CH618161A5 - Process for the preparation of azetidinone derivatives - Google Patents

Abstract

Compounds of the formula: <IMAGE> in which R1 is acylamino and A has the meaning given in Patent Claim 1, are prepared by acylation of corresponding amino compounds (R1 = NH2) or their Schiff's bases or acid addition salts on the amino group in the 3-position. The compounds have antimicrobial properties and are suitable for the treatment of infectious diseases in humans and animals.

Description

       

  
 

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

 



   PATENT CLAIMS
1.  A process for the preparation of azetidinone derivatives of the general formula (1) in which R1 is acylamino and A is hydrogen, - a saturated or unsaturated, normal or branched aliphatic or cycloaliphatic hydrocarbon radical which is substituted by at least one substituent from the group consisting of carboxy or a derivative thereof,
Cyano, hydroxy and amino is substituted, - an aliphatic or cycloaliphatic hydrocarbon residue which is substituted by carboxy or a derivative thereof and by a phenyl, the ring of which is substituted by one or more substituents from the group hydroxy, amino, benzyloxycarbonylamino, nitro, alkyl ,
Alkoxy, aralkoxy, alkylthio, halogen and sulfo can be substituted, mean characterized in that

   that you have a compound of the general formula
EMI1. 1
 in which A has the meanings given above, reactive groups which are not to be acylated are optionally protected in an intermediate manner, or a Schiff base of the amino group in the 3-position or a salt thereof with an acid is reacted with an acylating agent. 



   2nd  A method according to claim 1, characterized in that compounds of formula I are prepared in which R1 is acylamino and A is hydrogen or a group of the formula
EMI1. 2nd
 in which Ala is hydrogen, A2a is hydrogen, alkyl or phenyl, which can be substituted by at least one substituent from the group consisting of hydroxy, amino, benzoyloxycarbonylamino, nitro, alkyl, alkoxy, aralkoxy, alkylthio and halogen, or A1, and Aq together form an alkylidene and means A3a carboxy or a derivative thereof or cyano. 



   3rd  A method according to claim 2, characterized in that R1 represents acylamino and A for a group of the formula
EMI1. 3rd
 is in which Ala is hydrogen, A2a phenyl which can be substituted by at least one substituent from the group consisting of hydroxy, amino, benzyloxycarbonylamino, nitro, alkyl, alkoxy, aralkoxy, alkylthio and halogen and A3a is carboxy or a derivative thereof. 



   The invention relates to a process for the preparation of 3-acylamino-2-azetidinone derivatives with antimicrobial activity. 



   Recently, the chemical structure of the substance FR-1923 was successfully identified.  The substance FR-1923 is a well-known antibiotic that comes from the fermentation broth of a strain of the genus Nocardia (deposited with the American Type Culture Collection under ATCC no.  21806) can be isolated, further details being described for example in DE-PS 2 242 699.  In this PS, the substance FR-1923 is defined by its various physico-chemical properties, without containing information about its chemical structure. 



   After extensive investigations, it has now been possible to identify the chemical structure of the substance FR-1923 and to assign it the following chemical structure
EMI1. 4th
 which can be referred to as 1- (a-carboxy-4-hydroxybenzyl) -3- 2- {4- (3-amino-3- 1-carboxypropoxy) phenyl} -2-hydroxyiminoacetamidoj -2-azetidinone. 



   This made it possible for the first time to study some chemical modifications of the FR-1923 substance.  A group of new and uniquely modified compounds derived from the substance FR-1923 and related compounds has now been successfully synthesized. 



   Some known compounds derived from penicillins are given below with the associated literature references, which are intended to explain the current state of the art. 
EMI1. 5




  (U.S. Patent 3,487,072)
EMI1. 6
 (Journal of Organic Chemistry, Volume 38, pages 940-943, 1973)
EMI1. 7
 (Archives of Pharmacy and Reports of the German Pharmaceutical Society, Volume 303, p.  834)
EMI2. 1




  (The Chemistry of Penicillin, page 973)
EMI2. 2nd
 (Archives of Pharmacy and Reports of the German Pharmaceutical Society, Volume 303, p.  834). 



   The azetidinone derivatives obtained by the process according to the invention have a new and unique chemical structure which was not to be expected from the person skilled in the art in this field. 



   The 3-acylamino-2-azetidinone derivatives obtained according to the invention have the general formula
EMI2. 3rd
 wherein R1 is acylamino and A is hydrogen, a saturated or unsaturated, normal or branched aliphatic or cycloaliphatic hydrocarbon radical which is substituted by at least one substituent from the group of carboxy or a derivative thereof, cyano, hydroxy and amino, an aliphatic or cycloaliphatic hydrocarbon radical which by Carboxy or a derivative thereof and phenyl is substituted, the ring of which may be substituted by one or more substituents from the group consisting of hydroxy, amino, benzyloxycarbonylamino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo. 



   The process according to the invention is characterized in that a 3-amino-2-azetidinone derivative of the general formula
EMI2. 4th
 in which A has the meanings given above, reactive functional groups which are not to be acylated are optionally protected in an intermediate manner, or a Schiff base of the amino group in the 3-position or a salt thereof with an acid with an acylating agent, for. B.  under cooling or with heating and preferably in the presence of water, an organic solvent or a mixture thereof. 



   The amino, carboxy and / or hydroxy protecting group is removed from the compound obtained, if one is present. 



   Some of the compounds encompassed by formula I are new, but the other part is already known compounds.  Whether the end products of the process are new or were already known, it is the first time that they are produced by the acylation process according to the invention. 



   The new compounds correspond to the formula I in which (1) when A is hydrogen, Rl acylamino with the exception of phthalimido, formamido, 2- (2-nitrophenoxy) acetamido, benzyloxycarbonylamino and 2-methyl-2- (2-nitrophenoxy) propionamido means (2) when A represents a saturated branched aliphatic hydrocarbon residue which is substituted by carboxy or a derivative thereof, R1 is acylamino with the exception of acetamido, 2-phenylacetamido, 2-phenoxyacetamido, benzyloxycarbonylamino and 2-carboxybenzamido, ( 3) when A is an unsaturated branched aliphatic hydrocarbon radical which is substituted by carboxy, R 1 is acylamino with the exception of 2-phenylagetamido, and (4) when A is an aliphatic hydrocarbon radical,

   which is substituted by carboxy or a derivative thereof and by a phenyl whose ring is substituted by hydroxy, RX means acylamino with the exception of 2- [4- (3-amino-3-carboxypropoxy) phenyl] -2-hydroxyiminoacetamido. 



   An acyl group in the acylamino group for R1 may be an aliphatic acyl, an aromatic acyl, a heterocyclic acyl and an acyl whose aliphatic group is substituted by an aromatic or heterocyclic group. 



  Examples of such acyl radicals are given later. 



   An aliphatic or  cycloaliphatic radical in the aliphatic acyl radical can be a saturated or unsaturated acyclic or  cyclic hydrocarbon residue in which the acyclic hydrocarbon residue may be branched and partially cyclized.  Suitable examples of such acyclic or alicyclic hydrocarbon radicals are in particular the following:
Alkyl (e.g. B.  Methyl, ethyl, propyl, butyl, isobutyl, pentyl, neopentyl, octyl, undecyl, tridecyl, pentadecyl, cyclohexylmethyl, cyclohexylethyl, bornanyl and the like.  the like );
Alkenyl (e.g. B.  Vinyl, propenyl, isopropenyl, 3-methylbutenyl, butenyl, 2-methylpropenyl, pentenyl, octadecenyl. 



  3-cyclohexenylmethyl u.  the like );
Alkynyl (e.g. B.    Ethynyl, 2-propynyl and the like );
Cycloalkyl (e.g. B.  Cyclopropyl, cyclopentyl, cyclohexyl, indanyl, bornyl, adamantyl and the like.  the like ); and
Cycloalkenyl (e.g. B.    l-cyclopenten-l-yl, 2-cyclopenten-1-yl, 3-cyclohexen-l-yl, bornenyl and the like.  the like ). 



   A suitable aromatic group in aromatic acyl can be, for example, aryl such as phenyl, tolyl, naphthyl and the like.  the like 



  be. 



   A heterocyclic group in the heterocyclic acyl can be a monocyclic or polycyclic heterocyclic group which has at least one heteroatom from the group consisting of oxygen, sulfur, nitrogen and the like.  the like  contains, be.  Suitable examples of such heterocyclic groups are in particular the following: a 3- to 8-membered monocyclic heterocyclic group which contains at least one sulfur atom (e.g. B.  Thienyl, dihydrothiopyranyl and.  the like ); a 3- to 8-membered monocyclic heterocyclic group containing at least one oxygen atom (e.g. B.  Oxiranyl, furyl, dihydrofuryl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxanyl and the like.  the like ); a 3- to 8-membered monocyclic heterocyclic group containing at least one nitrogen atom (e.g. B.  

  Aziridinyl, azetidinyl, pyrrolyl, 2- or 3H-pyrrolyl, 2- or 3-pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, piperidinyl, pyridazinyl, tetrazolyl and the like.  the like ); a 3- to 8-membered monocyclic heterocyclic group containing at least one oxygen atom and at least one nitrogen atom (e.g. B.  Oxazolyl, isoxazolyl, oxadiazolyl, sydnonyl and the like.  the like ); a 3- to 8-membered monocyclic heterocyclic group containing at least one sulfur atom and at least one nitrogen atom (e.g. B.  Thiazolyl, isothiazolyl, thiadiazolyl and the like.  the like ); a polycyclic heterocyclic group containing at least one sulfur atom (e.g. B.  a heterocyclic group fused to benzene, such as benzothienyl, benzothiopyranyl and the like.  the like ); a polycyclic heterocyclic group containing at least one nitrogen atom (e.g. B. 

  Indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl, quinazolyl, 1- or 2H-indazolyl, 1- or 2H-benzotriazolyl, purinyl, carbazolyl and the like.  the like ); a polycyclic heterocyclic group containing at least one oxygen atom and at least one nitrogen atom (e.g. B.  Benzoxazolyl, benzoxadiazolyl and.  the like ); and a polycyclic heterocyclic group containing at least one sulfur atom and at least one nitrogen atom (e.g. B.  Benzothiazolyl, Benzothiadiazolyl and.  the like ). 



   An aliphatic radical in acyl, the aliphatic radical of which may be substituted by an aromatic or heterocyclic group, has the same meanings as given above in the explanation of the aliphatic radical in aliphatic acyl and includes the same suitable examples thereof as described above in individual are specified. 



  In the same way, the aromatic group and a heterocyclic group have the same meanings as given above in the explanation of the aromatic group in the aromatic acyl and the heterocyclic group in the heterocyclic acyl, and also include the same suitable examples thereof, such as they are specified in detail above. 



   The optionally present carbon chain of the aliphatic acyl defined above can be replaced and / or interrupted by one or more radicals from the group of a bivalent aromatic radical, a bivalent heterocyclic radical, -O-, -N =, -S-, -SO-, -SO2- and -NH-, the hydrogen atom of which can be substituted by alkyl or aryl. 



   In aliphatic acylamino, aromatic acylamino, heterocyclic acylamino and in aliphatic acylamino, the aliphatic radical of which is substituted by an aromatic or heterocyclic group as defined above, each of the aliphatic radical, the aromatic group and the heterocyclic group may, if desired, by one or more Substituents from the group halogen, nitro, amino, carboxy, esterified carboxy, hydroxy, Na, -CN, -NHNH2, = O, = NH, = S, sulfo and = NOH, whose hydrogen atom can be replaced by alkyl or aralkyl, are substituted and the heterocyclic group in the above acylamino group may, if desired, be substituted by alkyl and / or an aromatic group. 



   Particularly suitable examples of the acylamino R are the following: alkanoylamino; Alkenoylamino; Aroylamino; heterocyclic carbonylamino; alkanoylamino substituted with aryl or a heterocyclic group; alkenoylamino substituted with aryl or a heterocyclic group; Alkanoyl- or alkenoylamino, the carbon chain (s) which may be present is (are) interrupted by a divalent aromatic radical and / or a bivalent heterocyclic radical;

  Alkanoyl- or alkenoylamino which is substituted by aryl and / or a heterocyclic group, in which the optionally present carbon chain (s) of the acyclic hydrocarbon radical is (are) interrupted by a divalent aromatic radical and / or a bivalent heterocyclic radical; alkanoyl- or alkenoylamino substituted by aryl and / or a heterocyclic group, in which the optionally present carbon chain (s) of the acyclic hydrocarbon radical is one or more radicals from the group
EMI3. 1
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted;

   alkanoyl- or alkenoylamino substituted by aryl and / or a heterocyclic group, in which the optionally present carbon chain (s) of the acyclic hydrocarbon radical is (are) interrupted by an aromatic radical and / or a bivalent heterocyclic radical and also by one or more Leftovers from the group
EMI3. 2nd
 the hydrogen atom of which may be replaced by alkyl or aryl is interrupted; Alkanoyl- or alkenoylamino, the carbon chain which may be present through one or more radicals from the group
EMI3. 3rd
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted;

  Alkanoyl- or alkenoylamino, the optionally present carbon chain of which is interrupted by a bivalent aromatic radical and / or a bivalent heterocyclic radical and furthermore by one or more radicals from the group
EMI3. 4th
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted;

  Aroylamino or heterocyclic carbonylamino, in which the bond between the ring and the carbonyl is through one or more radicals from the group
EMI3. 5
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted; alkanoyl or alkenoylamino substituted by cycloalkyl, aryl and / or a heterocyclic group, wherein the bond between the ring and the acyclic hydrocarbon radical is by one or more radicals from the group
EMI3. 6
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted;

   alkanoyl or alkenoylamino substituted by cycloalkyl, aryl and / or a heterocyclic group, in each case the bond between the ring and the acyclic hydrocarbon radical and an optionally present carbon chain of the acyclic hydrocarbon radical by a bivalent aromatic radical and / or a bivalent heterocyclic radical and / or by one or more residues from the group
EMI3. 7
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted;

  Aroylamino or heterocyclic carbonylamino, wherein the bond between the ring and the carbonyl is interrupted by one or more residues from the group of the divalent aromatic residues and / or the bivalent heterocyclic residues; alkanoyl or alkenoylamino substituted by aryl and / or a heterocyclic group, wherein the bond between the ring and the acyclic hydrocarbon radical is by a bivalent aromatic radical and / or a bivalent heterocyclic radical and also by one or more radicals from the group
EMI4. 1
 whose hydrogen atom can be replaced by alkyl or aryl is interrupted;

   and aryl and / or a heterocyclic group substituted alkannyl or alkanoylamino, wherein the bond between the ring and the acyclic hydrocarbon radical is interrupted by one or more radicals from the group of the bivalent aromatic radicals and / or the bivalent heterocyclic radicals. 



   Any carbon atom of the acylamino group defined above can be substituted by one or more substituents from the group halogen, nitro, amino, carboxy, esterified carboxy, hydroxy, -N3, -CN, -NHNH2, = O, - = NH, = S, sulfo, = NOH, the hydrogen atom of which may be replaced by alkyl or aralkyl, may be substituted, and the heterocyclic group in the above-mentioned acylamino group may be substituted by alkyl if desired. 

  Particularly suitable examples of acylamino R1 are the following: alkanoylamino, in which any (optional) carbon chain is interrupted by phenylene and any (optional) carbon atoms are substituted by halogen and oxo; Phenylalkanoylamino, in which any carbon atom can be substituted by a substituent from the group consisting of amino, carboxy, esterified carboxy, hydroxy, halogen, nitro, sulfo, oxo, hydroxyimino and benzyloxyimino; Naphthylalkanoylamino; Dihydropyranylalkanoylamino, in which any carbon atom is substituted by hydroxy; Morpholinoalkanoylamino; Thienylalkanoylamino, in which any (possibly) carbon atom can be substituted by a substituent from the group consisting of amino, hydroxy, oxo and hydroxylimino; Furylalkanoylamino; Tetrazolylalkanoylamino;

  Indolylalkanoylamino, wherein any carbon atom is substituted by amino; Diphenylalkanoylamino; alkanoylamino substituted with phenyl and thienyl; 3-alkyl-l, 2,5-oxadiazol-4-yl- alkanoylamino; Phenylalkenoylamino; Phenylalkanoylamino, in which any (optionally present) carbon chain of the alkane radical is interrupted by phenylene; Phenylalkanoylamino, wherein any (optionally present) carbon chain of the alkane radical by one or two bivalent radicals from the group
EMI4. 2nd
 is interrupted and, moreover, any one or more C atoms of the group thus defined can be substituted by 1 to 4 substituents from the group amino 'carboxy, esterified carboxy, halogen, oxo and = NH;

  Thienylalkanoylamino, in which any (optionally present) carbon chain (s) of the alkane radical is interrupted by one or two divalent radicals from the group -O-, -S- and -NH- and also any C atom (s) of the one so defined Group is substituted by 1 to 4 substituents from the group amino 'carboxy, halogen and oxo; Dihydropyranylalkanoylamino, in which any (any) carbon chain of the alkane radical is interrupted by -NH- and any C atom in the group defined in this way is substituted by halogen;

  Diphenylalkanoylamino, in which an optionally present (any) carbon chain (s) of the alkane radical is interrupted by 1 to 3 bivalent radicals from the group ¯-O-, -N = and -NH- and also any C atom (s) of the kind defined group can be substituted by 1 or 2 substituents from the group carboxy, hydroxy and oxo; alkanoylamino substituted by phenyl and thienyl, in which any (any) carbon chain (s) of the alkane radical is interrupted by one or two divalent radicals from the group -O-, -N = and -NH- and in addition any carbon atom ( e) the group thus defined can be substituted by 1 to 5 substituents from the group amino, halogen, oxo and thioxo;

   alkanoylamino substituted by phenyl and indolyl, in which any (any) carbon chain (s) of the alkane radical is interrupted by -O- and -NH- and in addition any carbon atom in the group defined in this way is substituted by oxo; alkanoylamino substituted by phenyl and benzo- [d] -isoxazolyl, in which any (any) carbon chain (s) of the alkane radical is interrupted by -0- and -NH- and also any carbon atom in the group thus defined is substituted by oxo is;

  Phenylalkanoylamino, wherein an optionally present (any) carbon chain (s) of the alkane radical by one or two bivalent radicals from the group phenylene, 2-oxoazetidine-1,3-diyl, 1,3,4-thiadiazole-1,5-diyl and 1,3-oxazolidine-3,4-diyl and one to four divalent radicals from the group
EMI4. 3rd
 is interrupted and any carbon atom (s) of the group thus defined can be substituted by 1 to 6 substituents from the group amino, halogen, hydroxy, esterified carboxy, oxo, hydroxyimino, benzyloxyimino and hydrazino;

  Thienylalkanoylamino, in which an optionally present (any) carbon chain (s) of the alkane radical is interrupted by phenylene and two divalent radicals from the group -0- and -NH- and also any carbon atom (s) of the group defined in this way by carboxy, Oxo and hydroxyimino is substituted; Benzo- [cl-pyrrolidinylalkanoylamino, in which an optionally present (any) carbon chain of the alkane radical is interrupted by phenylene and -0- and also any esterified carbon atoms of the group thus defined by four substituents from the group amino, carboxy, hydroxy Carboxy, oxo, hydroxyimino and methoxyimino are substituted;

  Diphenylalkanoylamino, in which any (any) carbon chains of the alkane radical are interrupted by phenylene and -0- and -NH- and also a possible carbon atom (s) of the group thus defined by two to four substituents from the group amino, halogen, nitro , Oxo and hydroxyimino is substituted; alkanoylamino substituted by phenyl and furyl, in which the optionally present (any) carbon chains of the alkane radical are interrupted by phenylene and -NH- and -0- and also any C atom (s) of the group thus defined by three substituents from the group halogen and oxo is substituted;

  Alkanoylamino, wherein an optionally present (any) carbon chain (s) by one or two divalent radicals from the group
EMI4. 4th
 is interrupted and, in addition, any C atom (s) of the group thus defined can be substituted by 1 to 2 substituents from the group amino, azido, carboxy, hydroxyl, oxo, thioxo and = NH; Alkenoylamino, the carbon chain of which is present (any) is interrupted by -S;

  Alkanoylamino, in which an optionally present (any) carbon chain (s) by one or two phenylenes and 1 to 5 bivalent radicals from the group
EMI5. 1
 is interrupted, and in addition any carbon atom (s) of the group thus defined is substituted by 1 to 7 substituents from the group amino, carboxy, hydroxy, halogen, azido, sulfo, esterified carboxy, oxo, thioxo, hydroxyimino and methoxyimino can be; Alkanoylamino, in which any (optionally present) carbon chain is interrupted by 1,3,4-thiadiazole-2,5-diyl and one or two divalent radicals from the group -S- and -NH- and also any carbon atom (e) the group thus defined is (are) substituted by 1 to 6 substituents from the group amino, hydroxy and oxo;

  Alkenoylamino, in which any (optionally present) carbon chain is interrupted by phenylene and one or two divalent radicals from the group -0- and -NH- and also any carbon atom (s) of the group thus defined by I to 3 substituents the group carboxy, esterified carboxy, nitro, oxo and hydroxyimino is substituted; 1, 2-oxazolidinylcarbonylamino, in which the bond between the 1, 2-oxazolidinyl and the carbonyl is interrupted by -NH and, moreover, any C atom of the group thus defined is substituted by oxo;

  ; BicycloL2,2,11-heptylalkanoylamino.  wherein the bond between the Bi cycloL2,2,1] heptyl and the alkane radical is interrupted by -0- and in addition any carbon atom (s) of the bicyclo [2,2,1] heptane ring is substituted by three alkyl groups; Phenylalkanoylamino, in which the bond between the phenyl and the alkane radical is interrupted by one or two divalent radicals from the group -O-, -S-, -NH- and -SOz- and also any C atom of the group defined in this way by a substituent from the group halogen and nitro can be substituted; Naphthylalkanoylamino, wherein the bond between the naphthyl and the alkane radical is interrupted by a divalent radical from the group -0- and -NH;

  Pyridylalkanoylamino, wherein the bond between the pyridyl and the alkane radical is interrupted by; 1, 3,4-thiadiazolylalkanoylamino, wherein the bond between the 1,3,4-thiadiazolyl and the alkane radical is interrupted by -S-; 1 H-1, 2,3-benzotriazolylalkanoylamino, in which the bond between the IH-1,2,3-benzotriazolyl and the alkane radical is interrupted by -0-; Pyridyl-l-oxydalkanoylamino, wherein the bond between the pyridyl-l-oxide and the alkane radical is interrupted by -5-;

  Diphenylalkanoylamino, wherein the bond between the one or both phenyl and the alkane radical is interrupted by one or two bivalent radicals from the group -O-, -S-, -NH- and -SO- and also any C atom (s) group thus defined is substituted by one or two substituents from the group nitro, carboxy, halogen, hydroxy and oxo; alkanoylamino substituted by phenyl and naphthyl, wherein the bond between the naphthyl and the alkane radical is interrupted by -0-; alkanoylamino substituted by phenyl and pyrimidyl, in which the bond between the pyrimidinyl and the alkane radical is interrupted by -S- and in addition any C atom (s) of the group thus defined is substituted by amino and hydroxy;

   alkanoylamino substituted by bicyclo [2,2, 1 lheptyl and phenyl, in which the bond between the bicyclol 2,2,1 iheptyl and the alkane radical is interrupted by -o- and any (optionally present) carbon chain of the alkane radical by -NH- is interrupted and in addition any carbon atom of the alkane radical is substituted by oxo and any carbon atoms of the bicyclo [2,2, ljheptane ring are triple substituted by alkyl;

  Diphenylalkanoylamino, wherein the bond between the diphenyl and / or alkane radical by one or two bivalent radicals from the group
EMI5. 2nd
 is interrupted and an optionally present (any) carbon chain of the alkane radical is interrupted by one or two bivalent radicals from the group -NH- and -S- and also any carbon atom (s) of the group defined in this way by one to three substituents the group carboxy, esterified carboxy, halogen, nitro and oxo is (are) substituted; alkanoylamino substituted by 9H-purinyl and phenyl, wherein the bond between the 9H-purinyl and.  the alkane radical is interrupted by -S- and an optionally present (any) carbon chain of the alkane radical is interrupted by -NH- and in addition any carbon atom of the group defined in this way is substituted by oxo;

