JPS588085A - Manufacture of optically active trans-6- substituted-5(r)-2-penem-3-carboxylic acid derivatives, manufacture and compounds obtained thereby - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides optically active trans-6-substituted-5(R)-2
- A novel method for producing penem-localmenic acid derivatives and a novel optically active trans-6(S)-substituted-5(R)-2-penem-6-carbo/acid visit conductor.

[In the formula, R and R1 represent the same or different organic groups,
Rs is hydrogen, a cation, or a carboxy protecting group V*Wading]
This is a novel method for producing optically active trans-6-substituted-5(R)-2-penem-3-carboxylic acid derivatives.

2-penem-6-carzan fermentation conductors are a known group of synthetic β-lactamase derivatives with a broad spectrum of anti-1 activity against Durham-positive and Gram-positive bacteria and β-lactamase inhibitory activity.
It forms the essence of lactam compounds [e.g. Aota Pha
rma, 8ueo, 144! (Appendix), page 23 (19
1977) and J, Mm.

Ohem, Boa, vol. 100, p. 8214 (19
1978)].

In the above formula m, each organic group R and R1 represents, in particular: (1) an acyl group; (2) a free or esterified carboxy group; (3) a formula,
: -(OHa-) Knee Q-T (X HaO or 1~
is an integer of 10; Q is a bond; saturated or unsaturated, preferably saturated aliphatic chain, preferably 01-06 alkylene; #I element or sulfur atom; radical So- or -8O□-; R& branch chain 01""O: 1m alkyl group, preferably 01
~C6 alkyl); T is (a) a branched or linear saturated or unsaturated aliphatic hydrocarbon group; (tel aromatic group; ic) an alicyclic group; or ((11 heterocyclic group, in which each substituent (a
), (t)), (cl and ((1) are unsubstituted or preferably halogen, free or esterified carboxy group, free or protected amino group, free or protected carboxy group or mercapto group, 01 -C6 alkyl, 01-0.flukoxys O1-06 alkyl, optionally substituted with one or more substituents selected from the group consisting of lumerkabuto and free or protected oxo groups].

When R or R1 represents an acyl group, 4IK01~
06 alkanoyl, especially acetyl or zologionyl or benzoyl.

When R or R1 represents an esterified carboxy group, 'l'f K'1-c6 alkoxycarbonyl group, especially methoxy-, ethoxy-tert-f-toxycarbonyl, or as commonly used in peptide chemistry; For example, a carboxy group protected with a carboxy protecting group which may be trichloroethyl, benzyl, p-nitrobenzyl, benzhydryl, acetoxymethyl, acetonyl, pivaloyloxymethyl, trimethylsilyl, and others.

When R or R1 represents a group (OHm) (T is a branched or straight-chain saturated or unsaturated aliphatic hydrocarbon group), it may be particularly unsubstituted or substituted as described above. Cl1~Cl11 alkyl or os~01 alkenyl.

If T represents an aromatic radical, it may be mononuclear or polynuclear, preferably mononuclear, in particular: phenyl or naphthyl, preferably phenyl.

When T represents an alicyclic group, in particular a monocyclic aliphatic group,
Preferably 03-0 macycloalkyl, especially cyclohexyl or cyclopentyl or 03-0? It is a cycloalkenyl.

When T represents a heterocyclic group, in particular a heteromonocyclic group optionally shortened with a benzo moiety or other heterocyclic ring,
For example, furyl, chenyl, tetrazolyl, thiadiazolyl, triazolyl, pyridazinyl, triazinyl, or a five-atom heteromonocyclic ring having at least one heteroatom selected from N, O and S; Heterobicyclic groups formed by a six-atom bicyclic monocyclic ring having at least one heteroatom, such as tetrazologiridacynyl and triazolo-pyridazinyl.

R8 is a cation! When indicated, inorganic bases of pharmaceutically or veterinarily acceptable bases, such as alkali metals, especially sodium or potassium or alkaline earth metals, especially calcium and magnesium, hydroxides and organic bases, such as ammonia or other amines, especially diethylamine,
Triethylamine, 2-hydroxyethylamine, 1-
Ethylpiperidine, benzyl aquine, <lysine, collidine, and other cations.

When representing R2 carboxy anchoring group, preferably -
Together with COO, esterifications which readily decompose, for example by reduction, in particular hydrogenolysis, photolysis, solvent decomposition, in particular acidic hydrolysis or especially neutral or basic hydrolysis, or under physiological conditions, can be used. A group that forms an esterified carboxy group that is easily converted to a carboxy group or other functionally modified carboxy group.

Examples of carboxy protecting groups R2 are lower alkyl groups optionally substituted with halo in %, especially 01-06 alkyl, especially methyl, ethyl and tert-butyl and trichloroethyl; aralkyl groups, especially benzyl and 0- and p-Nitrobenzyl; aryloxy-alkyl group, especially aryloxyO1-06alkyl, especially phenoxy-methyl, phenoxy-ethyl and α-01-06alkyl-α
-phenoxy-methyl, such as α-methyl-α-phenoxy-methyl, α-ethyl-α-phenoxy-methyl,
α,α-dimethyl-α-phenoxy-methyl; or penzhiryl, 0-nitrobenzhyfryl, acetoxymethyl, acetonyl, piparoyloxymethyl, trimethylsilyl or dimethyl-tert-butylsilyl, and the like.

Amino, hydroxy, mercapto and carboxy groups are commonly protected with protecting groups used in penicillin and cephalin chemistry for this type of function,
hiroxy, methylekadet and carboxy groups.

In particular, protecting groups for the amine, heroxy and mercapto functions are, for example, optionally substituted, especially halo-substituted acyl groups, preferably acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl or benzyl;
triarylmethyl groups, in % trityl; silyl groups, especially trimethylsilyl or dimethyl-tert-butyl-silyl; or additionally tert-butoxycarvinyl or p-
It may also be a group such as nitrobenzyloxycarbonyl. The protecting group for the carboxy function may correspond to the above-mentioned substituent R,9 when it represents a carboxy protecting group.

Protected oxo groups are in particular oxo groups preserved in the form of [41-shaped or cyclic acetals, ketals, thioacetals or thioketals.

Many 2-penem-6-carboxylic acid derivatives are described in the literature, e.g. J, Am, ○hem, 8oa, 10111.629
6 pages (1979); 1 bid, vol. 101, 63
01 page (1979); 1bit, vol. 101, 6
606 pages (1979); 1bit, vol. 102,
2039 pages (1980); Tetrah@1ro
n Lett, vol. 1978, p. 4059; , y, o
,s,oh@m,oow.

Volume 1978, page 1101; T@trah@dron
L@tt,.

1979, p. 6777; J, Muntibiotios
, vol. 36, p. 456 (1980); J, 0.8゜Ohem, Oomm, 1980, 70 Sada; British Patent No. 1557559, Pits Published Patent No. 28
No. 19655 Ming Yutaka and UK Permanent Request @2013674A
listed in the number.

The literature shows that the stereochemistry at the 5-carbon atom of the penem nucleus is important for the development of pharmaceutical action, especially in the R-configuration at 05, i.e. the same configuration occurring in natural penicillins and cephalosporins.
It is scientifically shown that the penem isomer having this is an active isomer.

Optical activity 5 of formula (1) is obtained by the novel method according to the present invention.
(R)-2-penem-5-carbic acid is obtained 6
According to the present invention, the trans-
The 6-substituted-5(R)-2-penem-5-carzanoic acid conductor is produced by a novel method shown in the following scheme (2). In that case R, R and R are as defined above; each group R3
independently represents hydrogen or 01-C6 alkyl; represents a formula group or a lower alkyl group, preferably 01-C6 alkyl, especially VCn-decyl; 9 represents monoatom or a sulfur atom; Mn represents a cation of the heavy metal 114M of the usual oxidation letter; M is preferably represents a heavy metal selected from Ag, Hg, Au, Cu and pb; n+ represents the oxidation state χ of the heavy metal.

n is preferably an integer from 1 to 4; A is a group forming 5-AI84j which is unstable to 9 to heterolytic reactions of soluble metal salts or halogens; Preferably one is an organic group of the formula To express: I, in that case, ``
When represents charcoal JJg, each of the groups φ, φ8 and φ0 is a single aK, respectively unsubstituted or the father is C1F, Br,
aromatic or heteroaromatic groups substituted with one or several substituents selected from α- or β-naphthyl, piphenyl, chenyl, pyridyl, imidazolyl, thiapryl, furyl, and when π represents silicon, the groups φ”, φ8 and φ
0 independently represents a straight-chain or branched C1-012 alkyl group, preferably 01-C6 alkyl] or a branched C1-C12 alkyl group, preferably 00
~C6 alkyl; Rb and Ro may be the same or different and represent a monobranched alkyl group, preferably C0
~C0δ alkyl, %KCI~C4 alkyl, or especially an aryl group, preferably fluorinyl; an aralkyl group,
Preferably aryl-〇〇-C6 alkyl, especially benzyl; alicyclic groups, preferably C3-C7 monocycloalkyl, especially cyclopentyl or cyclohexyl; or heterocyclic groups, preferably C5-C? compound monomer group, % substituted with one or several organic groups selected from the group consisting of tetrahydropyranyl, represented by χ, and the groups Rd%, R8, R2 and Rg are each the same or different, hydrogen; alkyl, preferably C1-C6 alkyl; aryl, preferably phenyl:
Aralkyl, preferably aryl-01-C6 alkyl, 11? benzyl; alicyclic group, preferably 08-C
? Cycloalkyl group, 4IK cyclopentyl or cyclohexyl; heterocyclic group, preferably Cδ~C, heteromonocyclic group; or group -(CH)q-ORh or -(cH,)
q-8-Rh [: Rh is represented by the above Rd to Rg, or Rh is an acyl group, preferably C8-C
6 alkanoyl, especially acetyl or benzoyl]
, m, p and q may be the same or different and are 0.1 or 2), and Q'a represents the inflection (mono ga)] .

The group A can be represented, for example, by one of the following formulas: cH3 The use of certain groups A in the preparation of racemic penems is known (Tetrahedron Lett, 22).
- see page 1555 (1981)]. 4(R)・-isomer (1)'! The preparation of penems, including optically active 5(R)-penems of formula (1), by intramolecular Witschig reaction with 4-acylthioazetidinyl phosphoranes containing -3-lactam compounds χIl! ! An effective method for manufacturing is known from the literature (J, Am.

Chem, BoC, vol. 101, p. 6296 (197
9); 1btd, IC vol. 11, p. 6501 (1979); 1bia, vol. 101, 660
Page 6 (1979): 1 bid, Volume 102, 2
Page 059 (1980); British Patent No. 81557559, German Published Patent! No. 2819655 #Jm book:
UK Patent Application Nos. 2015674A and 8005476
issue〕.

Total synthesis of Penem Kaoru? According to these methods encompassing;
The racemic or optically active intermediate (frame) is obtained by a multi-step synthetic method, which produces a racemic compound of the formula (W): [wherein R represents a spinning compound] or a racemic compound of the formula (■a): The pre-divided 4(
R) - substitution of the nucleophilic leaving group L of the compound with a thiolic acid or dithioic acid results in a racemic compound of the formula (X): [wherein R, R and 9 are as defined above] or a racemic compound of the formula (Xa
): An optically active 4(R)-compound is obtained, in which R%R and ψ are as defined above.

Then, according to the known method, compound (X) or (Xa
) is subjected to other steps to form an azetidine ring.

On the other hand, the natural 6-amino-penicillane protease is, according to the known selection method for producing penem derivatives starting from penicillin, the intermediate (dragon) when a group R is introduced into the penem nucleus:
Formula (XI): The radical R1 is prepared by opening thiazolyl*V in the presence of an alkyne of the system [R' and CRx represents the above]
[UK Patent Application No. 8]
See No. 005476].

According to the known method, a further step is then carried out to regenerate the acylthio functionality of the compound of formula (XI), in which R and R1 are as defined above.

Therefore, in the above method, the 2-substituted portions R1 and 6 of the penem nucleus
- Permutation fairness is actually introduced at the beginning of the synthesis. This is due to the substituents R and R that must be introduced into the final product in order to produce 4(R)-compound (1) and finally 5(R)-penem (1) by known methods. means that the entire process needs to be repeated.

Furthermore, compound (x) from compound (IX) or (Dja)
or when said substitution reaction to obtain (Xa) is carried out directly with a suitable thiol or dithio acid.

Preparation and preparation often proceed with insufficient yields and/or in many cases with difficulty due to the use of suitable thiol or dithio acids. In a similar manner, the same substitution reaction can be carried out with thioenol via the intermediate thioenol ether, e.g.
-Am -Cham *8oc,, vol. 101, 650
6 (1979); 1bta, vol. 102, 20.5
9jj (1980); or Tetrahedron
Lett, 1979, 5777 ]
: [Represents the arrangement R and R1!21rlJ in the formula, ψ'
represents an optionally substituted methylene group] The advantage of obtaining a high yield of the azetizonylthioenol ether intermediate is that it is possible to obtain the appropriate amount necessary to regenerate the characteristic acylthio functionality of compound (■). The utilization of thioenol and the oxidative cleavage of the olefinic bond/C±ψ' are significantly limited.

Furthermore, additional problems often arise in this case due to unstable bases and/or oxidation-labile moieties of the radicals R1.

From the above description, the known method for obtaining the intermediate (Vl), that is, the intermediate for synthesizing the 2-penem derivative (I) Y, is as follows: 1
It is clear that two mum points will be suffered: a lack of flexibility and a lack of productivity.

With the new method according to the invention, these two difficulties are eliminated.

As can be seen from Scheme I, the novel process according to the invention yields a common intermediate in a specific synthesis process independent of that represented by the 2-11 component R1 of the final product, namely compound (VB).
Y can be produced from this C-R process in a single step involving any desired coupling with - (vM)
can be obtained.

As mentioned above, since the commonly used synthetic method for producing the intermediate (■) is independent of 'R1, contrary to the above-mentioned known methods, the unsubstituted R0 to be introduced into penem (1) K is For example, repetition of the entire method is unnecessary. This allows for great flexibility in the novel method of the present invention, whereby a wide selection of 5 (R) -2-penem-5-carvone 111ej conductors can be easily obtained.

Furthermore, the known processes result in extremely insufficient yields and/or only marginally progressed steps in the early stages of the synthesis.

Clearly, the presence of such an insufficient step has a significant negative consequence on the overall process yield, i.e. productivity, and this negative consequence is further compounded by the fact that the insufficient step Y takes place at an early stage of the synthesis. increase

On the contrary, according to the novel method of the present invention "li'"
As is clear from the diagram ■, R1 is introduced at a later stage (second-to-last step) in the busy method ψ method.
Its influence on the overall process productivity is therefore negligible. Moreover, this process no longer has a synthetic crisis point. A convenient use of the mercapto group (■) as a nucleophile is the use of thiol or dithio acids or thioenol or alkyne derivatives thereof in the substitution reaction in place of the thiol or dithio acids or thioenol or alkyne derivatives used in the above method. Make it 1f@. Acids and thioacids are easily prepared from thiolic acids, dithioacids, thioenols and alkynes and can be easily prepared in kg! Its use contributes to increasing the flexibility and productivity of the novel synthetic method of the present invention.

Furthermore, at the significantly large nucleophilicity value of the mercapto group (VW), the # conversion reaction proceeds in a better yield than the primary method;
This contributes to the productivity of trap synthesis. A suitable and original aspect of the present invention is a method for preparing optically active penemyl enzyme conductors with a 5(FO configuration) in a manner that does not have the disadvantages of the aforementioned methods, which provides tremendous flexibility and productivity. Optically active trans-6-substituted-5(R)
-Molecular %: The method of obtaining thiol A-
This is achieved by starting from compound (1), which is a suitable intermediate for the displacement reaction with 8H.

According to scheme IK, the novel process of the invention consists of the following steps: (al) of formula (I); Optical activity 4(R)-
Azenadin-2-one derivatives can be combined with a thiol or its salt of the formula % [wherein represents a soluble metal salt or a group forming an S-A bond that is unstable against the heterolytic reaction of a halogen]. By reacting, the optical activity 4(
R)-thioferment conductor is obtained, (b) formula (III)
The 4(R) compound has the formula: OHC'-C0OR.

By reacting with a glyoxyl SS conductor of [in the formula, R represents hydrogen, an ion, or a carboxy covalent group], the formula (■) is obtained.
: [In the formula, R, A and R2 represent III period] 4
The (R)-derivative is obtained.

lcl 4(R)-'#rubinol f of formula (Pi)
/%Olination, a 4(R)-derivative of the formula (V): [wherein R, A and R2 represent the above-mentioned ones, and X represents a halogen atom] is desired, and the idl formula (V ) of the 4(R)-compound with the formula: Pφ.

[In the formula, the group φ is singly aromatic, Lingsodan type, or alkyl group χ
phosphine of the formula (■): C'OOR.

4(R)-phosphorane of [in the formula, R, A% R2 and φ represent the above] was obtained, and (el formula (Vl)
4(R)-phospho277 formula: Mn"-yn- [in the formula M"! Reacting with a solution of a heavy metal salt of 2n valent polymerization@M, where yn- represents the anionic group 7 of the salt, formula 1 (■): [in the formula R, R2, φ and Mn
4(R)-mercapto salt of the formula (1) is obtained, and rfl is the 4(R)-mercapto salt of formula (1): ψ stands for oxygen or V/L yellow] or with a reactive derivative of a thioic acid to obtain the formula (Vl): C0OR.

A 4(R)-derivative of [in the formula, R, R1, R2, ψ and φ represent the above] is obtained, and bcl formula (Vl)
The 4(R)-compound of formula (■) is cyclized to form 5(
R)-penem derivatives are obtained, optionally of formula (I) C
R2 represents a water volume] and/or if necessary, the compound of formula (1) [Rg represents hydrogen or a cation]
and/or optionally from a compound of formula (I) in which R2 represents a carboxy protecting group, a compound of formula (I) in which R represents hydrogen or a cation is obtained and/or
Or, if necessary, the compound of formula (1) is converted to another compound of formula (1).

