CH624390A5 - Process for preparing alpha-ketocarboxylic acid compounds - Google Patents

Abstract

alpha -Ketocarboxylic acid compounds of the formula VIII <IMAGE> where the individual symbols are as defined in Claim 1, are prepared by eliminating in an acylthio compound of the formula VII <IMAGE> the 2-propylidene group by treatment with ozone, followed by a reducing agent. The alpha -ketocarboxylic acid compounds can be used as intermediates for preparing bicyclic thiaaza compounds.

Description

The present invention has for its object to produce new intermediates, which for the production of ß-lactam ring-containing bicyclic thia-aza compounds, which have a novel ring system, which are effective against both normal and resistant germs and which may have the other disadvantages of the previous ones Antibiotics with ß-lactam structure do not have, can be used.

The production of the new intermediate products according to the invention also opens up new fields in which research can be carried out for further, technically usable compounds.

The novel ring system has the formula and can be systematically called 5R, 6R-7-oxo-4-thia-l-azabicyclo- [3.2.0] hept-2-ene. For the sake of simplicity, it is referred to as "2-penem" in the following, using the following numbering, which is common in penicillin chemistry and is derived from the Penam:

R.

R.

(VIII),

wherein RXA represents an amino protecting group RiA and Rib represents hydrogen or an acyl residue Ac, or wherein RjA and Rjb together form a bivalent amino protecting group, R2a means a residue forming a protected carboxyl group together with the carbonyl group -C (= O) -, and R3 for Is hydrogen or an organic radical connected to the ring carbon atom via a carbon atom, and salts thereof.

The new a-ketocarboxylic acid compounds of the formula VIII can be used as intermediates for the preparation of bicyclic unsaturated thia-aza compounds, in particular 6-amino-2-penem-3-carboxylic acid compounds of the formula

- R,

(i),

The present invention relates to a process for the preparation of new a-ketocarboxylic acid compounds of the formula

0 = C - R,

where Rxa is hydrogen or an amino protecting group RjA and Rjb is hydrogen or an acyl residue Ac, 45 or where Rxa and Rjh together form a divalent amino protecting group, R2 hydroxyl or an R2A together with the carbonyl group -C (= O) - forming a protected carboxyl group means, and R3 is hydrogen or an organic radical connected via a carbon atom to the ring-carbon atom, or 1-oxides thereof, and salts of such compounds with salt-forming groups are used; see e.g. German Offenlegungsschrift No. 2 655 298.

An amino protecting group RjA is a group which can be replaced by hydrogen 55, primarily an acyl group Ac, furthermore a triarylmethyl group, and an organic silyl or stannyl group.

An acyl group Ac, which can also mean the radical R ^, is primarily the acyl radical of an organic carboxylic acid, 60 preferably having up to 18, and primarily having up to 10, carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic , cyclo-aliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid 65 and in particular stands for a N-acyl derivative which can be prepared in a naturally occurring or in a bio-synthetic, semi-synthetic or totally synthetic, preferably pharmacologically active 6-amino-penam-3-carboxylic acid or 7-amino

624 390

-3-cephem-4-carboxylic acid compound containing acyl radical of an organic carboxylic acid, preferably with up to 18, and primarily with up to 10, carbon atoms.

Such an acyl radical Ac is primarily a group of the formula Ra-C (Rb) (Re) -C (= O) - (IA),

wherein (1) Ra is an optionally substituted carbocyclic aryl e.g. corresponding phenyl, an optionally substituted, preferably unsaturated, cycloaliphatic hydrocarbon radical, e.g. corresponding cyclohexadienyl or cyclohexenyl, or an optionally substituted heterocyclic alyl radical, e.g. corresponding thienyl or fuiyl, Rb is hydrogen and Rc is hydrogen or optionally substituted, in particular protected hydroxy, amino, carboxyl or sulfo, or in which (2) Ra is cyano, etherified hydroxy or mercapto, such as optionally substituted phenyloxy, phentylthio or pyridylthio, or an optionally substituted unsaturated heterocyclic radical linked via a ring nitrogen atom, for example corresponding tetrazolyl, and Rb and Rc are hydrogen, or in which (3) Ra is an optionally substituted carbocyclic aryl radical, e.g. corresponding phenyl, or an optionally substituted heterocyclic aryl radical, e.g. corresponding thienyl, or fuiyl, and Rb and Rc together preferably mean O-substituted hydroxyimino in the syn configuration.

