

Methiμ ethyl ketone, diisopropyl ketone, cyclopropanone, cyclobutanone, cyclopentanone, cyclohexanone, etc.) f: Easily produced by using. In the following reaction, it is preferable to use compound α■) as a starting compound.

The first step is a step in which the 3-position of compound (1v) is sphenylated with a sphenylating agent to obtain (Vl-). 2
Disμphytes represented by.

2 Thiosulfonates represented by R'S-802R.

[same meaning].

This reaction is carried out for 1 mo μ of compound (■),
/L' amount of the oxidizing agent may be used.

The reaction is usually carried out in a solvent in the presence of a base. Examples of the base used include strong bases such as lithium diisopropylamide, lithium isopropylcyclohexylamine, sodium amide, and potassium hydride.

Suitable solvents include, for example, tetrahydrofuran and dimethoxyethane.

Ether, dimethylformamide, dimethyspphosphate, etc. are used.

The amount of base added is suitably about 1 to 3 mol per 1 mol of compound (■). The reaction temperature is about -80°C to θ°C. The reaction time is about 30 minutes to 6 hours. Compound (V) can theoretically exist in two types of diastereomers regarding the 3-position substituent. These isomers are kalamuku pmatoguffii.

They can be isolated by operations such as recrystallization, and each can be used in the next step reaction, but the mixture can also be used in the next step reaction without isolation.

The second step is a step of oxidizing the 3-position of compound (V) with an oxidizing agent to produce compound CM)i-. Aμki used! Examples of the converting agent include 2Y-8-X-A (wherein A is a halogen atom, a p-to-enes-honi-μ group, a methane-μ-honi-μ group, a trifluoromethanesulfonyl-p group, or an oxo-based p-group). , X and Y have the same meanings as above.

Examples of the halogen atom represented by A above include chlorine, bromine, and iodine.

In the reaction of this step, a strong base similar to that used in the first step,
Compound (V) using a solvent at a temperature of about -80° to 0°C
The reaction is carried out by reacting about 1 to 20 moles of the acylating agent per mole.

The above conversion reaction of Compound (■) - Compound (V) - Compound (VI) is converted into Compound (ff) - Compound (Vl) in the same container without isolating to Compound 1) 1 (see above figure). It is also possible to refer to the middle 1st step). At this time, compound (■7) was treated with the same strong base and solvent as used in step 1 at a temperature of about -80° to 0°C, and the amount was approximately equal to 1 mole of compound (■). Compound (VI) can be obtained by adding a mono-V amount of a sulfuric agent followed by about 1 to 20 moles of an oxidizing agent. In this case, the appropriate amount of the strong base to be used is 2 to 3 moles μ per 1 mole of compound (■). The resulting compound (Vl) may theoretically exist in two types of diastereomers depending on the substituent at the 3-position. In this reaction, these isomers can be isolated by operations such as column chromatography and recrystallization, and each can be used in the next step reaction, but even 1- of the mixture can be used in the next step reaction without isolation. can be used.

The third step is a step for selectively producing 3,4-cis-substituted azetidinone (■a)r by reacting compound (Vl)i with a reducing agent.

A suitable reducing agent is, for example, the organotin compound nickel μ.
Compounds, mercury compounds, zinc compounds, etc., preferably organic tin compounds represented by the formula % (wherein R7 represents a hydrocarbon group) are used. As the hydrocarbon group represented by R7, the same ones as mentioned for R can be used, and for example, methyl, ethyfi/,
n-propyl, isopropyl μ, n-butyl, t-buty/
A lower alkyl group having 1 to 6 carbon atoms such as I/, fi-bench/I/, phenyl group, or a lower alkyl group having 1 to 3 carbon atoms (for example, methyl).

Substituted phenyl groups (ethyl, propyμ groups, etc.) are used. More specifically, triphenytin hydride, F-n-butyltin hydride, diphenyltin hydride, di-n-butyltin hydride, triethyltin hydride! Tin, trimethyltin hydride, and n-butyltin hydride are used.

Among these, preferred is triphenyhydride/l'tin (hydrogenated)! J-n-buchi! such as tin. The reducing agent is usually used in an amount of about 1 to 107μ, preferably about 1.2 to 57μ per 17μ of compound (Vl). Water reaction tjO,1
It is suitably carried out in the presence of an MM group opening initiator such as azobisisobutylonitrile Iv or di-t-butyl peroxide having a molecular weight of 0.5 to 0.5 m. Alternatively, two light irradiations may be performed in addition to the use of this free radical initiator. Although the reaction may use the reducing agent itself as a solvent, it is usually carried out in a medium that does not participate in the reaction. A suitable solvent is, for example, acetone.

Ketones such as methyl ethyl ketone, dioxane.

Ethe/I/s such as tetrahydrofuran, methanol-μ.

Examples include alcohols such as ethanol-μ, aromatic hydrocarbons such as benzene, toluene, and xylene. The reaction temperature is usually about θ° to 130°C, especially about 10° to 1
00°C is preferred. If necessary, it can be carried out in an atmosphere of an inert gas such as nitrogen or argon. The reaction time is about 1 to 24 hours. This reaction mainly produces a compound (■a) having a cis configuration at the 3 and 4 positions, but a small amount of a compound (■b) having a 3,4-) Hunne configuration (O) is accompanied by a small amount of by-product gold. From the reaction mixture, compound (vI
Isolation of [a) is carried out according to methods known per se.

For example, compound (■a) ft can be easily isolated by distilling off the solvent of the reaction mixture and subjecting the residue to recrystallization or column chromatography.

Compound (malb) is produced by directly converting the 3-position of compound (IV) to 1〃μ-conjugating agent ($2'
process).

The conversion reaction from compound i) to compound (vlIb) was achieved by the same method as the conversion reaction from compound (V) to compound (Vl).

In other words, is it used for the second process? Similar strong bases.

solvent? compound (■) at a temperature of about -80° to 0°C.
Compound (■b) is obtained by reacting about 1 mol to 207 µm of an oxidizing agent per 1 mol µm.

In the following 4th to 12th reaction steps, each of the 3.4-cis isomer and the 3.4-)lance isomer or a mixture of the two may be used.

The fourth step is a reaction step in which, when the compound (■) has a hydroxyl group, the hydroxyl group is subjected to a protection reaction to produce the compound (W)t-. As the protecting group for the hydroxyl group in the compound (t'ill), the same groups as those mentioned above can be used, but among them, ethers such as β-methoxyethoxymemethyl, meFkiVmethiμ group, methiμthiomethyl group, etc. μ
Protecting groups that form bonds are preferred. Among these, β-methoxyethoxymethy/l' group is particularly preferred. The reaction for introducing a protecting group is accomplished by a method known per se. Furthermore, for example, in the case of the protecting group that forms the above-mentioned ether μ bond, β-methoxyethoxymethy! Chloride.

It is carried out to react halogenated acids such as methyl chloride, methylthiomethyl chloride, etc. This reaction can be performed with, for example, triethyl amine, diisopropyl ethylamine, and pyridine.

It is carried out in the presence of a base such as n-butymu lithium or sodium hydride. In this reaction, halogenated a
The amount of Ki and the base to be used is about 1 to 20 mo, preferably about 1 to 5 mo, per 17 μ of compound (■). The reaction is usually carried out in a solvent. The solvent used is dichloromethane.

Chloroform μ, carbon tetrachloride, tetrahydrofuran.

etherμ, dimethoxyethane, acetonitrile/I/.

Examples include dimethylformamide and dimethylformamide. The reaction temperature is about -2' to 100°C.

The reaction time is about 30 minutes to 72 hours.

The fifth step is the substituent at the 3-position of the compound (■), (formula y-s-x
This is a step of producing compound 1) by oxidizing the thio group of the group represented by '- with an oxidizing agent to convert it into a sulfonyμ group. This oxidation reaction of the thio group can be carried out using mild oxidizing agents that do not act on the β-lactam ring, such as perbenzoic acid, ozone, fedichloroiodide, hydrogen peroxide, sodium metaperiodate, and sodium hypochlorite. It is performed completely bent over. Among these, for example, perbenzoic acid 1 m-p-perbenzoic acid is particularly preferred. The oxidizing agent is used in an amount of about 27 ml or more per 0'x1l)l moμ of the compound. The reaction is usually with dichloromethane or chloroform, for example.

It is carried out in an inert solvent such as carbon tetrachloride. The reaction temperature is about -30'' to 25°C. The reaction time is about 10 minutes to 10 hours.

The 6th step is the protecting groups R and R of compound 1)? This step is to remove the compound CX) and produce compound CX)k. Removal of protecting groups R2 and R3 is carried out by applying various known deprotection methods. For example, when compound 1) is a compound derived from compound (X), the protective group is removed in a solvent such as an acetic acid aqueous solution at a temperature of about 0° to 75°C for a reaction time of about 5 minutes to 16 hours. It is carried out by acid hydrolysis.

The seventh step is a step in which the hydroxyethyl group at the 4-position of the compound (2) is converted into a poxymethyl group by an oxidation reaction to produce the compound (XI).

The oxidation reaction can be carried out using various known oxidizing agents such as Jones' reagent, potassium permanganate, and silver oxide. The reaction is carried out in a solvent such as aqueous tetrahydrofuran, aqueous dioxane, or acetone. The reaction temperature ranges from -10° to 40°C. The reaction time is 1
The period is from 0 minutes to about 24 hours. In particular, in a solvent such as acetone at a temperature of about -10° to 30°C for 10 minutes to 8
Preferably, the oxidation reaction is carried out using a Jones reagent reservoir for about an hour.

The target compound (1) includes both an optically active form and a racemic form.Although it is also possible to produce an optically active (1)r from an optically active ([), compound i) is a racemic form. In the case of (XI) (racemic form) of the intermediate raw material obtained
It is preferable to perform optical separation using sound. Optical resolution can be carried out using various known methods such as crystallization method or compound CM
) k, such as quinine, givvn, ephedrine,
A method for fractional crystallization of diastereomeric salts formed by reaction with optically active amines such as strychnine and heptaruphine;
It is optically resolved by physical separation methods such as chromatography.

The 8th step is the *exchange force ρ boxy μ at the 4th position of compound (n).
The group r is activated and then two atom atoms are extended to form the compound (
][) is the process of manufacturing.

This reaction is carried out between compound (Xi) and, for example, 1,1'-force
m-diimidazo or 1'-calponiμbis(2
-methylimidazo-1v) to give the imidazolide, and then without isolating the imidazophyte, the formula (R10COCH2Coo)2M
g [wherein R1 has the same meaning as defined above] is reacted with a magnesium salt of a malonic acid derivative.

The amounts of the imidazolide reagent and the magnesium salt of the malonic acid derivative used in the reaction are approximately 1 to 27 μ for the former and approximately 1 to 37 μ for the latter relative to 1 mo μ of compound (XI). The reaction is usually carried out in a solvent such as tetofhydrofuran or dimethoxyethane. The reaction temperature is about 06 to 50°C. The reaction time is about 1 to 48 hours. In the ninth step, the compound (■) is diazotized to form the compound (X
l[)t- is the reaction that produces. This diazotization reaction can be performed using, for example, triethylamine or diethylamine.

Compound (■) in the presence of a base such as pyridine, for example p-capoquinbenzene μhoniμ azide.

p, -) /l/This is carried out by reacting with an azide compound such as enesulfonyl azide or methanesulfonyl azide. The amount of base is usually used in large excess relative to (X[[). The amount of the azide compound is about 1 to 2 times mo/L/i relative to compound (XI). The reaction is usually carried out in a solvent such as acetonitrile, dichloromethane, or tetrahydrofuran. The reaction temperature is about -10 to 40°C. The reaction time is usually about 1 to 48 hours.

The 10th step is the step of removing all the protecting groups for the hydroxyl group of compound (XI) to produce compound (Xff)Th, but it is not essential to remove the protecting groups in this step, and it is a step that is pharmaceutically acceptable. If it is a protective group, it may remain in the target compound (1), and if necessary, the protective group can be removed in any step after this step. Removal of such protecting groups is carried out by applying various known deprotection methods.

When the protecting group for the hydroxyl group is β-methyne ethoxymemethyl, the reaction can be carried out by reacting with a p-is acid such as titanium tetrachloride or zinc bromide in a solvent such as chloroform, dichloromethane, or tetrahydrofuran. It will be done. When μ-is acid is used, the reaction temperature is approximately -10° to 40°.
It is ℃. The reaction time is about 5 minutes to 10 hours.

In the 11th step, compound 0[)k is subjected to a cyclization reaction to form compound (
This is the process of manufacturing XV).

The present cyclization reaction is carried out using a compound CXW) such as copper sulfate, copper powder, or rhodium acetate in a solvent such as benzene, toluene, or tetrahydrofuran.

This is carried out by cyclization in the presence of a catalyst such as badge ram acetate. The reaction temperature is approximately 50 λ et al. 11
It is 0°C. The reaction time is about 1 to 5 hours. It is usually carried out in an atmosphere of an inert gas such as nitrogen or argon. In addition, this cyclization reaction is carried out for compound (XIV) 1 in a solvent such as benzene, tetrahydrofuran, hydrogen tetrachloride, diethyl ether μ, etc. at about -10 to 40°C.
This can be carried out by irradiating light for 0 minutes to 2 hours.

The twelfth step is a step of activating the compound (X-man) with an activator to produce compound (1).

When 2 in compound (1) is a substituted sulfonyl poxy group, about 1 to 3 times the mole of compound CXV), for example, anhydrous p-)μ encephalic acid, anhydrous p-nitrophenyl μ
Sulfonic acid anhydride, 2,4-) lysoprobyl-phenylsulfonic acid, methane μphonic anhydride, p-)/Reenne μhoniμ chloride.

p-Glomophenylnuclear chloride 1"f) Sulfonyl plating agent, such as dichloromethane, chlorofluoro!
m, acetonitrile/L', dimethoxyethane.

For example, triethyl μ in a solvent such as tetrahydrofuran.
Amine, diisopropylethylamine, pyridine, 4-
The reaction is carried out in the presence of a base such as dimethylaminopyridine. Usually the reaction temperature is about -20 to 40°C. The reaction time is about 30 minutes to 5 hours. Compound(
When 2 in 1) is a halogen, a halogenating agent (e.g., oxalyl chloride + (Ca H5
)3P012, (C6H5), PBr2. (C6
Compound (IT) can be converted to compound (1) by reacting under the same conditions using H50)3PBr2゜thionyl chloride, etc.). Even when 2 in compound (1) is a di-substituted phosphoryμoxy group, a phosphorymu-izing agent (e.g., Diphenymu phosphate chloride.

Compound (XV) can be converted to compound (1) by reaction using dimethyl phosphoryl chloride, diethyl phosphoryl chloride, etc. under the same conditions.

Moreover, the 3,4-cis form (VIIa) of the above-mentioned scheme 1 is the scheme 2
It can also be manufactured by the method shown in or a method similar thereto.

Scheme 2 %Formula %) ) () (■a) 3.4-cis form [In the formula, X, Y, R2, R3 and Z have the same meanings as above] When described according to the above scheme 2, starting The substance (X■) is z
/l/, z-i-packet, etc. (L, A, Paque
ttet al,) Journal Op American
Chemica/L/-Society (, T, Amer, Ch
em, Soc, ) vol. 90, p. 3897 (1968
It can be manufactured by the method described in 2003). The steric configuration at the 1.6-position of compound (X) is cis, and this relationship is maintained in the following series of reactions, allowing it to be converted into a compound (■a) having a cis configuration.

The first step is a reaction step in which the amide group of compound (X) is subjected to a protection reaction to produce compound (XVffltr).

As the protecting group for the amide group represented by R2, the same groups as those mentioned above can be used, and among them, for example, t-buty-dimethylsili-μ group is particularly preferred. The reaction for introducing this protective group is carried out by reacting the compound 0) with, for example, 1 to 5 equivalents of t-butyμ dimethylsilyl chloride in the presence of 1 to 5 equivalents of a base. This reaction is usually carried out in a solvent. Suitable solvents include ether, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane, and the like. Examples of the base used in the reaction include tertiary amines such as triethyamine. Reaction time is usually -30℃ to 100℃
It is C. The reaction time is about several minutes to 24 hours.

The second step is to replace the double bond of compound (XVI[) with hydroxyV
This is a step for producing compound (X■)k by converting it into lv.

This hydroxy-μ conversion reaction is carried out using mild oxidizing agents that do not act on the protecting groups of the β-fucutam ring and the amide group, such as osmic acid, a combination of osmic acid-N-methymophorin N-oxide, and potassium permanganate. , a combination of hydrogen peroxide and formic acid, etc. Among these, in particular, for example, osmate-N-methymophorin N-
Oxides are preferred. The present oxidizing agent is compound (Xi) 1 moμ
About 17μ to 5-I:l'v is used. The reaction is usually carried out in an atmosphere of an inert gas such as argon, nitrogen, or the like. The reaction temperature is about -30° to 60°C. The reaction is usually carried out in a solvent. A suitable solvent is t-Getano! , acetone, dichloromethane, etc. are used. The reaction time is about several minutes to 24 hours.

The third step is a step of oxidizing the diol form of compound (I[) and converting it into a sia μdehyde form to produce compound (XX)'. As an oxidizing agent for this diol body, periodic acid,
Sodium periodate, lead tetraacetate.