The reaction of the azenadin-2-one of formula (II) with a thiol of formula A-8H or a salt thereof, preferably an alkali metal salt, especially a sodium salt or a potassium salt, is suitably carried out at a temperature varying from 0°C to room temperature. The reaction can be carried out in a suitable solvent such as water, acetone, tetrahydrofuran, dimethylformamyl, methylene chloride, trichloromethane, acetonitrile or mixtures thereof. Optionally, the salt of the thiol of formula A-Sho is prepared in situ with a base, such as sodium or potassium hydride or sodium hydride,
It can be obtained by carrying out one reaction in the presence of sodium or potassium carbonate or an organic base.

4(R)-compound of formula (III) and formula: (1!HO-
C'OOR,'s glyoxyl I! 1 [The combined reaction with the conductor is preferably carried out in an inert solvent, such as tetrahydrofuran, dimethylformamide, dioxane, methylene chloride,
It is carried out in the presence of a base such as triethylamine, zepericin, etc. in trichloromethane, acetonitrile or a mixture of these solvents.

The reaction temperature may range from about 0°C to about 1000°C, but room temperature is preferred.

The halogenation of the 4(R)-carbinol of formula (ff) to obtain the 4(R)-compound of formula (V) is carried out using a suitable halogenating agent. X represents a salt igt compound (
V) It is desirable to obtain The nucleation is preferably carried out using thionyl chloride as the chlorinating agent, either in the absence of a solvent or in the presence of an anhydrous inert organic solvent, such as tetrahydrofuran or benzene or toluene.

The reaction is carried out in the presence of a base, such as pyridine, at low temperature, preferably between -70 and 0°C, especially between -50 and 0°C. Formula; Pφ
Formula (V) <7) 4 by the reaction of 3 with phosphine
The conversion of (R)-compounds to 4(R)-phosphorane trout conductors of formula (Vl) is preferably carried out using a base, such as pyridine, in an anhydrous inert solvent, such as basic methylene, benzene, toluene, tetrahydroalane, It is carried out in the presence of 2.6-lutidine at a temperature of about 0-60°C, preferably 25-50°C.

The heavy metal salt of the formula Mn+-41 is an inorganic parent organic acid.

Preferably inorganic acids such as sulfuric acid, nitric a! , hydrochloric acid, formic acid or acetic acid.

As mentioned earlier, the heavy metals M are preferably fins, Hg, and C.
u% is a metal selected from the group consisting of Au and pb.

Preferred salts of formula: yn"-yn- are AgNo5 or ag
(ococa3)g. The reaction of the phosphorano of formula (VI) with the heavy metal salt of the formula M"-Y" is preferably carried out using a solution of an equivalent amount of the salt in a suitable polar solvent such as water, an aliphatic alcohol, preferably is carried out in a CelC6 aliphatic alcohol, especially methanol or ethanol, or a mixture thereof.Usually the reaction is carried out at a temperature between 40°C and reflux, and the preferred acids or reactive derivatives of thioacids are halides, especially chlorides or anhydrides. or a mixed anhydride.

The reaction is carried out in a bath agent such as acetonitrile, benzene, toluene, dimethylformamide, methylene chloride, chloroform, etc. at a temperature of 1°C to room temperature, preferably room temperature.

5( of formula (1) of the 4(R)-derivative of the desired formula (■)
f) Cyclization to R)-penem may occur spontaneously or by thermal or catalytic methods known in the art, e.g.
7JI]1IP1 in toluene by the Words method (J, Am.

Chem,' 8oc,, 101 elks 629
6 pages (1979); 1 bid, vol. 101, 6
301 pages (1979); 1btd, vol. 101, 6606 pages (1979); 1b1d, 10
2, 2069 (1980)).

optional salification and esterification steps and the corresponding 5(R)-benem derivatives of the formula (I) in which R2 represents a carboxy-linking group; R2 represents hydrogen or a cation; The conversion to [representation] can be performed by a known method.

In particular, 5(R)- of formula (r) (F12 represents hydrogen)
For example, from the corresponding compound (R2 represents a carboxy-protecting group), it can be determined by hydrogenolysis, for example when Rs represents a p-nitro-pencyl group, or by hydrogenolysis, for example when Rs represents an acetonidonyl group. is pH 7.5
can be obtained by hydrolysis in a phosphate buffer.

The optional conversion of compounds of formula (1) to other compounds of formula (1) can be carried out according to known methods of organic chemistry.

According to the method of the invention, intermediates of formula (1) are obtained by the following method: (1) Formula (XI): R.

[In the formula, R3 is I! 1JNe] of the compound of the formula (XIV): Conversion of the compound of the formula (XIV) to the compound of the formula (wherein R and R3 represent the above): (2) When the compound of the formula (XIV') is oxidized, the compound of the formula (XV
) : [In the formula, R and R3 represent the above-mentioned compounds] is obtained; (3) The N, 0-carrying group is removed from the compound of formula (XV').

The conversion of a compound of formula (XIII) to a compound of formula (XIV) is carried out by adding an excess of a suitable base, generally organic and inorganic gI
Bases such as NaH, LiH, KH, n-BuLi, t
-BuLi, lithium-diisopropylamide or ♂s(trimethylsilyl)-lithium amide in a suitable solvent by known methods, e.g. T. Durst.

RoV, D, Elzan and R, Legault:
Can, J., Chem.

Vol. 52, p. 52o6 (1974) React by K.
This is carried out by treating the obtained anion with an electrophilic agent having R units by a known method.

The electrophile having an R unit may be any compound having a positively charged R unit.

Special compound of formula (XIV) where KR is an alkyl group? To obtain the electrophile, the electrophile may be a suitable alkyl halide, such as chloride or bromide.

To obtain compounds (XIV) Y in which R is an acyl group, suitable activated acids such as esters, acyl halides, acylindazoles or anhydrides may be used.

For the compound (XIV) in which R is carboxy, a suitable activated formate may be used, for example a tetral formate.

If necessary, 1] initially introduced into the compound (XrV)
One exchange of R can be converted to other unsubstituted H by conventional reactions of organic chemistry.

Formula (Xff') to obtain a sulfone compound of formula (XV)
The oxidation of the sulfur compounds of ) can be carried out by the methods normally used in organic chemistry for the oxidation of this cypress, for example by inorganic or organic oxidizing agents preferably chosen from m-chloroperbenzoic acid or KMnO4. .

Removal of the N, O protecting groups of the compound of formula (XV) can be carried out in a conventional manner, for example by mild hydrolysis, preferably acidic hydrolysis.

As mentioned above, the compound of formula (XI) has 5(R)-2-
A novel intermediate useful in the synthesis of penem-3-carboxylic acid derivatives.

Particularly by said method, a compound of formula (Xl) can be prepared, for example, of the formula CXW>C, where R is a group: Rx-7°1°' (Rx
can be converted into a compound of the residue of an acyl group, in particular C1-C6 alkyl or phenyl). When the acyl fermentation conductor is subsequently reduced, depending on the reduction conditions used, it becomes a compound of the formula (Xff) (R is a group: TJ, and the carbon bearing the xy group is in the R-configuration).
and the carbon having the hydroxyl group is in the S-configuration] is obtained.

Starting from the optically active compound of formula (XIV) obtained by the method, formulas (Vl) and (■) are prepared following the reaction described in 1.
through the corresponding optically active intermediate represented by formula (1) and a hydroxy group? An optically active veneme is obtained in which 1 g of the carbon having a hydroxyl group represents a group of R-configuration and the carbon having a hydroxyl group has an S-configuration.

%IC, for example 8(R), 6(8)- and droxyethyl-5(R)-penem of formula (1), which are not described in the literature as single diastereomers.

The novel intermediates of the formula (X[[I) above can be prepared synthetically from 6-aminopenicillane flN (6-APA) or penicillin according to the invention.

The compound of formula (■) where R3 is methyl is 6-APA
It can be produced according to the following scheme starting from Ijl et al.

1 Scheme ■ a) 4 e) ↓ The method of Scheme H consists of the following steps: (a) Penicillanic acid (XVI), which is easily obtained by known methods from 6-aminopenicillanic acid or penicillin, is converted into the corresponding azide ( Convert to X■); (bl Aji)' (
When XVM) is rearranged in the presence of alcohol R,OH,
Urethane (XI) CR, represents a carboxy-protecting group which can be easily removed by e.g. reduction or solvent decomposition] or selectively azyl' (XIV)
Rearrangement in the presence of an inert solvent gives the corresponding isocyanate intermediate: lc) Urethane (XVI) 'Il-Decarboxylation gives the aldehyde (XllO (performed under reducing or hydrolytic conditions) ) or a selective pressure isocyanate intermediate?Acidic hydrolysis produces the aldehyde (XI
X) is obtained; (dl aldehyde (X[) Y: upon reduction, azetidinyl carbinol (XX) is obtained; (el
Azetidinyl carbinol (XX)v, ace corresponding to pink crow compound (■) [R3 represents CH3@]
Transform by the formation of nids.

Engineering! 1(al, (bl, (cl) is a chemical force, a process known under the name of Curtius degradation, by which the conversion of an acid to a 10-noramine via an azide half- and incyanate intermediate R- CH2COOH → R-CH2-NH2 becomes possible (T, Curtius: J, Chem, 8oc
, (A), vol. 60, p. 56 (1891)].

The corresponding intermediate 1C-noramine is not isolated. This is because it is unstable and easily converts into aldehyde (XI) K in the presence of water:
, > usually results in the aldehyde, e.g. borohydride)
This can be carried out by the method used in organic chemistry to reduce the primary alcohol with an aqueous IJ solution.

Examples of carboxy protecting group R6 in compounds of formula (XVI) are:
Lower alkyl radicals optionally substituted by halo, especially trichloroethyl, aralkyl radicals, especially benzyl and p-nitrobenzyl, lower alkyl radicals, especially Kt-decyl or acetonyl.

Formula (XX) Formula α■:R of meazetidinylcarpinol
The conversion of 3=CH3) into the bicyclic compound can be carried out by acetonization by known methods, e.g. in the presence of cypropane and boron trifluoride in 2,2-dimethane, in an organic solvent such as methylene chloride, chloroform, diethyl ether at a temperature of ca. The reaction can be easily carried out at -10°C to room temperature.

The compound of formula (XHI) where CRe represents hydrogen is 6
It can be produced starting from -aminopenicillanic acid by the method shown in the following scheme (1).

^ r) -p The method of the diagram '■ consists of the following steps: (a') Formula (X
Esterification of the compound of VI) results in formula (XXT) C
Rs represents C1-C6 alkyl or benzyl]; (1() the resulting formula (XX
Penicillate Y of I), formula: N2CHCOOR, (
: R, represents C0-C6 alkyl) is coupled with cyanoacetate to give secopenicylanate (XXII) = (a') secopenicylanate (XXI) yr isomerization produces azetidinone spindle (
XXIIA) is obtained; or selectively oxidation/esterification of the compound of formula (X■) (11′) provides benicilanate S-oxide of formula (XXIA) CR, represents the above. ;When combined,
Azetidine derivative (XXIA) is obtained; Ccf) 1 barrel (a') = (b') → (a') and step '(a') → (formula (X) IIA served by)
(a') the resulting ester C0 of the compound of formula (XXI);
When OR, is reduced, azetidinylcarpino-k (X
XIV) is obtained, azetidinyl carbinol <xxy
> v rcyclo-compound (Xllll: Ra=H)
K is converted by the formation of the corresponding acetonide.

The corresponding formula (XX I) of penicillanic acid of formula (XVI)
) to benicylate by combining compound (XVI) or its suitable linear conductor χ, an alcohol of the formula R50H [R, represents It can be obtained by reacting according to a method.

Obtained formula (XXI) f) Compound formula: Ni1C
HCOOR.

The coupling of with diazoacetate can be carried out as described in the chemical literature for analogous reactions [
Tetr, Let, tars, 19728%46
87 pages].

Isomerization of the free olefinic bond of the compound of formula (XXI) to obtain compound (XXIA)' is carried out by contacting an inorganic or organic group in a harsh solvent such as chloroform, methylene chloride, diethyl ether at low temperature or room temperature. Be prayed for by action.

Corresponding formula (XXIA) of penicillanic acid of formula (XVI)
is converted into penicylanate 8-oxide by a known method.
(XVI) 'k Oxidation followed by esterification (J, C, S, Chem, Comm, +
Vol. 1972, p. 601 10 Formula (XXIIA
) can be removed under oxidizing conditions in a suitable solvent such as methylene chloride, acetone at a temperature of -7
Perform at 8-+5°C.

Oxidation conditions are e.g. ozone or KMnO in a basic medium.
Obtained by the presence of 4. Compound (F) of formula (XXI[l)
Technique X Chil-COOR6f)-IF7c is prepared using known methods for reducing the carboxylic ester to the primary alcohol, such as using a hydride, preferably LlAIH, or borane, and a solvent such as diethyl ether, tetrahydrofuran, dioxane. The temperature underground is -20~+20℃
Let's do it.

Compound (xm) CR3 represents hydrogen] Preparation of azetidinyl carbinol (XXIV) to obtain Y is carried out in a known manner, e.g. by combining cypropane in 2,2-dimethane dissolved in an acidic medium and an organic solvent, e.g. The reaction is carried out in methylene, chloroform, or diethyl ether at a temperature of -10°C to room temperature.

As mentioned above, the intermediate of formula CXM) to be prepared by the method of schemes 1 and 2 starting from natural 6-amitupenyllanic acid or penicillin can also be obtained chemically synthesized by the method of scheme 2.

Scheme ■ The method of Scheme ■ consists of the following steps: (1) 2 of formula (XXV) CL represents a nucleophilic leaving group]
-Oxo-azetidine enzyme conductor? , into a mixture of enantiomers of formula (XXVIR) and (XXI78) = (2) The resulting racemic mixture is resolved and the separated enantiomers (XXV
IR) 'Y Esterification yields the formula (m) 4(R)-ester derivative: (3) Formula (XXVII)
or selectively reduce the optically active ester of formula (xx
vIR) to the optically active SV**, the formula (XXv
An optically active carbinol of formula (I) is obtained; (4) The desired compound of formula (XXI) is converted into a compound of formula (Xllll
:R, =H or C1-c6 alkyl) by formation of the corresponding acetonide.

The nucleophilic leaving group of the compound of formula (XXV) may be, for example, an acyloxy group, preferably an 01-c6 alkanoyloxy or benzoyloxy or a halogen or sulfonyl group. Compound (XXVI) of the compound of formula (XXV)
R) and the helical mixture of (XXvI8)], preferably the sodium or potassium salt, of thioglycolic acid. The reaction is preferably carried out in a suitable solvent selected from water, tetrahydrofuran, dimethylformamide, acetone, ethanol, acetonitrile or a mixture of these solvents at a temperature of -20 to
Perform at +20°C.

The resulting enantiomeric acids (XXVIR) and (XXvI8)
The resolution of the racemic mixture of
When reacted with, for example, ephedrine, prusin, cinchonine, methylamine, 1-phenyl-ethylamine, etc., mixtures of diastereomeric salts are obtained.

After separation of the diastereomeric salts by known methods, for example by fractional crystallization, the chain form χ of formula (XXVTR) is recovered by acidification of the corresponding salt.

Free acid (XXVIR) Y formula: R,OH[R,)'!
The ester of the formula (Xx■) can be obtained by esterification with the alcohol represented by the above formula (Xx■) in a conventional manner.

Formula CXXVI for invoking carbinol of formula (XXI)
Reduction of R) or its esters of formula (XX) is a method commonly used in organic chemistry to reduce carboxyl esters to primary alcohols (e.g. poranes, mixed hydrides, LiAIH).

Alternatively, the reaction with NaBH4 in an anhydrous inert solvent such as diethyl ether or tetrahydrofuran is carried out.

Optically active bicyclo compound of optically active carbinol of formula (XX■) (XI [[: R3=H or tt C1% c,
The conversion to amide or alcohol (alkyl) is carried out by a7tonation of the amide or alcohol moiety by known methods, e.g. 2,2-dimethoxypropane in an acidic medium, preferably in a solvent chosen from methylene chloride, chlorotetraform, diethyl ether. This is carried out by processing at a temperature of -10 to +20°C.

Enantiomer (XXVIR) and he (XXvI8) Noy *
Depending on the optical resolution, the mixture is individually divided into acids (XX
A diastereomeric salt of VIR) and a diastereomeric salt of acid (XXvI8) are obtained. The latter salt is this V#
(XXVIR) and [(XX■8) f) + i [[body a
The compound K may be destroyed by conversion to Y, and from this, the optically active ester of formula (XX) can be further recovered by the above-mentioned method.

Compound (XX
The conversion of VI') and (XXV[8) into an enantiomeric mixture can be carried out by the following step = tat The free acid of formula (X■R) is acidified from its diastereomeric salt in a conventional manner. (bl) Esterifying the radical 111111! of formula (XXVI8) with an alcohol of formula: R,OH (Re is as defined above) in a conventional manner; (c) The esters are reacted with suitable inorganic and organic oxidizing agents, such as m-chloroperbenzoic acid oglycol #di-salt of the cod conductor, in the same manner as shown in the reaction of Scheme 2 above.

The synthesis of the optically active intermediate of the formula (XI) by the method of scheme (2) further includes a 4(8)-configured enantiomer,
That is, the productivity of the entire process of the present invention can be increased by recycling the compound of formula (XXV[R).

The second object of the present invention is the following group of novel optically active trans-
Concerning the -5(R)-2-penem-3-carvone# derivative in 6(8)fll: Formula (I) [wherein R and R1 represent C1-C6 alkyl, R is hydrogen, C1-C6 Alkyl, optionally nitro-substituted benzyl group or pharmaceutical or veterinary! ! ! (b) a compound having the formula (i) [R)2 c1-C, Flu? #
t'l represents C1\C6 alkanoyloxymethyl, R2 is hydrogen, CelC6 alkanoylmethyl or optionally nitro-substituted benzyl J or a pharmaceutically or medically acceptable cation y! lc) Formula (1) CR represents C1-C6 alkyl χ.

R1 represents C1-C6 alkoxy monocarbonyl, R
2 represents hydrogen s C1-C6 alkyl, optionally a nitro-substituted benzyl group, or a pharmaceutically or veterinary acceptable cation): (d) Formula (1) CR
represents C106 alkyl, R1 represents thenylmethyl, R2 represents hydrogen, CelC6 atomyl, in some cases, a nitro-substituted benzyl group or J11 represents a medicinally or medically acceptable cation; Compound.