Cyclohexadienyl is especially 1,4-cyclohexadienyl, while cyclohexenyl is primarily 1-cyclohexenyl.

Thienyl is preferably 2-, furthermore 3-thienyl, and fuiyl means in particular 2-fuiyl, while pyridylthio e.g. 4-pyridylthio, and tetrazolyl e.g. Represent 1-tetrazolyl.

Substituents of a phenyl or phenyloxy group Ra can be present in any position and are i.a. aliphatic hydrocarbon radicals, such as optionally substituted, in particular protected aminomethyl, optionally functionally modified, such as etherified or esterified hydroxy or optionally substituted, in particular protected amino, such as acylamino.

Substituents of a cyclohexadienyl or cyclohexenyl group and a thienyl or fuyl group Ra are e.g. optionally substituted lower alkyl, such as optionally substituted, in particular protected aminomethyl, such a substituent, in particular optionally protected aminomethyl, primarily in the 2-position of a 1,4-cyclohexadienyl or 1-cyclohexenyl radical or in the 5-position of a 2-thienyl - or 2-Fuiylrestes is.

Optionally protected aminomethyl is primarily aminomethyl optionally substituted by lower alkyl, e.g. Methylaminomethyl, where amino is optionally protected, while etherified hydroxy e.g. Lower alkoxy such as methoxy and esterified hydroxy e.g. Lower alkanoyl-oxy such as acetyloxy, aroyloxy, e.g. Benzoyloxy, carbamoyloxy or halogen, e.g. Chlorine, and optionally substituted amino e.g. amino substituted by lower alkyl, e.g. Methylamino, or lower alkylsulfonylamino, e.g. Methylsulfonylamino, can be.

Protected hydroxyl, amino, carboxyl or sulfo groups in acyl radicals of the formula IA are those which are customary in penicillin and cephalosporin chemistry and which can easily be converted into free hydroxyl, amino, carboxyl or sulfo groups, without the 2 penile scaffold being destroyed or other undesirable side reactions taking place.

Amino groups can e.g. be protected by acyl residues, an acyl residue being primarily one by reduction, e.g. when treated with a chemical reducing agent or with catalytically activated hydrogen, or by solvolysis, e.g. by treatment with a suitable acid, also by means of irradiation, the acyl residue of a half ester which can be removed

Carbonic acid is, like a, preferably on the first carbon atom of the esterifying group multiply branched and /

or by aiyl, e.g. optionally, as by lower alkoxy, e.g. Methoxy, and / or nitro substituted phenyl or Bi-5 phenylyl or lower alkoxycarbonyl radical substituted by alylcarbonyl, especially benzoyl, e.g. tert-butyloxycarbonyl, tert-pentyloxycarbonyl, diphenylmethoxycarbonyl, a-4-biphenylyl-a-methyl-ethoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxy-benzyloxy-lo carbonyl or phenacyloxycarbonyl, or on the second carbon atom of the esterifying group halogen-substituted lower alkoxycarbonyl radical, for example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl (or a residue which can be converted into the latter, such as 2-chloro or 2-bromoethoxycarbo-15nyl), furthermore polycyclic cycloalkoxycarbonyl, e.g. Adaman-tyloxycarbonyl.

An amino group may also be substituted by an alylmethyl, such as polyarylmethyl, e.g. by trityl, a 2-carbonyl-vi-nyl group, such as a 1-lower alkoxycarbonyl-l-propen-20 -2-yl group, e.g. l-methoxycarbonyl-l-propen-2-yl, an aryl-thio or aryl-lower alkylthio group, e.g. 2-nitrophenylthio or pentachloiphentylthio, furthermore tritylthio, or an alylsulfonyl group, furthermore by an organic silyl or stannyl group, such as one by lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl, or optionally modified functional groups, such as lower alkoxy , e.g. Methoxy, or halogen, e.g. Chlorine, substituted silyl or stannyl group, primarily tri-lower alkylsilyl, e.g. Trimethylsilyl, halogen-lower alkoxy-lower alkylsilyl, e.g. 30 chloromethoxymethylsilyl, or tri-lower alkylstannyl, such as tri-n-butylstannyl, to be protected.

