DD152561A5 - PROCESS FOR THE PREPARATION OF PENICILIN DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of penicillin derivatives for use as antibiotics in humans and animals. The aim of the invention is the provision of new penicillin derivatives with improved antibiotic activity and a broad spectrum of activity, which are effective for a wide range of Gram-positive and Gram-negative bacteria, also against Pseudomonas. According to the invention, penicillin derivatives of the formula (III) and their salts and esters, for example 2 - & (2-aminoethyl) thio! -6- (1-hydroxyethyl) penem-3-carboxylic acid, are prepared, for example, by the heat-induced ring formation of a phosphorylidene compound which, if necessary, elimination of the protecting groups and salt formation or esterification follows. The compound exists as a variety of stereoisomers, of which (5R, 6S) -2 - & (2-aminoethyl) thio! -6 - & (R) -1-hydroxyethyl) penem-3-carboxylic acid and its salts and esters to be favoured.

Description

Berlin, 5 "11 · 1980

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Process for the preparation of penicillin derivatives Field of application of the invention

The present invention relates to certain novel penem-3-carboxylic acid derivatives, their preparation and use as antibiotics in the treatment of many diseases caused by both Gram-positive and Gram-negative bacteria. "

Characteristic of the known technical solutions

The penicillins are a well-known class of antibiotics that has been used extensively in human and animal therapy for many years. Benzylpenicillin, which was the first antibiotic to be commonly used therapeutically, is in fact still widely used today. Chemically, the penicillins share a β-lactam type structure, commonly called "penam", having the following formula (I):

Although penicillins are still a valuable weapon in the pharmaceutical arsenal, the development of new, often penicillin-resistant, pathogenic bacterial strains has increasingly required the search for new types of antibiotics. Recently, interest has been shown in compounds having a penile structure. d _# h. Compounds having a double bond between the carbon atoms on the

fi Γ. Π -: - W '" ! - ri Vi

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2- and 3-position of the basic penam structure have. The penem structure looks like this:

This penam structure and penem structure form the basis for the semi-systematic nomenclature of penicillin derivatives. This nomenclature is generally accepted by specialists in this field throughout the world. However, there is no universal agreement in the numbering system to be adopted with respect to the ring positions., The penem structure; so as not to be in doubt, the numbering system shown in formula (II) is used throughout the present invention *

The original discovery of penicillin (now called "benzyl-penicillin") by Fleming was only the first step in a continuous process that led to the discovery of a large fanilism of penicillins, i. h, both "natural" (produced by cultivation of microorganisms, especially fungi Peni Cillium nat ate and Penicillium chrysogenurn) as well as semi-synthetic (produced by chemical manipulation of "natural" penicillins), of which that most of at least one degree of antibiotic activity. However, despite the large number of penicillins currently available, there is still a need for new antibiotics and considerable efforts and sums are regularly invested in trying to meet these needs. The reasons for this are that many infectious microorganisms are either naturally resistant to the penicillins or capable of producing this resistance.

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long, and that some penicillins are restricted in their mode of administration due to a stability restriction. For example, the original benzylpenicillin is unstable to acids and thus largely ineffective when administered orally. Furthermore, the widespread use of penicillins in recent years has tended to promote the development of resistant strains. The 'development and rapid dissemination of penizillinresistenten gonococcal and Pneumokokkusstämmen, especially former caused many medical and social problems in the Western world and thus made the penicillins in the treatment of diseases for. they used to be the chosen antibiotic, ineffective.

Besides pathogenic microorganisms that are resistant to penicillin, there are many genera that have always been recognized as resistant to penicillin. The genus Pseudotnonas is the most important. Of the relatively commonly used penicillin derivatives, only carbenicillin has significant activity against microorganisms of the genus Pseudomonas, and this is possible only at relatively high concentrations - its minimum inhibitory concentration (MIC) is about 50 μg / ml fGarrod et al. "Antibiotic and Chemotherapy "4, Ed., Published by Churchill Livingstone, Edinburgh, (1973), p. 82j. Even then, resistance to carbenicillin in pseudomonas species develops, rendering the extended treatment ineffective. In addition, carbenicillin is poorly absorbed by the gastrointestinal tract and must therefore be administered intravenously or intramuscularly. "" Martindale, The Extra Pharmacopoeia, 26 "Edition, The Pharmaceutical Press, London, (1972), p 1327ff. Other penicillin derivatives, from it was reported that that they are rten against Pgeudomonasa active, have other disadvantages and

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have not yet been widely used (Garrod et al., pp cit, S, 85-86) *

In contrast to MIC = 50 pg / ml Karbenizillin opposite jP eeu d ^ moηas aerucjinosa, MIC of one of the preferred Peneinderivate the invention, only 6 ^ jg / ml over the same micro-organism, which means almost a tenfold improvement *

Certain penem derivatives are disclosed in GB Patent Application No. 2 013 _e G74A to Ciba Geigy. Other compounds are disclosed in US Patent Application Serial No., 852.274, No, 852 278, No., 852 427, No. _e 948.711, 948.712 and 948,713, all assigned to Merck and Co, Inc. USSN 852,427 was issued as US Pat. No. 4,168,314.

However, although the U.S. applications and patent referred to above and assigned to Merck and Co., Inc., describe the preparation and properties of penem compounds, including the preparation of 2- (2-aminoethyl) thio US Pat. No. 4,168,314, it has been shown that the processes of these applications and this patent produce only open-shell compounds. See, for example, S. Oida et al., Tetrahedron Letters 2jl, 619 (1980) and M. Lang et al., 3rd Amer. Chem, Soc. 101: 21, 6295-6301 (1979) and the information set forth below,

Target aer invention.

The aim of the invention is the provision of 'penicillin' derivatives with improved antibiotic activity and a

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broad range of activity »which are also effective against bacteria that are not attacked by the known penicillin derivatives.

Explanation of the essence of the invention

The invention has for its object to find new penicillin derivatives with the desired properties and to provide methods for their preparation.

We have now discovered a number of novel penem-3-carboxylic acid derivatives, a process for their preparation and pharmaceutical compounds containing these penem-3-carboxylic acid derivatives as active ingredients in admixture with a pharmaceutical

contain acceptable carriers or diluents.

The novel penem-3-carboxylic acid derivatives of the present invention are 2-C (2-aminoethyl) thio3-6- (1-hydroxyethyl) penem-3-carboxylic acid having the formula (III):

SCH ₂ CH ₂ NH ₂

(III)

"COOH as well as its pharmaceutically acceptable salts and esters"

The compounds of the invention can be prepared by heat-induced ring formation of a phosphorylidene compound of the formula (IV):

SCH ₀ CH ₀ R

be prepared, (in the

1 R represents a protected hydroxy group;

R represents a protected amino group or a protected hydroxy group; R represents a protected carboxy group and Z ⁴ * represents a trisubstituted phosphonium group »

or a doubly esterified phosphonium group having a cation) therewith a compound of the formula (V):

SCH ₂ CH ₂ R

(V)

arises

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Wherein R, R and R have the same meaning as above. The protected hydroxy group R is then transformed into a hydroxy group.

2 and the protected amino or hydroxy group R are converted into an amino group, and if desired, the protected carboxy group R is converted into a carboxy group to give the compound of formula (III) and an ester thereof. If necessary, this compound of formula (III) may then be salified or esterified to give a salt or ester therefrom.

The compound 2-f (2-aminoethyl) thio3-6- (1-hydroxyethyl) penem-3-carboxylic acid and thus its salts and esters may exist in the form of various stereoisomers, all of which are within the present invention. Due to asymmetric carbon atoms in the 5-position and 6-position, isomerism is possible in the ring system. The preferred isomers are those in which the carbon atom in the 5-position is arranged in the same way as the natural penicillins, ie in the R-arrangement, and thus the preferred isomers have the arrangement (5R, 6R) or (5R, 5S). There is also an asymmetric carbon atom in the 1-hydroxyethyl side chain at the 6-position, of the two possible arrangements for this carbon atom, the isomers with the R-arrangement are preferred. The most favorable isomers are those in which the 5-carbon atom is in the R-arrangement, the 6-carbon in the S-arrangement and the carbon in the side-chain in the R-arrangement, ie (5R, 6R) -2 ~ / "(2-aminoethyl) thioJ-6- (R) -1-hydroxyethyl) -penicarboxylic acid and its salts and esters.

A wide variety of salts and esters are possible, the selected ones take into account their pharmacological or other properties, and these are the specialists in the field

in connection with other penicillin derivatives so well known that no further explanation is required., preferred salts are: salts of stalls such as lithium, sodium ¹ , potassium or magnesium, ammonium salts and salts of organic amines such as cyclohexylammonium. "Diisopropylamonium or triethylammonium salts" The sodium and potassium salts are preferred. "" Suitable esters include the pivaloyloxymethyl ester and the titerarybenzyl ester because the pivaloyloxymethyl and p-nitrobenzyl groups are protected to protect the carboxyl group in the 3-position can be used in the course of the process of the invention.

As already noted, the compounds of the invention may be prepared via the ring-forming of a phosphorylidene compound of formula (IV). This in turn may be prepared from a ii-zetidin-2-one compound of formula (IV), viz the first four stages of the following reaction scheme, which also illustrates the preparation of the compounds of the invention:

(UfII)

\ 5

CW

(Wi

ca ^ Co,

Hi

0 "- - ^ a (Uia)

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12 3 + In the given formulas R ₁ R, R and Z are the same

as defined above and: \

3 a R represents a carboxy group or a protected carboxy group;

X represents an azyloxy group (eg, an acetoxy, propionyloxy or benzoyloxy group), an alkylsulfonyl group (z, B, a methylsulfonyl or ethylsulfonyl group) or an arylsulfonyl group (z ", a benzenesulfonyl or p-Toluolsulf onylgruppe) and

Y represents a halogen atom, _{e e} B "a chlorine _f bromoder Dodatorn"

V / o Z represents a trisubstituted phosphonium group, it is preferably a tri (lower alkyl) phosphonium group (z, B. a tributylphosphonic group) or a triarylphosphonium group (eg, triphenylphosphonic group). Where Z represents a di-esterified phosphonium group having a cation, the phosphono group is preferably a diethylphosphono group, and the cation is preferably a lithium or potassium atom,

In step (a) of the above reaction scheme, a 4'-acyloxyazetidin-2-one or 4-sulfonylazetidin-2-one derivative of the formula (IV) is reacted with an alkali metal trithiocarbonate of the formula (X):

MSC-SCH ₂ CH ₂ R ² (X)

2 "

where R has the same meaning as defined above and M is an alkali metal atom, e.g. As a sodium or

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Potassium atom, to give a compound of formula (VII).

The alkali metal trithiocarbonate of the formula (X) which is used as a starting material in this step can itself be obtained by a conventional method by reacting a mercaptan of the formula (XI):

HS - CH ₂ CH ₂ R ² (XI)

Where R is as defined above, carbon disulfide is formed in the presence of an alkali metal oxide (e.g., sodium, hydroxide or potassium hydroxide) or an alkali metal alcoholate (z, B, potassium methoxide, sodium ethylate or potassium ethylate).

Dip reaction in step (a) is carried out by contacting the azetidine-2-one derivative of formula (VI) with the alkali metal trithiocarbonate of formula (X), preferably in a molar ratio of 1: 1 to 1: 1.5 and preferably in the presence of a solvent. There are no particular limitations on the type of solvent, provided that the solvent does not adversely affect the reaction. Examples of suitable solvents include: water, alcohols such as methanol, ethanol or propanol, ketones such as acetone or methyl ethyl ketone and dialkyl (fatty acid) amides such as dimethylformamide or dimethylacetamide. It may be such a single solvent or a mixture of two or more solvents, e.g. B, a mixture of water with one or more of the above-mentioned organic solvents.