Preferred compounds of the ia1 group are those in which R and R1 represent methyl, ethyl or zo-4-pyl Y, in particular the following; - Cal♂Φsylate; Methyl (6B
) -6-Nithyl (5R) -2-ethyl-2-penem-3-carzoxylate: Methyl (6B) -6-Nithyl (5R) -2-propyl-2-penem-6-carboxylate; Methyl ( 6B) -6-methyl-(5
R) -2-Methyl-2-penem-5-carboxylate; Methyl (68> -6-methyl-(5R) -2-
Ethyl-2-penem-3-carmexylate; methyl (
6B) -6-methyl-(SR)-2-propyl-2
-Penem-6-carmexylate; methyl (6B) -
6-propyl-(5R)-2-methyl-2-penem-
5-carboxylate: methyl (6B) -6-fcl
Biru-(SR)-2-ethyl-2-penem-5-carzoxylate; Methyl(6B)-6-fropyru(S
R) -2-propyl-2-penem-5-carboxylate; p-nitrobenzyl (68) -6-nityl (
5R) -2-Methyl-2-penem-5-carboxylate; p-nitrobenzyl (6B) -6-nityl (5R)
-2-Ethyl-2-penem-5-carboxylate; p-nitrobenzyl (6B) -6-Nityru (5R)
-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl (6B) -6-methyl- (5R)
-2-Methyl-2-penem-6-carboxylate; p-nitrobenzyl (6B) -6-methyl- (5R)
-2-ethyl-2-penem-6-carboxylate; p-nitrobenzyl (6B> -6-methyl-(5R)
-2-propyl-2-penem-6-carboxylate; p-nitrobenzyl C6E3) -6-propyl-(5
R) -2-methyl-2-penem-5-merpoxylate; p-nitrobenzyl (6B) -6-zorobyl- (5R
) -2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl (6B) -6-f lobiru (5R
) -2-ly-pyl-2-penem-3-carboxylate: (6B) -6-nityl-(5R) -2-methyl-2
-penem-5-carzanoic acid; (68) -6-nityl-(5R) -2-ethyl-2
-penem-5-carboxylic acid; (68) -6-nityl-(5R) -2-7' lobi-2-penem-6-carboxylic acid; (6B) -6-methyl-(5R) -2-methyl-2
-penem-3-carboxylic acid; (6B) -6-methyl-(5R) -2-ethyl-2
-penem-5-carboxylic acid; (6B) -6-methyl-(5R) -2-propyl-
2-penem-5-carboxylic acid; (6B) -6-7' lobiru (5R) -2-methyl-2-penem-6-carzanoic acid; (68) -6-f lobiru (5R) -2 -Ethyl-
2-penem-5-carboxylic acid; (6B) -6-propyl-(5R) -2-propyl-2-penem-6-carboxylic acid; and pharmaceutically or veterinary mulberry-acceptable salts of the free acid, especially sodium salt.

Preferred compounds of the fbl group are those in which R represents methyl, ethyl or propyl and R represents acetoxymethyl or propionyloxymethyl, in particular p-nitrobenzyl (6B) -6-nityl (5R )
-2-acetoxy-methyl-2-penem-6-carboxylate; p-nitrobenzyl (6B) -6-methyl- (5R)
-2-acetoxy-methyl-2-penem-5-carboxylate; p-nitrobenzyl (6B) -6-zorobyl-(5R
) -2-acetoxy-methyl-2-penem-5-carboxylate; p-nitrobenzyl (6B) -6-methyl-(5R)
-2-propionyloxy-methyl-2-penem-5
-Carzoxylate; p-nitrobenzyl (6B) -6-Nityru (5R)
-2-7'ropionyloxy-methyl-2-penem-5
-carboxylate; p-nitrobenzyl (6B) -6-propyl- (5R
) -2-propionyloxy-methyl-2-penem-
5-carboxylate; acetonyl (6B) -6-nityl (5R) -2-
Acetoxy-methyl-2-penem-3-carboxylate; acetonyl (6B) -6-methyl-(5R) -2-
Acetoxy-methyl-2-penem-6-carboxylate; acetonyl (6B) -6-7'' lobiru (5R) -
2-acetoxy-methyl-2-penem-5-carboxylate; acetonyl (6B) -6-methyl-(SR) -2-
Propionyloxy-methyl-2-penem-5-carzoxylate; -acetonyl (6B) -6-nityl (5R) -2
-Propionyloxy-methyl-2-penem-5-carboxylate; acetonyl (68) -6-propyl-(5R) -2
-noropionyloxy-methyl-2-penem-5-calde sylate; (68) -6-nityl-(5R) -2-acetoxy-methyl-2-penem-6-carzanic acid; (68) −
6-Methyl-(5R)-2-acetoxy-methyl-2
-Penem-5-carboxylic acid; C68')-6-f lobi-(SR) -2-acetoxy-methyl-2-penem-
3-carbo7M: (68>-6-methyl-(5R)
-2-propionyloxy-methyl-2-penem-5-
Carboxylic acid: (6B) -6-Nitylu(5R) -2-broonyloxy-methyl-2-penem-3-carboxylic acid; (68) -6-propyl-(SR) -2-f ropionyl Oxymethyl-2''''penem-6-carboxylic acid; Methyl (68) -6-nityl (SR) -2-7cetoxymethyl-2-penem-3-carboxylate -
T: Methyl (68) -6-methyl-(5R) -2-acetoxy-methyl-2-penem-3-carzaxylene -
Methyl (6B) -6-propyl-(5R) -2-acetoxy-methyl-2-penem-3-calde sylate; Methyl (68> -6-methyl-(5R) -2-propionyloxy- Methyl-2-penem-5-carboxylate; Methyl (6B) -6-nityl-(5R) -2-f-onyloxy-methyl-2-penem-5-carboxylate; Methyl (6B) -6-propyl- (5R) -2-Propionyloxy-methyl-2-penem-3-carboxylate: and linear or veterinary tonic salts of the free acid, especially the sodium salt.

Preferred compounds of fcl#P are those in which R represents methyl, ethyl or propyl and R1 represents methoxycarbonyl, ethoxycarbonyl or zoloboxycarbonyl, in particular p-nitrobenzyl (6B)
-6-Nithyl (5R) -2-ethoxycarboxylate; p-nitrobenzyl (6B) -6-methyl- (5R)
-2-ethoxycarbonyl-2-penem-5-carzoxylate; p-nitrobenzyl C6B>-6--f lobiru(5R
) -2-ethoxycarbonyl-2-penem-5-carboxylate; p-nitrobenzyl (6B) -6-methyl- (5R)
-2-methoxycarbonyl-2-penem-6-carboxylate; p-nitrobenzyl (68) -6-nityl (5R)
-2-/tobodicarbonyl-2-penemu-5-carboxylate; 9-nitrobenzyl (6B) -6-f robi-(5R
) -2-methoxycarboxy-2-penem-5-carboxylate; p-nitrobenzyl C6B> -6-methyl-(5R)
-2-1'Ropoxycarbonyl-2-penem-6-carboxylate; p-nitrobenzyl (68) -6-Nityru (5R)
-2-, l'crobocycarbonyl-2-penem-5-
Carboxylate; p-nitropencyl (68) -6-propyl- (5R
) -2-froboxyl-,2-penem-5-
Carboxylate; (6B) -6-Nithyl (5R) -2-ethoxycarbonyl-2-penem-6-carboxylic acid; (68) -
6-methyl-(5FI)-2-ethoxycarbonyl-
2,-penem-3-carboxylic acid: (6B) -6-norobyl-(5R) -2-ethoxycarbonyl-2-penem-5-carboxylic acid; (6B) -6-methyl-(5R
) -2-methoxycarbonyl-2-penem-localmenic acid; (6B) -6-nityl-(5R) -2-methoxycarbonyl-2-penem-5-carzanoic acid; (6
B) -6-propyl-(5R)-2-methoxycar♂-2-penemu-3-carzanoic acid; (68) -6
-Methyl-(5R)-2-fC! Poxycarbonyl-
2-penem-6-carboxylic acid: (6B) -6-ethyl/
' -(5R) -2-7' o-poxycarbonyl-2
-penem-5-carboxylic acid; (68> -6-propyl-(5R) -2-propoxycarbonyl-2-penem-5-carboxylic acid; methyl (6B) -6-nityl-(
5R) -2-ethoxycarbonyl-2-penem-5-
Carpoxylate; Methyl (68) -6-methyl-(5R) -2-ethoxycarl! e-Flu 2-penem-6-carpoxylate; Methyl (6B) -6-propyl-(5R) -2-ethoxycarbonyl-2-penem-6-carpoxylate; Methyl (68) -6-methyl- (5R) -2-Methoxycarbonyl-2-penem-6-carpoxylate: Methyl (68) -6-Nityru (SR) 72-Methoxycarbonyl-2-penem-3-carboxylate -
Methyl (6B) -6-zorobyl-(5R) -2-methoxycarbonyl-2-penem-5-carboxylate; Methyl (6B) -6-methyl-(5FI) -2-dicarbonyl-2-penem in propo -5-carbo, xylate; Methyl (6B) -6-Nityru (5R) -2-propoxycarbonyl-2-penem-6-carboxylate; Methyl (6B) -6-propyl-(5R) -2-propoxycarbonyl -2-penem-3-carboxylate; and pharmaceutically or veterinary mulberry-acceptable salts of free acid, the special sodium salt.

(Preferred compounds of dl n are those in which R represents methyl, ethyl or propyl and R1 represents 2-thenylmethyl, Il?I#/c: p-nitrobenzyl (6B) -6 -Nityl-2'-yl-2-penem-6-carboxylate; p-nitrobenzyl (6B) -6-methyl-(5R)
-2-cheny2'-yl-methyl-2-penem-6-
Carboxylate; p-nitrobenzyl (6B) -6-propyl- (5R
) -2-cheny2'-yl-methyl-2-penem-
3-carboxylate; (68) -6-ef1- (5R) -2-ff-212'-yl-methyl-2-penem-5-carboxylic acid;
(68) -6-1fk-(5R) -2-f engineering=-7-
yl-methyl-2-penem-6-carboxylic acid; (68)
-6-7' Robi Lou (5R) -2-Cheney 2'--
(Methyl-2-penem-6-carboxylic acid; Methyl (6B) -6-Nithyl (5R) -2-cheny2'-yl-methyl-2-penem-5-carboxylate; Methyl (6B) -6- Methyl-(5R) -2-Cheney2'-yl-methyl""2""penem-5-carboxylate; Methyl C68> -6-propyl-(5R) -2°-
Cheney 2'-yl-methyl-2-methyl-3-carboxylate; and #1! Pharmaceutically or pharmaceutically acceptable salts of acids, especially the sodium salts.

All said compounds can be prepared by the general method which is the first object of the present invention. The novel optically active trans-6(8)-substituted-5(R)-2 of the present invention
-Penem-5-carboxylic acid can be used in animals and humans to produce Durum-positive and Durum-negative bacteria, such as Staphylococcus spp.
ataphy-1 ococci), streptococci (sirept, ococci), diplococci (
diplococci), Klebsiella (Klebs)
iella), Escherichia coli (gach-er
ichia coli), Zolotes mirabilis (
Proteus m1rabilia), Narmonella (8R1mo-nella), Sidera (5hid61
1a), Haemophilus
It has a great anti-horticultural effect against Neisseria (Nelsaer1a). Furthermore, the compounds according to the invention can be used in microorganisms that are significant beta-lactamase producers, such as Klebsiella aerogenes 1082 B (Klebale
lla aerogenesl 082g), Esch-erichia col tem
i Ten ), Enterobacter cloacani P 9
9 (Enterobacter cloacae P.
99) and Ingel-positive Zoloteus (protet
us ) Others and Zosoygemonas aerzenosa (
Pseudomonas aeruginosa)
It shows a large effect on Ic.

Owing to its strong antibacterial action against Durham's and Durham's microorganisms in animals or humans, the compounds of the invention are useful against infections caused by said microorganisms, such as respiratory tract infections, such as bronchitis, bronchial pneumonia, pleurisy; Biliary and peritoneal infections, e.g. sepsis; urinary tract infections, e.g. pyelonephritis, cystitis;
It is useful in the treatment of obstetric and gynecological infections, such as cervical infections, endometritis; ear, nose and throat infections, such as otitis, sinusitis, parotitis.

The toxicity of the compounds according to the invention is completely negligible;
It can therefore be safely used in therapy.

The compounds according to the invention can be administered to humans or animals in various administration forms.
For example orally in the form of tablets, capsules, lotus or syrup; rectally in the form of herbal medicines; parenterally, for example intravenously or intramuscularly (as a solution or suspension; if intravenous administration is urgent) (preferred); by inhalation in the form of aerodels or solutions; intravaginally, for example in the form of suppositories; or topically in the form of lotions, creams or ointments. Pharmaceutical or veterinary compositions containing the compounds according to the invention can be prepared in a conventional manner using conventional carriers or diluents used for other cephalosporins. Commonly used carriers or diluents are, for example, water, gelatin, lactose, starch, magnesium stearate, talc,
These include vegetable oil, cellulose, and others. Doses in the range of about 1 to 100 caps per kiloliter of body weight daily can be used in a variety of animals, the exact dose depending on the age, body weight and treatment conditions, as well as the frequency and route of administration. A preferred method of administration of compounds according to the invention is parenteral administration:
In this case, the compounds according to the invention can be administered, for example, in adults, in suitable vehicles for intramuscular injection, such as sterile water or ridecaine hydrochloride solution, and for intravenous injection in sterile water, physiological saline, dextrose, etc. It may be administered as a solution or in conventional intravenous fluids or electrolytes in an amount of about 100 to 200 cm per dose, preferably about 150 cm per dose, 1 to 4 times daily. Furthermore, the compounds according to the invention can be used as antibacterial agents in prophylactic methods, for example in cleaning or as surface disinfection compositions, for example mixed with conventional inert dry or aqueous carriers, suspended or dissolved. It can be used for washing or spraying at a concentration of ~1 wt. The compounds are also useful as feed supplements.

The invention will now be explained with reference to examples.

Determination of melting point has been difficult in some cases because the compound has a tendency to retain solvent. In this case K1 decomposition I was added after the melting point.

TI of candy omitted in examples (F'% AcOH and AcOgt represent tetrahydrofuran, acetic acid and ethyl acetate, respectively. I, R, are infrared rays, U, V are ultraviolet rays, N0M
, R, represents nuclear magnetic resonance, and m, p represent melting point.

Example 1 2.2-dimethyl-3-carbonylazoy-(5R)-
Penum.

Penicillanic acid (6.04 g, 307 moles) anhydrous TH
In a cooled (-15°C) solution dissolved in F (40d):
, wt5N (3.04g, 4.18go, 60mamol)
jtTHTPc5111) Add the dissolved K solution Y for 15 minutes while stirring. After 15 minutes of additional stirring, ethyl chloroformate (3,261!, 2.86 g, 60 moles)
Add the solution dissolved in THF (5M). The reaction mixture was stirred for 90 minutes at a temperature of -15 to -10°C and then diluted with NaN3 (61,92 mmol) χHmO (2Qd
)K: 7J drops of dissolved solution] (for 30 minutes). The resulting mixture was stirred for a further 45 min at 15-0 °C, then diluted with cold water (150 d) and extracted with benzene (4
x 1001), attached extract Y water (2 x 100d)
and saturated NaCl aqueous solution (1 x 1001 LJ) and dried over Na1804. 1! Evaporation of the agent yields an oily residue.

1, R, (CHC13g-1): 2150, 178
0.

1710゜Example 2 2',2',2'-)lichlorethyl-N(2,2-
Dimethyl-(5R)-penamy-6-yl)-urethane.

Azide (Example 1) χ In a solution dissolved in anhydrous benzene (100111), freshly distilled triglycerol ethanol (
Add 4.5 g, 30 moles).

Heat the resulting mixture at 70-7°C for ~5 hours;
It is then cooled and evaporated in vacuo to give a residue, which is chromatographed on silica gel (100, V) K. C, H6-Ac0Et (95: 5
Elution of ) gives a yellow solid, which is combined with penzene (4.4I, 42%).

m, p・: 1 62-4℃ DSC' 298 whisper purity chart analysis (calculated value of C1oHtsC1sN*Os8):
c 34.74 (34,55) Arrogant H3,73 (3
,77)%N 8-[13(8-05)% s
9.07(9,22)%C130,50(30,60)
91 [α) = +111.4°CC = 0.8, CHCl
3) 1, R, (cHcl,, m-”): 1780
, 1743N, M, R, (CI) C1, δ)
2 1.5 1 (5H, II) 1.57 (3
H, a) 3.14 (I H, dd, J = 2.5, 18
Hz) 3.58 (IH, dd, J= 5.18H2) 4.7! y(2H, m) 5.12 (I H, (1(1,:s = 2-5,
5 Hz ) 5-45 (I H, br ) 5-64 (IH, d,, T: 9 Hz) Example 3 2.2-zo)chitv-5-Hi'tPo*C<5R)-
Penum.

To a stirred suspension of trichlorurethane (4,1511,11,9 mol) χ90Il in AcOH (100d) was added 3% Zn powder C25II)pe in small portions at 5°C.
Added for 0 minutes. The resulting mixture is stirred at ambient temperature for 16-20 hours. Filter using a solid filter aid and wash several times with benzene. Drawn door liquid and washing liquid Y saturated N
Washed with aCl aqueous solution (4X5Qau), Na, So,
Dry on top. Evaporation of the bath agent γ gives a yellow solid, which is chromatographed on silica gel. Elution with C6H6-Ac0Et (9525) gave the white crystalline title product (1,97&,90
．． 7%).

m, p.: 58-60℃ [α)D=+2004°(C'=1-1,0MC
l! 5) 1, R, (CHCl3.CHIL-1):
3350, 1768N, M, R, (CDC13, δ)
: 1.49 (3H, 5) 1-53 (3H, s) 3.02 (IH, dd, J=2-5.18Hz) 3.
43 (IH, (1 (1, J = 5.18Hz) 4.00
(IH, br) 5.16 (IH, dd, J=2.5.5Hz) 5.2
9 (IH,br) Example 4 2.2-dimethyl-3-hydroxy-(5R)-2,2
-Zo/Tyl-3-carbonylic acid-5(R]-penam [prepared by adding 26.2 # (130 shoulder moles of benicilla heptacid) as in Example 1) V, C, a.

