CH662568A5 - Process for preparing aminomethyl compounds - Google Patents

Abstract

Compounds, which are essentially optically pure, of the formula <IMAGE> in which R1 is lower alkyl substituted by hydroxyl, R2 represents carboxyl and R3 denotes amino, amino which is substituted by lower alkyl, or substituted methylenamino, optical isomers of compounds of the formula I, mixtures of these optical isomers, and salts of compounds of the formula I, are prepared by treating a compound of the formula <IMAGE> in which Z is oxygen and R'2 is a protected carboxyl group, while temporarily protecting the functional groups, with an organic compound of trivalent phosphorus. In compounds thus obtained, the carboxyl group R2 can be converted by esterification into an esterified carboxyl group which is cleavable under physiological conditions. The (1R)-1-hydroxyethyl isomer can be isolated by isomeric resolution from a resulting isomeric mixture of compounds of the formula I in which R1 is 1-hydroxyethyl. The compounds of the formula I have antibiotic effects.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 



   PATENT CLAIMS
1.  Process for the preparation of essentially optically pure (SR, 6S) -configured compounds of the formula
EMI1. 1
 wherein R1 is lower alkyl substituted by hydroxyl, R2 represents carboxyl and R3 represents amino, amino substituted by lower alkyl or substituted methylene amino, optical isomers of compounds of the formula I which have a chiral center in the rest of R1, mixtures of these optical isomers and salts of such compounds of Formula I which have a salt-forming group, characterized in that a compound of the formula
EMI1. 2nd
 in which R1 and R3 have the meanings given under formula I, Z is oxygen and R2 'is a protected carboxyl group,

   treated with intermediate protection of the functional groups with an organic compound of trivalent phosphorus, and optionally converting an available compound with a salt-forming group into a salt or an available salt into the free compound or into another salt. 



   2nd  A process for the preparation of (SR, 6S) -2-aminomethyl-6 - [(IR) - l-hydroxyethyl3-2-penem-3-carboxylic acid according to claim 1. 



   3rd  Process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula
EMI1. 3rd
 wherein R1 and R3 have the meanings given in claim 1, and R2 "means esterified carboxy which is cleavable under physiological conditions, optical isomers of compounds of the formula I 'which have a chiral center in the rest R1, mixtures of these optical isomers and salts of such compounds of Formula I 'which have a salt-forming group, characterized in that a compound of the formula I is prepared by the process according to Claim 1 and the carboxy group R2 is converted by esterification into an esterified carboxy group which is cleavable under physiological conditions. 



   4th  Process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula
EMI1. 4th
 wherein R1 (lR3-1-hydroxyethyl, R2 and R3 have the meanings given in claim 1, and salts of those compounds of the formula I which have a salt-forming group, characterized in that the process according to claim 1 is an isomeric mixture of compounds of the formula I, in which R1 is 1-hydroxyethyl and R2 and R3 have the meanings given above, is separated into the individual isomers and the (1R) - 1-hydroxyethyl isomer is isolated. 



   The present invention relates to processes for the preparation of new 2-aminomethyl-penem compounds. 



   The present invention relates to a process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula
EMI1. 5
 wherein R1 is lower alkyl substituted by hydroxy, R2 represents carboxyl and R3 represents amino, amino substituted by lower alkyl or substituted methylene amino, optical isomers of compounds of the formula I which have a chiral center in the rest of R1, mixtures of these optical isomers and salts of such compounds of Formula I which have a salt-forming group, characterized in that a compound of the formula
EMI1. 6
 wherein R1 and R3 have the meanings given under formula I, Z is oxygen and R2 is a protected carboxyl group,

   treated with an intermediate protection of the functional groups with an organic compound of trivalent phosphorus, and optionally an available compound with a salt-forming group in a salt or he



  salt in the free compound or in another salt. 



   The invention further relates to a process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula
EMI2. 1
 wherein R1 and R3 have the meanings given under formula I, and R2 "means esterified carboxy which is cleavable under physiological conditions, optical isomers of compounds of the formula I 'which have a chiral center in the radical R, mixtures of these optical isomers and salts of such compounds of Formula I 'which have a salt-forming group, characterized in that the carboxy group R2 in a compound of the formula I is converted by esterification into an esterified carboxy group which is cleavable under physiological conditions. 



   Finally, the invention relates to a process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula
EMI2. 2nd
 wherein R1 is (1R) -l-hydroxyethyl, R2 carboxy and R3 have the meanings given above, and salts of those compounds of the formula I which are salt-forming
Have group, characterized in that an isomeric mixture of compounds of the formula I, in which R1 is 1-hydroxyethyl and R2 and R3 have the meanings given under formula I, is prepared by the process described above, this is separated into the individual isomers and the (1 R) -l-hydroxyethyl isomers isolated. 



   The definitions used above and below preferably have the following meanings in the context of the present description:
An esterified carboxyl group R2 which can be cleaved under physiological conditions protects the compounds of the formula I from salt formation in the gastrointestinal tract when administered orally, which prevents premature excretion, and is primarily an acyloxymethoxycarbonyl group, in which acyl z. B.  is the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxymethyl forms the residue of a lactone.  Such groups are e.g. B. 



  Lower alkanoyloxymethoxycarbonyl, amino lower alkanoyloxymethoxycarbonyl, especially a-amino lower alkanoyloxymethoxycarbonyl, 4-crotonolactonyl and 4-butyrolacton-4-yl.  Further esterified carboxyl groups R2 which can be cleaved under physiological conditions are e.g. B. 



  5-indanyloxycarbonyl, 3-phthalidyloxycarbonyl, I-lower alkoxycarbonyloxy lower alkoxycarbonyl l-lower alkoxy lower alkoxycarbonyl or 2-oxo- 1. 3-dioxolen-4-ylmethoxycarbonyl which is optionally substituted in the 5-position of the dioxolen ring by lower alkyl or phenyl. 



   Amino R3 substituted by lower alkyl is e.g. B. 



  Lower alkylamino or lower alkylamino. 



   In substituted methylene amino R3, the methylene radical is preferably mono- or disubstituted.  Substituted methylene amino is e.g. B.  a group of the formula
EMI2. 3rd
 wherein X is hydrogen, optionally substituted amino. 



  e.g. B.  Amino, Niederalkylamino, Diniederalkylamino, Niederalkylenamino, Nitroamino, Hydrazino or Anilino, etherified hydroxy, z. B.  Lower alkoxy or phenyl-lower alkoxy, etherified mercapto, e.g. B.  Lower alkylthio, optionally substituted lower alkyl, e.g. B.  Lower alkyl, amino-lower alkyl, N-lower alkylamino lower alkyl or N, N-di-lower alkylamino lower alkyl, lower alkenyl.     Phenyl or monocyclic heteroaryl, such as corresponding 5- or 6-membered heteroaryl with 1 to 2 nitrogen atoms and / or an oxygen or sulfur atom, such as pyridyl, e.g. B.  2- or 4-pyridyl, thienyl, e.g. B.  2-thienyl, or thiazolyl, e.g. B. 



  Is 4-thiazolyl, and X is optionally substituted amino. 



  e.g. B.  Amino, lower alkylamino.  Diniederalkylamino, Niederalkylenamino, Cyanamino.  Hydrazino or anilino, etherified hydroxy, e.g. B.  Lower alkoxy or phenyl-lower alkoxy, or etherified mercapto, e.g. B.  Lower alkylthio. 



   In preferred radicals of the formula (IA), X is hydrogen, amino, lower alkylamino or lower alkyl and X is amino. 



   Residues of the formula (IA) which have a hydrogen atom on the a atom of the substituent X and / or the substituent X, for. B.  Residues of formula (IA), wherein Xl is amino, lower alkylamino, nitroamino, hydrazino, anilino or optionally substituted lower alkyl and / or X2 is amino. 



  Lower alkylamino, hydrazino or anilino can also be in one of the tautomeric forms
EMI2. 4th
 where X1 or    X2 is corresponding substituted or unsubstituted methylene or imino. 