Potassium permanganate and the like are used. Among these, periodic acid is particularly suitable. The amount of periodic acid used is approximately 1 mole to 5 times the amount of compound (XI)! It is. Reactions usually involve water, tetrohydrofuran, methanol! ,
It is carried out in a solvent such as acetonitrile. The reaction temperature is -20° to 50°C. The reaction time is about 5 minutes to 24 hours. The produced compound CXX) may be isolated, but the reaction solution r can also be used directly in the next reaction without isolation.

Is the 3rd step the double bond of compound CXV'l)? This is a process of directly producing compound CXX)k by oxidation. As the double bond oxidizing agent, for example, ozone, potassium permanganate, chromyl trichloroacetate, etc. can be used. Among these, ozone is particularly preferred.

This oxidation reaction is usually carried out by introducing ozone gas into the compound CXIm) in a solvent. As a solvent,
For example, methanol-μ, ethanol, dichloromethane, e
Acid xt-μ etc. are used. The reaction temperature is about -80 to 10°C. The reaction time is about several minutes to 10 hours.

The fourth step is a step of stereoselectively ring-closing compound CXX) by an intramolecular Aμ-dol reaction to completely produce compound (XXI). Intramolecular aldo of compound (XX)! The reaction is usually carried out in a solvent in the presence of a catalyst. The catalyst used in this reaction is preferably a combination of an organic acid and two secondary amines, and examples of the organic acid include acetic acid, trifluoroacetic acid, octanoic acid, p-)ρenesulfonic acid, camphoric acid, etc. As the secondary amine, for example, pyrrolidine, piperidine, morpholine, dibenzi μamine, etc. are used, and these are used in combination as appropriate. Also used are proline and the like having both functional groups (a μboxyμ group and an amino group) in the molecule. Among these, for example, a combination of dibenzylamine and trifluoroacetic acid is particularly suitable. The amount of these catalysts used is approximately 0 per 1 mole of compound (XX)
．． 01 mo μ to 10 mo μ. Examples of the solvent used include toehabenzene, toluene, ether μ, methanol, tetrahydrofuran, dimethylformamide, and hexamethyltriamide phosphate. The reaction temperature is about -10° to 120°C.

The reaction time is about 5 minutes to 24 hours. The produced compound (XM) can be isolated, but it is also possible to use the entire reaction solution as it is in the next reaction without isolation.

The fifth step is to reduce the homi group of compound (XX[) with a reducing agent to convert it into a hydroxymethymu group, and to convert the
'This is the process of manufacturing. Suitable reducing agents include, for example, sodium borohydride, lithium borohydride,
Sodium cyanoborohydride.

Zinc borohydride and the like are used. Among these, sodium borohydride, sodium borohydride, and the like are preferred. The amount of reducing agent is approximately 1 for 17μ of compound (XXI).
It is used in moles to 5 moles/14. The reaction is usually methanol
It is carried out in a solvent such as μ, ethanol, tetofhydrofuran, or benzene. The reaction temperature is about -50° to 50°C. The reaction time is about 10 minutes to 10 hours.

The sixth step is a step of converting the hydroxy μ group of compound (XXI) into a substituent represented by oz to produce compound (XXIIDk).

This reaction is carried out according to the method of the 12th step in Scheme 1.

Dokuni compounds (compounds in which 2 in XXIID represents chlorμ or bromine include halogenating agents such as the above-mentioned thionyl chloride, N-chloroμsuccinimide and dimethylsulfite, or N-bromosuccinimide and dimethylsμ
It is manufactured using phyto etc.

The seventh step is a step in which the double bond of compound αXII) is oxidized to convert it into a ketoaldehyde form to produce compound CXXW)'x. This reaction is carried out according to the method of step 3' above. The generated compound (Hff) can be used in the next reaction without isolation, and is reduced by 1 to produce compound αm. This reaction can be carried out in the same manner as the reduction reaction in the fifth step.

The 9th step is a protecting group (R) for the amide group of compound (XXV).
= to produce compound 11) t-.

The protecting group for the amide group is, for example, t-glydimethylsili
In such cases, for example, fluorine 4L, such as tetophyl-n-butylammonium fluoride or potassium fluoride, @Plastic 1 or, for example, hydrochloric acid.

(by treatment with an acid such as sulfuric acid, vinegar, acid, or formic acid). Suitable solvents include tetrahydrofuran and dioxane. Reaction temperature is 0° to 60°C
That's about it. The reaction time is about 10 minutes to 24 hours.

The 10th step is a step of protecting the -class hydroxyl group and amide group of compound (XXVI/1) to produce compound C''mh). (XVI) It can be carried out according to the method of making ill!

The 10th step protects the -class hydroxyl group of compound (■V),
This is a process for producing the compound (:Gfl)Th. As the protecting group for this hydroxyl group, for example, the above-mentioned t-butydimethylsili[mu] group, 2-tetrahydrobilane, etc. can be used.

The 11th step is a step for producing compound (■a)k by substituting the group represented by 2 of compound (XllVl[) with the group represented by YS. In this substitution reaction, for example, dimethylformamide and dichloromethane are added to compound 01F[)'.

This is carried out by reacting with a mercaptan in the presence of sodium hydride, lithium hydride, etc. in a solvent such as acetamide or benzene, or with an aqueous solution of a sodium salt or potassium salt of a mercaptan in a solvent such as dimethylhopamide.

The amount of mercaptan or sodium salt or potassium salt of mercaptan to be used is about 17 to 107 μ per 1 mole of compound (m). The reaction temperature is -10° to 60°C. The reaction time is about 1° to 24 hours.

The starting material compound (XW) is racemic and optically t
An optically active compound (X
If W) is used, the optically active compound (■a) can be obtained by the above method, and therefore the optically active target compound (1) can be obtained.
'kff can be built. Optically active compound (Xv
II) can be produced, for example, by the method shown in Scheme 3 or by a method similar thereto.

Scheme 3 % formula %[) (4) [In the formula, -COOR1 has the same meaning as above, -COORQ
(S--,,0i, indicates a carboxyne μ group which may be monolithically layered. However, R1 and Rk are not the same protecting group at the same time).

Referring to Scheme 3 above, the starting material (i) can be prepared by reacting anhydrous cis-Δ-tetophhydrophthalic acid with alcohol-yvM denoted ROH. For example, when R1 is methyl, a known method [Chemical Abstracts, (Chem, Ab
struct) Volume 49.

5328i (1955)].

The first step is the step of optically resolving the racemic (1) and producing the optical antipodes ([) and (XXX).

This optical separation is performed by a method known per se. For example, after forming a diastereomeric salt of a habitant (XIXi) IC with a basic optical resolution agent, fractional crystallization can be performed to isolate each optical antipode. Cinchonidine is used as an optical resolution agent.

cinchonine, quinine, brucine, ephedrine.

Strychnine, Mopfin, L-aginine, etc. are used. Among these, cinchonidine and V-nchodine are particularly preferred. The optical resolution agent used is about Σmoμ to 17〃 per 1 moμ of compound (XW). Solvents used for fractional crystallization include, for example, meta/-/L/, ethano-ρ, acetone, acetonitrile μ, dichloromethane,
Examples include dioxane and tetrahydrofuran. Fractional crystallization is usually carried out at about -40° to 30"C. In this process, both optical antipodes can be led to the desired compound (XWn, i.e. compound -) in the manner shown in the figure. After conversion to the compound OD), a reaction known per se, such as ρTius reaction [Organic Reactions + 3rd
Vol., page 337, the compound (XXXII
) can be converted to The compound α■) can be converted into the compound (X:HVl) by enantioconversion and then converted into the compound (XXIm) in the same manner as described above.

The azidation reactions in the second and 11th steps are carried out by drying carboxylic acids such as acid chloride, mixed acid anhydrides, etc. to form active layer conductors, and then reacting them with sodium azide, or by azidation of diphenyl phosphoryl azide, etc. (by reacting with a reagent). The azidation reagent is a compound ('
In) or compound (approximately 17 to 3 molv per 17 μm is used. The reaction is usually carried out in a solvent. Suitable solvents are usually benzene, dioxane,
Dichloromethane, tetrahydrofuran, etc. are used. Furthermore, it is also suitable to carry out a reaction with sodium azide in a mixed solvent of water and dichloromethane using a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate. The reaction temperature is about -20° to 100°C. The reaction time is about 10 minutes to 10 hours.

The third step is a step of converting the compound αm) to the 6-position by an acid azide-based p-1 reaction, and then adding an alcohol-μ compound 2 to produce the compound (Xm).

This reaction is usually carried out by heating in a solvent and then adding an alcohol compound in the presence of a base such as triethylamine or triethylenediamine. Examples of solvents used include benzene, toluene, and dichloroethane. The reaction temperature is about 4σ to 130”C. As the μcoμ compound, for example, 2-methyl l′v
7. The /I/honyletha protecting group was removed to form the compound (XXXI
This is the process of manufacturing I[)k. The protective group can be removed by the above-mentioned methods, but among these, acid or alkali treatment is preferable. Alternatively, compound (XIXII) can be obtained by selectively deprotecting 7'C, for example via compound (XXXIV).

The fifth step is the step of subjecting the compound (■) to a ring-closing reaction to form a β-lactam ring to produce compound (FI). This ring-closing reaction involves combining compound (IXXII) with, for example, triphenyμ phosphine and 2. gauge viridi μ Combination of dislv phyto or tri-n-butylphosphine 2,2'-
This is carried out by heating a combination of dipyridyldisμphyto (equivalent to about two times the equivalent of compound αI), respectively), preferably in a solvent such as acetonitrile. The reaction temperature is about 60° to 150°C. The reaction time is about 1 hour to 24 hours.

The eighth step is a step of producing compound (XVI) by subjecting compound (XI) [) to a ring-closing reaction. This ring-closing reaction is carried out by reacting the compound αXXN) with a Grignard reagent. Echi as a Grignard reagent reagent!
Magnesium chloride, t-butylmagnesium chloride, phenylmagnesium chloride, etc. are used.

The reaction is carried out in a solvent such as ether, dioxane, or tetrahydrofuran. Reaction temperature is -30° to 50°C
That's about it.

Reaction time is 1 hour to 24 hours. Alternatively, the compound (XXXff) can be protected with a Vsu group such as trimethyμ chloride, and then reacted with the Grignard reagent.

The 9th and 10th steps describe the enantioconversion method. In the compound (XXD, if R1 is removable with an alkali, such as a methyl group,
An alkali-stable group, such as a t-butyl group, is introduced into RL of compound (XXXV), and then compound 00[
By treating XV) with alkali, the compound (XIXV
It can be converted to I). Introduction of t-methyl group is carried out in compound αXX
) with isobutyne in the presence of sulfuric acid in a solvent such as dichloromethane. The reaction temperature is about -10° to 40°C, and the reaction time is about 1 to 7 days. Compound (XXm) is shown above, fc (XXX[) -(XXX[[) -(XX
Xll[) (02m) Compound (X
XXM) (12th step).

Further, the lance body (Vlb) in 3.4-) of Scheme 1 can also be manufactured by the method shown in the figure below or a method similar thereto.

(XXF[[) (Vllb)3.4-tra=yy, [wherein R2, R3, X and Y have the same meanings as above].

The raw material compound CXXXVm) can be used, for example, in the Journal of Organic Chemistry (Journalof Organic Chemistry).
Organic Chemistry), Volume 45, 1
It can be produced according to the method described on page 130 (1980) or a method analogous thereto. The chemical reaction in this step is carried out by a method similar to the reaction for converting compound (IIjI) to compound (■a) described above.

The reaction product or its salt thus obtained can be isolated by means known per se, such as solvent extraction, liquid conversion, dissolution, crystallization, recrystallization, chromatography, etc. can.

REFERENCE EXAMPLES AND EXAMPLES The present invention will be explained in more detail by reference examples and examples.

Symbols used in Reference Examples and Examples have the following meanings.

8 Nisinglet d: Dap V, To dd: Dup μ doublet) ddd: Dup μ Dub μ doublet t Ni triplet q: Qua μ chit ABq: Qua μ chit of ABW m: μ triplet J: Coupling constant b2 Wide reference The packing material for cuff chromatography in Examples and Examples is Prolisi p (Florisi
l, IQ O-200 mesh, manufactured by Florizin Co., Ltd.
American, Diaion HP 20 (manufactured by Mitsubishi Chemical Industries),
Amberphyto
200 mesh, manufactured by Memulisha.

(West Germany).

Reference example 1 7-(1-hydroxy-8-thianclopentyl)-7
-phenylthio-8-oxo-2,2-dimethyl-8-
To a solution of 8.41 oxa-1-azabicyclo[4°2.0]octanediisopropylamine in anhydrous tetrahydro 7 run add, 15 g of 15% n-butyllithium/hexane is added at -78°C under a nitrogen atmosphere. To this solution is added a solution of 8-oxo-2,2-dimethyl-8-oxa-1-azavinchlo[4,2,01 octane 1.55 F in 10 ml of anhydrous tetrahydro 7 run over 10 minutes, and the mixture is stirred for 15 minutes. To this mixture was added a solution of 2.18 f/diphenyl disulfide in 10 ytl of anhydrous tetrahydrofuran over 10 minutes, and after stirring for 15 minutes, a-thiacyclopentanone 2,
Add 041 over 5 minutes and stir for 30 minutes. The reaction solution was added to acetic acid (21)-water (60m?) under water cooling.
Separate the organic layer and extract the aqueous layer with ethyl acetate. The organic layers are combined, washed successively with 0.5N aqueous sodium hydroxide solution and water, dried (Nag 804), and the solvent is distilled off. The residue is subjected to cuff chromatography using silica gel (hexane-ethyl acetate = a:1-1:1) to obtain the title compound s, oay as an oil.

I RJ/,, Xcm, a450, 174ON
M R (90 MHz, CDCl2) δ: 1.40,
1.56 (each aH.

sX2), 1.5-1.9 (2H, m), 2-2
-2-4 (2H, m), 2.8-8.2 (4EI, m)
, a-8-4,2(aH,m), ? -1-7,9
(51(.

m) Reference Example 2 7-(1-hydroxy-3-thiacyclopentyl)-8
-Oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4,2,0)octane 7- obtained in Reference Example 1
(1-Hydroxy-3-thianclopentyl)-7-phenylthio-8-oxo-2,2-dimethyl-a-oxa-1-azabicyclo(4,2,0:)octane s,o
ay.

A solution of 80 gt of azobisisobutyronitrile aoowv and 8.5 wrt of tri-n-butyltin hydride in acetone is refluxed under a nitrogen atmosphere. After 5 hours, 5.0 g of tri-n-butyltin hydride was added, and after refluxing for 14 hours, 4.0 g of tri-n-butyl tin hydride was added.
Reflux for an hour. Evaporation of the solvent and treatment with isopropyl ether yielded the 6.7-cis isomer of the title compound, 1.36
g is obtained as colorless crystals. The mother liquor was subjected to column chromatography using silica gel (hexane-ethyl acetate =
1:1), 348Hg of the 6,7-cis isomer of the title compound and 182q of the 6j7-)lance isomer of the title compound are each obtained as colorless crystals.

5j7-5/; L isomer: melting point 11a-115°C KBr
-1 Engineering RvmaXart: a410. 174 ON M
R (90MHz, CDC'13) δ: 1.4
G, 1.74 (3H each.

5X2), 1-6-2.2(2H,m), 2.
5-8-2 (6H, m) ja, a6 (IH, d, J
==6Hz), 8.7-4.1 (aH, m) Elemental analysis value C engineering 2H,, Calculated value (%) as No3S: C56゜0
1: H7,44i N 5.44 Actual value (%): C
56,28i H7-a5: N 5.406.7-)
Lance isomer: 工Ru豐到aii”: 8450. 1720HM
R (90MHz, CD C13) δ: 1.40,1
．． 69 (each anjsX2), 1.6-2-0 (2H,
m)j2. a-a-2 (7H, m), 3.5-4-0 (
aH, m) Reference Example 3 6.7-cis-7-(:1-(2-methoxyethoxymethquine)-3-thiacyclopentylcy8-oxo-2
,2-dimethyl-3-oxa-1-azabicyclo(4,
2,0,:)octane 6,7-V suit-(1-hydroxy-8-thiacyclopentyl)- obtained in Reference Example 2
8-oxo-2,2-dimethyl-8-oxa-1-azabicyclo(4,2,0:)octane 370q dichloromethane 7g, f? Diisopropylethylamine 0 in solution
．． After adding 75 ml and 0.49 ml of 2-methoxyethoxymethyl chloride and allowing it to stand at room temperature for 140 hours, the reaction solution was washed sequentially with water, 2% acetic acid and water, and dried (Na
g 5O4) L, the title compound is obtained as an oil when the solvent is distilled off.

IR Hat, -1:1745 NMR (90MHz, CDClρδ: 1.aB
, 1.71 (3H each).

1, 7 (2H, m), 2-0:3-2 (6H, m),
8.17 (IJd, J-5Hz), a, aB (aH, a
), a-a-8,9 (71T, m), 4-9 (21 (.

bs) Reference Example 4 6.7-cis-7-(1-(2-methoxyethoxymethoxy)-3-thiacyclopentyl-3.3-dioxide]-8-oxo-2j2-dimethyl-3-oxa-1-
6,7-cis-7-(1-(2-methoxymethoxymethyne)-3-thiacyclopentylcy-8-oxo-2,2-dimethyl obtained from Azabicyclo[4,2,0)octane Reference Example 3 -3-oxa-1-azabicyclo(4,2,Of octane dichloromethane 2
Dissolved in 800% of metatalorobenzoic acid and cooled with water. f
Add iN and stir for 1 hour. After sequentially washing the reaction solution with a saturated aqueous sodium hydrogen carbonate solution and water, drying with Rag 5o
4) L. The solvent is distilled off. The resulting residue was subjected to column chromatography using silica gel (ethyl acetate).
Upon treatment with chloroform (1:1 then ethyl acetate), the title compound 469W9 is obtained as an oil.