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The reaction temperature is not a particular problem and therefore we prefer to carry out the reaction at a temperature between 0 and 50 ^° C. The time required for the reaction depends mainly on the starting material and the reaction temperature. But normally the reaction is within one Time from 10 minutes to 2 hours ended *

After completion of the reaction, the desired product of formula (VII) can be recovered by conventional methods from the reaction mixture "Eim suitable method consists in that to the reaction mixture a water immiscible organic solvent (such as ethyl acetate) was added and water, Separate the organic layer, purify with water, dry with a desiccant and finally distill off the solvent to give the desired compound. If desired, this compound can be further purified by conventional methods such as recrystallization, preparative thin-layer chromatography or column chromatography.

In step (b) of the Reaction Scheme, a compound of formula (VIII) is prepared by reacting the compound of formula (VII) in in step (a) 3 with a glyoxylic acid ester of general formula (XII):

" ⁵ (XII)

wherein R is as defined above.

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The reaction in step (b) can be easily carried out by contacting the compound of formula (VI) with the glyoxylic acid ester of formula (XII) in the presence of a solvent. The type of solvent is not problematic provided it is does not adversely affect the reaction. Preferred solvents include: ethers, such as tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene or toluene; Dialkyl (fatty acid) amides and mixtures of any two or more organic solvents «

The reaction in step (b) can be accelerated by the presence of a base. Suitable bases include: organic bases such as triethylamine, diisopropylethylamine, pyridine, or a sodium silicate aluminum molecular sieve. The reaction temperature is not problematic, and we generally prefer to carry it out However, where a base is used, the preferred reaction temperature is approximately in the range of room temperature; on the other hand, if no base is used, the preferred reaction temperature is the reflux temperature of the solvent The time required for the reaction depends mainly on the nature of the starting material and the reaction temperature, but in the normal case the reaction is completed in a time of 1 to 6 hours.

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After completion of the reaction, the desired compound of formula (VIII) can be prepared by conventional methods from the

Be • reaction mixture recovered "At an appropriate method includes, for example - if necessary, first, the filtering of insoluble substances, and then purifying aer reaction mixture with 'water Tnocknen OCE mixture and distilling all the solvent and excess reagents, so that the desired compound is formed' If necessary, this connection can

• be further purified, which is done by conventional methods, for example recrystallization, preparative thin-layer chromatography or column chromatography »

In step (c) of the above reaction scheme, the compound of formula (VIII) is converted into the compound by halogenation

220 3 92

of the formula (IX) implemented. This reaction can be easily carried out by bringing the compound of formula (VIII), preferably in the presence of a solvent, into contact with a halogenating agent. There is no particular limitation on the nature of the halogenating agent, provided it does not affect other parts of the molecule. The preferred halogenating agents include: thionyl halides such as thionyl chloride or thionyl bromide; phosphorus oxyhalides such as phosphorus oxychloride; Phosphorus halides such as phosphorus pentachloride or phosphorous pentabromide and oxalyl halides such as oxalyl chloride. The reaction is preferably carried out in the presence of a base, more preferably an organic base such as triethylamine, diisopropylethylamine, pyridine or lutidine.

There is no particular limitation on the nature of the solvent to be used, provided it does not adversely affect the reaction. Preferred solvents are ethers, such as tetrahydrofuran or dioxane. The reaction temperature is also not problematic, but we prefer a relatively low temperature to control side reactions and therefore the reaction is preferably carried out at a temperature below ^{0 0} G, most preferably a temperature of about -15 ° C. If necessary, the reaction may be carried out under an atmosphere of an inert gas such as nitrogen. The time required for the reaction depends mainly on the starting material and the reaction temperature, but normally the reaction is completed in 10 to 30 minutes.

After completion of the reaction, the desired compound of the formula (IX) can be prepared by conventional methods from the reaction

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be recovered tion mixture. A suitable method consists, for example, in distilling off the solvent and any excess reagents from the reaction mixture. The resulting product can normally be used in the next reaction stage without further purification.

In uer thus prepared compound of formula (IX), the halogen atom represented by Y are converted by conventional methods into any ^ halogen atom. For example, a compound of formula (IX) in which Y represents a chloro atom can be prepared simply by treating the compound with an inorganic bromide salt or oxychloride salt (z, B "lithium bromide or potassium bromide) in the presence of an organic solvent such as Ether, z * B, diethyl ether, are converted into the corresponding compound in which Y represents a bromide or an oxygen atom.

In the step (d), the phosphorylidene compound of the formula (IV) can be obtained by the reaction of the compound of the formula (IX) with a phosphine or a phosphoric ester in the presence of a base and a solvent. Preferred examples of suitable phosphine compounds include: triphosphines Preferred examples of phosphorus esters include: triester (lower alkyl) of phosphoric acid, z "B, triethyl phosphite, and diester alkali metal salts (lower alkyl) of phosphoric acid, such as, for example, triethyl phosphine and triaryl phosphines Example of Sodium Dithiophosphite Where a phosphorus compound is used, preferred bases are organic bases such as triethylamine, diisopropylethylamine, pyridine or 2,5-lutidine.

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phorester, inorganic bases are preferred, for example: alkali metal hydrides, such as sodium hydride, or lower alkyl lithium compounds, such as butyl lithium.

There is no particular limitation on the solvent used in this reaction, provided that it does not adversely affect the reaction. Examples of suitable solvents are: aliphatic hydrocarbons, such as hexanes or cyclohexanes; Ethers, such as tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene or toluene, and dialkyl (fatty acid) amides, such as dimethylformamide or dimethylazetamide. "The reaction temperature is also not problematic, but normally we prefer to carry out the reaction at a temperature between 30 ⁰ C and 100 ⁰ C. and if necessary, under an atmosphere of an inert gas such as nitrogen. The reaction time depends mainly on the nature of the starting material and the reaction temperature, in the normal case the reaction is completed in a time of 1 h to 20 h.

Upon completion of the reaction, the desired compound of formula (IV) may be recovered from the reaction mixture by conventional methods. For example, one suitable method is to add a water immiscible organic solvent (such as ethyl acetate) and water to the reaction mixture, the organic Layer is separated, is cleaned with water and dried with a drying agent and then the solvent is distilled off, so that the desired compound is formed. If necessary, this compound can be further purified by conventional methods, for example by recrystallization, preparative thin-layer chromatography or suction filtration.

lenchromatografie. ·

In step (e) of the process of the invention, the compound of formula (IV) is cyclized to provide a penem-3-carboxylic acid derivative according to the compounds of the invention, without the hydroxy, amino and carboxy groups being all protected. This cyclization reaction can be carried out with or without solvent. When a solvent is used, its nature is not problematic to the reaction provided it has no adverse effect on the reaction. "Preferred solvents include ethers (such as dioxane) or aromatic hydrocarbons (such as benzene, toluene, or Zyol). The temperature to which the compound of formula (IV) is heated, is also not critical, but we normally prefer to carry out the reaction at a temperature of 10O ⁰ C to 200 ⁰ C. Where a solvent is used which may Reaktion- if necessary, under an atmosphere of an inert gas such as nitrogen or argon. On the other hand, when no solvent is used, the reaction may be carried out under reduced pressure, if desired. The time required for the reaction depends mainly on the nature of the starting material and the reaction temperature, but usually the reaction is completed in 5 to 12 hours.

After completion of the reaction, the desired compound of formula (V) can be recovered from the reaction mixture by conventional methods. A suitable process includes, for example, distillation of the solvent, if present, under reduced pressure from the reaction mixture, addition of a mixture of ethyl acetate and hexane to the residue, filtration of the precipitate, and distillation

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of the solvent from the filtrate. The compound of the formula (V) thus obtained may be further purified, if necessary, by conventional methods such as recrystallization, preparative thin-layer chromatography or column chromatography.

In step (f) of the Reaction Scheme, the carboxy-protecting group belonging to the protected carboxy group R is removed, if necessary, and the hydroxyl protecting groups and amino protecting groups are also removed, which is in an appropriate order. "For example, removal of the hydroxy and amino protecting groups may be before, after, or simultaneously with the elimination of the carboxy-protecting group.

The method used to remove the carboxy-protecting group is dependent upon the nature of the protecting group, but in general it can be removed by any of the methods known in eliminating carboxy-protecting groups for this type of compound. For example, where the protecting group is a group that can be removed by reduction, e.g. For example, a halogenated alkyl group, an aralkyl group or a benzhydryl group, the removal by contacting the compound of formula (V) with a reducing agent can be realized. When the carboxy-protecting group is a halogenated alkyl group (e.g., a 2,2-dibromoethyl or 2,2,2-trichloroethyl group), zinc and acetic acid are the preferred reducing agents. When the protecting group is an aralkyl group (eg, a benzyl or p-nitrobenzyl group) or a benzhydryl group, the preferred reducing agent is a catalytic reducing agent (such as a combination of hydrogen with palladium / carbon) or an alkali metal sulfide (ζ. Sodium sulfide or potassium sulfide) "This reaction can be in the presence

XO

a solvent, the type of which is not problematic, provided it has no adverse effect on the reaction. Preferred solvents are: alcohols, such as methanol and ethanol; Ethers, such as tetrahydrofuran or dioxane; Fatty acids, such as acetic acid, and mixtures of one or more of these organic solvents with water. The reaction is usually carried out at a temperature between 0 C and about room temperature. The time required for the reaction depends on the types of starting materials and the reducing agent, but the reaction is normally completed in 5 minutes to 12 hours.

After completion of the reaction, the desired product can be recovered by conventional methods. For example, one suitable method is to filter out the precipitate, purify the filtrate with water, dry the filtrate over a desiccant, and then distill off the solvent to produce the desired product. This product can be further purified, if necessary, by conventional methods, for example by recrystallization, preparative thin-layer chromatography or column chromatography.

The carboxy-protecting group can be removed as described above, coupled with elimination of hydroxy-protecting groups and amino-protecting groups.

Preferred protected hydroxy groups represented by R are azyloxy groups such as lower aliphatic "azyloxy groups (e.g., acetoxy, propionyloxy, butyryloxy, or isobutyryloxy groups) or aralkyloxycarbonyloxy groups (e.g.," "benzyloxycarbonyloxy or" "dihydroxycycloxycarbonyloxy groups).

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and trialkylsilyloxy groups, preferably tri (lower alkylsilyloxy groups (ζ, Β »a t-butyldimethylsilyloxy group). Such groups can be readily removed by conventional procedures to leave the desired hydroxy-dummy,

1 Where, for example, R is a lower aliphatic group

(z, β, an acetoxy group), it may be removed by treating the compound of formula (V) with a base in the presence of an aqueous solvent. Any solvent generally used for this type of hydrolysis reaction may be used Preferred solvents are water or a water mixture and an organic solvent, for example an alcohol (such as methanol, ethanol or propanol) or an ether (e.g., tetrahydrofuran or dioxane). There is no limitation on the type of base to be used provided it does not adversely affect any other part of the compound, particularly the β-lactam ring. Preferred bases are alkali metal carbonates such as sodium carbonate or potassium carbonate. The reaction temperature is not problematic; However, to control side reactions, we prefer a relatively low temperature, z, S, a temperature that is between 0 C and about room temperature. The required reaction time depends on the kind of the starting material and the reaction temperature, but the reaction is usually completed in 1 to 6 hours.

When the protected hydroxy group represented by R is an aralkyloxycarbonyloxy group, z, B, a benzyloxycarbonyloxy or ε-nitrobenzyloxycarbonyloxy group, it can be converted into a free hydroxy group by contacting the compound of the formula (V) with a reducing agent is brought. The reducing agents used and

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the reaction conditions are the same as used in the removal of an aralkyl group from the protected carboxy group represented by R. Thus, in this case, the hydroxy-protecting group and the carboxy-protecting group were simultaneously removed.

