DE3224055A1 - METHOD FOR PRODUCING OPTICALLY ACTIVE TRANS-6-SUBSTITUTED-5 (R) -2-PENEM-3-CARBONIC ACID DERIVATIVES, AND NEW OPTICALLY ACTIVE TRANS-6 (S) SUBSTITUTED-5 (R) -2-PENEM-3-CARBONATE ACID - Google Patents

Description

HOFFMANN · BITIJB & PARTNER

PAT E N TAN WALTE

DR. ING. E. HOFFMANN (1930-1976). DlPL-ING.W.EITLE · D R. R E R. NAT. K. H OFFMAN N · Dl PL.-ING. W. LEH N

DIPL.-ING. K. FOCHSLE DR. RER. NAT. B. HANSEN ARABELLASTRASSE 4 ■ D-8000 MD NCH EN 81. TELEPHONE (089) 911087 · TELEX 05-29619 (PATHE)

- 35 -

FARMITALIA CARLO ERBA S.p.Α., MILAN / ITALY

Process for the preparation of optically active trans-6-substituted-5 (R) -2-penem-3-carboxylic acid derivatives, as well as new optically active trans-6 (S) -substituted -5 (R) -Z-penem-S-carboxylic acid derivatives

The invention relates to a new process for the preparation of optically active trans-6-substituted-5 (R) -2-penem-3-carboxylic acid derivatives and new optically active trans-6 (S) -substituted-5 (R) ^ -penem-S-carbo acid derivatives.

The main object of the invention is a new process for the preparation of optically active trans-6-substituted-5 (R) -2-penem-3-carboxylic acid derivatives of the general formula (I)

6th N 1
S Ί 4th 7th I. , ^R ! COOR ₂

(I)

where R and R .. are identical or different organic groups and R ₀ - is a hydrogen atom / a cation or a carboxyl protecting group.

The 2-penem-3-carboxylic acid derivatives are a known class of synthetic ß-lactem compounds. With a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria and also with a ß-lactamase-inhibiting activity and are for example in Acta Pharma / Suec, j_4_ (Suppl.), 23 (1977) and in J. Am. Chem. Soc, 100 , 8214 (1978).

In the above formula (I) the organic groups R and R _{1 can} in particular mean:

(1) an acyl group;

(2) a free or esterified carboxyl group; or

(3) a group of the formula - (CH ₀ ) --- 0. "T / in which χ is 0 or an integer from 1 to 10, Q is a bond, a saturated or unsaturated, preferably saturated aliphatic chain, preferably

- 37 -

_1-6 H, an oxygen or a sulfur atom, a group -SO- or -SO--, a group -N = or a group -N-, in which R is hydrogen or a

R.
a

straight-chain or branched C., .. "-alkyl group, preferably C _1-6 -alkyl, and in which T means:

(a) a branched or straight chain, saturated or unsaturated aliphatic hydrocarbon group,

(b) an aromatic group,

(c) a cycloaliphatic group, or 15

(d) a heterocyclic group;

wherein each of the substituents (a), (b), (c) and (d) is unsubstituted or by one or more substituents may be substituted, which are preferably selected are composed of halogen, a free or esterified carboxyl group, a free or protected amino group, a free or protected hydroxy or mercapto group, C 1, C -alkyl, C, g-alkoxy, C, ^ -alkyl-mercapto and a free or protected oxo group.

If R or R- is an acyl group, then it preferably has the meaning of C ₁ - alkanoyl and in particular

I - o

Acetyl, propionyl or benzoyl.
30th

If R or R- is an esterified carboxyl group, then

it preferably means a C 1 -C 4 alkoxycarbonyl group and in particular a methoxy, ethoxy or tert-butoxycarbonyl group or a carboxy group, which is protected by one of the carboxy protecting groups commonly used in peptide chemistry, e.g. by trichloroethyl, benzyl, p-nitrobenzyl, benzhydryl, Acetoxymethyl, acetonyl, pivaloyloxymethyl, Trimethylsilyl and the like.

When R or R ₁ is a group - (CH _{2) X} ~ QT where T is a branched or straight chain saturated or unsaturated aliphatic hydrocarbon group, this is preferably a C, .. "" alkyl or Cp _-1 2 "" ^A lkenyl , which is either, as indicated above, unsubstituted or substituted.

. If T is an aromatic group, this can be mononuclear or polynuclear and is preferred mononuclear and is preferably phenyl or naphthyl, but particularly preferably phenyl.

If T is a cycloaliphatic group, it preferably represents a monocycloaliphatic radical, preferably C ₃ __ -cycloalkyl, in particular cyclohexyl or cyclopentyl, or C _{c n} -cycloalkenyl.

When T is a heterocyclic group, it is preferably a heteromonocyclic group, if so desired is condensed with a benzene radical or with another heterocyclic ring, in particular this heteromonocyclic group is a furyl,

Thienyl, tetrazolyl, thiadiazolyl, triazolyl, Pyridazonyl, triazinyl or a heterobicyclic Group consisting of a 5-atom heteromonocyclic ring containing at least one heteroatom from the Group N, O and S, or from a 5-atom or 6-atom heteromonocyclic ring containing at least a heteroatom from the group N, O and S, in particular, for example, ■ tetrazolopyridazinyl and triazolopyridazinyl.

If R "is a cation, this cation comes from one pharmaceutically or veterinarily acceptable base which can be inorganic, e.g. an alkali hydroxide, especially sodium or potassium hydroxide, or an alkaline earth hydroxide, especially calcium and magnesium hydroxide, or from an organic base, e.g. Ammonia, or another organic amine, in particular diethylamine, triethylamine, 2-hydroxyethylamine, 1-ethylpiperidine, benzylamine, pyridine, collidine and like that.

If R _{2 is} a carboxyl protective group, it is preferably a group which, together with the -COO group, forms an esterified carboxy group which can be easily split, for example by reduction or in particular by hydrogenolysis, by photoysis, by solvolysis, in particular by acid hydrolysis or especially by neutral or basic hydrolysis or under physiological conditions, or it is an esterified carboxy group which can easily be converted into another functionally modified carboxy group.

Examples of carboxy protective groups R ^ are in particular lower alkyl groups, optionally substituted by halogen, in particular C._g-alkyl, preferably methyl, ethyl and tert-butyl and trichloroethyl; Aralkyl groups, especially benzyl and o- and p-nitrobenzyl; Aryloxyalkyl groups, in particular aryloxy, C, _g -alkyl, particularly preferably phenoxymethyl, phenoxyethyl and O 1 -C ₆ -alkyl-pC-phenoxymethyl, for example oU-methyl-oC-phenoxymethyl, .90-EthyloL-phenoxy -methyl, oleoC-dimethyl- ot-phenoxy-methyl; or groups such as benzhydryl, o-nitrobenzhydryl, acetoxymethyl, acetonyl, pivaloyloxymethyl, trimethylsilyl or dimethyl-tert-butylsilyl and the like.

Protected amino, hydroxy, mercapto and carboxy groups are amino, hydroxy, mercapto and carboxy groups that carry protective groups, as they usually do used in penicillin and cephalosporin chemistry for this type of function. Suitable Protective groups for the amino, hydroxy and mercapto functions are, for example, if desired substituted, in particular halogen-substituted acyl groups, preferably acetyl, monochloroacetyl, dichloroacetyl, Trifluoroacetyl or benzoyl; Triarylmethyl groups, especially trityl; Silyl groups, in particular trimethylsilyl or dimethyl-tert-butylsilyl; or groups such as tert-butoxycarbonyl or p-nitrobenzyloxycarbonyl. Protection groups for the Carboxy functions can be those mentioned above for the substituent R "if this is a carboxy protective group represents.

- 41 -

Protected oxo groups are in particular oxo groups that are in the form of a linear or cyclic acetal, Ketals, thioacetals or thioketals are protected.

A number of 2-penem-3-carboxylic acid derivatives are known from the prior art, for example from J. Am. Chem. Soc, W ± _r 6206 (1979) '; ibid., W ±, 6301 (1979); ibid., 1-0, 6306 (1979); ibid., 01-0J2, 2039 (1980); Tetrahedron Lett., 1978 , 4,059; J: C: S: Chem. Comm., 1978 , 1101; Tetrahedron Lett., 1979 , 3777; J. Antibiotics, 33, 453 (1980); JCS Chem. Comm., 1980 , 70; GB-PS 1 557 559, DE-OS 28 19 655 and British patent application No. 2 013 674 A.

It is also known from the prior art that the stereochemistry of the 5-carbon atom in the penem nucleus for . the development of pharmacological activity is important and that in particular such penem isomers, which have an R configuration at C, -, i.e. the same configuration as occurs in natural penicillins and cephalosporins, especially pharmacologically are active isomers.

The new process according to the present invention makes it possible to obtain the optically active 5 (R) -2-penem-3-carboxylic acids of the formula (I). According to the invention, the trans-6-substituted-5 (R) -2- Penera-3-carboxylic acid derivatives of the above formula (I) are obtained by the process described below in accordance with scheme I, where R, R- and R _{2 have} the meanings given above have and each of the groups R ₃

- 42 -

independently of one another are hydrogen or C._g-alkyl. X is a halogen atom, in particular chlorine, 0 denotes an aromatic or heterocyclic group, preferably selected from phenyl, tolyl, cb- or β-naphthyl, pyridyl or thienyl; or a lower alkyl group, preferably C 1-4 alkyl, especially b-butyl; ψ denotes an oxygen or sulfur atom, M ⁿ denotes the cation of a heavy metal M in each of its normal oxidation states; M represents a heavy metal which is preferably selected from Ag, Hg, Au, Cu and Pb; n + denotes the oxidation state of the heavy metal, where η is preferably an integer from 1 to 4; A denotes a residue which makes the SA bond particularly labile to the heterolytic effect of a soluble metal salt or halogens. _

- 43 -

- 43 -

O

Scheme I.

OH (II)

"J

S-A

"H,

NH

>"SA ■ Nv / vs / OH

2 ·

j COOR

, S-A

I,

R,

-Ν-νγ ^, χ

COOR ₂ »SAT

R *.

COOR,

₆ S-

O ^

C00R2

(III)

(IV) (V)

(VI)

(VII)

(VIII)

(I)

44 _

A preferably denotes an organic group of the formula

(a) -J \ -0 , wherein TX 'is a carbon or SiIi-

Zium atom and wherein, when carbon is, each of the groups 0, 0 and 0 independently of one another is an aromatic or heteroaromatic group, for example phenyl, φ- or ß-naphthyl, biphenyl, thienyl, pyridyl, imidazolyl, thiazolyl, furyl, each are unsubstituted or with one or more substituents selected from Cl, F, Br, J, CF ₃ , CCl ₃ , NO ₂ , OR ¹ and in which R ¹ 'is a C ₁ - alkyl group. Is silicon, then

AB C

the groups 0, 0 and 0 independently of one another denote a straight-chain or branched C - ^ - alkyl group, preferably C _1- , -alkyl; or

R.

/ a
(b) ~ ^C ~ ^R b ' ^{where R} _{a is} ^a hydrogen atom or

R.
c

a straight-chain or branched C. _. ₂ ~ alkyl group, preferably a C ₁ _, - alkyl group, and where both R, and R, which may be the same or different, is a branched alkyl group, preferably C ₁ ^ _5, especially C ₁ _ ₄ alkyl, or a straight-chain alkyl group which is substituted by one or more organic radicals and which are specially selected for this group and consist of: an aryl group, preferably phenyl; one

- 45 -

Aralkyl group, preferably ArYl-C _1-6 -Al] CyI, especially benzyl; a cycloaliphatic radical, preferably C ₁ . - Monocycloalkyl, in particular cyclopentyl or cyclohexyl; or a heterocyclic radical, preferably a C ₅ _ ₇ -heteromonozyklischen group, in particular Tetrahydropyranoyl; or where R and

R, together or R, and R together are divalent Radical of the formula - (CH) -A- (CH) - mean in which

, m ι Ρ

^R d ' ^R e Y is -O-, -S- or -C- and wherein each of

^R f ^ g · ·

Groups R 1, R, R 1 and R, which can be identical or different, are hydrogen; Alkyl, preferably C, _ß- alkyl; Aryl, preferably phenyl; Aralkyl, preferably aryl-C 1, -alkyl, in particular benzyl; a cycloaliphatic group, preferably a C _3-7 cycloalkyl group, in particular cyclopentyl or cyclohexyl; a heterocyclic group, preferably a C1- heteromonocyclic group; or a group - (CH ₀ ) -OR, or - (CH ₀ ) -SR, where R, the 2 q η ζ q η η

Meaning which has previously been given for the groups R 1 to R, or R is an acyl group, preferably C ₂ _g-alkanoyl, in particular acetyl or benzoyl, and where each m, ρ and q, which can be the same or different, is 0 , 1 or 2 and Q ^{1 is} oxygen, sulfur or an iminic nitrogen = N- or a

Group -N- denotes in which R is the aforementioned 1 ^a

^R a
Has meaning.

The group A can have the following structures, for example.

- 46 -

- 46 -

/ ^0CH 3

^CH

CH.

The use of certain groups A in the preparation of racemic penem compounds is known (Tetrahedron Lett. 22.i ³⁵⁵ (1981)). The preparation of penem compounds, including optically active 5 (R) -penem compounds of the formula (I) by intramolecular Wittig reaction of a 4-acylthioazetidinylphosphorane, including the 4 (R) -isomers (VIII), is known and is the most effective method of presentation for Preparation of this class of β-lactam compounds (J. Am. Chem. Soc., KT [, 6296 (1979; ibid., J_OJ_, 6301 (1979); ibid., J_0_l, 6306 (1979); ibid., _1_0_2, 2039) (1980; GB-PS 1 557 559, DE-OS 28 19 655, British patent applications

30 according to No. 2 013 674 A and 80.05476).

- 47 -

In such processes, in which a total synthesis leads to the penem compounds, one obtains a racemic one or optically active intermediate (VIII) by a multi-step synthesis sequence which is carried out in an early Stage requires that a nucleofugal leaving group replace L with a thiolacid or a dithioacid is, either in a racemic compound of the formula (IX)

(IX)

wherein R has the meaning given above, or in a previously cleaved 4 (R) compound of the formula (IXa)

γΝΗ

(IXa)

pi / n inn

wherein R has the meaning given above, and then either a racemic compound of the general Formula (X)

K £ 4 ^ ^S -V ₁₁ Z ^ l

(X)

0 *

wherein R, R ₁ and vj / have the meanings given above, or an optically active 4 (R) compound of the formula (Xa)

- 48 -

<1

NH

(Xa)

where R,
to have.

and ψ the meanings given above

In the known processes, the compound (X) or (Xa) is then subjected to a further reaction sequence, in the setting of the acetidine ring the unit

P0O

COOR,

is introduced, which characterizes the compound (VIII).

On the other hand, one can use some known alternative processes for the preparation of the penem derivatives of natural 6-amino-penicillanic acids or penicillins go out to obtain intermediate (VIII) (see published British patent application 80.05476). The intermediate (VIII) is obtained in a multi-stage synthesis sequence in which in At an early stage, two essential stages are required, namely the introduction of the group. R in the Penemkern to obtain a compound of the formula (XI)

- 49 -

3224

(XI)

wherein R has the meaning given above, and the no less essential stage of the introduction of the group

nes Alkyns of type JjTT "1 wherein R ₁

₁ into the opening of the thiazoline ring in the presence of an alkyne of the type JjTT "1 wherein R _{1 is} the previously

has given meaning.

According to the aforementioned known method, the optically active compound of the formula (XII) obtained in this way

0 _

H 'cOOCH ,,'

(XII)

wherein R and R _{1 have} the meanings given above, then subjected to a further reaction sequence to remove the substituent in the 1-position of the acetidine ring through the unit

to replace and to restore the acylthio functionality characterizing the compound (VIII).

In the above-mentioned methods, the 2-substituent R ₁ and the 6-substituent R of the penem nucleus therefore occur in practice at the beginning of the synthetic route. This means, however, that for the preparation by the known process of the 4 (R) -compound (VIII) and finally the 5 (R) -penem compound (I) to introduce the substituents R ₁ and R in the end product, the whole sequence is repeated got to.

Furthermore, the aforementioned exchange reaction proceeds to obtain the compounds (X) or (Xa) from the Compounds (IX) or (IXa), if they are carried out directly with the respective thiolacid or dithioacid, often with poor yields and / or difficulties often arise, depending on the Production and / or the availability of the correct - thiolacid or dithioacid. One performs the same Exchange reaction with a thienol via one as an intermediate product thioenol ether formed by, e.g.

according to J. Am. Chem. Soc, 101 , 6306 (1979; ibid., 102 , 2039 (1980); or Tetrahedron Lett., 1979 , 3777, then there is the advantage of using the acetidinylthioenol ether of the formula (Xb) formed as an intermediate

R SR

(Xb)

0 '

wherein R and R .. have the meanings given above and ψ 'is an optionally substituted methylene group

- 51 -

means either as a racemate or in an optical way To obtain active form in high yields, largely lost due to the availability of the correct thienol and also through the further oxidative cleavage of the olefinic bond ^ C = γ 'which is required about the acylthio functionality which characterizes the compound (VIII) restore.

In addition, other problems often arise due to unstable and / or oxidation-sensitive radicals in the group R ₁ .

From the aforesaid it is evident that the known synthetic methods for obtaining the intermediate (VIII), namely the last intermediate for the synthesis of the 2-penem derivatives (I), two have significant disadvantages, namely the "lack of flexibility" and the "lack of productivity".

These two disadvantages can be eliminated by the method according to the invention.

It can be seen from Scheme I that by means of a unique synthesis sequence which is independent of the meaning of the 2-substituent R ₁ in the end product, a common intermediate, namely the compound (VII), can be obtained from which, in one step, in which the coupling _{takes place with every desired -CR 1} -EInIIeXt, every desired intermediate prov | /

duct (VIII) can be obtained.

Since, as already mentioned, the synthesis sequence for the preparation of the common intermediate (VII) is independent from the R. group is not a repetition of the entire synthetic sequence for the respective substituent R.J, who enters the penem compound (I), required quite in contrast to what takes place in the known processes.

For the method according to the invention, this results in a high flexibility, because you can easily get a large selection of 5 (R) ^ -penem-S-carboxylic acid derivatives can.

Furthermore, in the methods of the prior art, the introduction of the -CR ₁ -GrUpPe, which is responsible for the

Il>

Compound (VIII) is characteristic, made at an early stage of the synthesis and this represents represents a very critical stage which generally proceeds with poor yields and / or difficulties. Naturally, the necessity of this critical level has considerable negative effects on. the yield, i.e. on the productivity of the overall process, and this negative effect is reinforced by the fact that this critical level is in a very early stage of synthesis needs to be done.