(200R/) at 70-75℃ for 4 hours 2U heat-f'
or directly converted to the corresponding isocyanate by keeping it under vacuum for 48 hours. The crude incyanate (1,R, (EtOH)If
CH, C1,) not including f: 2245.1785c
1L-1lv dioxa y (1000 MJ) K', HaO (3000iu) and 2N-I(C'1(
130g] for 4 hours. When the addition is complete, the reaction mixture is stirred for 1 hour and then extracted with methylene chloride (4 x 500 m). The attached organic extract was washed with a saturated NaCl aqueous solution, Na, 80
．． The resulting 'rS residue is taken up in Y benzene (10014) and Ac0Pt (10 Ill), stirred for 1 hour and filtered.

Elute with a column of silica gel (50,!ii'). Furthermore, C,H,-AcOEt (90: 1
Elution with 0) yielded the title compound (5.1 g, 22.
6%) is obtained.

Example 5 (4R)-4-(β,β-dimethyl-3-hyroxyethylthio)azededinol-2-one.

2.2-dimethyl-6-hydroxy-(5R)-penam(1,87,9,10,8 mol) THF (25M)
Cool (ice bath) melt ff1K.

NaBH4 (440'%', 22111 mol l'HI○
(4d) Add the dissolved f# solution χ for 15 minutes while stirring. Mixed reaction+! r beggar, 50 liters of cold AcOH (1-5
117) and evaporated under vacuum to obtain a residue, which was absorbed in +1 CH Hayabusa C1 dew (100111J), washed with saturated NaCl aqueous solution, and treated with Na180
Dry over 4 and evaporate in vacuo to give a yellow oil. Purification by filtration through a short column of silica gel gives the title compound as a clear oil.

(1,81g, 95.71) [α]D=+184.0
°(C=1, CHCl5)1, R, (CHC
l5,1m-1): 3300.175 ON, M,
R, (CDCI,, δ): 1-26 (3Ls)1
．． 38 (3H, s) 2.81 (IH, ddd, J=1-5.

2.5 * 18Hz) 3.42 (IH, ddd, J=1.5.5.

18Hz) 6・56 (2H, a) 3-90 (IH, br) 5-DO (IH, dd, J=2.5.5H2) 7-58
(IH, br) Example 6 2.2.5.5-tetramethyl-(7R)-9-oxo-3-oxa-6-thia-1-azobiciclo[5,2,
OX・7] Nonane.

<4R)-4-(1,β-zomethyl-3-hyVoxyethylthio)azededinol-2-one (1,81 g, 10.
3 m-mol) and 2,2-dimethoxypropane (3,8
17, 3, 2, 9, 31 shoulder mole)y CH1+J1 (
Add boron trifluoride (0,25d) to the cooled (-10°C) solution. Reaction mixture Y - 0 reaction *V, stirred at 10°C for 30 minutes and at room temperature for an additional 2 hours.

CH, C11I (100d) ID, saturated NaC
tin salt by washing with 1 aqueous solution and drying over Na1SO4. When the solvent is evaporated in vacuum, the residue is
It is submerged and crystallized from hexane as a white solid (1.4C1,631&).

m-p, : 77-9°C D8C: Molar purity elemental analysis of better than 99 (calculated value of CtoHtyNO*B): C55,
68 (55,78) H7,99 (7-96)%N
6.48 (6,51)% 814.80 (1
4,89) 4[C1,=+137.52°(C=1
, C'MCI, )I-R-(C'HCl5. (
m-1): 174 ON, M, R, (CDCS,
δ): 1.20 (!H, a) 1-46 (3H
,5) 1-55 C5H,a) 1.71 (3H,a) 2.65 (IH, dd, J=2.5.15Hz)3
-18 (IH, dd, J=5, '5Hz) 5-6
0 (IH, d, J=12Hz14.14 (1H,
d, J=12Hz) 5-06 (IH, dd, J=2-
5.5Hz) Example 7 Ethyl α-(1-(1'α-methoxycarzenyl-2-
-methylprop-21-enyl)-2-oxoazetizony(4R)-4-ylthio]acetate.

Methyl penicillate (5,3Fl, 25 mmol) and C
u (acac) * Nakamoto (1,91-[water benzene (10
The reaction mixture was stirred at 80°C for 1 hour, cooled, and passed through the mixture for 7 hours. Liquid Y.

Absorb onto the top of a column of silicavir. Toluene-A
Elution with cOKt (98:2) yields unreacted methyl penicillate C2,569,48) followed by the title oil (1,9,!ii').

N, M, R, (CDCIs, δ): 1-29 (3
H, t, J=7Hz) 1-92 (3H, bra a) 3-07 (IH, dd, J=2.5. '16Hz)
! 1-39 (2H, Jl) 3-49 (IH, dd, J=5.16Hz) 3-80
(3H, g) 4-21 (2H, 9, J=7Hz) 4.80 (IH, a) 5.02 (IH, br 5) 5-15 (IH, br g) 5-19 (ILdd, J =2-5.5Hz) Monkey I (
acetylacetone 111112 steel) Example 8 Ethyl α-(1-(1'-methoxycaryl-2'-
Methylprop-11-enyl)-2-oxoavitisony(4R)-4-ylthio]acetate.

Ethyl α-(1-(1'-α-methoxycarzeni JL/
-21-7+Tylzolope-21-enyl)-2-Othaazethizoni-(4R)-4-ylthio]acet-)(1
, 9, @) solution Y in methylene chloride (40117) K, treated with triethylamine 2ffIl. After standing overnight, the solvent was evaporated in vacuo to give the title compound in large quantities.

N, M, R, (CD01g, δ): 1-28 (3
H, t, J = 7Hz) 2-03 (3H, a) 2-27 (3H, a) 3-02 (IH, cld, J = 2-5.16Hz) 3
．． 30 (2H, 5) 3-44 (IH, dd, J=5.16Hz) 3-81
(3H, s) 4.20 (2H, 9, J=7Hz) 5-29 (
IH, elei, J=2.5, 5Hz) Example 9 Ethyl α-(1-(1'-methoxycarbonyl-21-
Methylprop-1+-enyl)-2-oxoazetizony(4R)-4-ylthio]acetate.

Medyl penicillanate S oxide (2,311i.

10 moles of dioxane (801117) dissolved in 4C, heated at 80° C. for 24 hours under N in the presence of 2 moles excess of 1,1-zoethoxythene, cooled and the reaction mixture evaporated in vacuo. The residue was subjected to chromatography on silica gel.

Elution with toluene-AcOKt (98; 2) gave the title adduct (2 g, 6.6111 mol, 66 s
) is obtained.

Example 10 Ethyl α-[2-oxoazetisoni-(4R)-4-ylthio]acetate.

Ethyl α-(1-
(1'-Methocycarzanyl-21-methylde4pe-1
1-enyl)-2-oxoazetisony(4R)-4-
Ilthio]acetate) (1,5,!i', 5 book mol) was cooled to -78°C and treated with 0,5.2 mol. Zomethylan sulfide was added and the stirred mixture was allowed to come to room temperature. do.

Evaporate the solvent in vacuo, take up the residue in methanol and stir overnight at room temperature.Solvent? Evaporate in vacuo and take up the residue in methylene chloride, wash with water and give N1118
Drying over 04 and evaporation in vacuo gives the title compound.

[α]D=+90°(C=: 1,19, CHCl
4) 1, R, (CHCl4.c+a-”): 33
30, 1770, 173ON, M, R, (CDCI
s, δ): 1-! 13 (3H, t, J=7Hz)
2-96 (1a,aaa,,r=15.5e2.5.
1.3Hz) 3-40 (2H, s) 5.45 (IH, aaa,, r=15.5°5-0.
1-7Hz) 4.93 (IH, 1d, J=2-5.5.0Hz) 7.05 (IH, br) Example 11 (4R)'-4-(β-Hydroxyethyl-rethio)azenadino-2 -On.

LLAIH, (1.77 g , o, 0466 mol)YE
Add 1 g of a suspension of Y nitrogen dissolved in 3017 to an atmosphere of -20°C. The reaction mixture was stirred at -20 to 0°C for 2 hours, and again at -20°C. KMHIL, LiAla, (
1-77,! ii', 0.0466 mol) Y:Et,
0301j and left overnight at room temperature. Subsequently extracted with Ac OE t. Therefore, crystalline 1! ! Title product 7.51,! iil is obtained (
Yield 8(1).

m-p-: 47-49"0 [α), = +139° (C = = 0.1, CHCl5
)1, R, (CHCI, 4-1): 3300, 1
76ON, M, R, (CDCl2.9): 2-60
(IH, s) 2.70-3.30 (2H, m) 3-25-! 1.5 (2H, m) 3.7-3.9 (2H, m) 4-81 (IH, dd, J1=2-5Hz.

J@=5Hz) 7-52 (IH,s) Example 12 2.2-dimethyl-(7R)-9-okino-6-oxa-6-thia-1-azobiccyclo(5,2°Ol·〒]nonane.

(4R)-4-(β-hydroxyethylthio)azetylano-2O/(7,3F%0.0496%) and 2.2
-Zomethoxypropane [13,1i0.0125 mol)
? , dry CM without ethanol Y, C1, Ic, cooled and stirred solution 'i'-10', By
, -mt,,o (1wl) V/fil,? 1Oj
After additional stirring for 6°30 minutes, the reaction mixture YCH,C
1, (70 M'), washed with cold saturated aqueous NaHCOg (180117) and dried over Na1804. After evaporation of the solvent under vacuum a residue is obtained, which is χEt
The title product is obtained after crystallization from lO-n-hexane at 0°C. (6,7 71%), m-p,:
93-94°C.

[α) D = 107° (C = 1, CHCl5) 1-
R1 (CHCI3.cIL-”): 175ON, M
, R, (CDCIs, δ): 1.50 (3H,s
) 1.73 (3H, 5) 2-70 (IH, dd, J=2.15Hz) 2.71
(IH, dt, J=5.14Hz33.05 (IH
,dt,,r=5-5.14H)! 1.20 (IH
, 4d, J=5.15Hz) 4-16 (2H, dd,
J=3.5-5Hz)5.03 (IH, dd, J-2
, 5Hz).

Example 13 α-[2-oxo-(4R,5)-4-azetidinylthio]acetic acid.
0! ! Ll), thioglycolic acid (, 5Qil, 0
．． 47 mol)'t' 99% gtoH (400d)K aqueous solution of 7016? mx. After 5 minutes of additional stirring, 4-acetoxy-azetidinone (K, C1ausa et al., Liebig Ann, Chew, 197) dissolved in 99% gtOH (100 jL/).
4 years, 5391 [) (55g, 0-426 Motv)
yk:f*MJTru.

The resulting mixture was stirred at 0°C for 60 minutes and at room temperature for 1 hour. After cooling to -5°C, 2N-HC was added to the reaction solution.
Aqueous solution (490 m) Y: Add dropwise. Stir the resulting suspension for 11 hours when cool, remove the precipitate, and wash with water.

Mother liquor and washing liquid as a threat? Evaporation to dryness in vacuo gives a residue which is treated with zw, o 160yil. The resulting suspension is taken and washed with a small amount of hydrogen.The combined precipitate is dried in vacuo at 45°C (overnight). 58.5 g).

m, p, : j 30°C (decomposition) r, R, (KBr, c+a-1): 3450, 33
00, 1745.

1710.

N, M, R (CDC'13.δ): 2-89 (
IH, dd, J=2-5.16Hz) 3-38 (2H
+IH, a+m) 4.92 (IH, q, J:=2-5.5Hz) 7.8
8 (IH, br, replaced with DsO) 9-66 (IH,
br, D, O) Example 14 α-[2-oxo-(4R)-4-azetidinylthio]
Acetic acid D (→-7 nidoline salt.

α-[2-oxo-(4R,8)-4-azetidinylthio]acetic acid Cll0I/%0.248 mol]'i'99
%(DBtOHKtf)ht, T: molten gK, D(+)
-x Hue, Tori: /C45g, 0.272-r, Le)
Increases to 7+ at Y70℃. The resulting hot melt R? Cool and leave overnight at room temperature. A crystalline precipitate formed, which was removed from Y7, washed with a small amount of IICtOH at 99 °C, and incubated in vacuo for 40 °C.
Drying overnight at °C yields the title salt (32.1
．． 9).

m-p-: 160-2'0 [α]n = + 109.6s° (C'=0.1.99
16 KtOH) Example 15 α-[2-oxo-(4R)-4-azetidinylthio]
Acetic acid.

α-[2-oxo-(4R)-4-azetizonylthio]
Acetic acid D(+)-F V phosphorus salt (32.1 g) solution Y dissolved in distilled water, Amberli)
tej'' IR-20 and stir for 1 hour.

Polymer resin? P is removed using a filter aid and washed with distilled water.

Nuclearization of the combined P solution and washings in vacuo at 40° C. gives a residue, which is crystallized from 99 g of hot EtOH to give 13 g of the title compound.

[α)D” + 128° (C=0.10, 99% of] 1tOH) m, p,: 87-9°C Example 16 Methyl α-[2-oxoazetizoate (4R)-4-ylthio] acetate.

α-[2-Okynazetidiny(4R)-4-ylthio]acetic acid (10 g, 0.062 mol) was dissolved in anhydrous MeOH (2
Suspension Y dissolved in 00R1).

Amberlite pIR-120
Stir overnight in the presence of Polymer resin P removed, MeO
Wash with H. The extracted FM and washing liquid are evaporated in vacuo to give 10.8 g of methyl ester (100%
).

[α1. = +110° (C = 0.11, CHC!
15); [:α]0=+127°(C=0.
11, EtOH) 1, R, (C'HCI, 4-1)
: 3330, 1770, 173ON, M, R,
(C'DC15, δ): 2.96 (1) r, dd
d, J=2.0.

15H,) 3.41 (IH, aaa, J=1.5.

5.0, 15Hz) 3.42 (2H, a) 3-79 (3H, s) 4.94 (IH, aa, J=2.5, 5.0H1
) 7.35 (IH, br) Example 17 (4R)-4-(3-hydroxyethylthio)azetylanon-2-one.

Methyl α-[2-oxoazetidi= -(4R)-4-
[ylthio]acetate-1v, f111 to give the title compound.

m, p,: 47-9°C [α]. = + 130° (C = 1, 0HC1IB
).

Example 18 2.2-dimethyl-(7R)-(8B)-8-ethyl-
9-Oxo-3-oxa-6-thia-1-azoCcyclo(5,2,0m・mafnonane.

Seaiso-propylamine (4a!nt, 0.276
n-hexane (130 jL/, 0.2
06 mol) K-combined y,: i s s n-BuLi
am at -70°C under @liquid vNs.

After additional stirring for 15 minutes at -70°C, 2,2-dimethyl-(7R)-9-oxo-6-oxa-6-thia-1-
azobicyclo(5,2,0)]nonane(24,3,1
0,130 mol) Y tetrahydrofuran (150717
) and add the dissolved solution dropwise. Obtained yellowish solution Y
Stir for 15 minutes at -70°C and then add excess ethyl bromide dropwise. The reaction mixture is brought to room temperature, then poured into ice water and extracted several times with CH, σl. Combined extract f N
Drying over a1804 and evaporation in vacuo gives a pickle, which is crystallized from χEt@O-n-hexane at 0°C to give the title compound in a yield of 83%.

1, R, (CaC1 cloud-”): 176ON, M,
R, (CDC14, δ): 1-05 (3H, t,
J=7Hz) 1-51 (3H, a) 1.75 (3H, s) 1.89 (2H, m) 2-6-2-8 (2H, m) 2-9-3-5 (2H, m) 3-82 (IH, m) 5.05 (IH, dd, J=2.5Hz) Example 19 2.2-dimethyl-(7R)-(8B)-8-ethyl-9-oxo-3- Oxa-6-thea-1-azobiccyclo(5,2,OX·γ]nonane-6,6-dioxyr.

2.2-dimethyl-(7R)-(88)-ethyl-9-
Oxo-3-oxa-r6-thia-1-azobicyclo(
5,2,0m・tecononan (12,!i/,0.056
KMnO, (17,60,!i'
, 0-112% 7L/)Y water C200d), the solution χ was placed next to it at room temperature. After 2 hours of additional stirring, an excess amount of KMnO4χH@O@ was added to kill the
P is removed using precipitate Y filter aid, FiM'kC
Combined extract fully extracted with H Yuki CII Y HIO
Washing with water, drying over a cloud of CaCl and evaporation in air gives the title solid compound (11.8 g).

1, R, (CHCL3-″l): 1775, 13
35, 1150.

1090.

Example 20 (38)'-3-ethyl-(4R)-4-(β-hydroxyethylsulfonyl)azenadin-2-one.

2.2-dimethyl-(7R)-(88)-8-ethyl-
9-oxo-3-oxa-6-thia-1-azobicyclo(5,2,0'')nonane-6,6-dioxide (11
,8g) CH3CO0H (200117) and H,O
The solution χ dissolved in (43d) is heated at reflux temperature for 105 minutes. The cooled reaction mixture Y is evaporated in vacuo to
The title compound (10.1 g) is obtained.

Example 21 (3B)-3-ethyl-(4R)-4-(α-tetrahydrobilanylthio]azetidin-2-one.

<38>-s-ethyl-(4R)-4-(β-hyproxyethylsulfonyl)azeticuno-2-one (20,
7,! i+, 0.1 mol) and tetrahydrobyranthiol (12 g, 0.102 mol) [M, G, Mis
Sakian, R. Ketcham and A.R.

Martin: J, Org, Chem, 39
Volume, 2010 pages, 1974] Acetone (250d)
K dissolved mixture Y O-5M -NaOH aqueous solution (2
00d) and stir at room temperature for 14 hours. Na in the reaction mixture
Saturate with Cl and extract several times with AcOBt. Wash the extracted extract with a saturated aqueous solution of NaCl until it becomes neutral.
Drying over NallSO4 and evaporation in vacuo gives a residue, which is purified by column chromatography on silica sol. Toluene-hexay-Ac0Et (
Elution at 70:25:25 gives the title compound as an oil, which crystallizes on discharge (1
9.3,? ; yield 90%).

r, R, (CHCL3.cm-1): 5300,
2930, 2860.

1760.