Where the protected hydroxy group represented by R is a trialkylsilyloxy group (e.g., _e- t-butyldimethylsilyloxy), it may be converted to a hydroxy group by treating the compound of formula (V) with a fluorinated tetrabutylammonium fluoride, preferably in the presence of an organic carboxylic acid and a solvent. There is no particular limitation on the type of solvent to be used, preferred solvents are ethers such as tetrahydrofuran or dioxane. The reaction is preferably carried out at room temperature and normally takes 10 to 18 h,

Where the group represented by R is a protected hydroxy group, the protecting group may be removed simultaneously with the protecting group in the protected hydroxy group represented by R, after which the resulting hydroxy group in the side chain at the 2-position is converted to an azido group, which then is converted into an amino group. However, if both hydroxy protecting groups are removed simultaneously, then the reaction of the hydroxy group in the side chain at the 2-position into an azido group is accompanied by a reaction of the hydroxy group in the side chain at the 6-position, whereby the preparation of the desired compound of the Invention difficult

\ ger will. Consequently, it is better if the groups R

and R, where both are protected hydroxy groups, are different groups such that the

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group can be removed in R without interfering with the protected hydroxy group R to give a compound of formula (Va) shown below. In this context, it is particularly advantageous if R is an arsenic

2 alkyloxycarbonyloxy group, while R is a tri-.

represents alkylsilyloxygruppe. The conditions for the

2 removal of the hydroxy protecting group in R are the same,

which were described in connection with the group R above.

The hydroxy group in the side chain at the 2-position can be converted into an azido group by reacting a compound of the formula (Va):

SCH ₂ CH ₂ OH

(Va)

13

wherein R and R are as defined above, reacted with hydrazoic acid in the presence of a phosphine and an azodicarboxylic acid diester or with dipnenylphosphoryl azide. Suitable phosphines are tributylphosphine and triphenylphosphine and suitable Azodikarbonsäurediester are the dialkyl esters, particularly Dimethylazodikarboxylat or Diäthylazodikarboxylat, It is desirable that the reaction in the presence of a solvent, preferably a halohydrocarbon (e.g. _# B, methylene chloride or chloroform) or an ether (e.g., B, tetrahydrofuran or dioxane). The reaction temperature is preferably 0 C to 50 C, and the reaction time is

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depending on the type of reagents and the reaction temperature, is generally between 10 minutes and 2 hours «

Finally, the resulting azido group can be converted to an amino group by contacting the azido compound in the presence of a solvent in contact with a reducing agent

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is brought. The reducing agents and reaction conditions may be the same as those described for the removal of a carboxy-protective group in the case where the carboxy-protective group is an aralkyl group. In this case, it is possible to remove the carboxy-protecting group in the group R simultaneously with the reaction of the azido group into an amino group.

Alternatively, the azido group may be converted to an amino group using ammonium sulfide or hydrogen sulfide / triethylamine as a reducing agent at a temperature between OC and room temperature, in which case the carboxy-protecting group can not be removed.

Where R is a protected amino group, it is preferably an acylamino group, e.g. B. a lower aliphatic Azylaminogruppe (for example, acetylamino, propionylamino, butyrylamino or Isobutyrylaminogruppe) or a Aralkyloxykarbonyiaminogruppe (for example, Benzyloxykarbonylamino-, £ -Nitrobenzyloxykarbonylamino- or o-Nitrobienzyloxykarbonylaminogruppe). Such azylamino groups can be converted to free amino groups by conventional methods well known in the art for this type of reaction, especially by the conventional catalytic reduction using hydrogen in the presence of a palladium / carbon catalyst, and preferably in the presence of a solvent. The type of solvent is not particularly problematic, provided it has no adverse effect on the reaction. Suitable solvents include alcohols (such as ethanol), ethers (such as tetrahydrofuran or dioxane) and esters (such as ethyl acetate). The reaction temperature is also not particularly critical, for simplicity, the reaction will normally be at a temperature between 0 C and room temperature carried out. Depending on the type of

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Starting materials and the reaction temperature changes the time required for the reaction, but usually the reaction is completed in 1 h to 5 h. Since this reaction proceeds under the same conditions as the removal of an aralkyl protecting group from a protected carboxy group, in which appropriate protecting groups are selected, it is simultaneously possible to remove the amino-protecting group and the carboxy-protecting group in a single reaction.

It is also possible to remove certain amino-protecting groups, especially (> -nitrobenzyloxy-carbonyl groups, by photo-exposure from a protected amino group.

Where the process of the invention has produced a compound of formula ('11Ia) in which the ei- carbon atom in the side chain is at the 6-position in a specific arrangement, it is possible to reverse this arrangement by corresponding reactions For example, when a compound in which the ^ carbon atom in the 6- (1-hydroxyethyl) group is in the S-arrangement is reacted with an organic acid in the presence of a phosphine derivative (eg triphenylphosphine) and an azodicarboxylic acid diester ( eg diethyl azodicarboxylate), the corresponding 6- (1-acyloxyethyl) derivative can be obtained by having the oC carbon atom in the R arrangement, in other words, the reaction was reversed. Preferably, lower fatty acids (such as, for example, methanoic acid, acetic acid or propionic acid), aromatic carboxylic acids (such as benzoic acid) or aromatic fatty acids (such as phenylacetic acid) are used in this reaction. The same solvents and reaction conditions are used in this reaction as have already been described in connection with the reaction of a hydroxy group into an azide group. The ones achieved in this way

XV 10.12.1980

- 24 - 57 342/18/36

Azyloxy compounds can be reacted by the previously described reaction to remove hydroxy protecting groups to the corresponding hydroxy compounds in the new arrangement.

After completion of each of these reaction reactions, the desired products of each reaction can be recovered from the reaction mixture by conventional procedures. A suitable method includes, for example, distilling the solvent from the reaction mixture under reduced pressure, adding a water-immiscible organic solvent and water to the residue, separating the organic layer, cleaning the organic layer with water, drying it with a drying agent, and then distilling off the solvent.

If necessary, the compound thus obtained can be further purified by conventional methods such as recrystallization, preparative thin-layer chromatography and column chromatography.

Normally, each reaction reaction is carried out while the carboxy group is protected at the 3-position. After that, the protecting group can finally be removed by the methods already described.

The 4-azyloxyazetidin-2-ones or 4-sulphonylazetidin-2-ones of the formula (VI), which are the starting materials for the reaction scheme described above, can be synthesized by one of the following methods:

Method A

4-Azyloxyazetidine-2-non-derivatives of formula (VIa) can be synthesized as illustrated by the following reaction schemes:

X.

(XIII)

(XIV)

COCZ

. (XVII)

(Via)

In the above formulas, R represents a carboxy-protecting group such as an alkyl group (eg, methyl, ^1- ethyl or t-butyl) or an aralkyl group (eg benzyl) and R is - as previously defined - a protected hydroxy group, especially a υ-nitrobenzyloxy-carbonyloxy group or a t-butyldimethylsilyloxy group.

In this order of the reaction, the known 6cO-C (Roder S) -1-hydroxyethylsilyl penicillanate of the formula (XIII) [P. DiMnno et al, J. Org. Chem., 42, 2960 (1979)], into the corresponding protected compound of formula (XIV) by reacting the 1-hydroxy group on the side chain at the 6-position by conventional methods with a protective group (eg T). Kitrobenzyloxykarbonyl or t-butyldimethylsilyl) is protected. The compound of formula (XIV) is then oxidized with an organic peroxide (e.g., tri-chloroperbenzoic acid) to give the _S -oxydo compound of formula (XV). This jS-Oxydo

O 392

10.12.1980 57 342/18/36

Compound (XV) is then heated in the presence of trimethyl phosphite and acetic acid to give the open-ring compound of formula (XVZ). This compound (XVI) is heated with sodium periodate in the presence of potassium permanganate to give the 4-acetoxyazetidin-2-one compound of formula (VIa), which is one of the possible starting materials for the previously described reaction scheme.

Method B

Compounds of formula (VIa) and their 4-methylsulphonyl analogs can also be prepared as shown in the following reaction scheme:

,, Br

'''' .COOR ⁴

(XVIII)

OH

CH

CH

COOR

(XX)

(VIb)

^RJ

SCH.

COOR

(XIX)

CH.

CH.

COOR

(XXI)

OCOCH.

(Via)

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In the above formulas, R and R are as previously defined.

In this reaction scheme, the known 6cC bromicicillic acid ester of formula (XVIII) becomes £ 3. P. Clayton, D. Chem. Soc. (C), (1969), 21233 are sequentially treated with trimethyloxonium tetrafluoroborate and a base (e.g., basic alumina) to give the open-ring compound of formula (XIX). This compound of formula (XIX) is treated in the presence of a dialkylaluminum halide with zinc, a dialkyl copper lithium (e.g., dimethyl copper lithium) or a Grignard reagent (e.g., methyl magnesium bromide) to give an enolate anion which is reacted with acetaldehyde a compound of formula (XX) is formed. This compound of formula (XX) is converted to the compound of formula (XXI) by protecting the free hydroxy group as described in method A, then this compound of formula (XXI) is treated with mercuric acetate to give the 4-acetoxyazetidine -2-one ~ compound of the formula (VIa) is formed. In the other case, the compound of the formula (XXI) is oxidized in the presence of potassium manganate with potassium iodate, so that the corresponding 4-methylsulphonylazetidin-2-one derivative of the formula (VIb) is formed.

In this reaction, the compound of the formula (XX) resulting from the second step is predominantly one. Compound in which the oL-carbon atom is in the 3 - * (l-hydroxyethyl) side chain in the S-arrangement. However, if desired, it may be switched to the R-arrangement by treating the compound of formula (XX) in the presence of triphenylphosphine and diethyl azodicarboxylate with an organic acid and then treating the resulting 3-p- (R) -1-acyloxy -

31 - 26 -

is treated with an alcoholic solution of an alkali metal alkoxide (e.g., methanolic sodium methoxide) to give a compound corresponding to the compound of formula (XX) but having a 3-f (R) -I-hydroxyethyl group. This can be used in subsequent reactions as described above to give the corresponding compounds with the R arrangement.

Method C

A 4-benzenesulphonylazetidin-2-one derivative of the formula (VIc) can be obtained as illustrated by the following reaction scheme:. , ·

(XXII)

(XXIII)

(Γ

(XXV)

: no

22 0 3

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ι ** ·

In the above formulas, R is the same as previously defined

5, and R represents an amide-protecting group, e.g. A t-butyldimethylsilyl group,

As can be seen from the above reaction scheme, the known 4-phenylthioazetidin-2-one which has the formula (XXII) is protected by conventional methods by a protecting group, eg "B" t-butyldimethylsilyl group. The resulting compound of formula (XXIII) is then treated with a lithium amide (e.g., lithium diisopropylamide), the resulting enolate anion is allowed to react with acetaldehyde to give a compound of formula (XXIV), Due to the asymmetry of Side chain at the 3-position, this compound of formula (XXIV) can be cleaved in StereoisoiTiere. Each isomer can then be treated separately as described below to give different isomers of the compound of formula (VIc), one of which is shown in the above reaction scheme.

The hydroxy group of the compound of formula (XXIV) is protected as described in method A, and then the resulting compound of formula (XXV) is oxidised with an organic peroxide (e.g., m-chloroperbenzoic acid), the product is washed with Tetrabutylammonium fluoride is treated to remove the amino-protecting group and the desired 4-benzenesulphonylazetidin-2-one derivative of formula (VIc) is formed. This compound is racemic and may be cleaved into optical isomers, if required.