According to the process according to the invention, on the other hand, the introduction of the -CR ₁ -GrUPPe, as shown in y

Scheme I is shown in a later stage (in the penultimate stage) of the synthesis sequence and

- 53 -

therefore the influence on the productivity of the overall process is less in this case. Farther this stage is no longer a critical point in the synthesis. The trick, a mercapto salt Using (VII) as a nucleophilic agent enables an acid or a thioacid to be used or a reactive derivative thereof in the displacement reaction in place of the thiolacid or dithioacid or thioenol or alkylene derivative which had to be used in the known processes.

Since both acids and thioacids are easier to produce and more readily available than thiolacids, Dithioacids, thienols and alkynes, thereby increase the flexibility and productivity of the new synthesis process elevated.

Despite the very strong nucleophilic properties of the Mercapto salt (VII), the displacement reaction proceeds with better yields in the known processes and this increases the productivity in synthesis. It follows that the most important and original Aspect of the present invention is to be found in that optically active penem derivatives with the 5 (R) configuration can be obtained by a process which does not have the disadvantages of the known method and wherein the inventive method a has very high flexibility and very high productivity. The method according to the invention enables the preparation of optically active trans-6-substituted 5 (R) molecules starting from the chiral compound

(II), which is a particularly suitable intermediate for the exchange reaction with the thiol A-SH.

In accordance with the aforementioned Scheme I, the invention is characterized in the following way:

(A) that an optically active azetidin-2-one derivative of the formula (II)

pi

in which R and R _{3 have} the meanings given above, with a thiol of the formula A-SH or a salt thereof, in which A has the meaning given above, to give the optically active 4 (R) -thio derivative of the formula (III)

"> S-A

"I.

- ' ^NH (in)

wherein R and A have the meanings given above;

(b) that a 4 (R) compound (III) with a glyoxylic acid derivative of the formula
30th

OHC - COOR ₂

- 55 -

where R ~ has the meaning given above, converts, to obtain a 4 (R) derivative of the formula (IV)

COOR

wherein R, A and R _{0 have} the meanings given above;

(c) that a 4 (R) -carbinol (IV) is halogenated to give a 4 (R) derivative of the formula (V) 15th

~ '"> fr

(V)

JT

COOR ₂
20th

wherein R, A and R _{2 have} the meanings given above and X is a halogen atom;

(d) that a 4 (R) compound (V) with a phosphine derivative of the formula P0- ,, where 0 is the one given above Has meaning, converts, to obtain a 4 (R) -phosphorane of the formula (VI)

A. --L ^ d (VI)

COOR ₂

- 56 -

wherein R, A, R ~ and 0 have the meanings given above to have;

(e) that a 4 (R) -phosphorane of the formula (VI) is reacted with a solution of a heavy metal ^{salt of the formula M n} -γ ^η , in which M and η have the meanings given above and Y is the anionic radical of the salt, while obtaining the 4 (R) mercapto salt of the formula (VII)

COOR

(VII)

where R, R ^, 0, M and η have the meaning given above • have services;

(f) that one has a 4 (R) -mercapto salt of the formula (VII) with a reactive derivative of an acid or a thioacid of the formula

.OH

where R ^ and V | have the meanings given above, converts to obtain a 4 (R) derivative of the formula (VIII)

(VIII)

COOPv

- 57 -

wherein R, R. _f R " ₍ ψ and 0 have the meanings given above;

(g) that a 4 (R) -compound of the formula (VIII) is cyclized to give a 5 (R) -penem derivative of formula (I)

δ "COOR ₂ (i)

wherein R, R ^ and R _{2 have} the meanings given above, and

that, if desired, the compound of the formula (I) in which R _{2 is} hydrogen is converted into a salt and / or, if desired, the compound of the formula (I) in which R 1 is hydrogen or a cation, esterified and / or, if desired, a A compound of the formula (I) is obtained in which R _{2 is} hydrogen or a cation when R _{2 is} a carboxy protective group and / or, if desired, a compound of the formula (I) into another compound of the formula

(I) transferred.

The reaction of the azetidin-2-one of the formula (II) with the thiol of the formula ASH or a salt thereof, preferably an alkali salt such as sodium or. Potassium can be used at a temperature in the range from about 0 ⁰ C to room temperature in a suitable solvent

carried out, e.g. in water, acetone, tetrahydrofuran, dimethylformamide, methylene chloride, trichloromethane, Acetonitrile or mixtures thereof. If desired, the salt of the thiol of the formula ASH obtained in situ by carrying out the reaction in the presence of a base such as sodium or potassium hydroxide or from sodium or potassium hydride or from sodium or potassium carbonate or an organic Base.

The condensation reaction between a 4 (R) compound of the formula (III) and a glyoxylic acid derivative of the formula CHO-COOR- is preferably carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, dioxane, methylene chloride, trichloromethane, acetonitrile or in a mixture of these solvents made in the presence of a base, which can be, for example, triethylamine, piperidine or a similar compound. The reaction temperature can vary between about 0 ^° C. to the reflux temperature of the solvent used, room temperature being preferred.

The subsequent halogenation of the 4 (R) -carbinol of Formula (IV), to obtain a .4 (R) -compound of the formula (V) can by means of a suitable halogenating agent be performed. It is preferred to prepare the compound (V) in which X represents chlorine. Therefore, the chlorination is preferably carried out using thionyl chloride as the chlorinating agent, both in the absence

- 59 -

a solvent as well as in the presence of a

anhydrous, inert, organic solvent such as tetrahydrofuran or benzene or toluene can work. The reaction is in the presence of a base, for example pyridine, at a very low temperature, which is preferably between about -70 to 0 ⁰ C and preferably at -30 to. 0 ⁰ C, carried out. The conversion of the 4 (R) compound of the formula (V) into a 4 (R) -phosphorane derivative of the formula (VI) by reaction with a phosphine of the formula P0 ~ is preferably carried out in an anhydrous inert solvent such as methylene chloride, benzene , Toluene, tetrahydrofuran, in the presence of a base, for example pyridine or 2,6-lutidine, at a temperature between about 0 and 60 ⁰ C and preferably between 25 and 50 ⁰ C carried out.

The heavy metal ^{salt of the formula M n} -Y ⁿ ~ is a salt of an inorganic or organic and preferably an inorganic acid, for example of sulfuric acid, nitric acid, hydrochloric acid, formic acid or acetic acid.

As already mentioned, the heavy metal M is preferably selected from the group Ag, Hg, Cu, Au and Pb.

Preferred salts of the formula M ^{n +} -Y ⁿ ~ are AgNO ₃ or Hg (OCOCH-j) ₉ . The reaction of a 4 (R) -phosphorane of the formula (VI) with a heavy metal ^{salt of the formula M n} -Y ⁿ is preferably carried out using a solution of equivalent amounts of the salt in a suitable polar solvent, for example in water, an aliphatic alcohol a C «_g ~

aliphatic alcohol, in particular methanol or ethanol, or a mixture of these solvents taken. The reaction generally proceeds in quantitative yield at temperatures in the range from about 0 ° C to the reflux temperature and preferably wisely at room temperature. The reactive derivative of the acid or thioacid of the formula

OH R ₁ -C

is preferably a halide, in particular a chloride, or an anhydride or a mixed anhydride. 15th

The reaction between a 4 (R) mercapto salt of the formula (VII) and a reactive derivative of the compound of formula

OH

is preferably carried out using an excess of the latter reagent in an inert anhydrous organic solvent such as acetonitrile, benzene, toluene, dimethylformamide, methylene chloride, chloroform and the like, at a temperature between approximately 0 ^° C. and room temperature and preferably at room temperature.

The subsequent cyclization of the 4 (R) derivative of

- 61 -

Formula (VIII) into a 5 (R) -penem compound of the formula (I) occurs spontaneously or can be accelerated thermally or catalytically using known methods, for example by heating in toluene according to the Woodward process (J. Am. Chem Soc, 101 , 6296 (1979); ibid., Lpj_, 6301 (1979); ibid., _1-0_l, 6306 (1979); ibid., Lp_2, 2039 (1980)).

The desired salt formation or esterification stage and, if desired, the conversion of a 5 (R) -penem derivative of the formula (I) in which R _{2 is} a carboxyl protecting group into the corresponding 5 (R) -penem derivative in which R _{2 is} hydrogen or a Cation means, can be done in a known manner.

In particular, a 5 (R) -penem compound of the formula (I) in which R _{2 is} hydrogen can be obtained, for example, by hydrogenolyzing the corresponding compound in which R _{2 is} a carboxyl protecting group, in particular if R _{2 is} a p-nitrobenzyl group , or hydrolyzed, for example with a pH 7.5 phosphate buffer, especially when R _{2 is} an acetonyl group.

When converting a Compound of formula (I) into another compound of formula (I), one can use the known methods of apply organic chemistry.

According to the inventive method, the chiral

Key intermediate of formula (II) obtained by

(1) a compound of the formula (XIII)

Jf

er— "χ ⁰

wherein R _{3 has} the meaning given above, into a compound of the formula (XIV)

) / N. W - (X ₁ V)

. ^H 3 ° ^0H 3

wherein R and R _{3 have} the meanings given above, converts;

(2) a compound of the formula (XIV) into a compound of the formula (XV)

R-,

^z -> R., .. SO, ^{| 0}

^ ^J (XV)

^Cfl 3 ^CH 3

wherein R and R have the meanings given above, convicted; and

- 63 -

(3) the N / O protecting group of a compound of the formula (XV) removed.

The conversion of a compound of the formula (XIH) into a compound of the formula. (XIV) is through implementation carried out with an excess of a suitable base, generally a strong inorganic one or organic base, e.g. from NaH, LiH, KH, n-BuLi, t-BuLi, lithium diisopropylamide or bis (trimethylsilyl) lithium amide, in a suitable solvent and in a known manner, e.g. according to T. Durst, R.V.D. Elzen and R. Legault in Ca., J. Chem., ^ 2, 3206 (1974), and treating the formed anion with an electrophilic agent containing the R group.

An electrophilic agent bearing the R group can be any compound which is an R group positive loaded, carries.

For example, in order to obtain a compound of the formula (XIV) in which R is an alkyl group, that can electrophilic agents can be a suitable alkyl halide such as a chloride or bromide. To connect (XIV), wherein R is acyl, one can use a suitable activated acid such as an ester Use an acyl halide, an acylimidazole, or an anhydride .

To obtain a compound (XIV) in which R is carboxy, one can use a suitable activated formate, e.g. use chloroformate.

If desired or necessary, a substituent first introduced into the compound (XIV) To convert R into another substituent R, then one can use the usual organic methods Apply chemistry.

The oxidation of a sulfur compound of the formula (XIV) to a sulfon of the formula (XV) is carried out according to customary methods Organic chemistry processes for this type of oxidation are carried out, e.g. by means of an inorganic or organic oxidizing agent, in particular m-chloroperbenzoic acid or KMnO ..

The removal of the N, O protecting group in the compound of the formula (XV) can be carried out in a customary manner, in particular by weak hydrolysis, preferably acid hydrolysis.

The compound of formula (XIII) is a new chiral intermediate compound, those for the synthesis of all 5 (R) ^ -penem-S-carboxylic acid derivatives which are already substituted suitable is.

In particular, a compound of the formula (XIII) can be converted into, for example, a compound of the formula (XIV) in which R is the group R-C ' ¹ ' ¹ , in which R is the radical of a

X Il X

Acyl group, in particular a C1, - alkyl group or Phenyl means convert. The acid derivative obtained can then subsequently be reduced and yields

- 65 -

then under the reduction conditions used either a compound of the formula (XIV) in which R is group

OH
R -C ""'

is, wherein R has the meaning given above, and the carbon atom which carries the hydroxyl group in is in the R configuration, or a compound of the formula (XIV) in which R is the group

OH

' H

. means, in which R has the meaning given above, and the carbon atom bearing the hydroxyl group is in the S configuration.

Starting from an optically active compound of formula (XIV) thus obtained and then adding the following Reaction sequences as described above can be carried out using the appropriate optically active intermediates of the formulas (VI) and (VII) optically active penem compounds of the formula (I) obtained, wherein R is either a group of the formula

OH

R.

x ι H

wherein R has the meaning given above and the carbon which carries the hydroxyl group in the R configuration is obtained, or a group of the formula

OH

R -C ""
^x A
H

means in which R has the meaning given above and the carbon atom bearing the hydroxyl group is in the S configuration.

In particular, 8 (R), 6 (S) -hydroxyethyl-5 (R) -penem compounds can be used of the formula (I) obtained, that is to say compounds which have not yet been described as individual diastereoisomers.

The new key chiral intermediate of the formula (XIII) can be obtained according to the invention by either of 6-aminopenicillanic acid (6-APA) or starts from penicillin or through a total synthesis,

The chiral compound of formula (XIII) in which R, denotes methyl, can be obtained starting from 6-APA by the process described here, such as this is described in Scheme II below,

- 67 -

10 15

25 30

Scheme II

6-APA

CH,

} N

CH,

(XVI)

■ J

COOH CH.

d *

0
c)

CON.

CH,

NHCOOR

(XVIII)

CH.

CH

_(χΐχ)

d)

CH.

(f ^NH

(XX)

e)

- 68 -

The procedure in Scheme II is as follows:

(A) Conversion of penicillanic acid (XVI), which can be obtained in a simple manner from 6-aminopenicillanic acid or Penicillins can be obtained in known ways into the corresponding azide (XVII);

(b) Conversion of the azide (XVII) in the presence of an alcohol R ₄ OH to give the urethane (XVIII), in which R _{4 is} an easily cleavable carboxy protective group, for example by reduction or solvolysis, or, alternatively, conversion of the azide (XIV) into Presence of an inert solvent to give the corresponding isocyanate intermediate;

(c) Decarboxylation of the urethane (XVIII) to give the aldehyde (XIX), the decarboxylation is carried out either under reducing or hydrolytic conditions, or alternatively, aqueous acid hydrolysis of the isocyanate compound to give the aldehyde (XIX);

(d) Reduction of the aldehyde (XIX) to obtain the azetidinyl carbinol (XX) with the assistance of a Reducing agent;

(e) Conversion of the azetidinyl carbinol (XX) into the bicyclo compound (XIII), in which R-, CH ₃ is, by the formation of the corresponding acetonide.

The sequence (a), (b) and (c) is called Curtius degradation and is a well-known chemical method which

- 69 -

the conversion of an acid into an IC noramine

R-CH ₂ COOH

-> R-CH ₂ -NH ₂

made possible via the azide and isocyanate intermediate (T. Curtius, J. Chem. Soc. (A) 60, 56 (1891)).

The corresponding intermediate IC-noramine is not isolated because it is unstable and in the presence easily converted by water into the aldehyde (IX)

(XVII)

CH,

The reduction of the aldehyde (IX) to the carbinol (XX) is carried out in a known manner by the methods according to which an aldehyde is reduced in a primary alcohol, e.g. in aqueous solution in the presence of sodium borohydride.

Examples of carboxy protective group R in the compounds of the formula (XVIII) are, if desired, halogen-substituted lower alkyl groups, in particular Trichloroethyl, aralkyl groups, especially benzyl and p-nitrobenzyl, lower alkyl groups, especially

- 70 -

t-butyl and acetonyl.

The conversion of the azetidinyl carbinol of the formula (XX) into the bicyclic compound of the formula (XIII: R ₃ = CH ₃ ) can be carried out by acetonidation in a known manner, for example by reaction with 2,2-dimethoxypropane in the presence of boron trifluoride in an organic solvent , such as methylene chloride, chloroform, diethyl ether, at a temperature between -10 ⁰ C and room temperature.

The chiral compound of formula (XIII) in which R ^ Means hydrogen can be obtained by starting from 6-aminopenicillanic acid and following the reaction scheme III works.

- 71 -

Scheme III

6-AP A

I> CH. COOH

(XVt)

b)

CH,

COOR

N ₀ CHCOOR,

X ^CH 3

'S N

■ CH

³ (XXI A)

COOR _C

b ")

CH ₂ = C

/ ^0R 6

OR,

O ·

COOR.

d) I ^C00R 5

^{; H} 3 (XXIi a)

COOR,

(XXIII)

NH

j.

(XXIV)

'/ ~ NH

• I

(XIII: R ³ = H)

O η _c I o '

CH ₀

- 72 -

The procedure described in Reaction Scheme III is as follows:

(a ¹⁾ esterification of a compound of formula (XVI) to give the Penicillinats of formula (XXI), wherein R c represents a C ₁ _ _ß alkyl or benzyl;

(b ¹ ) coupling of the penicillanate obtained of the general formula (XXI) with a diazoacetate of the N ₂ CHCOORg type, in which Rg is a C ₁ -C -alkyl group, to obtain the seco-penicillinate (XXII);

(c ¹ ) isomerization of the seco-penicillinate (XXII) to give the azetidinone derivative (XXIIA); or alternatively

(a ") Oxidation / esterification of the compound of the formula (XVI) to give the penicillinate S-oxide of the formula (XXIA), in which R _{5 has} the meaning given above;

(b ") Condensation of the resulting penicillinate S-oxide of the general formula (XXIA) with a ketene dialkyl acetal of the type
25th

pTT fi

v-Ή <\ ~~ v-

where Rg has the meaning given above, with obtaining the azetidinone derivative (XXIIA);

(d ¹ ) oxidative removal of the 1-substituent in the compound of formula (XXIIA), obtained both by the sequence (a ') - ^ (b') -> (c ') and the sequence (a ") - ^ (b ");
5

(e ') Reduction of the ester group COORg in the obtained Compound of formula (XXIII) to give the azetidinyl carbinol (XXIV); and

(f) Conversion of the azetidinyl carbinol (XXIV) into the bicyclo compound (XIII: R ₃ = H) by formation of the corresponding acetonide.

The conversion of the penicillanic acid of the formula (XVI) into the corresponding penicillate of the formula (XXI) can be carried out by treating the compound (XVI) or a suitable derivative thereof with an alcohol of the formula R ₅ OH, in which R 1 - the previously Has given meaning, or a suitable reactive derivative thereof according to known Metho'den of organic chemistry.

The coupling between the compound of formula (XXI) with a diazoacetate of formula N ^ CHCOOR, - is carried out as described in the chemical literature for similar purposes (Tetrahedron Letters, 1972 , 4387).

The isomerization of the isolated olefinic bond in a compound of the formula (XII) to obtain the Compound (XXIIA) can be converted into one by the catalytic action of an inorganic or organic base

suitable solvents, e.g., chloroform. Methylene chloride, diethyl ether, in the cold or at room temperature carry out.