N, M, R, (C'DCI!s, δ) = 1.
04 (3H, t, J=7Hz) 1.60-1-90
(8H, br) 5-14 (IH, br m) 3-58 (IH, br m) 4.14 (IH, br m) 4.63 and 4-74 (IFl, (1, J=2
Hz) 5-10' (IH, br m) 6.47 and 6-60 (IH, br.

Example 22 Methyl 2-((3'8)-3'-ethyl-(41
R)-4'-(α-tetrahydropyranthio]-2-oxo-azeticny-1--yl)-2-)I)7x
Nylphosphoranylidene acetate.

(3B)-3-ethyl-C4-Cα-tetrahydrobilanthio]-azetizono-2\one (1,07 g, 5 mmol) and methylglyoxyle) (1,269,12 mmol) Y, Anhydrous tetrahydrofuran (40m) and anhydrous EtaO (10su)K
The molten mixture was cooled to 0-5"C under nitrogen atmosphere and treated with anhydrous triethylamine (0.70d, ~5 mmol). The resulting solution was stirred at room temperature for 24 h, and the Ac
diluted with Ogt (50 g) and saturated aqueous NaCl solution (
3 x 30 m) and dried over Na1SO4. Evaporation of the solvent γllc in air yields an oil of C1.1 g
;1. R.

(CHC]4, cm-"): 3200 (wide), 2910.1760], which was dissolved in anhydrous tetrahydro 7 run, cooled to -30"O, treated with pyridine (6 resistance) under nitrogen atmosphere, Thionyl chloride (0,451
115Y Anhydrous Tetrahydryl Vroalane (61) was added dropwise by force. Mixture Y - l/1 hour at 20°C and -
Stir at 5-0°C for 2 hours. The precipitate Y is filtered and the F solution is evaporated several times from benzene in vacuo.

The residue was dissolved in a dry CH window C1 (5 (111j)) and treated with triphenylphosphine (1,850,9).

Stir overnight at room temperature under NII. Solvent Y was evaporated in vacuo and the residue was purified by column chromatography on silica gel, first with benzene/hexane/AcOgt.
(70:25:25) followed by penzene/hexane/Ac0Bt (70:10:40). The title compound is obtained as a white foam.

1, R-(CHCL3.':m-") 2 174
Example 23 Silver(3B)-1-ethyl-1-methoxycarbonyltriphenylphosphoranylidenemethyl-2-oquin-azetisoni-(4R)-4-ylthiolate.

COOMe COOMe phosphorane (
561"?s1"%") Y MeOHC
611Ll) 0.25 M AgNO3 solution (4.2 cd) is added dropwise to the stirred solution, which has been cooled in a water bath outside the kettle. After stirring for 5 minutes, the mixture? Dilute with distilled water (5R1) and carefully filter with suction. Precipitate Y. Wash several times with distilled water, then with gtlo and dry on the filter.

The yield is about 90%.

Example 24 f”2-C(3'S)-3-xchitv-(4'R
)-4'-acetylthio-2+-oxo-azedediny-11-yl)-2-triphenylphosphoranylidene acetate.

Silver(38)-5-ethyl-1-methoxycarbonyl-triphenylphosphoranylidenemethyl-2-oxoazethizoni-(4R)-4-ylthiolate (500~,0
．． Acetyl chloride (1,3271 mol) Y# is added to stirred f@'#L which has been dissolved with acetonitrile (5114) Y. Stir the mixture until the white AgCl precipitate is well separated from the solution. This was then filtered through χ Celit and Ac0111! Wash with t. F solution saturated NaHCO3 solution (3x20m) and saturated NaCl@ solution (IX201+7)"q Wash, N
Drying over A1804 and evaporation in vacuo gives a residue, which is subjected to column chromatography on silica gel. Benzene/Hexane/Ac0
When eluted with F:t (70:25:25), f! A compound of 320 Da is obtained.

Example 25 MethylC6B)-6-nityl(5R)-2-methyl-
2-penem-3-carboxylate.

COOMe Methyl 2- ((3'8) -3-ethyl-(4'R
)-41-acetylthio-21-oquin-azetizony-1'-yl)-2-) liphenylphosphoranyridine acetate (320#19)'? A solution χN dissolved in toluene (150d) was stirred at 85-90°C for 10 hours. The cooled mixture is absorbed on top of a column of Y silica gel and eluted with toluene/Ac0Et (19:1) to give the title compound.

1,R,2 (C'HCl34-1): 178
0, 1705N, M, R, (CDCI!5.δ)
: 1-09 (3H, t, J=7Hz) 1-94
(2H, m, J=7Hz)2-38 (3H,s
) 3.69 (IH, m, J=7.1.7Hz) 3.8
5 (!H, 5s) 5-56 (IH, d, J = 1-7) 1z) Working in the same way, the following compound is obtained: Methyl (6B)-6-Nityru (5R)- 2-ethyl-
2-penem-6-carboxylate; methyl C6B)-
6-Nitylu(5R)″″22-deropyru-2-penemulboxylate; MethylC68)-6-methyl-(5R)-2-methyl-
2-penem-3-carboxylate: methyl C6B)-
6-Methyl-(5R)-2-ethyl-2-penem-3-
Dimethyl carboxylate (6B)-6-methyl-(5
R)-2-deof-2-benem-3-carboxylate; Methyl (6B)-6-propyl (5R) -2-methyl-2-penem-3-carboxylate; Methyl (6B)-6- Propyl-(5R)-2-ethyl-2-penem-6-carboxylate; Methyl(6B)-6-propyl-(5R)-2-propyl-2-penem-3-carzoxylate.

Example 26 p-Nitropencyl 2-((3'8)-3-ethyl-
(4'R) -4'-Cα-tetrahy)Foeranylthio]-2'-oxoazetidin-11-yl) -
2-) Riphenylphosphoranyridine (3B)-3-ethyl-(4R)-4-(α-tetrahyfropyranylthio)
-Azetidin-2-one (2-5Ii, i 1.6 w
hmotv) yl (anhydrous tetrahydro 7 run (100
111/) Add anhydrous triethylamine (1,60d, 11-611g%) to a solution that has been dissolved and cooled to 10°C.
A solution of benzyl glyoxylate (5,63 L 25 N 1 mol) in anhydrous tetrahydrofuran (40-) was added to the χ part. After the addition was complete, the reaction mixture Y was stirred at room temperature for 3 hours. , cooled with saturated NaCl solution fIL (5C1j), and AcOg
Tighten with t (3 x 50 go). The combined extracts are washed with saturated NaCl solution (3×50d) and dried over Na1804.

When the solvent is evaporated in vacuum, an oily residue is left behind.1.
R, (7th item, ctn-”): 3280 (
2900.1755), which was absorbed with anhydrous tetrahydrofuran (absorbed and cooled to -30 °C under 'l) and treated with dry pyridine (1.24 mmol),
Add thionyl chloride (1.45d, 20mol) dissolved in tetrafuran (1Qd) Ym. The reaction mixture Y is stirred at -30°C for 1/1 hour and at -5~0°C for 2 hours. The precipitate is passed through and the liquid is evaporated several times from benzene in vacuo.

Residue (LR, (film, equipment-1): 17601Y E
Dissolve in fIkCHeClm and stir overnight with triphenylphosphine <6.511.24 mol).

The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel using an oval knife 6 m' (7 m').
/ He'P f 7 / Ac011t (70: 2
5:25) gives the product as a cypress yellow foam (4.10 g).

1, R, (CI(C1,-2-1-1) = 17
45 Example 27 SilverC3B)-5-ethyl-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2
-Oxoazetizoni-(4R)-4-ylthiolate Host-t9y (9001v, 1.35mm Molecule) M
A stirred solution "3,.-25M -AgNOs, /!iR(
Add 6Ml)ytflR. After stirring for 5 minutes, the mixture is diluted with distilled water (51) and carefully suction-filtered. Precipitate V is washed several times with distilled water and then with gt- and dried on the filter. Convergence is 920 mg.

Example 28 p-Nitropencyl 2-((3'8)-3-ethyl-(
4'R) -4'-acetylthio-2+-oxoazetizony-11-yl]-2-triphenylphosphoranylidene acetate.

Silver (38)-! t-Ethyl-1-nitrobenzo-oxycarzanyltriphenylphosphoranylidenemethyl-2
-Soazetizony(4R)-ylthiolate(3
5011g, 0.5 Y, acetonitrile (41
Acetyl chloride (0.8 mol) is added to the stirred solution of R1-)K.

Mixture Y, white AgC1 precipitate is sufficiently separated from the solution @
Stir until
Wash with OKt. The filtrate was diluted with saturated NaHCO3 solution (3
X201j), saturated NaCl solution (lX20)
Washing with Na, So and evaporation in vacuo gives a residue which is purified by column chromatography on a .chi.silicon column.

He7 Sen/ HedF t N/ Ac0Et (70
: 25 : 25), the f1g conversion f19
5Iv is obtained.

1, R, (CHCI, 4-1): 2900,
1750, 1705.

Example 29 p-Nitrobenzyl(68)-6-Nityru(5R)-
2-Methyl-2-penem-3-carboxylate.

0OPNB p-nitrobenzyl 2-((3'8)-5-ethyl-(
4'R) -4'-acetylthio-2+-oisoazetizony 1--yl)-2-triphenylphosphoranylidene acetate (195IJ9) toluene (100,
Solution Y dissolved in w/).

Heat/cool mixture under N at 85-95°C for 48 hours 1xJ? Absorption on top of a column of silica sol and bathing with toluene/Ac0Bt (19:1) yields the title compound.

LR, (cHc'154-1): 1790, 17
1ON, M, R, (CDCIrJ, δ): L12
(3H, t, J=7-OHz) 1.91 (2H, m,
J = 7.0.7.0Hz) 2.36 (3H, 5) 3-69 (IH, m, J = 7.0.2-0Hz) 5-
34 (21(, dd, J=14-OHz)5-36
(IH, d, J=:2.OHz)7.6'5(2H
, d, J=8.0Hz) 8-22 (2((, d, J=
8-OHz) Working in the same way, the following compounds are obtained: p-nitrobenzylC68)-6-nityl(5R
)-2-ethyl-2-penem-3-carboxylate; p-nitrobensol (6B)-6-ethyl-2-carboxylate (5R)
-2-Propyl-2-penem-6-calxylate: p-nitropencyl (68)-6-medel-(5R)-
2-Methyl-2-penem-3-carzoxylate; p-nitrobenzyl (6B)-6-methyl-(SR)
-2-Ethyl-2-penem-6-kaJresoxylate; p-nitrobenzyl (6g) -6-methyl-(5R)-
2-Zologyl-2-penem-3-carboxylate: p-nitropencyl (6B)-6-zolopyru (5R)
'-2-methyl-2-penemu3-cal? Xylate; p-nitrobenzyl (6B)-6-rafzc (5R
)-2-ethyl-2-penem-6-cal xylate; p-nitrobenzyl (68>-6-propylene (5R)
-2-propyl-2-penem-3-hydrugexylate.

Example 30 (68)-6-Nitylu(5R)-2-methyl-2-penem-3-carboxylic acid.

p-Nitrobenzyl(6B)-6-Nithyl(5R)-
2-Methyl-2-penem-6-carboxy L/-(
30M9), 0.2 M-NaHCO3 solution (2d)
, Ac0Et (3II) and a mixture Y of 10% (7) palladium/carbon catalyst (60 ■).

Brovrn type automatic hydrogenation JxJa
Stir inside until absorption of NaBH4 stops. Catalyst YF was removed, and the residue Y was saturated with NaHCO3 solution and A ('0Fit
Wash with Separate the aqueous phase, wash with CH@C'l,
Acidify with 5 ml of citric acid solution and extract several times with CH, C1,. Drying the organic extract Y over Na@804 and am'r in vacuo gives the title compound.

1, R-(KBr, m-1): 3300, 17
70, 1660 - Working in a similar manner, the following compounds are obtained: C68)-6-Nithyl(5R)-2-ethyl-2-penem-3-carboxylic acid; 5R)-2-propyl-2-
Penem-3-carboxylic acid; (6B)-6-methyl-(5R)-2-methyl-2-panera-3-carzanoic acid; (6B)-6-methyl-(5R)-2-ethyl- 2-
Penem-3-carboxylic acid; (6B)-6-methyl-(5R)-2-propyl-2-
Penem-3-carzanoic acid; (6B)-6-propyl-(5R)-2-methyl-2-
Penem-3-carganic acid: (6B)-6-probyl-(5R)-2-ethyl-2-
Penem-6-carboxylic acid; C68)-6-propyl-(5R)-2-propyl-2
-penem-6-carboxylic acid.

By conventional acclimatization methods, the title compound of Example 30? The above-mentioned sodium salt of carboxylic acid is obtained.

Example 61 p-nitrobenzyl 2-((318)-is-ethyl-(
4'R) -4'-acetoxyacetylthio-2'-oxo-azetiny-11-yl]-2-triphenylphosphoranylidene acetate.

Silver(3B)-3-ethyl-1-
4
R)-4-ylthiole-) (340 Mg, 0.49 mol) and freshly vaporized 1 Lr[acetoxyacetyl (0,
75111 mol)Y, the title compound 216m9 is obtained.

Example 62 p-Nitrobenzyl(6B)-6-Nityru(5R)-
2-acetoxy-methyl-2-penem-3-cal? Xylate.

p-Nitrobenzyl 2- ((3'8) -3' -
Ethyl-(4'R)-2-triphenylphosphoranylidene acetate (21619)
Heat at 85-90° C. for 30 hours under a 7N solution of Y torzy (110 m). cooling? Absorb to the top of the column of silica and toluene/Ac0E.
Elution at t (19:1) gives the title compound.

1, R, ('CHCl3.CIR-''): 178
0. 1740.1710U, V, (EtOH, nm)
: 266. 322N, M, R, (CDC!l,,
δ): 1-09 (3H, t, J-8Hz) 1-9
3 (2H, m, J=8.7Hz)2-13 (3
H, s) 3.80 (IH, dt,, J=7.2Hz) 5.5
2 (2H,AB(center of l*57em=15Hz
) 5-37 (2H, ABQ center “gem= 14H
z) 5-45 (IH, d, J = 2 Hz) 7-95 (4H, center of ABq, J = 9 Hz) Working in the same way, the following compound is obtained: p-, nitrobenzyl (6B) -6-Methyl-(5R)-2-acetoxy-methyl-2-penem-3-cal? Xylate; p-nitropencyl (68)-6-brol-(5R)
-2-acetoxy-methyl-2-penem-3-cal? Xylate; p-nitrobenzyl (6B)-6-methyl-(5R)-
2-zorogionyloxy-methy1/-2-penem-6
-Mexilate; p-nitrobenzyl (68)-
6-nitel-(5R)-2-propionyl-reoxy-methyl-re2-penemu6-cal? Xylate; p-nitrobenzyl C68)-6-f Rohil-(5R)
-2-Meso-I-2-Penemu-6-CaJ/boxylate.

1605.1580.1520 tr, v, (mtoH, nm): 241, 264
,381N,M,R,(CDCI,,δ) 2 1
．． 04 (3H, t, J=7 Hg) 1.89 (2H,
m, J=7.8 BM) 3.82 (IH, lt,, 7=
8. 1.8 Hg) 4.38 (2H, center
of ABq.

-Tg, ln = hexadecimal) 5.33 (IH, 4, J = 1.8 Hst) 5.40 (
2H, ABq center e'gem=14 HM) 6.95 and 7.24 (3H,!11) 7.95 (4
m! , center of mu Bq 1'ge1m■9 Hz) Proceeding in the same manner, the following compound is obtained: p-nitrobenzylC6B)-6-methyl-(5R)-
2-cheny2'-yl-methyl-2-penem-3-carmexylate p-nitropencyl C6B)-6-p-tetravir-(5R)
-2-cheny2'-yl-methyl-2-penem-5-
Carboxylate.

Example 55 (6B)-6-Nichiru(5R)-2-Cheney2'-
yl-methyl-2-penem-3-carboxylic acid.

p-Nitrobenzyl (6B)-6-nithiru (5R″3
--2-Cheney 2'-ylacetylthio-2-penem-3-carboxylate (35+w).

A mixture of 0.2 M-MaHOQ3 solution (2.5 M), Muoomt (4S/) and 1091 palladium/carmene catalyst (801F) was added to Plow 7 (Br□
Wn ) jl automatic hydrogenation machine MaHOQ s
Stir until absorption has stopped. The catalyst is removed by F and the residue is washed with saturated MaHOQ3 solution and M001t.

The aqueous phase is separated, washed with s OH, O/, aqueous with a citric acid solution of 59I, and extracted several times with OH, O/. M organic extract! Dry over L z 8 Q 4 , filter and concentrate in vacuo to give the title compound U,V, (11itOH, nm): 233
, 313 By operating in the same manner, the following compound is obtained =
C6B)-6-methyl-(5R)-2-Cheney2'-
yl-methyl-2-penem-3-carboxylic acid; C6B)-6-propyl-(5R)-2-Cheney 2'
-yl-methyl-2-penem-6-carboxylic acid.

All carmenic acid methyl- and ethyl-esters and sodium salts obtained in Example 65 were prepared by conventional esterification and chlorination methods. -Methyl-2-penem-3-carboxylate methyl (6a)-6-methyl-C5R)-2-cheny2'-yl-methyl-2-penem-6-carboxylate methyl (6 days)-6-propyl -(5R)-2-cheny2'-yl-methyl-2-4nemu-3-carboxylate.

Example 36 Di p-nitropene 2-CC5'8)-3'-ethyl-
(4'R) -4'-ethoxycarbonyl-carboerthio-2'-oxo-7zetidin-1'-yl)-2-
) Riphenylphosphotnylidene acetate.

In the same manner as Example 28, silver(3B)-3-ethyl-1-p
-Nitrobenzyloxycarboeltri-7-elphospho-2-nylidenemethyl-2-oxoazetidine-(4R)
-4-ylthiole-) (380*, 0.55ml 1 mol)
and commercially available ethyl oxalyl chloride (0,9
11% /I/) gives the title compound 255.

Example 37 p-Nitrobenzyl(68)-6-Nityru(5R)-
2-Ethoxycarbonyl-2-penem-3-carboxylate.

p-Nitrobenzyl 2-((3'8)-3'-ethyl-
A solution of (4'R)-4'-ethoxycarbonylcarbonylthio-21-oxoazetizoether-1'-yl)-2-)riphenylphosphoranylidene acetate-) (2551F) in toluene (125 ml) The mixture was kept under normal M2 overnight and then heated at 80° C. for several minutes. The cooled mixture is absorbed on top of a column of silica sol and toluene/
Elution with mcO1t (19:1) gives the compounds in Table m.