IRνDing:'a-”: 1750.1820.1120
HMR (90MHz -CD'C13) δ: 1.
aB, 1.69 (each aH.

5X2), 1.9 (2H, m), 2-2-55 (, m)
, a, a6 (aH, s), 13, 0-4.0 (12H
, m), 4-86(2H,s)-Precedent 5 3.4-cis-4-carboxymethyl-3-(1-(2
-methoxyethoxymethoxy)-8-thiacyclopentyl-3#a-dioxide]azetidin-2-one 6,7-cis-7-(1-(2-methoxymethoxy)-3-thia) obtained in Reference Example 4 cyclopentyl-3.a-dioxide]-8-oxo-2,2-dimethyl-a-oxa-1-azabinclo C4,2,0,J octane 54 (1' in 7 txl solution of acetone under ice cooling, Dijeans reagent 0 .8 Add ttt and stir for 5 hours.

Gradually add 0.5 g of isopropanol to the reaction solution and bring to 1 g.
The minutes go by. After diluting the reaction solution with 10+ tons of dichloromethane, insoluble matter is filtered off using Celite, and the filtrate is concentrated.

Add 20tttl of chloroform to the residue and dry (Mg
so ) L, the solvent is distilled off to obtain the title compound 421q as an oil.

■Rp picture, a500-2800. 1760-17
aON MR (90MHz, CDC13) δ: 2-
4-4.0(1aH,m)ja,a6(aH-s)
a 415 (IHjm) -4,8 (2H,s)
j7.2 (IH, bs), 8.1 (IH, be) Reference Example 6 i3j4-cis-3-1:1-(2-methoxyethoxymethoxy)-3-thiacyclopentyl-3.8-dioxide) -4-[a-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one 3,4-cis-4-carboxinemethyl-3-(1-(2- methoxyethoxymethoxy)-2
-Thianclobenyl a,a-dioxide]azetidin-2-one 421q of anhydrous tetrahydrone 15g
1 solution of 1,1'-carbonyldiimidazole 2 at room temperature.
Add 36q and stir for 6 hours. To this solution was added 759q of magnesium salt of mono-4-nitrobenzyl ester of malonic acid, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate was added to the reaction solution, washed sequentially with dilute hydrochloric acid, water, saturated sodium bicarbonate water, and water, and then dried (tta2so4).
,, the solvent is distilled off. The residue was subjected to column chromatography using silica gel (ethyl acetate-chloroform = 1
:1 then ethyl acetate) to give the title compound 448q
is obtained as a pale yellow oil.

Neat -1 xRvmaXax: aa20, 1750-1720
゜1a50. 112O NMR (90MHz, CDCl3) δ: 2
．． 6 (2H, m), 3.30 (aH, s), 3.59
(2Ti, s), 3.2-8.9 (IIH, m), 4
-2 (IH-m) ja, 76 (2Ha e) -
5,26(2H,s) -6,86(IH.

bs), 7-55 (2H, d,, T=9Hz), 8.2
2 (2H, d, J = 9Hz) Reference Example 7 3.4-cis-4-[3-diazo-8-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3
-(1-(2-methoxyethoxymethoxy)-3-thiacyclobenzi/I/-a,a-dioxide]azetidin-2-one 3,4-nes a-(i-(2 -methoxyethoxymethoxy)-3-thiacyclopentyl-
3,3-dioxide)-4-1: To a solution of 470 q of 3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one in 14 g of anhydrous acetonitrile was added 208 q of anhydrous p-toluenesulfonyl azide at 0°C. Add 2 g of acetonitrile solution and then 0.45 ml of triethylamine. After stirring at room temperature for 1 hour, ethyl acetate was added to the reaction mixture, washed with saturated brine, and dried (Na25O4). The solvent was distilled off, and the residue was subjected to column chromatography (ethyl acetate) using silica gel to obtain the title compound 442 as a pale yellow foam.

IRv Hatakesha tatr1: aaaO, 2140, 176
0°, 1720. 1640. 1350. 112O
NMR (90MHz, CDCl5) δ: 2.6(
2H,m),,(,al(aHjs)ja, 0-3.
9 (IIK,, m), 4.2 (IH, m), 4-83 (
2H, bs), 5-36 (2H, s), 6.40 (IH
, bs), 7-54 (2H, d, J==9Hz), 8.
24 (2H, d, J = 9Hz) Reference Example 8 3.4-cis-4-[a-diazo-a-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3
-(1-hydroxy-3-thiacyclopentyl-3#3
a,4-cis-[3-diazo-3-dioxide) azetidin-2-one obtained in Reference Example 7
(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3-C1-(2-methoxyethoxymethoxy)-3-thiacyclopentyl-3,8-dioxide]
Azetidin-2-one 97% dry dichloromethane 18%
Titanium tetrachloride L, aOx was added to the m1 solution at 0°C under a nitrogen atmosphere.
Add t and stir for 1 hour. Ethyl acetate in the reaction solution: 30
Add trtl and stir for another hour. The reaction solution was added to 50 gt of 20% potassium carbonate water, the impurities were filtered off using Celite, and the organic layer was separated. After extracting the aqueous layer with ethyl acetate, the organic layers were combined and 20% potassium carbonate was added.
Wash sequentially with water (3 times), hydrogen carbonate, water, and water (3 times), dry (Na25O4), and concentrate the solvent to about 10. Then, LOtsl of benzene was added and the solvent was distilled off to obtain 6611 g of the benzene solvate of the title compound as a white foam.

■Rd company ff11: 8400. 2140. 175
0゜1720.1650'MR (90MHz, acetone-d6+CDC13)
δ: 2.5 (2H, m), a, a-3-8 (6H, m)
, a-59 (IH, d, J=6Hz), 4-4 (IH,
m), 5-51 (2H, s), 6.79 (IH, bs)
.

7-46 (a, peak due to benzene as a solvent).

7.71 (2H, djJ==9Hz), 8-28 (2H
, d, J=9Hz) Reference Example 9 7-(1-hydroxy-4-thiacyclohexyl)-7
-phenylthio-8-oxo-2,2-dimethyl-3-
Oxa-1-azabicyclo[4°2.0]octane 8-oxo-2,2-dimethyl-8-oxa-1-azabicyclo(4,2,01
Octane 620#, diphenyl disulfide 960Mg
The title compound 1.192F is obtained as colorless crystals from 511 g and 1 g of 4-thiacyclohexanone.

Melting point 191-192℃ Temperature: 3500.17'aON
M R (90 MHz, CDCLs) δ: 1. a8,1
．． 48 (3H1sX2 each), 1-6 (2H, m
), 1.7 a, a (8H, m), 1.7-4.2
(aH, m), 7.1-'I-9 (5H, m) Elemental analysis value C engineering 9 Calculated value (%) as H25'RO3"2
: C60,1a, H6,64i Na,69;S
16.89 Actual value (%): C6O-a9; H6,49; N
a, 68; S17.17 Reference Example 10 7-(1-hydroxy-4-thianclohexyl)-8
-Oxo-2,2-dimethyl-8-oxa-1-azabinclo(4,2,0)octane 7- obtained in Reference Example 9
(1-Hydroxy-4-thiacyclohexyl)-7-phenylthio-8-oxo-2,2-dimethyl-8-oxa-1-azavinchlo[4,2,0,:]octane 1.
The 6.7-cis form (542q) and the 6.7-) lance form (222#) of the title compound are obtained as colorless crystals using 192jF in the same manner as in Reference Example 2.

6.7-cis melting point 1aa-ia4°C IRvKBrot': a400, 1740ax NMR (90MHz a CDC13) δ: 1.
a8, 1.7a (each aH.

sX2), 1.6-a, a(IOH,m),
a-20 (LH, d, J”6Hz), 3.6
-8-9 (aH, m) Elemental analysis value C□3”2□N0
Calculated value as 3S (%): C57,54 electric H7,8
0; N 5.16; S 11.81 Actual value (%): Csy, ao+ H7,85i
N 5.42+812.05 6.7-. 1-Lance bodywork Ru: Br cf 1: a500, 1720H
M R (90MHz, CDC13) δ: 1.40
, 1.71 (each aH.

sX2), 1.6-a-a (IOH, m), 2.
81 (11, d, J=2Hz).

3.55 (IH, m), a-7-3,9 (2H, m) Reference Example 11 6.7-cis-7-CI-(2-methoxyethoxymethoxy)-4-thiacyclohexyl-8-oxo -2,
2-dimethyl-3-oxa-1-azabicyclo (:4.
2.0) Octane 6,7-V suit-(1-hydroxy-4-thiacyclohexyl)-8 obtained in Reference Example 10
The title compound is obtained in the same manner as in Reference Example 3 using -oxo-2,2-dimethyl-8-oxa-1-7zabicyclo[4,2,0)octane.

&at -1.

Engineering Rvmaxcm, 1745 NMR (90 electric H2, CDCl5) δ: 1. a
8, 1.71 (3■ each.

5X2), 1.5-3-HIOT(, m), a, 38
(aH, 8), a, 0-4, 0(i, m), 4.93(
2H, +3) Reference Example 12 6.7-cis-7-[1-(2-methoxyethoxymethoxy)-4-thiacyclohexyl-4,4-cyoxide]-8-oxo-2,2-dimethyl-3 -Oxa-1-
Azabicyclo[4,2,9)octane 6,7-cis-7-1:1 in the same manner as in Reference Example 4
-(2-Methoxyethoxymethoxy)-4-thiacyclohexyl]-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4°2.0]octane gave 780% of the title compound as an oil. It will be done.

IRvNeatairl: 1740,1a15,11
;130aX NMR (90MH2, CDCl3) δ: 1.8
8,1. TO (each aH.

5X2), 1.6-8-0 (8H, m), a-1-4,
0 (10Hjm), a, 36 (aH,s), 5-0
1(2H,s) Reference Example 13 3j4-cis-4-carboxymethyl-a-(1-(2
-methoxyethoxymethoxy)-4-thiacyclohequin/I/-4,4-dioxide]azetidin-2-one 6,7-cis-7-(1-
(2-Methoxyethoxymethoxy)-4-thiacyclohexyl-4j4-dioxide-8-oxo-2j2-
Dimethyl-a-oxa-1-7zabicyclo(4,2,0
) The title compound 362119 is obtained as an oil from octane 472111.

Reference Example 14 aj4-cis-a-(1-(2-methoxyethoxymethoxy)-4-thiacyclohexyl-4,4-dioxide)-4-i-(4-nitrobenzyloxycarbonyl)
-2-oxopropyl]azetidin-2-one 8.4-thia-4-carboxymethyl-a-CI-(2-methoxyethoxymethoxy)-4-thiacyclohexyl-4, 4-dioxide] azetidin-2-one a62 from the title compound 824
1 g of W is obtained as a pale yellow oil.

IRνNe&tcN1:aa20. 1750-172
0°ax ia5o, 112O NMR (90MHz-CDCIs) δ: 2.
0-3.0 (6H, m).

a, a4 (aH, s), 11-61 (2H, a), 3
．． 1-8-9 (9H, m).

4, 2 (LH, m), 4-92 (2H, s), 5-a
O(2H,s), 6-5(IH,b), 7-54(2H
jd, J=9Hz), 8-23(2H,d, J=9Hz
) Reference Example 15 aj4-cis-4-[3-diazo-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3
-[1-(2-methoxyethoxymethoxy)-4-thiacyclohexyl-4,4-cyoxide]azetidine-2
-on 3.4-cis-rho C1- in the same manner as in Reference Example 7
(2-methoxyethoxymethoxy)-4-thiacyclohexyl-4j4-dioxide]-4-(13-(4-nitrobenzyloxycarbonyl)-2-oxoglovir]azetidin-2-one from 1 g of 704I gives the title compound 724q as a pale yellow color. Obtained as a foam.

Neat-1 Engineering RI) maz CIJ: aa2θ, 2140,1
760°1720j 1650,1850.1120H
M R (90MHz, CDCl3) δ: 2-1
-3-0(6H,m)ja-36(aHjs),a,a
-3-9 (9H, m), 4.2 (IH, m).

4-98 (2H, s), 5-; 118 (2H, s),
6-4 (IH, bs), 7.54 (2H, d, J=9
H2), 8-26 (2H, d, J = 9Hz) Reference Example 16 6.7-) Lance-7-(1-hydroxy-2-methylthioethyl/I/)-8-oxo-2,2-dimethyl -3
-Oxa-1-7zabicyclo[4,2°0]octane diisopropylamine was added to 0.68 g of anhydrous tetrahydro7ran LOzl solution under nitrogen atmosphere at -78°C for 15 minutes.
% n-glylithium/hexane8. Add Otttl. Add 8-oxo-2,2-dimethyl-3- to this solution.
Oxa-1-azabicyclo(4,2,0)octane 31
Add 0 t1 g of anhydrous tetrahydro7rane 1 zl solution over 5 minutes and stir for -10 minutes. Methylthioacetaldehyde a60# was added to this reaction solution over 5 minutes, and after stirring for 30 minutes, saturated ammonium chloride water was added and the mixture was allowed to return to room temperature. The aqueous layer is separated and the aqueous layer is extracted with ethyl acetate. Combine the organic layers and
After sequentially washing with 5N sodium hydroxide aqueous solution and water, drying (
Na2.804)L, the solvent is distilled off. The residue was subjected to column chromatography using silica gel (hexane-
When applied to ethyl acetate (1:1 to 1:2), a mixture of two stereoisomers A and B (2634) was obtained based on the configuration of the hydroxyl group at the 7-position of the title compound.

and one stereoisomer A (21111 g) were obtained as oils. Hereinafter, two stereoisomers based on the configuration of the hydroxyl group (i or protected hydroxyl group) of this displacement valve will be tentatively named isomers A and B.

Mixture of isomers A and B: Neat -1.

Engineering R sea aX as, a440, 17aON M R
(90MH2jCDC13)δ: 1.45.1.78
(each aH.

5X2), 1-5-2-1 (2H, m), 2-18 (a
H,s), 2.6-3, 2(3H,m), a-6(IH
, m), 3.7-4.0 (2H, m), 4.1 (IH
, m) Isomer A: I Rv""thor 1: 3440. 173ON
M R (90MHz, CDCl3) δ: 1.40
．． 1.7a (each aH.

5X2), 1.5-2.1 (2H, m), 2-12
(aH,s), 2.6-3, 2(IH,m)J, 6(I
H, m), F3.7-4-0 (2H, m).

4,0(IH,m) Reference Example 17 6.7-) Lance-7-(1-(2-methoxyethoxymethoxy)-2-methylthioethylcy8-oxo-2
j2-dimethyl-8-oxa-1-azabicyclo(4,
2,0) Octane (isomer A) 6,7-) Lance-7-
The title compound was obtained as an oil from (1-hydroxy-2-methylthioethyl)-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo(4,2,0)octane (isomer A) 211q. It will be done.

Engineering Rj/NeatcIiT1: 1750ax NMR (90MHzj CDCI3) δ: 1.40
, 1.7.1 (each north.

5X2), 1.6-2.1 (211, m), 2.15 (
aH,s), 2.79 (2Hjd, J=6Hz), 3-
38 (aH, s), 1-1-4-a (9H.

m), 4.79 (2H, s) Reference Example 18 6.7-) Lance-7-C1-(2-methoxyethoxymethoxy)-2-methylsulfonylethylcy8-oxo-2,2-dimethyl-3 -Oxa-1-azabicyclo[4,2,0)octane (isomer) 6,7-Dransu-7-(1-(2-methoxy) obtained in Reference Example 17 in the same manner as in Reference Example 4) ethoxymethoxy)-2-methylthioethylcy8-oxo-2
,2-dimethyl-3-oxa-1-azabicyclo(4,
2,0':]octane gives 259 mg of the title compound as an oil.

Neat -1゜■Rvlnaxcm, 1745 NMR(90MI(z, CDCl3)δ:
1.40.1.71 (each aH.

sX2) -1-62,1(2H-m) 1 a
, OF3 (aHa s ) s a, a 6 (aH,
8), 3.1-4-0 (IOHjm), 4.45 (I
H, m), 4.86 (2H, m) Reference Example 19 3.4-trans-4-carboxymethyl-3-CI-
(2-Methoxyethoxymethoxy)-2-methylsulfonylethyl]azetidin-2-one (isomer A) 6.7. in the same manner as in Reference Example 5. -) Lance-7-
CI-(2-methoxyethoxymethoxy)-2-methylnulfonylethyl]-8-oxo-2,2-dimethyl-
190 mg of the title compound are obtained as an oil from 259 da-oxa-1-azabicyclo[4.2.0]octane.