The conversion of the penicillanic acid of the formula (XVI) into the corresponding penicillanate S-oxide of the formula (XXIA) can be carried out according to the usual methods of organic chemistry, e.g. by oxidation of the formula (XVI) and subsequent esterification to obtain the formula (XXIA) or, alternatively, by esterification with subsequent oxidation.

The condensation reaction between the compound of formula (XXIA) with a ketene dialkyl acetal of formula

CH ₂ =

"OR,

can be carried out by known methods, as described for similar reactions (JCS Chem. Comm., 1972 , 601). The removal of the 1-substituent from the compound of the formula (XXIIA) to give the compound of the formula (XXIII) is carried out under oxidative conditions in a suitable solvent, for example methylene chloride, acetone and at reduced temperature, preferably in the range between -78 and about + 5 ⁰ C carried out.

The oxidative conditions are, for example, in the presence of

- 75 -

75 -

Ozone or KMnO ^ achieved in a basic medium.

The reduction of the ester group -COORg in the compound of the formula (XXIII) can be carried out by customary methods of organic chemistry, as are known for converting a carboxylic acid ester group into a primary alcohol, for example using hydrides, preferably LiAlH ,, or boranes, in a solvent such as diethyl ether, tetrahydrofuran, dioxane and the like, at a temperature between about -20 and +20 ⁰ C.

Protection of the azetidinyl carbinol (XXIV) to form the compound. (XIII), in which R., is hydrogen, can be carried out in a known manner, e.g. by reacting with 2,2-dimethoxypropane in an acidic medium and in an organic solvent, e.g. methylene chloride, chloroform, diethyl ether, at a temperature of about - 10 ⁰ C to room temperature.

As already mentioned, one can use the chiral key interconnection of the formula (XIII) not only starting from natural 6-aminopenicillanic acid or Penicillins obtained according to the methods shown in schemes II and III, but also by a chemical Overall synthesis according to the following scheme IV.

76 -

Scheme IV

• NH

J / NH CO (

R,

R3 +

COOH

(XXVI ^R )

I, ^ NH COOH

(XXVI ^S )

R- (XXVII)

^ - NH

(XXVIII)

0> <

^H 3 ^{C CH} 3 (XIII: alkyl)

= H or

- 77 -

The procedure described in Scheme IV is as follows:

(1) converting a 2-oxo-azetidine derivative of formula (XXV), wherein L is a nucleofugal leaving group, into a mixture of the enantiomers of formulas (XXVI ^R ) and (XXVI ^S );

(2) Cleavage of the racemic mixture obtained and esterification of the separated enantiomer (XXVI) to obtain the 4 (R) -ester derivative of the formula (XXVII);

(3) Reduction of the optically active ester of the formula (XXVII) or, alternatively, direct reduction of the

TD

optically active acid of the formula (XXVI) to give the optically active carbinol of the formula (XXVIII); and

(4) Conversion of the compound of the formula (XXVIII) obtained into the bicyclo compound of the formula (XIII: R ₃ = H or Cg-alkyl) via the formation of the corresponding acetonide.

A nucleofugal leaving group L in a compound of formula (XXV), for example, an acyloxy group, preferably a C. _ _g alkanoyloxy or benzoyloxy group, a halogen or a SuIfonylgruppe be.

The conversion of a compound of the formula (XXV) into a racematic mixture of the formulas (XXVI ^R ) and (XXVI) can be carried out by reaction with a di-salt, preferably sodium or potassium salt, of a thioglycolic acid derivative of the formula

3/3

HS -C - COOH

in which each of the Rg groups has the meaning given above. The reaction may in a suitable solvent, .vorzugsweise water, tetrahydrofuran, dimethylformamide, acetone, ethanol, Aceto ^ nitril or a mixture thereof, a-approaching carried out at a temperature between about -20 ⁰ C to about +20 ⁰ C leads * will.

The separation of the thus obtained Razematgemisdhes into the enantiomeric acids (XXVI) and (XXVI) is carried out in a customary manner, for example by reaction with an optically active base, for example ephedrine, brucine, cinchonine _f menthylamine, 1-phenylethylamine and the like, to obtain a Mixture of diastereoisomeric salts. After the diastereoisomeric salts have been separated by known processes, for example by fractional crystallization, the individual enantiomer of the formula (XXVI) is then obtained by acidifying the corresponding salt.

R The esterification of the free acid (XXVI) by means of an alcohol of the formula RgOH, in which R _{g has} the meaning given above, takes place in the customary manner and leads to an ester of the formula (XXVII).

The reduction of the free acid of the formula (XXVI) or its ester of the formula (XXVII) to obtain a Carbinols of the formula (XXVIII) can in the usual way,

- 79 -

as are known for reducing a carboxylic acid ester to a primary alcohol, for example by reaction with a borane or a mixed anhydride, LiAlH ₄ or NaBH., for example in an anhydrous inert solvent such as diethyl ether or tetrahydrofuran.

The conversion of the optically active carbinol of the formula (XXVIII) into an optically active bicyclo compound (XIII: R ₃ = H or C ^ g -alkyl) can be carried out by acetonidating the amidic and alcoholic groups according to known methods, e.g. by treating with 2, 2-dimethoxypropane in an acidic medium and in a solvent such as methylene chloride, chloroform, diethyl ether, at a temperature between about -10 and +20 ⁰ C.

The aforementioned optical separation of the racemate mixture of the enantiomers (XXVI ^R ) and (XXVI ^S ) enables both the individual diastereoisomeric salt of the acid (XXVI) and the diastereoisomeric salt of the acid (XXVI) to be obtained separately. The latter salt can be reused by converting it into an enantiomeric mixture of the acids (XXVI ^R ) and (XXVI ^S ), from which a further amount of the otpically active ester of the. Formula XXVII) can win.

The conversion of the diastereoisomeric salts of the acid (XXVI) into the enantiomeric mixture of the compounds (XXVI ^R ) and (XXVI ^s ) can be carried out by the following sequence of steps:

(a) Liberation of the free acid of formula (XXVI ^s ) from the di
in the usual way;

c
(XXVI) from the dxastereoxsomeric salt by acidification

(b) esterifying the free acid of formula (XXVI ^S) with an alcohol of formula RgOH wherein R _g as defined above has;

(c) Oxidizing the ester obtained in this way with a suitable organic or inorganic oxidizing agent, e.g. with m-chloroperbenzoic acid or KMnO. in a known manner to obtain the corresponding sulfone of formula (XXIX)

(XXIX)

COOR,

wherein each of the R ₃ groups and the group Rg have the meanings given above;

(d) Reacting the sulfone (XXIX) with a di-salt of a thioglycolic acid derivative of the formula 25th

R ₃ R ₃
HS -C- COOH

in the same manner as described with reference to the analogous reaction in Scheme IV.

- 81 -

The synthesis of the optically active key intermediates of formula (XIII) by the reaction scheme described in IV enables a further increase in the productivity of the overall process of the invention due to the possibility of the enantiomer with the 4 (S) being obtained at an early stage of the synthesis -Configuration, namely the compound of the formula (XXVI ^s ), can return.

The second object of the invention relates to new optically active trans-6 (S) -substituted 5 (R) -2-penem-3-carboxylic acid derivatives of the following classes:

(a) Compounds of the formula (I) in which R and R _{1 are,} independently of one another, C 1-6 alkyl and R _{2 are} hydrogen, C 1-6 alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation;

(b) compounds of formula (I) wherein R is an alkyl Cj_g, R. is a C ₁ _ _ß alkanoyloxymethyl and R ₂ is hydrogen, C, g-Alkanoylmethyl, an optionally nitrosubstxtuierte benzyl group or a pharmaceutically or veterinarily acceptable cation;

(c) Compounds of the formula (I) in which R ^{c is} -i_g-alkyl, R _{1 is} C ₁ , alkoxycarbonyl and R 1 is hydrogen, C, g-alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation; and

- 82 -

(d) Compounds of the formula (I) / in which R is C.,, -alkyl, R _{1 is} a thienylmethyl group and R "is hydrogen, C .., -alkyl, a desired nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation thereof.

Preferred compounds of the above class (a) are those in which R and R ₁ independently of one another denote methyl, ethyl or propyl, in particular the following compounds:

Methyl (6S) -6-ethyl- (5R) -2-methyl-2 ~ penem ~ 3-carboxylate,
Methyl (6S) -6-ethyl (5R) -2-ethyl ~ 2-penem-3-carboxylate,

Methyl (6S) -6-ethyl- (5R) ^ -propyl - ^ - penem-S-carboxylate,

Methyl (6S) -6-methyl- (5R) ^ -methyl ^ -penem-carboxylate,

- 83 -

Methyl (6S) -6-methyl- (5R) - ^ - carboxylate, methyl (6S) -6-methyl (5R) - ^ - carboxylate, methyl (6S) -6-propyl- (5R) ^ - carboxylate, methyl (6S) -6-propyl- (5R) ^ - carboxylate, methyl (6S) -6-propyl- (5R) ^ - 0 carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) ^ -methyl ^ -penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-ethyl-2-penem-3-carboxylate, 5 p-nitrobenzyl (6S) -6-ethyl (5R) ^ -propyl ^ -penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-methyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl (5R) -2-ethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-propyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) ^ -methyl ^ -penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-ethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-propyl-2-penem-3-carboxylate, (6S) -6-ethyl- (5R) -2-methyl-2-penem-3-carboxylic acid, (6S) -6-ethyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-ethyl- (5R) -2-propyl-2-penem-3-carboxylic acid,

- 84 -

- 84 -

(6S) -6-methyl- (5R) ^ -methyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -ethyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -propyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) -2-methyl-2-peneIn-3-carboxylic acid, (6S) -6-propyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-propyl-2-penem-3-carboxylic acid

and pharmaceutically or veterinarily acceptable salts of the free acid.

Preferred compounds of class (b) are those in which R is methyl, ethyl or propyl and R _{1 is} acetoxymethyl or propionyloxymethyl, in particular the following compounds:

p-Nitrobenzyl (6S) -6-ethyl- (5R) ^ -acetoxy-methyl ^ - penem-3-carboxylate,

p-Nitrobenzyl (6S) -6-methyl- (5R) -2-acetoxy-methyl ~ 2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-propyl- (5R) -2-acetoxy-methyl-2-penem-3-carboxylate,

- 85 -

p-nitrobenzyl (6S) -6-methyl- (5R) -2-propionyloxymethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-propionyloxymethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl (5R) -2-propionyloxymethyl-2-penem-3-carboxylate, Acetonyl (6S) -6-ethyl- (5R) ^ - acetoxy-methyl ^ -penem-3-carboxylate,

Acetonyl (6S) -6-methyl- (5R) ^ -acetoxy-methyl ^ - penem-3-carboxylate,

Acetonyl (6S) -6-propyl- (5R) -2-acetoxy-methyl-2-penem-3-carboxylate,

Acetonyl (6S) -6-methyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylate ,
5 acetonyl (6S) -6-ethyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylate,

Acetonyl (6S) -6-propyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylate,

(6S) -6-ethyl- (5R) -2-acetoxy-methyl-2-penem ~ 3-carboxylic acid,

(6S) -6-methyl- (5R) ^ -acetoxy-methyl ^ -penem-S-carboxylic acid /

(6S) -6-propyl- (5R) -2-acetoxy-methyl-2-penem-3-carboxylic acid,
(6S) -6-methyl- (5R) ^ -propionyloxy-methyl ^ -penem-3-carboxylic acid,

(6S) -6-ethyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylic acid,

(6S) -6-propyl- (5R) ^ -propionyloxy-methyl ^ -penem-3-carboxylic acid,

Methyl (6S) -6-ethyl- (5R) ^ -acetoxy-methyl ^ -penem-3-carboxylate,

- 86 -

- 86 -

Methyl (6S) -6-methyl- (5R) ^ - acetoxy-methyl ^ -penem-3-carboxylate,

Methyl (6S) -6-propyl- (5R) • ^ -acetoxy-methyl ^ -penem-3-carboxylate,

Methyl (6S) -6-methyl- (5R) ^ rpropionyloxy-methyl ^ - penem-3-carboxylate,

Methyl (6S) -6-ethyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate,

Methyl (6S) -6-propyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate

and pharmaceutically or veterinarily acceptable salts of the free acids.

Preferred compounds of class (c) are those in which R is methyl, ethyl or propyl and R is methoxy • mean carbonyl, ethoxycarbonyl or propoxycarbonyl. In particular, such connections are:

p-nitrobenzyl (6S) -6-ethyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-methyl- (5R) -2-ethoxycarbonyl-

2-penem-3-carboxylate,
25th

-

p-nitrobenzyl (6S) -6-propyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, (6S) -6-ethyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylic acid, (6S) -6-methyl- (5R) ^ -ethoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) ^ - ethoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -methoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-Ethyl- (5R) ^ - methoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) - ^ - methoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -propoxycarbonyl ^ -penem-3-carboxylic acid, (6S) -6-ethyl- (5R) ^ -propoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylic acid,

- .88-

Methyl (6S) -6-ethyl- (5R) ^ -ethoxycarbonyl ^ - penem-3-carboxylate, methyl (6S) -6-methyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, Methyl (6S) -6-propyl- (5R) ^ -ethoxycarbonyl ^ - penem-3-carboxylate, methyl (6S) -6-methyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, Methyl (6S) -6-ethyl- (5R) ^ -methoxycarbonyl ^ -penem-3-carboxylate, Methyl (6S) -6-propyl- (5R) ^ -methoxycarbonyl ^ - penem-3-carboxylate, Methyl (6S) -6-methyl- (5R) ^ - propoxycarbonyl ^ -

penem-3-carboxylate, 15. methyl (6S) -6-ethyl- (5R) ^ -propoxycarbonyl ^ - penem-3-carboxylate, methyl (6S) -6-propyl- (5R) ^ -propoxycarbonyl ^ - penem-3-carboxylate

and pharmaceutically or veterinarily acceptable salts of the free acid.

Preferred compounds of class (d) are those in which R is methyl, ethyl or propyl and R _{1 is} 2-thienylmethyl. Such connections are in particular:

- 89 -

p-nitrobenzyl (6S) -6-ethyl- (5R) -2-thien-2'-ylmethyl-2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-methyl- (5R) -2-thien-2'-ylmethyl-2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-propyl- (5R) -2-thien-2'-ylmethyl-2-penem-3-carboxylate,

(6S) -6-ethyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylic acid,

(6S) -6-methyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylic acid,

(6S) -6 ~ propyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylic acid,

Methyl (6S) -6-ethyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate,
'Methyl (6S) -6-methyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate,

• Methyl (6S) -6-propyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate

and pharmaceutically or veterinarily acceptable salts of the free acid.

All of the above-mentioned compounds can be prepared by the process which is the main object of the present invention. The aforementioned new optically active trans-6 (S) -substituted-5 (R) -2-penem-3-carboxylic acid derivatives according to the invention have a high antibacterial activity in animals and humans against Gram-positive and Gram-negative bacteria such as staphylococci , Streptococci, Diplococci, Klebsiella , Escherichia coli, Proteus mirabilis, Salmonella,

- 90 -

Shigella , Haemophilus, and Neisseria . The compounds according to the invention also show a high activity against strong ß-lactamase-producing microorganisms, such as, for example, Klebsieila aerogenes 1082 E, Escherichia coli Tem , Enterobacter cloaca e P99 and indole-positive Proteus and the like, and also against Pseudomonas aeruginosa strains.

Due to their high antibacterial activity in animals or in humans against gram-positive and Gram-negative bacteria are the compounds according to the invention for the treatment of microorganisms caused by such caused infections effective, e.g. with infections of the respiratory tract, e.g. bronchitis, bronchopneumonia, Pleurisy, hepatobiliarie and intestinal infections, e.g. septicemia, urinary tract infections, e.g. pyelonephritis, Cystitis, in obstetric and gynecological infections, e.g. cervicitis, endometritis, for ear, nose and throat infections, e.g. otitis, Sinusitis and parotitis.

The toxicity of the compounds according to the invention is negligible and they can therefore be safely used in therapy.

The compounds of the invention can be administered to humans or animals in a variety of dosage forms e.g. orally in the form of tablets, capsules, drops or syrups, rectally in the form of Suppositories, parenteral, e.g. intravenous or intramuscular (as a solution or suspension), with intravenous

- 91 -

Emergency administrations are preferred; by inhalation in the form of aerosols or sprayable solutions, intravaginally in the form of vaginal tablets, or topically in the form of solutions, creams and ointments. The pharmaceutical or veterinärischen compositions containing the compounds of the invention may be used in a conventional manner using conventional carriers or diluents, as are used for other cephalosporins, are prepared.

Typical carriers or diluents are, for example Water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, cellulose and the like. The daily dosages range from about 1 to about 100 mg / kg of body weight, depending on the different patients, the exact doses depending on the age, weight and condition of the person being treated Depending on the subject and the frequency as well as the route of administration. Those according to the invention are preferred Compounds administered parenterally. In this case, the compounds can be, for example, adults in amounts from about 100 to about 200 mg per dose, preferably about 150 mg per dose one to four times daily, dissolved in a suitable solvent, e.g. in sterile water, or in lidocaine hydrochloride solutions for intramuscular injections and sterile water, physiological saline solution, dextrose solutions or conventional intravenous fluids or electrolytes for intravenous injections. Furthermore, the compounds according to the invention can

- 92 -

as antibacterial agents for prophylactic applications can be used, e.g. for cleaning or for surface disinfection, e.g. in concentrations of about 0.2 to 1% by weight of the compounds, mixed or dissolved or suspended in a customary dry or aqueous carrier, such agents then being carried out Apply washing or spraying.

The compounds according to the invention are also also approved as additives to animal feed (taking into account relevant official requirements are).

The determination of the melting points has been very difficult in that the compounds tend to be the solvent to hold on. In these cases, after • the specification of the melting point, the word "decomposition" attached. The abbreviations THF, AcOH and AcOEt were used to denote tetrahydrofuran, acetic acid and To designate ethyl acetate. The following examples describe the invention without restricting it.

25 Example 1

2_, 2-Dimethyl-3-carbonYlazide ~ (5R) -penam

COOH

-N-i

93 -

In anhydrous THF (, 6.04 g 30 mmol) to a cooled to -15 ⁰ C solution of penicillanic acid (40 ml) was added a solution of Et ₃ N (3.04 g, 4.18 ml, 30 mmol) in THF (5 ml) added with stirring over 15 minutes. After stirring an additional 15 minutes, a solution of ethyl chloroformate (3.26 g, 2.86 ml, 30 mmol) in THF (5 ml) was added dropwise. The reaction mixture was stirred for 90 minutes at -15 to -10 ⁰ C and then a solution of NaN, was added dropwise (6 g, 92 mmol) over 3 0 minutes in 20 ml of H ₂ =. The mixture was then kept at -5 to = ° C for 45 minutes and then mixed with 150 ml of cold water and extracted with 4 × 100 ml of benzene. The combined extracts were washed twice with 100 ml of water each time and once with 100 ml of a saturated aqueous NaCl solution and dried _{over Na 3} SO _4. Evaporation of the solvent gave an oily residue.