Hydroxy protecting groups are e.g. Acyl radicals, in particular one of the acyl radicals of carbonic acid semiesters mentioned in connection with a protected amino group, or 35 organic silyl or stannyl radicals, and also easily removable 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radicals, primarily 1-lower alkyl-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. 1-methoxy-ethyl, 1-ethoxy-ethyl, 1-methylthio-ethyl or 1-ethylthio-ethyl, 40 or 2-oxa- or 2-thiacyclone-lower alkyl with 5-7 ring atoms, such as 2-tetrahydrofuiyl or 2-tetrahydropyranyl or corresponding Thia analogues, as well as easily removable, optionally substituted ot-phenyl-lower alkyl radicals, such as optionally substituted benzyl or diphenylmethyl, the substituents of the phenyl radicals being, for example Halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.

A protected carboxyl or sulfo group is primarily one with an aliphatic, cycloaliphatic, cycloalipatic-aliphatic, aromatic or araliphatic alcohol such as a lower alkanol or with a silyl or stannyl group such as tri-lower alkylsilyl, esterified carboxyl or sulfo group. In a carboxyl or sulfo group, for example, the hydroxyl group can be etherified like the hydroxyl group in an esterified carboxy group of the formula -C (= 0) -R2.

An amino protecting group RjA can e.g. can also be an amino group protected by the acyl radical of a carbonic acid semi-ester, a 2-carbonyl - vinyl, aiylthio or alyl-lower alkylthio or aiylsulfonyl group, a triarylmethyl radical or an organic silyl-60 or stannyl group, such a protective group being analogous to that of a correspondingly protected amino group in can be an acyl radical of the formula IA.

O-substituted hydroxyimino is especially lower alkene oxyimino, e.g. Methoxyimino or ethoxyimino, further phenyloxyimino or phenyl-lower alkoxyimino, e.g. Benzyloxy-imino, such groups preferably being in the syn form.

A protected carboxyl group of the formula -C (= 0) -R2A is primarily an esterified carboxyl group, in which R2A is a hydrocarbon radical of this type which is substituted by an organic radical or an organic silyl or, in particular, optionally substituted hydrocarbon radicals, and heterocyclic or heterocyclic-aliphatic radicals , preferably with up to 18 carbon atoms.

An etherified hydroxy group R2A together with the carbonyl group forms a, preferably easily cleavable, e.g. reductive, such as hydrogenolytic, solvolytic, such as acidolytic or hydrolytically cleavable, or easily into another functionally modified carboxyl group, such as esterified carboxyl group convertible into a hydrazino carbonyl group. Such a group R2A is e.g. 2-halogeno-lower alkoxy, where halogen preferably has an atomic weight above 19, e.g. 2,2,2-trichloroethoxy or 2-iodoethoxy, furthermore 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter, or 2-lower alkylsulfonyl-lower alkoxy, e.g. 2-Methylsulfonylethoxy, or R2A is one, optionally substituted by hydrocarbon radicals, especially aliphatic or aromatic hydrocarbon radicals such as lower alkyl, e.g. Methyl and / or phenyl, polysubstituted or a carbocyclic ali group having an electron-donating substituent or a heterocyclic group of aromatic character with oxygen or sulfur as a ring member, mono-substituted methoxy group, such as tert-lower alkoxy, e.g. tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, e.g. Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, lower alkoxyphenyl lower alkoxy, e.g. Lower alkoxy-benzyloxy, such as methoxybenzyloxy (where methoxy is primarily in the 3-, 4- and / or 5-position), primarily 3- or 4-methoxy-benzyloxy, 3,4-dimethoxybenzyloxy, or especially nitro-benzyloxy , e.g. 4-nitrobenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy, or furfuryloxy, such as 2-fur-furyloxy. R2A can also 2-oxa- or 2-thia-cycloalkoxy or -cycloalkenyloxy with 5-7 ring members, such as 2-tetrahydrofuiyl-oxy, 2-tetrahydropyranyloxy or 2,3-dihydro-2-pyranyloxy or a corresponding thia group, or arylcarbonylmeth- oxy, in which ali is in particular an optionally substituted phenyl group, for example Phenacyloxy, or together with the -C (= 0) grouping forms an activated ester group and is, for example, nitrophenyloxy, e.g. 4-Ni-trophenyloxy or 2,4-dinitrophenyloxy. R2A can also be unbranched lower alkoxy, e.g. Be methoxy or ethoxy.