 

   In the present description, the term low used in connection with definitions of groups and compounds means that the corresponding groups or  Links.  unless explicitly defined otherwise, contain up to 7, preferably up to 4 carbon atoms. 



   Lower alkyl substituted by hydroxy R1 is in particular in the a-position to the Penem ring structure by hydroxy substituted lower alkyl and means, for. B.  l-hydroxyprop l-yl, 2-hydroxybut-2-yl and primarily hydroxymethyl and l-hydroxyethyl. 



   Lower alkanoyloxymethoxycarbonyl is e.g. B.  Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl. 



   a-amino lower alkanoyloxymethoxycarbonyl is e.g. B. 



  Glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl.   



     l-Lower alkoxycarbonyloxy lower alkoxyearbonyl is e.g. B. 



  Äthoxycarbonyloxymethoxycarbonyl or 1 -thoxycarbonylyloxyäthoxycarbonyl. 



     1-Lower alkoxy lower alkoxycarbonyl is e.g. B.  Methoxy methoxycarbonyl or 1-methoxyethoxycarbonyl.    



   In the case of a 2-oxo-1,3-dioxolen-4-ylmethoxy group, which may be in the 5-position of the dioxolen ring
Lower alkyl or phenyl is substituted, it is primarily a 5-phenyl and primarily a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxy group. 



   Lower alkylamino is e.g. B.  Methylamino, Athylamino, n Propylamino, Isopropylamino or n-Butylamino, while Diniederalkylamino z. B.  Dimethylamino, diethylamino, di-n-propylamino or di-n-butylamino means. 



   Niederalkylenamino has in particular 4 to 6 carbon chain links and means, for. B.  Pyrrolidino or Piperidino. 



   Lower alkoxy is e.g. B.  Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert. -Butoxy, while phenyl-lower alkoxy e.g. B.  Is benzyloxy. 



   Lower alkylthio is e.g. B.  Methylthio, ethylthio, n-propylthio, isopropylthio or n-butylthio. 



   Lower alkyl is e.g. B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl or tert. -Butyl. 



   Amino lower alkyl is e.g. B.  2-aminoethyl or 3-aminopropyl. 



   N-Niederalkylaminoniederaikyl is e.g. B.  2-methyl or 2-ethylaminoethyl, while N, N-di-lower alkylamino lower alkyl e.g. B.  2-dimethylaminoethyl or 2-diethylamino ethyl means. 



     Niederalkenyl is e.g. B.  Allyl, n-propenyl or isopropenyl. 



   Preferred esterified carboxyl groups R2 which are cleavable under physiological conditions are e.g. B.  Phthalidyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, e.g. B.  Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and l-lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. B. 



      1-ethoxycarbonyloxyethoxycarbonyl.    



   Preferred compounds of the formula 1 which can be prepared by the processes according to the present invention are those in which R1 is hydroxymethyl and R2 and R3 have the meanings given under formula I. 



   Further preferred compounds of the formula I which can be prepared by the processes according to the present invention are those in which R1 is 1-hydroxyethyl and R2 and R3 have the meanings given under formula I. 



   To carry out the processes according to the present invention, the functional groups present in the compounds of the formula I, such as hydroxyl, carboxy or amino groups, in particular the hydroxyl group in the radical R1 and the carboxyl group R2, are protected by protective groups which are in the penem, penicillin, Cephalosporin and peptide chemistry can be used.  Such protective groups protect the functional groups in question from undesired condensation reactions, substitution reactions and the like during the synthesis of the compound of the formula I from its precursors. 



   Such protecting groups are easy, i. H.  without unwanted side reactions taking place, for example solvolytically, reductively or even under physiological conditions, can be split off. 



   Protecting groups of this type and their introduction and splitting off are described, for example, in J. F. W.  McOmie, Protective Groups in Organic Chemistry, Plenum Press,
London, New York, 1973, T. W.  Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981, The Peptides, Vol.  I, Schroeder and Luebke, Academic Press, London, New York, 1965 and Houben-Weyl, Methods of
Organic Chemistry, Volume 15/1, Georg Thieme Verlag,
Stuttgart, 1974. 



   In compounds of the formula (I), the hydroxyl group in the radical R1 can be protected, for example, by acyl radicals. 



   Suitable acyl radicals are e.g. B.  lower alkanoyl optionally substituted by halogen, e.g. B.  Acetyl- or Trifluorace tyl, optionally substituted by nitro benzoyl, e.g. B. 



   Benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally substituted by halogen-substituted lower alkoxycarbonyl, e.g. B.  2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, lower alkenyloxycarbonyl, e.g. B.  Allyloxycarbonyl, or optionally substituted by nitro phenyl-lower alkoxycarbonyl, e.g. B.    4-nitrobenzyloxycarbonyl.     Other suitable hydroxy protective groups are e.g. B.  trisubstituted silyl, such as tri-lower alkylsilyl, e.g. B.  Trimethylsilyl or tert. -Butyl dimethylsilyl, 2-halogeno lower alkyl groups, e.g. B.  2-chloro,
2-bromo, 2-iodo and 2,2,2-trichloroethyl, and optionally by halogen, e.g. B.  Chlorine, lower alkoxy, e.g. B.  Methoxy, and / or nitro substituted phenyl-lower alkyl, such as corre sponding benzyl.  Preferred as hydroxy protecting groups
Tri-lower alkylsilyl, lower alkenyloxycarbonyl and through
Halogen substituted lower alkoxycarbonyl. 



   A carboxyl group R2 is usually esterified
Protected form, the ester group being gentle
Conditions, e.g. B.  under gently reductive, such as hydroge nolytischen, or gently solvolytischen, such as acidolyti rule or in particular basic or neutral hydrolytic
Conditions that is easily fissile.  A protected carboxyl group may also be a functionally modified carboxyl group easily esterified to another
Represent carboxyl group convertible, esterified carboxyl group. 



   Such esterified carboxyl groups contain as esterifying groups primarily branched lower alkyl groups in the 1-position or suitably substituted in the 1- or 2-position.  Preferred carboxy groups present in esterified form include lower alkoxycarbonyl, e.g. B. 



   Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert. -Butoxycarbonyl, and (hetero-) arylmethoxycar bonyl with 1 to 3 aryl radicals or a monocyclic heteroaryl radical, these optionally being, for. B.  by lower alkyl, such as tert. -Lower alkyl, e.g. B.  tert. -Butyl, halogen, e.g. B. 



   Chlorine, and / or nitro are mono- or poly-substituted. 



   Examples of such groups include z. B.  as mentioned above, substituted benzyloxycarbonyl, e.g. B.  4-Ni trobenzyloxycarbonyl, optionally, e.g. B.  as he thinks above, substituted diphenylmethoxycarbonyl, e.g. B.  Di phenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. B.  as mentioned above, substituted Pi colyloxycarbonyl, e.g. B.  4-picolyloxycarbonyl, or furfuryl oxycarbonyl, such as 2-furfuryloxycarbonyl.  More suitable
Groups are lower alkanoylmethoxycarbonyl, such as aceto nyloxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is preferably optionally, for. B.  benzoyl substituted by halogen such as bromine, e.g. B.  

  Phenacyloxy carbonyl, halogen-lower alkoxycarbonyl, such as 2-halogens deralkoxycarbonyl, e.g. B.  2,2,2-trichloroethoxycarbonyl,
2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or halogen. ederalkoxycarbonyl, which contains 47 carbon atoms in lower alkoxy, e.g. B. 



   4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, never deralkenyloxycarbonyl, e.g. B.  Allyloxycarbonyl, or in
2-position substituted by lower alkylsulfonyl, cyano or trisubstituted silyl, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. B.  2-methylsulfonylethoxy carbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxy carbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl.   



   Further protected carboxyl groups present in esterified form are corresponding organic silyloxycarbonyl groups and also corresponding organic stannyloxycarbonyl groups.  In these the silicon or  Tin atom preferably lower alkyl, especially methyl or ethyl, further lower alkoxy, e.g. B.  Methoxy, as a substituent.  Suitable silyl or  Stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl or dimethyl tert. butylsilyl, or appropriately substituted stannyl groups, e.g. B.  Tri-n-butylstannyl. 