Neat -1 ■RpIn&X3:8500-2800.1760-
700 HM R (90MHz jCDC13) δ: 8.00
(3H,s), 8.86(aH,a), 2.6-4.2
(IOH, m), 4.5 (IH, m), 4-88 (2H
, s), 7-0 (IH, bs) J, 5 (IH, bs) Reference Example 20 3.4-trans-3-, I: 1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl, :]
-4-(a-(4-nitrobenzyloxycarbonyl)
-2-oxoglovir]azetidin-2-one (isomer A) a,4-)trans-4-carboxymethyl-3-[1-(2-methquinethoxymethoxy)-2-methyl 158 Mg of the title compound is obtained as a pale yellow oil from sulfonylethyl]azetidin-2-one 190.

x n pW: enemy+cm': aB20. 1760-
1715゜1a50j 11aON M R (90MHz, CDCl3) δ: 2-9
6 (aHjs), 8.0 (2H, m), a-35 (3H
, s), a-56 (2H, s), a-1-a-8 (7H
, m), 4.0 (IH, m) j4-45 (LH, m),
4.87 (2H.

s), 5.26 (2Hjs), 6-25 (IH, bs)
j7-48 (2H, d.

9 Hz), 8.21 (2H-d n J=9
Hz) Reference Example 21 a, 4-) Lance-4-[3-diazo-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl,
1-3-[1-(2-methoxyethoxymethoxy)-2
-Methylsulfonylethyl]azetidin-2-one (isomer A) a, 4-) lance-8 in the same manner as in Reference Example 7
-(1-(2-Methoxyethoxymethoxy)-2-methylsulfonylethyl, :]-4-(a-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)azetidin-2-one from 158Mg to 148η of the title compound Obtained as a pale yellow oil.

Neat -1.

IRνmax C111, 3a50, 2140, 176
0°1720, 1640. 1850. 1120H
M R (90MHz, CDC13) δ: 2-97(a
H,s), 2.9-a-a(aH,m), a-aa(
8H, a), a-a-a, 8(6Ii, m).

4.0 (IH, m), 4-5 (LH, m), 4-86C
2H, a), 5-84 (2H, s), 6-a (IH,
bs), 7.52 (2H, d), 8.2a (2H.

d, J=9Hz) Reference Example 22 6.7-) Lance-7-(1-(2-methoxyethoxymethoxy)-2-methylthioethylcy8-oxo-2
j2-dimethyl-a-oxa-1-azabicyclo[4,
2,0) Octane (mixture of isomers and B) 6,7-Dransu-7-(l-hydroxy-2-methylthioethyl) obtained in Reference Example 16 in the same manner as in Reference Example 3
-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4,2,0)octane (isomers A and B
268 M/I gives the title compound as an oil.

The R and NMR spectra are consistent with those of the compound obtained in Reference Example 17.

Reference Example 28 6.7-) Ranme 7-C1-(2-methoxyethoxymethoxy)-2-methylnulfonylethyl]-8-oxo-2,2-dimethyl-8-oxa-1-azabicyclo[4, 2,0) octane (mixture of isomers A and B) 6,7-dransu-7-(1-(
2-Methoxyethoxymethoxy)-2-methylthioethylcy8-oxo-2,2-dimethyl-8-oxa-1
The title compound 303q is obtained as an oil from -azabicyclo(4,2°0)octane in the same manner as in Reference Example 4.

Engineering tax”: 1745 NMR (90MHz, CDCl3) δ: 1
．． 40j1.71 (each aH.

5X2), 1-6-2-1 (2H, m), 2-97
(aH, s), 3.36 (aH,, s), a, 14-0
(IOH, m), 4.45 (IH, m), 4-86 (2
H, s) Reference Example 24 a, 4-) Lance-4-carboxymethyl-3-(1-
(2-methoxyethoxymethoxy)-2-methylsulfonylethyl]azetidin-2-one (isomers A and B
6.7-) Wonnu 71 [: 1
-(2-methoxyethoxymethoxy)-2-methylsulfonylethyldi-8-oxo-2,2-dimethyl-8-
Oxa-1-azabicyclo[4°2.0]octane ao
The title compound 288 is obtained as an oil from a11y.

Reference Example 25 aj4-) Lannou 8-(1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl, :)-4-
(3-(4-nitrobenzyloxycarponi/L/)-
2-oxopropyl]azetidin-2-one (isomer A
and B) a, 4-) lance-4-carboxymethyl-a-(1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl) in the same manner as in Reference Example 6.
Title compound 181M from azetidin-2-one 28a
II is obtained as a pale yellow oil.

IRyNeatcIR:;3aaO, 1760-171
0°aX 1a50. 112O NMR (90MH2, CDCl5) δ: 2.97
(IIH, s), 2-8-a, 13 (3H, m), a
, aa (aH, s), 3.56 (2H, s), a-8
-3-9 (6H, m)j4-0 (IH, m), 4.40
(IH, m), 4-86 (2H, s), 5-25 (2H
,s), 6-a(IHjba), 7.51(2Hjd
-J=9 Hz) -8,21(2H, d#;
f=9 Hz) Reference Example 26 3.4-trans-4-[3-diazo-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)
-8-[1-(2-methoxyethoxymethoxy)-2-
Methylsulfonylethyl]azetidin-2-one (mixture of isomers A and B) aj4-trans-3-(1-(
The title compound 166q was obtained as a pale yellow oil from 181 mg of azetidin-2-one (2-methoxyethoxymethoxy)-2-methylsulfonylethyl)-4-[3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one. It will be done.

EngineeringRj/NeatcIr1:aaaO,2140,17
60°ax 1720, 1650. 1a40. 11aON M
R(90MHz, CDCl3)δ: 2-97(3
H,s), 2.8-a-a(aH,m), a-85(a
H,s), a-a-3-9(6H,m).

4.05 (IHjm), 4.46 (IH, m), 4.8
7 (2H, s), 5.35 (2H, a), 6.2 (IH
, bs), 7.51 (2H, d, J=9Hz).

8-24 (2H, d, J = 9Hz) Reference Example 27 6.7-) Funsu 7-(2-methylthioacetyl AI)
-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo(4,2,0)octane x element i flowing, -78
Dimethyl sulfoxide is dissolved in 0.241 I/l of dichloromethane (51 g/l) at 0.0°C, and a solution of 0.36 tel of trifluoroacetic anhydride in 1+l of dichloromethane is added to this mixture, followed by stirring for 10 minutes. 6,7-) lance-7-(1-hydroxy-2-methylthioethyl/I/)-8-oxo-2,2-dimethyl-3 obtained in Reference Example 16
-oxa-1-azabicyclo[4,2,0)octane (
Mixture of isomers A and B) A solution of 420111 g in 2 ml dichloromethane is added over a period of 10 minutes. 80
After stirring for a minute, 0.68 ml of triethylamine
Add over 10 minutes and stir at room temperature for 1.5 hours.

The reaction solution was poured into water, extracted with dichloromethane, washed with water, and dried (Na2SO4). The solvent was distilled off and the residue was subjected to column chromatography using silica gel (hexane-ethyl acetate = a:1) to yield the title compound (a
a 1#) is obtained as an oil.

Engineering Rν, 1750.1700 aX HMR (90MHz jCDC13) δ: 1.40,
1.69 (each aH.

5X2), 2-07 (IH, s), 1.5-2.0 (2
H, m), 3. aa(2H, ABq, J=19.8
．． 1B, 8Hz), 8.7-4.2 (3H, m).

4,25 (LH, d, J = 2.5Hz) Reference Example 28 6j7-) Lance-7-(1-hydroxy-2-methylated thioethyl)-8-oxo-2,2-dimethyl-3-oxa- 1-Azabicyclo(4,2°0]octane (isomer B) 6,7-) lance-7-(2-methylthioacetyl)-8-oxo-2,2-dimethyl- obtained in Reference Example 27
3-Oxa-1-azabicyclo[4°2.0)octane 42911i! To 23 ml of anhydrous diethyl ether solution was added 343 potassium iodide and 1
Add 4.9 ml of M potassium tri-5ea-butylporohydride tetrahydrofuran solution and stir for 30 minutes. 1M potassium tri-8eQ-butyl polyhydride tetrahydrofuran solution2. Add Oyxl and stir for 1 hour, then add another 2.0 ml. After stirring for 2 hours, acetic acid 0.49d, and ethyl acetate 10M
Add t and remove insoluble matter by filtration. After distilling off the beacon medium, 20 tttl of ethyl acetate is added, and the organic layer is washed successively with aqueous sodium bicarbonate and water, and dried (Na25o4). The solvent is distilled off, and the residue is subjected to column chromatography using silica gel (ethyl acetate-hexane=1=2→2:1) to obtain the title compound (a a 01F) as colorless prism crystals.

Melting point 106-107°C IRyKBran-”: a500. 1740aX HMR (90MHz, CDCl3) δ: 1.
40j1.71 (8H each.

5X2), 2.12 (3H, B), 1.5-2.1 (
2H,m), 2- a-8,2(aH,m), a-5-
4,2 (4H, m) Elemental analysis value Total X as CHH Engineering 9 No 3s, value C%): C5a-85 Master n 7.8
1i H5゜71; S1a, 07 'AIJJJfM (%): C54, Oa electric H7,
92i N s, yo; S12.77 Reference Example 29 6.7-) Lance-7-111-(2-methoxyethoxymethoxy)-2-methylthioethyl-8-oxo-
2,2-dimethyl-3-oxa-1-azabicyclo(4
,2,0) octane (isomer B) 6,7-) lance-7-(1-hydroxy-2-methylthioethyl)-8-oxo,-2 obtained in Reference Example 28
,2-dimethyl-3-oxa-1-azabicycloC4,
2,0) From octane (isomer B) 444q, Reference example a
The manure compound is obtained as an oil in a similar manner to the method of .

Engineering R record tllf1:1750 HM R (90MHz, CDC13) δ:1.40,1
．． 71 (each aH.

5X2), 1-6-2-1 (2H, m), 2.76 (2
H, d, J = 6Hz).

a-38(aH,s) -8,14a (9H-m)
#4.8 (2H-s) Reference example a0 6.7-) Lance-7-[1-(2-methoxyethoxymethoxy)-2-methylnulfonylethyl]-8-oxo-2,2-dimethyl -3-oxa-1~azabicyclo[4,2,0)octane (isomer B) 6,7-) Hunnu 7-CL-(obtained in Reference Example 29)
2-Methoxyethoxymethoxy)-2-methylthioethyl-8-oxo-2,2-dimethyl-3-oxa-1
- From azabincro (4,2゜0) octane, reference example 4
Manure compound 507H// is obtained as an oil in a similar manner to the method of .

Engineering RJ/InaxcI11: 1750, 1350.1
14ON MR (90MHz -CDC'J-3)δ
: 1.40, 1.70 (each AaH.

aX2), 1-6-2.1 (2H, m), 2.96 (a
n, s), 1.08 (IH, dd, J=1.5.7-5
Hz), a-86 (aH, s), a-a-4, 0 (9H
, m), 4.44 (IH, ddd, , T=7.5, 7.
5,4.5Hz), 4.83 (2Hjs) Reference example a1 8.4-Thranno-4-carboxymethyl-3-[1-
(2-Methoxyethoxymethoxy)-2-methylsulfokolethyl]azetidin-2-one (isomer B) 6j7-twonu7-(1-(
2-Methoxyethoxy(methoxy)-2-methylsulfonylethyl-8-oxo-2,2-dimethyl-3-oxa-1-azabiyrio(4°2.0)octane 207M
From I/, manure compound 1 was prepared in the same manner as in Reference Example 5.
9211v is obtained as an oil.

IRJ/maXOx, S500-2800.1760
-700 HMR (, 90MHz, CDCl3) δ: a
-00(aH,s),a,a6(aH,s),2.6-
8.9 (9H, m), 4.0HMIH, m), 4-5
2 (LH, m), 5.82 (2H, bs), 7.0 (I
H, be), 7.5 (IH.

bs) Reference example a2 a,4-) lance-8-(:1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl)-4-(
:3-(4-nitrobenzyloxycarbonyl)-2-
oxopropyl]azetidin-2-one (isomer B) a,4-) lance-4-carboxymethyl-a-(1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl) obtained in Reference Example a1 Manure compound 142 is obtained as an oil from 19211 g of azetidin-2-one in the same manner as in Reference Example 6.

IRvlgeatffi”:S440.1760-1
720°aX 1350.114O NMR (90MHz, CDCl 3) δ: 2
．． 94(i3H,s), 2.7-a, a(a[,m)
, l-aa(aH,s), 8.56(2H,s), 8-
a-a, 8 (6H, m), 4.1 (IH, m)
, 4-5 (LH, m), 4-80 (2H, s), 5.
26 (2H, s), 6.25 (IH, e), 7-51
(2H.

d jJ-9Hz) jIIL 21 (2H, d,, T=
9Hz) Reference Example 33 a, 4-) Lance-4-[a-diazo-3-(4-nitrobenzyloxycarboni#)-2-oxopropyl)
-a-CI-(2-methoxyethoxymethoxy)-2-
Methylsulfonylethyl]azetidin-2-one (isomer B) 8,4-)lanse-3-(1-(
2-Methoxyethoxymethoxy)-2-methylsulfonylethyl)-4-1: a-(4-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidine-2-
From onal1Mf/, in the same manner as the method of Reference Example 7,
284 Ml of manure compound are obtained as an oil.

IRpNeat” :a440j 2140,176
0゜AX 1720.1640, 1a50.11aON MR(
90MHz, CDCl3)δ: B-96(ill,
s), 2.8-3.4 (a H-m), a, a
a (a H# 8) # a-a ilk, 8
(6Ht m) $4, 1 (IH, m), 4-5 (I
H, m), 4-81 (2H, s), 5-86 (2H-s
) a 6 , a 9 (IHa a ) -7,
53 (2H-d-J4Hz).

8, 23 (21, d, J = 9 Hz) -Reference example a4 7-(1-hydroxy-2-methylthioethyl)-7-
Phenylthio 8-oxo-2,2-dimethyl-8-oxa-1-azabicyclo(4,2゜0)octane 8-oxo-2,2-dimethyl-8-oxa-1 in the same manner as in Reference Example 1 - From 1.00 f of azabicyclo[4°2.0]octane, the title compound 1.881 is obtained as colorless crystals. (The ice crystals are mostly composed of two isomers A and B.
(Although a very small portion is isolated as each isomer).

Melting point 8B-85℃ (mixture of isomers A and B)xyav
- &, ts: a500,17aO (mixture of isomers A and B) NMR (90MHz, CDC13) δ: isomer A
: 0.79, 1.58 (each It aH, 5X2),
1.6-2.0 (2H, m), 2-15 (aH, a)
, 2-89 (2H, d, J=7.5Hz).

a, 34.0 (aH, m), 4. al(IH, dd
, J=7-5.4-8Hz).

7-2-7.6 (5H, m) Isomer B: 1.47.1.76 (4 aH, aX each
2), 1-91 (aH.

s), 1-6-2.0 (2H, m), 2-96 (2H,
m), a-7-4-0 (3H, m), 4.1a (IH,
dd, J=10.5.5.1Hz), 7.2-'1.
7 (5H, m) Elemental analysis value C as E23N03S2 (mixture of isomer, B) Calculation i1 section C%): C57,76 pickled H6,56;
Ha, 96; S1B, 14 Actual value (%): C57-69; H6,68i N
4.14iS18.38 Reference Example 35 6.7-Sinu7-(l-hydroxy-2-methylthioethyl)-8-oxo-2,2-dimethy/I/-8-oxa-1-azabicyclo(4,2 ,03octane 7-(1-hydroxy-2-methylthioethyl)-7-phenylthio-8-oxo72, obtained in Reference Example 34
2-dimethyl-3-oxa-1-azabicyclo(4,2
, 0) Manure compound 560q is obtained as colorless crystals from 1.82 g of octane in the same manner as in Reference Example 2. At this time, a mixture 1 of 6.7-cis isomer and trans isomer is added.
65 da, and 6.7-) lance body 89119 is obtained.

Melting point 91-92.5℃ I RνKBr c+t': a420, 172
0LX 11 M R (90MHz, CDCl5) δ: 1
．． aa, 1.72 (each aH.

5X2), 2.15(aH,s), l-5-2-2
(2H, m), 2-68 (2H, d, J=6Hz),
a, aa (IH, dd, J=6.8j5.8Hz).

: 3.6-4-0 (aH, m), 4-12 (LH, m)
Elemental analysis value Calculated value C% as C engineering, H□, No3S)
: C5a, 85: H7-81; N 5-71;
S1a, 07 Actual value (%): C5a-85; H7, 81, N
The R and NMR spectra of the 5,6-) lance isomer obtained with 5.82SS IB, 0 are consistent with those obtained in Reference Example 16.

Reference Example 36 6.7-cis-7-(:1-(2-methoxyethoxymethoxy)-2-methylthioethyl)-8-oxo-2,
2-dimethyl-3-oxa-1-1 debicyclo(4,2
,0) Octane 6,7-cis-7-(1-hydroxy-2-methylthioethyl)-8-oxo-2,2- obtained in Reference Example 35
Dimethyl-3-oxa-1-azabicyclo(4,2,0
A manure compound is obtained as an oily substance in the same manner as in Reference Example 8 using octane 274~.

Furnace G-1: 1750 HMR (90 MHz, CDCl3) δ: 1. a
7.1.70 (each aH.