   Alkanoylamino substituted by phenyl and thienyl, in which the bond between phenyl and the alkane radical is interrupted by a divalent radical from the group -0- and -NH- and any C atom of the alkane radical is interrupted by -NH- and in addition any C Atom (s) of the group thus defined is (are) substituted by three substituents from the group of esterified carboxy, halogen, nitro and oxo; alkanoylamino substituted by phenyl and pyridyl-1-oxide, in which the bond between the pyridyl-1-oxide and the alkane radical is interrupted by -S- and any (any) carbon chain of the alkane radical is interrupted by -NH- and also a any carbon atom in the group thus defined is substituted by oxo;

   alkanoylamino substituted by naphthyl and phenyl, in which the bond between the naphthyl and the alkane radical is interrupted by a divalent radical from the group -0- and -NH- and an optionally present (any) carbon chain of the alkane radical by one or two divalent radicals the group
EMI5. 3rd
 is interrupted and any carbon atom in the group thus defined is substituted by oxo; Alkanoylamino substituted by phenyl and pyrimidinyl, in which the bond between the pyrimidinyl and the alkane radical is interrupted by -S- and any (arbitrary) carbon chain of the alkane radical is interrupted by -NH- and also any C atoms of the group defined in this way an amino, hydroxy and an oxo group are substituted;

  Triphenylalkanoylamino, in which the bond between one or both phenylene and the alkane radical is interrupted by one or two divalent radicals from the groups -0- and -NH- and any (any) carbon chain of the alkane radical is interrupted by -NH- and also any carbon atom (s) of the group thus defined is substituted by one or two substituents from the group halogen and oxo; alkanoylamino substituted by naphthyl and diphenyl, in which the bond between the naphthyl and the alkane radical is interrupted by -0- and an optionally present carbon chain of the alkane radical is interrupted by -NH-, and in which any carbon atom of the group thus defined is substituted by oxo ;

   alkanoylamino substituted by dinaphthyl and phenyl, in which the bond between the two naphthyl and the alkane radical is interrupted by -0- and an optionally present carbon chain of the alkane radical is interrupted by -NH- and in which any carbon atom in the group thus defined is substituted by oxo is; Phenylalkanoylamino, in which the bond between the phenyl and the alkane radical by a divalent radical from the group -O-, -NH and -S- and the optionally present carbon chains of the alkane radical by phenylene and one to three bivalent radicals from the group -0- and -NH- are interrupted and in addition any carbon atom (s) of the group thus defined is (are) substituted by one to five substituents from the group carboxy, esterified carboxy, halogen, nitro, oxo, thioxo and hydroxyimino;

  Naphthylalkanoylamino, in which the bond between the naphthyl and the alkane radical is interrupted by -NH- and the optionally present carbon chains of the alkane radical are interrupted by phenylene and three divalent radicals from the group -0- and -NH- and in which any C atoms of the so defined group are substituted by a carboxy, oxo and thioxo; alkanoylamino substituted by pyridyl and phenyl, in which the bond between the pyridyl and the alkane radical is interrupted by -S- and the carbon chains of the alkane radical which may be present are interrupted by two phenylenes and three divalent radicals from the group -0- and -NH- and also any C atoms of the group thus defined are substituted by four substituents from the group halogen and oxo;

   substituted by phenyl and benzo [cl-pyrrolidinyl
Alkanoylamino, in which the bond between the phenyl and the alkane radical is interrupted by -NH- and an optionally present carbon chain (s) of the alkane radical is interrupted by phenylene and -0- and in which any
C atoms of the group thus defined are substituted by five substituents from the group consisting of carboxy, esterified carboxy, nitro and oxo;

  Diphenylalkanoylamino, wherein the bond between the one or both phenyl radicals and the alkane radical is interrupted by one or two -NH- and an optionally present carbon chain (s) of the alkane radical by phenylene and one to three divalent radicals from the group -O and -NH- and where also any carbon atom (s) of the group defined in this way by one to five
Substituents from the group consisting of carboxy, nitro, esterified carboxy, oxo and thioxo are substituted;

  Dinaphthylalkanoylamino, in which the bonds between the two naphthyl radicals and the alkane radical are interrupted by -NH- and the carbon chains of the alkane radical which may be present are interrupted by phenylene and three bivalent radicals from the group -0- and -NH- and in which any C atoms of the thus defined are also interrupted Group are substituted by three substituents from the group carboxy and thioxo; by
Phenyl and thienyl substituted alkanoylamino, in which the bond between the thienyl and the alkane radical is interrupted by tetrazole-1,5-diyl and any carbon chain of the alkane radical which is present is interrupted by -NH-, and in which any C atom as defined in this way
Group is substituted by oxo;

  Phenylalkanoylamino, in which the bond between the phenyl and the alkane radical is interrupted by -0- and an optionally present carbon chain of the alkane radical is interrupted by -NH- and in which any carbon atoms in the group thus defined are substituted by halogen, nitro and oxo; Diphenyialkanoylamino, in which the bond between the phenyl and the alkane radical is interrupted by phenylene and -0- and in which any carbon chain of the alkane radical is interrupted by -NH- and in which any carbon atom in the group thus defined is substituted by oxo;

  Diphenylalkanoylamino, in which the bond between the phenyl and the alkane radical is interrupted by isoxazole-3,4-diyl which is substituted by alkyl, and an optionally present carbon chain of the alkane radical is interrupted by -NH- and in which any carbon atom is also present the group thus defined is substituted by oxo; Benzamido, in which the bond between the phenyl and the carbonyl is interrupted by isoxazole-3,4-diyl which is substituted by alkyl, and in which in addition any C atom of the group thus defined is substituted by halogen;

  Phenylalkanoylamino, in which the bond between the phenyl and the alkane radical by a bivalent radical from the group phenylene and 1,3,5-oxadiazole-2,4-diyl and one or two bivalent radicals from the group -O-, -NH- and -SO2- is interrupted and, in addition, any C atom of the group thus defined can be substituted by carboxy and hydroxy; Phenylalkanoylamino, in which the bond between the phenyl and the alkane radical is interrupted by 4,5-dihydro-1,2,4-oxadiazol--3,4-diyl and any C atom of the group thus defined is substituted by oxo; Thienylalkanoylamino, wherein the bond between the thienyl and the alkane radical is interrupted by 1 H-tetrazole-1,5-diyl. 



   Suitable examples of the saturated or unsaturated normal (or branched) aliphatic hydrocarbon radical A are e.g. B.  Alkyl which may be branched (e.g. B.  Methyl, ethyl, propyl, butyl, pentyl, isopropyl, l-methylpropyl, isobutyl, tert. Butyl, methylpentyl, ethyl propyl, methyl butyl, ethyl butyl, neopentyl, dimethyl butyl and the like.  the like ), and alkenyl, which can be branched (e.g. B.  1-propenyl, allyl, l-butenyl,
1-pentenyl, isopropenyl, methyl propenyl, methyl butenyl, methyl pentenyl, ethyl propenyl, ethyl butenyl, dimethyl propenyl, dimethyl butenyl and the like.     the like ). 



   Suitable examples of the derivative of carboxy in the saturated or unsaturated normal (or branched) aliphatic hydrocarbon radical, substituted by at least one substituent from the group carboxy or a derivative thereof, cyano, hydroxy and amino, are e.g. B.  an ester, an acid amide and a salt such as e.g. B.  the following: a) Esters: The esters are conventional esters including the silyl esters, the aliphatic esters and the esters containing an aromatic or heterocyclic ring.  Examples of suitable silyl esters are tri (low. ) alkylsilyl esters (e.g. B.  Trimethylsilyl-, Triäthylsilylester u.  the like ) u.  the like 

  Examples of suitable aliphatic esters are saturated or unsaturated acyclic or cyclic aliphatic esters, which may be branched or may contain a cyclic ring, such as. B.  aliphatic esters such as alkyl esters (e.g. B.  Methyl, ethyl, propyl, isopropyl, 1-cyclopropyl ether, butyl, tert. Butyl, octyl, nonyl, undecyl esters and the like.  the like ); Alkenyl esters (e.g. B.  Vinyl, l-propenyl, allyl, 3-butenyl ester and the like.  the like ): Alkinylester (such as. B.  3-butynyl, 4-pentinyl esters and the like.  the like ); Cycloalkyl esters (e.g. B.  Cyclopentyl, cyclohexyl, cycloheptyl esters and the like.  the like ) u.  the like , and aliphatic esters that contain at least one heteroatom from the group nitrogen, sulfur and oxygen, such as. B.  cute 

 

  Alkoxy alkyl esters (e.g. B.  Methoxymethyl, Äthoxyäthyl-, Methoxyäthylester u.  the like ); cute Alkanoyloxyalkyl esters (e.g. B.  Acetoxymethyl, propionyloxymethyl, pivaloyloxymethylester u.  the like ); Alkylthioalkyl esters (e.g. B.  Methylthiomethyl, ethylthioethyl, methylthiopropyl ester u.    the like ); Dialkylamino esters (e.g. B.  Dimethylamino, diethylamino, dipropylamino esters u.  the like ); Alkylidene amino esters (e.g. B.  Äthylidenamino-, Propylidenamino-, Isopropylidenaminoester u.  the like ); cute Alkylsulfinyl- (low. ) alkyl esters (e.g. B.  Methylsulfinylmethyl-, Äthylsulfi nyhnethylester u.  the like ) u.  the like   



   Suitable esters containing an aromatic ring include e.g. B.  Aryl esters (e.g. B.  Phenyl, xylyl, tolyl naphthyl, indanyl, dihydroanthryl esters and the like.  the like ); Aralkyl esters (e.g. B.  Benzyl, phenethyl and. the like ); Aryloxyalkyl esters (e.g. B.  Phenoxymethyl, phenoxyethyl, phenoxypropyl ester and.  the like ); Arylthioalkyl esters (e.g. B.  Phenylthiomethyl-, Phenylthioäthyl-, Phenylthiopropylester u.  the like ); Arylsulfinyl alkyl ester (Z. B.  Phenylsulfinylmethyl-, Phenylsulfinyläthylester u.  the like ); Aryloxyalkyl esters (e.g. B.  Benzoylmethyl-, Toluoyläthylester u.    the like 1; Aryloylamino esters (e.g. B.  Phthalimidoester u. 



  the like ) u.  the like 



   Suitable esters containing a heterocyclic ring include e.g. B.  heterocyclic esters, heterocyclic alkyl esters u.  the like , in which the suitable heterocyclic ester, for example, a saturated or unsaturated, condensed or uncondensed 3- to 8-membered heterocyclic group having 1 to 4 heteroatoms, such as. B.  May contain oxygen, sulfur or nitrogen atoms (such. B.  Pyridyl, piperidino, 2-pyiridon-1-yl, tetrahydropyranyl, quinolyl, pyrazolylesters and the like.  the like ) u.  the like , and the suitable heterocyclic alkyl esters can, for example, a saturated or unsaturated, condensed or uncondensed 3- to 8-membered heterocyclic group having 1 to 4 heteroatoms, such as. B. 

  Contain oxygen, sulfur and nitrogen atoms, such as. B.  by pyridyl, piperidino, 2-pyridon-l-yl, tetrahydropyranyl, quinolyl, pyrazolyl and the like.  the like  substituted alkyl esters (e.g. B.  Methyl, ethyl, propyl esters and the like.  the like ) u.  the like 



   The silyl esters, the aliphatic esters and the esters containing an aromatic or heterocyclic ring, as mentioned above, may contain 1 to 10 suitable substituents, such as. B.    cute Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl u.  the like ), cute Cycloalkyl (such as cyclopropyl, cyclohexyl and the like)  the like ), cute Alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert. Butoxy and the like the like ), cute Alkylthio (such as methylthio, ethylthio, propylthio and the like) the like ), cute Alkylsulfinyl (such as methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like.  the like ), cute Alkanesulfonyl (such as methanesulfonyl, ethanesulfonyl and the like) the like ), Phenylazo, halogen (e.g. B.  Chlorine, bromine, fluorine and.  the like ), Cyano, nitro and the like.  the like , and suitable examples are mono (or di or tri) halogen (low. ) alkyl ester (e.g. B. 



  Chloromethyl, bromoethyl, dichloromethyl, 2,2,2-trichloroethyl-2,2,2-tribromoethyl and. the like ), Cyano- (low ) alkyl esters (e.g. B.  Cyanomethyl, cyanoethyl and.  the like ), Mono (or di or tri or tetra or penta) halophenyl ester (e.g. B. 



     4-chlorophenyl, 3,5-dibromophenyl-2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl ester and the like.  the like ), cute 



  Alkanesulfonylphenyl ester (e.g. B.    4-Methanesulfonylphenyl-, 2 Athansulfonylphenylester u.  the like ), 2- (or 3- or 4-) phenylazophenyl ester, mono (or di or tri) nitrophenyl ester (e.g. B.  4-nitrophenyl, 2,4-dinitrophenyl, 3,4,5-trinitrophenyl ester and the like. the like ), Mono- (or di- or tri- or tetra- or penta-) halophenyl- (low. ) alkyl esters (e.g. B.  2-chlorobenzyl, 2,4-dibromobenzyl, 3,4,5-trichlorobenzyl, pentachlorobenzyl esters and the like.  the like ), Mono (or di or tri) nitrophenyl (low. ) - alkyl esters (e.g. B.    2-nitrobenzyl, 2,4-dinitrobenzyl, 3,4,5-trinitrobenzyl esters and the like. the like ), Mono (or Di- or Tri -) - (nied. ) -alkoxyphenyl- (low. ) alkyl esters (e.g. B. 

   2-Methoxybenzyl-, 3,4-Dimethoxybenzyl-, 3,4,5-Trimethoxybenzylester u.  the like ), Hydroxy- and Di- (nied. ) -alkylphenyl- (low. ) alkyl esters (e.g. B.    3,5- -dimethyl-4-hydroxybenzyl-, 3,5-di-tert. butyl-4-hydroxybenzyl ester u.  the like ) u.  the like 



   b) Acid amide: Examples of suitable acid amides are an N-unsubstituted acid amide, an N-nied. Alkyl acid amide (such as N-methyl acid amide, N-ethyl acid amide u.  the like ), an N, N-Di- (low. ) -alkyl acid amide (such as N, N-dimethyl acid amide, N, N-diethyl acid amide, N-methyl-N-ethyl acid amide and the like.  the like ), an N-phenyl acid amide or an acid amide with pyrazole, imidazole, 4-nied. Alkylimidazole (such as 4-methylimidazole, 4-ethylimidazole, and the like)  the like ) u.  the like 



   c) Salt: Suitable salts include a salt with an inorganic base (e.g. B.  a sodium, potassium, magnesium, ammonium salt and the like.  the like ) and a salt with an organic base (e.g. B.  a dicyclohexylamine, pyridine, ethanol amine salt u.  Like). 



   The compounds produced by the process according to the invention can in particular be represented by the general formula
EMI7. 1
 are shown, in which A has the above meaning, I) Ra hydrogen and Rb hydrocarbon sulfonyl (z. B.  Arenesulfonyl, etc. ) mean
2) Ra and Rb together form a divalent acyl group derived from a dicarboxylic acid (e.g. B. 

  Phthalic acid, etc. ),
3) Ra is hydrogen and Rb is an acyl group of the type explained as the acyl group for the symbol R1, in particular one of the following acyl groups:
EMI7. 2nd
 in which: n is an integer from 0 to 4, Rb hydrogen or carboxy or a derivative thereof (z. B.  a salt, ester, etc. ), R2b hydroxy; Halogen; Azido; Amino; aliphatic radical amino such as alkylamino, alkenylamino, cycloalkylamino, etc. ; Arylamino; Acylamino such as aliphatic acylamino (e.g. B.  Alkanoylamino, etc. ), aliphatic radical oxy- (thiocarbonyl) amino [e.g. B.  Alkoxy- (thiocarbonyl) amino, etc. ], Aryloxy aliphatic acylamino (e.g. B.  Aryloxyalkanoylamino, etc. ), Aryl aliphatic acylamino (e.g. B. 



  Aralkanoylamino, etc. ), Aryloxy aliphatic acylamino (e.g. B.    Aryloxyalkanoylamino), heterocyclic aliphatic acylamino (e.g. B.  heterocyclic alkanoylamino, etc. ), Aroylamino, etc. ; substituted ureido such as N'-arylureido, etc. ; substituted thioureido such as N'-arylthioureido, etc. ; or arylthio; R2 @ hydrogen; Hydroxy; Amino; Arylamino; Acylamino such as aliphatic acylamino (e.g. B. 

  Alkanoylamino, etc. ), aliphatic radical oxy- (thiocarbonyl) amino [e.g. B.    Alkoxy- (thiocarbonyl) amino, etc. S, aroylamino, etc. ; substituted ureido such as N'-arylureido, etc. ; or substituted thioureido such as N'-arylthioureido, etc. ; R4 "hydrogen or R3 @ and R4b together form oxo; hydroxyimino; or substituted hydroxyimino such as alkoxyimino, etc. , wherein the aliphatic hydrocarbon part can be substituted by at least one suitable substituent from the group carboxy or derivatives thereof (e.g. B.  

  Salts, esters, etc. ), Halogen, sulfo, and wherein the aryl and heterocyclic rings can be substituted by at least one suitable substituent from the group nitro, halogen, carboxy or derivatives thereof (e.g. B.  Salts, esters, etc. ).   
EMI8. 1




  where the symbols have the following meanings: R5b oxo; Hydroxyimino; or substituted hydroxyimino such as aliphatic radical oxyimino (e.g. B.  Alkoxyimino, etc. ), Aryl aliphatic radical oxyimino (e.g. B.  Aralkoxyimino, etc. ); R6b cyano; aliphatic radical such as alkyl, etc. ; Aryl; heterocyclic radical; aliphatic radical amino such as alkylamino, etc. ; Aryl aliphatic radical amino such as aralkylamino, etc. ; or aliphatic radical oxy such as alkoxy, etc. ; wherein the aliphatic part can be substituted by at least one suitable substituent such as hydroxy, carboxy or derivatives thereof (e.g. B.  Salts, esters, etc. ) and the aryl and heterocyclic ring can be substituted by at least one suitable substituent, such as
Hydroxy, aliphatic radical oxy (e.g. B. 

  Alkoxy, alkenyl oxy, etc. ) which may carry a carboxy group or a derivative thereof, aryl aliphatic radical oxy (e.g. B.  Aralk oxy, etc. ); iii) iii) where the symbol has the following meaning: R7b aryl;
Aryloxy; Aryl aliphatic radical oxy such as aralkyloxy, etc. ; Arylamino; heterocyclic radical; Guanidino; or substituted guanidino such as acylguanidino (e.g. B.  3-Aralka noylguanidino, etc. ), etc. ; wherein the aryl or heterocyclic radical may be substituted by at least one suitable substituent such as nitro, halogen, aliphatic radical (e.g. B.  Alkyl, etc. ), aliphatic radical oxy (e.g. B. 

  Alkoxy), etc. ;
EMI8. 2nd
 where the symbols have the following meanings: n2 and n3 are each integers from 0 to 4, R8b is hydrogen; aliphatic radical such as alkyl; Aryl; substituted oxy such as aryloxy, etc. ; heterocyclic radical; or N-substituted carbamoyl such as N-arylcarbamoyl, etc. , wherein the aryl and heterocyclic radical can be substituted by at least one suitable substituent (e.g. B.  Hydroxy etc. ); R9b is hydrogen; Amino; Azido; Halogen; Hydroxy; Carboxy or derivatives thereof (e.g. B.  Salt, ester, etc. ); Sulfo; substituted sulfo such as aryl sulfo, etc. ; aliphatic radical such as alkyl, alkenyl, etc. , which may be substituted by at least one suitable substituent from the group amino, protected amino, azido, halogen, hydroxy, carboxy or derivatives thereof (e.g. B.  Salts, esters, etc. ), Sulfo, acyl (e.g. B. 

  Aroyl), N, N-disubstituted amino (e.g. B. 



  N-alkyl-N-arylaminoalkyl, etc. ), Aryl, substituted aryl, heterocyclic radical, substituted heterocyclic radical, etc. ; Aryl, which can be substituted by at least one suitable substituent from the group consisting of hydroxy, nitro, carboxy or derivatives thereof, halogen, substituted sulfonamido, e.g. B.  aromatic ring sulfonamido (e.g. B.  Benzenesulfonamide, etc. ) that can carry at least one substituent (e.g. B.  Carboxy, hydroxy etc. ), etc; heterocyclic radical which can be substituted by at least one suitable substituent from the group aliphatic radical, aryl, heterocyclic radical, acylamino etc. 



  (e.g. B.  heterocyclic radical, alkyl heterocyclic radical, aryl heterocyclic radical, heterocycle heterocyclic radical, heterocycle aliphatic acyl (e.g. B.  Heterocycle alkanoyl, etc. ) Amino-heterocyclic radical, arylaliphatic acyl (e.g. B.  Aralkanoyl, etc. ), Amino-heterocyclic radical, where aryl and the heterocyclic ring can carry at least one suitable substituent (e.g. B.  Oxo, halogen, etc. )), etc. ; Acyl such as aroyl, etc. ; aliphatic radical oxy such as alkoxy, cycloalkyloxy, etc. , which can be substituted by at least one suitable substituent; Arvloxy, the aryl ring of which may be substituted by at least one substituent from the following group: nitro, halogen, acyl (e.g. B.  Formyl, alkanoyl, etc. ), Acylamino (e.g. B.  Alkanoylamino, etc. ), Aryl, aryl aliphatic radical (e.g. B. 

  Aralkylamino, etc. ), and aliphatic radical (e.g. B.  Alkyl, alkenyl, etc. ), which can be substituted by at least one suitable substituent [e.g. B.  Carboxy or derivatives thereof (salts, esters, etc. ), Amino, hydroxy, nitro, hydroxyimino, substituted hydroxyimino such as aliphatic radical oxyimino (e.g. B.  Alkoxyimino, etc. ), which can be substituted by carboxy, etc. , (N-Halo-N, N, N -trialiphatic radical ammonium) -aliphatic acylhydrazono (e.g. B.  (N-Halo-N, N, N-trialkylammonio) alkanoylhydrazono, etc. ), aliphatic radical thio-aliphatic acylamino (e.g. B.  Alkylthioalkanoylamino, etc. ), whereby the aliphatic thio part can be substituted by at least one suitable substituent (e.g. B. 

  Amino, carboxy, etc. ), etc. ]; heterocyclic oxy; aliphatic radical thio, which can be substituted by at least one suitable substituent from the group amino, carboxy, acyl, acylamino, etc. , lz. B.     Alkylthio, alkenylthio, acylamino aliphatic radical thio (e.g. B.  Aroylalkanoylamino alkylthio, etc. ), Acyl aliphatic radical thio (e.g. B.  Aroyl alkylthio, N-arylcarbamoylalkylthio, etc. ) that can carry at least one suitable substituent (e.g. B.  Halogen, nitro, etc. )]; aliphatic radical sulfinyl, which can be substituted by at least one suitable substituent from the group substituted carbamoyl, etc.  (e.g. B. 

  Alkylsulfinyl, N-arylcarbamoylalkylsulfinyl, etc. ); Arylthio, which may be substituted by at least one suitable substituent from the group carboxy, etc. ; heterocyclic thio, which can be substituted by at least one suitable substituent from the group amino, hydroxy, aminoaliphatic radical, acylamino-aliphatic radical, etc. 



  (e.g. B.  heterocyclic thio, aminoalkyl heterocyclic thio, alkanoylaminoalkyl heterocyclic thio, etc. ), which can carry at least one suitable substituent (e.g. B. 



  Hydroxy, etc. ); Arylamino, which may be substituted by at least one suitable substituent; heterocyclic
Amino, which can be substituted by at least one suitable substituent from the group oxo, aryl, etc. 

 

   (e.g. B.  Oxo substituted heterocyclic amino, aryl heterocyclic amino, etc. ); mono- or disubstituted amino such as aliphatic radical amino (e.g. B.  Alkylamino, etc. ),
N-aliphatic radical-N-protected amino (e.g. B.  N-alkyl-N-protected carboxamino, etc. ), N-substituted-N-arylamino, e.g. B.  N-aliphatic radical-N-arylamino (e.g. B.    N-alkyl-N-arylamino, etc. ), N-acyl-N-arylamino (e.g. B.  N-Alka noyl-N-arylamino, etc. ), N-aliphatic radical-N-aryl amino (e.g. B.  N-alkyl-N-arylamino, etc. ), wherein the aliphatic hydrocarbon portion can carry at least one suitable sub-substituent (e.g. B.  Azido, carboxy, etc. ), N-sub-substituted sulfonyl-N-arylamino (e.g. B.  N-alkane-sulfonyl-N -arylamino, etc. ); Acylamino from the group: aliphatic acylamino (e.g. B. 