IR (CHCl3,., Cm " ¹ ): 2150, 1780, 1710

Example 2 25

urethane

■ NHCOOCH CCl,

- 94 -

Freshly distilled trichloroethanol (4.5 g, 30 mmol) is added to a solution of the azide (Example 1) in 100 ml of anhydrous benzene. The mixture is heated for 3 to 5 hours at 70 to 75 ^° C. and then cooled and evaporated in vacuo, and the residue

is chromatographed over 100 g of silica gel using CgHg-AcOEt as the eluent 95: 5. A yellow solid is obtained which crystallizes from benzene (4.4 g, 42%).
10

F: 162-164 ° C

DSC: 98% molar purity

Elemental analysis calculated for C ₁₀ H ₁₃ Cl ₃ N ₂ O ₃ S:

H 3.73 (3.77) S 9.07 (9.22)

²⁰ L ^ Jo ^{= +111} · ⁴

C 34 , 74 , 1 (34 .65) N 8 , 03 (8th, 05) 0.30 , 50 (30 .60) 8, CHCl 3> 1780 740

IR (CHCl ₃ , cm " ¹ ):

NMR (CDCl ₃ , 6): 1.61 (3H, s)

'1.57 (3H, s)

3.14 (1H, dd, J = 2.5, 18 Hz)

3.58 (1H, dd, J = 5.18 Hz)

4.75 (2H, m)

5.12 (1H, dd, J = 2.5, 5Hz)

5.45 (1H, br)

5.64 (1H, d J = 9 Hz)

95 -

Example 3

NHCOOCH CCl

(G 4.15, 11.9 mmol) to a stirred suspension of Trichlorourethan in 90% AcOH (100 ml) was added 25 g Zn powder in small portions was added during 30 minutes at a temperature of 5 ⁰ C. The mixture is stirred for a further 16 to 20 hours at room temperature. The solid is then filtered off using a filter aid and washed with benzene. The combined filtrates and washing liquids were washed with a saturated aqueous NaCl solution (4 × 50 ml) and then washed over Na ₂ SO. dried.

Evaporation of the solvent gave a yellow solid which was chromatographed on silica gel. When eluting with C, E ₁ . -AcOEt 95: 5 is obtained

6 6

the title compound as white crystals (1.97 g, 90.7%)

Q:

6 / _D : +200.4

" ¹

IR (CHCl ₃ , cm " ¹ ):

NMR (CDCl ₃ , <£) :

58-60 ⁰ CI, CHCl ₃ ) 3350, 1768

1.49 (3H, s) 1.53 (3H, s)

- 96 -

3.02 (1H, ad, J = 2.5, 18 Hz)

3.43 (1H, dd, J = 5.18 Hz)

4.00 (1H, br)

5.16 (1H, dd, J = 2.6, 6 Hz)

5.29 (1H, br)

Example 4

CON,

OH

2,2, -Dimethyl-3-carbonylazido- (5R) -penam, prepared from 26.2 g (130 mmol) of penicillanic acid, as described in Example 1, is converted into the corresponding isocyanate, either by converting it to CVH ₁ - (200 ml) heated for 4 hours at 70 to 75 ^° C. or by treating it in vacuo for 48 hours. The crude isocyanate / IR (EtOH-free CH ₂ Cl ₂ ): 2245, 1785 cm −7 thus obtained is dissolved in dioxane (100 ml) and added to a stirred mixture of 3,000 ml of H ₃ O and 2N HCl (130 ml) for 4 Hours given. After the addition is complete, the reaction mixture is stirred for a further hour and then extracted 4 times with 500 ml of methylene chloride each time. The combined organic extracts were with a

- 97 -

- 97 -

aqueous saturated NaCl solution, _{dried over Na 3} SO ₄ and evaporated to dryness in vacuo.

The residue so obtained was dissolved in benzene (100 ml) taken up and stirred with 10 ml of AcOEt for 1 hour and then filtered. The filtrate was eluted through a silica gel column (50 g). When further eluting with CgHg-AcOEt 90:10 one receives the title compound (5.1 g, 22.6%).

Example 5

20 0

OH

NH

A solution of NaBH was added to an ice bath-cooled solution of 2,2-dimethyl-3-hydroxy- (5R) -penam (1.87 g, 10.8 mmol) in THF (25 ml). (44 0 mg, 22 mmol) in H ₃ O (4 ml) over the course of 15 minutes with stirring. 1.5 ml of cold 50% AcOH were added to the reaction mixture and then evaporated in vacuo to give a residue which was taken up in 100 ml of CH ₂ Cl ₃ and then washed with a saturated aqueous NaCl solution and dried over Na ₃ SO ₄ dried

- 98 -

became. After evaporation in vacuo, a yellow oil was obtained. Purification by filtering through a short silica gel column gives the title compound as a clear oil (1.81 g, 95.7%).

/ 5y? _D = + 184.0 ° (C = I, CHCl ₃ ) IR (CHCl ₃ , cm " ¹ ): 330, 1750

NMR

(CDCl ₃ , S)

1.26 (3H, s)

1.38 (3H, s)

2.81 (1H, ddd, J = 1.5, 2.5, 18 Hz)

3.4 2 (1H, ddd, J = 1.5, 5, 18 Hz)

3.56 (2H, s)

3.90 (1H, br)

5.00 (1H, dd, J = 2.5, 5 Hz)

7.58 (1H, br)

Example 6

To a cooled to -1O ⁰ C solution of (4R) -4- (ß, ß-dimethyl-3-hydroxyethylthio) azetidin-2-one (1.81 g,

- 99 -

10.3 mmol) and 2,2-dimethoxypropane (3.8 ml, 3.2 g,
31 mmol) in 20 ml of CH ₂ Cl ₂ were added 0.25 ml of boron trifluoride etherate. The reaction mixture turned 30
Stirred minutes at -10 ⁰ C and a further 2 hours at ambient temperature. 100 ml of CH ₂ Cl- were then added and then washed with a saturated aqueous NaCl solution and _{dried over Na 2} SO. Obtained after evaporation of the solvent in vacuo
a residue which crystallized from hexane in the form of a white pesticide (1.40 g, 53%).

F: DSC:

77-79 ° C

99% molar purity

Elemental analysis calculated for

C 55.68 (55.78) N 6.48 (6.51)

H 7.99 (7.96) S 14.80 (14.89)

_D = + 137.62 ° (C = 1, CHCl ₃ )
IR (CHCl ₃ , cm " ¹ ): 1740

NMR (CDCl ₃ ,

1.20 (3H, S)

1.46 (3H, S)

1.55 (3H, S)

1.71 (3H, S)

2.65 (1H, dd, J = 2.5, 15 Hz)

3.18 (1H, dd, J = 5.15 Hz)

3.60 (1H, d, J = 12 Hz)

4.14 (1H, d, J = 12 Hz)

5.06 (1H, dd, J = 2.5, 5 Hz)

- 100 -

Example 7

-2-oxoazetidine-j ^ R) _- 4-y_lthio7-aceta; t

cf.

• N

COOMe

COOMe

To a stirred mixture of methyl penicillanate (5.35 g, 15 mmol) and Cu (acac). ** (1 g) in anhydrous benzene (100 ml), a solution of ethyl diazoacetate (3g, 26 mmol) in 10 1 of benzene was added dropwise at 8O ⁰ C. The reaction mixture is stirred for an additional hour, then cooled and filtered. The filtrate is applied to the top of a silica gel column. Eluting with toluene-AcöEt 98: 2 gives unreacted methylpenicillanate (2.56 g, 48%) and then the title compound as an oily product

(1.9 g).

NMR (CDCl ₃ , S )

1.29 (3H, t, J = 7 Hz)

1.92 (3H, br s)

3.07 (1H, dd, J = 2.5, 16 Hz)

3.39 (2H, s)

3.49 (1H, dd, J = 5.16 Hz)

3.80 (3H, s)

4.21 (2H, 9, J = 7 Hz)

** (cupriacetylacetonate)

- 101 -

4.80 (1H, s)

5.02 (1H, br s)

5.15 (1H, br s)

5.19 (1H, dd, J = 2.5, 5 Hz)

Example 8
10

-COOEt 15

COOMe

A solution of ethyl O ^ / 1 ~ (1'öO-methoxycarbonyl-2'-methylprop-2'enyl) -2-oxoazetidin- (4R) -4-ylthio7 ~ acetate (1.9 g) in 40 ml of methylene chloride is treated with 2 drops of triethylamine. After getting the solution over Has left to stand overnight, the solvent is evaporated in vacuo, the title compound in quantitative yield is obtained.

NMR (CDCl ₃ , (J): 1.28 (3H, t, J = 7Hz)

2.03 (3H, s)

2.27 (3H, s)

3.02 (1H, dd, J = 2.5, 16 Hz)

3.30 (2H, s)

102 -

Example 9

102 -

3.44 (1H, dd, J = 5.16 Hz)

3.81 (3H, s)

4.20 (2H, 9, J = 7 Hz)

5.29 (1H, dd, J = 2.5, 5 Hz)

COOMe

COOEt

COOMe

A solution of Methylpenicillanat-S-oxide (2.31 g, 10 mmol) in 80 ml of dioxane is heated in the presence of a 2-molar excess of 1,1-Diethoxyethen under N2 for 24 hours at 8O ⁰ C. The cooled reaction mixture is evaporated in vacuo and the residue is chromatographed over silica gel. Eluting with toluene-AcOEt 98: 2 gives the title compound (2 g, 6.6 mmol, 66%).

- 103 -

Example 10

- 103 -

COOEt

'COOEt

"NH

COOMe

Ethyl oO - / T- (1'-methoxycarbonyl-2'-methyIprop-1'-enyl) -2-oxoazetidin- (4R) -4-ylthio / acetate (1.5 g, 5 mmoles), dissolved in 150 ml of methylene chloride is cooled to -78 ⁰ C and treated with 5.2 mmol O_. Dimethyl sulfide is then added and the mixture is stirred until it reaches room temperature. The solvent is evaporated off in vacuo and the residue is taken up in methanol and stirred overnight at room temperature. The solvent is evaporated off in vacuo and the residue is taken up in methylene chloride, washed with water and dried over Na 2 SO 4 and evaporated in vacuo to give the title compound.

_D = ⁺⁹⁰ ° (C = 1.19, CHCl ₃ )
IR (CHCl ₃ , cm " ¹ ): 3330, 1770, 1730

NMR (CDCl ₃ , 6)

1.33 (3H, t, J = 7 Hz)

2.96 (1H, ddd, J = 15.5, 2.5, 1.3 Hz)

3.4o (2H, s)

3.45 (1H, ddd, J = 15.5, 5.0, 1.7 Hz)

4.92 (1H, dd, J = 2.5, 5.0 Hz)

7.05 (1H, br)

- 104 -

Example 11

(4R) -4- (β-HydroxYethYlthio) _- azetidin-2-one

jm cooEt

A suspension of LiAlH is added to a stirred solution of ethyl oC - / 2-oxo- (4R) -4-azetidinylthio7-acetate (11.7 g, 0.062 mol) in anhydrous EtpO (250 ml). (1.77 g, 0.0466 mol) in 30 ml Et ₂ O at -20 ⁰ C under nitrogen atmosphere. The reaction mixture is stirred for 2 hours at -20 ⁰ C to 0 ⁰ C, then cooled again to -20 ⁰ C and then a suspension of LiAlH. (1.77 g, 0.0466 mol) in 30 ml Et ₃ O was added and the mixture was left to stand at room temperature overnight. Customary work-up and subsequent extraction with AcOEt gives 7.13 g of the crystalline title compound in 80% yield.

Q:

47-49 ⁰ C

/ 5 ^ 7 _D = + 139 ° (C = 0.1, CHCl ₃ )
IR (CHCl ₃ , cm " ¹ ): 3300, 1760

NMR (CDCl ₃ , £)

2.60 (1H, s) 2.70-3.30 (2H, m) 3.25-3.5 (2H, m) 3.7-3.9 (2H, m) 4.81 (1H, dd, J ₁ = 2.5 Hz, J ₂ = 5 Hz)

7.32 (1H, s)

- 105 -

Example 12

2i2-dimethyl _- (7R) _{_; ::} 9-oxo 3-oxa-6-thia 2iazabicYclo _{= =} _ /5.2.0 ¹ⁱ⁷ 7nonan

NH N) H

A solution of (4R) -4- (ß-hydroxyethylthio) -azetidin-2-one (7.3 g, 0.0469 mol) and 2,2-dimethoxypropane (13.1 g, 0.0125 mol) in dry ethanol-free CH ₂ Cl ₂ is cooled to -10 ⁰ C and decomposed dropwise with stirring with BF-J-Et ₂ O (1 ml). After stirring for a further 30 minutes, the reaction mixture is _{diluted with 70 ml of CH 2} Cl ₂ , washed with 180 ml of a cold, saturated, aqueous NaHCO ^ solution and dried over Na ₂ SO. dried.

Evaporation of the solvent in vacuo gives a residue which, after crystallization from Et ₂ On-hexane at 0 ^° C., gives the title compound (6.7 g, 71%).

F: / ρθ7 _Ό = 107 ° (C = 1,

IR (CHCl ₃ , cm " ¹ ):

NMR (CDCl-., 5) :

93-94 ° C

1750

1.50 (3H, s)

1.73 (3H, s)

2.70 (1H, dd, J = 2.15 Hz)

- 106

2.71 (1H, dt, J = 3, 14 Hz)

3.05 (1H, dt, J = 5.5, 14 Hz)

3.20 (1H, dd, J = 5.15 Hz)

4.16 (2H, dd, J = 3, 5.5 Hz)

5.03 (1H, dd, J = 2.5 Hz)

Example 13 10

DAc

0OH

To a stirred aqueous 2N NaOH solution, which was cooled to ⁰ -4 C, a 70% aqueous solution of thioglycolic acid (50 ml, 0.47 mol), diluted in 99% EtOH (400 ml) was added dropwise. After stirring for a further 5 minutes, 4-acetoxy-azetidinone was obtained
(K. Clauss et al., Liebig. Ann. Former., 1974 , 539)

(55 g, 0.426 mol) dissolved in 99% EtOH (100 ml) dropwise admitted.

The mixture is stirred for 30 minutes at 0 ^° C. and for a further hour at room temperature. After cooling to -5 ⁰ C, the solution is treated dropwise with a 2N aqueous HCl solution (490 ml) is decomposed. The suspension obtained

- 107 -

is stirred in the cold for 1.5 hours, the precipitate is filtered off and washed with water.

The combined mother liquors and washing liquids are evaporated to dryness in vacuo and the residue obtained is treated _{with 160 ml of H 3 O.} The suspension is filtered off and washed with a little HO. The combined precipitates are ^{dried in vacuo at 45 °} C. overnight. The title compound is obtained in 85% yield (58/5 g).

Q:

-1

IR (KBr, cm ')

NMR (CDCl ,, 6)

Example 14

130 ⁰ C (decomposition) 3450, 3300, 1745, 1710

2.89 (1H, dd, J = 2.5, 16 Hz)

3.38 (2H + 1H, s + m)

4.92 (1H, q, J = 2.5, 5 Hz)

7.88 (1H, br, exchange with D ₃ O)

9.66 (1H, br, exchange with D "O)

To a solution of 00- / 2-OxO- (4R, S) -4-azetidinylthio? Acetic acid (40 g, 0.248 mol) in 99% EtOH is added D (+) - ephidrine (45 g, 0.272 mol) 70 ⁰ C added. The hot solution is allowed to cool and overnight

- 108 -

- 108 -

ditched. The crystalline precipitate formed is filtered off, washed with a little 9 9% EtOH and dried at 40 ⁰ C in vacuo overnight to give (32.1 g) afforded the title salt.

Q: 160-162 ⁰ C

- + 109.58 ° (C = 0.1, EtOH 99%)

Example 15

A solution of 0 ^ - / 2-OxO- (4R) -4-acetldinylthio / -acetic acid-D (+) - ephedrine salt (32.1 g) in distilled water was stirred with Amberlite® IR-20 for 1 hour.

The polymeric resin is filtered off with a filter aid and washed with distilled water.

The combined filtrate and washings were evaporated in vacuo at 40 ⁰ C to give a residue which sodium from hot 99% E tOH crystallized and 13 g of the title compound.

^ ^{= +} 128 ° (C = O.10, EtOH 99%) F: 87-89 ° C

- 109 -

Example 16

MethYl_c ^ - / 2-oxoazetidine -_ (4R) _- 4-ylthio7iacetate

NH

COOH

<f

'NH

COOMe '

A suspension of oO- / 2-oxoazetidin- (4R) -4-ylthio7-acetic acid (10 g, 0.062 mol) in 200 ml of absolute MeOH was overnight in the presence of Amberlite IR-120 touched. The polymeric resin was filtered off and washed with MeOH. The combined filtrates and washing liquids were evaporated in water to give 10.8 g of the methyl ester (100%).

/ pü7 _D = + 110 ° (C = O, 1/1, CHCl ₃ )

= + 127 ° (C = 0.11, EtOH)

IR (CHCl ₃ , cm " ¹ ): 3330, 1770, 1730

NMR (CDCl ₃ , 6 "):

2.96 (1H, ddd, J = 2.0, 2.5, 15 Hz)

3.41 (1H, ddd, J = 1.5, 5.0, 15 Hz)

3.42 (2H, s) 3.79 (3H, s)

4.94 (1H, dd, J = 2.5, 5.0 Hz)

7.36 (1H, br)

- 110 -

- 110 -

Example 17

COOMe

Methyl o ^ - / 2-oxoazetidin- (4R) -4-ylthio7 ~ acetate is reduced to the title compound as in Example 11.

F: 47-49 ° C

/ ° ϋ_7 _Ό = + 130 ° (C = 1, CHCl ₃ ) 15

Example 18

2 ^ 2-DimethYl- (7R) - (8S) _- 8 ₌ ethYl-9-oxo-3-oxa-6 _:: thia-2z azabicYclo / 5 _i 2 _i 0 _ "_ / nonane

To a stirred solution of di-isopropylamine (40 ml, 0.276 mol) in anhydrous tetrahydrofuran (400 ml) a 15% n ~ BuLi solution in n-hexane (130 ml, 0.206 mol)

- 111 -

- 111 -

added dropwise at -70 ⁰ C under N ".