5X2), 2-14(aH,s), 1.5=2-1(
2H, m), 2.75 (2H, aa,, T = 5-3,5
．． 3Hz), i3°aa(aH,s)J, 4~4-0(
8H, m), 4.2 (IH, m), 4.87 (2H, m
) Reference example a7 6.7-Sinu7-[1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl]-8-oxo-
2,2-dimethyl-3-oxa-1-azabicyclo(4
,2,0)octane 6,7-cis-7-[1-(2-methoxyethoxymethoxy)-2- obtained in Reference Example 36
Methylthioethylcy8-oxo-2,2-dimethyl-
Manure compound 81 was prepared in the same manner as in Reference Example 4 using 3-oxa-1-azabicyclo(4,2,0)octane.
09 is obtained as an oil.

IRv':,::"cm': 1746.1a50
．． 118ON MR (90MHz, CDCl5
) δ: 1. a6, 1.69 (each aH.

s), 1-Fr=2.2(2H,m),;3-01
(aH, s), a-36 (3H.

s), 3.1 to 4-0 (IOH, m), 4-5 (IH,
m), 4.90 (2H.

ABq, J=6, 12Hz) Reference Example 38 3.4-cis-4-carboxymethyl-8-(1-(2
-methoxyethoxymethoxy)-2-methylsulfonylethyl azetidin-2-one 6 obtained in Reference Example 37
, 7-cis-7-[1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl)-8-oxo-2
,2-dimethyl-3-oxa-1-azabicyclo(4,
Manure compound 205 is obtained as an oil in the same manner as in Reference Example 5 using 266 ml of 2°0] octane.

I Rv”atct 1: 3500-2800, 1
760-1700aX HMR (90MH2, CDCl3) δ: 2°85(
2H, m), a-00 (3H, s), a-36 (aH,
s), a, a~4.0 (7:H, m), 4-1 (IH,
m), 4.4 (IH, m), 4-86 (2H, s), 6
．． 2 (IH.

bs), 6-9(IH, bs) Reference example a9 3.4-cis-8-(1-(2-methoxyethoxymethoxy)-2-methylsulfonylethyl]-4-[:a-
(4-'nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one 3,4-cis-4-carboxymethyl-3-[1-(2-methoxyethoxymethoxy)- obtained in Reference Example 38
2-methylsulfonylethyl]azetidin-2-one 2
Using aUI9 and following the same method as in Reference Example 6, 18'l/ of the manure compound is obtained as an oily substance.

Engineering R bow coin tα-1: aa20.1760.1720゜1
a50,11aO KMR (90MHz, CDCl5) δ: 2.
96 (aHjs) j8.11 (2H, d, J=7Hz)
, a, aa(aH,s), a-57(2H,s).

a-1 to 4.0 (7H, m), 4-1 (LH, m), 4
-4 (IH, m).

4.83(2H,5)j5.25(2H,s),6.3
3(LH,'bs).

7, 50 (2H, d, J = 9Hz), 6-20 (2H
, d, J=9Hz) Reference Example 40 3j4-77, -4-CB-diazo-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl) 3
-[1-(2-Methoxyethoxymethoxy)-2-methylsulfonylethyl]azetidin-2-one 8,4-cis-a-[1-(2-
methoxy)-2-)z-tylsulfonylethyl:)-4-(a-(4-2F lobenzyloxycarbonyl)-2-oxopropyl]azetidine-2
Manure compound 172q is obtained as crab oil in the same manner as the method of Reference 41+17 using -one 87.

■Rp furnace tWT1: a220.2140.1750゜1715.1650j 185O N M R (90MEz, CDC13) δ: 2.9.
6 (aH, s), a, a5 (3H, s), a, 2-4
．． 0 (9H, m), 4.15 (ITl, m), 4.35
(IH,m)s4-87(2HjABq, J=lO,5
,7-5Hz), 5.3a(2H,s), 6.21(I
H, bs), 7-51 (2H, d, J=9Hz) j8.
2a (2)1. d, J=9Hz) Reference Example 41 1.6-cis-7-t-butyldimethylsilyl-8-oxo-7-azabicyclo(4,2,0)oct-3-ene 1.6-cis-8- Oxo-7-azabicyclo(4,2
, 0) Oct-8-ene 2.46 g, t-butyldimethylsilyl chloride 3°0(1,) ethylamine 8.
Dissolve Orxl in 10 gJ of dimethylformamide and add 0
Stir for 1 hour at .degree. C. and then 1 hour at room temperature. The reaction solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried (Na2S04), and the solvent was distilled off to obtain the title compound 4.701 as an oil.

ENG RowaX cm, 1740j 1720HM R
(90MHz, CDCl3)δ: 0-92(9H,
a), 1-9-2.7 (4H, m), 3.86 (LH,
m), 8.89 (IH, m), 5.6-6, 1 (2Hj
m) Reference Example 42 1, 6-; Suit-t-butyldimethylsilyl-3,
4-dihydroxy-8-oxo-7-azabicyclo(4
,2,0,:) octane N-methylmorpholine N-oxide s, 4 oy of t-butanol 4 osmic acid 106 MI
The solution was added dropwise under argon flow with water cooling and stirring. Then, to this, 1,6-cis-7-t- obtained in Reference Example 41
Butyldimethylsilyl-8-oxo-7-azabicyclo(4,2,0)oct-3-ene 4.7Of a7tone 10g? Add the solution and stir for 10 minutes. The precipitate is filtered off using Celite, and the filtrate is extracted with chloroform.

After drying the organic layer (MgSO,), the solvent is distilled off and the resulting residue is subjected to column chromatography (ethyl acetate) using silica gel to obtain 8.4 (l) of manure compound.

Melting point: 8a-85℃ IRyKBrOf”: a420, 17aO, 170
0ax NMR (90MHz, CDCl3) δ: 0
．． 96 (9H, s), 1-8-2.4 (4H, m), a
-18 (2H, bs), 8.4a (LH, m), a-6
4,8(aH,m) Reference Example 43 1.5-cis-6-t-butyldimethylsilyl-2-hydroxymethy/I/-7-oxo-6-azabicycloC
B, 2.0. : ] Hept-2-ene 1,6-cis-7-7-butyldimethylsilyl-3 obtained in Reference Example 42,
4-dihydroxy-8-oxo-7-azabicyclo(4
, 2,01 octane 2.089 tetrahydro 7 run 6
Periodic acid 2.16 (/) was added to the o11Il solution at 0°C and stirred vigorously. After stirring at room temperature for 45 minutes, the reaction solution was added to water and extracted with chloroform. The organic layer was washed with saturated brine and then dried ( Mg804) L, when the solvent is distilled off, a dialdehyde derivative is obtained. (Ip vHe&
'b (1tt 1aX :27aO, 1730).

After dissolving the ice crystals in 140 g of benzene, 465 tty of dibenzylamine trifluoroacetate was added to the ice crystals.
Heat at ℃ for 50 minutes. After bringing it to room temperature, methanol 30
Then add 540 Da of sodium borohydride and stir for 90 minutes. After distilling off the solvent, ethyl acetate and dilute hydrochloric acid are added. After filtering out the sediment using Celite,
The filtrate is extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (Mg5O4), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (
Ethyl acetate-chloroform=1:1) gives the title compound 1.104F.

KBr -1 Engineering Rνmax: 3400.172ON MR (
90MHz, CDC13) δ: 0-94 (9H, s)
, 2-50 (2H, m), 2.88 (IH, be), 4
．． 1 (2H, m), 4.26 (2H.

m), 5-59 (IH, be) Reference Example 44 1j5-cis-6-t-butyldimethylsilyl-2-chloromethyl-7-oxo-6-azabicyclo (a, 2.
0) Hebut-2-ene (a) method 1,5-cis-6-7-butyldimethylsilyl-2-hydroxymethyl-7- obtained in Reference Example 43
To oxo-6-azabicyclo[a, 2.0]] Buta 2-2736 was dissolved in a mixture of tetrahydrofuran'Itl and 7 txl of ether, cooled to -25°C, and 0.12 ml of pyridine was added thereto. Thionyl jn 0.1
Add 1 ml. After stirring at room temperature for 80 minutes, the mixture was poured into water and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried (Mg804), and the solvent is distilled off. When the residue was subjected to column chromatography (chloroform) using silica gel, the title compound 172tI was obtained.
Jg is obtained as an oil.

I RvN8'LtaiT 1: 1740ax NMR (90MHz, CD013) δ: 0
-94 (9H, s), 2-58 (2H, m), 3.9
-4-4(4H,m)j5-74(LH,m)(b)=
t N-chlorosuccinimide 65 da methylene chloride 4
111/Dimethyl sulfide 0.0]9m in solution at 0℃
After adding l, cool to -20°C.

Then 1,5-cis-6-t-butyldimethylsilyl-
To 2-hydroxymethyl-7-oxo-6-azabicyclo(3,2,01, add 2xl of dichloromethane solution of 112q of but-2-ene and stir at 0°C for 1 hour. Add the reaction solution to ethyl acetate and add water. After addition, the organic layer was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, and then dried (l
fag 5o4) L, evaporate the solvent. When the residue is subjected to column chromatography using silica gel, 75% of the manure compound is obtained.

Reference Example 45 1.5-cis-2-bromomethyl-6-t-gutyldimethy/I/V lylu-7-oxo-6-azabicyclo[8,
2.,0] Hebuta-2-dyne N-glomsuccinimide 555Hy was added to a solution of methyl chloride vy 10 m#J at 0°C.
After adding 0.27 g of dimethyl sulfide at -20
Cool to ℃. Then, 1,5- obtained in Reference Example 43
Cino 6-t-butyldimethylsilyl-2-hydroxymethyl-7-oxo-6-azabicyclo(a, 2.0)
Add 5*1 solution of Hebuta-2-27526 Da in dichloromethane. Open at 1 o'clock, return to 0°C, and stir at the same temperature for 8 hours. After performing the same post-treatment as in Reference Example 44(b), manure compound 444# is obtained as an oily substance.

I RvNeatctx 1: 1740ax NMR (90MHz - CDC'Ls) δ: 0
．． 9a (9H, s), 2-58 (2H, m), a-9-
4-4 (4H, m), 5.76 (IH, m) Reference Example 46 6.7-cis-7-(2-chloro-1- and droxyethyl)-8-oxo-2,2-dimethyl-3 -Oxa-1
-Azabicyclo[4,2,0)octane To 1,5-cis-6-7-butyldimethylsilyl-2-chloromethyl-7-oxo-6-azabicyclo(a, 2.0) obtained in Reference Example 44 Ozone is introduced into a solution of 239 ml of but-2-ene in methanol at -78°C.

When the reaction solution turns blue, stop introducing ozone. Then nitrogen was introduced and sodium borohydride aa was added at -40°C.
Add ri and bring to room temperature. After further stirring for 1 hour, the solvent was distilled off, ethyl acetate and dilute hydrochloric acid were added, and the mixture was extracted with ethyl acetate. After washing Uteng 1 with water and saturated saline, dry fMgS
O4)L, the diol derivative 288 is obtained by distilling off the solvent.

I RvNoatarl: aa70. 17aOax' HMR (90MHz, CDCl3) δ:
0.94 (9H, s), 1-8-2.2 (2H, m)j
8-8-4-4 (7H, m) Next, the diol derivative was dissolved in 3 liters of tetrahydrofuran, 297# of tetrahydrofuran n-butylammonium fluoride was added, and the mixture was stirred at room temperature for 45 minutes. The solvent is distilled off and the residue is subjected to column chromatography using silica gel (ethyl acetate-methanol=20:1) to obtain desilylated product 17aWv.

I RuNeathcurl: aaoo, 1740a
X N M R (90 MHz, acetone-d6) δ: 1.8
-2.8 (2H, m), 2.87 (2H, be),
a-aa(IH,m), ;3-5-4-8(6H,m
), 7-. 11 (IH, be) then desilylated form 105
q was dissolved in 2 wl of dichloromethane, 0.09 gt of dimethquine broban, and then 1 liter of boron trifluoride ether.
Add dropwise and stir at room temperature for 80 minutes. The reaction solution I) H6
, 86 buffer and extracted with dichloromethane.

After washing with saturated saline, drying (Ha2SO4) and distilling off the solvent. The residue is subjected to column chromatography using silica gel (ethyl acetate-n-hexane = 1:1) to obtain manure compound 86.

Melting point: 121-12℃ KBr -1.

Engineering Rνmaxas, 8400.174ON MR(
90MHz, CD'C13) δ: L-40(aH,
s), 1.71 (an, s), 1.6-2-1 (2H,
m), 2-5 (IH, bs), a, al (IH, dd,
J = 11Hz, 6Hz), a-5-4-FJ (6H, m
) Reference Example 47 6.7-ph7--7-(2-bromo-1-hydroxyethyl)-8-oxo-2,2-dimethyl-3-oxa-
1-Azabicyclo[4,2,0]octane To 1,5-dis-2-bromomethyl-6-t-gutyldimethylsilyl-7-oxo-6-azabicyclo (a, 2.0) obtained in Reference Example 45 Dio/L' derivative 478 III is obtained in the same manner as in Reference Example 46 using but-2-ene 444q.

Engineering Rtt”atcf”: 8B40. 1740aX NMR (90MHz-CDCl3) δ: 0.97
(9H, s), 2-0 (2H, m), a, a-4-4
(7H,m) Diol derivative 105011! Dissolve + in 20 g of methanol, add 846 q of potassium heptafluoride,
Stir for 1 hour at room temperature. The solvent is distilled off and the residue is subjected to column chromatography using silica gel (ethyl acetate-methanol=20:1) to obtain desilylated product 656Mf/.

I RvNoa” ai 1: aaoo, 1740
ax NMR (90MHz, acetone-d6) δ: 1.
7-2.1 (2H, m), a-1-4,2 (7H,
m), 7.2 (IH, bs ) and then the desilylated form 6
56 Misaki is treated in the same manner as in Reference Example 46 to obtain the title compound 482Wl.

Melting point: 1a3-115℃ KBr -1 1Rνmax cM: a400.1740M M
R(90MHz, CDCl3)δ: 1.40(
3■, s), 1.69 (aH, s), 1-70-2-0
(2H, m), 2-5 (IH, bs).

3, 29 (IHjdd, J=11Hz, 6Hz), 8-
5-4-3 (64m) Elemental analysis 1iii C1oH,6
B, :, Calculated as pxo3 (%): C4a, 1
8 Tolerance H5-80+ N 5.04 Actual measurement tli [(%)
: C4a, a4+ H5,59+ N 5.11 Reference example 48 6.7-cy--7-(1-hydroxy-2-phenylthioethyl)-8-oxo-2,2-dimethyl-3-oxa- 1-azabicyclo[4,2°0]octane sodium hydride 128q dimethylformamide 20
Add 0.3 a tel of thiophenol to ml solution and add 5
Stir for a minute. Then, in this solution, 6j7-cis-7-(2-profney-1-hydroxyethyl)-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[: 4. 2゜0〕Octane 44
5H1! and stir at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (NA3SOa), and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (ethyl acetate-n-hexane = 1:1).
The manure compound 492MI is obtained as an oil.

I RvN8atcm”: a420.1740
ax HMR (90MHr, , CDCl3) δ: 1-8
6(aH,s), 1-69(aH,s), 1.7-2.
0(2H,m)j2.7(LH,bs)j2-8a(2
H-dd, J=14Hz -9Hz) #a, 2
a (I H-dd jJ=11 Hz -6Hz)
, 8.5-4.2 (4H, m), 'I-1-7, 5 (5
H, m) Reference Example 49 6.7-cis-7-(2-ethylthio-1-hydroxyethyl)-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo(4,2,0) Octane 6#7-cis-7-(2-bromo-1-and-droxyethyl)-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0)octane obtained in Reference Example 47 250q and ethyl mercagutan 0.20 m
When treated in the same manner as in Reference Example 48 using 1, manure compound 28a# is obtained.

Melting point 60-62℃ RJ/KB"car": a420. 1740
aX engineering NMR (90MHz, CDCl5) δ: 1.
20 (3H, t, , T = 7.5Hz), 1-86 (aH
,s), 1.59(aH,s), 1-7-2.0(2
H # m ) s 2.57 (I Hldd jJ=
14 Hz -7p 5 Hz) #2-59(2
H,q, J-7y 5Hz), 2-90(IH,s
), a-04 (IHj'ddjJ=14Hz, 1lH
z), 3.28 (IH, dd, J=10Hz, 5Hz)
.

3.6-4.8 (4Hjm) Elemental analysis value Calculated value as Cl2H2□N03S (%)
2c 55.57; H8,16; N 5.40 Actual value (%): C55-74; H8,29; H5,a
6 Reference Example 50 (IR, 28)-1,2-Cyclohex-4-enedicarboxylic acid 1-Methyl ester racemic 1,2-cis-1j2-cyclohex-4-enedicarboxylic acid 1-
Methyl ester 82,;3f and cinchonidine 186. a
g was dissolved in 400 ml of methanol and then concentrated. The residue was dissolved in 700 g of acetone and left at 5° C. for 4 days. The precipitated crystals are collected by filtration, washed with acetone, dissolved in a hot solution in a mixture of 75 grams of methanol and 150 grams of acetone, and then left at 5° C. for one day. The precipitated crystals are collected by filtration and washed with acetone to obtain 62 g of cinchonidine salt of a manure compound. (Melting point 156-157°C1[α]24°-88,
4° (c-0,57, methanol)).

D + The crystals were then suspended in ethyl acetate aO'Ogt for 1H.
After washing twice with hydrochloric acid and once with brine and drying (MgSO4), the solvent is distilled off to obtain manure compound 281/ as an oil.