  Alkanoylamino, etc. ), which can be substituted by at least one suitable substituent (e.g. B. 



  Halogen, amino, etc. ); aliphatic radical oxy-aliphatic acylamino (e.g. B. , Cycloalkyloxyalkanoyl, etc. ), which can be substituted by at least one suitable substituent; aliphatic radical-thio-aliphatic acylamino (alkylthioalkanoylamino, etc. ), wherein the aliphatic hydrocarbon part can be substituted by at least one suitable substituent (e.g. B.  Amino, halogen, carboxy, etc. ); Aryl-aliphatic acylamino, where the aryl ring can be substituted by at least one suitable substituent from the group aliphatic radical oxy, aryloxy, etc.  (e.g. B.  Alkoxyaralkanoylamino, aryloxyaralkanoylamino, etc. ), wherein the aliphatic hydrocarbon part and the aryl ring can carry at least one suitable substituent, e.g. B.  Halogen, aryl aliphatic radical oxyimino (e.g. B. 

  Aralkoxyimino, etc. ), Arylamino, amino, hydroxy, etc. ; Arylamino aliphatic acylamino (e.g. B. 



  Arylaminoalkanoylamino, etc. ), wherein the aryl ring and the aliphatic hydrocarbon part can be substituted by at least one suitable substituent (e.g. B.  Halogen, carboxy, amino); Aryloxy-aliphatic acylamino, the aryl ring of which may be substituted by at least one substituent from the group aliphatic radical (e.g. B.  Alkyl, etc. ), Aryl, arylaliphatic radical (e.g. B.  Aralkyl, etc. ), heterocyclic radical, acyl (e.g. B.  aliphatic acyl, substituted aroyl, heterocyclic carbonyl, etc. ), Aryl aliphatic radical amino aliphatic radical (e.g. . B aralkylaminoalkyl, etc. ), etc. such as aryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. B.  Halogen, nitro, carboxy, formyl, carbazoyl, etc. ); Alkylaryloxyalkanoylamino, which can be substituted by at least one suitable substituent (e.g. B. 



  Hydroxy, etc. ); Arylaryloxyalkanoylamino; Aralkylaryloxyalkanoylamino, which may be substituted by at least one suitable substituent (e.g. B.  Hydroxyimino, halogen, etc. ); Formylaryloxyalkanoylamino; Alkanoylaryloxyalkanoylamino; Aroylaryloxyalkanoylamino, which may be substituted by at least one suitable substituent (e.g. B. 



  Nitro, amino, halogen, etc. ); Alkylthioalkanoylaminoaroyl-aryloxy-alkanoylamino, which may be substituted by at least one suitable substituent (e.g. B.  Halogen, amino, carboxy, etc. ); Alkylthioalkylaminoaroylaryloxyalkanoylamino, which may be substituted by at least one suitable substituent (e.g. B.  Amino, halogen, etc. ); (N-Halo-N, N, N-trialkylammonio) alkanoylaminoaroylaryl oxyalkanoylamino, which may be substituted by at least one suitable substituent (e.g. B.  Halogen, etc. ); heterocyclic carbonylaryloxyalkanoylamino, which may be substituted by at least one suitable substituent (e.g. B.  Halogen, etc. ); Aralkylaminoalkylaryloxyalkanoylamino, which may be substituted by at least one suitable substituent (e.g. B. 

  Alkoxy, carboxy-alkoxy, carboxy, etc. ); heterocyclic aryloxyalkanoylamino, where the heterocyclic ring may be substituted by at least one suitable substituent [e.g. B.  Alkyl, aryl, substituted (e.g. B.  by halogen) aryl, etc. ], and the alkane portion can be substituted by at least one suitable substituent (e.g. B.  Halogen, amino, etc. ); Diaryloxyaliphatic acylamino (e.g. B.  Diaryloxyalkanoylamino, etc. ), wherein the aliphatic hydrocarbon part can be substituted by at least one suitable substituent (e.g. B. 



  Halogen, amino, etc. ); Arylthio aliphatic acylamino (e.g. B.    Arylthioalkanoylamino, etc. ) which can be substituted by at least one suitable substituent (e.g. B.  Carboxy, etc. ); heterocyclic-aliphatic acylamino, where the heterocyclic radical can carry at least one suitable substituent, e.g. B.  an aliphatic radical (e.g. B.  Al alkyl, etc. ), Aryl, which can carry a substituent (e.g. B. 



  Halogen, etc. ), etc. , and wherein the aliphatic hydrocarbon part can carry at least one suitable substituent (e.g. B.  Halogen, amino, etc. ); heterocyclic-heterocyclic-aliphatic acylamino (e.g. B.  heterocyclic-heterocyclic-alkanoyl, etc. ); heterocyclic thio-aliphatic acylamino (e.g. B.  Heterocyclicthioalkanoylamino, etc. ), which can be substituted by at least one suitable substituent, e.g. B.  Hydroxy, amino, aliphatic radical (alkyl) which can carry at least one suitable substituent (e.g. B.  Amino, etc. ); Acylamino aliphatic acyl amine, e.g. B.  arylaliphatic acylamino-aliphatic acylamino (e.g. B.  Aralkanoylamino-alkanoylamino, etc. ), wherein the aliphatic hydrocarbon part and / or aryl ring can be substituted by at least one suitable substituent (e.g. B. 

  Amino, halogen, carboxy, etc. ); substituted sulfinyl aliphatic acylamino (e.g. B.  Arylsulfinylalkanoylamino, etc. ), which can be substituted by at least one suitable substituent (e.g. B.  Carboxy, etc. ); substituted sulfo-aliphatic acylamino, e.g. B.  Arylsulfoalkanoylamino, etc. ; N, N-disubstituted amino aliphatic acylamino, e.g. B.  (N-aryl-N-arylsulfonylamino) alkanoyl amine, etc. ); substituted glyoxyloylamino (e.g. B.  Arylglyoxyloylamino, etc. ); substituted oxalylamino (e.g. B. 



  Alkoxalylamino, aralkylaminooxalylamino, etc. ); N-substituted carbamoyl (e.g. B.  N-arylcarbamoyl, etc. ); Guanidinocarbonylamino; substituted sulfonamido, e.g. B.  aromatic ringsulfonamido (e.g. B.  Benzenesulfonamido, etc. ), aliphatic hydrocarbon sulfonamido (e.g. B.  Alkanesulfonamido, etc. ), which can carry at least one suitable substituent (e.g. B.  Hydroxy, carboxy, halogen, etc. ); substituted ureido, e.g. B.  Acylureido (e.g. B.    N'-aroylureido, etc. ); substituted aminoxy, such as acylaminoxy, e.g. B.  aliphatic acylaminoxy, which may be substituted by aryloxy (e.g. B.  Aryloxyalkanoylaminoxy, etc. ), Alkylidene aminoxy, which may be substituted by aryl, heterocyclic radical (e.g. B. 



  Alkylidene aminoxy, heterocyclic alkylidene aminoxy, aralkylidene aminoxy, etc. ), which can have at least one suitable substituent (e.g. B.  Carboxy or a derivative thereof, alkoxy, etc. ), in which the aryl and heterocyclic ring can be additionally substituted by at least one suitable substituent from the group carboxy or derivatives thereof (e.g. B.  Salts, esters, etc. ), Amino or protected amino, hydroxy or protected hydroxy, halogen, nitro, oxo, carbazyl, acyl [e.g. B.  Alkanoyl (e.g. B.  Formyl, alkanoyl, etc. ), etc. , aliphatic radical (e.g. B.  Alkyl, etc. ), aliphatic radical oxy (e.g. B.  Alkoxy, etc. ), Aryl, aryl aliphatic radical (e.g. B.  Aralkyl, etc. ), Acylamino (e.g. B. 

  Alkanoylamino, etc. ], etc. ; and wherein the aliphatic part or the radical can contain 1 to 8 C atoms, preferably 1 to 4 C atoms and can additionally be substituted by at least one suitable substituent from the group carboxy or derivatives thereof (salts, esters, etc. ), Amino or protected amino, azido, nitro, halogen, hydroxy, sulfo, etc. 

 

   In the above definition, the term heterocyclic radical preferably denotes monoaliphatic or aromatic heterocyclic radicals, which can be 5- to 7-membered heterocycles and contain at least one heteroatom from the group consisting of oxygen, nitrogen and sulfur, and polyaliphatic or aromatic heterocyclic radicals, for example aryl fused with heterocycle, heterocycle fused with heterocycle, etc. , wherein the heterocycle can be a 5- to 7-membered heterocycle and contains at least one heteroatom from the group consisting of oxygen, nitrogen and sulfur. 



   Furthermore, A can be represented in particular by the following formula:
EMI10. 1
 wherein Ala is hydrogen, A2a is hydrogen, an aliphatic or cycloaliphatic group (e.g. B.  Alkyl, alkenyl, cycloalkyl and the like.  the like ), or phenyl which is substituted by at least one suitable substituent from the group consisting of hydroxy or protected hydroxy, amino or protected amino, nitro,
Halogen, an aliphatic group, an aliphatic oxy group (e.g. B.  Alkoxy and  the like ), an aliphatic thio group (e.g. B. 

  Alkylthio, u.  the like ) u.  the like  is substituted, or Ala and A2a together form a methylene group, an alkylidene or cycloalkadienylidene, and A3a carboxy or a derivative thereof (e.g. B.  the salt, the ester, the azide or.  the like ), Cyano, optionally protected amino or optionally protected hydroxy. 



   In particular, in the compounds of the formula I A obtainable according to the invention is hydrogen or a group of the formula
EMI10. 2nd
 in which Ata is hydrogen and A2a is hydrogen, alkyl or phenyl, which may optionally have at least one substituent from the group consisting of hydroxyl, amine and benzyloxycarbonylamino,
Nitro, alkyl, alkoxy, aralkoxy, alkylthio and halogen is substituted, or Ala and A2a together represent alkylidene and A3a is carboxy or a derivative thereof or cyano. 



   The process according to the invention is explained in more detail below. 



   According to the invention, the 1-substituted 3-amino-2-azetidinone (a), which can be derived from the substance FR-1923, the 1-substituted 3-amino-2-azetidinone (b) and the 3- Amino-2-azetidinone (c), which can be derived from the 3-acylamino-2-azetidinone.  These starting compounds can be prepared, for example, by processes as shown in the following reaction scheme: (1)
EMI10. 3rd

EMI10. 4th
  wherein X represents an acid residue and A 'has the same meaning as A with the exception of hydrogen. 



   Examples of acylating agents which can be used according to the invention are an organic carboxylic acid, an organic sulfonic acid and the corresponding thio- or imido acid and in particular an aliphatic acid, an aromatic or heterocyclic carboxylic acid and the corresponding sulfonic acid, carbamic acid, carbonic acid and thio acid and reactive derivatives thereof .  Examples of reactive derivatives are an acid anhydride, an activated amide, an activated ester, an isocyanate and an isothiocyanate and the like.  the like 



   Examples of reactive derivatives are as follows; An acid azide; a mixed acid anhydride with an acid such as e.g. B.  Dialkylphosphoric acid, phenylphosphoric acid; Diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphosphoric acid, sulfurous acid, thiosulfuric acid, hydrohalic acid, e.g. B.  Hydrochloric acid, hydrobromic acid and.  the like ), Sulfuric acid, monoalkyl carbonic acid, an aliphatic carboxylic acid (e.g. B.  Acetic acid, piva linic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid), an aromatic carboxylic acid (e.g. B. 

  Benzoic acid) or a symmetrical acid anhydride; an acid amide with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; and an ester (e.g. B.  a cyanomethyl, methoxymethyl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, methanesulfonylphenyl, phenylazophenyl, phenylthio, p-nitrophenylthio, p-cresylthio, Carboxymethylthio, pyranyl, pyridyl, piperidyl, 8-quinolylthioester or an ester with N, N-dimethylhydroxylamine, I-hy droxy-2- (1H) -pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide) and the like.  the like 



   The reactive derivatives indicated above are selected depending on the type of acid used.  In the reaction, if a free acid is used as the acylating agent, the reaction can preferably be carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '- (4 -diethylaminocyclohexyl) -carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide, N, N'-carbonyldi- (2-methylimidazole), pentamethylene ketene-N-cyclohexylimide, diphenylketene-N-cycohexylimine, alkoxyacetylene, 1-alkoxy-1-dichlorethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine

   2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide (chloromethylene) dimethylammonium chloride, 2,2,4,4,6,6-hexachloro-2,2,4,4 , 6,6-hexahydro-1,3,5,2,4,6-triazatriphosphorin or a mixed condensing agent such as. B.  Triphenylphosphine and a carbon tetrahalide (such as carbon tetrachloride, carbon tetrabromide and the like)  the like ) u.  the like , be performed. 



   An example of an acyl group which can be introduced into the amino group in the compound (I) by the above-mentioned acylating agent is a dehydroxylated group of an aliphatic, aromatic and heterocyclic carboxylic acid or the corresponding sulfonic acid, carbonic acid, carbamic acid and thioic acid and the like.  the like  and the acyl group can in particular be the same acyl group as that given for the explanation of the acyl group in the acylamino group for R1.  Certain derivatives on the amino group in the 3-position of compound II, namely a Schiff base and a salt with an acid (e.g. B.  Hydrochloric acid). 



   The acylation can be carried out according to the invention in a conventional manner, such as. B.  the acylation of 6-aminopenicillanic acid or 7-aminocephalosporanic acid to form the 6-acylaminopenicillin or the corresponding / 7-acylaminocephalosporin compounds. 



   That is to say that the reaction according to the invention is carried out in such a way that the compound (II) or its reactive derivative on the amino group is reacted with an acylating agent, generally in a solvent which has no adverse effect on the reaction, such as water, acetone , Dioxane, acetonitrile, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine and the like.  the like , implemented, wherein the above-mentioned hydrophilic solvent can be used in a mixture with water. 



   The reaction according to the invention can also in the presence of a base, such as. B.  an inorganic base (such as an alkali metal bicarbonate and the like)  the like ) and an organic base such as a trialkylamine (e.g. B.  Trimethylamine, triethylamine, tributylamine u.  the like ), N-methylmorpholine, N-methylpiperidine, N, N-dialkylaniline (such as N, N-dimethylaniline, N, N-diethylaniline and the like).  the like ), N, N-dialkylbenzylamine (such as N, N-diethylbenzylamine and the like.  the like ), Pyridine, picoline, lutidine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,8-di azabicyclo [5.4 , 0] undecen-7 u.  the like , be performed. 



  In the reaction according to the invention, a liquid base or a liquid condensing agent can also be used as the solvent in the reaction.  There are no restrictions with regard to the reaction temperature and the reaction according to the invention can preferably be carried out with cooling or at ambient temperature. 



   It should be noted that the product obtained in the acylation described above may then subsequently be subjected to a treatment to remove the protective group on the amino, hydroxy and carboxy group in R1 and A, whereby a compound is obtained which has the corresponding free amino -, Hydroxy- and carboxy group contains. 



   This means that if the compounds of the formula (I) obtained in the acylation are compounds in which the group R1 and / or A have protected amino, protected hydroxyl and / or protected carboxy functions, these compounds are subjected to a treatment in order to remove a protecting group of the protected amino, protected hydroxy and / or protected carboxy functions, whereby compounds are obtained which have the corresponding free amino, hydroxyl and / or carboxy group in the group (s). 



   The term protecting group on the hydroxy, amino or carboxy group as used herein means a group attached to the terminal hydroxyl, amino or carboxy function; suitable examples of such a protective group on the hydroxyl or.  Amino groups can be conventional alkanoyl (e.g. B.  Formyl, acetyl and the like.  the like ), conventional haloalkanoyl (e.g. B.  Dichloroacetyl trifluoroacetyl u.  the like ), conventional aroyl (e.g. B.  Benzoyl u.  the like ), conventional alkoxycarbonyl (e.g. B.  Ethoxycarbonyl, tert. Butoxycarbonyl, adamantyloxycarbonyl and the like.  the like ), conventional haloalkoxycarbonyl (e.g. B.  Trichloroethoxycarbonyl u.  the like ), conventional optionally substituted aralkoxycarbonyl (e.g. B.  Benzoyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like.  the like ) u.  the like  be. 

 

   Suitable methods for removing a protecting group are the commonly used ones, e.g. conventional solvolysis, conventional reduction and conventional methods using a heavy metal and the like.  the like 



   Suitable examples of reagents that can be used are as follows:
For solvolysis:
The solvolysis is carried out in the presence of an acid or a base.  Suitable acids are inorganic acids (e.g. B.  Hydrochloric acid, sulfuric acid and.  the like ), organic acids (e.g. B.  Formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.  the like ), acidic ion exchange resins u.  the like 



   Suitable bases are inorganic bases, such as a hydroxide, carbonate or bicarbonate of an alkali metal (e.g. B. 



  Sodium, potassium and  the like ), an alkaline earth metal (e.g. B.  Magnesium, calcium and.  the like ) u.  the like , inorganic bases, such as an alkoxide of the above metals, a tert. Amine such as trialkylamine (e.g. B.  Trimethylamine, triethylamine u.  the like ), a disubstituted arylamine (e.g. B.  N, N-dimethylaniline and the like.  the like ) or a heterocyclic amine (e.g. B.  N-methylmorpholine, N-methylpiperidine, N, N-dimethylpiperazine, pyridine and the like.  the like ), basic ion exchange resins u.  the like 



   For the reduction:
The reduction is carried out with a conventional chemical reducing agent or by conventional catalytic reduction.  Suitable reducing agents are a metal (e.g. B.  Tin, zinc, iron u.  the like ) or a combination of metallic compounds (e.g. B.  Chromium chloride, chromium acetate and.  the like ) and organic or inorganic acids (e.g. B.  Acetic acid, propionic acid, hydrochloric acid and the like.  the like ). 



   Suitable ones used in the catalytic reduction
Catalysts are those commonly used, such as platinum catalysts (e.g. B.  Platinum plates, platinum sponge, platinum black, colloidal platinum, platinum oxide or platinum wire), palladium catalysts (palladium sponge, palladium black, palladium oxide, palladium-on-activated carbon, colloidal palladium, palladium-on-barium sulfate or palladium-on-barium carbonate), nickel catalysts (e.g. B.  reduced nickel, nickel oxide or Raney nickel), cobalt catalysts (e.g. B.  reduced cobalt or Raney cobalt), iron catalysts (e.g. B.  reduced iron or Raney iron), copper catalysts (e.g. B. 



  reduced copper, Raney copper or Ullman copper) or other conventional catalysts. 



   Suitable examples of heavy metals are copper, zinc and the like.  the like 



   Although there are no particular restrictions on the reaction temperature for deprotection, and a preferred temperature depends on the type of protecting group to be removed and the method used, the reaction is usually carried out under cooling, at ambient temperature or at a slightly elevated temperature. 



   The compounds of the formula (I) obtainable according to the invention have antimicrobial activities against various pathogenic microorganisms and are suitable for the treatment of infectious diseases which are caused by such microorganisms in humans and animals.  For some representative compounds obtainable according to the invention, the antimicrobial activities against pathogenic microorganisms in the form of the minimal inhibitory concentration (M. I. C. ), which was determined in a conventional manner as indicated below.  The following stitches I. C.  Values refer to pg / ml.    



   Compound (end compound) according to Example 39: Pseudomonas aeruginosa (3),
Compound according to Example 51, Bacillus subtilis (12, 5),
Compound according to Example 112: Escherichia coli (60), Proteus vulgaris ( <3), Staphylococcus aureus (60),
Compound according to Example 157: Bacillus subtilis (7.5), Staphylococcus aureus (7.5),
Compound according to Example 158: Bacillus subtilis (80), Staphylococcus aureus (80),
Compound according to Example 161: Escherichia coli (16), Proteus vulgaris (8), Staphylococcus aureus (8).



   The compounds of formula (I) can be formulated for administration in a conventional manner like other antibiotics.



   The compounds obtained according to the invention can therefore be used in the form of pharmaceutical preparations, for example in solid, semi-solid or liquid form, which contain the active compounds of the formula (I) in admixture with a pharmaceutical organic or inorganic carrier or excipient, for external or internal use Application are suitable. The active ingredient can be processed, for example, with conventional carriers or auxiliaries to give tablets, pills, capsules, suppositories, solutions, emulsions, aqueous suspensions and other suitable forms for administration.

  The carrier can be, for example, glucose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea and other carriers that are suitable for the production process and in solid, semi-solid or liquid form , be used. In addition, any auxiliary substances, stabilizing agents, thickening agents, coloring agents and taste and smell substances can be used. The preparations can also contain preservatives or bacteriostatic agents, whereby the active ingredients in the desired preparations are stabilized with regard to their activity.

  The preparations contain the compounds of formula (I) in an amount sufficient to exert the desired therapeutic effect on the process or condition caused by bacteria. The dose or therapeutically effective amount of the compounds of formula (I) varies depending on the age and condition of the patient to be treated. Generally, a dose of about 0.5 to 5 g, preferably 1 to 2 g, of active compound is administered daily for the treatment of diseases against which the compounds of formula (I) are active.



   The following examples are intended to explain the present invention in more detail.



   example 1
0.94 g of 3-amino-1- (a-carboxy-4-hydroxybenzyl) -2-azetidinone (hereinafter referred to as 3-aminolactacillanic acid) was suspended in 10 ml of water. Then 0.80 g of sodium bicarbonate were added to the suspension. 10 ml of acetone was added to the solution and it was then cooled to -7 "C., whereupon 5 ml of acetone containing 0.80 g of 2-phenylacetyl chloride was added to the solution. The reaction mixture was stirred at the same temperature for 2 hours. Then the acetone was distilled off under reduced pressure, the remaining aqueous layer was washed with ether and then adjusted to pH 2 with 10% hydrochloric acid, followed by extraction twice with 15 ml of ethyl acetate.

  The extracts obtained were combined and washed successively with water and a saturated aqueous saline solution. Then it was dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract and the residue obtained was treated with a small amount of a mixture of ethyl acetate and ether, whereby 0.53 g of 3- (2-phenylacetamido) -actacillanic acid, mp 134-141 ° C., were obtained.



   The following compounds were obtained using essentially the same procedure:
EMI13.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 2 <SEP> CH3CH2CHCONH- <SEP> - <SEP> CH <SEP> OH
 <tb> <SEP> Br <SEP> 1 <SEP> 156-158
 <tb> <SEP> COOH
 <tb> <SEP> 3 <SEP> CHCÖNH- <SEP> 146-148
 <tb> <SEP> N1HCOOC'2
 <tb> <SEP> 4 <SEP> -Ch'CONH- <SEP> 159-162
 <tb> <SEP> 4S>
 <tb> <SEP> SCH3
 <tb> <SEP> 3
 <tb> <SEP> ChCONF
 <tb> <SEP> 5 <SEP> 1 <SEP> <SEP> 173-175
 <tb> <SEP> I? R
 <tb> <SEP> -CHcCON
 <tb> <SEP> 6 <SEP> 195 <SEP> 1 <SEP> (sodium salt)
 <tb> <SEP> C1
 <tb> <SEP> 7 <SEP> OCHCONJI <SEP> <SEP> (sodium salt)
 <tb> <SEP> 7 <SEP> L <SEP> -QQ <SEP> 186-189
 <tb> <SEP> S02HW
 <tb> <SEP> 8 <SEP> C = C02s <SEP> - <SEP> 181-185
 <tb> <SEP> - <SEP> CCOIL'E
 <tb> <SEP> OC.i3
 <tb> <SEP> 9 <SEP> ore <SEP> CECOWII- <SEP> 95-96
 <tb> <SEP> 0 <SEP>

   Ch'O
 <tb> <SEP> X <SEP> CHCON <SEP> 174.175
 <tb> <SEP> d <SEP> f
 <tb> <SEP> C; g3v <SEP> 7i- <SEP> TI <SEP> 8sCONU
 <tb> 11 <SEP> 1 <SEP>. <SEP> 167-168
 <tb> <SEP> I
 <tb> <SEP> OZ
 <tb> 12 <SEP> V <SEP> C, OOCOC; -2cGfi <SEP> 85-89
 <tb>
EMI14.1


 <tb> example <SEP> Rl <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> 13 <SEP> 00CN9CRCH2CONH- <SEP> -CH <SEP> g <SEP> OH <SEP> 169-173
 <tb> <SEP> A <SEP> COOH
 <tb> <SEP> CH <SEP> 2CONH
 <tb> 14 <SEP> e <SEP> <SEP> 199-201
 <tb> 15 <SEP> CH2OOCE'H (CH2) 5COUIS- <SEP> <SEP> 1730, <SEP> 1660
 <tb> <SEP> 2 <SEP> YCHZOuCNI! <SEP> (CH2) rCOH- <SEP> 2 <SEP> 5 <SEP> 1730.1660
 <tb> 16 <SEP> WCH2CON'S- <SEP> 180-183
 <tb> <SEP> S
 <tb> 17 <SEP> CII2C0NII- <SEP> -CH2COOH <SEP> 144-145
 <tb> 18 <SEP> <SEP> -C: <SEP> < <SEP> 174-175
 <tb> <SEP> I
 <tb> <SEP> CCOR
 <tb> 19 <SEP> HOOCCH2CH2CONH- <SEP> -CH-Y <SEP> (disodium salt)
 <tb> <SEP> I.R.