   Preferred protected carboxyl groups R2 are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, in particular allyloxycarbonyl, and the 2-position by lower alkylsulfonyl, cyano or tri-lower alkylsilyl, e.g. B. 



  Trimethylsilyl or di-n-butyl-methylsilyl, substituted ethoxycarbonyl group. 



   A protected amino group in the radical R3 can be present, for example, in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or stannylamino group or as an enamino, nitro or azido group. 



   In a corresponding acylamino group, acyl is, for example, the acyl residue of an organic acid with, for. B.  up to 18 carbon atoms, in particular one optionally z. B.  by halogen or phenyl, substituted alkane carboxylic acid or optionally, e.g. B.  by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic acid semi-ester.  Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halogen-lower alkanoyl, such as 2-haloacetyl, in particular 2-fluoro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2 -Trichloracetyl, optionally substituted benzoyl, e.g. B.  Benzoyl, halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl.  In particular, lower alkenyloxycarbonyl, e.g. B. 

  Allyloxycarbonyl, or optionally substituted in the 1- or 2-position lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. B.  Methoxy or athoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. B.  Benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. B.  benzoyl substituted by halogen such as bromine, e.g. B.  Phenacyloxycarbonyl, 2-halogeno lower alkoxycarbonyl, e.g. B.    2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) ethoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, e.g. B.  2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-tri phenylsilylethoxycarbonyl.    



   In an acylimino group, acyl is, for example, the acyl residue of an organic dicarboxylic acid with e.g. B.  up to 12 carbon atoms, in particular a corresponding aromatic dicarboxylic acid, such as phthalic acid.  One such group is primarily phthalimino. 



   An etherified mercaptoamino group is primarily an optionally by lower alkyl, such as methyl or tert.  Butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and / or nitro-substituted phenylthioamino group or a pyridylthioamino group.  Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino.    



   A silyl or stannylamino group is primarily an organic silyl or  Stannylamino group, in which the silicon or  Tin atom preferably lower alkyl, e.g. B. 



   Methyl, ethyl, n-butyl or tert. -Butyl, also lower alkoxy, e.g. B.  Contains methoxy as a substituent.  Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, and also dimethyl tert. butylsilyl, or appropriately substituted stannyl.  e.g. B.  Trin-butylstannyl. 



   Other protected amino groups are e.g. B.  Enamino groups which contain an electron-withdrawing substituent, for example a carbonyl group, on the double bond in the 2-position.  Protecting groups of this type are, for example, l-acyl-lower alk-l-en-2-yl radicals, in which acyl z. B. 



  the corresponding residue of a lower alkane carboxylic acid.  e.g. B. 



  Acetic acid, one optionally, e.g. B.  through lower alkyl.  such as methyl or tert. -Butyl, lower alkoxy, such as methoxy.  Halogen, such as chlorine, and / or nitro substituted benzoic acid, or in particular a carbonic acid semi-ester, such as a carbonic acid lower alkyl half ester.     e.g.  B.  methyl half-ester or ethyl half-ester, and lower alk-l-ene means in particular l-propene.  Corresponding protective groups are primarily l-lower alkanoylprop-l-en-2-yl, e.g. B.  I-acetylprop-l-en-2-yl, or l-lower alkoxycarbonyl-prop-l-en-2yl, e.g. B.  l-ethoxycarbonyl-prop-l-en-2-yl. 



   Preferred protected amino groups are e.g. B.    Azido, phthalimido, nitro, lower alkenyloxycarbonylamino, optionally substituted by nitro benzyloxycarbonylamino, l-lower alkanoyl-lower alk-l-en-2-ylamino or l-lower alkoxycarbonyl-lower alk-1-en-2-ylamino. 



   Salts of compounds which can be prepared according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of the formula I.  Such salts are, for example, from the acidic groups present in compounds of the formula I, e.g. B.  of the carboxyl groups R2, are formed and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, for. B.  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. B.  Triethylamine, hydroxy-lower alkylamines, e.g. B.    2-hydroxyethylamine, bis- (2hydroxyethyl) amine or tris- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B.  4-aminobenzoic acid, 2-diethylaminoethyl ester, lower alkylene amines, e.g. B.    l-ethyl piperidine, cycloalkylamines, e.g. B. 

  Dicyclohexylamine, or benzylamines, e.g. B.  N. N'-dibenzylethylenediamine, dibenzylamine or N-benzyl-t3-phenethylamine.    



  Compounds of formula I with a basic group, e.g. B. 



  with an amino group, acid addition salts, e.g. B. 



  with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carbon or sulfonic acid, e.g. B.  Acetic acid, succinic acid.  Fumaric acid, maleic acid, tartaric acid.  Oxalic acid, citric acid, benzoic acid, mandelic acid.  Malic acid.  Ascorbic acid. 



  Form methanesulfonic acid or 4-toluenesulfonic acid.  Compounds of formula 1 with an acidic and with a basic group can also be in the form of internal salts. 

 

  d. H.  in zwitterionic form. 



   For isolation or purification, pharmaceutically unsuitable salts can also be used.  Only the pharmaceutically acceptable, non-toxic salts are used therapeutically.  which are therefore preferred. 



   The penem compounds of the formula I have the R configuration on carbon atom 5 and the S configuration on carbon atom 6.  The compounds of the formula I may have another chirality center in the substituent R,  S or the racemic R, S configuration can be present.  In preferred compounds of the formula I, a radical R 1 which is asymmetrically substituted by hydroxy in the a position (at the carbon atom 1 '), in particular l'-hydroxyethyl.  the R configuration. 



   The compounds of formula I are in essentially optically pure form, i. H.  they are essentially free of isomers with a configuration other than the (5R, 6S) configuration, in particular free of the corresponding (5R, 6S) isomers. 



  Cyclization of the compound of formula III
An organic compound of trivalent phosphorus derives e.g. B.  from phosphorous acid and is in particular an ester thereof with a lower alkanol, e.g. B. 



  Methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, e.g. B.  Phenol or pyrocatechol, or an amide ester thereof of the formula P (ORa) 2-N (Rb) 2, in which Ra and Rb independently of one another are lower alkyl, e.g. B.  Methyl, or aryl, e.g. B.  Phenyl.  Preferred compounds of trivalent phosphorus are tri-lower alkyl phosphites, e.g. Trimethyl phosphite or triethyl phosphite. 



   The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, e.g. B. 



  Toluene or xylene, an ether, e.g. B.  Dioxane or tetrahydrofuran, or a halogenated hydrocarbon, e.g. B. 



  Methylene chloride or chloroform, at a temperature of about 20 to 150 "C, preferably from about 40 to about 120" C, wherein 1 mol equivalent of a compound of formula III is reacted with 2 mol equivalent of the phosphorus compound.  Preferably, the compound of formula III is placed in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a longer period of time, e.g. B. 



  over a period of 2 to 4 hours. 



   The starting material of the formula III is preferably prepared as indicated below and reacted with the organic compound of trivalent phosphorus without isolation from the reaction mixture, the end products of the formula I being formed. 



   Those starting materials of the formula III are preferably used which lead to the compounds of the formula I mentioned at the beginning as being particularly preferred. 



   In an available compound of formula I in which one or more functional groups are protected, these, e.g. B.  Protected carboxyl, hydroxyl and amino groups are released in a manner known per se by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis or chemical reduction, if appropriate in stages or simultaneously. 



   In a compound of the formula I obtainable according to the process, in which R2 denotes a protected carboxyl group, the protected carboxyl group can be released in a manner known per se.  So you can tert. -Lower alkoxycarbonyl or in the 2-position by a trisubstituted silyl group or in the 1-position by lower alkoxy-substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl z. B.  by treatment with a carboxylic acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole, into free carboxyl.  Optionally substituted benzyloxycarbonyl can e.g. B.  by means of hydrogenolysis, d. H.  can be cleaved by treatment with hydrogen in the presence of a metallic hydrogenation catalyst such as a palladium catalyst. 