NMR (90MHz, CDC1a) δ: 2
．． 1-2.9 (4H, m), 2.93-2 (2H, m)
, 8-70 (3H, s), 5.67 (2H, s).

11-68 (IH, s) [α:) V: 18.6 (c = 2.4, Et
OH).

The recrystallized mother liquor of the cinchonidine salt is treated with an acid in the same manner as above, and the crystals precipitated from n-hexane-ether (4:1) are filtered off. (Return this operation twice). When the filtrate was concentrated, (IS, 2R)-1,2-cyclohex-4-enedicarboxylic acid-1-methyl ester 16.5
F is obtained as an oil.

[α)9: +18.4° (c=2.3, EtOH)
.

Reference Example 51 (18,2R)-2-methylsulfonylethoxycarbonylamino-1-cyclohex-4-enecarboxylic acid
(IR,2S)-1,2-cyclohex-4-enedicarboxylic acid 1-methyl ester 2 obtained in t-butyl ester reference example 50
5.7 f was dissolved in 280 g of dichloromethane, 1.5 w of sulfuric acid was added while stirring under water cooling, and then about 3 g of isobutyne was dissolved.
Lasts for 0 minutes. After sealing the bottle and leaving it for 3 days, add isobutine again and leave it for 1 day. The reaction solution was concentrated under reduced pressure, 800 g of etherμ was added to the residue, and the mixture was diluted with sodium hydrogen carbonate.
After washing twice with saturated saline, drying (Mgso, ) L,
When the solvent is distilled off, the diester ao, 6f is obtained as an oil.

Next, dissolve the crystal in 250 g of methanol and add 100 g of water containing 8.34 F sodium hydroxide. Add the solution and leave at room temperature for 2
Leave it for 0 hours. Methanol was distilled off under reduced pressure, the residue was diluted with water, and impurities were extracted with ether. Next, 2 L of concentrated hydrochloric acid (5xt) was added to the aqueous layer under ice cooling, and the mixture was extracted twice with a filter. After washing the organic layer with saturated saline, drying < Mg804
)L, 26.99% of 7-butyl ester carboxylic acid is obtained by distilling off the solvent.

The crystals were dissolved in 400 g of dichloromethane, and cooled with 12.61 g of triethylamine under ice-cooling. Then, 18.5F of ethyl chloroformate was added and stirred for 40 minutes. Next, a 16.1F aqueous solution of sodium azide 80w1. Add 8.4 f of tetrabutylammonium hydrogen sulfate and stir for 1 hour under ice cooling. Add ice water to the reaction solution, separate the dichloromethane layer, and extract the aqueous layer with dichloromethane. The organic layers are combined, washed with saturated brine, and dried (MgSO4). The solvent was distilled off and the residue was dissolved in 180ml of toluene. Dissolved in 10
Stir for 15 minutes at 0°C. After cooling, 2-methylsulfonylethano-/I/441 tetrahydrone 180+w
/ solution and triethylenediamine 3f were added at room temperature for 1
Stir for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel (n-hexane-ethyl acetate = 1:1) to yield the title compound a9. af
is obtained.

Engineering RvKBrcf”: aa50,1725,1520
゜m&X 1806.1150,11aON M R (90MHz, CDC1,s) δ:
1.44 (9H, s), 2.6-2, 9 (IH, m),
2.97 (aH, s), a, a2 (2H, t, J=5H
z), 4.0-4.4 (IHjm), 4.48 (2H,
t, J=5Hz).

5-5-5.8 (2H, m) Reference example 52 (Isj2R)-2-amino-1-cyclohexa-4-
(Is, 2R)-2-methylsulfonylethoxycarbonylamino-1-cyclohexa- obtained in Encarboxylic Acid Reference Example 51
4-2-carboxylic acid, yl/8.69
g was dissolved in a mixed solution of 210 g of dioxane and 758 g of methanol, and 15 g of 5H sodium hydroxide was added thereto, followed by stirring at room temperature for 15 minutes. After adding 4.6 txt of acetic acid, the mixture was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform.

The organic layer was washed with saturated brine, dried (Mg5O4), and the solvent was distilled off. 15 grams of trifluoroacetic acid was added to the residue and left at room temperature for 24 hours. Dow, X 50W (H”) resin (manufactured by Dow Chemical Company, USA) 7 was added to the reaction solution under water cooling.
Add 5 ml and 50 ttzl of water, and stir at room temperature for 30 minutes. After filtering the resin and washing with water, add 800ml of 5% ammonia water.
The eluate was concentrated to dryness. Acetone is added to the residue and the precipitated crystals are collected by filtration to obtain manure compound 2.561.

Melting point: 225°C (decomposition) xxv KBr aiT 1 2 aaoO, 1700
,1G2o.

ax 1550.1440,1415,1850,690HM
R (90MHz, CDCl3 +CF3 C00
H) δ: 2. a-8,0(4)I,m),1. O
−3,4 (ILm), a, 84.3 (LH, m).

5, 5-6-1 (2H, m), 7.15 (aII, bs
) Elemental analysis value Calculated value (%) as C7H engineering N02/TM01: c 55.98? H8,06±N9. aa
Actual value (%): C55,55i H7,9a: N 9
．． al [α) “I)’: + 36.6’ (c
=0.56 jH20) Reference example 5a (18j6R)-7-t-butyldimethylsilyl-8-
Oxo-7-7zabicyclo(4,2,0)octa-8-
(Is, 2R)-2-amino-1 obtained in Reference Example 52
-cyclohex-4-enecarboxylic acid 424η, triphenylphosphine 997IIg.

2.2 A suspension of 838 W of dipyridyl disulfide, 652 W of manganese dioxide, and 60 ml of a7tonitrile was heated under reflux for 8.5 hours with vigorous stirring.

After cooling, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was subjected to mudgraphy (ethyl acetate) using silica gel. When the eluate is concentrated and treated in the same manner as in Reference Example 41, manure compound 485 is obtained as a colorless oil.

The R1 NMR spectrum of the ice crystals matched that of the compound obtained in Reference Example 41.

[α]. , -45-2° (c=1.525.ethanol).

Reference Example 54 (6R, 7R)-7-(2-bromo-1- and droxyethyl)-8-oxo-2,2-dimethyl-8-oxa-
1-Azabicyclo(4,2,0]octane (18,6R)-7-t-butyldimethylsilyl-8-oxo-7-azabicyclo(4,
When reacting in the same manner as in Reference Examples 42 and 43 using 2,(D oct-3-ene, (Is, 5R)-6-t
-butyldimethylsilyl-2-hydroxymethyl-7-
Buta-2- to oxo-6-7f bicyclo(a,2.0)
You can get en.

[α] Sweet +88.6° (c=1.35.chloroform).

Then, when ice crystals are reacted in the same manner as in Reference Example 45, (I
S,5R,)-2-bromomethyl-6-t.

-Butyldimethylsilyl-7-oxo-6-azabicyclo(a, 2.01) is converted into but-2-ene.

[α] Back knee 32.1° (c=1.05.Chloroform).

The ice crystals are then reacted in the same manner as in Reference Example 47 to obtain the title compound.

Melting point: 141-142°C ("]"n: +I B, C (c = 0-54 s chloroform).

Reference Example 55 6.7-) Lance-7-(1-methylsulfonylethyl)-8-oxo-2,2-dimethyl-8-oxa-1-
Azabicyclo[4,2,0,)octane 7-ethylidene-8-oxo-2j2-dimethyl-3-
Oxa-1-1zabicyclo(4,2,0)octane (Z
:E=2:21 isomer mixture) 0.251 dimethy/I
Add 1 ml of 15% methylcagutan sodium solution to the formamide solution and stir at room temperature for 1 hour.

The reaction solution was diluted with ethyl acetate, washed with water, and dried (1ia28
After 04), the solvent is distilled off, and 6.7-) Lance-7
-(1-methylthioethyl)-8-oxo-2,2-dimethyl-8-oxa-1-7zabicyclo[4,2,0)
Octane is obtained as a pale yellow oil. Then, in the same manner as in Reference Example 4, 0.279 of the compound mentioned above (isomer mixture: 2=1) was obtained as a colorless oil.

Engineering Rv'4gj0rcm-': 1740HM R(
90MHz, CDCl3) δ: 1.40 (aHjs
), 1.58 (aH, d,, T=6Hz), 1.78
(aH, s), 2.0 (2H, m).

2B7 (2H, s), 2.93 (IH, s), a-0-
4-0 (5H, m) Reference Example 56 6.7-cis-7-(1-(2-methoxyethoxymethoxy)-2-phenylthioethyl]-8-oxo-2,
2-dimethyl-8-oxa-1-1zabicyclo(4,2
,0)octane 6,7-V suit-(1-hydroxy-2-phenylthioethyl-8-oxo-2,2 obtained in Reference Example 48)
-dimethyl-8-oxa-1-azabicyclo(4,2,
By using 01 octane 667Iy and treating in the same manner as in Reference Example 3, compound 858 is obtained.

■"νmHx"3": 1750IT MR (
90MH2, CDCl,)δ: L, 86(aH,s)
, 1-69 (3H, s), 1-7-2-1 (2H, m)
, a-86(aH,s), a-a-8-9(10Hj
m), 4-2 (LH, m), 4-81 (2H, m), 7
．． 1-7.6 (5H, m) Reference Example 57 6.7-cis-7-C1-(4-nitrobenzyloxycarbonyloxyV)-2-ethylthioethylcy8-oxo-2,2-dimethyl -8-Oxa-1-azabicyclo(4,2,0)octane Obtained from Reference Example 49 90,7
-cis-7-(2-ethylthio-1-hydroxyethyl)-8-oxo-2,2-dimethyl-8-oxa-1-
Azabicyclo[4,2,0]ocP723aWI (D dichloromethane 16w1 solution under water cooling, dimethylaminopyridine 829Iv, 4-nitrobenzyl chloroformate 29
Add 111Ig and stir at room temperature for 18 hours. The solvent was distilled off and extracted with ethyl acetate. The organic layer is washed successively with dilute hydrochloric acid, water, dilute sodium bicarbonate solution, water, and saturated brine, and dried (Na2804). The solvent was distilled off, and the residue was subjected to #kikuwa chromatography using silica gel (
Ethyl acetate-n-hexane:/=1:1) By adding K, 29211 g of the compound mentioned above is obtained as an oil.

x Rv'i Tar': 1760. 1740H
M R (90MHz, CDCl5) δ: 1.21
(aH, t, J=7.5Hz).

1-40 (aH, s), 1-72 (aH, s), 1-
8-2-0 (2H, m).

2.56 (2H,q, J=7.5Hz), 2-7
4 (IH, dd, , T = 15Hz.

7.5Hz)j8.2a(IH, dd, J==15Hz
, a, 5Hz), a-5-4,2 (4H, m), 5-2
6 (2H, e), 5.25 (IHjm), 7.58 (2
H, d,, T = = 9Hz), 8.21 (2H, dj, T
=9Hz) Reference Example 58 6.7-cis-7-(1-(2-methoxyethoxymethoxy)-1-methylthiomethyl-2-methylthioethylcy8-oxo-2,2-dimethy/l/-8- Oxa-
Using 450q of 1-7zabicyclo(4,2,0,)octane bis-1,8-dithiomethylacetone,
When the reaction treatment is carried out according to the method of Reference Examples 1 and 2,
6,7-cis-7-(1-hydroxy-1-methylthiomethyl-2-methylthioethyl/L/)-8-oxo-2
,2-dimethyl-8-oxa-1-azabicyclo[4,
205 wf of 2,0,1 octane is obtained as colorless crystals.

Melting point: 82-83℃ RvKBrtstt-': a400, 1710a
x NMR (90MHz, CDCl3) δ: 1-8
8 (8 ■, 5) jl-76 (aH, e), 1.90 (2
I (, m), 2.18 (aH, s), 2.22 (8H.

s), 2.88 (IH, s), 2-76 (2H, e),
8-17 (2H, s).

3,55 (IH, d, J=6Hz), a-68-4,9
By using 200 Da of 5(8H,m) crystal and treating in the same manner as in Reference Example 3, crude compound 221 is obtained as an oil.

Reference Example 59 (1) The following compound is obtained according to the method described in Reference Example 4.

(2) The following compound is obtained according to the method described in Reference Examples 5 and 6.

Example 1゜5,6-cis-8-(2-acetamidoethylthio)-
6-(1-hydroxy-8-thiacyclobenzene 3#
3-dioxide)-7-oxo-1-azabicyclo(a
, 2.0. : ]] Buta-2-dyne-2-carboxylic acid sodium salt (a) 5.6-cis-6-(1-hydroxy-8-thiacyclobenthyl-3.a-dioxide)-1-azabicyclo(a, 2.0) Production of hebutane-3,7-thion-2-carboxylic acid 4-nitrobenzyl ester 3,4-cynu-4-(3-diazo-
a-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3-(1-hydroxy-3-thianclopentyl-3,3-dioxide)azetidin-2-one 60q (benzene solvate) and rhodium (I[)
A mixture of 5 Mf acetate, 4 parts anhydrous tetrahydrofuran, and 6 parts anhydrous benzene was deoxygenated by passing nitrogen through it for 10 minutes.

Then, the mixed solution was heated at 80°C for 7 days while stirring under a nitrogen atmosphere.
Heat for a minute. After the reaction, the solvent is distilled off, and the compound mentioned above is quantitatively obtained as a foam.

Engineering Rshi7shiytt': a470.1770.1740
゜1a50,1120 MMR (90MHz, acetone-d6) δ: 2-
4-a, a (8H.

m), a-69 (11, d, J=6Hz), a-9 (
IH, m), 4-2a (IH, s), 4.86 (2H
, bs), 7-18 (2H, d), 7.74 (2'H,
d, J=9Hz) (b) 5,6-cis-3-(2-acemidoethylthio)-6-(1-hydroxy-3-thiacyclobenzyl-3,3-dioxide)-7-oxo- Production of 1-azabicyclo[:'a, 2.0)hebut-2-ene-2-carboxylic acid 4-nitrobenzyl ester, 3,4-cis-4-(a-diazo obtained in Reference Example 8) −
From 60q of 3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3-(1-hydroxy-8-thiacycloben-3,8-dioxide)azetidin-2-one (benzene solvate) to the above 5.6-cis-6-(1-hydroxy-3-thiacyclobenti-a,a-dioxide)-1 produced according to method (a)
-Azabicyclo(a, 2.0) to a solution of butane-3,7-sion-2-carboxylic acid 4-nitrobenzyl ester in 6 liters of anhydrous acetonitrile was added 0.016we of diisopropylethylamine at 0°C under a nitrogen atmosphere, and then Add 0.019 g/diphenyl phosphoryl chloride to 2
Stir the time. To this mixture were added 0.016 g of diisopropylethylamine and 11 #' of N-acetyl cysteamine at 0° C., and the mixture was stirred for 1 hour. -120% reaction solution
After standing for 14 hours at °C, the solvent was distilled off, the residue was diluted with ethyl acetate, washed with water, dried (Na28o4), and the solvent was distilled off. The residue was subjected to column chromatography using 70 reseal (acetone-chloroform-1:1) to obtain the title compound (2aII, 1 g) as an oil.

IRyq'q3-1: aa80. 1770. 170
0°1650.1a30. 1120 UVλ FZ nm: 269. a20HM R(9
0MHz, acetone-d6) δ: 1-90(aH,s
).

2.7 (2H, m), 2.8=3.8 (10H, m
) j408 (I H, d).

4-4(IH,m)j5-38(2H,ABq,J=
22.14Hz), 7.4 (LH, m), 7-78 (2
H, d, J=9Hz)j8-25(21(,d,,T=
9Hz) (c) 5.6-nes-8-(2-acetamidoethylthio)-6-(1-hydroxy-3-thiacyclopentyl-3,8-dioxide)-7-oxo-1-azabicyclo(a,2 .Ol hepta-2-nin-2-carboxylic acid
Preparation of sodium salt 5,6-cis-3-(2-acetamidoethylthio)-6-(1-hydroxy-3-thiacyclopentyl-3,3-dioxide)-7-oxo- obtained in (b) above 1-azabicyclo(a, 2.0) but-2-en-2-1 rubonic acid 4-nitrobenzyl ester 57M1 in tetrahydrofuran, pH 7,
10% Pd-C30Wl was added to a mixture of 2.6 g of 0 phosphate buffer and 2.6 ml of water, and the mixture was heated at room temperature and under normal pressure.
Hydrogenate for 1.5 hours. Filter off the catalyst and wash with a small amount of water. The filtrate and washing liquid are combined, and tetrahydrofuran is distilled off under reduced pressure. After washing the aqueous layer with ethyl acetate, it was concentrated under reduced pressure, and the concentrated 1 ml solution was subjected to column chromatography using Amberlite XAD-2 (eluent) (20).

Both components having an absorption at 298 nm in the UV spectrum are collected and freeze-dried to obtain powder 21q. When the ice crystals are further subjected to column chromatography using Diaion IP-20 (eluent, H2O), the compound (12W) is obtained as a colorless powder.

x: attKBbrct': a4aO, 1750
, 1640ax UVλ5ignm (Ei!): 298 (1a4)N
MR (9σM Hz s D 20 ) δ: 2-
01 (3H, e), 2.5 (2H.

m), 2.8-3.9 (IOH, m), 4.00 (IH
, d, J=6Hz).