   <SEP> v <SEP> cm-1 <SEP> (KBr):
 <tb> <SEP> COOH <SEP> 1740, <SEP> 1660, <SEP> 1585
 <tb> 20 <SEP> C1CII2C0JCII2CONH- <SEP> 136-139
 <tb> 21 <SEP> CH2CONK- <SEP> <SEP> 171-173
 <tb> <SEP> I
 <tb> 22 <SEP> C, HSOCOCONH- <SEP> <SEP> 210-213
 <tb> <SEP> <SEP> NCH <SEP> CONIS
 <tb> 23 <SEP> 1 <SEP> 2 <SEP>.

   <SEP> 116-119
 <tb> <SEP> S02CH3
 <tb> 24 <SEP> CH3OCH2CONH- <SEP> <SEP> 125-129
 <tb> 25 <SEP> CHSSO2NHCH2CONH- <SEP> <SEP> (sodium salt)
 <tb> <SEP> 160-164
 <tb>
EMI15.1


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> 26 <SEP> OCX2CONH- <SEP> -CHOH <SEP> 195-198
 <tb> <SEP> CQOH
 <tb> 27 <SEP> XOCH2CONU- <SEP> <SEP> 143-146
 <tb> 28 <SEP> O <SEP> - <SEP> OCEi2CONEi- <SEP> <SEP> 180-184
 <tb> <SEP> OClI2 <SEP> toOC2COK
 <tb> 29 <SEP> c <SEP> 181-183
 <tb> <SEP> C0
 <tb> <SEP> / 7n
 <tb> 30 <SEP> 1 <SEP> 2 <SEP> 00L72C0Nh'- <SEP> 134-135
 <tb> <SEP> '2
 <tb> <SEP> O <SEP> CH200CNH
 <tb> 31 <SEP> \ <SEP> / ry <SEP>> <SEP> 136-140
 <tb> <SEP> CHCKzeP-OCIiZCOS
 <tb> <SEP> CH, OOC
 <tb> <SEP> 3
 <tb> <SEP> O <SEP> C <SEP> ^ 05CN. *
 <tb> <SEP> L
 <tb> 32 <SEP> Ch <SEP> <OCH2CONH- <SEP> too <SEP> 80-85
 <tb> <SEP> l
 <tb> <SEP> CF <SEP> 000
 <tb> <SEP> 3
 <tb> 33

    <SEP> OHC <SEP> OCE2CONH- <SEP> 145-146
 <tb> <SEP> 34 <SEP> ci-V <SEP> y-so, fiKcK, COEi- <SEP> 168-173
 <tb> 35 <SEP> CH2 = CHCH2SCH2CONH- <SEP> 178-183
 <tb> 36 <SEP> CH3SCH2CONH- <SEP> <SEP> 154-155
 <tb> 37 <SEP> 2NoCEi2CONH- <SEP> <SEP> 137-140
 <tb> 38 <SEP> N3CH2CONH- <SEP> <SEP> 171-173
 <tb> 39 <SEP> BrCH2CONH- <SEP> <SEP> 145-150
 <tb>
EMI16.1


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> 40 <SEP> OcIICON: - <SEP> N.M.R.

   <SEP> 6 <SEP> ppm <SEP> (CDCl):
 <tb> <SEP> 2 <SEP> 2 <SEP> CH <SEP> S <SEP> OCH <SEP> 3.14 <SEP> (1H, <SEP> d, <SEP> d, <SEP> J <SEP> =
 <tb> <SEP> 3Hz, <SEP> 6Hz), <SEP> s), <SEP> 3.76 <SEP> (3H, <SEP> s),
 <tb> <SEP> COOCH <SEP> 3.81 <SEP> (3H, <SEP> s), <SEP> 3.96 <SEP> (1H,
 <tb> <SEP> t, <SEP> J <SEP> = <SEP> 6Hz, <SEP> 6Hz), <SEP> 4.46
 <tb> <SEP> (2H, <SEP> s), <SEP> 5.08 <SEP> (1H, <SEP> hep
 <tb> <SEP> tet), <SEP> 5.59 <SEP> (1H, <SEP> s), <SEP> 6.80
 <tb> <SEP> 7.40 <SEP> (9H, <SEP> m)
 <tb> 41 <SEP> C <SEP> H <SEP> OOCCH = CHOC. = <SEP> CONH- <SEP> ¯ct <SEP> CH <SEP> 109-110
 <tb> <SEP> 2 <SEP>:

  > <SEP> 2 <SEP> CCoL1
 <tb> 42 <SEP> ClCH2CONH- <SEP> <SEP> 165-167
 <tb> 43 <SEP> SCh'2CONII- <SEP> 183-185
 <tb> 44 <SEP> S <SEP> Y <SEP> CH = CF.CO'NII- <SEP> 192-193
 <tb> 45 <SEP> OCH CONHiCONH- <SEP> <SEP> 179-180
 <tb> <SEP> NO
 <tb> 46 <SEP>> <SEP> CON <SEP> 170-175
 <tb> <SEP> 2
 <tb> 47 <SEP> 0 <SEP> 2N-CCN: 'd- <SEP> 195-197
 <tb> 48 <SEP> CH3OCONr.- <SEP> 160-165
 <tb> <SEP> 48 <SEP> CH30 <SEP> - \ Z7Y
 <tb> <SEP> 49 <SEP> I.R. <SEP> <SEP> (sodium salt)
 <tb> BY-ce, <SEP> l <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 1735, <SEP> 1735, <SEP> 1655, <SEP> 1610
 <tb> 50 <SEP> Cl2CHCONH- <SEP> <SEP> 178-183
 <tb> <SEP> ¹ <SEP> CHCON:
 <tb> 51 <SEP> - · <SEP> 135-140
 <tb>
EMI17.1


 <tb> example <SEP> Ri <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 52 <SEP> t <SEP> ChCoN: - <SEP> ¯Cx <SEP> n <SEP> I.R.

   <SEP> v <SEP> cm-1 <SEP> (CHCl3):
 <tb> <SEP> 2 <SEP> 1, <SEP> 1755, <SEP> 1745, <SEP> 1675
 <tb> <SEP> COOCi- :; <SEP> 'r'
 <tb> <SEP> 2
 <tb> <SEP> -CII <SEP> OH
 <tb> <SEP> 53 <SEP> SO <SEP> CH <SEP> 1 <SEP> whether <SEP> 172-174
 <tb> <SEP> CCOF
 <tb> <SEP> 54 <SEP> ¯ <SEP> OC () gg- <SEP> <SEP> 198-200
 <tb> <SEP> 55 <SEP> CH2CONH- <SEP> -H <SEP> 178-184
 <tb> <SEP> 56 <SEP> CLCYC N'H- <SEP> CiH <SEP> < <SEP> OH <SEP> 171-176
 <tb> <SEP> NIICOOCH <SEP> 2CC13 <SEP> COOH
 <tb>
Example 57
492 mg of N-phenylglycyl chloride hydrochloride was suspended in 10 ml of methylene chloride and the suspension was cooled to 150C. A solution which had been obtained by dissolving 472 mg of 3-aminolactacillanic acid and 2.03 g of N, 0-bis (trimethylsilyl) acetamide in 17 ml of methylene chloride was added to the suspension all at once.

  The mixture was stirred for 1 h while the reaction temperature of the mixture was kept at 0 to -100C. Then, after removing the cooling bath, stirring was continued for 1/2 h.

 

  The methylene chloride was distilled off from the reaction mixture, and the residue obtained was dissolved in ethyl acetate. The solution was washed with water and a saturated saline solution successively, and then dried. The solvent was distilled off and a small amount of acetone was added to the residue, whereby 116 mg of crystals of 3- (N-phenylglycinamido) -actacillanic acid, mp. 194 to 194.5 ° C., were obtained. The filtrate was left to stand under cooling , whereby 60 mg of crystals of the same desired compound, mp. 193 to 194.5 "C., were obtained. The overall yield was 176 mg.



   The following compounds were obtained using essentially the same procedure:
EMI18.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> 58 <SEP> / \ <SEP> * 2 <SEP> o \ <SEP> (D <SEP> isomer) <SEP> 145-146
 <tb> <SEP> CH, COrUEI- <SEP> -CII <SEP> OCH <SEP> (L <SEP> isomer)
 <tb> <SEP> 1 <SEP> I <SEP> ç <SEP> 3 <SEP> I.R. <SEP> vcm-1 (CHCI,):
 <tb> <SEP> wOOCrI <SEP> 1760, <SEP> 1740, <SEP> 1680
 <tb> <SEP> -approx <SEP> (D <SEP> = <SEP> L / <SEP> isomer) <SEP> 129-130
 <tb> 59 <SEP> <SEP> ' <SEP> \ cm =; <SEP> (L <SEP> isomer) <SEP> I.R. <SEP> v <SEP> cm-1
 <tb> <SEP> 1 <SEP> (liquid film):
 <tb> <SEP> COOCII2 <SEP> 3300, <SEP> 1760-1740, <SEP> 1665
 <tb> 60 <SEP> <SEP> CH <SEP> I.R. <SEP> ycm-1 (CHCI,):
 <tb> <SEP> 60 <SEP>
 <tb> <SEP> t; 2nd <SEP> 1525, <SEP> 1350
 <tb> <SEP> COOCH-3
 <tb> <SEP> CH <SEP> ¯ <SEP> isomer <SEP> A)
 <tb> <SEP> I.R.

   <SEP> I.R. <SEP> v <SEP> I.R. <SEP> cm- ' <SEP> (CHCI3):
 <tb> <SEP> 1760 <SEP>, z77j \ <SEP> 1760 <SEP> (s), <SEP> 1745, <SEP> 1710 <SEP> (s),
 <tb> <SEP> 61 <SEP> <SEP> 1675
 <tb> 61 <SEP> <SEP> 1675
 <tb> <SEP> CCC <SEP> OH <SEP> isomer <SEP> B)
 <tb> <SEP> I.R. <SEP> v <SEP> cm-l <SEP> (CHCI3):
 <tb> <SEP> 1755 <SEP> (s), <SEP> 1745, <SEP> 1710 <SEP> (s),
 <tb> <SEP> 1675
 <tb> -CH <SEP> < <SEP> CH3 <SEP> isomer <SEP> A)
 <tb> <SEP> 62 <SEP> <SEP> | <SEP> isomer <SEP> B) <SEP> 148
 <tb> <SEP> I.R. <SEP> v <SEP> cm-l <SEP> (CHCl,):
 <tb> <SEP> CCOCi-f, <SEP> 1755, <SEP> 1745, <SEP> 1675
 <tb> <SEP> J
 <tb> <SEP> isomer <SEP> A) <SEP> 138-140
 <tb> <SEP> CC <SEP> isomer <SEP> B)
 <tb> <SEP> * 2 <SEP> 3 <SEP> N.M.R.

   <SEP> b <SEP> ppm <SEP> (CDCl3):
 <tb> <SEP> / <SEP> o <SEP> Oc <SEP> i- <SEP> Cit ', <SEP> 3.54 <SEP> (2H, <SEP> m), <SEP> 3.59 <SEP> (2H,
 <tb> 63 <SEP> <SEP> CH <SEP> 3 <SEP> s), <SEP> 3.73 <SEP> (3H, <SEP> s), <SEP> 3.82
 <tb> <SEP> ¯s <SEP> r <SEP> - <SEP> (9H, <SEP> s), <SEP> 4.96 <SEP> (1H, <SEP> m),
 <tb> <SEP> CCH3 <SEP> 5.45 <SEP> (1H, <SEP> s), <SEP> 6.13 <SEP> (1H, <SEP> d,
 <tb> <SEP> COOC <SEP> J <SEP> = <SEP> 8Hz), <SEP> 6.43 <SEP> (2H, <SEP> s), <SEP>
 <tb> <SEP> 3 <SEP> 7.10-7.45 <SEP> (SH, <SEP> m)
 <tb> <SEP> * 2
 <tb> <SEP> -C. <SEP> ScH3
 <tb> 64 <SEP> <SEP> isomer <SEP> A) <SEP> 115-117
 <tb> <SEP> isomer <SEP> B) <SEP> 157-159
 <tb> <SEP> CCCC: -: 3
 <tb> <SEP> * 2 <SEP> 4 <SEP> isomer <SEP> A) <SEP> 138-140
 <tb> 65 <SEP> s <SEP> -0 ' <SEP> isomer <SEP> B)
 <tb> <SEP> I.R.

   <SEP> v <SEP> cm-l <SEP> (CHCl8):
 <tb> <SEP> 1770, <SEP> 1745, <SEP> 1678
 <tb> <SEP> CCOCI: 3
 <tb> 66 <SEP> <SEP> -CH2COOQH, <SEP> 104-105
 <tb>
EMI19.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> 67 <SEP> OCH2CON <SEP> \ 3-CH, COrVK- <SEP> 114-115
 <tb> <SEP> -CH <SEP> <
 <tb> <SEP> 7 / <SEP> isomer <SEP> A) <SEP> 96-98
 <tb> 68 <SEP> <SEP> 0 <SEP> 7 = <SEP> isomer <SEP> B)
 <tb> <SEP> CCOCII <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (CHCl3):
 <tb> <SEP> coocs <SEP> 1740 <SEP> (s), <SEP> 1678
 <tb> 69 <SEP> <SEP> -CH2CN <SEP> 175-179
 <tb> 70 <SEP> NC-C-CONH- <SEP> CHO: <SEP> (sodium salt)
 <tb> <SEP> II <SEP>} <SEP> 240-245
 <tb> <SEP> N-OH <SEP> CCOH
 <tb> 71 <SEP> N <SEP> N-Ctt2C0N- <SEP> <SEP> 177-181
 <tb> <SEP> 72 <SEP> H2NCH2CONH- <SEP> <SEP> I.R.

   <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 1730, <SEP> 1665, <SEP> 1610
 <tb> 73 <SEP> o'mu <SEP> N- <SEP> CH2CCNH- <SEP> <SEP> 201-203
 <tb> 74 <SEP> N {CH2CONtt <SEP> <SEP> 198-199
 <tb> <SEP> Ch> 3
 <tb> 75 <SEP> (CH3) tCCONH- <SEP> <SEP> 187-188
 <tb> <SEP> * 1
 <tb> 76 <SEP> C / <SEP> - <SEP> C: -:

   <SEP> CONH- <SEP> <SEP> 193-196
 <tb> <SEP> L- <SEP> I
 <tb> <SEP> 'H2
 <tb> 77 <SEP> OfHCli2C0NH- <SEP> 179-185
 <tb> <SEP> 2
 <tb> 78 <SEP> H2NCONH- <SEP> <SEP> 190-194
 <tb> <SEP> 79 <SEP> ao- <SEP> CEXC0NH- <SEP> <SEP> 97-101
 <tb> <SEP> Nit
 <tb>
EMI20.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 80 <SEP> 9 <SEP> CR2ECH2COSH- <SEP> -CHOH <SEP> 154-157
 <tb> <SEP> CH3 <SEP> COOH
 <tb> <SEP> 81 <SEP> HN <SEP> zCH2c x <SEP> a <SEP> 182-185
 <tb> <SEP> o <SEP> 0 $ - <SEP> N "'.. CON
 <tb> <SEP> 82 <SEP> H <SEP> <SEP> 189-198
 <tb> <SEP> o
 <tb>
Example 83
A mixture of 320 mg of N, N-dimethylformamide and 780 mg of thionyl chloride was heated to 40 to 50 ° C. for 30 minutes and the excess thionyl chloride was distilled off from the mixture. The residue obtained was suspended in 10 ml of methylene chloride.

  370 mg of 4-hydroxyphenylglyoxylic acid were added to the suspension with cooling to −15 to −20 ° C., and the mixture was stirred for 15 minutes.



  After the reaction temperature of the mixture rose to -5 to - 100 ° C, the mixture was stirred for 10 minutes, whereby a clear solution containing 4-hydroxyphenylglyoxyloyl chloride was obtained. The solution was then cooled to -45 to -50 ° C. and a solution of 440 mg of triethylamine and 2 ml of methylene chloride was added dropwise over a period of 5 minutes. The reaction mixture was then stirred for 30 minutes. To this solution was added a temperature of - 45 to -500C at once, a solution was obtained by dissolving 470 mg of 3-aminolactacillanic acid and 1.2 g of N, O-bis (trimethylsilyl) acetamide in 10 ml of dry methylene chloride at room temperature with stirring for 1 h had been.



  The reaction mixture was stirred for 30 min and then for a further 1/2 h, the reaction temperature being allowed to slowly rise to room temperature after removal of the cooling bath. The methylene chloride was distilled off from the reaction mixture, and the residue obtained was dissolved in 20 ml of 5% aqueous sodium bicarbonate solution.



  The solution was washed twice with 10 ml of ethyl acetate.



  Then 50 ml of ethyl acetate was added to the solution, and the aqueous layer was adjusted to pH 1 with 5% hydrochloric acid with sufficient shaking. The ethyl acetate layer was separated and the aqueous layer extracted twice with 20 ml of ethyl acetate. The ethyl acetate layers were combined, washed with a saturated aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, whereby 460 mg of crude crystals of 3- (4-hydroxyphenylglyoxyloylamino) actacillanic acid were obtained. 760 mg of this product obtained in the same manner as described above was dissolved in 3 ml of ethyl acetate and the solution was subjected to column chromatography using silica gel.

  Various fractions containing the desired compound were obtained and collected by elution with ethyl acetate. The residue obtained by distilling off the solvent from the eluate was dissolved in acetone. Then, an acetone solution of sodium 2-ethylhexanate was added to the solution, whereby a solution of the sodium salt of the desired compound was obtained. Then the acetone was distilled off from this solution. The residue was pulverized by adding ether and the powder was collected by filtration and washed with acetone to give 170 mg of 3- (4-hydroxyphenylglyoxyloylamino) actacillanoic acid sodium salt, mp 220-225 ° C. The following compounds were obtained in essentially the same procedure as described above.
EMI21.1


 <tb>



  example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 84 <SEP> CHCONH- <SEP> -CH- <SEP> 0: - = <SEP> 187-191
 <tb> <SEP> OH <SEP> COOH
 <tb> <SEP> 85 <SEP> W - COCO?! 11- <SEP> <SEP> 203-204
 <tb> <SEP> 86 <SEP> CHsCOCONH- <SEP> a <SEP> 162-166
 <tb> <SEP> 87 <SEP> Cr <SEP> o0 ° 'CX <SEP> CU30COC <SEP> <SEP>> 3 <SEP> (sodium salt)
 <tb> <SEP> LR. <SEP> 300 300r, U20 <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 1735, <SEP> 1655, <SEP> 1595
 <tb> <SEP> 88 <SEP> CH <SEP> = CKCX <SEP> OoCOCONH- <SEP> 151-157
 <tb>
Example 89
0.453 g of sodium bicarbonate was dissolved in 10 ml of water and the solution was cooled to 50C. 0.427 g of 3-aminolactacillanic acid and then 10 ml
Given acetone. A solution of 0.38 g of butyric anhydride in 5 ml of acetone was then added dropwise to this solution over 5 minutes.

  G, 04 g of sodium bicarbonate were added to the reaction mixture. Then at 1/2 h
50C stirred. The acetone was distilled off from the reaction mixture, and the aqueous layer was washed with ether and then adjusted to pH 1 to 2 with 10% hydrochloric acid. The aqueous layer was washed twice with each
Extracted 30 ml of ethyl acetate. The extracts were combined with 50 ml of water and then with a saturated aqueous
Washed sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was concentrated, where at 112 mg crystals of 3-butyramidolactacillanic acid, mp.



   178 to 178.5 "C (dec.) Were obtained.



   Example 90
0.350 g of pivaloyl chloride was dissolved in 15 ml of methylene chloride, and to this solution was added a solution which had been prepared by dissolving 0.520 g of 4-meth oxyphenylglyoxylic acid and 0.290 g of triethylamine in 10 ml
Methylene chloride. The mixed solution was allowed to react for 1 hour to obtain a mixed anhydride solution with S methoxyphenylglyoxylic acid and pivalic acid. On the other hand, 2.3 g of N, O-bis (trimethylsilyl) acetamide was added to a suspension which was prepared by suspending 0.680 g of 3-aminolactacillanic acid in 10 ml of methylene chloride and this suspension - Was stirred for 1 hour at room temperature.

  The received
Solution became that obtained as described above
Solution of the mixed anhydride was added, and the reaction mixture was allowed to react for 2 hours, the reaction temperature being kept at -10 to -15 ° C.
Methylene chloride was distilled off from the reaction mixture, and the residue obtained was dissolved in ethyl acetate.



   The solution was washed successively with 5% hydrochloric acid and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, about 30 ml of diisopropyl ether was added to the residue, and the mixture was stirred for 1 hour. The precipitated material was collected by filtration to obtain 1.14 g of powder. This powder was dissolved in 30 ml of ethyl acetate, and the solution was treated with 0.11 g of activated carbon and filtered. The filtrate was concentrated to a volume of about 2 ml, and crystals were obtained by rubbing the wall of the vessel containing the solution.

  The crystals were collected by filtration and recrystallized from a small amount of ethyl acetate, 0.16 g of crystals of 3- (4-methoxyphenylglyoxyloylamino) -actacillanic acid, mp.



  178 to 181 "C (dec.). The following compounds were obtained in substantially the same procedure as described above.
EMI22.1


 <tb>



  example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> 91 <SEP> CH300CCH <SEP> (CH2) <SEP> 20oCssiC02J- <SEP> -CHoC! CX¯ <SEP> I.R. <SEP> v <SEP> cm-l <SEP> (CHCl3):
 <tb> <SEP> 1 <SEP> 1 <SEP> 1745, <SEP> 1667
 <tb> <SEP> NIICOCH <SEP> NIICCCH <SEP> CCCc: 3
 <tb> <SEP> 3
 <tb> <SEP> 'CI-ICONH- <SEP> / rC \
 <tb> 92 <SEP> S <SEP> | <SEP> -CH <SEP> 4 <SEP> 0.i <SEP> (sodium salt)
 <tb> <SEP> NHCOC, CH <SEP> | <SEP> r <SEP> 224-227
 <tb> <SEP> 7 <SEP> OO'ri
 <tb> HO- <SEP> CIICCNH- <SEP> <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 93 <SEP> 1 <SEP> 1760, <SEP> 1730, <SEP> 1680
 <tb> <SEP> y77 \ <SEP> 1760, <SEP> 1730, <SEP> 1680
 <tb> <SEP> NHC00CS <SEP> Y <SEP> \)
 <tb> 94 <SEP> EIOCEI; COSH- <SEP> <SEP> 171-176
 <tb> 95 <SEP> <SEP> CCcH <SEP> 2Cg2C () M¯ <SEP> <SEP> 157-161
 <tb> <SEP> N.M.R.