Engineering, R0(oucx,,,at-1): 1790 e
1755.

725 0, v, (ltOH, nm): 264 * 556M
, M, It, (OD013.δ): 1.09 (3m!
, t, J= 8 Hll) 1.27 (31!, t, T-
7H dew) 1.93 (211, 11, J= 8, 7 HM) 3
．． 92 (IH, ILt, JW 7, 2 IH B) 4
．． 27 (2H, q, J = 7 M1 + 1) 5.38 (2
L shiketamu Bq, Jg, l! −.

1Hg) 5.44 (IH, +1.J= 2 HM) 7.93 (4
H, center of 5Bq, J = 8Hg) Working in the same way, the first compound is obtained: p-nitrobenzyl (68)
-6-methyl-(SR)-2-ethoxycarbonyl-2
-Penem-3-carzoxylate zero p-nitrobenzyl C6B)-6-f lovir-(5R)
-2-Ethoxycarbonyl-2-penem-3-carboxylate zero anitropendyl (6B) -6-methyl-(5R)-
2-Methoxycarbonyl-2-penem-5-carboxylate; p-nitrobenzyl(6B)-6-nityl(5R)-
2-methoxycarbonyl-2-penem-3-carboxylate; p-nitropencyl (6B)-6-propyl-(5R)
-2-methoxycarbonyl-2-penem-3-carboxylate p-nitrobenzyl (6B) -6-methyl-(5R)-
2-Propoxycarbonyl-2-penem-6-carboxylate p-nitrobenzyl (6B)-6-nityl (5R)-
2-fa &xycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6B)-6-propyl-(5R)
-2-7'lopoxycarbonyl-2-penem-3-carboxylate.

Example 38 <68)-6-Nityru(C3R)-2-ethoxycasimenyl-2-penem-3-carbonyl p-Nitotabenzyl(6B)-6-Nityru(5R)-2-ethoxycarbonyl-2- penem-3-carboxylene) (45v),
0.2M-NaHOO3 solution (3d) s AaOl
A mixture of t (4ysl ) and 10 g of palladium/carbon catalyst (100 cape) is stirred in a Braun-type automatic hydrogenator until 3 equivalents of hydrogen have been absorbed. The catalyst was removed from F, and the residue was mixed with a saturated MaHOOs solution and MuC0
Wash with ylt. Separate the aqueous phase, OH, Or,
Wash with water and acidify with citric acid solution for 5 hours.
Extract 1 dew several times. Organic extract 1ia18Q4
Dry SL on top.

- and evaporation in vacuo to give the title compound.

JT, (ltOH, nm): 259 m! 156
゜Working in the same manner, the following compound is obtained: C68)-6-)fk-C5B)-2-ethethoxycarponyl-2-pe$um-3-carboxylic acid τ (6B)-6- f ropyru(5R)-2-ethoxycarbonyl-2-penem-6-carboxylic moiety (6B)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (68)-6 -Nityru(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid IC6B)-6-propyl-(5R)
-2-methoxycarbonyl-2-penem-3-ttlM
(6B)-6-methyl-(5R)-2-propoxycarbonyl-2-penem-6-carboxylic acid <68)-6-nityl-(5R)-2-propoxycarbonyl-2-penem-3 -Carboxylic acid (6B)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-6-carboxylic acid.

All the methyl esters and sodium salts of carboxylic acid obtained in Example 38 were obtained by conventional esterification and chlorination methods: MethylC6B>-6-Nityru(5R)-2-4)-?
Dicarbonyl-2-peramum-3-1zrubo silate methyl (6B)-6-methyl-(SR)-2-ethoxycarbonyl-2-pe-3-carboxylate methyl (68)-6-propyl-( 5R)-2-ethoxycarbonyl-2-penem-3-carboxylate (6B)-6-methyl-C5R)-2-methoxycarbonyl-2-penem-3-carboxylate (6g)-6 -Nityru(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; MethylC6B)-6-f-Nichiru(SR)-2-methoxycarbonyl-2-pe$A-3-carzoxylate Methyl (Ss)-6-methyl-C5R)-2-propoxycarbonyl-2-pe$A-3-1 lupoxylate methyl (6B)-6-nityl-2-penem -3-carboxylate; Methyl (6B)-6-zolopyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate.

Example 39 Acetonyl 2-((3'8)-3'-ethyl-(4'R
)-4'-(α-tetrahydropyranyl-thiocou2'
-oxoazetidin-1'-yl)-2-)riphenylphospho2-nyritene acetate.

7K1B) i-ethyl-(4R)-4-(α-tetraquidropinylthio]-azetidin-2-one (8611F,
4!11 mol) and acetonylglyoxyle) (1,
4#, 9.45 mmol) in anhydrous tetrahydrofuran (5
0g? ) Add anhydrous triethylamine to the dissolved K solution under N2.

If the organic solution is neutral or slightly basic and reacts, further triethylamine (0.6 s/4.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The reaction was then quenched with saturated Na0j #* (25sr) and ^cos
Extract at t(,x25g/). The combined extracts were washed with saturated Mac/$ solution (3 x 25 Wl) for 1 Ma, 8
04 Dry on top. Evaporation of the solvent in vacuo gave an oily residue, which was dissolved in anhydrous tetrahydro 7 run (30
ml/) K, cooled to -30°C under N2,
Thionyl chloride (0,54+++/) treated with dry pyridine (0,54+++/) and dissolved in tetrahydrofuran (5g/)
34 s/) is added dropwise.

The reaction mixture was heated at -60°C for 1/2 hour and at -5 to 0°C for 2 hours.
Stir for an hour. The precipitate is removed from P and the F solution is evaporated several times from benzene in vacuo.

Dry the residue (900 Da) with CH*O1m (50s/
) and 1M, then add triphenylphosphine (1,8
F) is stirred at room temperature for 19 hours. The solvent is evaporated in vacuo and the residue is purified by column chromatography on silica gel. The product was converted into benzene/hexane/muco
Elution at lt (70:25:25) gives a white foam (1,03f) after evaporation of the elution solvent.

Example 40 Silver (3B), -5-ethyl-1-acetonyloxycarbonyltriphenylphospho2nylidenemethyl-2-
Oxoazetidie-(4R)-4-ylthiolate.

Phosphorane (257 Da, 0.44111 cells) was Mso
A 0.25 M-Ag1iOs solution (2 s/) is added dropwise to the stirred solution cooled in a water bath from the outside. After stirring for 5 min, the mixture is diluted with distilled water (3 wl) and carefully aspirated-filtered. The precipitate is washed several times with distilled water, then It2, O, and dried on the filter. Yield is 25C1w.

Example 41 Acetonyl 2-((3'8)-1'-ethyl-(4'R
)-4'-acetoxyacetylthio-2'-oxo-azedediny-1'-yl)-2-) liphenylphosphoranylidene acetate.

Proceed as in Example 28, silver C", B)-5-ethyl-1
-acetonyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxoazetidin-(4R)-4
-ylthiolade (220 da, 0.36 mmol) and freshly distilled acetoxyacetyl chloride (0,611
1 mol) gives the title compound 1431F.

Example 42 Acetonyl C6B)-6-nityl-(5R)-2-acetoxymethyl-2-penem-6-carboxylate.

Acetonyl 2-((3'8)-3'-ethyl-(
4'R)-4'-acetoxyacetylthio-2'-oxo-azedediny-1'-yl)-2-)riaenylphosphoranylidene acetate (143) was dissolved in toluene (8
0m) K solution was heated under Ng at 85-90℃ for 2 hours.
Cook for 4 hours. The cooled mixture is absorbed on top of a column of silica gel and eluted with toluene/Cot (19:1) to give the title compound.

I, R, (OHO13, cIr")', 1790 m
1745.

715 υ, V, (t□H, am): 5 2 3°N,
M, R, (opo15.δ): 1.03 (5m!, t,
J-7MM) 1.94 (21, m, 7M7 * 8 N
12.06 (5H, @) 2.16 (3H, In) 3.67 (IH, dt, , T = 8.2 HM)
4.67 (2m!, θ) 5.17 (2H, M B (center of L 1' = 15 H'
) 5.50 (1M, +1., T = 2 Hm).

Working in a similar manner, the following compounds are obtained: acetonyl (6B)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl (6B)-6- G-bil-(5R)-2-
Acetoxy-methyl-2-penem-3-carboxylate-acetonyl (611)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate storage acetonyl (6 days)-6 -Nityru(5R)-2-propionyloxy-methyl-2-penem-3-carboxylatet acetonyl C68)-6-propyl-(5R)-2-f
Robionyloxy-methyl-2-penem-3-carboxylate.

Example 43 (6B)-6-:c? Ru(5R)-2-7*toxymethyl-2-penem-3-carzanoic acid.

Acetonyl (6g)-6-nityl(5R)-2-acetoxymethyl-2-penem-3-carxylene) (
151F) in acetonitrile (5st) and water (1d)
into a stirred solution.

Q, 1M-MaOH solution (1 volume) at M, under coC.
Add for 20 minutes. Stir the mixture for 10 minutes.

Wash with OR, Or. The aqueous phase is separated, acidified with 5 portions of citric acid solution and extracted several times with OR.

Dry the organic extract over Na2804, filter and concentrate in vacuo to give the title compound.

1, R, (011014, Qw-1): 3300,
1775.

1745.1 680 U, V, (IetOHln”)' 254 e 315
゜'1M-R-(ODClssJ): 1-07(3)
1. t, J=8 a+i)1.92(2m1.1
m, -7=8 HM)2.13(:5m11.8
) 3.78 (IH, dt, J=8.2 HM) 5-10 (
211, Center of Mu Bq e Jgem = 14 HIS) 5.43 (IH, (19J = 2 HM) 9.16 (1
H1br, replaced with D20).

Working in the same way, the following compound is obtained: (6B)
-6-methyl-(5R)-2-acetoxy-methyl-2
-penem-3-carboxylic acid C6B)-6-zotetravir-
(5R)-2-acetoxy-methyl-2-penem-3-
Carboxylic acid grave C6B)-6-Methyl-(5R)-2-propionyloxy-methyl-2-penem-3-Carboxylic acid grave C61/J)-6-nityl-C3R)-2-da gastric pionyloxy-methyl-2 -Penem-3-carboxylic acid (C6B)-6-propyl-(5R)-2-zologionyloxy-methyl-2-penem-3-carboxylic acid.

The methyl- and ethyl-esters and sodium salts of all the carboxylic acids obtained in Example 43 were prepared by conventional esterification and chlorination methods: methylC6B)-6-nityl-(5R)-2-acetoxy-methyl- 2-penem-3-
Carboxylate; Methyl (6B)-6-methyl-(SR)-2-acetoxy-methyl-2-penem-3-carzoxylate methyl (6B)-6-propyl-C3R)-2-acetoxy-methyl- 2-penem-3-carboxylate; Methyl (6B)-6-methyl-(SR)-2-de-onyloxy-methyl-2-penem-5-carboxylate (6B)-6-nityl-(5R) -2-! Lowonyloxy-methyl-2-penem-3-carboxylate Methyl (68)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate.

Example 44 2.2,5,5-tetramethyl-(7R)-(8B)-
8-acetyl-9-oxo-3-oxa-6-thia-1
-Azobicyclo (5,2°O1°〒]nonane.

G-iso-! Robilua Den (2.02f, 2.8s/
, 29 mmol) was dissolved in anhydrous THF (15 m#), and 15 ml of the rl-BuLi solution dissolved in Hemesan (9.5 s/, j 5 mmol) was added under M2R while stirring with a 17-meter tube. Add for 15 minutes. After stirring for 15 minutes, 2.
2.5.5-tetramethyl-(7R)-9-oxo-5
-oxa-6-thia-1-azobicyclo(5,2,OL
・Mafnonane (1,4Of, 5.5 mmol) was converted into TlrF
(5 s/) solution is added for 15 minutes. The resulting reaction mixture was stirred at -70°C for 50 minutes and then stirred at 70°C.
OBt (5s/, 4.5f, 5Qm mol)
(5s/)K, add the dissolved solution dropwise.

After the addition was complete, the mixture was heated at -70°C for 15 min and at 0°C for 15 min.
Stir for an hour and add cold water (75s/).

0HzO1s (5X 501Il/) Te extraction i6
The combined organic extracts are dried over 11a1804 and evaporated in vacuo to give a yellowish oil which is subjected to chromatography on silica gel (5(1)).

0616/Ao011t (95: 5) “t”
The crystalline product (1,04f, 6
2) can be obtained.

m, p, 65-72℃ [α) D = + 111.9 @ (o = 1, O
HO/, )■, R1 (OHO1s+”-1): 1
750.172 ON8M, R (ODO13, δ):
'1.22(3H,!3)1.47(31,#) 1.57(3H,su1.71(31,1 2,33(31,su3.65(IH,(L,J= 13 II 3.91 (
1m! , 1. J= 2.511M) 4.11(IL(1
, J = 2.5 H.

Example 45 2.2.5.5-tetramethyl-(7R)-<s s
)-s-[i'-<1's>-hydroxyethyl-9-oxo-3-oxa-6-thia-1-azobiccyclo(5,2,Ol-'')nonane.

-78. 1 Obtainable at the cooling market b t'L 6 M-8
1F block H of e'1eotrle'is/, 311 mol)
1 Add TIP (8s/)K to the stirring solution 2, 2.5
．． 5-Tetramethyl-C7R)-C8B)-8-acetyl-9-oxo-3-oxa-6-thia-1-adevisic H (5,2,0"〒]nonane (5351F.

Add 2.08114 liters of N2 dropwise. The obtained reaction mixture was stirred at -78°C for 3 hours, and 0 [1d] and 30
Calm down with 1!20 feng (3s/) of %. After stirring for 1 h at 0 °C, the mixture was diluted with H*O (!ios/) and 0 H
x012 (5X50s/) Extract. The combined extracts are dried over OaO/ and evaporated in vacuo to give a solid residue, which is chromatographed on silica gel (20f).

Elution with 0,H,/AQO1t (95:5) yields unreacted raw material (160 sv, 11%).

By elution with 06!16/Ac()Ilt("90:10).

The title compound (355q, 66%) was obtained, 4m, p,
: 97-102℃ Elemental analysis (calculated value of 0112m121NOs8): 05
5.55 (55,57) II, H8,12 (8,1
) IsN 5.38 (5,40) Regret, 812.07 (
12,36) Excellent (ff), = + 111.16° (0
= 0.8, 0HOI, )1, R9(OHOl4.
cII″″l): 3400.174ON0M, R(OD
(n3.δ): 1.21 (3H, 1.55 (5■, 6
．． J = 7 Hss ) 1.49 (3H, 8) 1.55 (5H, S 1.71 (3H, S 2.68 (1ii + bra, J = 5 ul, exchanged with D2o) 2.88 (IH, ( L(1,7=2.5.25 R13
,60(In,a,J=12 mg)4,. 16(I
H1+1.1=121;IN)4,17(IH,br
m) 5.02 (IH,a,,y=2 Hts).

Example 46 2.2.5.5-Tetramethyl-(7R)-(8B)-
C-(1'R)-hydroxyethyl-9-oxo-
6-oxa-6-thia-1-azobicyclo(5,2,0
Tochi] Nonan.

-8・・・・・1d−■ (20s/
, 10 mmol) in 0.5 M -THF stirring solution, anhydrous 1et2Q (125 s/)
-Tetramethyl-(7R)-(8B)-8-acetyl-
9-oxo-3-oxa-6-thia-1-7 devisicou(5,2,Ol・7)nonane (1,44f, 5.6
The mixture is placed under M2 at room temperature. 2 of the reaction mixture
Stir for 0 hours and process as in Example 45.

The residue is chromatographed on silica gel (50p). Elution with o,H,/AaOlt (95:5) yields unreacted raw material (397''F).

0.1! ,,4c01! lt (90: 10)
Elution at gives the title compound (602sy).

m, p,: 126-160°C [α)I) = + 80 (0 = 1. cnol,)
1, R-(OHOls,'1l-1): 3600 *
3460 * 174ON, M, Ro (ODOI3.
δ): 1.18(3H,S1.27(3H,(L,,
T= 6 H 1.47 (!IH, 1.58 (3m!, 1.67 (3H, 8) 2.85 (IH, dtl, J=2.2, 4.0 HE
) 3.60 (1H, 6, J = 12 III) 3.62
(Exchanged with IH1t'r DgO) 4.09 (1 town (1,
J = 12 H 4-22 (II!, br) 5.17 (11!, L, J = 2.2 H Example 47 2.2.5.5-tetramethyl-(7R)-(8B) −
(D-(1'R)-p-nitropenzoloxycarpoeloxyethyl)-9-1-so-3-oxa-6-thia-1-adepisic a(5,2,OX·te)nonane.

2.2,5.5-tetramethyl-C7R)-(88)-
(1'-(1'R)-to=Po-?sixtil)-9-
Oxo-6-thia-1-azobicyclo(5,2,01,
7) Nona7C1,501/, 5.78 mmol) in MtO
H-free tnOH + 10 zl (30d) in a stirred solution cooled to 15°C with % p-=tropendyl chloroforme-) (1, < 56.f.

7.7 mmol) followed by 4-N,M-dimethylaminopyridine (9401F, 7.7 mmol) over 30 minutes. The reaction mixture was stirred for 18 hours at *m and 0H20t
a (150ml) “Q dilution L, iuo.

Wash with NaO2 solution (2X50m) and dry over Na1804. Evaporation of the solvent gives a residue which is chromatographed on silica gel (100j).

Or+Hs/kcO'lt (97,5: 2-5)
Elution at 30% yields the title compound as a yellow oil (2.20 g, 87 mm).

1, R, (01(C!13.cII-1): 17-5
0*152D.

1350° Example 48 2.2.5.5-tetramethyl-(7R)-(8B)
-(1'-(1'R) -p-nitrobenzyloxy-carbonyloxyethyl-9-oxo-3-oxa-6-thia-1-adebicylo(5,2,0X-7)nona:ys , 8-?) Odt.