  You can also suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, also by chemical reduction, e.g. B. 



  by treatment with an alkali metal, e.g. B.  Sodium dithionite, or with a reducing metal, e.g. B.  Tin, or metal salt, such as a chromium II salt, e.g. B.  Chromium (II) chloride, usually in the presence of a hydrogen donor that can generate nascent hydrogen together with the metal, such as a suitable carboxylic acid, e.g. B.  one if necessary, e.g. B.  lower alkane carboxylic acid substituted by II ydroxy, e.g. B.  Convert acetic acid, formic acid or glycolic acid, or an alcohol or thiol, preferably with water, into free carboxyl. 



   The cleavage of an allyl protecting group can, for. B.  by reaction with a compound of palladium, e.g. B.  Tetrakis (triphenylphosphine) palladium, in the presence of tri phenylphosphine and with the addition of a carboxylic acid, e.g. B. 



  2-ethylhexanoic acid, or a salt thereof.  By treatment with a reducing metal or metal salt as described above, 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into free carboxyl, while aroylmethoxycarbonyl can also be converted by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, can be cleaved. 



  Substituted 2-silylethoxycarbonyl can also be prepared by treating with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. B. 



  Sodium fluoride, in the presence of a macrocyclic poly ether (crown ether) or with a fluoride of an organic quaternary base, such as tetraniederalkylammonium fluoride, e.g. B.  Tetrabutylammonium fluoride, can be converted into free carboxyl.  Carboxyl esterified with an organic silyl or stannyl group, such as tri-lower alkylsilyl or stannyl, can be solvolytically, for. B.  by treatment with water or an alcohol. 



  A lower alkoxycarbonyl group substituted in the 2-position by lower alkylsulfonyl or cyano can, for. B.  by treatment with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. B.  Sodium or potassium hydroxide or sodium or potassium carbonate, can be converted into free carboxyl. 



   On the other hand, compounds of the formula I in which R 2 is carboxy can also be converted into compounds of the formula I in which R 2 is an esterified carboxyl group which is cleavable under physiological conditions.  So you can the free carboxyl z. B.  by treatment with a suitable diazo compound, such as a diazo lower alkane, e.g. B.  Diazomethane, or a phenyldiazone lower alkane, e.g. B.  Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, such as. B.  Boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B.  Esterify dicyclohexylcarbodiimide and carbonyldiimidazole. 

  Esters can also be prepared by reacting an optionally in situ salt of the acid with a reactive ester of an alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid.  Furthermore, acid halides such as chlorides (made e.g. B.  by treatment with oxalyl chloride), activated esters, (formed e.g. B.  with N-hydroxy nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (obtained e.g. B.  with halogenoformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with suitable alcohols, optionally in the presence of a base such as pyridine, into an esterified carboxyl group. 

 

   Furthermore, in compounds of the formula I which contain a carboxyl group protected in esterified form, the carboxyl protecting group can be split off as described above and a resulting compound of the formula I can be converted into a free carboxyl group or a salt thereof by reaction with the reactive ester of a corresponding alcohol Transfer compound of formula I, wherein R2 represents an esterified carboxyl group cleavable under physiological conditions. 



   In available compounds of the formula 1, a protected hydroxyl group contained in the radical R1 can be converted into the free hydroxyl group in a manner known per se.  For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is released, such as a correspondingly protected amino group (see. u. ); a tri-lower alkylsilyl group e.g. B. 



  also with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected by trisubstituted silylethoxy are not split).  A 2-halogeno lower alkyl group and an optionally substituted benzyl group are cleaved reductively. 



   In an available compound of formula I with a protected amino group R3, this can be carried out in a manner known per se, e.g. B.  depending on the type of protective group, preferably by means of solvolysis or reduction, can be converted into the free amino group.  For example, 2-halogeno lower alkoxycarbonylamino (optionally after converting a 2-bromo-lower alkoxycarbonylamino group to a 2-3 or lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino by treating with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid be cleaved with hydrogen in the presence of a palladium catalyst. 

  Aroylmethoxycarbonylamino can also be treated by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. B. 



  Sodium dithionite can be split.  Optionally substituted benzyloxycarbonylamino z. B.  by means of hydrogenolysis, d. H.  by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino by reaction with a compound of the palladium, e.g. B.  Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. B.  2 ethylhexanoic acid, or a salt thereof. 



  An amino group protected with an organic silyl or stannyl group may e.g. B.  by means of hydrolysis or alcoholysis, a by 2-halogeno lower alkanoyl, e.g. B. 



  2-Chloroacetyl, protected amino group can be released by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal thiolate, of the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the condensation product formed.  An amino group protected by 2-substituted silylethoxycarbonyl can be treated by treatment with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. B.  Sodium fluoride, in the presence of a macrocyclic polyether (crown ether) or with a fluoride of an organic quaternary base such as tetraniederalkylammonium fluoride, e.g. B.  Tetraethylammonium fluoride, are converted into the free amino group. 

  A protected in the form of an azido or nitro group Ami z. B.  converted into free amino by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide or palladium or by treatment with zinc in the presence of an acid such as acetic acid.  An amino group protected in the form of a phthalimido group can be converted into the free amino group by reaction with hydrazine.  Furthermore, an arylthioamino group can be treated with a nucleophilic reagent.  like sulphurous acid, to be converted to amino. 



   Furthermore, a free amino group R3 can be converted into a substituted amino group in a manner known per se.  For example, amino can be reacted with an appropriate acyl halide, such as chloride.     in acylamino R3 and with a -dicarbonyl compound.     such as a 1-lower alkanoyl acetone or a lower alkyl acetoacetate, in 1-lower alkanoyl or    Transfer l-lower alkoxycarbonylprop-l-en-2-ylamino.  The conversion of amino groups into amidino, guanidino, isourea, imido ether and imidothio ether groups can be carried out, for example, according to one of the methods described in German Offenlegungsschrift No. 



  26 52 679 procedures are performed.  For example, compounds of the formula I in which R3 is amino can be reacted with an imidohalide or ester of the formula [(X1, Y1) C = X2, H] 0 + Y2o.     wherein X is hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl, X2 is optionally substituted imino, Yl halogen, e.g. B. 



  Chlorine, or lower alkoxy, e.g. B.  Athoxy, and Y is an anion, e.g. B.  Chloride, means in amidines or by reaction with a thiourea of the formula X1-C (- S) X2, where X and X2 are identical or different.  optionally substituted amino radicals, or with an isourea or  Isothiourea of the formula (X, Y3) C = X2 ', in which Y3 is lower alkoxy or lower alkylthio, X denotes optionally substituted amino and X2, optionally substituted imino, are converted into guanidines.  Furthermore, a free amino group R3 can be converted into an amino group mono- or disubstituted by lower alkyl. 

  The introduction of the lower alkyl group (s) takes place, for example, by reaction with corresponding reactive lower alkyl esters, such as halides, for. B.  chlorides or bromides, or sulfonates, e.g. B.  methane or p-to toluenesulfonates, in the presence of a basic condensation agent such as an alkali or alkaline earth metal hydroxide or carbonate, e.g. B.  Potassium hydroxide or sodium carbonate, in an inert solvent such as a lower alkanol, at room temperature or higher or lower
Temperature z. B.  at about - 20 "to + 80 C.    



   Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se.  So you can salts of compounds of formula I with a free carboxyl or sulfo group z. B.  by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. B.  the sodium salt of a-ethyl caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. B.  Sodium bicarbonate.  or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts of compounds of the formula I are obtained in a conventional manner.  e.g. B.  by
Treat with a suitable acid or a suitable
Anion exchange reagent.  

  Internal salts of compounds of formula I can e.g. B.  by neutralizing salts such as acid addition salts to the isoelectric point.  e.g. B. 



   with weak bases.  or are formed by treatment with ion exchangers. 



   Salts can be converted into the free compounds in the usual way.  Metal and ammonium salts e.g. B. 



   by treatment with suitable acids and acid addition salts z. B.  by treatment with a suitable basic
Medium. 