The compounds of the present invention have excellent antibiotic activity against both Gram-positive and Gram-negative bacteria. This activity can be demonstrated by a dilution method using an agar plate as a result

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It has been shown that the compounds have a broad spectral activity against such gram-positive bacteria as Staphylococcus aureus or Bacillus subtilis and such Gram-negative bacteria as Escherichia coli , Shiqella species, Klebsiella pneumoniae , Proteus species or Pseudomonas aeruqinosa . Thus, the minimum inhibitory concentrations of the preferred compound of the invention, (5R, 6S) -2- (2-aminoethyl) thioJ-6-f (R) -l-hydroxyethylpiperem-3-carboxylic acid are shown in the following table:

table

Microorganism MIC μg / ml

Staphylococcus aureus 209P 0.012

Staphylococcus aureus 56 0.012

Escheriehia coli NIHO 0.4

Escherichia coli 609 0.8

Shigella flexneri 2A 0.8

Pseudomonas aeruqinosa 6.2

Klebsiella pneumoniae 806 0.8

Klebsiella pneu m oniae 846 0.8

Proteus vulqaris 6.2

Salmonella enteritidis 1.5

19 0 3'9ä 5.11.1980

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The results presented in this Table demonstrate the extremely broad activity spectrum of this compound over bacteria that can not be attacked by many known penicillins. Even P ^ eu ^ omo-rja ^ £ U £ inos_a and Kl e bsie 11 ^ a species show considerable sensitivity to this compound.

Accordingly, the compounds of the present invention prove to be antibacterial agents against these pathogenic bacteria. These compounds can be administered orally (for example, in the form of tablets, capsules, granules, powder or syrup) or subcutaneously (for example, in the form of intravenous or intramuscular injections). The dose will vary depending on the age, weight and condition of the patient, the route and the time of administration, but generally, in adults, the compounds of the invention may be administered at a dose of from 250 mg to 3,000 mg per day in a single dose or in separate doses.

Embodiment

The invention is further illustrated by the following examples, examples 12 and 23 of which illustrate the preparation of compounds according to the present invention.

example 1

/ ? , ξ. C £ fi) ^ 3rJi * £ 22zl · ri. ~ !? lI · I ¹ P. ^ y, K ^a f fb ο ny 17 2 - methy 1 ρ r ο ρ -1 - e η y 1) 4-Hethy11 hi ο azetidin-2 ~ one

0 3

5,11,1980

AP C 07 D / 220 392 57 342/18/36

COOCH.

8.55 g of methyl bromo-distillate were dissolved in 61 ml of nitromethane, after which 4.52 g (1.05 equivalents) of triroethyloxonium tetrafluoroborate were added to the solution under a nitrogen atmosphere with ice-cooling and stirring. After stirring for about 10 minutes, the mixture remained at 5 ° C for 48 hours. To the reaction solution was then added sequentially 60 ml of nitromethane and 24 g of basic alumina (activity, degree 1), then the mixture was added with ice-cooling for 15 minutes and then The reaction mixture was then adsorbed on a column containing 114 g of basic alumina (activity, grade 1) and eluted with ethyl acetate until the eluate contained no trace of the desired product. The eluates were combined and, under reduced pressure, the solvent was distilled off to provide 5.95 g (65 % yield ) of the desired product as an oil which was recrystallized from a mixture of diisopropyl ether and hexane to give a powder having a melting point of 55%. 55 C is created *

Elemental analysis:

Calculated for CH ^ BrNO ₃ S: ·

C, 38.96 %; H, 4.55 %; N, 4.55 %; Br, 25.97 %; S, 10.39 %. detected: .

C ₁ 38.85 %; H, 4.54%; N, 4.37 %, Br, 26.14%; S, 10.57%.

5.W.1980

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Infrared absorption spectrum (KBr) V * _v cm

1770, 1730, 1640, 1380, 1360, 1210, 1080

Nuclear Magnetic Resonance Spectrum (CDCl-) </ ppm:

2.00 (3H singlet); 2,1'6 (3H, singlet); 2.27 (3H, singlet);

3 ^ 10.12.1980

22 0 392 - S * - 57 342/18/36

3.80 (3H, singlet);

4.85 (IH, doublet, 3 = 2 Hz); 5.13 (IH, doublet, Ό = 2 Hz).

Example 2

(3S, 4R) -5- (S) -1-Hydroxyethyl-3- (1-methoxycarbonyl-2-methyl-1-propenyl) -4-methylthioazetidin-2-one

OH

00CH ₃

1.96 g (6.38 mmol) of (3S, 4R) -3-bromo-1- (1-methoxycarbonyl-2-methylprop-1-enyl) -4-methylthioazetidin-2-one and 843 mg (3 "equivalent Acetaldehyde was dissolved in 20 ml of tetrahydrofuran and the resulting solution was added to a solution of 625 mg (1.5 equivalents) of zinc and 6.68 ml (1.5 equivalents) of 15% during a 40 minute period in 15 ml tetrahydrofuran v / v hexane solution from diethylaluminumurochloride was added, stirring at 15 to 20 C. After stirring for 1 hour, water and then ethyl acetate were added to the solution and the resulting white precipitate filtered off using a celite (trademark) filter aid after which the extract was treated by conventional methods to give 2.05 g of the crude product as an oily substance, which was purified by column chromatography in about 30 g of silica gel and eluted with a 5: 1 by volume mixture of chloroform and ethyl acetate t 1.04 g (60 % yield) of the desired product as a colorless, oily substance. The product was a mixture of the l'S isomer and the l'R isomer (4: 1),

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Elemental Analysis: Calculated for ^C ₁ 2 ^H 19 ^NO 4 ^S:

C, 52.74%; H, 6.96%; N, 5.13 %; S, 11.72%. found: C, 52.81 %; H, 7.21 %; N, 5.43%; S, 11.78%.

Infrared absorption spectrum (liquid film) qf cm: 3450, 1760, 1710, 1380, 1360, 1225.

Nuclear magnetic resonance spectrum (COCl ₃ ) cTppm: l'S isomer:

1.30 (3H, doublet, 0 = 6 Hz);

1.93 (3H, singlet);

2.05 (3H, singlet);

S, 14 (IH, double doublet, 0 = 6 and 3 Hz);

3.72 (3H, singlet);

4:12 (IH, multiplet);

4.92 (IH, doublet, 0 = 3 Hz).

l'R-isomer:

1.26 (3H, doublet, 0 = 6 Hz);

1.93 (3H, singlet); 2.05 (3H, singlet); 2.16 (3H, singlet);

3.14 (IH, double doublet, 0 = 6 and 3 Hz);

3.72 (3H, singlet);

4:12 (IH, multiplet);

5.04 (IH, doublet, 0 = 3 Hz).

392 35 10.12.1980

- 35 · - 57 342/18/36

Example 3 «

(3S, 4R) -l- (1-methoxycarbonyl-2-methylprop-1-enyl) -4-methylthio-3-f (S) -p-nitrobenzyloxycarbonyloxyethyl] azetidin-2-one?

CO ₂ CH ₃

2.57 g (9.4 mmol) of (3S, 4R) -lf (S) -1-hydroxyethyl-1- (1-nethoxy-carbonyl-2-methylprop-1-enyl) -4-methylthioazetidin-2-one, 1.19 g (11.8 mmol) of triethylamine and 1.04 g (8.5 mmol) of 4-dimethylaminopyridine were dissolved in 30 ml of methylene chloride. To the solution were then added - while cooling with ice - 3.79 g (17.6 mmol) of p_-nitrobenzyloxykarbonylchlorid, then the mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was diluted with methylene chloride and washed successively with weak aqueous hydrochloric acid and saturated brine, and then dried. The solvent was distilled off and the residue was purified by column chromatography in 70 g of silica gel eluted with a 20: 1 by volume mixture of chloroform and ethyl acetate to provide 3.40 g (result 80 %) of the desired product as an oily substance were.

Infrared absorption spectrum (CHCl ₃ ) tf cm: 1760, 1722, 1627.

Nuclear Magnetic Resonance Spectrum (COCl-) cTppm: 1.42 (3H, doublet, D = 6 Hz);

10.12.1980 57 342/18/36

1.92 (3Η, singlet); 2.03 (3Η, singlet); 2.16 (3H, singlet); 3.39 (IH, double doublet, 3 = 5 and 3 Hz);

3.71 (3H, singlet); 4.94 (IH, doublet, D = 3 Hz);

5.26 (2H, singlet);

7.58 (2H);

8.22 (2H).

Ex iel 4

(3R e 4Rj-4-acetoxy-1- (1-methoxycarbonyl-2-methylpropyl-1- enyl ) -ZC ( S) -1-p-nitrobenzyloxycarbonyloxyethyl-3-azetidine- 2-one

₀ CO ₀ CH, H ₃ C

CO ₂ CH ₃

4.16 g (9.20 mmol) of (3S, 4R) -1- (1-methoxycarbonyl-2-methylprop-1-enyl) -4-methylthio-3-f (S) -1-nitrobenzyloxycarbonyloxyethylazazidine-2 -one and 4.40 g (13.8 mmol) of mercury acetate were dissolved in 42 ml of acetic acid. The solution was heated at 110 C for 30 minutes. After completion of the reaction, the acetic acid was distilled off. The residue was partitioned between ethyl acetate and water. The organic layer was rinsed with water and dried. The solvent was distilled off, and the resulting residue was purified by column chromatography in 60 g of silica gel eluted with a 3: 0 volume mixture of chloroform and ethyl acetate to give 3.87 g (result 91 %) of the desired product as an oily one Substance that was a mixture of isomers, which is about 20 % of the cjLs _--

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Isomers (3R, 4S) contained *

Nuclear magnetic resonance spectrum (CDCl,) ο ppm:

trans isomer (main component):

1.42 (3H, doublet, D = 6 Hz);

1.88 (3H, singlet);

1.99 (3H, singlet);

2/15 (3H, singlet);

3.40 (IH, double doublet, 0 = 5 and 2 Hz); 3.69 (3H, singlet);

5.27 (2H, singlet) j

6.09 (IH, doublet, O = 2 Hz);

7.59 (2H);

8.25 (2H).

Example 5

(3R> 4R) -4-acetoxy-3-C (S) -p "" nitrobenzyloxy-carbonyloxy-thyl-1-yr-yrazetide in-2-one e

HC P ^C0 2 ^CH 2

1 ^ =

• '>. -r OCOI

- «OCOCH-H ' ³

.NH

2.18 g (4.70 mmol) of (3R, 4R) -4-acetoxy-1- (1-methoxy-carbonyl-2-methylprop-1-enyl) -3- / (S) -p-nitrobenzyloxycarbonyloxyethyl-2-yl-2-yl One T with about 20 % of the cis isomer (3R, 4S) 3 was dissolved in 158 ml of acetone. To the resulting solution was added a solution of 4.52 g (21.1 mmol) of sodium metaperiodate _t 48 mg of potassium permanganate, 58 ml of 0.1 M phosphate buffer (pH 7.0) and 115 ml of water while cooling with ice. The temperature of the mixture was immediately raised to room temperature, and then the mixture was stirred at room temperature for 3.5 hours.

After completion of the reaction, the reaction mixture was neutralized by the addition of 0.6 ml of a 5% w / v aqueous sodium bicarbonate solution, and the precipitate generated was filtered out using a Celite (trademark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with a small amount of saturated brine and dried. The solvent was distilled off and the resulting residue was purified by column chromatography in 30 g of silica gel eluted with mixtures of chloroform and ethyl acetate in ratios of 10: 1 to 5: 1. Thus, 1.22 g of the desired trans-isomer (3R, 4S) as an oily substance and 0.30 g of the desired cis isomer (3R, 4S) as crystals (total result 91 %) .The latter isomer was recrystallized from a mixture of diethyl ether and ethyl acetate to give colorless prisms , which melt at 117 - 120 ⁰ C, can be achieved.