After stirring for a further 15 minutes at 70 ^° C., a solution of 2,2-dimethyl- (7R) -9-oxo-3-oxa-ö-thia-i-azabicyclo / S ^ .O * _7nonane (24, 3 g, 0.130 mol) in tetrahydrofuran (150 ml) was added. The yellowish solution is stirred 15 minutes at -70 ⁰ C, and then an excess of ethyl bromide is added dropwise. The reaction mixture is allowed to reach room temperature and then poured into ice water, where it is extracted _{thoroughly with CHpCl 2.} The combined extracts are over Na ₂ SO. dried and evaporated in vacuo, giving a residue which, from Et ₂ On-hexane at ⁰ ° C., gives the title compound in 83% yield.

-1,

IR (CHCl ₃ , cm '): NMR (CDCl ₃ ,):

1760

1.05 (3H, t, 3 = 1 Hz) 1.51 (3H, s) 1.75 (3H, s) 1.89 (2H, m) 2.6-2.8 (2H, m) 2.9 -3.5 (2H, m) 3.82 (1H, m) 5.05 (1H, dd, J = 2.5 Hz)

- 112 -

112

Example 19

2 _i 2 ₌ DimethYl ₌ _ {7R) _ ₌ j (8S) _ ₌ 8 _;; ethYl ₌ 9-oxo _:: 3-oxa _:: 6 ₌ thia ₌ 2: azabicYclo / 5_ ₁ 2_ ₁ 0_ "Z

To a stirred solution of 2,2-dimethyl- (7R) - (8S) -

- 1 7 - 8-ethyl-9-oxo-3-oxa-6-thia-1-azabicyclo / 5.2.0 * _ / nonane (12 g, 0.056 mol) in 80% Cl ₃ COOH (400 ml) becomes a solution from KMnO. (17.60 g, 0.112 mol) in H ₉ O (200 ml) was added dropwise at room temperature. After stirring for a further 2 hours, the excess KMnO is destroyed by adding H ₃ O ₀ and the precipitate is filtered off using a filter aid and the filtrate is extracted _{thoroughly with CH 2} Cl _2. The combined extracts are washed with HO, _{dried over CaCl 2} and evaporated in vacuo, the title compound being obtained in solid form (11.8 g).

IR (CHCl ₃ , cm " ¹ ): 1775, 1335, 115O ₇ 1090

- 113 -

Example 20

-

2-on

A solution of 2,2-dimethyl- (7R) - (8S) -8-ethyl-9-oxo-3-oxa-6-thia-1-azabicyclo / 5.2.0 * _7nonane-6,6-dioxide (11 , 8 g) in 200 ml of CH ₃ COOH and 40 ml of H ₃ O is heated under reflux temperature for 105 minutes. The resulting reaction mixture is cooled and evaporated in vacuo to give the title compound (10.1 g).

Example 21

2-on

A mixture of (3S) -3-ethyl- (4R) -4- (ß-hydroxyethylsulfonyl) -azetidin-2-one (20.7 g, 0.1 mol) and 2-tetrahydropyranthiol (12 g, 0.102 mol) (M.G. Missakian, R.

- 114 -

- 114 -

Ketcham and A.R. Martin, J. Org. Chem., J39, 2010 (1974)) in 250 ml of acetone is stirred with 200 ml of a 0.5M aqueous NaOH solution for 1 hour at room temperature. the The reaction mixture is saturated with NaCl and extracted several times with AcOEt. The combined extracts are washed with a saturated aqueous NaCl solution until they are neutral, dried over Na ^ SO ^ and im Evaporated in vacuo to give a residue which is purified by column chromatography over silica gel will. When eluting with toluene-hexane-AcOEt 70:25:25, the title compound is obtained as an oil, which on standing crystallized (19.3 g, 90% yield).

IR (CHCl ₃ , cm ¹ )

NMR (CDCl ₃ , S) :

3300, 2930, 2860, 1760

1.04 (3H, t, J = 7 Hz) 1.60-1.90 (8H, br) 3.14 (1H, br m) 3.58 (1H, br m) 4.14 (1H, br m)

4.63 and 4.74 (1H, d, J = 2 Hz)

5.10 (1H, br m)

6.47 and 6.60 (1H, br, exchange

with D ₀ O)

4Lt

Example 22

denacetate

Ji

COOMe

COOMe

A mixture of (3S) -3-ethyl- (4R) -4- (o ^ -tetrahydropyranthio) -azetidin-2-one (1.07 g, 5 mmol) and methyl glyoxylate (1.26 g, 12 mmol) in anhydrous tetrahydrofuran (40 ml) and 10 ml anhydrous Et ₂ ^{O are cooled to 0-5} ° C. under a nitrogen atmosphere and then treated with anhydrous triethylamine (0.70 ml, approximately 5 mmol). The solution is stirred for 24 hours at room temperature, diluted with 50 ml of AcOEt, washed with a saturated aqueous NaCl solution (3 × 30 ml) and dried _{over Na 3} SO _4. Evaporation of the solvent in vacuo gives an oil / T, 1 g; IR (CHCIo,

-1 -

cm): 3200 (broad), 2910, 1760 /, which dissolved in anhydrous tetrahydrofuran, is cooled to -30 ⁰ C and treated under a nitrogen atmosphere with pyridine (0.6 mL) and to which was then added dropwise a solution

- 116 -

- 116 -

of thionyl chloride (0.45 ml) in 3 ml of anhydrous tetrahydrofuran. The mixture is stirred for 0.5 hours at -20 ⁰ C and further 2 hours at -5 to 0 ⁰ C. The precipitate is filtered off and the filtrate is evaporated several times in vacuo from benzene. The residue is dissolved in dry CH ₃ C ^ (50 ml), 1,830 g of triphenylphosphine are added and the mixture is stirred overnight under an N ~ atmosphere at room temperature. The solvent is evaporated off in vacuo and the residue is purified by column chromatography over silica gel by eluting with initially benzene-hexane-AcOEt 70:25:25 and then with benzene-hexane-AcOEt 70:10:40. The title compound is obtained as a white foam (1.36 g).

IR (CHCl ₃ , cm " ¹ ): 1740

20 Example 23

Γ '3 COOMe

To a stirred solution of the phosphorane (561 mg, 1 mmol) in 6 ml of MeOH, cooled with an external water bath,

- 117 -

- 117 -

4.2 ml of an aqueous solution of a 0.25M AgNO ₃ solution are added dropwise. After stirring for an additional 5 minutes, the mixture is diluted with 5 ml of distilled water and then carefully filtered with suction. The precipitate is washed several times with distilled water and then with Et ₃ O and dried on the filter to give the title compound in about 90% yield.

Example 24

^ s-Ag ⁺ · / ^ rr s

COOMe COOMe

1.32 mmol are added dropwise to a stirred solution of silver (3S) -3-ethyl-1-methoxycarbonyltriphenylphosphoranylidenemethyl-2-oxoazetidin-4R) -4-yl-thiolate (500 mg, 0.88 mmol) in 5 ml of acetonitrile Acetyl chloride added. The mixture is stirred until white AgCl precipitates and separates out well from the solution. It is then filtered through Celite and washed with AcOEt. The filtrate is washed with a saturated aqueous NaHCO ₃ solution (3 × 200 ml) and then with a saturated aqueous NaCl solution (1 × 20 ml), over Na ₃ SO.

- 118 -

dried and evaporated in vacuo and the residue obtained is purified by column chromatography over silica gel cleaned. Eluting with benzene-hexane-AcOEt 70:25:25 gives 320 mg of the title compound.

Example 25

COOMe

A solution of methyl ~ 2- / T3 ¹ S) -3-ethyl- (4 ¹ R) -4'-acetylthio ~ 2'-oxo-azetidine-IÄ-yjiy-a-triphenylphosphoranylidene acetate. (320 mg) in 150 ml of toluene is ^{heated to 85 to 90 °} C. for 10 hours under a nitrogen atmosphere. The cooled solution is poured onto the top of a silica gel and then eluted with toluene-AcOEt 19: 1 to give the title compound.

IR (CHCl ₃ , cm " ¹ ): 1780, 1705

NMR (CDCl ₃ , 6)

1.09 (3H, t, J = 7 Hz)

1.94 (2H, m, J = 7 Hz)

2.38 (3H, s)

3.69 (1H, m, J = 7, 1.7 Hz)

3.85 (3H, s)

5.36 (1H, d, J = 1.7 Hz)

- 119 -

By working as indicated earlier, the following compounds are obtained:

Methyl (6S) methyl (6S) methyl (6S) Methyl (6S) methyl (6S) methyl (6S) methyl (6S) Methyl (6S)

6-ethyl- (5R) -6-ethyl- (5R) -6-methyl- (5R) 6-methyl- (5R) 6-methyl- (5R) 6-propyl- (5R) 6-propyl- (5R) 6-propyl- (5R) 2-ethyl-2-penem-3-carboxylate, 2-propyl-2-penem-3-carboxylate, -2-methyl-2-penem-3-carboxylate, -2-ethyl-2-penem-3-carboxylate, -2-propyl-2-penem-3-carboxylate, -2-methyl-2-penem-3-carboxylate, -2-ethyl-2-penem-3-carboxylate,

example

COOPNB

COOPNB

- 120 -

To a solution of (3S) -3-ethyl- (4R) -4- (ei / -tetrahydropyranylthio) -azetidin-2-one (2.5 g, 11.6 mmol) in 100 ml of anhydrous tetrahydrofuran, cooled to 10 ⁰ C, anhydrous triethylamine (1.60 ml, 11.6 mmol) is added under a nitrogen atmosphere and a solution of p-nitrobenzyl glyoxalate (5.63 g, 25 mmol) in 40 ml of anhydrous tetrahydrofuran is then added dropwise. After the addition is complete, the reaction mixture is stirred for 3 hours at room temperature and then washed with a saturated aqueous NaCl solution (50 ml) and extracted with 3 × 50 ml of AcOEt. The combined extracts are washed with a saturated aqueous NaCl solution (3 × 50 ml) and dried _{over Na 3} SO _4.

Evaporation of the solution in vacuo an oily residue / IR (film cm) one obtains: 3280 (broad), 2900, 17557, and the residue is then taken up in 150 ml of anhydrous tetrahydrofuran, cooled under a nitrogen atmosphere to -30 ⁰ C, with dry pyridine (1.92 ml, 24 mmol) is added and then thionyl chloride (1.45 ml, 20 mmol) dissolved in 10 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 0.5 hours at -30 ⁰ C and then a further 2 hours at -5 to 0 ⁰ C. The precipitate is filtered and the filtrate is evaporated several times in vacuo from benzene.

The residue / IR (film, cm): 1760 / is dissolved in dry ^CH 2 ^C1 2 ⁽¹⁵ ° ^ml) g ^and stirred with triphenylphosphine (6.3 g, 24 mmol) under nitrogen overnight.

- 121 -

The solvent is evaporated in vacuo and the residue is purified by column chromatography over silica gel cleaned. Eluting with benzene-hexane-AcOEt 70:25:25 gives the product as a yellow foam (4.10 g).

IR (CHCl ₃ , cm " ¹ ): 1745

Example 27

S-Ag-ί

y -

COOPNB COOPNB

To a stirred solution of phosphorane (900 mg, 1.35 mmol) in MeOH (6 ml), cooled with an external water condenser, was added dropwise 6 ml of an aqueous 0.25M AgNO, solution added. After another 5 minutes While stirring, the mixture is diluted with 5 ml of distilled water and carefully suctioned off on the filter. Of the The precipitate is washed several times with distilled water and then with Et ~ O and dried on the filter, whereby 920 mg of the title compound are obtained.

- 122 -

- 122

Example 28

oxo-azetidine-1 'l

5 Ag +

ο COOFNB COOPNB

To a stirred solution of silver (3S) -3-ethyl-1-nitrobenzyioxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin- (4R) -4-yl-thiolate (350 mg, 0.5 mmol) in 4 ml of acetonitrile are added dropwise 0.8 mmol of acetyl chloride admitted. The mixture is stirred until a white AgCl precipitate clears from the solution separated and then filtered through Celite and washed with AcOEt. The filtrate is saturated with a aqueous NaHCCu solution (3 × 20 ml) and then with a saturated aqueous NaCl solution (1 χ 20 ml) washed, over Na-SO, dried and evaporated in vacuo and the residue is purified by column chromatography over silica gel.

On elution with Benzene-Hexane-AcOEt 70:25:25 obtained one 195 mg of the title compound.

IR (CHCl ₃ , cm " ¹ ): 2900, 1750, 1705

- 123

Example 29

JY ³

N °

^ f ¹ ~ 3

_? p _h Ö COOpNB

. COOpNB

A solution of p-nitrobenzyl-2- / 73 ¹ S) -3-ethyl- (4 ¹ R) 4'-acetylthio-2'-oxo-azetidin-1'-yl / -2-triphenylphosphoranylidene acetate (195 mg) in ^{100 ml of toluene is heated to 85 to 90 °} C. for 48 hours under a nitrogen atmosphere. The cooled mixture is added to the top of a silica gel column and eluted with toluene-AcOEt 19: 1 to give the title compound.

IR (CHCl ₃ , cm " ¹ ): 1790, 1710

NMR (CDCl ₃ , ^): 1.07 (3H, t, J = 7.0 Hz)

1.91 (2H, m, J = 7.0, 7.0 Hz)

2.36 (3H, s)

3.69 (1H, m, J = 7.0, 2.0 Hz)

5.34 (2H, dd, J = 14.0 Hz)

5.36 (1H, d, J = 2.0 Hz)

7.63 (2H, d, J = 8.0 Hz)

8.22 (2H, d, J = 8.0 Hz) 30

If you work in the same way, you get the following

Links.

- 124 -

p-nitrobenzyl (6S) -6-ethyl- (5R) ^ -

carboxylate /

p-Nitrobenzyl (6S) -6-ethyl- (5R) -2 ~ propyl-2-penem-3-

carboxylate,

p-Nitrobenzyl (6S) -6-methyl- (5R) - ^ - methyl ^ -penem-S

carboxylate,

p-Nitrobenzyl (6S) -6-methyl- (5R) -2-ethyl ~ 2-penem-3-

carboxylate,

p-nitrobenzyl (6S) -6-methyl- (5R) ^ -

carboxylate,

p-nitrobenzyl (6S) -6-propyl- (5R) ^ -

carboxylate,

p-Nitrobenzyl (6S) -6-propyl- (5R) -2 ~ ethyi-2-penem-3-

carboxylate,

p-nitrobenzyl (6S) -6-propyl- (5R) ^ -

carboxylate.

Example 30

-S-carboxylic acid

'"Τ

, N-

^ COOpNB

N-

COOH

A mixture of p-nitrobenzyl (6S) -6-ethyl- (5R) -2-methyl-2-penem-3-carboxylate (30 mg), 0 / 2M of an aqueous

- 125 -

NaHCO ₃ solution (2 ml), AcOEt (3 ml) and 10% palladium-carbon catalyst (60 mg) is stirred in an automatic Brown hydrogenation device until the uptake of NaBH solution ceases. The catalyst is filtered off and the residue is washed with a saturated liquid NaHCOo solution and with AcOEt. The aqueous phase is separated off, _{washed with CH 2} Cl ₂ and acidified with 5% aqueous citric acid solution and then extracted _{several times with CH 2} Cl _2. The organic extracts are obtained via Na “SO. dried, filtered, and concentrated in vacuo to give the title compound.

IR (KBr, cm " ¹ ): 3300, 1770, 1660 15

The following connections are obtained in an analogous manner fertilize.

(6S) -6-ethyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-ethyl- (5R) -2-propyl-2-penem-3-carboxylic acid, (6S) -6-methyl- (5R) -2-methyl-2-penem-3-carboxylic acid, (6S) -6-methyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-methyl- (5R) -2-propyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-methyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-propyl-2-penem-3-carboxylic acid,

All of the aforementioned carboxylic acids including the title compound of Example 30 can be converted into the sodium salts.

- 126 -

Example 31

S Ag / ti, .. »s ^ ^^ _o ^ _c

l ^ T ^PPh 3 I ^Ν >

> 3 COOpNB COOpNB

Following the procedure described in Example 28 were
using silver (3S) -3-ethyl-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-οχο-
azetidin- (4R) -4-yl-thiolate (340 mg, 0.49 mmol) and
freshly distilled acetoxyacetyl chloride (0.75 mmol)
216 mg of the title compound were obtained.

Example 32

^S ^^ oAc "" \ Ϊ "Ύ 'oAc

N 0

J 0 30

COOpNB

* y _/ N Il

^ pPPh. 0 'COOpNS

- 127 -

A solution of p-nitrobenzyl-2- / 73 ¹ S) -3'-ethyl- (4 ¹ R) 4'-acetoxyacetylthio-2'-oxo-azetidin-1'-yl7-2-triphenylphosphoranylidene acetate (216 mg) in Toluene (107 ml) is ^{heated at 85 to 90 °} C. for 30 hours under a nitrogen atmosphere. The cooled mixture is poured onto the top of a silica gel column and eluted with toluene-AcOEt 19: 1 to give the title compound.

IR (CHCl ₃ , cm " ¹ ): UV (EtOH, nm):

NMR (CDCl ₃ , 6)

1780, 1740, 1710

266, 322

1.09 (3H, t, J = 8 Hz)

1.93 (2H, m, J = 8.7 Hz)

2.13 (3H, s)

3.80 (1H, dt, J = 7.2 Hz)

5.32 (2H, center of ABq, J = 15 Hz)

5.37 (2H, center of ABq, J _em = 14 Hz)

5.45 (1H, d, J = 2 Hz)

7.95 (4H, center of ABq, J = 9 Hz)

If one works in an analogous way, one can do the following Get connections:

p-Nitrobenzyl (6S) -6-methyl- (5R) -2-acetoxy-methyl-2-

penem-3-carboxylate,

p-Nitrobenzyl (6S) -6-propyl- (5R) -2-acetoxy-methyl-2-

penem-3-carboxylate,

p-Nitrobenzyl (6S) -6-methyl- (5R) -2-propionyloxy-methyl-

2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-ethyl- (5R) -2-propionyloxy-methyl-

2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-propyl- (5R) -2-propionyloxy-methyl-

2-penem-3-carboxylate.

- 128 -

Example 33

acetylthio-2 '~ oxo-azetidine-1__ | _yl / -2-trighenYlghosghora-

COOpNB COOpNB

The procedure of Example 28 is followed Use of silver (3S) -3-ethyl-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidine- (4R) -4-yl-thiolate (350 mg, 0.506 mmol) and freshly distilled Thien-2-yl-acetyl chloride (0.9 mmol). Included 224 g of the title compound are obtained.