4-4(IH,m) Example 2゜5.6-V no 8-(2-pyrimidinylthio)-6-(
1-Hydroxy-8-thiacyclopentyl (3-a-dioxide)-7-oxo-1-azabicyclo[a, 2.
0) Hebut-2-en-2-carboxylic acid sodium salt (a) 5.6-cis-3-(2-pyrimidinylthio)-
6-(1-hydroxy-a-thiacyclopentyl-3,
3-dioxide)-7-oxo-1-azabicyclo[a
, 2.0) hebut-2-ene-2-IF rubonic acid 4-
Production of nitrobenzyl esters.

3,4-cis-4-(a-diazo-
3-(4-Nitrobenzylox7carbonyl)-2-oxopropyl, l-3-(1-(2-methynethoxymethoxy)-3-thiacyclopentyl-8,3-dioxide)azetidin-2-one 110011I 5,6-cis-6-(1-hydroxy-a-thiacyclobenthyl aja-dioxide)-1-azabinclo(
a.

2.0] Hebutane-a, 7-thion-2-carboxylic acid
To a solution of 4-nitrobenzyl ester in anhydrous acetonitrile at 0°C under a nitrogen atmosphere, 0.014 ml of diisopropylethylamine was added, followed by 0.017 g 7 of phenylphosphoric acid chloride, and the mixture was stirred for 9°. Lithium 2-mercaptopyrimidine 4209 is added to this mixture and stirred at 0°C for 18 hours. The reaction solution was diluted with ethyl acetate, added to ice water, and the organic layer was separated. Wash the vA layer with water.

After drying (1ia2so4), the solvent was distilled off and the residue was
Column chromatography using 0 reseal (acetone-chloroform = 1:1) and compound (ft)
5q) is obtained as an oil.

IRyKBr[-1:a450,1780,1710a
x EtO]( tllVλrnaX nm:262.alBN MR
(90MHz, CDCl5) δ: 2-4 (2H, m
), a-1 to a, 8 (6H, m), a-86 (LH, d
, J=6Hz), 4.5 (IH, m).

5.36 (2H, ABq, J-25j14Hz), 7.
09 (IH, t, , T = 5Hz) j7.61 (2H, d
, J=9Hz), 8.21 (2H, d, J=9Hz),
8.56 (2H, d, J=5Hz) (b) 5. ．． 6-
Vno8-(2-pyrimidinylthio)-6-(1-hydroxyV-8-thiacycloben-3,8-dioxide)--7-oxo-1-azabicyclo[:a, 2.0]
Production of hebut-2-ene-2-carboxylic acid sodium salt 4-nitrobenzyl ester obtained in the above (a) 50
From Iv, the title compound (611 g) is obtained as a pale yellow powder, analogously to the method of Example 1(c).

IRvKBrtytr': a400, 1750ax UVλH2°nm (El, :): 290 (106) aX NMR (90MHz jD20) δ: 2. r
r"2.8 (2H, m), a, 1-4.0 (6Hjm)
, 4.26 (IH, d, J=6Hz), 4.5
(IH, m).

7, 56 (IH, t, J = 5Hz), 8.89 (2H,
d, J=5Hz) Example 3゜5.6-V no 3-(2-aminoethylthio)-6-(
1-Hydroxy-8-thiacyclobenthyl a,a-dioxide)-7-oxo-1-azabicyclo[a,2.
Ofbut-2-ene-2-carboxylic acid (a) 5,6-cis-3-[:'2-(4-nitrobenzylox7carbonyl)aminoethylthio]-6-(1
-hydroxy-3-thiacyclopentyl-3,3-dioxide)-7-oxo-1-azabicycloCa, 2.0
) hebut-2-en-2-force/L = boric acid Production of 4-nitrobenzyl ester 3,4-cinu-4-(a-diazo-8-(4-nitrobenzyloxycarbonyl) obtained in Reference Example 7 )-2-oxopropyl)-8-[1-(
2-methoxyethoxymethoxy)-8-thiacyclopentyl-3,8-dioxide]azetidin-2-one 18
From aq, compound (811) is obtained as an oil in the same manner as in Example 2(a).

■R, vmax cII, a400j 1770.
1710U Vl”OHnm: 268, a
18ax HMR (90MH2, acetone-d6) δ: 1-9
5 (2H, m).

2.1y=3-1(IOH, m), a-59(IH, d
,,T=6Hz), 3-9(IH-m) j4.7B
(2Hja) s 4.87 (2H, ABq s
J=29-14Hz), 6-8(IH, be), 7
-12 (2H, d, J=9Hz).

7, 59 (2H, d, , T = 9Hz), 7.71 (4H
, d, J=9Hz) (b)5. , s-cis-3-(2-
aminoethylthio)-6-(1-hydroxy-a-thiacyclobenthyl a,a-dioxide)-7-oxo-
1-azabicyclo(a, 2.0) to but-2-ene-2
-Production of carboxylic acid 4-nitrobenzyl ester obtained in (a) above 87
From q, the compound (
18) is obtained as a colorless powder.

I RνFna'x'flL': a400. ．． 17
5520 Uvλrnag nm (E 1 Order: 295 (109)
NMR (90MHz, D20) δ: 2-6
(2H, m>, 8.0 to 4.0 (IOH, m), 4.1
5 (IH, d, T = 6 Hz), 4.5 (LH, m) Example 4 5.6-cis-3-(2-formimidoylaminoethylthio)-6-(1-hydroxy- a-thiacyclopentyl-a,a-dioxide)-7-oxo-1-azabicyclo(8,2,0) to but-2-ene-2-carboxylic acid 5,6-cis-a obtained in Example 3 -(2-aminoethylthio)-6-(1-hydroxy-a-thiacyclopentyl-3.a-dioxide)-7-oxo-1-azabicyclo(:a, 2.0)but-2-ene- To a solution of 18 Mg of 2-carboxylic acid in pH 7.0 phosphate buffer 8.5 d, IN sodium hydroxide aqueous solution was added under water cooling to pH &
Adjust to 5. Add benzylformimidate hydrochloride 6aW to this solution and adjust the pH of the solution with IN sodium hydroxide aqueous solution.
While maintaining the temperature at 8.5, add it little by little over 10 minutes. After stirring for 5 minutes, the reaction solution was adjusted to pH 7.0 with 1M hydrochloric acid and washed with ethyl acetate.

After concentrating the aqueous layer, it is subjected to column chromatography using Diaion HP-20, and the fractions eluted with 8% acetone are collected and freeze-dried to obtain the compound (12q) as a colorless powder.

xRvKBrciil: a400, 1750, 1720
°max 1a00,1120 UVλH2°nm (E): 298 (110)
max 1α HMR (90MHz, D20) δ: 2.6 (2
Hjm), a-0 to 4.0 (IOH.

m), 413 (IH, d, J = 6EIz), 4.5 (I
H, m), 7.95 (LH, s) Example 5゜5.6-cis-3-(2-acetamidoethylthio)-
6-(1-hydroxy-4-thiacyclohexyl-4,
4-dioxide)-7-oxo-1-7zavinclo(a
, 2.0) Hebut-2-ene-2-carboxylic acid sodium salt (a) to 5.6-cis-a-(2-acetamidoethylthio)-6-(1-hydroxyV-4-thiacyclo xyl-4,4-dioxide)-7-oxo-1-7zabicyclo(a, 2゜0]but-2-en-2-1rubonic acid
Production of 4-nitrobenzyl ester 3j4-cis-4-[3-diazo-a-(4-nitrobenzyloxycarbonyl)-2- obtained in Reference Example 15
From Example 2 (
Analogously to method a), the compound (1811v) is obtained as a foam.

Engineering RDl? lax 011: 3400, 177
0, 1690.

1650, -1350. 1140 U4λmaLxnm: 268, a 19HM
R(90MHzjacetone-d6)δ: 1.90(a
H,s).

2, 1-8-7 (14H, m), a-84 (IH, d,
J=6Hz), 4.4 (IH, m), 5.40 (2H,
ABq,, T=24.14Hz), 7.4(LH.

m), 7-78 (2H, d, J = 9Hz), 8.23 (
2H, d, J = 9Hz) (b) 5.6-cis-3-(2
-acetamidoethylthio)-6-(1-hydroxyT
4-Thiacyclohexy/I/-4,4-dioxide)-
7-oxo-1-azabicyclo(a,2.0)buta-
E for production of 2-ene-2-carboxylic acid sodium salt (
From the 4-nitrobenzyl ester 40q obtained in a), the compound (12
11y) is obtained as a colorless powder.

I R1mhx 'El-': a400.1750
．． 1640UVλH=2 nm(E”IN):;300
(166) HM R (90MHz, D20) δ: 2.
1a (aH, s), 2.2 to a-9 (14H, m), a
-97 (LH, d, J=6Hz), 4.4 (IH, m)
Example 6゜5.6-) Lance-3-(2-acetamidoethylthio)
-6-(1-hydroxy-2-methylsulfonylethyl)-7-oxo-1-azabicyclo(a, 2.0)hept-2-ene-2-carboxylic acid sodium salt (M column A) (a) '5, β-trans-3-(2-acetamidoethylthio)-6-(1-hydroxy-2-methylsulfonylethyl)-7-oxo-1-azabicyclo(a
, 2. Production of Ol hepta-2-en-2-carboxylic acid 4-nitrobenzyl ester a obtained in Reference Example 21
, 4-) lance-4-(a-schif'so-3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-a-(1-(2-methquinethoxymethoxy)-2
-Methylsulfonylethyl]azetidin-2-one (isomer A) 121q is obtained as a white foam in the same manner as in Example 2(a).

KBr -1- Engineering RI/, 1axcIII, a440, 1790,
1700°1640.1a40. 1130 UVλ”OHnm: 269.a21 ax (b) 5.6-) lance, a-(2-acetamidoethylthio)-6-(1-hydroxyV-2-methylsulfonylethyl)-7-oxo- 1-Azabicyclo [J, 2.0
: ] to] buta 2-2-2-cal.

Preparation of bonic acid sodium salt (isomer A) From the 4-nitrobenzyl ester 52η obtained in (a) above, the compound (161
q) is obtained as a pale yellow powder.

T, RpKBrctl: a400,1760.16a
Onx UVλ blood♀nm (Ei!): a 00 (11
2) NMR(90MHz-D20)δ: 2-
13(alH,s), 8.31(2H.

s), 2. '/=4-0 (9H, m), 4. a5(IJ
m), 4-70 (IH.

m) Example 7゜5.6-) Lance-8-(2-acetamidoethylthio)
-6-(1-hydroxy-2-methylsulfonylethyl)-7-oxo-1-7zabicyclo(3,2,0)but-2-en-2-carboxylic acid sodium salt (isomers A and B mixture) (a) 5,6) Rannou 3-(2
-acetamidoethylthio)-6-(1-hydroxy-2
-methylsulfonylethyl)-7-oxo-1-azabicyclo(a, 2.0) but-2-ene-2-carboxylic acid 4-nitrobenzyl ester (a, 4-) obtained in Example 26 Lance-4-(3-diazo-3-(
4-nitrobenzyloxycarbonyl)-2-oxopropyl)-3-1: 1-(2-methquinethoxymethquine)-2-methylsulfonylethyl]azetidine-2-
Analogously to the method of Example 2(a) using 1164 (mixture of isomers A and B), the compound 289 is obtained as a white foam.

IRJ/KBrCt”: 34aO, 1770j17
00゜ax 1640.1140.1110 UVλEtOHnm: 258, a 21aX (b) 5.6-) Wonnu 8-(2-acetamidoethylthio)-6-(1-hydroxy-2-methylsulfonylethyl)-7 -oxo-1-azabicyclo(j, 2.0
) hebut-2-ene-2-carboxylic acid sodium salt (
Preparation of the mixture of isomers A and B) 4-nitrobenzyl ester obtained above (al) 44
Using M1, in the same manner as in the method of Example 1 (c),
The compound (151V) is obtained as a pale yellow powder.

IHvAh)Z1 :a400. 1755. 16a
OUVλH2°nm (Es7;r): a 00
(147) ax HM R (90MHz, DJ! O) δ: 2.1
0(aHj8)ja,al(2H.

s), 2-9 to 4.0 (9H, m), 4-35 (IH,
m), 4.70 (IH.

m) Example 8゜5.6-cis-a-(2-piperazinoethylthio)-6
-(1-hydroxy-8-thiacyclopentyl-3,3
-dioxide)-7-oxo-1-azabicyclo(3,
2,0) Hebut-2-ene-2-carboxylic acid (a) 5,6-cis-3-(2-[4-(4-nitrobenzyloxycarbonyl)hiberazino]ethylthio)-
6-(1-hydroxy-3-thiacyclopentyl-3#
3-dioxide)-7-oxo-1-azabicyclo[:
a, 2.0:] to] but-2-ene-2-carboxylic acid 4
-Production of nitrobenzyl ester 3,4-cis-4-1:a-diazoni3-(4-nitrobenzyloxycarbonyl)-2- obtained in Reference Example 7
From 15,011 g of azetidin-2-one (oxopropyl)-3,-(1-(2-methoxyethoxymethoxy)-3-thiacyclopentyl-8,8-dioxide), the method was repeated in the same manner as in Example 2(a). Compound (55~)
is obtained as an oil.

Neat -1゜IRI1m&X 3. 3a50, 1770. 171
0UVλEt"'nm: 268, a 20aX
SHM R (90 MHz, acetone-d6) δ: 2.
a~4.0 (20H.

m), 4.07 (IH, d, J==6Hz), 4-4(
LH, m), 5-28 (2H, B), 5-88 (2H,
ABq, J=24.15Hz), 7.6a (2H-d
s J=9 Hz), 7.74 (2H-d-J
=9Hz) 18.21(2H, d, J=9Hz
) (b) 5,6-cis-3-(2-piperazinoethyl?,
d-) -6-(1-Hydroxy-8-thiacyclopentyl-8ja-dioxide)-7-oxo-1-azabicycloCB, 2.0) Production of but-2-ene-2-carboxylic acid (a) ) 4-nitrobenzyl ester 55 obtained by
From #, compound (8,69) is obtained as a pale yellow powder in the same manner as in Example 1(c).

I RJ/KB"cut-': a440.17
55ax UVA"°nm (E s', s): 299 (
110) aX NMR (90MHz, D20) δ: 2-5
~4-0 (20H, m).

4.15 (11(,d, J=6Hz) a 4-
5 (IYi, m) Example 9゜5.6-cis-a-(2-hydroxyethylthio)-6
-(1-hydroxy-8-thia7 clobenthyl-3,3
-dioxide)-7-oxo-1-azabicyclo[B,
2. CD Hebut-2-en-2-carboxylic acid sodium salt (a) 5j6-cis-3-(2-hydroxyethylthio)-6-(1-hydroxy-3-thiacyclopentyl-8,8-dioxide) -7-oxo-1-azabinclo(a,2.0)but-2-ene-2-carboxylic acid 4
-3,4-cis-4-(a-Schif)' obtained in Reference Example 7 for the production of nitrobenzyl ester
-3-14-nitrobenzyloxycarbonyl)-2-
Example 2 (
Similar to the method of a), the compound (84~) was obtained as a foam KBr-x.

Engineering Rvmaxtyx, 3450. 1755UVλ”
tOHnm: 267, a20ax NMR (90MHz, acetone-d6) δ: 2.5 (
2H, m) 2-8 to 3.9 (8H, m), 3.7a (2
H, t, J=6Hz), 4-07(IH, d, J=6H
z) jd-4 (IH4m), 5.38 (2H, ABq.

1=28, 12 Hz) e 7.78 (2Hz
d-X;9 Hz)-8,21(2H.

d,, T-9Hz) (b) 5.6-nes 3-(2- and droxyethylthio)-6-(1-hydroxy-3-thiacyclopentyl-
8,3-dioxide)-7-oxo-1-azabicyclo(a, 2.0) Preparation of but-2-ene-2-carboxylic acid sodium salt 4-nitrobenzyl ester obtained in (a) above 51 da The following compound (20) is obtained as a pale yellow powder in the same manner as in Example 1(c).

KBr -1.

Engineering RJ/maXayt, 3420, 1755U
VλH2°nm(El,i):aoo(91)maxNMR(90M)lz,DzO) 6:2.
65 (2H-m) e 2.9N4.0 (6H, m),
a-17 (2H, t, J = 6Hz), 3.91 (2I (
, t, J=6 Hz) −”L, 1G (I Hjd
, J'==6Hz), 4.5 (L H1m)
Example 10゜5.6-cyno-3-ethylthio-6-(1-hydroxy V
-3-thianclopentyl-3,3-dioxide)-7
-oxo-1-azabicyclo [a.

2.0,1 hepta-2-en-2-carboxylic acid sodium salt (a) 5.6-cis-3-ethylthio-6-(1-hydroxy-a-thiacyclopentyl-8,3-dioxide)- 7-Oxo-1-azabicyclo IJ, 2.0) Production of hebut-2-ene-2-carboxylic acid 4-nitrobenzyl ester a,4-cis-4-[
a-di1cya-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-8-(1-(2-methynethoxy)-3-thiacyclopentyl-3,
8-dioxide] azetidin-2-one, the compound (8) was prepared in the same manner as in Example 2(a).
is obtained as an oil.