   Mixtures of isomeric compounds obtained can be separated into the individual isomers by methods known per se.   



   For example, a racemate obtained can be reacted with an optically active auxiliary, the resulting mixture of two diastereomeric compounds using suitable physico-chemical methods (e.g. B.  separate fractional crystallization, adsorption chromatography) and then split the individual diastereomeric compounds into the optically active compounds.  Racemates which are particularly suitable for separation into antipodes are those which have an acidic group, such as, for. B.  Racemates of compounds of formula I, wherein R2 is carboxy.  These acidic racemates can with optically active bases, for. B. 



  Esters of optically active amino acids, or (-) -Brucin, (+) -quinidine, (-) - quinine, (+) -quinchonine, (+) - dehydroabietylamine, (+) - and (-) - ephedrine, (+ ) - and (-) - l-phenylethylamine or their N-mono- or N, N-dialkylated derivatives to form mixtures consisting of two diastereomeric salts. 



   In racemates containing carboxyl groups, this carboxyl group can also be esterified by an optically active alcohol, such as (-) - menthol, (+) - borneol, (+) - or (-) - 2-octanol, after which the desired diastereoisomer has been isolated Carboxyl group is released. 



   For racemate separation, an existing hydroxyl group can also be esterified with optically active acids or their reactive, functional derivatives, with the formation of diastereomeric esters.  Examples of such acids are (-) - abietic acid, D (+) - and L (-) - malic acid, N-acylated optically active amino acids, (+) - and (-) - camphanic acid, (+) - and (-) - Ketopic acid, L (+) - ascorbic acid, (+) -camphoric acid, (+) -campher-1 0-sulfonic acid (ss), (+) - or (-) - a-bromocampher-R-sulfonic acid, -) -quinic acid , D (-) -isoascorbic acid, D (-) - and L (+) - mandelic acid, (+) - 1-menthoxyacetic acid, D (-) - and L (+) - tartaric acid and their di-O-benzoyl- and Di-op-tolyl derivatives. 



   By reaction with optically active isocyanates, such as with (+) - or (-) - 1-phenylethyl isocyanate, compounds of the formula (I) in which R 2 is protected carboxy and R 1 is hydroxy-substituted lower alkyl can be converted into a mixture of diastereomeric urethanes. 



   Basic racemates, e.g. B.  Compounds of the formula I in which R3 is amino can form diastereomeric salts with the optically active acids mentioned. 



   The separated diastereomers are also cleaved into the optically active compounds of the formula I by customary methods.  The salts or the bases are freed from the salts, for. B.  by treatment with stronger acids or  Bases than the originally used.  The desired optically active compounds are obtained from the esters and urethanes, for example after alkaline hydrolysis or after reduction with a complex hydride, such as lithium aluminum hydride. 



   Another method for separating the racemates consists in chromatography on optically active adsorption layers, for example on cane sugar. 



   According to a third method, the racemates can be dissolved in optically active solvents and the less soluble optical antipode can be crystallized out. 



   A fourth method uses the different responsiveness of the optical antipodes to biological material, such as microorganisms or isolated enzymes. 



   According to a fifth method, the racemates are dissolved and one of the optical antipodes is crystallized by inoculation with a small amount of an optically active product obtained by the above methods. 



   The resolution of the racemates into the optical antipodes can be carried out at any stage in the process, i. H.  e.g. B.  can also be carried out at the stage of the starting compounds of the formula III or at any stage of the processes described below for the preparation of the starting compounds of the formula III. 



   In all subsequent conversions of compounds of the formula I obtained, preference is given to those reactions which take place under alkaline or, in particular, neutral conditions. 



   The starting compounds of Formula III can be prepared as indicated in Reaction Scheme I below: Reaction Scheme I
EMI7. 1
 Level I
A thioazetidinone of the formula V is obtained by reacting a compound of the formula IV with a compound introducing the radical -S = = Z) -CH2-R3.    



   In a starting material of the formula. 1V, W is a nucleofugic radical that can be replaced by the group -S-Cf = Z) -CH, -RX.  Such radicals W are, for example, acyloxy radicals, sulfonyl radicals R0-SO2-, in which Ro is an organic radical, azido or halogen.  In an acyloxy radical W, acyl is e.g. B.  the rest of an organic carboxylic acid and means, for example, lower alkanoyl, e.g. B.  Acetyl or propionyl, optionally substituted benzoyl.  e.g. B.  Benzoyl or 2,4-dinitrobenzoyl, or phenyl-lower alkanoyl, e.g. B.  Phenylacetyl. 

  In a sulfonyl radical Ro-SO2-, Ro is, for example, lower alkyl optionally substituted by hydroxy, such as methyl, ethyl, tert. Butyl, 1-hydroxyprop-2-yl, l-hydroxy-2-methyl-prop-2-yl or 2-hydroxyethyl, benzyl or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl.  A halogen radical W is e.g. B.  Bromine, iodine or especially chlorine.  W is preferably methyl, tert. Butyl- or 2-hydroxyethylsulfonyl, acetoxy or chlorine. 



   A compound introducing the radical -S-C (= Z) -CH2R3 is, for example, an acid of the formula R3 CH2 C (= Z) -SH or in particular a salt, e.g. B.  an alkali metal salt such as the sodium or potassium salt thereof.  The substitution can be carried out in an organic solvent, such as in a lower alkanol, e.g. B.  Methanol or ethanol, a lower alkanone, e.g. B.  Acetone, a lower alkanecarboxamide, e.g. B.  Dimethylformamide, a cyclic ether, e.g. B.  Tetrahydrofuran or dioxane, or in a similar inert solvent.  The reaction is usually carried out at room temperature, but can also be carried out at elevated or reduced temperature, e.g. B. 



  at about 0 "to about 40" C.  By adding a salt of hydroiodic acid or thiocyanic acid, e.g. B.  an alkali metal such as sodium salt, the reaction can be accelerated. 



   The incoming group-S-C (= Z) -CH2R3 is preferably directed by the rest R1 into the trans position.  Therefore, both (3S, 4R) and (3S, 4S) -configured starting compounds of the formula IV can be used.  Although most of the trans isomers are formed, small amounts of the cis isomer can occasionally be formed.  As described above, the cis isomers are removed by conventional methods, in particular by chromatography and / or by crystallization. 



   Suitable starting compounds of the formula IV are known, for example, from European Patent Application No. 



  82 113, German Offenlegungsschrift No.  3,013,997 or German Offenlegungsschrift No.  3,224,055 are known or can be produced in an analogous manner.  They can also be prepared by the methods described in the examples. 



  Level 2
A starting compound of formula (III) is obtained by an azetidinone of formula (V), with an acid of formula R2'-COOH or in particular a reactive derivative such as an ester or acid halide, e.g. B.  the acid chloride, thereof at a temperature of from -20 "to 80" C, preferably at -20 "to 40" C, treated in an inert solvent, such as one of those mentioned in the reaction of compounds of formula III to compounds of formula I. .  When using an acid halide, it is preferred to work in the presence of an acid-binding agent, such as a tertiary aliphatic amine, e.g. B. 



  Triethylamine or diisopropylethylamine (Hünig base), an aromatic amine, e.g. B.  Pyridine, or in particular an alkali metal or alkaline earth metal carbonate or bicarbonate, e.g. B.  Potassium carbonate or calcium carbonate. 



   The functional groups contained in the intermediates of the formulas III-V can be protected in a manner analogous to that described for the end products of the formula I by conventional protective groups. 



   In the compounds of the formulas III-V, existing functional groups can be converted into protected functional groups or existing protected functional groups can be converted into the pure or into other protected groups. 



  Furthermore, in compounds of the formulas III V ei len radical R3 can be converted into another radical R3.  In these conversions, taking into account the other substituents contained in the molecules, the same methods can be used as in the corresponding shirt conversions in the compounds of formula (I). 