2.2,5.5-tetramethyl-(7R)-(8B)-
Nonane 2,2Of, 5.Qm moles) to 01!20!m'(
Stirred solution 1 [[, II-chloroperbenzoic acid (12,5
111 mol) was added little by little with stirring. The reaction mixture is stirred for 1 hour in the cold and 30 minutes at room temperature. OOH
After diluting with 20j (150g/), the 1st solution was diluted with 8-Na
HOQs solution (1 x 50g/), 10% Ma11
005 solution (1x50s/l.

8 drops of MaHOQ3 solution (1 x 50s/), washed with saturated 11ao/*t (I x 50g/), and washed with N
IL, So.

Dry on top. By evaporating the solvent in vacuo, an amorphous solid is obtained (2.3f).

98%).

Engineering, R, (OI!013.cm-1): 1775,1
750°520 11, M, R, (GD (313, δ): 1.31 (3
H, II) 1.45 (51, a, y 7H dew) 1.46 (!DH, I) 1.55 (3I!, s) 1.69 (5H, 3.44 (IH, a, r=14 3.78 (la, aa, J=2.2.4.2HI)4,
16 (IH, a, J = 14 Hz) 4.92 (1 g, a
J = 2.2Bg) 5.27C2H, Su 5.29 (IH, m) 7-51 (2Ht 6 J: 8Hz) 8.22 (2
1,a:r=8 Hz).

Example 49 (3s)-3-(1'-(1'u)-p-nidopenzyloxycarbonyloxyethyl)-(4R)-4-(
α,α-dimethyl-3-t-droxyethylsulfonyl)
Azenadin-2-one 0 In the same manner as in Example 20, the title compound 1 was obtained.
(011013,g”):5400.1780.175
ON, M, Ro (ODO15, δ): 1.51 (31
1,8) 1.42 (311,5) L45 (!'JdeJ= 7 H dew) 3.60 (1B, d, J= 12 H depth) 3.82 (I
lll, dd,, T=2 HM)-3,91(loincloth, a,
J = 12 mm) 5.02 (IH, (LtJ = 2 H
M) 5.24 (21!, S5.26 (111, m) 7.38 (11!, I) r) 7.52 (2 m! I11.J-8all) 8.18 (2
i, a, J-8111゜Example 50 (38) -3-(1'-(1'R) -a -
Diethyl in etropenzyloxycarponyl]-
(4R)-4-(g-nato2hydrobin2ruthio)azetidic-2-one 0 In the same manner as Example 21, the title compound 1 is obtained.

[α)n: +52@(a-1,caax3),
R, (OHOI, t:II”1): 3400.29
40.2B60°1775.175O N, M, R, (CDOl, s, δ): 1.45 (31
1, (1, J=, S, 5 II 1.3-2.1 (61
! , m) 3.25-3.70 (2H, m) 4.04 (IH,!II) 4.92 and 5.00 (IH, dd, , T = 7.2II
I) 5.0-5.5C2H,1m) 5-27(2H,s) 6.52 and 7.02(IH,1)r) 7.55(2H
,d,,T=8HM)8.23(2H,a,y-B
m dew).

Example 51 Cynitrobenzyl 2-((3'5)-3'-[(1"
R)-1"-p-nitobenzyloxy-carponyloxyethyl)-(4'R)-4'=(α-tetrahydropyranylthio)-7-oquin-azeteny-1'-yl)-2-) Rif style Nylphospho-2-nylidene acetate.

In the same manner as Example 25, the 11 title compound is obtained as an amorphous solid.

x, x, Ccmcx,,cx-”): 1750, 1
74.5゜Example 52 *(3B)-5-C(1'R)-1'-p-nitrobe/
Zoloxy7carbonyloxyethyl]-1-p-nitropenozyloxycarbonyltriphenylphosphoranylidenemethyl-2-oquin-azetizoni-(4R)-4-ylthiolate.

C00PNB In the same manner as C00PNB Example 27, the title compound is obtained.

Example 56 p-nitrobenzyl 2-((5'8)i'-[(1"-
R)-1"-p-nitrobenzyloxycarbonyl-oxyethylcheny-7-yl-acetylthio-2'-oquin-azedezony-1-yl)-2-triphenylphosphoranylidene acetate.

Using the same method as Example 33, the title compound is obtained in a yield of 65 cm.

Example 54 p-nitrobenzyl (6B)-6-(
(1'R)-1'-P-nitrobenzyloxycarbonyloxy]-2-1thieny21-ylmethyl-
2-penem-3-calcaxylate.

Using the same method as Example 34, the title compound is obtained in a yield of 70 ml.

1. R9 (CHOI3.gl): 1790.1750
．． 171ON0M, R, (ODC14, δ): 1.4
8 (3H, d,, r = 6.5 III) 3.91 (IH
, d(L, J=7.211.81111)4.36(2
1,muBq,J= 1f) 1rin) 5.24(21,b
s) 5.38 (21, ABll) 5.59 (IH, (1,7=1.8 HM) 6.93 (
2H, 1m) 7.21 (1m!, d(L) 7.56 (44m) 8.20 (41, a) Continuation of page 1 @Int, C1, 3 identification code Internal serial number (C
07D 515104 05100 291100 ) (C07D 409/12 05100 333100 )

Claims (1)