Elemental analysis, cis isomer (3R, 4S):. , "->

Calculated for C., -IL gligOg:

C, 51, H #; H, 4.58 #, -H, - 7.95 %. found: C, 50.86 %; H, 4.56 fi; N, 7.63 %.

Infrared absorption spectrum (CHClOv cm: * * .. _j "max

trans isomer (3H, 4R):

3410, 1789/1747, 1609, 1528 jGis isomer (3R, 43):.

3410, 1738, 1743, 1607, 1523.

Nuclear magnetic resonance spectrum (CDGIo); fppm: _t r ans isomer (3R, 4R):

1.39 (3H, Düblett, J = 6Hz);

2.01 (3H, singlet); . '

3.36 (1K, double doublet, J = 4 and 1 Hz);

5.18 (2H, singlet);

5.59 (1H, doublet, J = 1 Hz);

7,12 (1H, broad singlet);

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7.63 (2H); 8.27 (2H)

cis. isomer (ZR ₁ 4S):

1.37 (3H ₁ doublet, O = 6 Hz); 1.93 (3H, singlet);

3.46 (IH, multiplet);

5.24 (2H, singlet);

5.88 (IH, doublet, D = 4.5 Hz); 6.84 (IH ₁ broad singlet); 7.58 (2H);

8.24 (2H).

Example 6

(3S, 4R) -4- (2-t-butyldimethylsilyloxyethylthio) thiokarbonyi; 3-S-T (S) -1-P-nitrobenzyl oxy karbonyloxyäyne Haze t id intone //

OCO ₂ CH ₂ - ^ / - ^NO 2

H_C- ³ > - H

- SCH _o CH _o 0Si (2 2 j

JH * " ^C 4 ^H 9

590 mg (3.07 mmol) of 2-t-butyldimethylsilyloxyethylmercaptan were added to a sodium isopropoxide solution, which was prepared from 63.5 mg (2.76 mmol) of sodium metal and 15 ml of isopropanol, under ice-cooling and stirring under a nitrogen atmosphere. After 5 minutes, 233 mg (3.07 mmol) of carbon disulfide were added to the mixture, which was then stirred for 10 minutes. Thereafter, a mixture of 1.14 g of (3R, 4R) -4-acetoxy-3- £ (S) - was added. L-nitrobenzyloxycarbonyloxyethyl 3-azetidin-2-one in 6 ml of tetrahydrofuran was added slowly and the mixture was then stirred for 20 minutes. After completion of the reaction, 200 ml of a 1: 1 volume mixture of hexane and ethyl acetate was added to the reaction mixture. The mixture was then washed with saturated brine and dried.

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The solvent was distilled off and the residue was purified by column chromatography in 30 g of silica gel eluted with a 15: 1 by volume mixture of benzene and ethyl acetate to give 1.27 g (69 % yield ) of the desired product which was recrystallised from a mixture of cyclohexane and Diisopropyläither, so that 680 mg (yield 37%) of the pure product having a melting point 94.5 to 95.5 C ⁰ arise * the mother liquor was purified by liquid chromatography using a Lober B ~ « Column, eluted with a 12: 1 by volume mixture of benzene and ethyl acetate to give an additional 220 mg (12 % yield ) of the desired product,

Elemental analysis:

Calculated for C _oo H_ "N _o 0_, S_Si:

C, 47.12 % i H, 5.75 %; N ₁ 5.00%; S, 17.15 % detected: C, 47.27 % -, H, 5.76 %; N, 5.00 %; s, 17.27 % _t

Infrared Absorption Spectrum (Nujol Trademark) γ cm 3210, 1781, 1740 '

Nuclear magnetic resonance spectrum (CDC1_) <f ppm: 0.08 (5H, singlet); 0.89 (9H, singlet);

1.48 (3H, Düblett, 0 = 6 Hz);

3.49 (2H, multiplet);

3.82 (2H, multiplet); '

5.22 (2H, singlet);

5.48 (IH, doublet, 0 = 3 Hz);

6.68 (IH, broad singlet); 7.57 (2H);

_8f 25 (2H),

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Example 7

(3S, 4R) -4- (2-t-Butyldimethylsilyloxyethyl thio ) thiocarbonyl 3- thio-1- hydroxy (p-nitrobenzovloxy carbonyl) methyl-1,3-f (S) -I-nitrobenzyloxycarbonyloxyethyl] azetidin-2-one

S (CH ₂ ) ₂ O Si (CH ₃ ) ₂

1.22 g (2.18 mmol) (3S, 4R) -4- (2-t-butyldimethylsilyloxyethylthio) thiocarbonylthio-3-r (S) -1-nitrobenzyloxycarbonyloxyethyl-2-yl-1-one and 0.721 g (3 , 18 mmol) of ε-nitrobenzylglyoxylate hydrate were refluxed for 4 h in 14 ml of benzene. After completion of the reaction, the solvent was distilled off and the residue was adsorbed on a column chromatograph using 20 g of silica gel and eluted with a 12: 1 by volume mixture of benzene and ethyl acetate to give 1.49 g (result 89 %) of the yellow oil arise

Infrared absorption spectrum ( ^CHC lx) V _max ^cm ~ ^: 3530, 1787, 1760, 1510, 1522, 1354.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) d ppm:

0.04 (6H, singlet);

0.90 (9H, singlet);

1.45 (3H, doublet, D = 6.5 Hz);

3.53 (2H, multiplet);

, 3.86 (2H> multiplet);

4.21 and 4.35 (4: 3, IH, singlet);

5.26 and 5.29 (4: 3, 2.H, singlet);

10.12.1980 57 342/18/36

6.01 and 6.09 (4: 3, IH, doublet, 0 = 2.5 Hz); 7.60 (2H); ,

8.29 (2H).

Example 8

(3S, 4R) -4-r (2-t-butyldimethylsilyloxyethylthio) thiocarbonyl3-3- £ '(S) -IP-with robenzyloxykarbonyloxyathyU1-C (p-nitrobenzylcyclohexyl) -triphenylphosphoranylidene methyiacetamide-one

335 mg (0.44 mmol) of (3S, 4R) -4- / ² -t :( ^B "tyldimethylsilyloxyäthylthio) thiokarbonylJthio-l- / liydroxy- (£ -nitrobenzyloxykarbonyl) methyl ^ | -3-f (S) - l-> £ -nitrobenzyloxykarbonyloxyäthyl3 azetidin-2-one was dissolved in tetrahydrofuran 5 ml. of 2,6-lutidine and then 86 mg (0 were to the solution at C cooling and stirring at -10 ⁰ 80 mg (0.75 mmol) The mixture was stirred at said temperature for 50 minutes and then at room temperature for 30 minutes, to the mixture was added an additional 91 mg (0.85 mmol) of 2,6-lutidine together with 224 mg (0.85 mmol). triphenylphosphine and 101 mg (0.85 mmol) of potassium bromide added. the mixture was stirred at a temperature of 70 to 80 ⁰ C in a nitrogen atmosphere for 6 ih. After completion of the reaction, ethyl acetate was added to the reaction mixture, which was then washed with water * the The organic solvent layer was dried and the solvent was distilled off, and the resulting residue was used adsorbed by 13 g of silica gel on a chromatography column and with

29 0 3 92 « ^? - 10.12.1980

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eluted with a 20: 1 volume mixture of benzene and acetone to give 204 g (46 % yield ) of the desired product as a yellow oil.

-1 infrared absorption spectrum (CHCl-) if _ma "cm:

O Πια Χ

1759, 1622, 1608, 1513, 1342.

Example 9

p-Nitrobenzyl (5R, 6S) -2-r (2-t-butyldimethylsilyloxyethyl) - thioJ-6-C (S) -l ~ p-nitrobenzyloxykarbonyloxyäthyl3penem-3-

carboxylate

Ultraviolet ^{absorption spectrum} (ethanol) ^ _max ^nni:

263 ( t , 25,300); 338 (έ, 10,300).

-1

Infrared absorption spectrum (CHCl ₃ ) V _ffla ice:

1790, 1748, 1690, 1602, 1512, 1343 *

Nuclear Magnetic Resonance Spectrum (CDCl-) cTppm:

0.04 (6H, singlet);

0.84 (9H, singlet);

1.46 (3H, doublet, 3 = 6.5 Hz);

3.07 (2H, triplet, D = 6 Hz);

3.84 (2H, triplet, 0 = 6 Hz);

4.04 (IH, double doublet, 3 = 5 and 1.5 Hz);

5.24 (IH, doublet, 0 = 15 Hz);

10.12.1980 57 342/18/36

5.27 (2H, singlet);

5.49 (IH, doublet, 3 = 15Hz);

5.61 (IH, doublet, O = 1.5 Hz);

7.56 (2H);

7.63 (2H);

8.21 (4H).

Specific rotation:

= + 98 ° (c = 1.03, CHCl ₃ ).

(5R _f nitrobenzyloxyka rbonyloxyäthylj penem-3 ° ka rboxylat

Example 10

165 mg (0.23 mmol) of N-nitrobenzyl (5R, 6S) = 2 (2-t-butyldimethylsilyloxyethyl) thio] -6-r (S) -1-nitrobenzyloxycarbonyloxyethylpiperpene-3-carboxylate were added to 0, Dissolved 45 ml of tetrahydrofuran. To the solution was added a solution of 413 mg (6.9 mmol) of acetic acid and 156 mg (0.60 mmol) of tetrabutylammonium fluoride in 1.1 ml of tetrahydrofuran. The resulting solution remained at room temperature for 3.5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with dilute aqueous sodium bicarbonate to remove the acetic acid, washed with saturated brine and dried. The solvent was distilled off. The crystalline residue was converted from a mixture of chloroform and ethyl acetate.

au 10.12.1980

- 57 342/18/36

crystallized to give 87 mg of colorless needles, which melt at 158 to 160 ⁰ C. The filtrate was concentrated and the residue was adsorbed on a chromatography column using 3 g silica gel and eluted with a 3: 2 volume mixture of benzene and ethyl acetate to provide an additional 35 mg of the product. The overall result was 122 mg (88 %) .

Elemental Analysis: Calculates för

C, 49.58 %; H, 3.83 %; N, 6.94 % ·. S, 10.59 % ₀

Detected:

C, 49.19 % t H, 3.73 %; N, 6.49 %; S, 10.71 %.

-1 infrared absorption spectrum (Nuiol-Vvarenzeichen) Vl "cm:

3520, 1764 _# 1755, 1682, 1607, 1520, 1260.

Nuclear magnetic resonance spectrum (CDCl ₃₎ ei ppm: 1.48 (3H, doublet, D = 6.5 Hz); 3.10 (2H, multiplet); 3.36 (2H, multiplet);

4, O3 (IH, double doublet, 0 = 4 and 1.5 Hz); 5.21 (IH, doublet, G = 15 Hz); 5.29 (2H, singlet); 5.45 (IH, doublet, D = 15 Hz); 5.61 (IH, doublet, ö = 1.5 Hz); 7.65 (2H); 7.71 (2H);

8.27 (2H);

8.28 (2H) _#

Specific rotation:

so

10 "12" 1980 57 342/18/36

Example 11

p-nitrobenzyl (5R, 6S) "2-ff 2 ~ azidoäthy3l) t: h'io;) ^^^ 6 ~ £ (6) ^ - ^ ^ ^ p- ^ nitroben; sylexykarbonyloxyäthy] Jpenem ^ -3 '' l <arboxylat

OCO ₂ CH ₂

COOCH

112 mg (0.19 mmol) of N-nitrobenzyl (5R, 6S) -2 - / - (hydroxyethyl)

$ 1

O -392 -4 *.