   <SEP> Ï <SEP> ppm <SEP> (CDCl3):
 <tb> <SEP> 1.95 <SEP> (3H, <SEP> s), <SEP> 2.25 <SEP> (2H,
 <tb> <SEP> m), <SEP> 3.15 <SEP> (1H, <SEP> d, <SEP> d, <SEP> J <SEP> =
 <tb> <SEP> / 5 \ <SEP> 2-0-G7a <SEP> 3Hz, <SEP> 6Hz), <SEP> 3.70 <SEP> (3H, <SEP> s),
 <tb> <SEP> 211 <SEP> OOCC <SEP> H <SEP> (CE <SEP>) <SEP> ¯0S <SEP> 3.89 <SEP> (3H, <SEP> s), <SEP> 3.78
 <tb> 96 <SEP> CII <SEP> 3OOCCH <SEP> s), <SEP> 0CX <SEP> s), <SEP> 3.89 <SEP> (3H, <SEP> s), <SEP> 3.96 <SEP> (3H,
 <tb> <SEP> NMCOCH3 <SEP> (2H, <SEP> I <SEP> 3 <SEP> ((1H, <SEP> (2H, <SEP> t, <SEP> J <SEP> = <SEP> 6Hz), <SEP> 4.70
 <tb> <SEP> COOC <SEP> (IH, <SEP> q, <SEP> J <SEP> = <SEP> 8Hz), <SEP> 4.92
 <tb> <SEP> (IH, <SEP> m), <SEP> 5.52 <SEP> (iH, <SEP> s),
 <tb> <SEP> 6.75 <SEP> (2H, <SEP> d, <SEP> J <SEP> = <SEP> 9Hz),
 <tb> <SEP> 6.86 <SEP> (2H, <SEP> d, <SEP> J <SEP> = <SEP> 9Hz),
 <tb> <SEP> 7.20 <SEP> (2H, <SEP> d,

    <SEP> J <SEP> = <SEP> 9Hz),
 <tb> <SEP> 7.45 <SEP> (2H, <SEP> d, <SEP> J <SEP> = <SEP> 9Hz)
 <tb> <SEP> N.M.R. <SEP> 8 <SEP> ppm <SEP> (CDCl3):
 <tb> <SEP> CU3O0CClt <SEP> (CH> <SEP> 0 <SEP> C-CO \ 'II- <SEP> 2.70 <SEP> (2H, <SEP> m), <SEP> 3.15 <SEP> (1H,
 <tb> <SEP> 1 <SEP> II <SEP> d, <SEP> d, <SEP> J <SEP> = <SEP> 3Hz, <SEP> 6Hz),
 <tb> <SEP> N-OCH <SEP> 3.7 <SEP> (1H, <SEP> m), <SEP> 3.75 <SEP> (6H,
 <tb> <SEP> O <SEP> / <SEP> \ <SEP> 3 <SEP> s), <SEP> 3.78 <SEP> (3H, <SEP> s), <SEP> 3.88
 <tb> <SEP> (3H, <SEP> s), <SEP> 3.94 <SEP> (2H, <SEP> m),
 <tb> 97 <SEP>, / <SEP> <SEP> 5.05 <SEP> (1H, <SEP> m), <SEP> 5.16 <SEP> (1H,
 <tb> <SEP> t, <SEP> t, <SEP> J <SEP> = <SEP> 6Hz), <SEP> 5.56 <SEP> (1H,
 <tb> <SEP> s), <SEP> 6 / <SEP> s), <SEP> 6.62 <SEP> (2H, <SEP> d, <SEP> J =
 <tb> <SEP> 9Hz), <SEP> 6.84 <SEP> (2H, <SEP> d, <SEP> J =
 <tb> <SEP> 9Hz), <SEP> 7.20 <SEP> (2H, <SEP> d,

    <SEP> J =
 <tb> <SEP> 9Hz), <SEP> 7.38 <SEP> (2H, <SEP> d, <SEP> J =
 <tb> <SEP> 9Hz), <SEP> 7.74 <SEP> (4H, <SEP> m)
 <tb> <SEP> -CII
 <tb> 98 <SEP> 1 <SEP> 182-185
 <tb> <SEP> COO; S
 <tb>
EMI23.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp. <SEP> (C) <SEP> (dec.)
 <tb> <SEP> 99 <SEP> C1 <SEP> 9 <SEP> 0CH <SEP> CONHC2CCNn ' <SEP> ¯CH <SEP> o <SEP> OM <SEP> 149-153
 <tb> <SEP> 2 <SEP> CCOH
 <tb> <SEP> 100 <SEP> HO-N = CH <SEP> OOCH2CON <SEP> <SEP> 150-155
 <tb> <SEP> 101 <SEP> NCE12COSH¯ <SEP> too <SEP> 176-180
 <tb> <SEP> 176-180
 <tb> <SEP> I <SEP> L
 <tb> <SEP> N <SEP> LSCiI, CONH
 <tb> <SEP> v
 <tb> <SEP> 0
 <tb> <SEP> N-N
 <tb> <SEP> 103 <SEP> 163-167
 <tb> <SEP> s <SEP> SCH2CONH
 <tb> <SEP> 104 <SEP> c2H5oCII = N-oCH2C0N- <SEP> 130-135
 <tb> <SEP> 105
 <tb> <SEP> <SEP> 179-181
 <tb> <SEP> O-CH2CON'H
 <tb> <SEP> 106 <SEP> o <SEP> CH <SEP> CY, COC.iHL'a2COiI- <SEP> COCNUC;

  ; R <SEP> CON
 <tb> <SEP> 2 <SEP> 2 <SEP> vcm- ' <SEP> (Nujol):
 <tb> <SEP> 2 <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 1740, <SEP> 1675, <SEP> 1610
 <tb> <SEP> 107 <SEP> 1 <SEP> 197.5-198
 <tb> <SEP> 197.5-198
 <tb> <SEP> 107 <SEP> 1 <SEP>
 <tb> <SEP> CH2CONH
 <tb> <SEP> 108 <SEP> CH3SCH <SEP> = <SEP> CHCONH- <SEP> <SEP> 174-177
 <tb>
Example 109 0.944 g of 3-aminolactacillanic acid was suspended in 60 ml of dry methylene chloride, and to this suspension were added 7 g of N, O-bis (trimethylsilyl) acetamide and 0.7 ml of N, N dimethylformamide, after which the mixture was stirred for 2 hours Was stirred at room temperature.

  On the other hand, a solution of 1.40 g of N-benzyloxycarbonyl-2- (2-thienyl) glycine and 0.485 was added dropwise to a solution of 0.523 g of ethyl chloroformate in 30 ml of dry methylene chloride over 7 minutes while cooling to -5 to -10 ° C. g of triethylamine was placed in 30 ml of dry methylene chloride, and this mixture was stirred at the same temperature for 20 minutes to obtain a mixed acid anhydride solution, to which solution the solution obtained above was added dropwise over about 20 minutes, and the reaction mixture The reaction mixture was then stirred at the same temperature for 3 hours, and then slowly allowed to rise to room temperature with stirring, and the reaction mixture was washed with dilute hydrochloric acid and water, and then dried.

  The solution was concentrated to give 1.40 g of crystals of 3- [2- (2-thienyl) -N-benzoyloxycarbonylglycine-amido] -actacillanic acid.



   IR absorption spectrum v cm- '(liquid film): 1730, 1710, 1650.



   The following compounds were prepared in essentially the same procedure as described above.
EMI24.1


 <tb> example <SEP> Rt <SEP> A <SEP> I.R.
 <tb> <SEP> 110 <SEP> i <SEP> CCC-NCì <SEP> NIi- <SEP> -CII <SEP> I.R. <SEP> V <SEP> cm-1 <SEP> (liquid film)
 <tb> <SEP> 2 <SEP> l <SEP> COOH <SEP> 1740, <SEP> 1710, <SEP> 1690, <SEP> 1650
 <tb> <SEP> 3 <SEP> CXX) H
 <tb>



   Example 111
500 mg of 2- (4-methoxyphenyl) -2-methoxyiminoacetic acid and 495 mg of N, N'-dicyclohexylcarbodiimide were dissolved in a mixture of 9 ml of chloroform and 3 ml of dioxane, and the solution was stirred under ice cooling for 1/2 hour. To the solution was suddenly added a solution which was prepared by dissolving 472 mg of 3-aminolactacillanic acid and 1.22 g of N, O-bis (trimethylsilyl) acetamide in 10 ml of chloroform. Then the reaction mixture was stirred for 4 h at room temperature. The solvent was distilled off from the reaction mixture, and an aqueous sodium bicarbonate solution and ethyl acetate were added to the residue. After the mixture was stirred, the aqueous layer was separated, adjusted to pH 1 to 2 with 10% hydrochloric acid and then extracted with ethyl acetate.

  The extract was washed with water and then dried. The solvent was distilled off from the extract, and ether was added to the residue, whereby crude crystals were obtained. The crystals were collected by filtration and washed with ether to give 150 mg of crystals of 3- [2- (4-methoxyphenyl) -2-methoxyiminoacetamido] actacillanic acid, mp 157-1610C (dec.).



   The following compound was obtained in substantially the same procedure as described above.
EMI24.2


 <tb>



  example <SEP> R1 <SEP> A <SEP> I. <SEP> R.
 <tb>



    <SEP> 112 <SEP> [7% 1 <SEP> WHCONI <SEP> CII + EI <SEP> (sodium salt)
 <tb> <SEP> MHCOCI1.0- <SEP> CO <SEP> 1730, <SEP> 1730.1660y
 <tb> <SEP> 2 <SEP> ¯¯¯ <SEP> COO! I <SEP> 1730, <SEP> 1660.1610
 <tb> <SEP> 02
 <tb>
Example 113
0.472 g of 3-aminolactacillanic acid was suspended in 10 ml of methylene chloride, and 1.22 g of N, O-bis (trimethylsilyl) acetamide were added to this suspension at room temperature. Then the solution was cooled to -15 "C.

  To the solution was added dropwise a solution of 935 mg of triethylammonium salt of the acid anhydride prepared from 2-phenyl-2-sulfoacetic acid and ethyl chloroformate in 10 ml of methylene chloride over 25 minutes, and the reaction mixture was continued at the same temperature for 1 hour and then another I stirred for 1/2 hour at room temperature. 50 ml of water was added to the reaction mixture and the aqueous layer was separated. The aqueous layer was washed with ethyl acetate and adjusted to pH 5-6 with an aqueous sodium bicarbonate solution. Then the solution was filtered. The filtrate was concentrated and the residue obtained was adsorbed on a column filled with 20 ml of non-ionic adsorbent resin (Amberlite XAD-4) which had been previously treated with methanol.



  The desired compound was eluted with water. The eluate was concentrated under reduced pressure and ethanol was added to the eluate, after which the solvent was distilled off from the eluate under reduced pressure.



  Ethanol was added to the residue, whereby crystals were obtained. The crystals were collected by filtration, whereby 120 mg of crystals of 3- (2-phenyl-2-sulfoacetamido) -actacillanoic acid disodium salt were obtained. In addition, the filtrate was concentrated and the resulting oily material was treated with acetone to obtain 0.45 g of powdery crystals of 3- (2-phenyl-2-sulfoacetamido) -actacillanoic acid disodium salt, mp. 144 to 1520C.



   The following compounds were obtained using essentially the same procedure:
EMI25.1


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. <SEP> (OC) <SEP> (dec.)
 <tb> <SEP> 114 <SEP> (3CHCoNH- <SEP> -CH-Oll <SEP> 180-183
 <tb> <SEP> OII <SEP> COOH
 <tb> <SEP> 115 <SEP> 2, <SEP> wN- <SEP> -CHtOH <SEP> 196-199
 <tb> <SEP> COOll
 <tb>
Example 116
652 mg of 2- (benzo [d] isoxazol-3-yl) -N-benzyloxycarbonylglycine and 202 mg of triethylamine were dissolved in 8 ml of dry tetrahydrofuran. To the solution was added 690 mg of 6-chloro-1 - (4-chlorobenzenesulfonyloxy) benzotriazole with stirring and ice-cooling, and the solution was then stirred at the same temperature for 3 hours.

  To this solution, while being kept under ice-cooling, was added a solution obtained by dissolving 472 mg of 3-aminolactacillanic acid and 202 mg of triethylamine in 10 ml of a mixed solvent of acetone and water (1: 1).



  The reaction mixture was stirred for 1 hour, and the solvent was then distilled off from the reaction mixture. 20 ml of water were added to the residue obtained. Then, ethyl acetate was added to the solution, and the solution was acidified by dropwise addition of 1N hydrochloric acid with shaking. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby a residue of 1.2 g was obtained.



  The residue was subjected to column chromatography using silica gel. It was eluted with ethyl acetate containing 10% methanol (500 ml) to give fractions with the desired compound.



  The residue obtained by concentrating the eluate was treated with ether, whereby 180 mg of crystals of 3 - [2- (Benzo Fd] isoxazol-3-yl) -N-benzyloxycarbonylglycinamido] -actacillanic acid, mp 159 to 1680C, were obtained.



   The following compound was made using essentially the same procedure:
EMI25.2


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. <SEP> (OC) <SEP> (dec.)
 <tb> <SEP> cJ.
 <tb>

 

    <SEP> 117 <SEP> CIIZC; IICONiI-2 <SEP> OI <SEP> 235-240
 <tb> <SEP> NNCOCClI2 <SEP> C1001I
 <tb> <SEP> II
 <tb>
Example 118
0.472 g of 3-aminolactacillanic acid was suspended in 20 ml of water, and 0.420 g of sodium bicarbonate was added to the solution. Then 20 ml of acetone was added to the solution and the solution was cooled to 0 to 5 ° C.



  Then 2 ml of acetone solution containing 0.286 g of phenyl isocyanate was added dropwise. Then the mixture was stirred at the same temperature for 2/2 h. The acetone was distilled off from the reaction mixture and the residue obtained was filtered to remove insoluble matter.



   The obtained aqueous solution was washed with ethyl acetate and then adjusted to pH 1 with 10% hydrochloric acid. The mixture was then extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crystalline residue. The residue was washed with diisopropyl ether and collected by filtration to give 0.470 g of crystals of 3- (N'-phenylureido) actacillanic acid, mp. 167 to 172 ° C.



   Example 119
0.38 g of guanidinocarbohydrazide dihydrochloride was dissolved in 2 ml of water, and to the solution was added 0.14 g of sodium nitrite with cooling to 0 to 5 "C. Then, the solution was stirred for 15 minutes to prepare a solution of guanidinocarbonyl azide. On the other hand 0.240 g of 3-aminolactacillanic acid was suspended in 7 ml of water, and 0.170 g of sodium bicarbonate was added to the suspension. The aqueous solution was cooled to 0 to 5 ° C., and the solution of guanidinocarbonylazide described above was added dropwise to the solution over the course of 10 minutes. The reaction mixture was then stirred for 2 hours. Then the reaction mixture was washed with 10 ml of ethyl acetate and concentrated until the remaining solution became transparent.

  Then the ethyl acetate with which the aqueous oily layer was saturated was completely distilled off, whereby crystals separated. The solution containing crystals was allowed to stand for a while, and then the crystals were collected by filtration to obtain 0.15 g of 3- (guanidinocarbonamido) actacillanic acid, mp 206 to 2100C.



   Example 120
A solution containing 1.42 g of 2-phenyl-N- (2,2,2-trichloroethoxycarbonyl) glycine and 15 ml of thionyl chloride was heated under reflux for 1 hour. The excess thionyl chloride was then distilled off from the solution under reduced pressure, and the residue obtained was dissolved in acetone.



  A solution containing 1 g of 3-aminolactacillanic acid, 0.9 g of sodium bicarbonate, 40 ml of water and 40 ml of acetone was added dropwise to the solution while cooling to 0 to 5 ° C. The acetone was distilled off from the reaction mixture under reduced pressure, and the remaining solution was washed with ethyl acetate, the solution was adjusted to pH 1 to 2 with 10% hydrochloric acid, and then extracted with ethyl acetate, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate.



  The solvent was distilled off from the ethyl acetate solution, and 2.1 g of the residue obtained was dissolved in ether. The ether solution was concentrated to give a residue. This residue was washed with diisopropyl ether, giving 1.69 g of crystals of 3- [2-phenyl-N- (2,2,2-trichloroethoxycarbonyl) -glycinamidoJ -actacillanic acid, mp. 130 to 1320C (dec.).



   The following compounds were made using essentially the same procedure.
EMI26.1


 <tb>



  example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 121 <SEP> CH2CONH- <SEP> C.wO.i <SEP> 234-236
 <tb> <SEP> CK <SEP> COOn
 <tb> <SEP> 122 <SEP> CH3C3 <SEP> oCH2CoN: - <SEP> <SEP> 106-109
 <tb> <SEP> a3
 <tb> <SEP> 123 <SEP> CF.CCNH- <SEP> <SEP> 139-143
 <tb> <SEP> S <SEP> h
 <tb> <SEP> v <SEP> CMCONX
 <tb> <SEP> 124 <SEP> CF'CCNH- <SEP> 1 <SEP> <SEP> (disodium salt)
 <tb> <SEP> 1 <SEP> <SEP> 209-214
 <tb> <SEP> COOH
 <tb> <SEP> /Ta.CC:I,COB
 <tb> <SEP> 125 <SEP> \ t <SEP> 2 <SEP> (sodium salt)
 <tb> <SEP> NO2 <SEP> 116
 <tb>
EMI27.1


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> CH
 <tb> <SEP> 126 <SEP> C2CONh'- <SEP> ¯CH-CH-CX <SEP> 106-109
 <tb> <SEP> -CP-CH-CH3
 <tb> <SEP> COLOR
 <tb> <SEP> 127 <SEP> <SEP> -Ye <SEP> RO2 <SEP> 151-153
 <tb> <SEP> CCCC: -: 3
 <tb> <SEP> 128 <SEP> <SEP> ¯C.v.

   <SEP> 4 <SEP> CE <SEP> 161-162
 <tb> <SEP> CSY; i
 <tb> <SEP> CR,
 <tb> <SEP> 129 <SEP> aa <SEP> I
 <tb> <SEP> 129 <SEP> OCN2CON <SEP> C = CCIC3: -: 3 <SEP> 155.5-156.5
 <tb> <SEP> CCOCU
 <tb> <SEP> Cl
 <tb> <SEP> 130 <SEP> .C " <SEP> CO \ 'H- <SEP> H <SEP> OH <SEP> I.R. <SEP> v <SEP> cm-1
 <tb> <SEP> .2 <SEP> 1 <SEP> (liquid film)
 <tb> <SEP> Cl <SEP> 3270, <SEP> 1760
 <tb> <SEP> COOCN3 <SEP> 1735, <SEP> 1665
 <tb>
Example 131
700 mg of 3-aminolactacillanic acid were suspended in 15 ml of dry methylene chloride and 3.6 g of N, O-bis (trimethylsilyl) acetamide were added to the suspension. Then the mixture was stirred for 3 hours. The solution was cooled to -50 to -400C, and 630 mg of 2- (2-pyridyloxy) acetyl chloride hydrochloride was added to this solution all at once, and the reaction mixture was stirred at the same temperature for 20 minutes.

  Then the reaction temperature was allowed to slowly rise to -100 ° C over 40 minutes and the reaction mixture was stirred at the same temperature for 1 hour and then for an additional hour with ice cooling. The methylene chloride was distilled off from the reaction mixture, and 25 ml of pentagonal aqueous sodium bicarbonate solution and 30 ml of ethyl acetate were added to the residue. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was adjusted to pH 3 with 10% hydrochloric acid with ice cooling. Then the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was separated and the remaining aqueous layer was adjusted to pH 1 to 2 with 1OC / c hydrochloric acid.



  Then the aqueous solution was extracted with ethyl acetate several times. These ethyl acetate layers and the ethyl acetate layer obtained as described above were combined, and the solution was washed with a saturated sodium chloride aqueous solution and then dried over what was free magnesium sulfate. The solvent was distilled off from the ethyl acetate layer, and 330 mg of the residue obtained was pulverized with ether. The powder was washed with acetone, 130 g of crystals of 3- [2- (2-pyridyloxy) acetamido] actacillanic acid, mp.



   192.5 to 1 930C (dec.).



   Example 132
A mixture of 292 mg of N, N-dimethylformamide and 710 mg of thionyl chloride was heated to 500C for 30 min. The excess thionyl chloride was distilled off from the mixture, whereby a residue was obtained. The residue was washed with ether. 7 ml of methylene chloride were added to the residue. Then the solution was cooled to 0 to 50 ° C, after which the solution was added dropwise, which was prepared by dissolving 455 mg of 2- (5,6-dihydro-2H-pyran-3-yl) glycolic acid in 5 ml of methylene chloride. A solution of 600 mg of triethylamine in 5 ml of methylene chloride was added dropwise to the reaction mixture over the course of 10 minutes while cooling to -50 ° C., and the solution was stirred at the same temperature for 30 minutes.

  The solution was added all at once to a mixture of 472 g of 3-aminolactacillanic acid, 1.22 g of N, O-bis (trimethylsilyl) acetamide and 10 ml of methylene chloride, which had been stirred for 2 hours at room temperature. The reaction mixture was stirred at -50 "C for 2 hours and then continued for 2 hours while allowing the reaction temperature to slowly rise to OOC. The solvent was distilled off from the reaction mixture, and an aqueous solution of sodium bicarbonate and ethyl acetate was added to the remaining solution. The resultant aqueous solution was adjusted to pH 1 to 2 with 10ax hydrochloric acid and the solution was then extracted with ethyl acetate, the extract was washed with water and then dried over anhydrous magnesium sulfate.

  Then the solvent was distilled off to obtain 80 mg of crystals of 3- [2- (5,6-dihydro -2H-pyran-3-yl) glycolamido] actacillanic acid.



   IR absorption spectrum: v cm-l (Nujol): 1740, 1685, 1660.



   Example 133
A mixture of 576 mg of 2- (2-bromoacetamido) -2-phenylacetic acid, 200 mg of triethylamine, a drop of N, N dimethylbenzylamine and 8 ml was added dropwise to a solution of 10 ml of methylene chloride containing 216 mg of ethyl chloroformate while cooling to -30 ° C. Methylene chloride was added and the reaction mixture was then stirred at the same temperature for 30 minutes A mixture of 472 mg of 3-aminolactacillanic acid, 1.2 g of N, O-bis (trimethylsilyl) acetamide, 10 ml of methylene chloride and 1 ml of N, N -Dimethylformamide, which had been stirred at room temperature for a while and cooled to 00C, was added to the reaction mixture all at once while the temperature of the reaction mixture was kept at -30 ° C.

  The reaction mixture was stirred at -25 "C for 2 h and then for an additional hour while allowing the reaction temperature to slowly rise to 00 C. The reaction mixture was concentrated and to the residue obtained was added ethyl acetate and water. Then the mixture was added with 10% Hydrochloric acid adjusted to pH 1 to 2. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue obtained was washed with diisopropyl ether and then pulverized with ethyl acetate, whereby 400 mg of 3- [2- (2-bromoacetamido) -2-phenylacetamido] -actacillanoic acid were obtained. In addition, 188 mg of the same compound were obtained from the mother liquor. The overall yield was 588 mg, mp 156 to 161 "C (dec.).



   The following compounds were made using essentially the same procedure.
EMI28.1


 <tb>



  example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 134 <SEP> oa-C = N-OC, COK- <SEP> -Cn <SEP> OH <SEP> (sodium salt)
 <tb> <SEP> I <SEP> 1 <SEP> 5 / <SEP> 157-160
 <tb> <SEP> COOC2H5 <SEP> CCCII
 <tb> <SEP> 135 <SEP> n <SEP> CHCONH- <SEP> <SEP> (sodium salt)
 <tb> <SEP> 183-187
 <tb> <SEP> CONH
 <tb> <SEP> / 7a-CHCONK
 <tb> <SEP> 136 <SEP> 7 / <SEP> 1 <SEP> <SEP> 103-107
 <tb> <SEP> CCCC2F5
 <tb> <SEP> 137 <SEP> CYCOH
 <tb> <SEP> 137 <SEP> ol <SEP> ss <SEP> <SEP> 211-217
 <tb> <SEP> Nh'CCCII <SEP> 2C1
 <tb> <SEP> C1F.CON. <SEP> 138 <SEP> r <SEP> <SEP> I.R.