IR (CHCl ₃ , cm " ¹ ): 1750, 1680

Example 34
25th

t in · ■ - * '^ t -. ^ t / f

COOpNB

- 129

- 129 -

A solution of p-nitrobenzyl-2 - / (3 ¹ S) -3'-ethyl- (4R) 4'-thien-2 "-ylacetylthio-2'-oxo-azetidin-1'-yl7-2-triphenylphosphoranylidene acetate ( 224 mg) in toluene (110 ml) is heated under a nitrogen atmosphere for 24 hours 85 to 90 ⁰ C. the cooled mixture is added to the head of a column of silica gel with toluene-AcOEt. 19: eluted 1 to obtain the title compound.

IR (CHCl ₃₇ cm ¹ ): UC (EtOH, nm):

1785, 1710, 1605, 1580, 1520 241, 264, 381

NMR (CDCl ₃ , 6 ~): 1.04 (3H, t, J = 7 Hz)

1.89 (2H, m, J = 7.8 Hz)

3.82 (1H, dt, J = 8, 1.8 Hz)

4.38 (2H, center of ABq, J _em = 17 Hz)

5.33 (1H, d, J = 1.8 Hz)

5.40 (2H, center of ABq, J _m = 14 Hz)

6.95 and 7.24 (3H, m)

7.95 (4H, center of ABq, J _m = 9 Hz)

If you work in an analogous way, you get the following compounds:

p-nitrobenzyl (6S) -6-methyl (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate,

p-nitrobenzyl (6S) -6-propyl- (5R) -2-thienyl-2'-yl-methyl-2-penem-3-carboxylate.

- 130 -

Example 35

carboxylic acid

^ COOpNB

A mixture of 35 mg of p-nitrobenzyl (6S) -6-ethyl- (5R) 2-thien-2 ^l -ylacetylthio-2-penem-3-carboxylate, 2.5 ml of an aqueous 0.2M NaHCO ^ solution, 4 ml of AcOEt and 10% palladium-carbon catalyst (80 mg) are stirred in a Brown-type hydrogenation device until the uptake of the NaHCO-3 solution subsides. The catalyst is filtered off and the residue is washed with a saturated aqueous NaHCO ₃ solution and with AcOEt. The aqueous "phase is separated off, _{washed with CH 2} Cl ₂ , acidified with 5% aqueous citric acid solution and _{extracted several times with CH 2} Clp. The organic extracts are dried over Na 3 SO., Filtered and concentrated in vacuo, whereby the title compound receives.

UV (EtOH, nm):

233, 313

The following compounds are obtained in an analogous manner

(6S) -6-methyl- (5R) -2-thien-2 ^l -yl-methyl-2-penem-3-carboxylic acid,

- 131 -

(6S) -6-Propyl- (5R) -2-thien-2'.yl-methyl-2-penem-3-carboxylic acid.

The methyl and ethyl esters and the sodium salts can be obtained by conventional esterification or salt formation obtained in Example 35 obtained carboxylic acids, in particular:

Methyl (6S) -6-ethyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate,

Methyl (6S) -6-methyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate,

Methyl (6S) -6 ~ propyl- (5R) -2-thien-2'-yl-methyl-2-penem-

3-carboxylate.
15th

Example 36

/ '"". _{) r} _. ^ S-Ag ⁺ / '/. " S S - ^ COOEt

N "

COOpNB COOpNB

The procedure according to Example 28 is followed and silver (3S) -3-ethyl-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin- (4R) -A- yl thiolate (380 mg, 0.55 mmol) and is used commercially available

- 132 -

Ethyl oxalyl chloride (0.9 mmol). 255 mg of the are obtained Title compound.

Bei Piel 37

/ '"ο, · f S ■ ^^ - COOEt

j _/ Ii ο

0 Γ ^PPh 3 COOpNB

255 mg of a solution of p-nitrobenzyl-2- / 73 ¹ S) -3 '-ethyl- (4'R) -4'-ethoxycarbonylcarbonylthio-2'-oxoazetidin-1'-yl7-2-triphenylphosphoranylidene acetate in 125 ml of toluene is kept overnight under a nitrogen atmosphere and then heated for a few minutes at 8O ⁰ C. The cooled mixture is poured onto the top of a silica gel column and eluted with toluene-AcOEt 19: 1 to give the title compound.

IR (CHCl- -1
, cm): 1790 , 1735, 1 725 UV XEtOH, nm): 264, 336 NMR (CDCl , .6). 1, 09 (3H, t, J = 8

1.27 (3H, t, J = 7 Hz)

1.93 (2H, m, J = 8.7 Hz)

- 133 -

- 133 -

3.92 (1H, dt, J = 7.2 Hz)

4.27 (2H, q, J = 7 Hz)

5.38 (2H, collapsed ABq,

5.44 (1H, d, J = 2 Hz)

7.93 (4H, center of ABq, J = 8 Hz)

The following compounds are obtained in an analogous manner:

p-nitrobenzyl (6S) -6-methyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, p-Nitrobenzyl (6S) -6-methyl- (5R) ^ - methoxycarbonyl ^ - penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) ^ - methoxycarbonyl ^ - penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, p-Nitrobenzyl (6S) -6-propyl- (5R) ^ -propoxycarbonyl ^ - penem-3-carboxylate.

- 134 -

Example 38

(6S) -6-Εϋιγ1- (5R) ^ -

jf S ^ s ^

ι T

COOEt> ^>. / »S \ ^" COOEt

_σ * ^ COOpNB

A mixture of 45 mg of p-nitrobenzyl (6S) -6-ethyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, 3 ml of an aqueous 0.2M NaHCO ₃ solution, 4 ml of AcOEt and 100 mg 10% palladium-carbon catalyst is stirred in a Brown-type automatic hydrogenator until 3 equivalents of hydrogen are adsorbed. The catalyst • is filtered off and the residue is washed with a saturated aqueous NaHCO -.- solution and then with AcOEt. The aqueous phase is separated off, _{washed with CH 2} Cl ₂ , acidified with 5% aqueous citric acid solution and extracted _{several times with CH 3} Cl _2.

The organic extracts are over Na ₃ SO. dried, filtered and evaporated in vacuo to give the title compound.

UV (EtOH, nm): 259, 336

The following compounds are obtained in an analogous manner:

- 135 -

(6S) -6-methyl- (5R) ^ -ethoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) ^ - ethoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6- Methyl- (5R) - ^ - methoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-ethyl- (5R) ^ - methoxycarbonyl ^ -penem-S-carboxylic acid , (6S) -6-propyl- (5R) ^ -methoxycarbonyl - ^ - penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -propoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-ethyl- (5R) ^ -propoxycarbonyl ^ - penem-S-carboxylic acid, (6S) -6-propyl- (5R) ^ -propoxycarbonyl ^ -penem-S-carboxylic acid.

The methyl esters and sodium salts of the above can be obtained by normal esterification or salt formation Example 38 produce the carboxylic acids obtained, in particular:

Methyl (6S) -6-ethyl- (5R) ^ -ethoxycarbonyl ^ -penem-S-carboxylate, Methyl (6S) -6-methyl- (5R) ^ -ethoxycarbonyl ^ -penem-S-carboxylate, Methyl (6S) -6-propyl- (5R) ^ -ethoxycarbonyl ^ -penem-S-carboxylate, Methyl (6S) -6-methyl- (5R) ^ - methoxycarbonyl ^ -penem-S-carboxylate, Methyl (6S) -6-ethyl- (5R) ^ -methoxycarbonyl ^ -penem ^ - carboxylate,

- 136 -

- 136 -

Methyl (6S) -6-propyl- (5R) -Z-methoxycarbonyl - ^ - penem-a-

carboxylate,

Methyl (6S) -6-methyl- (5R) - ^ - propoxycaxbonyl - ^ - penem-S-

carboxylate,

Methyl (6S) -6-ethyl- (5R) - ^ - propoxycarbonyl - ^ - penem-S-

carboxylate,

Methyl (6S) -6-propyl- (5R) ^ -propoxycarbonyl ^ -penem-S-

carboxylate.

Example 39

denacetate

.NH

• ro

COOCH CCH,

> P

N. °

0 COOCH CCH

.Cl

COOCH CCH

To a solution of (3S) -3-ethyl- (4R) -4- (o (/ ~ tetrahydropyranylthio) -azetidin-2-one (861 mg, 4 mmol) and acetonyl glyoxylate (1.4 g, 9.45 mmol) in 50 ml anhydrous

- 137 -

Tetrahydrofuran was added dropwise to anhydrous triethylamine under a nitrogen atmosphere.

After the organic solution reacted neutral or weakly basic, more triethylamine (0.6 ml, 4.5 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture is then washed with a saturated aqueous NaCl solution (25 ml) and extracted 3 times with 25 ml AcOEt each time. The combined extracts are washed with a saturated aqueous NaCl solution (3 × 25 ml) and dried _{over ^ 2SO 4.} Evaporation of the solvent in .Vakuum obtained 900 mg of was added to anhydrous tetrahydrofuran (30 ml), under nitrogen 'atmosphere to -30 ⁰ C of an oily residue, cooled with dry pyridine

(0.54 ml) is treated, whereupon 0.34 ml) of thionyl chloride dissolved in 5 ml of tetrahydrofuran is then added dropwise. The reaction mixture is stirred for 0.5 hours at -30 ^e C and further 2 hours at -5 to 0 ⁰ C. The precipitate is filtered off and the evaporated in vacuo FiItrat several times from benzene.

900 mg of the residue are dissolved in 30 ml of dry CH2Cl2 dissolved and under a nitrogen atmosphere with 1.8 g Triphenylphosphine stirred for 19 hours at room temperature. The solvent is evaporated in vacuo and the The residue is chromatographed on a column over silica gel cleaned. Eluting with benzene-hexane-AcOEt 70:25:25 gives the title compound in the form of a white Foam (1.03 g) after evaporation of the eluant.

- 138 -

- 138 -

Example 40

- COOCH ₂ COCH3 O COOCH ₂ CCH ₃

To a stirred solution of phosphorane (257 mg, 0.44 mmol) in 3 ml of MeOH, cooled on an external water bath, 2 ml of an aqueous 0.25M AgNO ^ solution are added dropwise. The mixture is then stirred for a further 5 minutes and the mixture is diluted with 3 ml of distilled water and carefully filtered off with suction. The precipitate is washed several times with distilled water and then with Et ₃ O and dried on the filter.

250 mg of the title compound are obtained.

Example 41
25th

acetate

- 139 -

Τ β

COOCH CCH "CQOCH ₂ CCH ₃

CCH

The procedure is as in Example 28, but using silver (3S) -3-ethyl-1-acetonyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin- (4R) -4-ylthiolate (220 mg, 0.036 mmol) and freshly distilled Acetoxyacetyl chloride (0.6 mmol). 143 mg of the title compound are obtained.

Example 42

OAc

——. J. ■ »- K ^

PPh,

³ i?
· ^C0OCH 2 ^CCH 3

A solution of 143 mg of acetonyl-2- / 13 ¹ S) -3'-ethyl- (4 ¹ R) -4'-acetoxyacetylthio-2'-oxo-azetidin-1'-yl7-2-triphenylphosphoranylidene acetate in 80 ml of toluene is heated to 9O ⁰ C under a nitrogen atmosphere for 24 hours at 85th The mixture is cooled and put on top of a

- 140 -

Silica gel column added with toluene-AcOEt 19: 1 eluted to give the Txtelverbindungen.

IR (CHCl ₃ , cm " ¹ ): 1790, 1745, 1715 UV (EtOH, nm): 323

NMR (CDCl ₃ , O): 1.03 (3H, t, J = I Hz)

1.94 (2H, m, J = 7.8 Hz)

2.06 (3H, s)

2.16 (3H, s)

3.67 (1H, dt, J = 8.2 Hz)

4.67 (2H, s)

5.17 (2H, center of ABg, J = 15 Hz)

5.30 (1H, d, J = 2 Hz) '

If you work in an analogous way, you get the following compounds:

Acetonyl (6S) -6-methyl- (5R) - ^ - acetoxy-methyl - ^ - penem-3-carboxylate,

Acetonyl (6S) -6-propyl- (5R) - ^ - acetoxy-methyl - ^ - penem-3-carboxylate,

Acetonyl (6S) -6-methyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate,
Acetonyl (6S) -6-ethyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate,

Acetonyl (6S) -6-propyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylate.

- 141 -

- 141 -

Example 43

acid

f ^p

^N XOOCH CCH
2 ο

COOH

1 equivalent of a 0.1M aqueous NaOH solution is added to a stirred solution of 15 mg of acetonyl (6S) -6-ethyl- (5R) -2-acetoxymethyl-2-penem-3-carboxylate in 5 ml of acetonitrile and 1 ml of water added in the course of 20 minutes at 0 ⁰ C under a nitrogen atmosphere. The mixture is stirred for a further 10 minutes and then washed _{with CH 0} Cl _0. The aqueous phase is separated off and acidified with 5% aqueous citric acid solution and then extracted several times _{with CH 0} Cl _0. The organic extracts are _{dried over Na 0} SO ₄ , filtered and evaporated in vacuo to give the title compound.

IR (CHCl ₃ , cm " ¹ ): UV (EtOH, nm):

NMR (CDCl ₃ , 6)

3300, 1775, 1745, 1680 254, 315

1.07 (3H, t, J = 8 Hz)

1.92 (2H, m, J = 8 Hz)

2.13 (3H, s)

3.78 (1H, dt, J = 8.2 Hz)

- 142 -

5.10 (2H, center of ABq, J = 14 Hz)

^ according to

5.43 (1H, d, J = 2 Hz)

9.16 (1H, br, exchange with D ₂ O)

The following compounds are obtained in an analogous manner:

(6S) -6-methyl- (5R) ■ ^ -acetoxy-methyl - ^ - penem-S-carboxylic acid,
(6S) -6-propyl- (5R) - ^ - acetoxy-methyl - ^ - penem-S-carboxylic acid,

(6S) -6-methyl- (5R) ^ -propionyloxy-methyl ^ -penem-ßcarboxylic acid,

(6S) -6-ethyl- (5R) ^ -propionyloxy-methyl ^ -penem-S-carboxylic acid,

(6S) -6-Propyl- (5R) -2 ~ propionyloxy-methyl-2-penem-3-carboxylic acid.

The methyl esters and ethyl esters as well as the sodium salts can be obtained by conventional esterification and salt formation according to the above example 4 3 obtained compounds. Examples of these are:

Methyl (6S) -6-ethyl- (5R) ~ 2-acetoxy-methyl-2-penem-3-carboxylate,

Methyl (6S) -6-methyl- (5R) ^ -acetoxy-methyl - ^ - penem-S-carboxylate,

Methyl (6S) -6-propyl- (5R) ~ 2-acetoxy-methyl-2-penem-3-carboxylate,
Methyl (6S) -6-methyl- (5R) ^ -propionyloxy-methyl ^ -penem-3-carboxylate,

143

Methyl (6S) -6-ethyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate,

Methyl (6S) -6-propyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate.

Example 44

2i2 _{J i} .5 _{5-tetramethyl:;} _ (7R) _-_ (8S) _- _8-acetyl;: 9 _:: 3 _{:: =} oxo oxa-

(G 2.02, 2.8 ml, 20 mmol) to a solution of diisopropylamine in 15 ml of anhydrous THF are added strength in the course of 15 minutes with stirring and under a N ₂ atmosphere at -70 ⁰ C, a 15% n -BuLi solution in hexane (9.5 ml, 15 mmol) was added. After stirring for a further 15 minutes, a solution of 2,2,5,5-tetramethyl- (7R) -9-oxo-

- 17 - 3-oxa-6-thia-1-azabicyclo / 5.2.0 "_ / nonane (1.40 g, 5.5 mmol) in 5 ml of THF was added over the course of 15 minutes. The reaction mixture was allowed to last for 30 minutes stirred at -70 ⁰ C and then treated dropwise with a solution of AcOEt (5 mL, 4.5 g, 50 mmol) in THF (5 ml).

After the addition is complete, the mixture is 15 minutes

- 144 -

- 144 -

stirred at ⁰ C at -70 ⁰ C and 1 hour at O and then worked up by adding 75 ml cold water and then extracted 5 times with 50 ml CH ^ Cl _2. The combined organic extracts are _{dried over Na 3} SO ₄ and evaporated in vacuo, giving a yellow oil which is chromatographed on silica gel (50 g). Eluting with CgHg-AcOEt 95: 5 gives the title compound in the form of crystals (1.04 g, 92%).

Q:

Ä _D = + 111.9 ° IR (CHCl, cm " ¹ )

NMR (CDCl ₃ , S)

65-72 CHCl ⁰ C S) J = 1 3 Hz) 750 3 * s) J = 2 , 5 Hz) 1 , 22 s) J = 1 3 Hz) 1 , 47 s) J = 2 , 5 Hz) 1 , 57 1720 Ξ) 1 , 71 (3H, d, 1 , 33 (3H, d, 2 , 65 (3H, d, 3 , 91 (3H, d, 3 , 11 (3H, 4th , 70 (ΊΗ, 5 (1Η, (1Η, (1Η,

- 145 -

- 145 -

Example 45

- -

nonan

SvJ

O N

To a stirred 1M THF solution of commercially available Li-Selectride® (3 ml, 3 mmol), cooled to -78 ° C, becomes 2,2,5,5-tetramethyl- (7R) - (8S) -8-acetyl-9-oxo-3

- 17-6-thia-1-azabicyclo / 5.2.0 _ / nonane (535 mg, 2.08 mmol) in 8 ml of THF was added dropwise under N ₂ . The mixture is stirred for a further 3 hours at -78 ⁰ C and then treated with 1 ml of water and 3 ml of 30% H ₂ O ₂ treated.

After stirring for a further hour at 0 ^° C., the mixture is _{diluted with 30 ml of H 2} O and extracted 5 times with 50 ml of CH ₂ Cl _{2 each time.} The combined extracts are _{dried over CHCl 2} and evaporated in vacuo to give a solid residue which is chromatographed over 20 g of silica gel. Eluting with CgHg-AcOEt 95: 5 gives unreacted starting material (160 mg, 11%). Eluting with CgHg-AcOEt 90:10 gives the title compound (355 mg, 66%).