Thiol-6-f (S) -1-O-nitrobenzyloxycarbonyloxyethyl-3-phenylcarboxylate was dissolved in 5 ml of tetrahydrofuran. Successively, with stirring, 53 mg (0.20 mmol) of triphenylphosphine, 0.22 ml (0.24 mmol) of a 1.1M hydrazoic acid solution in benzene and 35 mg (0.20 mmol) of diethyl azodicarboxylate were added to the solution. The mixture was stirred at room temperature for 10 minutes, then diluted with ethyl acetate, washed with water and dried. The solvent was distilled off and the residue was adsorbed on a chromatographic column using 3 g of silica gel and eluted with a 8: 1 by volume mixture of benzene and ethyl acetate to afford 58 mg (50 % yield ) of the desired product as an oil.

) I) ICm "" *

Infrared absorption spectrum

2110, 1795, 1700, 1β10, 1520, 1345.

Nuclear magnetic resonance spectrum (CDCl-,) oppm:

T, 50 (3H, doublet J = 7 Hz);

3.11 (2H, multiplet);

3.60 (2H, multiplet);

4.08 (1H, double doublet, J = 4 and 2 Hz) 5.23 CtH, doublet, J = 15Hz);

5.31 (2H, singlet);

5.54 (1Ή, doublet, J = 15 Hz);

5.68 (1H, doublet, J = 2 Hz);

7.63 (2H);

7.70 (2H);

8.32 (4H). '

Specific rotation: 20

+ 69 ° (c = 1.12, CHCl ₃ ).

5,11.1980

AP C 07 D / 220

57 342/18/36

Example 12

(5R _{1 f} 6S) -2 - / (2-aminoethyl) t -Hiol-6-E (6) -l-hydroxyethyl-3-penicarboxylic acid

43 mg of p-nitrobenzyl (5R, 6S) -2- {(2-azidoethyl) thioj ~ 6 ~ £ (S) -lj) with robenzyloxykarbonyloxyäthylj penem ~ 3 ~ carboxylate were dissolved in a mixture of 3.5 ml of tetrahydrofuran and 2 , Emulsified 5 ml of a 0.1 M phosphate buffer. To the resulting emulsion was added 100 mg of 10% w / vv palladium / carbon, then hydrogen was passed through the mixture under atmospheric pressure for 2.5 hours to achieve catalytic reduction. After completion of the reaction, the reaction mixture was filtered, and the catalyst was washed with a 0.1 M phosphate buffer. The filtrate was combined with the rinses, compacted by evaporation under reduced pressure to a volume of about 4 ml, and adsorbed onto a chromatographic column using 8 ml of HP = 20AG. The fractions eluted with 5% aqueous solution of acetone were lyophilized to give 7.1 mg (result 35 %) of the desired product in the form of a powder *

Ultraviolet absorption spectrum (HpO) A nm

320 ( t , 5,700); ,

252 (ε, 4,700),

0 3 92

^v **. ₅ 3 AP C 07 D / 220 392

5 * 11.1980 AP C 07 Ο, 57 342/18/36

-1

Infrared absorption spectrum (KBr) y cm: ^{rr Λ} · 'max

3400, 1762, 1561.

Nuclear magnetic resonance spectrum (D_0) {/ "ppm

1.34 (3H, doublet, 3 = 6.5 Hz); 2.9 - 3.5 (4H, Muitiplett); 4.02 (IH, double doublet, 0 = 4 and 2 Hz) i

4.25 OH, doublet quad, J = 4 and 6.5 Hz) j 5.70 (1H, doublet, J = 2Hz),

Specific rotation.

20. ·

[ct] _D = + 198 ° (c =. 0.57, H ₂ O).

EXAMPLE · 13 .

Benzyl βο ^, Γ (ΐΟ ~ 1 ~ t-b uty Idirae t hy lsi Iy loxyäfthy 11 penizi 11anat

261 mg (0.78 mmol) of an isomer mixture whose main constituent

Benzyl 6Or - [(E) -1-hydroxoethyl] penicillanate was dissolved in 1.3 ml of dimethylformamide. To. to the resulting solution was added 164 mg (10.9 mmol) of t-butyldimethylchlorosilane and 74 mg (10.9 mmol) of imidazole. The mixture remained at room temperature for 5 hours. After completion of the. Reaction of the reaction mixture diluted with ethyl acetate, washed with water and dried. The solvent was distilled off and the residue was adsorbed on a chromatography column using 5 g of silica gel and eluted with a 10: 1 by volume mixture of benzene and hexane followed by benzene to give 310 mg (result: 89) of the desired product as an oily substance,

Elemental Analysis: Calculated for GpoHonOJiSSi:,

, ·· C, 61.43%; H, l ^ ö% \ N, 3,12? S; S, 7.13%. Found: C, 60.96>i; H,?, 80 % \ Έ, 2.93; i; S, 7.38 %.

- -49- -

Infrared absorption spectrum (liquid film) V cm ""

1780, 1750. - ^ ·

Nuclear magnetic resonance spectrum of the main component

_(GdCl3) S ppm:

0.05 (6H, singlet);

0.85, (9H, singlet); '

1.25, (3H, doublet, J = 6Kz);

1.40 (3H, singlet); '. ,

1.60 (3H, singlet); '

3.24 (1H, double doublet, J = 5 & 2 Hz);

4.2 (TH, multiplet);

V. 4.49 CiH, singlet);

5.21 (2H, singlet);

5.30 (1H, doublet, J = 2 Hz);

7.43 (5H, singlet).

EXAMPLE 14

Benzyl 6-if (R) -1-t-butyldimethylsilyloxyethylphenyl- 1- oxide

CO, CH ₁ C ^ H ₅ .

192 mg (0.43 in mol) of an isomeric mixture whose main constituent is benzyl βα- [(R) -1-t-butyldirnethylsilyloxyethyl] penicillanate were dissolved in 4 ml of methylene chloride. To the solution at 0 ⁰ G 100 mg (0.49 mmol) of m-Ghloroperbenzoesäure (Reinheit.85 / 0) were added and then the mixture was stirred for one hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and then washed successively with dilute aqueous sodium carbonate and water, and dried. The solvent was distilled off and the residue was purified by preparative thin layer chromatography developed with a 1: 3 volume mixture of acetone and hexane to give 187 mg (94% yield) of the desired compound as an oily substance.

Sb 10:12, 1980

- 5β - 57 342/18/36

Elemental Analysis: Calculated for C ₂₃ H ₃₅ O ₅ NSSi:

C, 59.31 %, H, 7.58 %; N, 3.01%; S, 6.89 %. Detected:

C, 59.22 %: H, 7.73 %; N, 2.94 %; S, 6.59 % _t

Infrared Absorption Spectrum (Liquid Film) ycm ": 1781, 1751

Nuclear magnetic resonance spectrum of the main constituent (CDCl ₃ ) tf ppm:

0.07 (6H, singlet); 0.89 (9H, singlet); 1.10 (3H, singlet); 1.25 (3H, doublet, D = 6 Hz); 1.63 (3H, singlet); 3.59 (IH, double doublet, 0 = 4 & 2 Hz); 4.4 (IH, multiple); 4.55 (IH, singlet); 4.98 (IH, doublet, α = 2 Hz); 5.28 (2H, singlet); 7.44 (5H, singlet),

Example 15

(3R _f 4RS) -4-acetoxy. 1 -. /! (Rj _- -l ^ benzy 1 pxyka rbpηy 1 »2 ~ methy 1 _r _ £ P-j & r2 ^ enyl3 ~ 3 ~ C ( R) - 'l ~ t -butyldime _t hyl ^ silylpxyä t hy 13 azet idin-2-one

5?

10.12.1980 57 342/18/36

0Si (CH ₃ ) ₂

OCOCH.

 Η

'2

4.54 g (9.76 mmol) of an isomeric mixture containing as the main ingredient benzyl 6 & + [(r) -l-t-butyl-dimethylsilyloxyethyl] penicillanate 1-oxide was dissolved in 200 ml of benzene , 3 dlL (61.5 mmol) of trimethyl phosphite and 2.30 g (38.3 mmol) of acetic acid, the mixture is then heated under reflux for 8 hours. After cooling the reaction mixture, it was washed successively with aqueous sodium bicarbonate and water and then The solvent was distilled off and the oil residue was adsorbed on a chromatography column using 50 g of silica gel and eluted with a 30: 1 Yolumen mixture of benzene and ethyl acetate to give 3.91 g (result 84%) of the desired product as an oily substance The major component of the product was a 1: 1 mixture of the 4S isomer and the 4B isomer.

Elemental analysis: Calculated for CgcH-oO

C, -63.125 Si H, 7.84%; N, 2.95%. Placed: C, 63.37%; H, "7.92%; N, 2.84%.

Infrared ^{Absorption Spectrum} ( ^CHC1 -5) i / i _ila v _: ^CCL * ~ 1777, 1750.

Nuclear magnetic resonance spectrum (CDClO) cT ppm: 3,4-6Os isomer

0.05 (6H, singlet); ·

0.85 (9H, singlet); , ,

1.35 (3H, doublet, J = 6.5 Hz) 5 1.82 (3H, singlet);

2.08 (3H, singlet);

3.39 (1H, double doublet, J = 8.5 &5Ha);

_S a 10.12.1980

392 - i »- 57 342/18/36

4.3 (IH, multiplet); 4.87, 4.99 (IH, broad singlet); 5.1 (IH, multiplet); 5.23 (2H, singlet); 6.34 (IH, doublet, 0 = 5 Hz); 7.42 (5H, singlet);

3.4 t rans isomer

0.08 (6H, singlet);

0.85 (9H, singlet);

1.26 (3H, Düblett, 0 = 6 Hz);

1.82 (3H, singlet);

1.98 (3H, singlet);

3.10 (IH, double doublet, 3 = 5 & 1 Hz);

4.3 (IH, multiplet);

4.87, 4.99 (IH, broad singlet);

5.1 (IH, multiplet);

5.23 (2H, multiplet;

6.60 (IH, doublet, 0 = 1 Hz);

7.42 (5H, singlet).

Example 16

(3R, 4Η5) -4- »Αζβΐοχγ-1» (1-Benzyl-oxy-carbonyl-2-methylpyryl-1- enyl) -3-f (R) -1-t-butyldimethylsilyloxyethyl-azetidine «»

OCOCH

CO ₂ CH ₂ C ₆ H ₅

60 10,12,1980

~ _; 57 342/18/36

3.91 g of an isomeric compound containing as its main constituent (3R, 4RS) -4-acetoxy-1-C (R) -1-benzyloxy-carbonyl-2-methyl-prop-2-enyl3-3-f (R) -lt- butyldimethylsilyloxyethyl 3azetidine · 2 «one were dissolved in 50 ml of methylene chloride and then '

''^; .: - '·, - ·' · '- -64

22 0 392 .- -

1 g of trimethylate was added to the solution. The mixture remained at room temperature for 1 hour. After completion of the reaction, the solvent and triethylamine were distilled off under reduced pressure. The oily residue was adsorbed on a chromatography column using 20 g of silica gel and eluted with a 20: 1 by volume mixture of benzene and ethyl acetate to give 3.91 g (result 100%) of the desired product as an oily substance. The major component of the product was a 1: 1 mixture of the 4-S isomer and the 4-E isomer.