[Claims] 1. Formula (■): [In the formula, R and R1 represent the same or different organic groups,
R11 represents hydrogen, a cation or a carboxy anchoring group] A method for producing an optically active trans-6-substituted-5(R)-2-penem-3-carboxylic acid derivative of (
IL) Formula (I[): [In the formula, R represents the above 4, and R3 independently represents hydrogen or 01 to 06 alkyl] Optical activity 4(R)-7
The zetidin-2-one derivative is reacted with a thiol or a salt thereof of the formula: Then, the optical activity 4(
R)-thio-derivative is obtained (11) 4 of formula (1)
(R) Compound 411Ft Formula: OHO-GOOR. Glyoxyl +1 of [in the formula, R2 represents the above]
React with vIj conductor to form formula (■) 2000R. 4 (R
)-derivative is obtained, (C) 4(R)-carbinol of formula (IV) is converted to Herod/
to obtain a 4(R)-derivative of the formula (■): 00R2 [wherein R, M and R2 are represented by the above 1, and X represents a halogen atom 'Ik], and (d) a 4(R)-derivative of the formula (V ) is reacted with a phosphine of the formula: PφS [in the formula, the group φ independently represents an aromatic, heterocyclic, or alkyl group] to form a compound of the formula (■): 00Rg [in the formula, R, 4, Rs and φ represent the above.
(R)-phosphorane is obtained (e) 4(R) of formula (Vl)
)-phosphorane is reacted with a solution of a heavy metal salt of the formula: Mn" ++ yn- [in the formula, y, n+ represent the cation of the n-valent heavy metal M, and yn- represents the anionic group of the salt]. , formula (button: [in the formula R, R2, φ and Mn
4(R)-mercapto salt of the formula (vM) is obtained, wherein 10 and n represent the above-mentioned 4(R)-mercapto salt of the formula: , ψ represents oxygen or sulfur] or a reactive derivative of a thio acid of the formula (■): 00R11 [wherein R%R1%R1, ψ and φ represent the above] A (R)-derivative is obtained, and the 4(R)-compound of formula (■) is cyclically dissolved, and if necessary, the obtained compound of formula (I) (R, represents hydrogen) is converted into a salt (? and/or optionally esterify a compound of the formula (D (R1 represents hydrogen or a cation)) and/or optionally esterify a compound of the formula (D (R1 represents hydrogen or a cation) with A compound of formula (I) is obtained and/or optionally a compound of formula (1) is obtained and/or optionally a compound of formula (I)
) into another compound. 2. Mercapto salt with formula (■) vV, formula: [wherein R1
and ψ represent the above-mentioned acid or thioic acid, and the resulting compound having the formula (■)'%: is cyclized, according to claim 1. Optically active trans-6-substituted-5(R) having formula (I)v of
-Production of 2-penem-6-carzanoic acid derivative tert-
Butyl-silyl, trityl, α-methoxy-ethyl, tetrahydropyranyl-2-yl, 4-methoxy-tetrahydropyranyl-4-yl, 2-oxa-bicyclo(3,3
,0) octany 6-yl and 2-oxa-bicyclo(3,3,0)offchy6. 3. The method according to claim 1 or 2, wherein the group is a group selected from F-22-6-yl, and the cation is a heavy metal cation selected from Ou and Pb. 5. Formula (■): 0001g [In the formula, R and R1 represent the same or different organic groups,
R2 represents hydrogen, a cation or a carboxy group,
[psi] represents V bulk or sulfur, and [phi] independently represents an aromatic, heterocyclic or alkyl group] 4(R)-compound having V 64 Formula (■): 000R. [In the formula, R and R1 represent the same or different organic groups,
R11I represents hydrogen, a cation or a carboxyl protecting group, ψ represents oxygen or sulfur vk, φ is solely aromatic,
Heterocyclic or alkyl group] In the method for producing a 4(R)-compound of the formula (■); represents the cation of Mj)'k
Vj')4 (R)-mercapto salt t, formula: [in the formula R1
4(R)- of formula (■) consisting of reacting with a reactive fat conductor of an acid or thio acid of
(Method for producing a mercapto compound. Z 4(R)-mercapto231 of formula (vl)!'!
Ag. 7. The method of claim 6, wherein the blind metal field is selected from Hg, Mud, Ou, and P). 8. Formula (title): [In the formula, R represents an organic group, an R2kt hydrate, a cation, or a carboxycarboxylic group, and φ is independently an aromatic group, a multi-X ring, or an alkyl group! 4(
R)-mercapto salt. 9 Formula (■mu): [In the formula, R 1, φ, M and n represent the above, R
〈〉 represents a residue of an acyl group, and the carbon atom having the hydroxy group) lf- is in the R-configuration]V! [
Item 118 1K) 4(R)-mercapto salt. 10, Formula (Duck B): [In the formula, R2, φ, M and n represent the above, RX
represents the residue 1 of an acyl group, and the carbon atom supporting the hydroxyl group is in the B-configuration]. 4(R)-mercapto salt according to claim 8. 11. The 4(R)-compound according to claim 9 or 10, wherein RX is c1-C6 alkyl or phenyl. 12. Claim 9 or 1 in which RX is methyl
4(R)-compound according to item 0. The compound according to any one of claims 8 to 12, wherein 16.1 is a salt of a heavy metal selected from Ag, Hg, MuU, ○U, and Pt+. 14, Formula (■); [In the formula, R represents an organic group, R2 represents hydrogen, a cation or a carboxy protecting group, φ independently represents an aromatic, atom cyclic or atomyl group V, Mn+ is In the method for producing the 4(R)-mercapto salt of nJi (representing the cation of the predetermined heavy metal M), the formula (■): 00Rs [wherein R is an organic group and M is a soluble metal salt or a halogen S- is unstable to the heterolyte ink reaction of
4(R)-phosphorane, which represents a group forming a direct bond, Rs represents hydrogen, a cation or a carboxy protecting group, and φ independently represents an aromatic, heterocyclic or alkyl group; Formula; Mn+ -yn- (in the formula, Mn + represents the above and yn- represents the anionic group of the salt)
(Vl[
) 4(R)-Mercapto salt manufacturing method. 15, Formula (■): [In the formula, R represents an organic group, and the group is a soluble metal or
＼ Represents a group that forms a direct bond that is unstable against the hetero I3 tick reaction of Rodene, R11 represents a water moiety, a cation or i carboxy protecting group, φ is independently aromatic,
Heterocyclic or alkyl group] shoulder, b4 (R
) - Compound. 16, formula (■mu); n'to00R2 [in the formula, R1, mu and φ! The first range of patent tf4 has the above expression, R represents the residue of an acyl group, and the carbon atom representing the hydroxyl group is in the R-configuration.
4(R)-compound according to item 5. 17 Formula (VIB): 001s [In the formula, R2, Mu and φ represent the above, R represents the residue of an acyl group, and the carbon atom in the hydroxyl group 1 is in the S-configuration] 4(R)-compound according to claim 15. 18. The 4(R)-compound according to claim 16 or 177, wherein Rx is C1-w06 alkyl or phenyl. 19. The 4(R)-compound according to claim 1j416 or 17, wherein R is methyl. 20, A is zomethyl-tert-butylsilyl, tolyl, α-methoxy-7-ethyl, tetrahydrobyran-2-2-
yl, 4-methoxy-tetrahydrobyranyl-4-yl,
2-oxa-bicyclo(3,,3,0)octany6-
6. A 4(R)-compound of formula (VI) according to any one of claims 15 to 19, wherein the group φ is phenyl. 21, Formula (■): 000R. [In the formula, R represents an organic group, A represents a group that forms a soluble range [or a group that forms an S-A bond that is unstable against the heterolytic reaction of halogen, and R2 represents an aqueous, cationic, or carboxy anchoring group] and φ represents a mono-Inc aromatic, heterocyclic or alkyl group], the method for producing a 4(R)-compound v of formula (■): 000R. [In the formula, R, M and R represent the above-mentioned ones, and X represents a halogen atom]. !!Process for producing a 4(R)-compound of formula (Vl), which comprises reacting with a phosphine derivative of cyclic or alkyl group.22.The phosphine derivative is triphenylphosphine. The method according to claim 21. 23. The method according to claim 21, wherein 710 den of the compound of formula (V) is chlorine. 00R8 [wherein R represents an organic group and M represents a soluble metal salt. Or - Al is unstable to heterolytic reactions of halogens.
4(R)-compounds in which R2 represents hydrogen, a cation or a carboxy-linked group V, and X represents a ).logen atom 1]V. 25. (5,3,0
) 4(R)-compounds of octany-3-yl and 2-oxabicuclo [6°. 26, Formula (V): 00R2 [In the formula, R represents an organic group, M represents a group Y that forms an 8-A bond that is unstable against heterolytic reactions of soluble metal salts or halogens R2 is water , a cation, a cation or a carboxy protecting group, and X represents a ).rodene atom]. A process for producing a 4(R)-compound of the formula (V), which comprises rhodanizing 4(R)-carbinol. 27 The carbinol group of formula (IV) is zomethyl-t
ert-butylsilyl, tolyl, α-methΦcyethyl, tetrahydropyranyl-2-yl, 4-methoxytetrahydrovyranyl-4-yl, 2-oxa-bicyclo(
S, 3.0) octany-6-yl and 2-oxa-bicyclo(3,3,0)offchy6. 27. The method of claim 26, wherein the group is selected from hooniny-6-yl. 28, Formula (■): [In the formula, R represents an organic group, M represents a group forming an 8-, direct bond that is unstable to the heterolytic reaction of a soluble metal salt or a halogen, and R2 represents hydrogen. , representing a cation or a carboxy protecting group]. 29 The group is dimethyl-tert-butyl-silyl, tolyl, α-methoxy-ethyl, tetrahydrogyrany 2
-yl, 4-methoxytetrahydrolaniy4-yl, 2-oxa-bicyclo[663,0]octany6-yl
6. A 4(R)-compound of formula (IV) according to claim 28, which is a group selected from f-uni-6-yl. 30, Formula (■): 000R Snow [In the formula, R represents an organic group, M is a group 1ks that forms an S-direct bond that is unstable against heterolytic reactions of soluble metal salts or halogens, and R2 is 4(R)-compounds of the formula (I): wherein M and R are as defined above;
)-compound of the formula: 0)IC-00OR. 4(R)- of formula (mV), which consists of reacting with a glyoxylic acid derivative in which Rs represents the above-mentioned
Method of manufacturing compounds. ! 119 The base of the compound of formula (1) is dimethyl-tart.
-butyl-silyl, tolyl, α-meth, fucy-ethyltetrahyropyrany-2-yl, 4-methoxy-tetrahydrobyranyl-4-yl, 2-oxa-bicyclo(3,3
,0) octany-3-yl and 2-oxa-bicyclo[
60. The method according to claim 60, wherein the group is selected from 6°3.0]oct-6,7-uni-3-yl. 32, Formula (Seal): 4( R)-Compound. 35m is dimethyl-tart-butyl-silyl, tolyl, α-methoxy-ethyl, tetrahydrobyranyl-2-yl, 4-methoxytetrahyrrovyl-4-yl, 2
-oxa-bicyclo(3,3,0)octany-6-yl and 2-oxa-bicyclo(3,3,0)ofchy6.
A 4(R)-compound of formula (III) according to claim 52, which is a group selected from 7-uni-3-yl. 34, Formula (I): [In the formula, R represents an organic group 1. 4(R)-compound V represents a group forming an 8-direct bond which is unstable to a soluble metal salt or a heterolytic reaction of a halogen. R represents the above-mentioned Y: and R3 is independently hydrogen or CelC6 alkyl"?representsf)'eV4(R)
- reacting the compound with a thiol of the formula A-8HC, wherein the compound is as defined above.
(R)-Production method of compound. 65, thiol A〉-111-, the group A is dimethyl-t
ert-butyl-silyl, tolyl, α-methoxy-ethyl, tetrahydropyranyl-2-yl, 4-methoxy-tetrahydrobyranyl-4-yl, 2-oxa-bicycloC
65. The method of claim 64, wherein the group is selected from 5,3°0]octany-3-yl and 2-oxa-bicycloC5,6, DJ ocd-6,7-enyl-6-yl. 66, Formula (I): [In the formula, R represents an organic group, and RIS is independently hydrogen or 0
l-06 alkyl t! ! The 4(R)-compound found in ゎf)'. 37 Formula (I): [In the formula, R represents an organic group, B and H are independently hydrogen or 0
1-06 alkyl], a method for producing a 4(R)-compound of the formula (X
ff): [In the formula, R and R3 represent the above-mentioned compounds], (bl
) : [In the formula, R and R3 represent the above-mentioned compounds] is obtained, and (C1 from the compound of formula (XV) N, 0fflNongki'
A method for producing a 4(R)-compound of formula (1), which comprises removing T'. 38. A compound having the formula (XV) according to claim 67. 39. A method for producing a compound of formula (XV) according to claim Ii!l, claim 68, in which the compound qlJ having formula (XIV) is treated with an acid (Claim Ii!l). 40. )′
%: Compound with. 41, Formula (XI) 'i according to claim 37
'Shoulder compound. 42, (a) Curtius degradation is applied to the compound of formula (XVT): oon to obtain the aldehyde of formula (): (1)) The aldehyde of formula (Xi[) is converted to formula (XX)
Formula (Xn[m):43, (a
) A compound having the formula (XVI) described in claim 42 is converted into a compound of the formula (XX[[A):0015 [wherein R6 and R6 independently represent an ax-as alkyl group]] , fbl The 1-substitution of the compound of formula (Door A) is removed by oxidation to yield a compound of formula (XX[[[) where R6 represents the above book], (cl formula (XXIII) +7) Compound 11mkR With element L, a compound of 2〇〇〇V): is obtained, and the compound of formula (XXIV) is acetonized. [B)
: A method for producing a compound. 44, (a) A 2-oxo-azetidine derivative of the formula (XXV): [wherein represents a nucleophilic leaving group V] is converted into a 2-oxo-azetidine derivative of the formula: [wherein R3 represents hydrogen or 01-06 alkyl] When reacted with a glycolic acid derivative, the formula (xXvI
R) and he (XXvIS): (xxvIR) (XxvIs
) A mixture of enantiomeric compounds of the formula (XXVI) is obtained, in which R3 represents the above-mentioned compound;
IR) The cQ enantiomers are separated by resolution to give a compound of formula (XXVIR) of the formula: R,
When esterified with alcohol of OR (in the formula, R6 is 01-06 alkyl t1!), a compound of the formula (da): 1 [in the formula, R3 and R6 represent the above-mentioned tl7)tl-] is obtained, and (( 11 Compound V reduction of formula (XXW) A compound of formula 1 (X): [In the formula, R5 represents the above] is obtained, (8) Ace)y conversion of the compound of formula (Xm) Process for producing a compound of formula (XI) as described in claim 41. 45. Formula (XXVI) as described in claim 44
! Claim 3 in which the compound t having the compound t is acetonized
A method for producing a compound of formula (Xlll) described in item 7. 46, a 4(R)-compound having the formula (XXi) according to claim 44. 47. Formula (XXVI) according to claim 44
A method for producing a compound of formula (■) according to claim 46, which comprises reducing a compound having V. 48, Formula (XX) “k” described in claim 42
4(R)-metallic compound having. 49 Formula CX according to claim 48, which reduces the compound having the formula (rei) according to claim 42
Method for producing the compound of X'). 50, #Claim 20C)"ik
4(R)-compound having 1. 51. A method for producing a compound of formula (XI[) according to claim 50g1, which comprises subjecting a compound having formula (XVI)v according to claim 42 to Curtius degradation. 52, a 4(n)-compound having the formula (XXI) according to claim 46 or the formula (XXVI) t- according to claim 44. 56, Formula (XXIIm) according to claim 43
53. A process for producing a compound of formula (XXI) according to claim 52, wherein the compound having the formula (XXI) is removed by 1-displacement vWl conversion. 54, *Claim No. 44 1c (7) Formula (XX
VIR) to the compound 'IE' having the formula: Ra1n
(In the formula, 16 represents the above) The formula according to claim 52 is esterified with alcohol <x false)
manufacturing method for chemical compounds. 55, formula (Xllm)V according to claim 43
4(R)-compound with 56, Formula (XX[I): [In the formula, R6 and R6 represent an 01-C6 alkyl group]
Compound qI! Jt isomerization patent claim ah No. 5
A method for producing a compound of formula (XXiA) according to item 5. 57. Formula (xXII) according to claim 56
! A compound with 58, Formula (XXI): [In the formula, Re represents an 01-C6 alkyl group] Compound is reacted with a compound of the formula: N20B-000R6 (Ra represents an oz-c6 alkyl group) Claims: A method for producing a compound of formula (XXII) according to claim 57. 59 Formula (XXiA): 00R5 A method for producing a compound of formula (extended l) according to claim 55. Box No. 44 Current SCO Ceremony (XXVI
)! ! 4(R)-compound. 61, Formula (X[Vm): Ma [wherein R3 represents hydrogen or a 01-C6 alkyl group,
7(R)-8(8
)-9-oxo-6-oxa-6-thia-1-pudebicyclo(5,2,01.7) nonane derivative. 62, Formula (XIVB): R on, 5 [In the formula, R3 represents hydrogen or 01-06 alkyl, R
7(R)-8(8) with x represents the residue of an acyl group, and the carbon atom representing the hydroxyl group is in the S-configuration]
68. The compound of formula (defined) according to claim 67, which is a -9-oxo-6-oxa-6-thia-1-azo-bicyclo(5,2,01.7)nonane derivative. 66. The compound according to claim 28, item 61 or 62, wherein Rx is 01-C6 alkyl or phenyl. 64. The compound according to claim 61 or 62, wherein Rx is methyl. 65,! Claims 61-- ts is methyl
Formula (XIVm) or (Xff
B) Compound. 66 Formula (XXX) [In the formula, R represents hydrogen or 01-o6 alkyl, R
7(R)-8<a>-s-acyl-9-oxo-3-oxo-6-?x represents an acyl residue, 01-o6 alkyl or phenyl] 7-1-7r -Wtyl
ac5.2.0'') nonane derivative is stereoselectively reduced at room temperature in a weak solvent using a complex hydride χ of a weakly polar cation.Formula CXIVA) according to claim 61
A method for producing the compound. 6Z The complex hydride is a complex metal of potassium, sodium or ammonium. Claim 66
The method described in section. 68. The method according to claim 67, wherein the complex hydride is a potassium complex hydride. 69 Potassium complex hydride is K-seleatr
69. The method according to claim 68, which is ide■. 70. The method according to any one of claims 66 to 69, wherein the reaction temperature is +20 to +40°C. 71. The method according to any one of claims 66 to 70, wherein the weak solvent is diethyl ether. 72, %iFF Formula (XXX) described in claim 66
63. A process for producing a compound of formula (XIV B ) according to claim 62, which comprises stereoselectively reducing a compound having v with a complex hydride of a strongly polar cation in a strong solvent at a low temperature. 76. The method according to claim 72, wherein the complex hydride is a lithium complex hydride. 74, lithium complex hydride is Li-a・1・ctr
77. The method of claim 76, wherein idls■. 75. Claim that the reaction temperature is -80 to -60°C! The method according to any one of Items 72 to 74. 76. Claims 72 to 7, wherein the strong bath agent is a solvent selected from tetrahydrofuran and dimethoxyethane.
The method described in any of Section 5. 77, R and R1 are 01-o, alkyl, and R
Formula (I)t according to claim 12ill 1, wherein s is hydrogen, 01-C6 alkyl, optionally a linitro-substituted benzyl group, or a pharmaceutically or veterinarily acceptable cation.
'trans-6(Ei)-5(R)-2-penem-6-carboxylic acid derivative. 78. The compound according to item 77, wherein R and R1 are methyl, ethyl or probyl. 79 Methyl(6B)-6-nityl(5R)-2-
Methyl-2-penem-6-carzoxylate; Methyl(6B)-6-nityl(5R)-2-ethyl-
2-penem-3-carboxylate; Methyl (68)-6-nityl-(5R)-2-propyl-2-penem-6-carboxylate; Methyl (6B)-6-methyl-(5R)-2-methyl −
2-penem-3-carboxylate; Methyl (6S)-6-methyl-(5R)-2-ethyl-
2-Pe$mu6-carboxylate; Methyl(6B)-6-methyl-(5R)-2-propyl-2-penem-6-carboxylate; MethylC6B>-6-propyl-(5R)-2- Methyl-2-penem-3-carboxylate; Methyl (6B)-6-7'lobi-(5R)-2-ethyl-2-penem-3-carzoxylate; Methyl (6B)-6-propyl-(5R )-2-progyl-2-penem-6-carzoxylate; p-nitrobenzyl (6B)-6-nityl-(5R)-
2-Methyl-2-penem-3-carboxylate; p-nitrobenzyl (6B)-6-nityl (5R)
-2-Ethyl-2-penem-3-carboxylate; p-nitrobenzyl (6B)-6-nityru (5R)-
2-Propyl-2-penem-3-carboxylate; p-nitrobenzyl (6B)-6-methyl-(5R)-
2-Methyl-2-penem-6-carboxylate: p-nitrobenzyl(6B)-6-methyl-(5R)-
2-ethyl-2-penem-6-carzoxylate; p-nitrobenzyl (+5B)-6-methyl-(5R)
-2-propyl-2-penem-6-carzoxylate; p-nitrobenzyl (6B) -6-propyl- (5R)
-2-Methyl-2-penem-3-carboxylate; p-nitrobenzyl (6B)-6-propyl-(5R
)-2-ethyl-2-penem-6-carpxylate; p-nitrobenzyl (6B)-6-propyl-(5R)
-2-Propyl-2-penem-6-carboxylate; (6B)-6-Nithyl(5R)-2-methyl-2-penem-6-carboxylate; (68)-6-Nithyl(5R' )-2-ethyl-2-
Penem-6-carboxylic acid; (68)-6-nityl-(5R)-2-propyl-2-
Penem-3-carboxylic acid; (6B)-6-methyl-(5
R)-2-Methyl-2-penem-6-carzanoic acid; (68)-6-methyl-(5R)-2-ethyl-2-penem-localmenic acid; (68)-6-methyl- (5R)-2-propyl-2-
Penem-6-carbo/acid; (6B)-6-f robi-(
5R)-2-methyl-2-penem-6-carzanoic acid; (
68)-6-propyl-(5R)-2-ethyl-2-penem-3-carzanoic acid; (6B)-6-probyl-C5
B”)-2-zorobyl-2-penem-3-carmenic acid;
and optically active trans-6-substituted-5(R) of formula (1) of claim 1, which is a compound selected from the group consisting of pharmaceutically or veterinarily acceptable salts of free acids. -2-
Penem-6-carvone g1! Fermented conductor. 80, R is 01-w05ak * There is Rute, R1 is o
x-<6 alkanoyloxymethyl, "l is hydrogen, O1'=C6 alkanoylmethyl, and the optionally nitro-substituted benzyl group is a pharmaceutically or veterinary poultry-acceptable cation. Equation (1)-) 5y
x-6CB)-5(R)-2-penem-3-carboxylic acid cast conductor. 81. The compound of claim 80, wherein R is methyl, ethyl or zolyl, and R1 is acetoxymethyl or propionyloxymethyl. 82, p-nitrobenzyl(6B)-6-nithylu(
5R)-2-acetoxy-methyl-2-penem-3-carxylate; p-nitrobenzyl(6B)-6-methyl-(5R)-
2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6B)-6-propyl-(5R)
-2-acetoxy-methyl-2-penem-3-carboxylate; 1-nitrobenzyl (6B)-6-methyl-(5R)-
2-f robionyloxy-methip-nitrobenzyl (6
B) -6-Nityru (5R)-2-propionyloxy-methyl-2-penem-6-carzoxylate; p-
Nitrobenzyl (68)-6-propyl-(5R)-2
-propionyloxy-methyl-twopenem-6-carboxylate; acetonyl(6B)-6-nityl(5
R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl (68)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl (6B) -6-propyl-(5R)-2-acetoxy-methyl-2-penem-6-carboxylate; acetonyl(6B)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-6- Carboxylate; Acetonyl (6B)-6-nityl-(5R)-2-propionyloxy-methyl-2-penem-6-carpoyacylate; Acetonyl (6B)-6-propyl-(5R)-2-propionyloxy-methyl -2-penem-6-carboxylate; (6B)-6-nityl-(5R)-2-acetoxy-methyl-2-penem-6-carboxylic acid; (6B)-6-methyl-(5R)-2- Acetoxy-methyl-2-penem-6-carboxylic acid; (613')-6-propyl-(5R)-2-acetoxy-methyl-2-penem-6-carzanoic acid; (6s)-6-methyl -(5R)-2-propionyloxy-methyl-2-penem-6-carboxylic acid; (6s)-6-nityl-(5R)-2-propionyloxy-methyl-2-penem-6-carboxylic acid; (6B '1-6-Propyl-(5R)-2-de 0%!Nionyloxy-methyl-2-penem-3-carmenic acid; Methyl(6B)-6-nityl-(5R)-2-acetoxy-methyl-2- Penem-6-cardoxylate; Methyl (6B)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-6-carboxylate; Methyl (68)-6-probyl-(5R)-2- Aryutoxymethyl-2-penem-3-carboxylate; Methyl(6B)-6-methyl-(SR)-2-propionyloxy-methyl-2-4nemu-3-carboxylate; Methyl(6B)-6-nityl( 5R)-2-propionyloxy-methyl-2-/J!nemu 3-carboxylate; Methyl (6B)-6-propyl-(5R)-2-propionyloxy-methyl-2-penemu 6-carboxylate; and Optically active trans-6-substituted-5(R) of formula (1) according to claim H, which is a compound selected from the group consisting of pharmaceutically or veterinarily acceptable salts of free acids.
-2-penem-3-carboxylic acid derivative. 86, R is 01-C6 alkyl, R1 is 01-C
Trans-6(S)-5(R)-2-penem-6-carboxylic acid of formula (1) according to claim 1pJ1, which is 6 alkoxycarmenyl and %R2 is a water cation. 84. The compound of claim 86, wherein R is methyl, ethyl or propyl, and R1 is ethoxycarbonyl, ethoxycarbonyl or propoxycarbonyl. 85, p-nitrobenzyl(68)-6-nithylu(5
R)-2-ethoxycarbonyl-2-penem-6-carboxylate; p-nitrobenzyl(68)-6-methyl-(5R)-
2-ethoxycarzanyl-2-penem-6-carboxylate; p-nitrobenzyl (6g)-6-zorobyl (5R)
-2-Ethoxycarbonyl-2-penem-6-carmexylate; p-nitrobe/zyl(68)-6-methyl-(5R')
-2-methoxycarbonyl-2-penem-6-carboxylate; p-nitrobenzyl (6B)-6-nityl (5R)-
2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6 days)-6-zolopyl-(5R)
-2-methoxycarbonyl-2-penem-6-carboxylate; p-nitrobenzyl(68')-6-methyl-(5R)
-2-1"lopoxycarbonyl-2-penem-6-carboxylate; p-nitrobenzyl (68)-6-nithil (5R)-
2-propyl-2-penem-6-carboxylate; p-nitrobenzyl (6 days)-6-propyl-(5R'
)-2-f roboxycarbonyl-2-penem-3-carboxylate; (6B)-6-nityl-(5R)-2-ethoxycarzanyl-2-penem-localmenic acid; (6B)-6-methyl -(5R)-2-ethoxycarbonyl-2-penem-6-carbo/#I; (6B)-6-foi-(5R)-2-ethoxycarbonyl-2-penem-6-carzanoic acid; ( 6B)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-6-carbo/acid; (6B)-6-nityl-(5R)-2-methoxycarzanyl-2-penem-localmenic acid (6th day) -6-zorogyru(5R)-2-methoxycarvinyl-2-penem-6-carbo/acid; (6B)-6-methyl-(5R)-2-propoxycarbonyl-2- Penem-6-carboxylic acid; (6s)-6-nityl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6B)-6-propyl-(5R)-2-propoxycarzanyl -2-penem-3-carboxylic acid; Methyl (6B)-6-nityl-(5R)-2-ethoxycarbonyl-2-penem-6-carboxylate; Methyl (6B)-6-methyl-(5R)- 2-Ethoxycarzanyl-2-penem-5-carboxylate; Methyl (6B)-6-zorobyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; Methyl (68)-6-methyl -(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; Methyl (68)-6-nityl-(5R)-2-methoxycarbonyl-2-penem-6-carboxylate; Methyl (68) -6-propyl-(5R)-2-methoxycarbonyl-2-penem-6-carboxylate; Methyl (,5B)-/, -methyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate Methyl (6s)-6-nityl-(5R)-2-proboxycarmenyl-2-penem-6-carpoxylate: Methyl (6B')-6-propyl-(5R)-2-proxycarzanyl -2-penem-3-carzoxylate; optically active trans-6-substituted-5(to))
-2-penem-6-carboxylic acid rust conductor. 86, R is 01-C6 alkyl, 'R1 is thenylmethyl group, R2 is water s, cl-06 alkyl,
Trough X-6(8)-5(R)-2-penem of formula (1) according to claim 1, optionally a nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation -3-carboxylic acid derivative. 87, R is methyl, ethyl or propyl, I
Claim 86, wherein Ll is 2-thenylmethyl
Compounds described in Section. 88, p-nitrobenzylC6B)-6-nithylu(5
R)-2-cheny2'-yl-methyl-2-penem-
3-carboxylate; p-nitrobenzyl (68)-
6-Methyl-(5R)-2-cheny2'-yl-methyl-2-penem-3-carboxylate;p-nitrobenzyl(68)-6-depvir-(5R)-2-cheny2'-yl-methyl-2-penem-6-carboxylate; (613)-6-nityl-(5R)-2-cheny21-yl-methyl-2-penem-6-carboxylic acid; (6B)-6- Methyl-(5R)-2-Cheney2'-
yl-methyl-2-penem-3-carboxylic acid; (6B)-6-propyl-(5R)-2-Cheney 2
'-1-Methyl-2-penem-3-carboxylic acid; Methyl (6B'')-6-Nity-2-2-cheny2'-yl-methyl-2-penem-6-carboxylate; Methyl (6B) -6-Methyl-(5R)-2-cheny2'-yl-methyl-2-penem-3-carboxylate;Methyl(6B)-6-propyl-(5R)-2-cheny2'-yl-methyl-2-penem-3-carboxylate; and a pharmaceutically or veterinarily acceptable salt of the free acid. -6-substituted-5(R
)-2-penem-3-carvone fermentation conductor. 89. The method according to claim 1 for producing the compound according to any one of claims 77 to 80. A pharmaceutical or veterinary composition comprising a compound according to any one of claims 77 to 80 and a pharmaceutically or veterinarily acceptable carrier and/or diluent. 91, a compound or salt of formula (I) according to claim 1 as specified above. 92, formula 1. as recited in any one of the preceding claims and as specified above. I, ■, V, Vl,
W, ■, ■, Bean, XV, XI, XX, XXIA, XX
I, XXVI, xxw, top or door compounds or salts. 93, a method for producing a compound or salt of formula (1) according to claim 1 or 2. 94% Claim No. 6.14.21.26.60,
34.67, 42.46.44.45.47.49.5
1.56.54.56.58.59.66 or a method for producing the compound or salt according to any of 72. 95, the composition according to claim 90. 96. The compound or salt according to any one of claims 77 to 88, which is used in a method for surgically treating a human body or an animal or diagnosing a human body or an animal.