   The procedure described in Reaction Scheme 1 for the preparation of the compounds of the formulas (III) and (V) can also be carried out using optically inactive compounds and at any process stage from a diastereomer mixture or racemate obtained.  as described above, isolate the optically active compounds according to the present invention. 



   Such starting materials are preferably used and the reaction conditions selected in this way.  that one arrives at the compounds listed as particularly preferred above. 



   The compounds of formula I have valuable pharmacological properties or can be used as intermediates for the preparation of such compounds with valuable pharmacological properties.  Compounds of the formula 1, in which R1 is hydroxy-lower alkyl, R2 is carboxyl or an esterified carboxyl group which is cleavable under physiological conditions, and R3 is amino.  Lower alkylamino, di-lower alkylamino or substituted methyleneamino as indicated, and pharmacologically acceptable salts of such compounds having salt-forming groups have antibacterial effects. 

  For example, they are in vitro against gram-positive and gram-negative cocci, e.g. B.    Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Strepto coccusfaecalis, Neisseria meningitidis and Neisseria gonor rhoaea, against enterobacteria, e.g. B.  Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, against Haemophilus in ftuenzae Pseudomonas aeruginosa and anaerobes, e.g. B.  Bacteroides sp. , and Clostridium sp.  in minimal concentrations of approx.  0.02 to approx.  64 µg / ml effective. 

  In vivo, in the systemic infection of the mouse, e.g. B.  due to Staphalococcus aureus Escherichia coli or Streptococcus pS ogenes, EDsO values of approx.  0.3 to approx.  30 mg / kg. 



   For example, (5R, 6S) -2-aminomethyl-6 - [(1 'R) - I -hydroxy-ethyl] - 2-penem-3-carboxylic acid (compound A) and (5R, 6S) 2-aminomethyl-6 -hydroxymethyl-2-penem-3-carboxylic acid (Compound C) in vitro compared to that from the U. S.  Patent 4,272,437 previously known racemic (1'R. 5R. 6S + 1'S, 5S, 6R) - 2-aminomethyl-6- (l'-hydroxyethyl) - 2-penem3-carboxylic acid (Compound B) have the following superior effects:

  : Table I Antibiotic activity of compounds of formula I and the previously known comparative compound B in vitro in vitro MIC (Fug / ml) microorganism compound A compound B compound C Staphylococcus aureus 10 B 0.05 0.1 0.2 Staphylococcus aureus 2999i + p + 0.05 0.2 0. 5 Staphylococcus aureus A 124 0.1 0.2 Staphylococcus aureus Wood 46 0.05 0.1 0.2 Streptococcus pyogenes Aronson 1129 0.2 0.5 2 Streptococcus pneumoniae III / 84 0.1 0.2 0.5 Neisseria meningitidis 1316 0.5 1 Neisseria gonorrhoeae 1317/4 0.5 1 1 Haemophilus influenzae NCTC 4560 1 2 1 Table 1 (continued) Antibiotic activity of compounds of the formula I and the previously known comparative compound B in vitro in vitro MIC (, ug / ml) microorganism

   Compound A Compound B Compound C Escherichia coli 205 2 8 1 Escherichia coli 205 R + TEM 4 8 2 Escherichia coli 16 4 8 2 Escherichia coli 2018 2 4 1 Escherichia coli UB 1005 4 16 2 Escherichia coli DC 2 8 16 4 Escherichia coli B -1385 4 8 2 Klebsiella pneumoniae 327 2 4 1 Serratia marcescens 344 4 8 2 Enterobacter cloacae P 99 4 8 4 Enterobacter cloacae ATCC 13 047 4 16 4 Proteus mirabilis 774 1 4 1 Proteus mirabilis 1219 2 8 4 Proteus rettgeri 856 0.5 1 0.5 Proteus morganii 2359 0.5 2 1 Proteus morganii 1518 2 4 2 Pseudomonas aeruginosa ATCC 12 055 0.05 0.1 0.2 Pseudomonas aeruginosa K 799/61 0.1 0.2 0.5 Pseudomonas aeruginosa 143 738 R 0.5 2 2 Clostridium perfringens 2 4 32 Bacteroides fragilis L 01 0.5 1 2
Compared to the corresponding previously known racemate (compound B), the optically active compound A

   activity increased by a factor of 2-4 in all strains tested.  The optically active compound C according to the invention shows a remarkably constant activity in all the strains tested and is superior to the previously known racemic homolog (compound B), in particular in the gram-negative range, by a factor of 2-8. 



   Compounds A, B and C have the following stabilities (expressed in half-lives tal / 2) against the enzyme dehydropeptidase from human kidneys: t112 (hours) compound A 6.75 compound B 2.20 compound C 5.50
Compared to the rademat (compound B) described above, the compounds A and C according to the invention surprisingly have a considerably longer half-life when exposed to renal dehydropeptidase. 



   The compounds can therefore be administered orally or parenterally as antibacterial antibiotics, e.g. B.  in the form of appropriate pharmaceutical preparations, used to treat infections. 



   Compounds of the formula I in which at least one of the functional groups present is in protected form, a protected carboxyl group being different from a physiologically cleavable esterified carboxyl group, can be used as intermediates for the preparation of the above-mentioned pharmacologically active compounds of the formula I. 



   The pharmacologically usable compounds can e.g. B.  be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for oral or parenteral, i.e. H.  intramuscular, subcutaneous or intraperitoneal, administration are suitable. 



   For oral administration, tablets or gelatin capsules are used, which contain the active ingredient together with diluents, e.g. B.  Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. B.  Have silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. B.  Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacant, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, e.g. B.  Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, colors, flavors or sweeteners. 



   For parenteral administration are primarily infusion solutions, preferably isotonic aqueous solutions or suspensions, these z. B.  from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. B.  Mannitol can be prepared before use.  Such preparations can be sterilized and / or auxiliary substances, e.g. B.  Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. 



   Pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are made in a manner known per se, e.g. B.  by means of conventional mixing, solution or lyophilization processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. 



   Depending on the type of infection and the condition of the infected organism, daily doses of 125 mg to about 5 g are used to treat warm-blooded animals (humans and animals) weighing about 70 kg. 



   The following examples serve to illustrate the invention.  Temperatures are given in degrees Celsius. 



   The following abbreviations are used in the examples: TLC: thin-layer chromatogram, IR: infrared spectrum, UV: ultraviolet spectrum, NMR: nuclear magnetic resonance spectrum, DBU: 1,5-diazabicyclo [5.  1,5-diazabicyclo [5. 4th tundec-5-ene, THF: tetrahydrofuran, DMF: dimethylformamide. 



   Example I N-p-methaxybenzyl-N-tert-butylthiomethylammanium chloride
A solution of 10.69 g (23.9 mmol) of 1,3,5-tris (p-methoxybenzyl) hexahydro-1,3,5-triazine, which is analogous to the instructions in German Offenlegungsschrift DE A-2 431 862 can be prepared, in 170 ml of acetonitrile, a solution of 2.88 g (78.8 mmol) of hydrogen chloride in 20 ml of acetonitrile and 6.45 g (71.66 mmol) of tert-butyl mercaptan is added at room temperature. 



  The mixture is stirred for 22 hours.  Undissolved material is filtered off and the filtrate is concentrated under reduced pressure.  A crystalline residue is obtained, which is stirred with ether and suction filtered.  F.    142 ".    



   Example 2 (2S, 3R) -N-p-methoxybenzyl-N-tert-butylthiomethyl-2-hrom-3-hydroxybutyramide
A solution of 1.83 g (10 mmol) (2S, 3R) -2-bromo-3-hydroxybutyric acid, prepared analogously to a specification by Shimohigashi et al. , Bull  Chem.  Soc.  Japan 52, 949 (1979), in succession at room temperature with 2.76 g (10 mmol) of Np-methoxybenzyl-N-tert-butylthiomethylammonium chloride, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and dropwise with 1.40 ml (10 mmol ) Triethylamine added.  The reaction mixture obtained is stirred at room temperature for two hours.  The precipitated dicyclohexylurea is filtered off, the filtrate is diluted with methylene chloride and washed with water and pH 8 phosphate buffer solution.  The organic phase is dried over sodium sulfate, evaporated and the oily residue is chromatographed on silica gel with toluene / ethyl acetate. 