Elemental _analysis : Calculated for C _0n -H _0n O ^ HSi:

- C, 63.12%; H, 7.84 % \ N, 2.95%. Found: C, 63.46%; H ₁ 7.73 . % \ N, 2.86 %. Infrared spectrum spectrum (CHCl3) -if _mri cm "":

3 "4 cis isomer

0.10 (3H, singlet); 0.14 (3H, singlet); 0.90 (9H, singlet) \ "1.40 (3H, doublet, J = 6 Hz); 1.98 (3H, singlet); 2.01 -GH, singlet); 2.25 (3H, singlet) 3.37 (1H, double doublet, J = 8 & 4.5 Hz); 4.25 (1H, multiplet) i 5.2? - (2Hj singlet); 6.35 (IH, doublet, J = 4 , 5 Hz); 7.44 (5H, singlet);

3,4-trans isomer

0.05 (6Hj singlet);

0.09 (9H, singlet);

, 1.98 (3H ₁ singlet); '

2.01 gh., Singulets) s

10.12.1980 57 342/18/36

2.25 (3H ₁ singlet); 3.21 (IH, double doublet, D = 6.5 & 1.5 Hz);

4.25 (IH, multiplet); 5.27 (2H, singlet);

6.26 (IH, doublet, D = 1.5 Hz); 7.44 (5H, singlet).

szetidin "2" one

H ,

₄₉ OSi (CH,)

CH.

OCOCH

3.79 g (7.98% BiMoI) (3R, 4RS) -4-Acetoxy ~ l ~ (1-benzyloxy-carbonyl ~ 2-methylprop-1-enyl) ~ 3-T (R) -It-butyldimethylsilyloxyethyl-azetidine ~ 2 -one were dissolved in 300 ml of acetone. This solution was then added to a solution of 9.50 g (44.4 mmol) of sodium metaperiodate and 100 mg (0.63 mmol) of potassium permanganate in a mixture of 220 ml of water and 110 ml of an O, IM phosphate buffer (pH 7.0). was added, then the mixture was stirred at room temperature for 23 h. The reaction mixture was then filtered and the filtrate was compressed by evaporation at reduced pressure to a volume of about 400 ml. The concentrate was extracted twice with ethyl acetate, which was saturated with sodium chloride, and then the organic layer was washed with saturated brine and dried. The solvent was distilled off and the oil residue was adsorbed on a chromatography column using 40 g of silica gel and treated with a 1: 3

> 3

22 0.392

Volimiermiischung eluted from acetone and hexane, so that 1.8G g (! Result 81%) of the desired product as an oily substance. The main "ingredient this Produktes.ist a 1: 1 mixture of the 4S-isomer, and the 4-E-Isom.er The product warde dissolved in hexane and then cooled to -15 ⁰ C, so that a part of the 4-B. krjstalliert isomer (3 "4" trans isomer), and 312 mg! Blame emerged that oiling at 102 -104 ⁰ C.

Element aranaly se: Calculated for C ^ H ₂₅ O ₄ ISi:

- C, 54 * 32%} H, 8.77%; N, 4.87%. Found: C, 54.04%; H, 8.79%; K, 4,71 '%.

Infrared absorption spectrum (lTuool-v '.' Sign) ir _mo cm "":

Max

3175, 1783, 1743o

Specific Eotation: ... ,

[oj | ° = + 235 ° (c = 0.52, CECl ₃ ).

Nuclear magnetic resonance spectrum (CDCl ^) (Tppm:

3,4 tran3- "isomer 0.07 (6H, singlet); 0.88 (9H, singlet); 1.25 (3H, doublet, J = 5.5 Hz); 2.13 (3H singlet ₁₎ 5 3.10 (IH, double doublet, J = 3.5 & 1.5 Hz); 4.3 (^ H, multiplet); 5.9S (1H, doublet, J = 1.5 Hz); 7, 24- (1H ₁ wide).

3,4 cis- IsoTaer:

0.0? (6Ii, singlet);

0.88 (9H, singlet);

1 | 3> (3E, doublet, J = 6 Hz); , _:

2.10 (3H, singlet);

ΙΟ »12.1980 57 342/18/36

3.38 (IH, double double doublet, 0 = 9, 5 & 2 Hz); 4.3 (IH, multiple);

5.99 (IH, doublet, D = 5 Hz);

7.24 (IH, wide).

Example 18

JZS , 4R) -3- £ (R) -1-1 - Budy 1 d in et hy1 giily 1 oxyäthyl] -4- { f2- (pnitrO _| benzyloxycarbonylamino) ethylthio3t_hiocarbonyl} thio · azetidinedione

H OSi (CH ₃ ) ₂

CH

S (CH ₂ ) ₂ NHC0 ₂ CH ₂

.NH

712 mg (2.78 mmol) of 2- (p-nitrobenzyloxycarbonylamino) ethanethiol were added at ⁰ ° C. to a methanolic solution of sodium methoxide prepared from 60.9 mg (2.64 mmol) of sodium metal and 6 ml of methanol was stirred for 5 min. after the addition of 211 mg (2.78 mmol) of carbon disulfide at 0 C to the mixture, the mixture after 20 min was stirred. the resulting yellow solution was cooled to -10 ⁰ C, and then were added 800 mg (2.79 mmol) of (3R, 4R) -4-.Azetoxy-3-n ^R) * 'l ~ t ~ butyldimethylsilyloxyäthy3jazetidin-2-one added to the solution and the mixture was stirred at -10 C for 40 min. After After completion of the reaction, the solution was acidified by the addition of acetic acid and was then diluted with ethyl acetate, washed with saturated brine and dried The solvent was distilled off and the residue was adsorbed on a chromatographic column using 25 g of silica gel 10: 1 Volumen--

eluted from benzene and acetone to give 1.37 S (= 88% yield) of the desired product as an oil-containing acid. '

Elemental analysis;

Calculate for C ₂₂ H ^ IaLO ₆ SoSi:

C, 47.22%; H, 5.90%; IT, 7.51%; S, 17.17%. Found: C, 47.97%; H, 5.89 % \ N, 7.39%; S, 17.10%.

Infrax-otabsorptionsspektrum. '3400 (broad), 1770, 1720.

Nuclear Magnetic Resonance Spectrum (CDClO cTppm

0.05 (5H, singlet) i 0.90 (9Ej singlet); 1.20 (3H, doublet, J = δ Ha); 3.23 (1H, double doublet, J = 4 & 2 Ha); 3.55 (4H, broad singlet); 4 * 20 (1H, multiplet); 5.52 (2H ₁ singlet); 5.69 (1H, doublet, J = 2Hz);

7.15 (1H, broad singlet); 7.50 (2H, doublet, J = 9Ha);

8.16 (2H, doublet, J = 9 Hz).

EXAMPLE 19QS, 4R) 3 - [(B) 1 - t-- ^ P-nitrobenzylo ^ / carbonyl) methyl) -4- \ f2- (p-nitrobenzyloy / - karbonolanino) ethylbiolcarbonylthioamidine-2-one

fv-Νβ,

29 O 3 92 (whether 10.12.1980

- 58 - 57 342/18/36

A solution of 1.0 g (1.78 mmol) of (3S, 4R) -3- (R) -I-butyldimethylsilyloxyethyl 3-4- {2- (p-nitrobenzyloxycarbonylamino) ethylthio] thiocarbonylthioazetidine-2 -one and 404 mg (1.78 mfiol) of p-nitrobenzylglyoxylate hydrate in 10 ml of benzene were heated at reflux for 5 h. After completion of the reaction, the solvent was distilled off and the residue was adsorbed on a chromatography column using 15 g of silica gel and eluted with a 1: 3 volume mixture of acetone and hexane to give I ₁ OS g (result 78 %) of the desired product be provided in the form of a yellow oily substance »

Elemental analysis:

Calculated for C ₁ H ₄₀ N ₄ O .S ₃ Si:

C, 48.44 %; H, 5.20%; N ₁ 7.30%; S, 12.50%, Found:

C, 48.42 % i H, 5.95 %; N, 7.66 %; S, 12.28%.

-1 infrared absorption spectrum (liquid film) V _ax cm:

3350, 1770, 1720.

Nuclear magnetic resonance spectrum (CDCl ₃ ) ^ T ppm:

0.04 (3H, singlet);

0.06 (3H, singlet);

0.82 (9H, singlet);

1.15 (3H, doublet, ö = 6 Hz);

3.30 (IH, multiplet);

3 _f 50 (4H, broad singlet); 3.9-4.3 (2H, multiplet);

6.2 (IH, multiplet);

7.48 (2H, doublet, Ο = 9 Hz);

7.54 (2H, doublet, D = 9 Hz);

8.18 (2H, doublet, D = 9 Hz);

8.20 (2H, doublet, D = 9 Hz).

'22 -0 392; ".." ..-. , -

EXAMPLE 20

(3S, 4R) -3-r (R) -T-butyldimethylsilyloxyäthyil-4- | [2- (ώ- nitrobenzylbxycarbonyl) -tinol ) ethylthio] thiocarbonyl-thio-1- [(p-nitrobenzyloxycarbonyl) -triphenylphosphoranylidene-

methyl, azetidin-2-one

865 mg ('1.12 mmol) of (33.4R) -3-f (R) -1-t-butyldimethylsilyloxyethyl] -1- [hydroxy (p -nitrobenzylosylcarbonyl) -methyl "] -4-i ^: [2 -. (j) nitrobenzyloxykarbonylamino) ethylthio] thiokarbonyljthioazetidin-2-one 'ifurden dissolved in 32 ml of tetrahydrofuran at a temperature of ~ 18 ° C to -15 ⁰ C were added to this solution, 181 mg (1.69 mmol) of 2,6 After the completion of the reaction, the solvent was distilled off under reduced pressure and low temperature, and the resulting residue was dissolved in 25 ml of tetrahydrofuran To this solution was added 241 μl / g (2.24 mmol) of 2,6-lutidine and 590 mg (2.24 mmol) of triphenylphosphine, which was then refluxed under a nitrogen atmosphere for 42 hours at a temperature of 75 ° C. After completion of the reaction, the reaction mixture was diluted with ethyl acetate nt, washed with water and dried, and then the solvent was distilled off. The resulting residue was adsorbed on a chromatographic column containing 15 times silica gel compared to the weight of the residue and was eluted with a 20% volume mixture of chloroform and ethyl acetate. There were obtained 705 mg (result 61.3 / S) of the desired product in the form of a yellow oil-containing substance.

Elementary ^analysis

Calculated for C ₄₉ H ₅₃ N ₄ O ₁₀₃

C, £ 58.10; H, £ 5.23; 1ί, -5.53 #; S, 9.48 ^. Found: C, 58.29%; H, 5.31%; H, 5.66%; S, 9.65 #.

Infrared Absorption Spectrum (Liquid Film) '/ - ", _-, cm" : 1760, 1710.

Nuclear magnetic resonance spectrum (CDGIo) ^ " ppm:

o, 05 (3H, singlet); 0.08 (3H, singlet); 0.90 (9H, singlet); 1.16 (3H ₅ doublet, J = 6Hz); • 3.65 (4H, multiplet), 4.45 (1H ₅ multiplet), 5.28 OH, doublet, J = 12 Hz), 5.30 (2H, singlet), 5.58 (1H, doublet, J = 12 Hz), 6.35 OH, multiplet), 7.7 (19H, multiplet), 8.4 (4H, doublet, J = 9Hz).

EXAMPLE 21

p-Ititolobenzyl (5R, 6S) -2- [2 - (p- nitrobenzyloxycarbonylamino) -jatji ylthio | -β- \ (H) -it-butyldimethylsilyloxyethyl -penera-3-carboxylate and its (55) -isomer

κ.