   <SEP> v <SEP> cm-l <SEP> (Nujol)
 <tb> <SEP> S-CEf <SEP> 1740, <SEP> 1720, <SEP> 1665
 <tb> <SEP> s <SEP> 3
 <tb> <SEP> 0
 <tb> <SEP> Q3-CI! COfl
 <tb> <SEP> 139 <SEP> CPCONH- <SEP> 1 <SEP> <SEP> 77-81
 <tb> <SEP> NHCOCH2O <SEP> n <SEP> Cl
 <tb> <SEP> NO2
 <tb> <SEP> IC-Q- <SEP> Ch'CONH <SEP> 140 <SEP> sj <SEP> <SEP> 147-150
 <tb> <SEP> NEICOCH2Br
 <tb>
Example 141
A mixture of 537 mg of N-pheylinidinodiacetic acid, 495 mg of N, N'-dicyclohexylcarbodiimide, 9 ml of chloroform and 3 ml of dioxane was stirred under ice-cooling for 1 l for 2 h. The insoluble portions were filtered off. and a mixture of 472 mg of 3-aminolactacillanic acid, 10 ml of methylene chloride and 1.2 g of N, O-bis (trimethylsilyl) - acetamide was added to the filtrate all at once. Then the reaction mixture was stirred for 4 h at room temperature.

  The solvent was distilled off and the residue was dissolved in ethyl acetate. An aqueous sodium bicarbonate solution was added to the solution.



  The mixture was adjusted to pH 4 with 10X hydrochloric acid and the ethyl acetate layer was separated. The remaining aqueous layer was adjusted to pH 1-3 with 10% hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The layers of ethyl acetate were combined, washed with water and dried. Then the solvent was distilled off, whereby 260 mg of crystals of 3- (N-carboxymethyl-N-phenylglycinamido) -actacillanic acid, mp. 142.5 to 145 C (dec.), Were obtained.



   Example 142
A solution prepared by dissolving 300 mg of 2 - [4- (3-bromopropoxy) phenyl] acetic acid and 300 mg of thionyl chloride in 2 ml of chloroform was heated under reflux for 2 hours. The solvent and excess thionyl chloride were distilled off, and the residue obtained was dissolved in 1 ml of dry acetone. The solution was added dropwise with cooling to 0 to 50 ° C and stirring to a solution prepared by dissolving 240 mg of 3-aminolactacillanic acid and 210 mg of sodium bicarbonate in a mixture of 10 ml of water and 10 ml of acetone. The reaction mixture was stirred at the same temperature for 45 minutes. The acetone was distilled off from the reaction mixture, and 30 ml of ethyl acetate was added to the remaining aqueous layer. The mixture was adjusted to pH 1 with 10% hydrochloric acid.

  The ethyl acetate layer was separated, and the aqueous layer was then extracted with 20 ml of ethyl acetate. The ethyl acetate layers were combined and washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off and 510 mg of residue were washed with ether, giving 420 mg of crystals of 3- [2- (4- (3- bromopropoxy) phenyl} acetamidoj-lactacillanic acid, mp 120 to 1230 ° C. (dec.) , were obtained.



   The following compounds were obtained following essentially the same procedure.
EMI29.1


 <tb>



  example <SEP> R1 <SEP> A <SEP> Fp. <SEP> (OC) <SEP> (dec.)
 <tb> <SEP> 143 <SEP> .SC3CH2CCNII- <SEP> CHECH <SEP> - <SEP> 142.5-144
 <tb> <SEP> COOH
 <tb> <SEP> 144 <SEP> N3 <SEP> (CH2) <SEP> 3OH2C * 'r¯ <SEP> <SEP> 113-116
 <tb> <SEP> 145 <SEP>> N¯CS2CON <SEP> <SEP> 128-132
 <tb> <SEP> No>
 <tb> <SEP> 146 <SEP> A <SEP> CH2CCC¯N * <SEP> (Cn2) <SEP> 3 < <SEP> 2C <SEP> NS <SEP> a <SEP> 142-146
 <tb> <SEP> CCC \ rH <SEP> I.R <SEP> v <SEP> cm- '
 <tb> <SEP> NH- <SEP> / Tn
 <tb> <SEP> 147 <SEP> too <SEP> I <SEP> <SEP> a <SEP> (Nujol):
 <tb> <SEP> mc <SEP> ll <SEP> J <SEP> 1738, <SEP> 1680,
 <tb> <SEP> Well <SEP> 1618
 <tb>
Example 148
A mixture of 472 mg of 3-aminolactacillanic acid, 1.2 g of N, O-bis (trimethylsilyl) acetamide, 10 ml of methylene chloride and 1 ml of N, N-dimethylformamide was stirred at room temperature for 1 hour.

  The solution was cooled to 0 to 50C, and then 3 ml of methylene chloride solution containing 548 mg of hexadecanoyl chloride was added dropwise. Thereafter, the reaction mixture was allowed to react at the same temperature for 1/2 hour and further at room temperature for 30 minutes. The reaction mixture was concentrated, and ethyl acetate and water were added to the remaining solution. Then the mixture was adjusted to pH 1-2 with 10% hydrochloric acid. The separated ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. The solution was concentrated to give 0.95 g of crude 3-hexadecanoylaminolactacillanic acid.

  In addition, 600 mg of the product was subjected to column chromatography using silica gel and by eluting with ethyl acetate. The solvent was distilled off from the eluate to give 110 mg of the desired purified compound having an mp. Of 157 to 161 "C (dec.).



   Example 149
To a solution of 400 mg of 2- [N- (2-thenylidene) amino oxyj-2-phenylacetic acid, 155 mg of triethylamine and 10 ml of tetrahydrofuran was added dropwise a solution for 5 minutes while cooling to -2 to 00C, which was prepared was by dissolving 184 mg of pivaloyl chloride in 3 ml of tetrahydrofuran. Then the mixture was stirred for 30 minutes. A solution of 320 mg of 3-aminolactacillanic acid, 825 mg of N, O-bis (trimethylsilyl) acetamide and 10 ml of methylene chloride was added to this solution all at once while cooling to -30 ° C., and the reaction mixture was left to react for 2 hours, allowing the reaction temperature to slowly rise to 100C.

  The solvent was distilled off from the reaction mixture, and an aqueous sodium bicarbonate solution and ethyl acetate were added to the remaining solution. The aqueous layer was separated, adjusted to pH 1 to 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and dried. The solvent was then distilled off, leaving a residue of
300 mg was obtained. This residue was dissolved in acetone. Then, sodium 2-ethylhexanate was added to this solution, whereby 160 mg of crystals of 3- [2- (N- (2-thenylidene) aminooxy} -2-phenylacetamidoj -actacillanoic acid sodium salt were obtained.



   IR absorption spectrum v cm- '(Nujol): 1730, 1650, 1600.



   Example 150
355 mg of 3-aminolactacillanic acid, 0.92 g of N, O-bis (trimethylsilyl) acetamide and 0.23 ml of N, N-dimethylformamide were added to 7 ml of methylene chloride and the solution was stirred at room temperature for 2 hours. On the other hand, 380 mg of 2- (2-nitrophenoxy) -2-phenoxyacetic acid, 132 mg of triethylamine and 2 drops of N, N-dimethylbenzylamine were dissolved in 10 ml of methylene chloride and the solution was cooled to -30 ° C. 141 mg was added dropwise to the solution Ethyl chloroformate was added and the mixture was stirred at the same temperature for 40 minutes, to which solution the solution prepared as described above was added rapidly and the reaction mixture was stirred at -40 "C to -20" C for 5/2 hours.

  The solvent was distilled off from the reaction mixture under reduced pressure, and to the residue was poured ethyl acetate and an aqueous sodium bicarbonate solution. The aqueous layer that separated was adjusted to pH 1 to 2 with 10% hydrochloric acid. Then the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then the solvent was distilled off from the solution. 540 mg of residue was dissolved in a small amount of acetone and sodium 2-ethylhexanate was added.

  Ether was added to the solution and the precipitated crystals were collected by filtration and washed with a mixed solvent of ether and acetone, 380 mg of crystals of 3- [2- (2-nitrophenoxy) -2-phenoxyacetamido] -actacillanoic acid sodium salt, mp 169 to
1720C (dec.).



   The following compounds were obtained using essentially the same procedure:
EMI31.1


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP>.
 <tb> 151 <SEP> N'HCOCO <SEP> N <SEP> COOR <SEP> H <SEP> OH <SEP> 143-146
 <tb> <SEP> NZIC <SEP> - <6 <SEP> 1 <SEP> OH
 <tb> <SEP> CCOH
 <tb> 152 <SEP> 1 <SEP> C1HCONH- <SEP> <SEP> 115-118
 <tb> <SEP> CON <SEP> (C <SEP> w2) <SEP> 2N <SEP> oCOCH24
 <tb> 153 <SEP> Q ± cCCH2 <SEP> SCF2CONH <SEP> <SEP> 3 <SEP> COR- <SEP> 130-135
 <tb> <SEP> 154 <SEP> \ - <SEP> CHCOKH154 <SEP> I <SEP> / rn <SEP> 111-116
 <tb> <SEP> NECO <SEP> (CH2) <SEP> 5NHCCOCH2
 <tb> <SEP> 5 <SEP> L <SEP> t- /
 <tb> 155 <SEP> C1HCCNX- <SEP> <SEP> (sodium salt)
 <tb> <SEP> NHCOC2- <SEP> S <SEP> 221-224
 <tb> <SEP> NH ( <SEP> 221-224
 <tb> 156 <SEP> BYCbCXISD <SEP> A <SEP> too <SEP> 160-164
 <tb> <SEP> ag-CHCONH
 <tb> <SEP> I
 <tb> <SEP>

   NHCOCEI-C / <SEP> ¯y
 <tb> 157 <SEP> l <SEP> EC =; Z <SEP> D <SEP>. <SEP> 112-116
 <tb> <SEP> 0
 <tb> <SEP> FC1
 <tb> <SEP> C1
 <tb> 158 <SEP> OrHCECOSK- <SEP> + <SEP> t <SEP> 122-124
 <tb> 159 <SEP> <SEP> 77-81
 <tb> <SEP> 159 <SEP> CISCONE¯ <SEP> <SEP> 77-81
 <tb> <SEP> s (crr2) <SEP> .h'HCoCHiO - (/
 <tb> <SEP> - <SEP>, Y
 <tb> <SEP> C = CONK <SEP> AcOtlz
 <tb> <SEP> CII
 <tb> 160 <SEP> 1 <SEP> l <SEP> 3 <SEP> <SEP> 130-134
 <tb> <SEP> NBC6CK20
 <tb>
EMI32.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp.

   <SEP> (0C) <SEP> (dec.)
 <tb> <SEP> CIiCONH- <SEP> 0H
 <tb> 161 <SEP> -Cli <SEP> 135-137
 <tb> <SEP> .NHCCCH2O <SEP> | <SEP> 1
 <tb> <SEP> P <SEP> COOH
 <tb> <SEP> CCOH
 <tb> <SEP> CKCOSH
 <tb> 162 <SEP> X <SEP> / 75 \ <SEP>> <SEP> / rn <SEP> 127-130
 <tb> <SEP> NHCOCEiiO <SEP> y
 <tb> <SEP> L
 <tb> <SEP> S <SEP> NHCOCEXCOW
 <tb> 163 <SEP> 1 <SEP> <SEP> (sodium salt)
 <tb> <SEP> 183-188
 <tb> <SEP> NHCOCH2C /
 <tb> <SEP> eG <SEP> CHCONES
 <tb> <SEP> 164 <SEP> 1 <SEP> 27n <SEP> j \ <SEP> <SEP> (sodium salt)
 <tb> <SEP> 0 <SEP> y <SEP> 192-197
 <tb> <SEP> 'HCOCH3
 <tb> <SEP> DCHC NH
 <tb> 165 <SEP> 1 <SEP> NHCOC1H <SEP> <SEP> 165-169
 <tb> <SEP> NIICCOCH2 <SEP> CCl3
 <tb> 166 <SEP> CHCOWiX- <SEP> D <SEP> 118-123
 <tb> <SEP> NIlCCCCCC2IIS
 <tb> 167 <SEP> N <SEP> CHC RH <SEP> - <SEP> <SEP> 149-154
 <tb> <SEP> N'EiCOCONEiCH2
 <tb> <SEP> C1liCONH
 <tb> 168 <SEP> I <SEP> <SEP> 107-111
 <tb>

    <SEP> NHCOCH2O
 <tb> <SEP> CliCONIt
 <tb> 169 <SEP> 1 <SEP> / 7T \ <SEP> <SEP> 151-155
 <tb> <SEP> NECOC.S20S02 <
 <tb>
EMI33.1


 <tb> example <SEP> R1 <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> CHCOSH¯ <SEP>.
 <tb> <SEP> 170 <SEP> 1 <SEP> / 7n <SEP> OH <SEP> 191-195
 <tb> <SEP> NFCCCH <SEP> 20 <SEP> 1
 <tb> <SEP> Cr: 0 <SEP> COOH
 <tb> <SEP> SC <SEP> SCOSH <SEP>
 <tb> <SEP> 171 <SEP> 1 <SEP> <SEP> 125-130
 <tb> <SEP> SHCOCHSO <SEP> w
 <tb> <SEP> CCC <SEP> 2H5
 <tb> <SEP> 172 <SEP> C: -tC0Nh'- <SEP> 154-159
 <tb> <SEP> LJ <SEP> 1 <SEP> n
 <tb> <SEP> NtICOCX20oCOo
 <tb> <SEP> C1HCONH
 <tb> <SEP> 173 <SEP> NHCOCH, O <SEP> too <SEP> 125-130
 <tb> <SEP> -CHCONH
 <tb> <SEP> 174 <SEP> NHCOCH2O <SEP> 143-148
 <tb> <SEP> COO <SEP> e
 <tb>



   Example 175
260 mg of 2- [4- (3- (4-nitrophenylthio) propoxy) pheny - acetic acid and 300 mg of thionyl chloride were dissolved in 10 ml of chloroform and the solution was refluxed for 2 hours. The chloroform and the excess thionyl chloride were distilled off from the reaction mixture under reduced pressure, and the residue obtained was dissolved in 1 ml of acetone. The acetone solution was added dropwise to a solution of 180 mg of 3-aminolactacillanic acid, 160 mg of sodium bicarbonate, 5 ml of water and 5 ml of acetone while cooling to 0 to 5 ° C., and the reaction mixture was then stirred at the same temperature for 45 minutes.



  The acetone was distilled off from the reaction mixture under reduced pressure, and 40 ml of ethyl acetate was poured into the residue obtained. Then the solution was adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was deposited and the remaining aqueous layer was extracted with 20 ml of ethyl acetate. The ethyl acetate layers were combined, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, 400 mg of crystals of 3 - <2- [4- {3- (4-Nitrophenylthio) -propoxy} -phenyl] -acetamido> -lactacillanoic acid, mp 142 to 146 "C (dec.).



   Example 176
A solution of 351 mg of 2- [2- (2-naphthoxy) acetamido oxy] -2-phenylacetic acid and 101 mg of triethylamine in 10 ml of dry tetrahydrofuran was cooled to -100 ° C., and a solution of 120 mg was added dropwise to this solution Pivaloyl chloride in 5 ml of dry tetrahydrofuran. The mixture was stirred at the same temperature for 1 hour. The solution was cooled to -30 ° C., and 236 mg of 3-aminolactacillanic acid and 600 mg of N, O bis- (trimethylsilyl) -acetamide were added all at once to this solution in 5 ml of dry methylene chloride. The reaction mixture was stirred at -10 for 1 h "C and stirred at 00C for 1 h.

  The solvent was distilled off from the reaction mixture under reduced pressure, and a saturated aqueous sodium bicarbonate solution was poured into the residue. The aqueous solution was washed with ethyl acetate, adjusted to pH 1 to 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution and the residue obtained was pulverized with ether, 340 mg of crystals of 3- [2- (2- (2-naphthoxy) acetamidooxy -2-phenylacetamido] - -actacillanic acid, mp 109 bis 112 "C (dec.).



   Example 177
455 mg of 2- 2-oxo3- (2-phenylacetamido) - 1-azetidinyl] -3- -methyl-butyric acid, 151 mg of triethylamine and 2 drops of N, N-dimethylbenzylamine were added to 10 ml of methylene chloride and the solution was made up to - Cooled to 30 ° C. To the solution was added dropwise a solution of 163 mg of ethyl chloroformate in 5 ml of methylene chloride. The solution was cooled to -40 ° C. and to the solution was added all at once a solution which had been prepared by dissolving 389 mg of 3-aminolactacillanic acid, 1 g of N, O-bis - (trimethylsilyl) acetamide and 0.25 ml of N, N-dimethylformamide in 10 ml of methylene chloride and then stirring the solution at room temperature for 3 hours. The reaction mixture was allowed to react with stirring for 1/2 hour.

  The solvent was distilled from the reaction mixture, and ethyl acetate and an aqueous sodium bicarbonate solution were added to the residue. Then the aqueous layer was separated. The obtained aqueous layer was adjusted to pH 1 to 2 with 1N hydrochloric acid, and extracted by adding ethyl acetate to the solution. The ethyl acetate layer was separated and the remaining aqueous layer was also extracted with ethyl acetate. These ethyl acetate layers were combined, washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate.

  The solvent was distilled off from the solution, and 480 mg of the powder obtained was washed with ether, giving 359 mg of crystals of 3- [2- {2-oxo-3- (2-phenylacetamido) -1-aztidiriyl} -3-me - - Thylbutyramido] -actacillanoic acid, mp. 160 to 164 "C (dec.), were obtained.



   The following compounds were made using essentially the same procedure:
EMI34.1


 <tb> example <SEP> Rs <SEP> A <SEP> Fp. <SEP> (0C) <SEP> (dec.)
 <tb> <SEP> CHCONII
 <tb> <SEP> 178 <SEP> I <SEP> N, RCOCH2S <SEP> -Cli <SEP> 141-146
 <tb> <SEP> 178 <SEP> NIICOC <SEP> 1
 <tb> <SEP> COOI <SEP> t <SEP> COOH
 <tb> <SEP> 3H
 <tb> <SEP> 179 <SEP> NHCOCH, - <SEP> 137-142
 <tb> <SEP> SOz <SEP> <
 <tb> <SEP> BCHC SH
 <tb> <SEP> 180 <SEP> NHCOCH <SEP> "Qg: C1 <SEP>. <SEP> 148-153
 <tb> <SEP> CON02
 <tb> <SEP> CHCON '} I¯
 <tb> <SEP> 181 <SEP> sr; coca-o-c ( <SEP>. <SEP> 102-105
 <tb> <SEP> <SEP> 102-105
 <tb> <SEP> 181 <SEP> N'n'C0CH <SEP> oD
 <tb> <SEP> CHCONH
 <tb> <SEP> 182 <SEP> NBCOCH <SEP> 158-161
 <tb> <SEP> 1
 <tb> <SEP> 0m
 <tb>
EMI35.1


 <tb> example <SEP> Rt <SEP> A <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> CKCONH
 <tb> <SEP> 1.
 <tb>



    <SEP> ERCOCH-O <SEP>> <SEP> OH
 <tb> <SEP> 183 <SEP> 1 <SEP> 1 <SEP> COOH <SEP> 135-139
 <tb> <SEP> COOH
 <tb> <SEP> CHC NH¯ <SEP> N? \ N
 <tb> <SEP> 184 <SEP> l <SEP> 11 <SEP>. <SEP> n <SEP>> <SEP> 170-174
 <tb> <SEP> U'HCOCHZ
 <tb> <SEP> CHCO> JY;
 <tb> <SEP> 185 <SEP> HCOCV2 <SEP> < <SEP> C1 <SEP> 158-162
 <tb> <SEP> KIICOC: <SEP> 7 ± Cl
 <tb> <SEP> CO <SEP> NE; COCH2Br
 <tb> <SEP> 4a-CEICO
 <tb> <SEP> 186 <SEP> C1HCONTj <SEP> 118-121
 <tb> <SEP> NHCO-C <SEP> OCH3
 <tb> <SEP> ii
 <tb> <SEP> N¯OCH <SEP> 2
 <tb> <SEP> b <SEP> C1HCONH
 <tb> <SEP> 187 <SEP> NL'HCOCH2OCl <SEP> 141-144
 <tb> <SEP> COs
 <tb>
Example 188
0.320 g of 2-methyl-5,6-dihydro-1,4-oxathiin-3-carboxylic acid was dissolved in 10 ml of chloroform. A dry solution of 5 ml of methylene chloride containing 7 ml of thionyl chloride was added to the solution.

  The mixture was refluxed for 4 hours and then concentrated to give a solution of an acid chloride of 2-methyl-5,6-dihydro-1,4-oxathiin-3-carboxylic acid. On the other hand, 0.236 g of 3-aminolactacillanic acid was suspended in 20 ml of dry methylene chloride, and 1.5 g of N, O-bis - (trimethylsilyl) -acetamide was added to the suspension. Then the mixture was stirred at room temperature for 4 hours. To the obtained solution was added dropwise, while cooling to -5 to 00C, the acid chloride solution prepared as described above, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 50 minutes.

  The reaction mixture was concentrated under reduced pressure to obtain a residue. Ethyl acetate and an aqueous sodium bicarbonate solution were added to the residue, and the mixture was stirred sufficiently, after which the aqueous layer was separated. The aqueous layer was washed with ether and adjusted to pH 1 to 2 with dilute hydrochloric acid. Then the solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a powder. 5 ml of hot ethyl acetate was added to the powder, and insolubles were removed from the solution by filtration. In this way, 240 mg of crude 3- (2-methyl-5,6-dihydro-1,4-oxathiin-3-carbonylamino) -lactacil- lanoic acid were obtained.

  This product was recrystallized from acetone to give 172 mg of a purified desired compound. Mp 172.5 to 175.0 C (dec.).



   Example 189
0.708 g of 3-aminolactacillanic acid was suspended in 20 ml of dry methylene chloride. To the suspension was added 2 g of N, O-bis (trimethylsilyl) acetamide and the mixture was stirred for a while to dissolve it. On the other hand, 1.212 g of N- [4- (3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl) butyrylj-succiuimide was dissolved in 15 ml of dioxane and the solution was cooled to 0 to 5 "C. To this solution, the solution obtained above was added dropwise, and the mixture was stirred at the same temperature for 6 hours, and the reaction mixture was concentrated under reduced pressure to obtain a residue, to which an aqueous 5% sodium bicarbonate solution and ethyl acetate were added given.

  The aqueous layer was separated and washed twice with ethyl acetate.



  The aqueous layer was adjusted to pH 1-2 with dilute hydrochloric acid and then extracted with ethyl acetate.



  The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution, and 0.470 g of the oily material was subjected to column chromatography using 10 g of silica gel. It was eluted with a mixture of ethyl acetate and methanol (50: 1 by volume) and the fractions containing the desired compound were collected. These fractions were combined and the solvent was distilled off from the solution to obtain 0.1 g of 3- [4- (3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl) -butyramidoj -actacillanoic acid .



   IR absorption spectrum: v cm-1 (Nujol): 1730, 1720,
1700 to 1680, 1650.



   Example 190
472 mg of 3-aminolactacillanic acid, 458 mg of 2- (2-propionylphenoxy) acetic acid and 238 mg of ethyl chloroformate were treated in essentially the same manner as described in Example 109, with 40 mg of 3- [2- (2-propionylphen oxy) -acetamido] 4actacillanoic acid, mp. 114 to 118 "C (dec.).



   Example 191
0.236 g of 3-aminolactacillanic acid, 0.610 g of 2- [4- {4-chloro-N- (2,2,2-trichloroethoxycarbonyl) anilinomethyl} phenoxy] -2-methylpropionic acid and 7 ml of thionyl chloride were essentially in the same way, treated as described in Example 120, 450 mg of 3- [2- {4- <4-Chloro-N- (2,2,2-tri chloroethoxycarbonyD-anilinomethyl> -phenoxy -2-methylpropionamidol-lactacillanic acid, mp. 76 to 82 "C (dec.)).

 

   Example 192
25 mg of 10% palladium-on-carbon was added to a solution of 220 mg of 3- (6-benzyloxycarbonylaminohexanamido) -actacillanic acid in 10 ml of methanol and the theoretical volume of hydrogen gas was passed into the mixture for 2 hours at normal temperature and normal pressure. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with acetone, washed with acetone and filtered to give 100 mg of 3- (6-aminohexanamido) -actacillanic acid, mp. 118 to 122 "C (dec.).