An organic silyloxy or organic stannyloxy group R2A is, in particular, a silyloxy or stannyloxy group which is optionally substituted by 1 to 3 hydrocarbon radicals, preferably having up to 18 carbon atoms. As substituents, it preferably contains optionally substituted, for example by lower alkoxy, such as methoxy, or by halogen, such as chlorine, substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl, and is the first Line tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, Ha-logen-lower alkoxy-lower alkylsilyloxy, e.g. Chloro-methoxy-methyl-silyloxy, or tri-lower alkylstannyloxy, e.g. Tri-n - butylstannyloxy.

The group R2A can also be an etherified hydroxyl group, which together with the carbonyl group -C (= Quine forms cleavable esterified carboxyl group under physiological conditions, primarily an acyloxymethoxy group, where acyl is, for example, the rest of an organic carboxylic acid, primarily one if appropriate Substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the remainder of a lactone. Hydroxy groups etherified in this way are lower alkanoyloxy-methoxy, for example acetyloxymethyloxy or

624 390

Pivaloyloxymethoxv, amino-lower alkanoyloxymethoxy, especially ot-amino-lower alkanoyloxymethoxy, e.g. Glycyl-oxymethoxy, L-valyloxymethoxy, L-leucyloxymethoxy, also phthalidyloxy.

A radical R2a which forms an optionally substituted hydrazinocarbonyl group together with a -C (= 0) grouping is e.g. Hydrazino or 2-lower alkylhydrazino, e.g. 2-M ethylhydrazino.

A bivalent amino protecting group formed together by the residues RtA and R ^ 1 is in particular the bivalent acyl residue of an organic dicarboxylic acid, preferably having up to 18 carbon atoms, primarily the diacyl residue of an aliphatic or aromatic dicarboxylic acid, e.g. the acyl residue of a lower alkane or lower alkenedicarboxylic acid, such as succinyl, or an o-aylenedicarboxylic acid, such as phthaloyl, or is furthermore the acyl residue of a, preferably substituted in the a-position, e.g. an aromatic or heterocyclic radical containing a-aminoacetic acid, wherein the amino group is substituted via a, preferably substituted, e.g. two lower alkyl, such as methyl group-containing methylene radical is attached to the nitrogen atom, e.g. a, especially in the 2-position, substituted, e.g. optionally substituted phenyl or thienyl, and in the 4-position optionally by lower alkyl, such as methyl, mono- or disubstituted l-oxo-3-aza-l, 4-butylene, e.g. 4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.

The radicals RXA and Rtb together can also represent an organic, such as an aliphatic, cycloaliphatic, caclo-aliphatic-aliphatic or araliphatic ylidene radical, preferably having up to 18 carbon atoms.

An organic radical R3 connected via a carbon atom to the ring carbon atom is primarily an optionally substituted aliphatic, cycloaliphatic, cacloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, in particular optionally substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl or phenylnyl or phenylnyl. Substituents of such residues are e.g. optionally functionally modified, such as etherified or esterified hydroxy or mercapto groups, e.g. Hydroxy, lower alkoxy, e.g. Methoxy or ethoxy, lower alkanoyloxy, e.g. Acetyloxy or propionyloxy, halogen, e.g. Chlorine or bromine, or lower alkyl mercapto, e.g. Methoxy, or optionally functionally modified carboxyl groups, such as carboxyl, lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, carbamoyl or cyan.