  The title compound is obtained as a colorless, viscous oil.  Rf (toluene-ethyl acetate 1: 1): 0.55; IR (in methylene chloride): 3550-3200, 2950-2850, 1632, 1608, 1508, 1457, 1438, 1407, 1360, 1242, 1202, 1175, 1150, 1028. 



   Example 3 (2S, 3R) -N-p-methoxybenzyl-N-tert-butylsulfonylmethyl-2-bromo-3-hydroxybutyramide
A solution of 1.97 g (4.89 mmol) of (2S, 3R) -Np-methoxybenzyl-N-tert-butylthiomethyl-2-bromo-3-hydroxybutyramide in 50 ml of methylene chloride is stirred at - 140 with 2.06 g (approx.  2.2 equivalents) 90% m-chloroperbenzoic acid added.  The reaction mixture is stirred at 0 for 80 minutes.  The precipitated m chlorobenzoic acid is filtered off, the filtrate is diluted with methylene chloride and shaken successively with 3% aqueous sodium hydrogen sulfite and 8% aqueous sodium hydrogen carbonate solution.  The organic phase is dried over sodium sulfate, evaporated under reduced pressure and the residue is chromatographed on silica gel with toluene / ethyl acetate (7: 1) and (6: 1). 

  The title compound is obtained as a colorless, viscous oil.  Rf (toluene-ethyl acetate 1: 1): 0.43; [cc] = +88 i 10 (1.01% in chloroform).  The IH NMR spectrum (400 MHz in CDC13) indicates the existence of two rotamers in a ratio of 1.3: 1. 



   Example 4 (2R, 3R) -N-p-methoxybenyl-N-tert-but) isulfone 1 lmeth 61-3,3-epoxybutyramide
To a solution of 486 mg (1st 1 mmol) (2S. 3R) -N-p methoxybenzyl-N-tert-butylsulfonylmethyl-2-bromo-3-hy droxybutyramide in 8 ml of tetrahydrofuran are 340 ml of 1,5-diazabicyclo at -14 and moisture exclusion [5. 4th 0] undec-5-ene in 1 ml of tetrahydrofuran.  The solution is stirred for 75 minutes at room temperature.  After adding methylene chloride, the organic phase is shaken out with 15% aqueous citric acid solution and 8% aqueous sodium hydrogen carbonate solution.  The organic phase is dried over sodium sulfate and evaporated under reduced pressure. 

  After chromatographing the residue on silica gel with toluene-ethyl acetate (4: 1), the title compound is obtained as a colorless. 



  viscous oil.  Rf (toluene-ethyl acetate 1: 1): 0.29; [u] = +45 i 13 (1.065% in CHCl3).     The IH NMR spectrum (400 MHz in CDC13) indicates the existence of two rotamers in a ratio of 1: 2.8. 



   Example 5 (3S. 4R) - lp-methoxybenzyl-3- [(1 R) - I -hydroxyethyl] - 4-tert-butyisulfonyl-2-azetidinone
A solution of 398 mg (1.12 mmol) (2R, 3R) -Np methoxybenzyl-N-tert-butylsulfonylmethyl-2,3-epoxybutyramide in 2.5 ml of tetrahydrofuran is added dropwise with 7 ml of a mixture at 0 "while stirring and excluding moisture Solution of dehydrated tetra-n-butylammonium fluoride in THF, prepared by dewatering 5 g of tetra-n-butylammonium fluoride trihydrate at 55C and 0.1 Torr and making up to 20 ml of tetrahydrofuran.  The reaction mixture is mixed with activated 4 Å molecular sieve and stirred for two hours.  The molecular sieve is filtered off and washed four times with 20 ml of methylene chloride. 

  Each filtrate is mixed separately with 5 parts of diethyl ether and washed successively with an aqueous phosphate buffer solution of pH 8.  The combined organic phases are dried over magnesium sulfate and evaporated under reduced pressure.  The residue is chromatographed on 20 g of silica gel with toluene-ethyl acetate (3: 1) and the crystalline title compound is obtained. 

  F.    112'-113 (Kofler, from methylene chloride, diethyl ether, pentane); Rf (toluene-ethyl acetate 1: 1): 0.27; [a] = +9 i 10 (1st 105% in chloroform); IH NMR spectrum (400 MHz in CDC13): 8 = 4.65 for proton (a) on the 4 (R) -C atom, 8 = 3.61 for proton (b) on the 3 (S) -C- Atom and 6 = 4.09 for proton (c) on the 1 '(R) -C atom of the hydroxyethyl group; J a-b: approx.  2, J b-c: approx.  7. 



   Example 6 (3S, 4R) - I-p-methoxybenzyl-3- [(I 'R) - I -allyloxyearbonyl-oxyethyl) - 4-tert-butylsulfonyl-2-azetidinone
A two-phase system consisting of a solution of 1.77 g (5 mmol) (3S, 4R) -lp-methoxybenzyl- 3 - [(l'R) l-hydroxyethyl] - 4-tert-butylsulfonyl-2-azetidinone in 20 ml Methylene chloride and from 20 ml of a 1 N aqueous sodium hydroxide solution are mixed with 0.68 g (2 mmol) of tetra-n-butylammonium hydrogen sulfate.  While stirring vigorously, 0.8 ml (7.5 mmol) of allyl chloroformate are added.  After 20 and 40 minutes, another 0.8 ml of allyl chloroformate is added.  

  After a reaction time of 60 minutes, the mixture is mixed with methylene chloride, the aqueous phase is separated off and the organic phase is washed successively with 5% aqueous citric acid solution and with 8% aqueous sodium hydrogen carbonate solution.  After drying the organic phase over sodium sulfate and evaporation under reduced pressure, the crude product is obtained as a residue, which is purified chromatographically on Merck silica gel using toluene / ethyl acetate (9: 1).  F.  90-91 "; Rf (toluene-ethyl acetate 4: 1): 0.43; [a] = +46 i 10 (1.49% in chloroform). 



   Example 7 (3S, 4R) -3 - [(1'R) 1-Allylaxycarbonylaxyällzyl] - 4-tert-hutylsulfonSl- 2-azetidinone
A solution of 518 mg (1.18 mmol) (3S, 4R) -1-p methoxybenzyl- 3 - [(1'R) - 1-allyloxycarbonyloxyethyl] - 4-tert-butylsulfonyl-2-azetidinone in 12 ml of acetonitrile a solution of 2.46 g (4.48 mmol) of cerium (IV) ammonium nitrate in 6 ml of water was added at 0 and the mixture was stirred at room temperature for one hour.  After extraction with ethyl acetate, drying of the organic phase over sodium sulfate and evaporation under reduced pressure, the crude product is obtained, which is purified by chromatography on 20 g of Merck silica gel with toluene / ethyl acetate (4: 1 and 1: 1). 

  F.    137-138; [a] = +49 i 10 (1.067% in chloroform); Rf (toluene-ethyl acetate 1: 1): 0.48. 



   Example 8 (5R, 6S) -2- (Allyloxyearbonylaminomethyl) - 6- [(1'R) - l-allyloxycarbonyloxyethyl] - 2-penem-3-carboxylic acid allyl ester
317 mg (0.852 mmol) (3S, 4R) -3- (1-allyloxycarbonyloxyethyl) - 4-allyloxycarbonylaminoacetylthio-azetidin-2-one are dissolved in 5 ml methylene chloride and cooled to - 15.  Then 0.143 ml (1.28 mmol) of allyloxyoxalyl chloride and 0.217 ml of Hünig base are added and the mixture is stirred at -15 for 30 minutes.  The reaction solution is washed once with 0.1 N HCl (cooled) and twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator.  The residue is extracted twice with toluene on a rotary evaporator. 