   The following compounds were made in essentially the same manner as described above:
EMI36.1


 <tb> R <SEP> i <SEP> R <SEP> 1coli
 <tb> <SEP> L2 <SEP>) D {oIIoOlz1 <SEP> 3
 <tb> <SEP> CII- "
 <tb> <SEP> (rxx:
 <tb>
EMI37.1

 example <SEP> R12 <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> <SEP> R13 <SEP> R12, <SEP> R13 <SEP> Fp. (C) <SEP> (dec.)
 <tb> 193 <SEP> # <SEP> -H <SEP> H2NCH2CO- <SEP> like <SEP> I.R.

   <SEP> @ <SEP> cm-1
 <tb> <SEP> R13 <SEP> the <SEP> Ver <SEP> (Nujol):
 <tb> <SEP> bond <SEP> 1730, <SEP> 1665,
 <tb> <SEP> (XIII) <SEP> 1610
 <tb> 194 <SEP> # <SEP> <SEP> # <SEP> <SEP> 193-196
 <tb> 195 <SEP> # <SEP> <SEP> <SEP> 205-209
 <tb> 196 <SEP> # <SEP> <SEP> # <SEP> <SEP> 179-185
 <tb> 197 <SEP> # <SEP> <SEP> <SEP> I.R.v <SEP> cm-1
 <tb> <SEP> (Nujol):
 <tb> <SEP> 1730, <SEP> 1660,
 <tb> <SEP> 1600
 <tb> 198 <SEP> # <SEP> <SEP> CH3NHC2CO- <SEP> <SEP> I.R.

   <SEP> v <SEP> cm-ê
 <tb> <SEP> (KBr):
 <tb> <SEP> 1740, <SEP> 1660,
 <tb> <SEP> 1620
 <tb>
EMI38.1

 example <SEP> R12 <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> <SEP> R13 <SEP> R12, <SEP> R13 <SEP> Fp. (C) <SEP> (dec.)
 <tb> 199 <SEP> # <SEP> -H <SEP> # <SEP> like <SEP> 194-196
 <tb> <SEP> R13 <SEP> the <SEP> Ver <SEP> bond
 <tb> <SEP> (XIII)
 <tb> 200 <SEP> # <SEP> <SEP> # <SEP> <SEP> 175-180
 <tb> 201 <SEP> # <SEP> <SEP> # <SEP> <SEP> 172-178
 <tb> 202 <SEP> # <SEP> <SEP> # <SEP> <SEP> 75-76
 <tb> 203 <SEP> # <SEP> <SEP> # <SEP> <SEP> 150-153
 <tb> 204 <SEP> # <SEP> <SEP> # <SEP> <SEP> 196-199
 <tb>
EMI39.1

 example <SEP> R12 <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> <SEP> R13 <SEP> R12,

    <SEP> R13 <SEP> Fp. (C) <SEP> (dec.)
 <tb> 205 <SEP> # <SEP> # <SEP> like
 <tb> <SEP> R13 <SEP> the <SEP> Ver <SEP> bond
 <tb> <SEP> (XIII)
 <tb> 206 <SEP> # <SEP> <SEP> # <SEP>
 <tb> 207 <SEP> # <SEP> <SEP> # <SEP>
 <tb> 208 <SEP> # <SEP> <SEP> H2NCH2CH2SCH2CO- <SEP>
 <tb> 209 <SEP> # <SEP> <SEP> # <SEP> <SEP> I.R. <SEP> @ <SEP> cm-1
 <tb> <SEP> (Nujol):
 <tb> <SEP> 1730, <SEP> 1660,
 <tb> <SEP> 1610
 <tb>
Example 210
0.250 g of 3- [2- (2-thienyl) -N- (2,2,2-trichloroethoxycarbonyl) glycinamidoj-lactacillanic acid was dissolved in 13 ml of 90% aqueous acetic acid and the solution was cooled to 100C. 1.2 g of zinc powder was gradually added to the solution over 50 minutes, and the mixture was allowed to react at the same temperature for 1 hour.

  0.50 g of zinc powder was added to the reaction mixture over 30 minutes, and the mixture was allowed to react for a further 2 hours. The zinc powder was filtered off. Hydrogen sulfide gas was introduced into the filtrate. The precipitate was filtered.



  The filtrate was washed with ethyl acetate and the remaining aqueous layer was concentrated. The residue was crystallized from a mixture of methanol and ether, whereby 35 mg of 3- [2- (2-thienyl) glycinamido] - actacillanic acid were obtained. In addition, the ethyl acetate layer was extracted with water and the aqueous layer was concentrated to isolate 15 mg of the same compound. Total yield 50 mg, mp. 184 to 189 "C (dec.).



   The following compounds were prepared in essentially the same manner as described above.
EMI40.1


 <tb> example <SEP> R12 <SEP> connection <SEP> (III) <SEP> R13 <SEP> Ro2 <SEP> connection <SEP> (IV) <SEP> Fp. (C) <SEP> (dec.)
 <tb> <SEP> C <SEP> CHCO¯ <SEP> CE: CO
 <tb> <SEP> 211 <SEP> 1 <SEP> ss <SEP> -H <SEP> S <SEP> -HSj <SEP> like <SEP> 198-202
 <tb> <SEP> l <SEP> CO <SEP> N11'CO <SEP> R13 <SEP> the
 <tb> <SEP> connection
 <tb> <SEP> Cl3CCr; 200CE'HCE { <SEP> 4 <SEP> H <SEP> NCH <SEP> (XIII)
 <tb> <SEP> Ci3CCII2COCNIICHCO- <SEP> H2NCHCO
 <tb> <SEP> 212 <SEP> g <SEP> D <SEP> Ö <SEP> 193-196
 <tb>



   Example 213
0.50 g 1 - (x-carboxy-3,5-dibromo-4-hydroxybenzyl) -3- [2- - {4- <3-carboxy-3- (2,2,2-trifluoroacetamido) -propoxy, -phenyl} - -2-hydroxyiminoacetamidol -2-azetidinone were suspended in 3 ml of water, and 3 ml of 1N were added to this suspension
Given sodium hydroxide solution. Then the solution was stirred for 30 min and then adjusted to pH 3 with ice-cooling with 10% hydrochloric acid. The precipitated crystals were filtered and dissolved with a small amount of aqueous sodium bicarbonate solution. The solution was treated with activated carbon. After this treatment, the solution was adjusted to pH 4 with 10% hydrochloric acid while cooling with ice.

  The
Precipitate was filtered, 40 mg of l- (a-carboxy-3,5-dibromo-4-hydroxybenzyl) -3- [2- {4- (3-amino-3-carboxypropoxy) phenyl} -2-hydroxyiminoacetamido] -2-azetidinone were obtained. 60 mg of the same compound were obtained from the
Mother liquor obtained. Total yield 100 mg, mp. 190 to 194 "C (dec.).



   Example 214
25 mg of 10% palladium-on-carbon was added to a solution of 230 mg of 3- [2- (4-benzyloxycarbonyloxyphenyl) acetamido] actacillanic acid in 15 ml of methanol. The theoretical volume of hydrogen gas was introduced into this mixture during 2 at normal temperature and normal pressure. The reaction mixture was filtered off, the filtrate was concentrated under reduced pressure, and the residue was crystallized from a mixture of acetone and ethyl acetate. The crystals were collected by filtration and washed with ethyl acetate to give 90 mg of 3- [2- (4-hydroxyphenyl) acetamido] actacillanic acid, mp 171-176 "C (dec.).

 

   Example 215
A solution consisting of 213 mg of 3- (2-ethoxycarbonyl -2-phenylacetamido) -actacillanic acid, 5 ml of ethanol and the like. 1.4 ml of 1N sodium hydroxide solution was reacted at room temperature for 114 h. After the reaction, the reaction mixture was cooled and adjusted to pH 1 by adding 1.4 ml of 1N hydrochloric acid. Then the mixture was adjusted to pH 6-7 by adding 1N sodium hydroxide solution and concentrated.



  The residue was washed in water and the solution was adjusted to pH 1-2 with 1N hydrochloric acid and then washed with ethyl acetate. The remaining aqueous layer was adjusted to pH 6 with 1N sodium hydroxide solution and concentrated. For isolation and purification, the residue was subjected to column chromatography using 30 ml of non-ionic adsorbent resin (Amberlite XAD-2) which had been previously washed with methanol and water. The water eluted fractions were collected and the water was distilled off from the eluate to give 159 mg of the disodium salt of the carboxy group of 3- (2-carboxy-2-phenylacetamido) actacillanic acid, m.p. 209 to 2140C (dec.).



   The following compounds were prepared in essentially the same manner as described above.
EMI41.1


 <tb> example <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> R13 <SEP> R12 <SEP> R13 <SEP> R12, <SEP> Ril <SEP> Fp. (OC) <SEP> (dec.)
 <tb> <SEP> 216 <SEP> CH3OCC-CH. > CH2CO- <SEP> -H <SEP> NaOOC-CH2CH2CO- <SEP> like <SEP> I.R. <SEP> v <SEP> cm
 <tb> <SEP> R, <SEP> the <SEP> (KBr):
 <tb> <SEP> connection <SEP> 1740, <SEP> 1660,
 <tb> <SEP> (XIII) <SEP> 1585
 <tb> <SEP> 217 <SEP> CH3CCOCOCO- <SEP> rrn-coco- <SEP> <SEP> 220-225
 <tb>



   Example 218
170 mg of 3- 12- {2- (2-ethoxycarbonylphenoxy) acetamido} -2-phenylacetamido] actacillanoic acid were dissolved in 0.9 ml of 1N sodium hydroxide solution and the solution was stirred for 3 hours at room temperature. Then about 10 ml of water was added to the reaction mixture. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate.



  The extract was washed twice with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the ethyl acetate solution and the residue was crystallized from diisopropyl ether. 120 mg of 3- [2- {2- (2-carboxyphenoxy) acetamido) -2-phenylacetamido] actacillanic acid, mp. 130 to 135 "C. (dec.), were obtained.



   The following compounds were prepared in essentially the same manner as described above.
EMI42.1

 example <SEP> R12 <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> <SEP> R13 <SEP> R12 ' <SEP> R13 <SEP> Fp. (C) <SEP> (dec.)
 <tb> 219 <SEP> # <SEP> -H <SEP> # <SEP> like <SEP> 90-95
 <tb> <SEP> R13 <SEP> the
 <tb> <SEP> connection
 <tb> <SEP> (XIII)
 <tb> 220 <SEP> # <SEP> <SEP> # <SEP> <SEP> 144-147
 <tb> 221 <SEP> # <SEP> <SEP> # <SEP> <SEP> 117-121
 <tb> 222 <SEP> # <SEP> <SEP> # <SEP> <SEP> 143-146
 <tb> 223 <SEP> # <SEP> <SEP> # <SEP> <SEP> 150-154
 <tb> 224 <SEP> # <SEP> <SEP> # <SEP> <SEP> 175-181
 <tb>
EMI43.1

 example <SEP> R12 <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> <SEP> R13 <SEP> R12 ' <SEP> R13 <SEP> Fp. (C) <SEP> (dec.)
 <tb> 225 <SEP> # <SEP> -H <SEP> # <SEP> like <SEP> 162-166
 <tb>

    <SEP> R13 <SEP> the
 <tb> <SEP> connection
 <tb> <SEP> (XIII)
 <tb> 226 <SEP> # <SEP> <SEP> # <SEP> <SEP> 202-106
 <tb> 227 <SEP> # <SEP> <SEP> # <SEP> <SEP> 193-196
 <tb> 228 <SEP> # <SEP> <SEP> # <SEP> <SEP> 139-140
 <tb> 229 <SEP> # <SEP> <SEP> # <SEP> <SEP> 95-101
 <tb> 230 <SEP> # <SEP> <SEP> # <SEP> <SEP> 90-95
 <tb> 231 <SEP> # <SEP> <SEP> # <SEP> <SEP> 180-183
 <tb>
EMI44.1

 example <SEP> R12 <SEP> connection <SEP> (III) <SEP> connection <SEP> (IV)
 <tb> <SEP> R13 <SEP> R12 ' <SEP> R13 <SEP> Fp. (C) <SEP> (dec.)
 <tb> 232 <SEP> # <SEP> -H <SEP> # <SEP> like <SEP> 187-191
 <tb> <SEP> R13 <SEP> the
 <tb> <SEP> connection
 <tb> <SEP> (XIII)
 <tb> 233 <SEP> # <SEP> <SEP> # <SEP> <SEP> I.R. # <SEP> cm-1
 <tb> <SEP> (Nujol):

  :
 <tb> <SEP> 1740, <SEP> 1685,
 <tb> <SEP> 1660
 <tb> 234 <SEP> # <SEP> <SEP> # <SEP> <SEP> 150-154
 <tb> 235 <SEP> # <SEP> <SEP> # <SEP> <SEP> 162-166
 <tb> 236 <SEP> # <SEP> <SEP> # <SEP> <SEP> 90-93
 <tb>



   Example 237
0.19 g of 1 - (x-methoxyearbon) l-4-methoxybenzyl) -3- 2-, 4- - {3-methoxycarbonyl-3- (2,2,2-trifluoroacetamido) propoxy} phenyl, -2 -methoxyiminoacetamido] -2-azelidinone were dissolved in 2 ml acetone. At room temperature, 9 ml IN sodium hydroxide solution were added to this solution () and the mixture was stirred for 5 min. The acetone was distilled off from the reaction mixture, and the remaining solution was adjusted to pH 3 with 10% hydrochloric acid.

  The separated oily material was isolated by decantation, washed with acetone and water and then pulverized with acetonitrile, whereby 0.02 g of 1 - (α-carboxy-4-methoxybenzyl) -3- [2- {4- (3-amino -3- -carboxypropoxy) -phenyl} -2-methoxyiminoacetamido] -2-azetidinone, mp. 170 to 176 C (dec.).



   Example 238
320 mg of 3- [2- (4- {4-chloro-N- (2,2,2-trichloroethoxycarbonyl) anilinomethyl} phenoxy) -2-methylpropionamido] actacillanic acid were prepared in essentially the same manner as in Example 192 described, treated to give 110 mg of 3- [2- {4- (4--chloroanilinomethyl) phenoxy} -2.methylpropionamidoj -actacillanic acid, mp. 130 to 136 C (dec.).



   Example 239
200 mg of 3- [4- (3-benzyloxycarbonyl-5-oxo-1,3-oxazol-4-yl) -butyramido] -actacillanic acid were dissolved in 15 ml of methanol, and to the solution was added 50 mg of 10 Cf palladium carbon as Given catalyst. The mixture was hydrogenated at normal pressure in a hydrogen atmosphere. After 4 h, the theoretical volume of hydrogen gas was taken up by the mixture. Then it was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was pulverized with acetone and the powder was filtered off, whereby 97 mg of 3- (5-amino-5-carboxyvalerylamino) - -actacillanic acid were obtained.



     Nuclear Magnetic Resonance Spectrum: ppm (D20 + NaHCO3): 1.64 to 1.90 (4H, m), 2.24 (2H, t, J = 4Hz), 2.90, 2.94 (1H, d, d , J2Hz, 6Hz), 3.67 (1K, t, 3 = 6Hz), 5.19 (IH, s), 6.79 (2H, d, J = 8Hz), 7.12 (2H, d, J = 8Hz).



   Example 240
200 mg of 3- [2- {4- (1-benzyloxycarbonylamino-1-methoxycarbon'lmethy1) -phenoxy -acetamido} -lactacillanic acid were dissolved in 15 ml of methanol. 35 mg of 10% palladium-carbon as a catalyst were added to the solution, and the mixture was hydrogenated in a hydrogen atmosphere at atmospheric pressure and temperature for 2 h. After the calculated amount of hydrogen was absorbed by the mixture, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was pulverized with acetone and treated with acetone, 90 mg of 3-12-xf4- (l-amino-1-methoxycarbonylmethyl) -phenoxy} -acetamido] -actacillanic acid. Mp 190-1,940C (dec.).



   Example 241
1.35 g of 3- [2- {4- (2-benzyloxycarbonylamino-2-methoxycarbonylethyl) -phenoxy'1-acetamido I-actacillanic acid were dissolved in 6.7 ml of 1N sodium hydroxide solution. and the solution was stirred at room temperature for 1 h. A small amount of water was added to the reaction mixture, and the solution was then washed with ethyl acetate, after which the aqueous solution was adjusted to pH 1 with 1N hydrochloric acid. The solution was extracted with ethyl acetate, and the ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from chloroform, 1.07 g of 3- [2- {4- (2-benzyloxycarbonylamino--2-carboxyethyl) -phenoxy} -acetamidoJ -lactaci l lansliure, mp.



  125 to 1300C (dec.)., Were obtained in the form of crystals.



   Example 242
118 mg of 3- [2- {4- (1-benzyloxycarbonylamino-1-methoxycarbonylmethyl) phenoxy} acetamido 1 -actacillanic acid were dissolved in 4 ml of 0.1N sodium hydroxide solution and the solution was stirred at room temperature for 2 h. Then 4 ml of 0.1 N hydrochloric acid was added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from a small amount of acetone.



  The crystals were treated with ethyl acetate to give 30 mg of crystals of 3- [2- {4- (1-benzyloxycarbonylamino-1-carboxymethyl) phenoxy} acetamido] acetacillanic acid, mp 134-138 C (dec.) were.



   Example 243
1.15 g of 4- (3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy) phenylglyoxylic acid were suspended in 10 ml of methylene chloride; 0.31 g of triethylamine and 2 drops of N, N-dimethylbenzylamine were added to the suspension.



  A solution of 0.33 g of ethyl chloroformate in 5 ml of methylene chloride was added dropwise to the solution at -600C over the course of a few minutes. The reaction temperature was gradually increased to -40 ° C. over the course of about 1 h with stirring. On the other hand, 0.71 g of 3-aminolactacillanic acid was suspended in a mixture of 15 ml of methylene chloride and 0.5 ml of N, N-dimethylformamide.



  1.83 g of bis (trimethylsilyl) acetamide were added to the suspension while stirring, and the mixture was stirred at room temperature for 3 hours. The solution thus obtained was mixed with the previously prepared solution at -70.degree. C., after which the mixture was stirred at the same temperature for half an hour. While gradually increasing the reaction temperature, the mixture was reacted at about -50 C for one hour. The reaction mixture was then warmed to -200C while stirring for half an hour. The reaction mixture was poured into ice water and then sodium bicarbonate was added to adjust the pH to 8. The aqueous layer was separated from the mixture, brought to pH 2 with hydrochloric acid and then extracted with 200 ml of ethyl acetate.



  The extract was washed with water and then dried over magnesium sulfate. The solvent was removed from the solution by distillation under reduced pressure to obtain a residue which was powdered with diisopropyl ether. The powder was isolated by filtration to give 1.54 g of 3- [4- (3-tert.

 

  Butoxycarbonylamino-3-methoxycarbonylpropoxy) phenylglyoxyloylamino I-lactacillanic acid.



   IR absorption spectrum v (cm-1) (Nujol): 1740, 1680, 1660.



   Nuclear Magnetic Resonance Spectrum: [internal standard: sodium .2,2,3,3.tetradeutero-3- (trimethylsilyl) .propionate] 8 (ppm) (D..O + NaHCO @): 1.26 (9H, s), 2.14 (2H, m), 3.06 (1H, q, J = 5Hz, 2Hz), 3.60 (3K, s). 3.4 to 4.4 (4K, m), 5.04 (1H, q, J = SHz, 2Hz), 5.34 (IH, s), 6.89 and 7.24 (4H. ABq, J = 8Hz), 6.82 and 7.86 (4H, ABq, J = 8Hz).



   The following compounds were obtained in practically the same way.
EMI46.1


 <tb> <SEP> Physical
 <tb> example <SEP> Rt <SEP> A <SEP> Physical
 <tb> <SEP> constant
 <tb> 244 <SEP> CH <SEP> ooc-c1? (CH) / \ - CoCoNH- <SEP> CH <SEP> IR. <SEP> cm ' <SEP> (film):
 <tb> <SEP> 3 <SEP> 22 <SEP> 1 <SEP> 3400-3300,
 <tb> <SEP> 1760, <SEP> 1740, <SEP> 1710,
 <tb> <SEP> XHOOOO (Cfl3) 3 <SEP> COOH <SEP> 1680-1660
 <tb> <SEP> cFocH2ooc- <SEP> -CH- <SEP> I <SEP> I.R. <SEP> v <SEP> cm- ' <SEP> (film):
 <tb> 24s <SEP> U <SEP> g <SEP> \ = / <SEP> - <SEP> 3400, <SEP> 1760, <SEP> 1740,
 <tb> <SEP> No: COOC (C: <SEP> 3) 3 <SEP> tOOCHo <SEP> 1710, <SEP> 1680, <SEP> 1660
 <tb> <SEP> s <SEP> 1710, <SEP> 1680, <SEP> 1660
 <tb> 246 <SEP> xIO <SEP> - <SEP> C-COINH- <SEP> -Ctt-OH <SEP> I.R.

   <SEP> v <SEP> cm-l <SEP> (Nujol):
 <tb> <SEP> II <SEP> í <SEP> 1740 <SEP> 1695
 <tb> <SEP> S-OH <SEP> 1.ooHCOOH
 <tb> <SEP> N-flat
 <tb> 247 <SEP> ssc-coN11 <SEP> Fp. <SEP> (l 4Cg)
 <tb> <SEP> N-O1l <SEP> COOLI <SEP> ("C)
 <tb> 248 <SEP> 011111- <SEP> 149 <SEP> Fp. <SEP> (0C)
 <tb> <SEP> 248 <SEP> C1130 <SEP> O <SEP> Coofl <SEP> COOHob <SEP> 138-148
 <tb> <SEP> 2 <SEP> 1 ' <SEP>: r <SEP> (dec.)
 <tb> 249 <SEP> ¯¯ <SEP> C-COlIIi- <SEP> <SEP> Fp. <SEP> ("C)
 <tb> <SEP> II <SEP> ¯ <SEP> 210-213 <SEP> (dec.)
 <tb> <SEP> 2 <SEP> x <SEP> too <SEP> (sodium salt)
 <tb> <SEP> 250 <SEP> (3- <SEP> COCON <SEP> a <SEP> Fp. <SEP> (OC)
 <tb> <SEP> 190.5-192
 <tb> <SEP> (dec.)
 <tb> 251 <SEP> BrCH2COCONH- <SEP> <SEP> Fp. <SEP> (OC)
 <tb> <SEP> 188-192
 <tb> 252 <SEP> OCI <SEP> ocH <SEP> 2CONH- <SEP> <SEP> I.R.

   <SEP> v <SEP> cm- ' <SEP> (KBr):
 <tb> <SEP> ZNHCOOCH2CCL3 <SEP> 3275, <SEP> 1740, <SEP> 1715,
 <tb> <SEP> 223 <SEP> 1660
 <tb> <SEP> QOCH <SEP> 2COt {H
 <tb> 2s3 <SEP> CH2-N-CH2-g3) <SEP> <SEP> Fp. <SEP> (OC)
 <tb> <SEP> 141.5-144
 <tb> <SEP> Cl3CH20CO <SEP> OC112COOH <SEP> (dec.)
 <tb> 254CHCONH- <SEP> <SEP> I.R.I.R. <SEP> vcm- ' <SEP> (KBr):
 <tb> <SEP> Ol <SEP> 0 <SEP> CltCONH- <SEP> 3350, <SEP> 1735, <SEP> 1615,
 <tb> <SEP> OH <SEP> 1380, <SEP> 1240, <SEP> 743
 <tb> <SEP> (sodium salt)
 <tb> 255CHCONH- <SEP> Fp. <SEP> (0C)
 <tb> <SEP> 120-125
 <tb> <SEP> NHCOCH2N3 <SEP> NHCOCH <SEP> 2N3 <SEP> (dec.)
 <tb> <SEP> C113 <SEP> I.R. <SEP> v <SEP> cm-l <SEP> (KBr):
 <tb> 256 <SEP> zu2-CHCOSH- <SEP> -CSlCll <SEP>, Cri3 <SEP> I.R.