Q: 97-102 ⁰ C

- 146 -

Elemental analysis calculated for C] ₂ H ₂

C 55.55 (55.57) N 5.38 (5.40)

/ dü7 _n = + 111.16 ° (C = 0.8, CHCl,)

-D

IR (CHCl ₃ , cm): 3400, 1740

H 8.12 (8.16) S 12.07 (12.36)

NMR (CDCl ₃ , S):

1.21 (3H, s)

1.35 (3H, d, J = 7 Hz)

1.49 (3H, s)

1.55 (3H, s)

1.71 (3H, s)

2.68 (1H, br d, J = 5 Hz, exchange

with D ₂ O)

2.88 (1H, dd, J = 2, 5.25 Hz)

3.60 (1H, d, J = 12 Hz)

4.16 (1H, d, J = 12 Hz)

4.17 (1H, br m) 5.02 (IH, d, J = 2 Hz)

- 147 -

Example 46

2 _i 2 _i 5,5-tetramethYl- (7R) - (8S) - / T_l ₌ (1 ¹ R) -hydroxyethyl? -

- - _ ^ T ~ 7- ~ ~

2 ^ 0_ * _ / nonane

• OH

To a stirred 0.5M THF solution of commercially available K-Selectride ^> (20 ml, 10 mmol) will 2,2,5,5.Tetramethyl- (7R) - (8S) -e-acetyl-g-oxo-S-oxa-

- 17 -

ö-thia-i-azabicyclo / S.2.0 * _7nonane (1.44 g, 5.6 mmol) in 125 ml of anhydrous Et ₂ O was added dropwise and under N ₂ at room temperature. The mixture is stirred for 20 hours and then worked up as in Example 45. The residue obtained is chromatographed over 50 g of silica gel. Eluting with CgHg-AcOEt 95: 5 gives unreacted starting material (397 mg). Eluting with CgHg-AcOEt 90:10 gives 602 mg of the title compound.

Q: 126-130 ⁰ C

= + 80 ° (C = 1,

- - υ j

IR (CHCl ₃ , cm '): 3600, 3460, 1740

NMR (CDCl ₃ , 8) ι 1.18 (3Η, s) 1.27 (3Η, d, J = 6 Hz)

1.47 (3H, s)

- 148 -

- 148 -

1.58 (3H, s)

1.67 (3H, s)

2.85 (IH, dd, J = 2.2, 4.0 Hz)

3.69 (1H, d, J = 12 Hz)

3.62 (1H, br, exchange with

4.09 (1H, d, J = 12 Hz)

4.22 (1H, br)

5.17 (1H, d, J = O, 2 Hz)

Example 47

_ - ι ~] -

2 ___ 2_X_2_Y ___ y_ / z2z2_2z_z25_Z§Z_i} i_zlz _____ 2Y2_ ° Z ^ · 2 · O '_ / ~

nonan

O
OC-OPNB

To a stirred solution of 2,2,5,5-tetramethyl- {7R) < 8S) - / T '- (1'Rj-hydroxyethylZ-g-oxo-S-oxa-e-thia-i-aza-

~ - 17— ""
bicyclo / 5.2.0 * _ / nonane (1.50 g, 5.78 mmol) in 30 ml of EtOH-free CH ₃ Cl ₂ , cooled to -15 ° C, p-nitrobenzyl chloroformate (1.66 g, 7, 7 mmol) and then 4-N, N-dimethylaminopyridine (940 mg, 7.7 mmol) is added over the course of 30 minutes. The mixture is stirred for a further 18 hours at room temperature,

- 149 -

then diluted with 150 ml of CH ₂ Cl ₂ , washed with 2 times 50 ml of a saturated aqueous NaCl solution and dried _{over Na 2 SO 4.} Evaporation of the solvent gives a residue which is chromatographed over 100 g of silica gel.

Eluting with C ^ H - AcOEt 97.5: 2.5 gives the

b ο

Title compound as a yellow oil (2.20 g, 87%). IR (CHCl ₃ , cm " ¹ ): 1750, 1520, 1350

Example 48
15 '

. oxvcarbonyloxyethyl / ^ - oxo-S-oxa-e-thia-i -azabicyclo- / 5 _Λ 2 _Λ 0_ _7nonane-2_, 2-dioxide

0 "'0-C-0PN3 ο 0

OC-OPNB Λ \ #

To a stirred solution of 2,2,5,5-tetramethyl- (7R) (8S) - / T '- (1' R) -p-nitrobenzyloxycarbonyloxyethyiy ^ -oxo-

~ -17-

3-oxa-6-thia-1-azabicyclo / 5.2.0 * _ / nonane (2.20 g, 5.0 mmol) in 30 ml CH ₃ Cl ₂ , cooled on an ice / NaCl bath, are 12, 5 mmol of m-chloroperbenzoic acid were added in small portions with stirring. The reaction mixture

- 150 -

10

is stirred for 1 hour in the cold and then for a further 30 minutes at room temperature. After dilution with 150 ml of CH ₂ Cl ₂ , the solution is mixed 1 time with 50 ml of an 8% aqueous NaHCO ₃ solution, 1 time with 50 ml of an aqueous 10% NaHCO ₃ solution, 1 time with 50 ml an 8% aqueous NaHCO solution and then washed once with 50 ml of a saturated aqueous NaCl solution and then _{dried over Na 2} SO ^. Evaporation of the solvent in vacuo gives a non-crystalline pesticide (2.3 g, 98%).

IR (CHCl ₃ , cm " ¹ ): 1775, 1750, 1520

NMR (CDCl ₃ ,

15th

1.31 (3H, s)

1.45 (3H, d, J = 7 Hz)

1.46 (3H, s) 1.55 (3H, s) 1.6 9 (3H, s)

3.44 (1H, d, J = 14 Hz)

3.78 (1H, dd, J = 2.2, 4.2 Hz)

4.16 (1H, d, J = 14 Hz)

4.92 (1H, d, J = 2.2 Hz)

5.27 (2H, s)

5.29 (1H, m)

7.51 (2H, d, J = 8 Hz) '

8.22 (2H, d, J = 8 Hz)

- 151 -

example

lf ony_l) _- a.zetidin-2-one

OC-OPNB \\ // 3, "*, .. ^S '

3 H

In a manner similar to Example 20, the above Title compound obtained.

IR (CHCl ₃ , cm " ¹ ): 3400, 1780, 1750

NMR (CDCl ₃ , 6)

1.31 (3H, s)

1.42 (3H, s)

1.45 (3H, d, J = 7 Hz)

3.60 (1H, d, J = 12 Hz)

3.82 (1H, dd, J = 2 Hz)

3.91 (1H, d, J = 12 Hz)

5.02 (1H, d, J = 2 Hz)

5.24 (2H, s)

5.26 (1H, m)

7.38 (1H, br)

7.52 (2H, d, J = 8 Hz)

8.18 (2H, d, J = 8 Hz)

- 152 -

example

0-fi-OPNB

^H 3 ° 'H

-NH

- 152 -

O-6-OPN3

HC ³ H

-NH

The procedure is similar to that in Example 21, wherein the title compound is obtained.

= ⁺⁵²

IR (CHCl ₃ , cm " ¹ ) NMR (CDCl ₃ , 6)" 3400, 2940, 2860, 1775, 1750

1.45 (3H, d, J = 6.5 Hz) 1.3-2.1 (6H, m) 3.25 - 3.70 (2H, m) 4.04 (1H, m) 4.92 and 5.00 (1H, dd, J = 7.2 Hz) 5.0-5.3 (2H, m) 5.27 (2H, s) 6.52 and 7.02 (1H, br) 7.55 (2H, d, J = 8 Hz) 8.23 (2H , d, J = 8 Hz)

- 153 -

- 153 -

example

carbony_loxYethyl / -_ (4

acetate

OCO-PNB X NH

vt "*

O OÖO-PNB

N N = PPh.

COOPNB

OCO-PNB

₀ CrI ti

• Ν

0
0C0-PN3

OH

COOPNB

-N

Cl C00PN3

Following a procedure according to Example 25, the title compound is obtained obtained as a non-crystalline solid.

IR (CHCl ₃ , cm " ¹ ): 1750, 1745

- 154 -

- 154 -

example

0C0-PN3

<f

OCO-PNB
X

COOPNB CGOPNB

This compound is obtained in a manner analogous to Example 27.

example

OCO-PNB I. SA ₉ ⁺ · / N 0 ^ PPh ₃
COOPNB

H _Ä cr

OCOPNB

0
_r PPh

I **

COOPNB

This compound is obtained in a 65% yield in a manner analogous to the process according to Example 33.

- 155 -

example

ο ■

OCOPNB

^H 3 ^C

r ν OCOPNB

COOPNB COOPNB

This compound is obtained in a manner analogous to Example 34 in a 70% yield.

IR (CHCl ₃ , cm " ¹ ):

NMR (CDCl ,, δ):

1790, 1750, 1710

1.48 (3H, d, J = 6.5 Hz)

3.91 (1H, dd, J = 7.2, 1.8 Hz)

4.36 (2H, ABq, J = 16 Hz)

5.24 (2H, bs)

5.38 (2H, ABq)

5.59 (1H, d, J = 1.8 Hz)

6.93 (2H, m)

7.21 (1H, dd)

7.56 (4H, m)

8.20 (4H, d)

Claims (1)