A lower alkyl radical R3 contains, for example: up to 7, in particular up to 4 carbon atoms, and is i.a. Methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl or pentyl. Substituted lower alkyl is primarily substituted methyl, such as hydroxymethyl, lower alkoxymethyl, e.g. Methoxymethyl, lower alkanoyloxymethyl, e.g. Acetyloxymethyl or propionyloxymethyl, or halomethyl, e.g. Chloromethyl or bromomethyl, lower alkoxycarbonylmethyl, e.g. Methoxycarbonylmethyl or ethoxycarbonylmethyl, or cyanomethyl.

A cycloalkyl radical R3 has e.g. 3 to 7 carbon atoms and is e.g. Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, while a cycloalkyl-lower alkyl radical R3 contains for example 4 to 7 carbon atoms and e.g. Cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl or cyclo-hexylmethyl.

A phenyl, naphthyl, e.g. 1- or 2-naphthyl, or a phenyl-lower alkyl, e.g. Benzyl or 1- or 2-phenylethyl radical R3 can, preferably in the aromatic radical, e.g. by lower alkyl such as methyl or ethyl, lower alkoxy, e.g. Methoxy, or halogen, e.g. Fluorine or chlorine.

A radical R3 can also be a heterocyclic or heterocyclic-aliphatic bonded via a carbon atom

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

624 390 6

Represent the rest, preferably aromatic, such as those that can be produced totally synthetically, in particular pharmacologically

Pyridyl, e.g. 2-, 3- or 4-pyridil, thienyl, e.g. 2-thienyl, or active, such as highly active N-acyl derivative of a 6ß-amino

Furyl, e.g. 2-fuiyl, or corresponding pyridyl-, thienyl- -penam-3-carboxylic acid- or 7ß-amino-3-cephem-4-carbon-

or furyl-lower alkyl, especially methyl, represent. Acyl radical containing acid compound, such as one of the above

The compounds of the formula VIII can be used to produce acyl radicals of the formula (IA), where in this formulation of 2-penem compounds of the formula I Ra> Rb ™ d Rc primarily uses the emphasized meanings

which have valuable pharmacological properties gene, Rj6 stands for hydrogen, or in which Rja and R ^

exhibit. Compounds of formula I wherein e.g. R} a for together one preferably in the 2-position, e.g. by a in pharmacologically active N-acyl derivatives of aromatic or heterocyclic radical, such as phenyl, and in

6β-amino-penam-3-carboxylic acid or 7ß-amino-3-cephem- w 4-position preferably, e.g. through two lower alkyls, such as

-4-carboxylic acid compounds occurring acyl radical Ac and thyl, substituted l-oxo-3-aza-1,4-butylene radical, R2

Rj '11 is hydrogen, or wherein Rxa and Rxb together are hydroxy, preferably by an organic radical or one in the 2-position, e.g. hydroxy group etherified by an aromatic-organic silyl or stannyl group

or heterocyclic radical, and in the 4-position preferred Pe or for an optionally substituted hydrazino group, e.g. is 15 ^ 2A substituted by 2 lower alkyl, such as methyl, and Rs is hydrogen, optionally by etherified

represent l-oxo-3-aza-l, 4-butylene radical, R3 represents the above-mentioned tes or esterified hydroxy, such as lower alkoxy or lower

Has meaning, and R2 hydroxy or a substituted with the alkanoyloxy, lower alkyl, or optionally

Carbonyl group is an esterified carboxyl group, phenyl or phenyl-lower alkyl, which is easily cleavable under physiological conditions, substituted by lower alkyl, lower alkoxy or halogen, and represents salts of the etherified hydroxy group R2A, in which 20 such compounds with salt-forming groups.