   <SEP> vcm- <SEP> (KBr):
 <tb> <SEP> ClI <SEP> 3300-3200, <SEP> 1735,
 <tb> <SEP> NHCoocll2cci3 <SEP> COOII <SEP> 1715, <SEP> 1700, <SEP> 1660
 <tb>
EMI47.1


 <tb> example <SEP> R, <SEP> Physical
 <tb> <SEP> constant
 <tb> 257 <SEP> - <SEP> CH <SEP>, OCONH- <SEP> CC-C / CH3 <SEP> Fp. <SEP> (C)
 <tb> <SEP> Zool = "3 <SEP> 135-137
 <tb> 258 <SEP> CH3OrCH <SEP>; 20OC-CH <SEP> (CH <SEP> 2) <SEP> OCOCONH <SEP> -CH <SEP> tD <SEP> I.R. <SEP> r <SEP> cm-l <SEP> (film):
 <tb> <SEP> NHCOOC <SEP> (CH3) <SEP> 3 <SEP> COOH <SEP> 3400-3300, <SEP> 1760,
 <tb> <SEP> 1740, <SEP> 1710,
 <tb> <SEP> 1680-1660
 <tb> <SEP> Hooc-crr (c,) <SEP> 20 - COCONH
 <tb> 259 <SEP> HOOC-C11 ( <SEP> (Cl '?.) <SEP> 2OCOCONM- <SEP> 1 <SEP> <SEP> I.R.

   <SEP> v <SEP> cm- ' <SEP> (film):
 <tb> <SEP> NHCOOC <SEP> (cm3) <SEP> 3 <SEP> 3450-3300, <SEP> 1750,
 <tb> <SEP> 1740, <SEP> 1700,
 <tb> <SEP> 1690-1660
 <tb> 260 <SEP> <SEP> -CH42 <SEP> on <SEP> I.R. <SEP> vcm-1 (Nujol):
 <tb> <SEP> 3350-3200, <SEP> 1710,
 <tb> <SEP> coon <SEP> 1680, <SEP> 1660
 <tb> <SEP> -CM <SEP> OCM2
 <tb> 261 <SEP> <SEP> COOH <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 3300-3200,
 <tb> <SEP> 1740-1710,
 <tb> <SEP> 1690, <SEP> 1660
 <tb> 262 <SEP> CH3OOC-CM <SEP> (CM2) <SEP> 2OC-COt1M- <SEP> COO <SEP> Fp. <SEP> (OC)
 <tb> <SEP> II <SEP> 1 <SEP> \ - <SEP> 143-146
 <tb> <SEP> NHCOOC (CH3) 1 <SEP> N-OU <SEP> CH3
 <tb> <SEP> HCOC-CH <SEP> (C1IZ) <SEP> .O <SEP> 2O-C-COl1M
 <tb> 263 <SEP> NCOC-Cll (c1l2) <SEP> II <SEP> 2 <SEP> 1l <SEP> 8 <SEP> I.R.

   <SEP> v <SEP> cm- ' <SEP> (film):
 <tb> <SEP> NH <SEP> COOC <SEP> ( <SEP> CH <SEP> 3) <SEP> 3 <SEP> N-OH <SEP> COOH <SEP> 3450-3300, <SEP> 1760,
 <tb> <SEP> 1740, <SEP> 1700, <SEP> 1660
 <tb> <SEP> 264 <SEP> 1 <OoC-Cll <SEP> COIQH <SEP> -Cl; OCH43
 <tb> <SEP> NHCOOC (CH3) <SEP> Fp. <SEP> COOH
 <tb> <SEP> 149.5-153
 <tb> <SEP> 3 <SEP> ll-O <SEP> COOH <SEP> (dec.)
 <tb> 265 <SEP> / \ MCNxCHCowM <SEP> f <SEP> OH <SEP> Fp. <SEP> (C)
 <tb> <SEP> l1Illi <SEP> COOH <SEP> 175-178.5
 <tb> <SEP> (dec.)
 <tb> 266 <SEP> (ö <SEP> OCH2CONM- <SEP> * <SEP> Fp. <SEP> (OC):
 <tb> <SEP> CH2NHCOCH2 no <SEP> 152-155.5
 <tb> / <SEP> \ µ-OCH <SEP> CONH- <SEP> <
 <tb> <SEP> 267 <SEP> NMCoCMO / \ <SEP> Fp.

   <SEP> 117.5-122
 <tb> <SEP> Cll2NHCOCH <SEP> COOH <SEP> | <SEP> (sodium salt)
 <tb> <SEP> 1102
 <tb> <SEP> llO2
 <tb>
EMI48.1


 <tb> Bl <SEP> R <SEP> Physical
 <tb> eispie <SEP> 1 <SEP> A <SEP> constant
 <tb> 268 <SEP> (3CHCONH- <SEP> -CHi <SEP> OH <SEP> Fp. <SEP> (OC):
 <tb> <SEP> NIlCCCO'Lll ( <SEP> SOD <SEP> 155-159 <SEP> (dec.)
 <tb> <SEP>) = / <SEP> COOH
 <tb> <SEP> fl02
 <tb> 269 <SEP> CM <SEP> NIlCOco; lll- <SEP> a <SEP> Fp. <SEP> (C):
 <tb> <SEP> 125-129 <SEP> C'NHCOCO: II <SEP> 125-129 <SEP> (dec.)
 <tb> t% -CHC'ONH- <SEP> / CH3 <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 270 <SEP> I <SEP> I.R.

   <SEP> vcm- ' <SEP> (Nujol):
 <tb> <SEP> lnrcocll2o-t <SEP> ct <SEP> 1 <SEP> N <SEP> 3400, <SEP> 3300, <SEP> 1740,
 <tb> <SEP>; / <SEP> COOH <SEP> CM3 <SEP> 1670, <SEP> 1610
 <tb> <SEP> NO2 <SEP> (sodium salt)
 <tb> <SEP> 271 <SEP> OOC-C (C2) <SEP> 2O-.c-ccti- <SEP> ll-COIAH- <SEP> -fHgOH <SEP> Fp. <SEP> (OC):
 <tb> <SEP> II <SEP> 1 <SEP> 193-197 <SEP> (dec.)
 <tb> <SEP> NHCOOC <SEP> (Cl13) <SEP> 3 <SEP> N-Otl <SEP> COOII
 <tb> <SEP> 272 <SEP> -CH2CoNH- <SEP> -CII - OM <SEP> Fp. <SEP> (OC):
 <tb> <SEP> COOCM3 <SEP> 171.5-175
 <tb> <SEP> CMCM / C113
 <tb> <SEP> -Cl4CH
 <tb> <SEP> 273 <SEP> <SEP>; <SEP> CH <SEP> 3 <SEP> Fp. <SEP> (OC):
 <tb> <SEP> COOCH <SEP> 3 <SEP> 105-107
 <tb> <SEP> 274 <SEP> 1 <SEP> -CH <rCX) <SEP> 3 <SEP> Fp. <SEP> (OC):
 <tb> <SEP> COOC113 <SEP> 150.5-154.5
 <tb> <SEP> 275 <SEP> <SEP> -CH-C) <SEP> Fp.

   <SEP> ("C):
 <tb> <SEP> OOiI <SEP> 182-183
 <tb> <SEP> 0
 <tb> <SEP> CH3
 <tb> <SEP> 276 <SEP> " <SEP> f <SEP> XCH <SEP> lF2Pi <SEP> Fp. <SEP> (whether):
 <tb> <SEP> j <SEP> CM3
 <tb> <SEP> COOC113
 <tb> <SEP> o
 <tb> 277 <SEP> C <SEP> N- <SEP> -C = C / <SEP> 3 <SEP> I.R. <SEP> cm- '
 <tb> <SEP> o <SEP> | <SEP> XCH <SEP> 3 <SEP> 1780,
 <tb> <SEP> 0 <SEP> 1720
 <tb> 278 <SEP> 1 <SEP> (\ 11 <SEP> 203-204.5
 <tb> <SEP> Fp. <SEP> <SEP> I <SEP> FP <SEP> (whether):
 <tb> <SEP> COOC: H <SEP> 3 <SEP> 203-204.5
 <tb> <SEP> CM
 <tb> 279 <SEP> - <SEP> OCH <SEP> CONtIZ <SEP> -C: C <SEP> Fp. <SEP> (C):
 <tb> <SEP> 2 <SEP> 1 <SEP> CH3 <SEP> 154-155
 <tb> <SEP> COOCM3
 <tb>



   Example 280
1.10 g of 3- [4- (3-tert-butoxycarbonylamino-3-carboxypropoxy) -phenylglyoxyloylamino] -lactacillanic acid were suspended in a mixture of 15 ml of benzene and 0.5 ml of anisole. 5.5 g of 2,2,2-trifluoroacetic acid were added to the suspension while cooling with ice, after which the mixture was stirred at the same temperature for 1 hour. Diethyl ether was added to the reaction mixture, and the precipitated materials were separated by decantation and then washed with diethyl ether. The materials were poured into water and the solution brought to pH 3 with sodium bicarbonate.

  The aqueous solution was left for a while; the precipitated crystals were isolated by filtration and then washed with water and acetone to obtain 0.60 g of crystalline 3- [4- (3-amino-3-carboxypropoxy) phenylglyoxyloylamino] actacillanic acid. Mp 225 to 2300C (dec.).



   IR absorption spectrum v cm- '(Nujol): 1725, 1650.



   The following compounds were obtained in practically the same manner as described above.
EMI49.1

EMI49.2


 <tb> <SEP> connection <SEP> (V) <SEP> connection <SEP> (VI)
 <tb> example <SEP> R12 <SEP> Rs2 ' <SEP> Fp. <SEP> (OC)
 <tb> <SEP> HOOC-CK <SEP> (c112) <SEP> 24 / Dc-CoN- <SEP> HOOC-C <SEP> (C2)
 <tb> <SEP> 281 <SEP> f <SEP> OOC-CONH- <SEP> zOOC-C35 <SEP> - <SEP> 2 ^ <SEP> CONH- <SEP> 214-216
 <tb> <SEP> HCDCC <SEP> (Cn,) 3 <SEP> '-OW <SEP> SH2 <SEP> N-OH
 <tb> <SEP> Cu CuC-CH (C2) 2O - CHt3N- <SEP> HOOC-CH <SEP> t'CN2) <SEP> oTHCo> X <SEP> 222-226
 <tb> <SEP> NCOOC (CX3) 3 <SEP> NHC1 <SEP> NHr <SEP> c "HC //
 <tb> <SEP> Cr;

   <SEP> CH
 <tb> <SEP> HOOC-CH <SEP> (CH2) <SEP> 2OoCMCON <SEP> YCOC-C (CH2) <SEP> 2OCCONll
 <tb> <SEP> 283 <SEP> 1 <SEP> 1 <SEP> 2
 <tb> <SEP> wlICOOC4'cH3) 3 <SEP> 1HCONE1 / NV <SEP> NIll <SEP> SHCGN <SEP> (dec.)
 <tb> <SEP> 0
 <tb> <SEP> .gOOC-CH <SEP> (CH2) <SEP>> FCflt <SEP> CDiB- <SEP> HOOC-CH <SEP> (CH2) <SEP> HCOIA
 <tb> <SEP> 284 <SEP> (clI) <SEP> 3 <SEP> NEfCOU} <SEP> NW <SEP> NH ^ ONSe <SEP> 1 <SEP> I.R. <SEP> v <SEP> cm-l
 <tb> <SEP> 284 <SEP> 2 <SEP> (Nujol):
 <tb> <SEP> 3300, <SEP> 1730,
 <tb> <SEP> 1650 <SEP> (wide),
 <tb> <SEP> 1610 <SEP> (school
 <tb> <SEP> ter), <SEP> 1600
 <tb>



   Example 285
A solution of 1.50 g of 3- [4- (3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy) phenylglyoxyloylaminoj -actacillanic acid in 20 ml of methanol was added dropwise with about 10 ml of 1N over the course of 5 hours with ice cooling and stirring Sodium hydroxide added. The reaction mixture was brought to pH 7 with 1N hydrochloric acid and the methanol was distilled off from the mixture. The resulting solution was mixed with water, brought to pH 2 with 1N hydrochloric acid and then extracted with ethyl acetate.

  After the extract was dried over magnesium sulfate, the extract was evaporated to dryness under reduced pressure, whereby a residue was obtained which was crystallized from diisopropyl ether and 1.20 g of 3- [4- (3-tert-butoxycarbonylamino-3-carboxypropoxy) - phenylglyoxyloylaminoj-lactacillanic acid.



   IR absorption spectrum v cm-1 (Nujol): 1710, 1680,
1660.



   Example 286
300 mg 3- [2- {2- <N- (2,2,2-Trichloroethoxycarbonyl) -2- - (carboxymethoxy) -benzylaminomethyl> -plienoxy} -acet-amido] -lactacillanic acid was dissolved in 2 ml of acetic acid. 500 ml of zinc powder were added to the solution at 15 to 20 ° C., and the mixture was stirred at the same temperature for 2 hours. The unreacted zinc powder was filtered off from the reaction mixture and the filtrate was washed with ethyl acetate ml of ice water was poured, the mixture was filtered, the filtrate was washed with ethyl acetate and evaporated to dryness under reduced pressure on a water bath.

  The resulting residue was powdered with acetone to give 205 mg of 3- [2- {2- <2- (carboxy-methoxy) -benzylaminomethyl, -phenoxy} -acetamido] -lactacillanoic acid. Mp 159.5 to 164.5 C.



   Example 287
0.09 g of 3- [2- (2-aminomethylphenoxy) acetamido] -lactacil-lanoic acid was obtained by adding 0.250 g of 3- [2- {2- (2,2,2-trichloroethoxycarbonylaminomethyD-phenoxy-acetamido] - -actacillanic acid and 3 ml of 90% acetic acid in practically the same manner as described in Example 286.



   IR absorption spectrum v cm-1 (Nujol): 1725, 1650, 1600.



   The following compounds were obtained by reacting 3-amino-lactacillanic acid or its methyl ester with the corresponding acylating agent and removing the protecting groups for amino, hydroxyl or carboxyl groups in a conventional manner from the resulting product without isolating the same.
EMI51.1





  example <SEP> acylating agent
 <tb> <SEP> R1 <SEP> A <SEP> Fp. (C)
 <tb> 288 <SEP> # <SEP> # <SEP> # <SEP> 163-170
 <tb> 289 <SEP> # <SEP> # <SEP> <SEP> 218-223
 <tb> <SEP> (dec.)
 <tb> 290 <SEP> # <SEP> # <SEP> <SEP> I.R. # cm-ê
 <tb> <SEP> (Nujol):
 <tb> <SEP> 3300, <SEP> 1730,
 <tb> <SEP> 1660 <SEP> (school <SEP> ter), <SEP> 1610
 <tb> 291 <SEP> # <SEP> # <SEP> <SEP> 188-191
 <tb> <SEP> (dec.)
 <tb> 292 <SEP> # <SEP> # <SEP> <SEP> 194-196
 <tb> <SEP> (dec.)
 <tb> 293 <SEP> # <SEP> # <SEP> <SEP> 162-169
 <tb> <SEP> (dec.)
 <tb>
EMI52.1

 example <SEP> acylating agent
 <tb> <SEP> R1 <SEP> A <SEP> Fp. (C)
 <tb> 294 <SEP> # <SEP> # <SEP> # <SEP> 178-182
 <tb> 295 <SEP> # <SEP> # <SEP> <SEP> 210-215
 <tb> <SEP> (dec.)
 <tb> <SEP> (sodium <SEP> salt)
 <tb> 296 <SEP> # <SEP> # <SEP> <SEP> I.R. # cm-ê
 <tb> <SEP> (Nujol):
 <tb> <SEP> 3400.3300.
 <tb>



    <SEP> 3200, <SEP> 1740,
 <tb> <SEP> 1720, <SEP> 1660.
 <tb>



    <SEP> 1640, <SEP> 1600
 <tb> 297 <SEP> # <SEP> # <SEP> <SEP> 180-184
 <tb> <SEP> (dec.)
 <tb> 298 <SEP> # <SEP> # <SEP> # <SEP> 191-193
 <tb> <SEP> (dec.)
 <tb> 299 <SEP> # <SEP> # <SEP> # <SEP> 178-180
 <tb> <SEP> (dec.)
 <tb>
EMI53.1

 example <SEP> acylating agent
 <tb> <SEP> R1 <SEP> A <SEP> Fp. (C)
 <tb> 300 <SEP> # <SEP> # <SEP> # <SEP> 195-198
 <tb> <SEP> (dec.)
 <tb> 301 <SEP> CH2COOCH2CH2NHCOCCOK <SEP> HOCH2CH3NHCOCONH- <SEP> <SEP> I, R.

   <SEP> # <SEP> cm-1
 <tb> <SEP> (KBr):
 <tb> <SEP> 3300, <SEP> 1735,
 <tb> <SEP> 1660, <SEP> 1510
 <tb>
Example 302
280 mg of 3- [2- {2- (2,2,2-trifluoroacetamido) -4thiat: olyl} -2- -methoxyiminoacetamidoJ-lactacillanic acid were obtained by combining 236 mg of 3-aminolactacillanic acid with 265 mg of 2- [2 - ( 2,2,2-trifluoroacetamido) 4-thiazolylj -2-methoxyiminoacetic acid and 180 mg of thionyl chloride in practically the same manner as described in Example 243.



   IR absorption spectrum v cm- '(film): 1750, 1730, 1690, 1670.



   Example 303
A mixture of 240 mg of 3- [2- (2- (2,2,2-trifluoroacetamido) -44hiazolyl} -2-meffioxyiminoacetamidoj-lactacillanic acid, 340 mg of sodium acetate and 4 ml of water was stirred at ambient temperature for 8 hours. The reaction mixture was brought to pH 3.2 with dilute hydrochloric acid, the precipitated materials were removed by filtration, the filtrate was concentrated and a small amount of ethanol was added, the insoluble materials were removed by filtration, and the resulting filtrate was then removed under reduced pressure Evaporation to dryness gave a residue which was dissolved in 3 ml of water and the aqueous solution was subjected to column chromatography on 25 ml of the adsorption resin (Amberlite XAD-2).

  It was eluted with water and then with methanol, collecting the fractions containing the desired compound. The solvent was removed by distillation under reduced pressure to give a residue; this was converted into a powder with ethanol and gave 110 mg of 3-F2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidoj-lactacillanic acid.



   IR absorption spectrum v cm- '(Nujol): 1740, 1660, 1620.



   Nuclear Magnetic Resonance Spectrum: 8 ppm (D2O + NaHCO3): 3.12, 3.20 (1H, d, d, J = 2Hz, 5Hz), 3.88 (3H, s), 3.88 (1H, t) , 5.02, 5.10 (IH, d, d, J = 2Hz, 5Hz), 5.32, (1H, s), 6.82 (1H, s), 6.90 (2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz).



   Example 304
1.3 g of 3-amino-1 - (2-methoxycarbonyl-1-phenylethyl) -2 -azetidinone was added to 30 ml of methylene chloride, after which 3.05 g of bis (trimethylsilyl) acetamide was added. The solution was added dropwise at -40 to -35 "C over 5 minutes with a solution of 1.9 g of 2- (2,2-dichloroacetoxyimino) -2-phenylacetic acid in 30 ml of methylene chloride. The mixture was run at the same Temperature was stirred for 15 minutes and at 50C for an additional 15 minutes. An aqueous sodium bicarbonate solution was added to the reaction mixture, after which the mixture was stirred at ambient temperature for 5 minutes Washed water and then dried over magnesium sulfate.

  The solvent was removed by distillation under reduced pressure to obtain a residue which was subjected to column chromatography on 100 g of silica gel. It was eluted with chloroform and the fractions containing the desired compound were collected. The solvent was distilled off from the eluate under reduced pressure, whereby 0.74 g of crystals of 3- (2-hydroxyoxy-2-phenylacetamido) -1 - (2-methoxycarbonyl-1-phenylethyl) -2-azetidinone were obtained , M.p. 161 to 163 "C.



   IR absorption spectrum v cm- '(Nujol): 3220, 1730, 1720, 1620.

 

   The following compounds were obtained in practically the same way:
EMI54.1


 <tb> example <SEP> R <SEP> Physical
 <tb> elspte <SEP> 1 <SEP> A <SEP> constant
 <tb> <SEP> constant
 <tb> 305C-CONH- <SEP> -Cn - '\ <SEP> I.R. <SEP> v <SEP> cm-1 <SEP> (Nujol):
 <tb> <SEP> 11 <SEP> 1 <SEP> - <SEP> 3180, <SEP> 1720, <SEP> I.R. <SEP> v <SEP> 1710,
 <tb> <SEP> N-OH <SEP> lES2CO <SEP> CM <SEP> 2C0011 <SEP> 1635
 <tb> <SEP> K
 <tb> '(N <SEP> < <SEP> -CHO
 <tb> <SEP> 306 <SEP> -CH
 <tb> <SEP> r <SEP> COOH <SEP> 164-171.5
 <tb> <SEP> CONM
 <tb> <SEP>) <SEP> 0 <SEP>) .. O
 <tb> 307 <SEP> CH3OOC-CK <SEP> (C112 <SEP> 2 <SEP>) <SEP> IWrC-CONII
 <tb> <SEP> 1 <SEP>. <SEP> I.R. <SEP> v <SEP> 3400, <SEP> 1750,
 <tb> <SEP> NHCOOC <SEP> (CH3) <SEP> OCOn <SEP> 3400, <SEP> 1750,
 <tb> <SEP> 3 <SEP> 1720-1700,
 <tb> <SEP> 1680, <SEP> 1660
 <tb>


    

Claims (3)

PATENT CLAIMS 1. A process for the preparation of azetidinone derivatives of the general formula (1) ## STR1 ## in which R1 is acylamino and A is hydrogen, a saturated or unsaturated, normal or branched aliphatic or cycloaliphatic carbon hydrogen radical which is substituted by at least one substituent from the group carboxy or a derivative thereof, Cyano, hydroxy and amino is substituted, - an aliphatic or cycloaliphatic hydrocarbon residue which is substituted by carboxy or a derivative thereof and by a phenyl, the ring of which is substituted by one or more substituents from the group hydroxy, amino, benzyloxycarbonylamino, nitro, alkyl , Alkoxy, aralkoxy, alkylthio, halogen and sulfo can be substituted, mean characterized in that that you have a compound of the general formula EMI1.1 in which A has the meanings given above, reactive groups which are not to be acylated are optionally protected in an intermediate manner, or a Schiff base of the amino group in the 3-position or a salt thereof with an acid is reacted with an acylating agent. 2. The method according to claim 1, characterized in that compounds of the formula I are prepared in which R1 is acylamino and A is hydrogen or a group of the formula EMI1.2 in which Ala is hydrogen, A2a is hydrogen, alkyl or phenyl, which can be substituted by at least one substituent from the group consisting of hydroxy, amino, benzoyloxycarbonylamino, nitro, alkyl, alkoxy, aralkoxy, alkylthio and halogen, or A1, and Aq together form an alkylidene and means A3a carboxy or a derivative thereof or cyano. 3. The method according to claim 2, characterized in that R1 denotes acylamino and A for a group of the formula EMI1.3 is in which Ala is hydrogen, A2a phenyl which can be substituted by at least one substituent from the group consisting of hydroxy, amino, benzyloxycarbonylamino, nitro, alkyl, alkoxy, aralkoxy, alkylthio and halogen and A3a is carboxy or a derivative thereof. The invention relates to a process for the preparation of 3-acylamino-2-azetidinone derivatives with antimicrobial activity. Recently, the chemical structure of the substance FR-1923 was successfully identified. The substance FR-1923 is a known antibiotic which can be isolated from the fermentation broth of a strain of the genus Nocardia (deposited with the American Type Culture Collection under ATCC No. 21806), further details for example in DE- PS 2 242 699 are described. In this PS, the substance FR-1923 is defined by its various physico-chemical properties, without containing information about its chemical structure. After extensive investigations, it has now been possible to identify the chemical structure of the substance FR-1923 and to assign it the following chemical structure EMI1.4 which can be referred to as 1- (a-carboxy-4-hydroxybenzyl) -3- 2- {4- (3-amino-3- 1-carboxypropoxy) phenyl} -2-hydroxyiminoacetamidoj -2-azetidinone. This made it possible for the first time to study some chemical modifications of the FR-1923 substance. A group of new and uniquely modified compounds derived from the substance FR-1923 and related compounds has now been successfully synthesized. Some known compounds derived from penicillins are given below with the associated literature references, which are intended to explain the current state of the art. EMI1.5 (U.S. Patent 3,487,072) EMI1.6 (Journal of Organic Chemistry, Volume 38, pages 940-943, 1973) EMI1.7 (Archives of Pharmacy and Reports of the German Pharmaceutical Society, Volume 303, p. 834) ** WARNING ** End of CLMS field could overlap beginning of DESC **.