   The oily residue, containing crude 2 - [(3S, 4R) 3 - [(1'R) - 1-allyloxycarbonyloxyethyl] - 4-allyloxycarbonylaminoacetylthio-2-oxo-1-azetidinyl] - 2-oxo-acetic acid allyl ester, becomes in 20 ml of toluene dissolved, mixed with 0.32 ml of triethyl phosphite and heated to 103 for 17 hours under argon.  The solution is concentrated and purified on silica gel by preparative thin layer chromatography (system: toluene / ethyl acetate 3: 1).  IR (CH2C12): 3435; 1780; 1740; 1720; 1580 cm-Ú. 



   The starting material (3S, 4R) -3- (1-allyloxycarbonyloxyethyl) - 4-allyloxycarbonylaminoacetylthio-azetidin-2-one is prepared as follows:
450 mg (2.57 mmol) of allyloxycarbonylamino-thioacetic acid are suspended in 4 ml of water, and 2.5 ml of 1N sodium hydroxide solution are added at room temperature and under a nitrogen atmosphere; a solution of 585 mg (1.83 mmol) (3S, 4R) - 3 - [(1'R) - 1-allyloxyearbonyloxyethyl] - 4-tert-butylsulfonyl-2-azetidinone (cf.  Example 4 g) in 5 ml of methylene chloride and the emulsion is stirred vigorously for 1 h at room temperature under a nitrogen atmosphere.  The reaction mixture is separated and the org. 



  Phase washed twice with saturated saline. 



  The aqueous phases are extracted twice with methylene chloride.  The organic solutions are dried over sodium sulfate and concentrated on a rotary evaporator.  The crude product is purified by preparative thin layer chromatography (system: hexane / ether 1: 9). 



   Example 9 (5R, 6S) -2-aminomethyl-6- [(1'R) - 1-hydroxyethyl] - 2-penemem-3-carboxylic acid
A solution of 425 mg (5R, 6S) -2-allyloxycarbonylaminomethyl-6 - [(1'R) -1-allyloxycarbonyloxyethyl] - 2-penem-3-carboxylic acid allyl ester in 20 ml abs.  At -10 THF is mixed with 60 mg tetrakis (triphenylphosphine) palladium and then with 1.07 ml tributyltin hydride. 



  After 20 minutes of stirring at -10, 0.3 ml of acetic acid are added and the reaction mixture is stirred for a further 30 minutes after the cooling bath has been removed.  After concentrating on a rotary evaporator, the residue is taken up in water-ethyl acetate, the aqueous phase is separated off and the organic phase is extracted 3 more times with water.  The combined aqueous phases are lyophilized after briefly concentrating on a rotary evaporator. 



  UV (phosphate buffer pH 7.4): # mas = 308 nm 6 20
D (0.07% in water): + 220 i 110.    



   Example 10
In an analogous manner, as described in the preceding examples, the following compounds can be prepared starting from the corresponding starting compounds: (5R, 6S) -2- (N-acetamidinomethyl) - 6-hydroxymethyl-2-penem-3-carboxylic acid
UV (phosphate buffer pH 7.4) X max.  = 307 nm. 



      65R, 65) -2- (N-Acidnidüiomelliyl) -6 - [(1'R) -1 -llydroxy-Ritllyl] - 2-penem-3-carboxylic acid
UV (phosphate buffer pH 7.4) X max.  = 311 nm. 



     (5R, 6S) -2- (N-guanidinylmethyl) - 6-kvdroxytnedz- '. l-2-pe eni-3-carboxylic acid
UV (phosphate buffer pH 7.4) X max.  = 306 nm. 



  (5R, 6S) -2- (N-guanidinylmethyl) - 6- [(1 'R) - 1-kvdroxy-ethyll7-2-penem-3-carboxylic acid
UV (phosphate buffer pH 7.4) X max.  = 310 nm. 



      (5R, 6S) -2- (N-A tllylanl inometllyl) - - 6-! (1'R) - 1-hydroxyethyl] - 2-penem-3-carboxylic acid
UV (phosphate buffer pH 7.4) X max.  = 310 nm. 



  (5R, 6S) -2- (N-ethylaminomethyl) - 6-hydroxymethyl-2-penem-3-carboxylic acid
UV (phosphate buffer pH 7.4) X max.  = 311 nm. 



      (5R, 6S) -2- (N-propylaminomethyl) -6 - [(1'R) - 1-liydroxy-ethyll] - 2-pene'ii-3-carboxylic acid
UV (phosphate buffer pH 7.4) # max.  = 312 nm. 



  (5R, 6S) -2- (N-Propylamioniethyl) - 6-hydroxymethyl-2-pe neni-3-carboxylic acid
UV (phosphate buffer pH 7. 4) X max.  = 311 nm. 

 

   (5R, 6S) -2- (N-methylanzinomethyl) - 6-hydroxymethyl-2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) X max.  = 306 nm.   



   Example 11
Dry ampoules or vials containing 0.5 g (5R, 6S) -2 aminomethyl-6 - [(l'R) - 1-hydroxyethyl] - 2-penem-3-carboxylic acid as the active substance are prepared as follows: Composition (for 1 Ampoule or vial): active substance 0.5 g mannitol 0.05 g
A sterile aqueous solution of the active substance and the mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml vials and the ampoules or  Vials sealed and checked. 



   Instead of the above-mentioned active ingredient, the same amount of another active ingredient from the preceding examples can also be used.  


    

Claims (4)

 PATENT CLAIMS 1. Process for the preparation of essentially optically pure (SR, 6S) -configured compounds of the formula EMI1.1  wherein R1 is lower alkyl substituted by hydroxyl, R2 represents carboxyl and R3 represents amino, amino substituted by lower alkyl or substituted methylene amino, optical isomers of compounds of the formula I which have a chiral center in the rest of R1, mixtures of these optical isomers and salts of such compounds of Formula I which have a salt-forming group, characterized in that a compound of the formula EMI1.2  in which R1 and R3 have the meanings given under formula I, Z is oxygen and R2 'is a protected carboxyl group,  treated with intermediate protection of the functional groups with an organic compound of trivalent phosphorus, and optionally converting an available compound with a salt-forming group into a salt or an available salt into the free compound or into another salt.  2. A process for the preparation of (SR, 6S) -2-aminomethyl-6 - [(IR) - l-hydroxyethyl3-2-penem-3-carboxylic acid according to claim 1.  3. Process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula EMI1.3  wherein R1 and R3 have the meanings given in claim 1, and R2 "means esterified carboxy which is cleavable under physiological conditions, optical isomers of compounds of the formula I 'which have a chiral center in the rest R1, mixtures of these optical isomers and salts of such compounds of Formula I 'which have a salt-forming group, characterized in that a compound of the formula I is prepared by the process according to Claim 1 and the carboxy group R2 is converted by esterification into an esterified carboxy group which is cleavable under physiological conditions.  4. Process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula EMI1.4  wherein R1 (lR3-1-hydroxyethyl, R2 and R3 have the meanings given in claim 1, and salts of those compounds of the formula I which have a salt-forming group, characterized in that the process according to claim 1 is an isomeric mixture of compounds of the formula I, in which R1 is 1-hydroxyethyl and R2 and R3 have the meanings given above, is separated into the individual isomers and the (1R) - 1-hydroxyethyl isomer is isolated.  The present invention relates to processes for the preparation of new 2-aminomethyl-penem compounds.  The present invention relates to a process for the preparation of essentially optically pure (5R, 6S) -configured compounds of the formula EMI1.5  wherein R1 is lower alkyl substituted by hydroxy, R2 represents carboxyl and R3 represents amino, amino substituted by lower alkyl or substituted methylene amino, optical isomers of compounds of the formula I which have a chiral center in the rest of R1, mixtures of these optical isomers and salts of such compounds of Formula I which have a salt-forming group, characterized in that a compound of the formula EMI1.6  wherein R1 and R3 have the meanings given under formula I, Z is oxygen and R2 is a protected carboxyl group,  treated with an intermediate protection of the functional groups with an organic compound of trivalent phosphorus, and optionally an available compound with a salt-forming group in a salt or he ** WARNING ** End of CLMS field could overlap beginning of DESC **.