HOFFMANN · EITLE Oc PaKxNER 3 2 2 4 P 5 PAT E Ν TAN WALTE DR. ING. E. HOFFMANN (1930-1976). Dl PL.-ING. W. EITLE. DR. RER. NAT. K.HOFFMANN DI PL.-1N G. W. LEHN DIPL.-ING. K. FDCHSLE DR. RER. NAT. B. HANSEN ARABELLASTRASSE 4 · D-8000 MO NCHEN 8]. TELEPHONE (089) 911087. TELEX 05-29519 (PATHE) 36 884 o / wa FARMITALIA CARLO ERBA S.p.A., MILAN / ITALY Process for the preparation of optically active trans-6-substituted-5 (R) -2-penem-3-carboxylic acid derivatives, as well as new optically active trans-6 (S) -substituted- 5 (R) ^ -penem-S-carboxylic acid derivatives PATENT CLAIMS 1.) Process for the preparation of optically active trans-6-substituted-5 (R) -2-penem-3-carboxylic acid derivatives of the general formula (I). ¹ row ⁰ 7 4 3 COOR ₂ wherein R and R- identical or different organic groups and R _{2 is} hydrogen, a cation or - 2 - 10 30 mean a carboxy protective group, characterized in that g e · denotes that one (a) an optically active 4 (R) -azetidin-2-one derivative of the general formula (II) L ^: in which R has the meaning given above and each R ₃ group independently of one another is hydrogen or a C ₁ -alkyl, with a thiol of the formula A-SH where A denotes a radical which makes the S-A bond unstable to the heterolytic effect of soluble metal salts or of halogens, or converts a salt thereof, with formation of an optically active 4 (R) -thxoderxvate of the formula (III) - A wherein. A and R have the meanings given above; (b) a 4 (R) compound of the formula (III) with a glyoxylic acid derivative of the formula OHC - COOR ₂ wherein R _{2 has} the meaning given above, reacts to obtain a 4 (R) derivative of the formula (IV) "" γ Γ. γ-w OH COOR ' Y N wherein R, A and R _{2 have} the meanings given above; (c) a 4 (R) -carbinol of the formula (IV) halogenated to give a compound of the formula (V) 20th S-A ^ (V) wherein R, A and R _{2 have} the meanings given above and X is a halogen atom; (d) a 4 (R) compound of the formula (V) with a phosphine of the formula - 4th -Α wherein each of the groups 0 independently of one another is an aromatic, heterocyclic or alkyl radical means, converts, to obtain a 4 (R) -phosphorane of the formula (VI) .S-A ^ 3 (VI) COOR wherein R, A, R ~ and 0 have the meanings given above to have; (e) a 4 (R) -phosphorane of the formula (VI) with a solution of a heavy metal of the formula ^{n +} wherein M is a cation of a heavy metal M with
the valency η and Y ⁿ denote an anionic radical of the salt, converts, to obtain a 4 (R) -mercapto salt of the formula (VII) .S- C00R2 (VII) »Η + wherein R, R ", 0, M and η are those given above Have meanings; (f) a 4 (R) mercapto salt of the formula (VII) with a reactive derivative of an acid or a thioacid of the formula OH R ₁ - C in which R _{1 has} the meaning given above and y / is oxygen or sulfur, converts to obtain a 4 (R) derivative of the formula (VIII) Cf * »* Y ^ 3. (VIII) COOR ₂ wherein R, R, R ₂ '^ ^{ulil (^} ^ ^^ ^e h ^{before he} stated meanings; and (g) a 4 (R) compound of the formula (VIII) cyclized and, if desired, a compound of the formula (I) in which R _? Is hydrogen, converted into a salt and / or, if desired, a compound of the formula (I) in which R ₂
Hydrogen or a cation means esterified
and / or, if desired, a connection of the
Formula (I) is obtained in which R _{2 is} hydrogen or a cation in the event that R _{2 is} a carboxy protecting group and / or, if desired, a Compound of the formula (I) converted into another compound of the formula (I). - 6 - Process for the preparation of an optically active trans-6-substituted-5 (R) -2-penem-3-carboxylic acid derivatives of the formula (I) according to claim 1, characterized in that one a mercapto salt of the formula (VII) according to claim 1 with a reactive derivative of an acid or a thioacid of the formula ^0H R ₁ -C in which R ₁ and Vi / have the meanings given in claim 1, reacted and the compound of formula (VIII) obtained cyclized. 3. The method according to claims 1 and 2, characterized in that the remainder A from a radical is selected from the thiol-A-SH group and the compounds of the formulas (III), (IV), (V) and (VI) from dimethyl-tert-butylsilyl, trityl, CO-methoxy-ethyl, Tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, 2-oxa-bicyclo / 3.3.07octan-3-yl and 2-oxa-bicyclo / 3.3. 0_7oct-6,7-en-3-yl is. 25th 4. The method according to claims 1 or 2, characterized in that the metal cation M ^{n +} in the metal salt M ^{n +} -Y ⁿ ~ and the mercapto salt of the formula (VII) is a cation of a. Heavy metal from the group Ag, Hg, Au, Cu and Pb. 5. A 4 (R) compound of the formula (VIII) according to claim 1 . 6. Process for the preparation of a 4 (R) compound of the formula (VIII) according to Claim 1, characterized in that a 4 (R) mercapto salt is used of formula (VII) according to claim 1 with a reactive derivative of an acid or a Thioacid of the formula OH R ₁ -C wherein R ₁ and ψ have the meanings given in claim 1, reacts. 7. The method according to claim 6, characterized in that the 4 (R) mercapto salt Formula (VII) is a salt of a heavy metal selected from Ag, Hg, Au, Cu and Pb. 8. A 4 (R) mercapto salt of the formula (VII) according to claim 1 . 9. A 4 (R) mercapto salt according to claim 8 of the formula (VIIA) OH • 4, .S- "V COOR, (VIIA) - 8th where R _? , 0, M and η have the meanings given in claim 1, R denotes a radical of an acyl group and the carbon atom which bears the hydroxyl group is in the R configuration. 10. A 4 (R) mercapto salt according to claim 8 of the following Formula (VIIB) OH χ χ H s- COOR Mf ¹⁺ wherein R2 ι Φι M and η have the meanings given in claim 1, R denotes the remainder of an acyl group and the atom bearing a hydroxyl group is in the S configuration. 11. A 4 (R) compound according to claims 9 and 10, wherein RC is ₁ , -alkyl or phenyl. 12. A 4 (R) compound according to claims 9 or 10, wherein R is methyl. 13. A compound according to claims 8 to 12, wherein the salt is a salt of a heavy metal from the group Is Ag, Hg, Au, Cu and Pb. 9 - 14. A process for the preparation of a 4 (R) -mercapto salt of the formula (VII) according to any one of claims 8 to 13, characterized in that a 4 (R) -phosphorane of the formula (VI) according to claim 1 is mixed with a solution of a heavy metal salt of the formula M ^{n +} -Y ⁿ , in which M ⁿ and Y ⁿ ~ have the meanings given in Claim 1. 15. A 4 (R) compound of the formula (VI) according to claim 1. 16. A 4 (R) compound of the formula (VI) according to claim 1 of the formula (VIA) OH
J. (VIA) wherein R ~, A and 0 have the Be given in claim 1 have meanings, R denotes the remainder of an acyl group and the carbon atom bearing a hydroxyl group is in the R configuration. 25th 17. A 4 (R) compound of the formula (VI) according to claim 1 of the formula (VIB) ul I (VIB) - 10 - wherein R ", A and 0 are those given in claim 1 Have meanings, R denotes the remainder of an acyl group and the carbon atom bearing the hydroxyl group is in the S configuration. 5 18. A 4 (R) compound according to claims 16 and 17, wherein R is a C - ^ - alkyl or phenyl. 19. A 4 (R) compound according to claims 16 and 17, wherein R is methyl. 20. A 4 (R) compound of the formula (VI) according to claims 15 to 19, in which A is a radical selected from dimethyl-tert-butyl-silyl, trityl, o ^ -Methoxy-ethyl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, 2-oxa-bicyclo / 3.3.0 / octan-3-yl and 2-Oxa-bicyclo / 3.3.07oct-6-en-3-yl and each group 0 is phenyl. 21. A process for the preparation of a 4 (R) compound of the formula (VI) according to any one of claims 15 to 20, characterized in that a 4 (R) compound of the formula (V) according to claim 1 is mixed with a phosphine derivative of the formula P0 ₃ , wherein 0 has the meaning given in claim 1, converts. 22. The method according to claim 21, characterized in that the phosphine derivative tripheny! Phosphine is. 11 - 23. The method according to claim 21, characterized in that the in formula (V) contained halogen is chlorine. 24. A 4 (R) compound of the formula (V) according to claim 1. 25. A 4 (R) compound of the formula (V) according to claim 24 / in which X is chlorine and A has the meaning given in claim 20. 26. Process for the preparation of a 4 (R) compound of the formula (V) according to Claims 24 or 25, characterized in this characterized in that one 'a 4 (R) -carbinol of the formula (IV) according to claim 1 halogenated. 27. The method according to claim 26, wherein the group A in the carbinol. of formula (IV) has the meaning given in claim. 28. A 4 (R) compound of the formula (IV) according to claim 1 . 29. A 4 (R) compound of the formula (IV) according to claim 28, wherein the group A has the meaning given in claim. 30. A process for the preparation of a 4 (R) compound of the formula (IV) according to claims 28 or 29, thereby marked that one a 4 (R) compound of the formula {III) according to claim 1 with a glyoxylic acid derivative of the formula OHC-COOR ₂ , in which R _{2 has} the meaning given in claim 1. 5 31. The method according to claim 30, characterized in that the group A in the compound of formula (III) has the meaning given in claim 20. 32. A 4 (R) compound of the formula (III) according to claim 1. 33. A 4 (R) compound of the formula (III) according to claim 32, wherein the group A has the meaning given in claim 20. 34. A process for the preparation of a 4 (R) compound of the formula (III) according to claims 32 or 33, characterized in that a 4 (R) compound of the formula (II) according to claim 1 with a thiol of the formula ASH, in which A has the meaning given in claim 1, is reacted. 35. The method according to claim 34, characterized in that the group A in the thiol A-SH has the meaning given in claim 20. 36. A 4 (R) -compound of formula (II) - 13 - -NH OH (II) 37. Process for the preparation of a 4 (R) compound of the formula (II) "IiH 3 3 OH (II) wherein R and R _{3 have} the meanings given in claim 1, characterized in that one (a) ■ a compound of the formula (XIII) .R- (XIII) wherein R _{3 has} the meaning given above, into a compound of the formula (XIV) τ> ■ R. H ₃ C ^X CH ₃ (XIV) - 14 - wherein R and R. have the meanings given above have convicted; (b) a compound of the formula (XIV) to give a compound of the formula (XV) ö * ZV__c / ^(xv) VbT ₃ wherein R and R _{3 have} the meanings given above, oxidized; and (c) the Ν, Ο-protecting group removed from a compound of the formula (XV). 38. A compound of the formula (XV) according to claim 39. A process for the preparation of a compound of the formula (XV) according to claim 38, characterized in that g e k e η η draws that a compound of the formula (XIV (according to claim 37) is oxidized. 40. A compound of the formula (XIV) according to claim 41. A compound of the formula (XIII) according to claim 37. 42. Process for the preparation of a compound of formula (XIIIA) Cf CH. H ^H 3 ^C CH. (XIIIA) 10 15 characterized in that one (a) a compound of formula (XVI) // N (XVI) COOH subjected to a Curtius degradation, to obtain an aldehyde of the formula (XIX) 20th ■ NH 3 CH. (XIX) CHO 25 30 (b) the aldehyde of the formula (XIX) to one Alcohol of formula (XX) CH S ^ ³ "NH "CH. • OH (XX) - 16 - reduced; and (c) subjecting the compound of the formula (XX) thus obtained to acetonidation. 43. Process for the preparation of a compound of formula (XIIIB) < (XIIIB) H ₃ C CH ₃ characterized in that one 15 (A) a compound of the formula (XVi) according to claim 42 into a compound of the formula (XXIIA) J N ^ / ₃ ° (XXIIA) COOK wherein R ₅ and R _ß independently of one another are C, g 'groups, converts; (b) the 1-substituent in a compound of the formula (XXIIA) is oxidatively removed to obtain a compound of formula (XXIII) 30 ^ COOR. -NH (XXIII) wherein R _{g has} the meaning given above; (c) a compound of the formula (XXIII) is reduced to give a compound of the formula (XXIV) "OH -NH (XXIV) and 20th (d) subjecting the compound of the formula (XXIV) thus obtained to an acetone oxidation. 25 30 44. Process for the preparation of a compound of formula (XIII) (XIII) H ₃ C CH ₃ wherein R _{3 has} the meaning given above, characterized in that one - 18 - (a) a 2-oxo-azetidine derivative of the formula (XXV) NH ^(XXV) wherein L is a nucleofugal leaving group with a thioglycolic acid derivative of the formula R R HS-C-COOH wherein each R ₃ group has the meaning given in claim 1, reacts to obtain a mixture of enantiomeric compounds of the formula (XXVI) and (XXVI ^s ) ^R ^ Q ^R 3 ^E 3 NH <f ^Wil COOH cf "" COOH (XXVI ^R ) (XXVI ^S ) wherein R _{3 has} the meaning given above; 25th (b) the enantiomer of formula (XXVI) of separating the enantiomer of formula (XXVI) by cleavage; (C) a compound of the formula (XXVI ^R ) is esterified with an alcohol of the formula R ₆ OH, in which R _{6 is} a C] _g-alkyl, to give a - 19 - Compound of formula (XXVII) j? NH j (XXVII) ⁰ COOR ₆ wherein R ₃ and R _{g have} the meanings given above;
10 (d) a compound of the formula (XXVII) to a compound of the formula (XXVIII) —NH j ^K 3 (XXVIII) OH Wherein R _{3 has} the meaning given above, reduced; and (e) subjecting the compound of formula (XXVIII) to acetonidation. 45. A process for the preparation of a compound of the formula (XIII) according to claim 37, in which the Acetonidation of a compound of the formula (XXVIII) according to claim 44 is carried out. 46. A 4 (R) compound of the formula (XXVIII) according to claim 44. 47. Process for the preparation of a compound of the formula (XXVIII) according to Claim 46, characterized in that a compound of the formula (XXVII) according to claim 44 reduced, 48. A 4 (R) compound of the formula (XX) according to claim 42. 49. Process for the preparation of the compound of formula (XX) according to claim 48, characterized in that a compound of Formula (XIX) according to claim 42 reduced. 50. A 4 (R) compound of the formula (XIX) according to claim 42. • 51. Process for the preparation of a compound of the formula (XIX) according to Claim 50, characterized in that a compound of the formula (XVI) according to claim 42.subjected to a Curtius degradation. 52. A 4 (R) compound of the formula (XXIII) according to claim 42 or of the formula (XXVII) according to claim 44. 53. A process for the preparation of a compound of the formula (XXIII) according to claim 52, characterized in that in a Compound of the formula (XXIIA) according to claim 4 removes the 1-substituent oxidatively. 54. Method of making a compound of Firmel (XXVII) according to claim 52, characterized in that a compound of the formula (XXVI) according to claim 44 with an alcohol of the formula RcOH, in which R, the in claim 44 has given meaning, esterified. 55. A 4 (R) compound of the formula (XXIIA) according to claim 4 3. 56. A process for the preparation of a compound of the formula (XXIIA) according to claim 55. characterized by having a connection of formula (XXII) (XXII) wherein R, - and R _{g have} the meanings given in claim 43, isomerized. 57. A compound of the formula (XXII) according to claim 56. 58. Process for the preparation of a compound of the formula (XXII) according to claim 57, characterized in that one. Connecting formula of formula (XXI) (XXI) in which R ₁ - has the meaning given in claim 4 3, with a compound of the formula KLCH-COOR _n , in which R has the meaning given in claim 43, reacts. 59. Process for the preparation of a compound of the formula (XXIIA) ge-äss claim 55, characterized in that one compound of formula (XXIA) CH- (XXIA) COOR _r wherein Rj- has the meaning given in claim 43 has, with a compound of the formula OR, = C wherein R, - has the meaning given in claim 43 has implemented. 60. A 4 (R) compound of the formula (XXVI ^R ) according to. Claim 44. 61. A 7 (R) -8 (S) -9-Oxo-3 ~ oxa-6-thia-1-aza-bicyclo- / 5.2.0 '_ / - nonane derivative of the following formula (XIVA) (XIVA) ^J 'CH ₃ wherein R- has the meaning given in claim 1 has, R means the remainder of an Acy! group and the carbon atom bearing the hydroxyl group is in the R configuration. .62. A 7 (R) -8 (S) -9-oxo-3-oxa-6-thia-1-aza-bicyclo ~ /5.2.0 ^1/ 7_7-nonane derivative of the formula (XIVB) ° ^H A N yS ■ (XIVB) egg?! \ . . - 3 CH wherein R-. the meaning given in claim 1 has, R denotes the remainder of an acyl group and that which carries the hydroxyl group. Carbon atom in the S configuration is available. 63. A compound according to claims 61 and 62, wherein R is a C, - alkyl or phenyl. 64. A compound according to claims 61 or 62. wherein R is methyl. 65. A compound of the formula (XIVA) or (XIVB) according to claims 61 to 64, wherein each R., - group Means methyl. 66. Process for the preparation of a compound of the formula (XIVA) according to claim 61, characterized in that a 7 (R) -8 (S) - - 1 7 - e-Acyl-g-oxo-S-oxa-e-thia-i-aza-bicyclo / 5.2.0 _ / - nonane derivative of the formula (XXX) (XXX) • / s i \ S wherein R-. and R those in claims 61 to 65 • j X given meanings. have, by means of a complex hydride from a weakly polarizing cation at ambient temperature to a weakly solvating medium stereoselectively reduced. 67. The method according to claim 66, characterized in that g e k e η η that the complex hydride is a potassium or sodium or ammonium complex hydride. - 25 - 68. The method according to claim 67, characterized in that the complex hydride is a Is potassium complex hydride. 69. The method according to claim 68, characterized in that the potassium complex hydride K-Selectricidev5) is. 70. The method according to any one of claims 66 to 69, characterized in that the Reaction temperature is between +20 and + 40 ° C. 71. The method according to any one of claims 66 to 70, characterized in that the the weakly solvating medium is diethyl ether. 72. A process for the preparation of a compound of the formula (XIVB) according to claim 62, characterized in that a compound Preparation of the formula "(XXX) according to claim 66 by means of a complex hydride from a highly polarizing one Cation stereoselectively at a low temperature in a highly solvated medium reduced. 73. The method according to claim 72, characterized in that the complex hydride is a Lithium complex hydride is. 74. The method according to claim 73, characterized in that the lithium complex hydride is Li-Selektride ®. 75. The method according to any one of claims 72 to 74, characterized in that the reaction temperature is ^{between -80 and -6 0 0 C.} 76. The method according to any one of claims 72 to 75, characterized in that the The highly solvated medium is tetrahydrofuran or dimethoxyethane. 77. A trans-6 (S) -5 (R) -2-penem-3-carboxylic acid derivative of the formula (I) according to claim 1, wherein R and R- are, independently of one another, C _1-6 -alkyl and R 2 is hydrogen, C ._g-alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation. 78. A compound according to claim 77, wherein R and Usually, independently of one another, methyl, ethyl or propyl mean. 79. A compound selected from the group consisting of: Methyl (6S) -6-ethyl- (5R) -2-methyl-2-penem-3-carboxylate, Methyl (6S) -6-ethyl (5R) -2-ethyl-2-penem-3-carboxylate, Methyl (6S) -6-ethyl- (5R) ^ -propyl ^ -penem-S-carboxylate, Methyl (6S) -6-methyl- (5R) ^ -methyl ^ -penem-carboxylate, - Methyl (6S) -6-methyl- (5R) - ^ - carboxylate, methyl (6S) -6-methyl (5R) ^ - carboxylate, methyl (6S) -6-propyl- (5R) - ^ - carboxylate, methyl (6S) -6-propyl- (5R) ^ - carboxylate, methyl (6S) -6-propyl- (5R) ^ - 0 carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) ^ - 3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-ethyl-2-penem ~ 3-carboxylate, p-nitrobenzyl (6S) -6-ethyl (5R) ^ -propyl - ^ - penem- 3-carboxylate,. p-nitrobenzyl (6S) -6-methyl- (5R) ^ -methyl ^ -penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl (5R) -2-ethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-propyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-methyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-ethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-propyl-2-penem-3-carboxylate, (6S) -6-ethyl- (5R) -2-methyl-2-penem-3-carboxylic acid, (6S) -6-ethyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-ethyl- (5R) -2-propyl-2-penem-3-carbojic acid, (6S) -6-methyl- (5R) -2-methy1-2-penem-3-carboxylic acid, (6S) -6-methyl- (5R) ^ -ethyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ - propyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) -2-methyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-ethyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-propyl-2-penem-3-carboxylic acid and pharmaceutically or veterinarily acceptable salts of the free acid.
10 80. A trans-6 (S) -5 (R) -2-penem-3-carboxylic acid derivative of the formula (I) according to claim 1, wherein R is C.-_g-alkyl, R * is C ₁ -alkanoyloxymethyl and R ₂ is hydrogen, C ₁ _g-Alkanoylmethyl, an optionally nitro-substituted benzyl group, or a pharmaceutically or veterinarily acceptable cation. 81. A compound according to claim 80, wherein R is methyl, Ethyl or propyl and R _{1 are} acetoxymethyl or propionyloxymethyl. 82. A compound selected from the group consisting of: p-Nitrobenzyl (6S) -6-ethyl- (5R) ^ -acetoxy-methyl ^ - penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-acetoxy-methyl-2-penem-3-carboxylate,
p-nitrobenzyl (6S) -6-propyl- (5R) -2-acetoxy-methyl-2-penem-3-carboxylate, - 29 - p-nitrobenzyl (6S) -6-methyl- (5R) -2-propionyloxymethyl-Z-penem-S-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-propionyloxymethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl (5R) -2-propionyloxymethyl-2-penem-3-carboxylate, Acetonyl (6S) -6-ethyl- (5R) ^ -acetoxy-methyl ^ -penem-3-carboxylate, Acetonyl (6S) -6-methyl- (5R) ^ - acetoxy-methyl ^ - penem-3-carboxylate, Acetonyl (6S) -6-propyl- (5R) ^ -acetoxy-methyl ^ - penem-3-carboxylate, Acetonyl (6S) -6-methyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylate _/
Acetonyl (6S) -6-ethyl- (5R) -2-propionyloxy-methy1- 2-penem-3-carboxylate, Acetonyl (6S) -6-propyl- (5R) -2-propionyloxy-methyl-2-penem-3-carboxylate, (6S) -6-ethyl- (5R) ^ -acetoxy-methyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -acetoxy-methyl ^ -penem-S-carboxylic acid /
(6S) -6-propyl- (5R) -2-acetoxy-methyl-2-penem-3-carboxylic acid,
(6S) -6-methyl- (5R) ^ -propionyloxy-methyl ^ -penem-3-carboxylic acid, (6S) -6-ethyl- (5R) ^ -propionyloxy-methyl ^ -penem-3-carboxylic acid, (6S) -6-propyl- (5R) ^ -propionyloxy-methyl ^ -penem-3-carboxylic acid, Methyl (6S) -6-ethyl- (5R) ^ -acetoxy-methyl - ^ - penern-3-carboxylate, Methyl (6S) -6-methyl- (5R) ^ -acetoxy-methyl ^ -penem-3-carboxylate, Methyl (6S) -6-propyl- (5R) - ^ - acetoxy-methyl ^ -penein-3-carboxylate, Methyl (6S) -6-methyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate, Methyl (6S) -6-ethyl- (5R) ^ - propionyloxy-methyl ^ - penem-3-carboxylate, Methyl (6S) -6-propyl- (5R) ^ -propionyloxy-methyl ^ - penem-3-carboxylate and pharmaceutically or veterinarily acceptable salts of the free acids. 83. A trans-6 (S) -5 (R) -2-penem-3-carboxylic acid of the formula (I) according to claim 1, wherein RC, - alkyl, RJ Ο .. _g-alkoxycarbonyl and R _{2 is} hydrogen , C, g-alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation. 84. A compound according to claim 83, wherein R is methyl, ethyl or propyl and R _{1 is} methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl. 85. A compound selected from the group consisting of: p-nitrobenzyl (6S) -6-ethyl- (5R) -2-ethoxy carbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, - τ ι _ p-nitrobenzyl (6S) -6-propyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-propoxycarboriyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-ethyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate, (6S) -6-ethyl- (5R) - ^ - ethoxycarbonyl ^ -penem-S- carboxylic acid, ■ (6S) -6-methyl- (5R) ^ -ethoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) ^ - ethoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ - methoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-ethyl- (5R) -2-methoxycarbonyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) ^ -methoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-methyl- (5R) ^ -propoxycarbonyl ^ -penem-3-carboxylic acid, (6S) -6-ethyl- (5R) ^ -propoxycarbonyl ^ -penem-S-carboxylic acid, (6S) -6-propyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylic acid, Methyl (6S) -6-ethyl- (5R) -2-ethoxycarbonyl-2-penem-3-carboxylate, Methyl (6S) -6-methyl- (5R) - ^ - ethoxycarbonyl ^ - penem-3-carboxylate,
Methyl (6S) -6-propyl- (5R) ^ - ethoxycarbonyl ^ - penem-3-carboxylate, Methyl (6S) -6-methyl- (5R) ^ -methoxycarbonyl ^ - penem-3-carboxylate, Methyl (6S) -6-ethyl- (5R) ^ -methoxycarbonyl ^ -penem-3-carboxylate, Methyl (6S) -6-propyl- (5R) ^ -methoxycarbonyl ^ - penem-3-carboxylate, Methyl (6S) -6-methyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate,
Methyl (6S) -6-ethyl- (5R) ^ -propoxycarbonyl ^ - penem-3-carboxylate, Methyl (6S) -6-propyl- (5R) -2-propoxycarbonyl-2-penem-3-carboxylate and pharmaceutically or veterinarily acceptable Free acid salts. 86. A trans-6 (S) -5 (R) -2-penem ~ 3 - carboxylic acid of the formula (I) according to claim 1, in which RC, _{g is} alkyl, R. is a thienylmethyl group and R _{2 is} hydrogen, C ₁ , -alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation. 87. A compound according to claim 86, wherein R is methyl, ethyl or propyl and R _{1 is} 2-thieny! Methyl. - 33 ■ 88. A compound selected from the group consisting of: p-nitrobenzyl (6S) -6-ethyl- (5R) -2-thien-2'-ylmethyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-methyl- (5R) -2-thien-2'-yl- methyl-2-penem-3-carboxylate, p-nitrobenzyl (6S) -6-propyl- (5R) -2-thien-2'-yl- methyl-2-penem-3-carboxylate,
(6S) -6-ethyl- (5R) -2-thien-2'-yl-methyl-2-penem- 3-carboxylic acid, (6S) -6-methyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylic acid, (6S) -6-propyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylic acid, Methyl (6S) -6-ethyl- (5R) -2-thien-2'-yl-methyl-2- penem-3-carboxylate, Methyl (6S) -6-methyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate,
Methyl (6S) -6-propyl- (5R) -2-thien-2'-yl-methyl-2-penem-3-carboxylate and pharmaceutically or veterinarily acceptable salts of the free acid.
25th 89. The method according to claim 1, characterized in that g e k e η η indicates that it is used for the production of a compound according to claims 77-88 will. 90. A pharmaceutical or veterinary composition from a connection according to one of the preceding claims 77 to 88 with a pharmaceutically or veterinarily acceptable carrier or diluents. 91. A compound or a salt according to formula (I) in claim 1 of the type specifically mentioned here. 92. A compound or a salt of the formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (XIII), (XIV), (XV), (XIX), (XX), (XXIIA), (XXIII), (XXVI ^R ), (XXVII), (XXVIII) or (XXII) of the kind described and particularly mentioned here. 93. A process for the preparation of a compound or a salt of the formula (I) according to claims 1 or 2, according to the embodiments in the examples. 94. Method of making a compound or a salt according to any one of claims 6, 14, 21, 26, 30, 34, 37, 42, 43, 44, 45, 47, 49, 51, 53, 54, 56, 58, 59, 66 or 72 of the type described herein, with reference to the examples. 95. Composition according to claim 90, in the type essentially described above. 96. Use of a compound or a salt according to any one of claims 77 to 88 for treatment of the human or animal body during operations or for therapy or for diagnostic purposes. - 35 -