ί-

A solution of 1.33 g of (3S, "4R) -3 - [(R) -1-t-butyldimethylsilyloxyethyl] -4- (Τ2- (ρ -nitrobenzyloxylcarbonylaminoj-ethylthio) carbonyl" thio-1 - (p-) Nitrobenzyloxycarbonyl-triphenylphosphoranylidenemethyl-2-azadione and 92 g of hydroquinone in 130 ml of xylene were heated under nitrogen atmosphere for 15 hours at a temperature of 125 to 130 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was adsorbed on a chromatographic column containing 20 g of silica gel and eluted with benzene to give 717 mg (result: 76 %) of the desired (5R) -I rs and 158 mg (16.9 %) of its (5S) - Isomers arise as oil-containing substances.

Elemental analysis:

Calculated for G -, - H-gN.O ^ ₀ SpSi :.

C, 51.8155; H, 5.29%; H, 7, SO ^; 3, 8.91%.

(5R) isomer:.

Plagued: C, 51.68%; H, 5,3Of; II, 7.71%; S, 9,20%.

(5S) isomer: ...

Plagued: G, 51.70%; H, $ 5.42; N, 7.91%; S, 9,

Infrared Absorption Spectrum (Hujol Trademark) '$ ^.

Max

(5R) isomer: 1780, 1710, 1670.

(5S) isomer: 1780, 1730, 1690.

> 0

EXAMPLE 22

p-Mtrob enyl (5H, 6S) -2-j 2- (t -nitrobenzyloxy carbonylamino) ethylthiol-6-Γ (R) -1-hydroxyethylphenyl-3-carboxy7 / lat

A solution of 200 mg (0.278 mmol) of O-methylbenzyl (5R, 6S) -2- [2- ( 2- nitrobenzyloxycarbonylamino) ethylthio] -6-L (R) -1-t-butyldimethylsilyloxyethyl]] penem-3 Carboxylate, 167 mg (2.78 ml of violet) acetic acid and 218 mg (0.835 ml. 5 mol) of tetrabutylammonium fluoride in 5 ml of tetrahydrofuran was stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was diluted with 40 ml of ethyl acetate and then washed successively with water and a saturated aqueous sodium bicarbonate solution. After the mixture was dried ιψ, τ / -ö-e-, the solvent was distilled off. The crystalline residue was recrystallized from a mixture of benzene and methanol, thereby 156 mg (yield 92%) of the desired product as a pale yellow powder with a melting point of 189 - 190 ⁰ C are formed.

Elemental analysis:

Calculated for C ₂₁ -H ₂₄ U ₄ O ₁₀ S ₂ :

, C, 49, 67> S; H, 3.97%; N, 9.27%; S, 10.59%. , Plagued: C, 49.84%; H, 4.02%; N, 9.30% S, 10, 48%.

Infrared absorption spectrum (KBr) τΓ cm:

Max

3425, 3275, 1780, 16O. ,

Specific rotation:

[Α *!) ^{5 = +} 7 ¹ ° (° = °, S3, dimethylformamide).

Nuclear magnetic resonance spectrum (CDdO vT ppm: (5R) isomer:

0.03 (3H, singlet);

, 0.07 (3H, singlet);

0.30 (9H, singlet); '

1.20 (3H, doublet, J = 6Hz);

3.04 (2H, multiplet); ·

3.38 (2H, triplet, J = 5Hz);

3.66 (1H, double doublet, J = 4 &2Hz);

• 4.12 (1H, multiplet);

5.04 (1H, doublet, J = 14 Hz); 5.10 (2H, singlet);

5.37 (1H, doublet J = 14 Hz);

5.57 (1H, doublet, J = 2Hz);

7.38 (2H, doublet, J = 9 Hz); 7.50 (2H, doublet, J = 9 Hz);

8.58 (4H, doublet, J = 9Hz).

(5S) -isomer:

0, i0 (6h, singlet);

0.81 (9H, singlet);

1.32 (3H, doublet J = 6 Hz);

3.01 (2H, multiplet);

3.36 (2H, triplet, J = 5Hz);

3.74 (1H, double doublet, J = 10 & 4 Hz);

4.22 (1H, double quartet, J = 10 & 6 Hz);

5.01 (1H, doublet, J = 14 Hz);

5.05 (2H, singlet);

5.40 (1H, doublet J = 14 Hz);

5.58 (1H, doublet, J = 14 Hz);

7.34 (2H, doublet, J = 9Hz);

7.47 (2H, doublet, J = 9Hz);

8,60 '(4H ₁ doublet, J = 9Hz).

10.12.1980 - 72 - 57 342/18/36

Nuclear magnetic resonance spectrum (deuterated dimethylformamide) / ppm:

1.28 (3H, doublet, O = 6 Hz);

3.3 (4H, wide); '

3.79 (IH, double doublet, 0 = 6 & 2 Hz); 4.0 (IH, multiplet);

5.18 (2H, singlet);

5.2.0 (IH, doublet, D = 14 Hz);

5.54 (IH, doublet, D = 14 Hz);

5.80 (IH, doublet, 0 = 2 Hz); 7.60 (2H, doublet, D = 9 Hz); 7.72 (2H, doublet, 0 = 9 Hz); 8.20 (4H, doublet, 0 = 9 Hz).

Example 23

/ 5R _"i 6S)""2-C (2 ~ aminoethyl) th _i io3 ~ 6 ° C _i (R) 'l ~ hydrox yäthyl3penem" 3-carboxylic acid

120 mg of ^ -nitrobenzyl (5R, 6S) -2-i'p_-nitrobenzyloxycarbonylamino) ethylthio] 6-r (R) -1-hydroxyethyl] -penemic acid 3-carboxylate were dissolved in a mixture of 10 ml of tetrahydrofuran and 10 ml an O, 1 M phosphate buffer (pH 7.1) dissolved "240 mg of 10% w / vv palladium / carbon were added to the solution, and then hydrogen gas was passed at atmospheric pressure for 5.5 hours through the mixture" After completion of the reaction, the Reaction mixture filtered, the catalyst was washed with an O, 1M phosphate buffer. The washes were combined with the filtrate, and the «

^ 99 ^; - 10.12.1980

V '* - · 3 - 57 342/18/36

The combined mixture was washed with ethyl acetate and condensed by evaporation under reduced pressure and a low temperature to a volume of about 5 ml. The residue was chromatographed on a column,

5:11 * 1980

AP C 07 D / 220

57 342/18/36

containing 20 ml of HP-20AG adsorbed. ♦ The fractions eluted with water were lyophilized to give 28 mg (result 48.6 %) of the desired product in the form of a powder,

Ultraviolet absorption spectrum (FUO) A _m _nm:

253.0 ( i , 4790); 320.5 ( i _f 6130),

Infrared absorption spectrum (KBr) γ cm " : 3400 - 2300 (wide), 177O ₄

Specific rotation:

Md ^{5 = +175} ° ( ^{c =} ° ' ⁴⁴ ' ^H 2 ⁰⁾ ·

Nuclear magnetic resonance spectrum ( ^D ₂ °) ^ PP ^m (tetramethylsilane as external standard):

1.34 (3H, Dufalett, 0 = 6.5 Hz); 3.32 (4H ₄ multiplet);

3.90 (IH, double doublet, 0 = 6 & 2 Hz); 4.26 (IH, multiplet;

5.75 (IH, doublet, 0 = 2 Hz) «,

Using standard procedures, the hydroxy, amino and carboxy groups in the compound prepared in Example 23 were protected and the physical properties of the resulting compound were determined. These physical properties were compared with those of the corresponding protected compound described in U.S. Pat

d "$ 10.12.1980

220 ^ - ^ - - 57 342/18/36

U.S. Patent No. 4,168,314. It has thus been seen that the protected compound prepared by the process of the present invention is a penem compound, while the compound described in US Pat. No. 4,168,314 is an isopenem compound. The corresponding formulas and relevant information are as follows; particularly relevant information is marked with * ";

Ultraviolet absorption spectrum Λ rna-x: ^nm:

(Dioxane) (tetrahydrofuran)

265 (E & 292) 264 (636400)

^S 315 (Ef 91.5) * 339 (£ 11500).

Specific rotation

=. + 88 °. (C = ι

PIP = j) -Nitrophenyl PlTB = £ -Fitrobenzyl

Claims (2)

.5.11.1980 AP C 07 D / 220 57 342/18/36 Erfindunqsanspruch 1 »Process for the preparation of penicillin derivatives of the formula (III): OH      I · ... M ι ^CH 3 III (III) O COOH and their salts and esters, characterized in that the process has the following steps: (a) heating a phosphorylidene compound of the formula • '2 ^ CH _> ^ S. ^ SCH _n CH ^ lT CH (IV) wherein 1
R represents a protected hydroxy group; R represents a protected hydroxy group or a protected ameno group; R represents a protected carboxy group and Z represents a trisubstituted phosphoniogroup or a doubly esterified phosphono group with a cation, 05/11/1980 AP C 07 D / 220 392 57 342/18/35 a compound of formula (V): (V) manufacture, (b) in any order, implementation of the protected 1
Hydroxy group R into a hydroxy group and reaction of the protected hydroxy group or the protected amino 2
group R into an amino group and if necessary. Reacting the protected carboxy group R in a carboxy group to give a compound of the formula (IIIa): CH ₉ N HL · (purple) wherein R represents a carboxy group or a protected carboxy group; (c) if necessary, salt formation or esterification of the A compound of the formula (IIIa) in which R represents a carboxy group for the preparation of a salt or ester of the compound of the formula (III) » 20 3 * Z 5,11,1980 AP C 07 D / 220 392 - 13 ~ 57 342/18/36 2. The method according to item I ₁ "characterized in that the 12
protected hydroxy represented by R or R is an acyloxy group or a trialkylsilyloxy group; 2
that the protected amino group represented by R is an acylamino group and that the protected carboxy group represented by R is an alkoxycarbonyl group, an aralkyloxycarbonyl group or a benzhydryloxycarbonyl group, 3 »method according to item 1 or item 2, characterized in that in step (a) at a temperature of 100 to 200 ⁰ C is heated. 4t method according to one of the items 1, 2 and 3, characterized in that R represents a protected hydroxy group and in step (b) removes the hydroxy protecting group in order to convert the group R into a free hydroxy group, the free hydroxy group is converted into an azido group and the azido group is reduced to an amino group, 5 * Process according to item 4, characterized in that the free hydroxy group is mixed with azoimide or diphenylphosphorazide in the presence of a phosphine or an azodicarboxylic acid diester to convert it into an azido group, 6, method according to any one of items 1, 2 and 3, characterized is characterized in that R represents an azylamino group and that the protection is removed by entazylation. ... 5.11.1980 AP C 07 D / 220 392 - SO - 57 342/18/35 7, Method according to one of the preceding points, characterized in that the carbon atom in the 4-position of the phosphorylidene compound of formula (IV) and the 5-position of the compounds of formula (V), (IIIa) and (III) in the R Arrangement is, 8, "method according to item 7, characterized in that the c? C-carbon atom in the side chain in the 3 ~ position of the phosphorylidene compound of the formula (IV) or the position of the compound of the formula (V), (IIIa) and (III) is in the R arrangement; the carbon atom in the 4-position of the phosphorylidene compound of the formula (IV) and in the 5-position in the compounds of the formula (V), (HIa) and (III) in the R-arrangement and the carbon atom in the 3- Position of the phosphorylidene compound of the formula (IV) or the 5-position of the compounds of the formula (V), (IIIa) and (III) in the S-arrangement. 9 «method according to any one of the preceding points, characterized in that it in the preparation of (5R, 5S)" 2 ~ n2 ~ aminoethyl) thio3 ~ 5- £ (R) "l-Hydroxyäthyl ^ Penem-S-carboxylic acid whose Salts and esters are used,.