I Rv""tci": 1760 ax tOH UVλrnaXnm: 267, a 21HM
R(90MHz, acetone-d6)δ: 1.2G(a
H, t, J-7Hz), 2-56 (2Hjq, J=7
Hz), 2-6 (2H, m), 2-9 to 3-4 (6
H, m), 4.07 (IH, djJ=6Hz), 4.4
5 (IH.

m), 5.88 (2H, ABqjJ=22.14Hz)
, 7.78 (2H, d.

J = 9Hz), 8-23 (2H, d, J = 9Hz) (b
)5.6-V no 3-ethylthio-6-(1-hydroxy-3-thiacyclopentyl-8,8-dioxide)-
7-oxo-1-azabinclo(a,2.0)
1H Preparation of 2-ene-2-carboxylic acid sodium salt 4-nitrobenzyl ester obtained in (a) above 40
If 1f is treated in the same manner as in Example 1(c), compound (4q) is obtained as a pale yellow powder.

KBr -1- Engineering R,y max "" -a 440 # 1750
UVλ♀nm(E[):ao2(to4)M M R
(90MHz, D20) δ: 1.40 (aHj
t, J=7Hz).

2-6 (24m); 3-00 (2H,q, J=7
Hz), a-2~4.0(6H,m), 4.12(
IH, d, J = 6 Hz), 4-4 (IH, m) Example 11゜5.6-) Lance-3-(2-acetamidoethylthio)
-6-(1-hydroxy-2-methylsulfonylethyl/
I/)-7-oxo-1-azabicycloCa, 2.0.
1:l hept-2-ene-2-carboxylic acid sodium salt (isomer B) (a) 5.6-) lance-a-(2-acetamidoethylthio)-6-(1-hydro etc. S /-2-methylsulfoniethyl)-7-oxo-1-azabicyclo(a, 2.
0) Production of hebut-2-ene-2-carboxylic acid 4-nitrobenzyl ester a, 4-) obtained in Reference Example 3B
Lance-4-(a-!/azo3-C4-nitrobenzyloxycarpony/l/)-2-oxopropyl)-8
-(1-(2-methynethoxymethoxy)-2-methylsulfonylethyl)azetidin-2-one 108
Isomer B) is treated analogously to the method of Example 2(a) to give the manure compound (32 da) as a white foam.

IRytipicf' :a400. 1770. 170
L1640.1a50,1120 UVAi, iQ"nm: 268,321(b) 5.6-
) lance-a-(2-acetamidoethylthio)-6-(
1-Hydroxy-2-methylsulfonylethyl)-7-
Oxo-1-azabicyclo(:a, 2.03 to but-2
Preparation of -ene-2-carboxylic acid sodium salt (isomer B) From 5211 g of 4-nitrobenzyl ester obtained in (a) above, in the same manner as in Example 1 (c),
Manure compound (1411 g) is obtained as a pale yellow powder.

I R"yl(lx' 1: a 400 + 17
55 + 16 a OUVλH2°nm (Etta
x ): a 00 (155) ax N M R (90 MHz, D2d) δ: 245 (
aH,s), a-aa(aH.

5) j2.9~4-0 (9H, m) j4.4 (IH, m
), 4-8 (IH, m) Example 12゜5.6-cis-3-(2-acetamidoethylthio)-6
-(1-hydroxy-2-methylsulfonylethyl)-
7-oxo-1-azabicyclo(a, 2.0.)but-2-ene-2-carboxylic acid sodium salt (aj5,6-cis-8-(2-acetamidoethylthio)-6-( 1-Hydroxy-2-methylsulfonylethyl)-7-oxo-1-7zabicyclo(a,2.0)but-2-en-2-carboxylic acid 4-nitrobenzyl ester obtained in Reference Example 40 8,4-cis-4
-[8-Diazo-8-(4-nitrobenzyloxycarbonyl-2-oxopropyl, :]-8-(1-(2-
Example 2 (
A manure compound (25 Da) is obtained as a powder in a similar manner to method a).

KBr −λ.

Engineering RJ', aXcIJ, a440j 1765,169
5゜1640.1840,118G UVλ"OHnm: 267, a 20ax (b) 5.e-cis-8-(2-acetamidoethylthio)-,6-(1-hydroxy-2-methylsulfonylethyl) -7-oxo-1-azabicyclo(, a, 2.0
) Production of hebut-2-ene-2-carboxylic acid sodium salt 4-nitrobenzyl ester obtained in the above (a) 56
Using a cape, manure compound (16 Mg) is obtained as a white foam in a similar manner to the method of Example 1(c).

KBr-1゜IRumaxan, a400,1?60,1640U
VλH2°nm (to E): 299 (169) ax HMR (90MHz, D20) δ: 2.15 (
aH,s), a-31(aH.

s), 8-0 to 4.1 (9H, m), 4-45 (IH,
m), 4-8 (11, m) Example 1B.

5.6-cis-8-((E)-2-acetamidovinylthio,:l-6-(1-hydroxy-3-thiacyclopentyl/I/-8.a-dioxide)-7-oxo -1-
Azabicyclo(a, 2.OJ but-2-ene-2-carboxylic acid sodium salt (a) 5,6-cis-3-((
E)-2-acetamidovinylthio:)-6-(1-hydroxy-3-thiacycloben-8,3-dioxide)-7-oxo-1-7zabicyclo(a,2.0)hepta- Production of 2-ene-2-carboxylic acid 4-nitrobenzyl ester a, 4-V no 4-Ca-diazo- obtained in Reference Example 7
From 3-(4-nitrobenzyloxycarbonyl)-2-oxopropyl)-8-(1'-(2-methoxyethoxymethoxy)-8-thianclobenyl 3j3-dioxide]azetidin-2-one 12aη, Example 2(
In the same manner as in method a), the manure compound (4511!i)
is obtained as a foam.

XRuKB"CWT': 1765, 1690, 16
20ax UV”WagHnm: 280s 265n
a 26M M R (90MHz, acetone-d6)
δ: 1-97(aH,s).

2, 45 (2H, m), 2-. 7-a-9 (6H, m)
,4-06(IH,d,,T=611[z),4.4(
IH, m), 5, a8 (2H, ABq, I=22.1
4Hz), 5.97 (11, d, J=14Hz), 7.
17 (IH, dd, J=14.18Hz), 7-7a'
(2E, d, J = 9Hz), 8-21 (21, (1°J
=9Hz), 9.76 (IH, d, I=b
3Hz ) (b) 5.6-Vy, -a-((E) -
2-1-kllmidovinylthio)-6-(1-hydroxy-3-thiacyclopentyl-a,a-S)oxide'
)-7-oxo-1-azabinclo(a,2.0:) Preparation of hepta-2-en-2-carboxylic acid sodium salt 4-nitrobenzyl ester obtained in above (a) 61M
The manure compound (19ri) is obtained as a colorless powder from Example 1(c) in the same manner as in Example 1(c).

Engineering nu'@,,"caT": 1755. 1670
．． 1620U V X max nm (E: t
rx ): 229 (a 12 ) -a 06 to 312 ) HMR (90MHzjDgO) δ: 2-
20(aH,s), 2-65(2H-m) = a
, needle (,0(611-m) s 4.12 (I H
, d a J = 6 Hz) -4-50 (IH, m), 6
．． 15 (IH, d, J = 18Hz), 7-28 (IHj
d, J=13Hz) Example 14゜5.6-cis-8-((Z)-2-acetamidovinylthio)-6-(1-hydroxy-3-thiacyclobenthioyv-8.a- (dioxide)-7-oxo-1-azabicyclo(a,2.0)but-2-en-2-carboxylic acid phthorium salt (a)5.6-cis-a-C(z)-
2-acetamidovinylthio)-6-(1-hydroxy-
8-Thiacyclobenthyl a,a-dioxide)-7-
oxo-1-azabinclo(a,2.0) getator-2-
2-carboxylic acid 4-nitrobenzyl ester/L
10 3, 4-5/X-4-(a-
diyy-a-(4-nitrobenzyloxycarbonyl)
-2-oxopropyl)-8-(1-(2-methoxyethoxymethoxy)-3-thiacyclopentyl-3,8-
From 9011 g of azetidin-2-one [dioxide], the compound (2'1
M9) is obtained as a foam.

IRJ/art, 1775, 1700, 16aOa
x trvW, axnm: 2a7, 26a, a26N M
R(9(1'MHz, acetone-d6)δ: 2.0
6(an,s).

L 45 (2H, m), 2-8-; 3.9 (6H, m)
, 4.08 (LH, d, J = 6 Hz) -440 (
IHjm) -5,42(2H-ABq, J=2
4.14Hz), 5.46 (IH, d, J=8Hz),
7.28 (IH, dd, T=8°12Hz), 7-7
8 (2H, djJ=9Hz), 8.23 (2H, d, J
=9Hz), 9.10(IH,m) (b) 5.6-Vy, -8-((Z)-2-1 set
midovinylthio)-6-(1-hydroxy-3-thiacyclobenchyv-a,a-dioxide)-7-oxo-
1-azabicyclo(a, 2.0) to but-2-ene-2
-Preparation of carboxylic acid sodium salt.

4-nitrobenzyl ester 5 obtained in above E (a)
From 9'lF, manure compound (1911v) is obtained as a colorless powder in a similar manner to the method of Example 1(C).

IRy"rcml: 1760. 1680. 16a
Oax 20 UVλ] naX (El, ): 28B (291), 805
(274) N M R (90 MHz, D20) δ 2 2.26 (aH, a) , 2.65 (21 yo [.

m), 8.0-4-0 (6■, m), 4.1a (LH,
d, J==6Hz).

4.50 (IHjm), 5.86 (IHjd, J=8H
z), 7-aO(IH.

d, , T=8Hz) Examples 15 to 21 (a) Compounds obtained in the same manner as in the method described in Example 1(b) are shown below.

(b) A compound obtained in the same manner as in Example 2(a) is shown below.

Example 22゜5,6-cis-3-(2-acetamidoethylthio)-
6-(1-hydroxy-8-thiacyclopentyl-3,
3-dioxide)-7-oxo-1-azabicic g(,
1,2,0) Add 250q of but-2-ene-2-carboxylic acid sodium salt to a sterile vial (inner volume 17xl) and seal the vial.

At the time of use, the sterile vial is unsealed and 1+l of distilled water from which pyrogen has been removed is added to prepare a solution for injection.

Example 23゜5.6-cis-3-(2-formimidoylamineethylthio)-6-(1-hydroxy-3-thiacyclopentyl-3,3-dioxide)-7-oxo-1-azabicyclo IJ , 2.0) was added to a sterile vial (inner volume: 12 g/) and the vial was sealed. When in use, seal the sterile vial and add 1 g of distilled water from which the pyrogen has been removed to prepare a solution for injection.

Test Example 1 for Effects of the Invention MC (malAl) of the target compound (It) obtained in the example was measured by the following method.

(a) Measurement method The test compound M-C was measured using the agar dilution method (agardilut method).
ion method). That is, 1.0 ml of sequentially diluted aqueous solutions of test compounds were poured into a petri dish, and then Trypticase soy agar was poured into a petri dish.
agar ) 9. Pour Owt and mix. A suspension of test bacteria (approximately 10 8 CFU/go) is smeared onto the mixed agar plate. Culture at 37°C for 18 hours (1 ncubat
ion), the lowest concentration of the test compound that completely inhibits the growth of the test bacteria was determined as the minimum inhibitory concentration (M-C: min).
imalinhitory concentration
n).

(b) Test bacteria (1), Staphylococcus aureus (dan, au
reus) FDA 209P (2) Enerihia collie (Dan, Dandan 1 back) O-111 (3) Cito w < 9 ter, 70 in die - CC, freundii) ■ 1'0
12681 (4) Rini Guzira Niseha Seven Pue (flea)
Table 1 shows the Mc (minimum inhibitory concentration) of the test compound.

Table 10 MIC value (mallAl) Test Example 2 The stability of a representative example of the target compound (υ) obtained in Example 2 in mouse kidney homogenate was determined by the following method.

(a) Measurement method 50g of mouse kidney was cooled in 0.05M phosphate buffer (
The kidney homogenate was crushed in 2QO*l (pH 6,9) and stored at -20°C.

After thoroughly mixing 200 μl of this mouse kidney homogenate and 200 μl of an aqueous solution (1 liter/ml) of the test compound, the mixture is kept at 30°C. Every 10 minutes, 25 μl of the mixture is taken and added to 25 μl of methanol cooled in a water bath to stop the reaction between renal enzymes and test compound. The amount of test compound remaining is determined by the amount of test compound remaining in Proteus vulgaris G.
H441a or Entylobacter cloacani (Ent
erobacter cloacae) T N12
Measurement of inhibitory effect on β-octamase produced by 82 (measurement method: Journal of Antibiotics)
34.212-217 (1981)).

(b) Results The half-lives of the test compounds are shown in Table 2.

Table 2゜Test Example 8゜Measurement of inhibitor concentration required to inhibit enzyme activity by 50% Typical examples of cephalosporinase include Enterobaccu cloacani, TN1282, and typical examples of beninlinase include Staphylococcus・Beta-lactamase produced by P. aureus 1840 was mixed with an appropriate dilution of compound (I) in phosphate buffer (0.05 mol, pH 7j) and incubated at 30°C for 10 minutes, and the final concentration was 0.1 Millimoles of cephalothin (Enterobacter cloacani TN
When using β-lactamase produced by 1282)
or ampicillin (Staphylococcus aureus 1)
When using β-lactase produced by No. 840), the enzyme reaction was carried out for 10 minutes. Enzyme activity is measured using a microbial assay, Journal of General Microbiology, Vol. 83, p. 121 (196a). Thereafter, the concentration of inhibitor required to inhibit the enzyme activity by 50% was determined. It is abbreviated as

Table 3 shows the coefficient values for β-lactamases produced by Bacter cloacani and Sta.

Claims (1)

[Claims] 1. General formula [In the formula, a lower alkylene group or a lower aμ-kenylene group which may have a hydroxyμ group, Y represents (1) a lower alkylρ group (2) a carbon a3 to 8 cycloaμ group (3) lower γμ group 4) ary μ group (5) aph
The kill group tfc is (6), a 3- to 8-shell heterocyclic group t, or a partial structural formula, and y-so2-x- is a formula in which X and Y are bonded [where t is an integer from 0 to 3] The needle, m, and n are each integers from 0 to 6, and the sum of m and n is 2 to 6. , R is an optionally substituted hydrocarbon group, and R represents a 3- to 8-membered heterocyclic group, or a salt thereof. 2. R is (1) a lower alkoxy group (2) a lower 1p koxy group (3) (a) a lower alkoxy group which may be substituted with an imino group (b) which may be protected Ami 7
A 3- to 8-membered heterocyclic group optionally substituted with a substituent of the group (c) a lower γμ Kanoi μ group or (d) an oxo group (
4) Acy μoxy group (lower alkyl imino group or lower alky imino group which may be substituted with an imino group)
Group (6) Lower aμkiμthio group (7) Arylthio group (3
) A force p pamoi μ which may be substituted with a lower aμ group
Group (9) p-bamoi μ amino group QO azide group (2) which may be substituted with a phenyl group or a lower amine group
optionally protected hydroxy group Vfi/group Q4 optionally substituted imino group with a lower alkyl group α optionally protected μ poxy μ group (2) halogen (2) optionally protected amino group 7. The compound or salt thereof according to claim 1, which is a hydrogen ashing group optionally substituted with a substituent of QI acyp amino group. 3. General formula [wherein, (3) lower a[mu]ke di[mu] group (4) aryl group (5) aralkyl group or (6) 3- to 8-shell heterocyclic group t, or the partial structural formula y-so2-x- means that X and Y are A brush that is combined and expressed by the formula (where t is an integer a from 0 to 3, m and n are each an integer from 0 to 6, and the sum of m and n is 2 to 6), Z is Leaving group? , -COOR1 represents an optionally protected carboxy μ group] or a salt thereof, and a compound represented by the general formula [wherein R is an optionally substituted hydrogen ashing group or 3
[indicates an 8-membered heterocyclic group] fc
is reacted with a salt thereof, and optionally subjected to a deprotecting group reaction [symbols in the formula have the same meanings as above]
Method 4 for producing a compound or a salt thereof represented by the general formula [wherein, X is a lower alkylene group or lower alkenylene group which may have a hydroxy Vlv group, and Y is (1)
Lower alkyl group (2) Ncroalkyl group having 3 to 8 carbon atoms (3) Lower γμ kenyl group (4) Aryl group (5) Aralkyl group or (6) Heterocyclic group having 3 to 8 shells, or a moiety The structural formula, Y-802-X-, is a combination of X and Y, where t is an integer from 0 to 3, i1m is an integer from 0 to 3, n is an integer from 0 to 6, and the sum of m and n is 2 or more. 6), R represents an optionally substituted hydrocarbon group or a 3- to 8-membered heterocyclic group], or a salt thereof. thing. 5. General formula [In the formula, or a lower alkylene group or a lower alkenylene group which may have a hydroxy μ group, Y is (1) a lower aμ group (2) a cycloalkyl μ group having a prime number of 3 to 8 Group (3) lower alkyl group (4) aryl group (5) aralkyl group or (0) 3- to 8-shell heterocyclic group, or the partial structural formula y-so2-x- means that X and Y are R is a group represented by the formula (in the formula, t is an integer from 0 to 3, m and n are each an integer from 0 to 6, and the sum of m and n is 2 to 6). A β-lactamase-injurious composition comprising a compound represented by the following formula or a salt thereof: an optionally substituted hydrocarbon group or a 3- to 8-shell heterocyclic group.