Acyl residue Ac functional groups which may be present. In the first place in a 2-penem compound the

such as amino, carboxy, hydroxy and / or sulfo, usually with I or in a salt of such a compound with

are in free form, or pharmacologically usable groups Rja for hydrogen or an acyl radical of

Salts of such compounds with salt-forming groups, formula IA, in which (1) Ra primarily has the emphasized inhibition, for example, of the growth of gram-positive meanings, and, for example, if appropriate

Germs, such as Staphylococcus aureus, and gram-negative Kei-Hydroxy, protected Hydroxy, Niederalkoxy, Niederalkano-

men, such as Escherichia coli, Klebsiellapneumonia or Salmoyloxy, Carbamoyloxy, Halogen, Niederalkylsulfonylamino nella typhimurium, where they are in vitro up to or aminomethyl substituted Thienyl, Fuiyl, Cyclohexa-

about 0.5 mcg / ml and in vivo against gram positive bacteria, dienyl or cyclohexenyl, Rb is hydrogen and Rc e.g. Staphylococcus aureus, (e.g. in mice) in doses of about 30 hydrogen, optionally protected hydroxy, given

wa 0.003 g / kg, and against gram-negative bacteria, e.g. if protected amino or, if appropriate, protected

Escherichia coli, (e.g. in mice) in doses of about 0.065 carboxyl or sulfo, or wherein (2) cyano, 1-tetra-

g / kg, are effective with low toxicity. These new verzolyl, optionally substituted like phenyl phenyloxy,

Bonds, especially the preferred ones, or their pharma- or 4-pyridylthio and Rb and R0 represent hydrogen, or ecologically usable salts, can therefore e.g. in form 35 in which (3) Ra represents phenyl, thienyl or fuiyl and Rb and antibiotic-active preparations, for the treatment of Rc together mean syn-lower alkoxyimino, R ^ stands for corresponding system infections, furthermore as feed hydrogen, R2 stands for hydroxy, optionally a-polyver

kits, for food preservation or as disinfected lower alkoxy, e.g. Find methoxy or tert-butyloxy, or fection agents. 2-halogeno-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodine

1-oxides of compounds of the formula I in which Ria, Rib '40 ethoxy or the 2-chloroethoxy k2 and R3 which can easily be converted into them are those given in connection with the formula I or 2-bromoethoxy, furthermore phenacyloxy, 1-phenyl-lower alk-

Have meanings, or compounds of formula I, wherein 0XY with 1 "3, optionally by lower alkoxy and / or

R3 has the meaning given above, the radicals R ^ and R ^ nitro substituted phenyl radicals, e.g. 4-methoxybenzyloxy,

stand for hydrogen, or Rja one of one in pharma- 4-nitrobenzyloxy, 2-nitro-4,5-dimethoxy-benzyloxy, diphe-

ecologically active N-acyl derivatives of 6β-amino-penam-45 nylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy,

-3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid-lower alkanoyloxymethoxy, e.g. Acetyloxymethoxy or Pi

bonds occurring acyl residue various amino-valoyloxymethoxy, a-amino lower alkanoyloxymethoxy, e.g.

protecting group and Rjh are hydrogen, or R ^ and R ^ glycyloxymethoxy, 2-phthalidyloxy, further tri-lower alkyl

together one, preferably from one in the 2-position, e.g. silyloxy, e.g. trimethylsilyloxy, and R3 represents hydrogen,

by an aromatic or heterocyclic radical, and in 80 lower alkyl, e.g. Methyl, lower alkoxy lower alkyl, e.g. Meth-4 position preferably, e.g. by 2-lower alkyl such as methyl, oxymethyl, lower alkanoyloxymethyl, e.g. Acetyloxymethyl,

Substituted l-oxo-3-aza-1,4-butylene radical represent various biva- or optionally by lower alkyl, lower alkoxy or lent amino protective groups, and R2 for hydroxy halogen substituted phenyl or phenyl-lower alkyl.

is, or R ^ and R ^ have the meanings given above- The invention relates primarily to a process for ben, R2 for a, together with the -C (= 0) grouping 55 preparation of compounds of the formula VIII usable, preferably easily cleavable, protected carboxyl groups for the preparation of 2-penem compounds of the formula I,

pe forming radical R2A, one so protected wherein Rxa is hydrogen or especially an acyl group of the carboxyl group of a physiologically cleavable carboxyl formula IA, wherein (1) Ra is phenyl, hydroxyphenyl, e.g. group is different, and R3 has the meanings given above- 3- or 4-hydroxyphenyl, lower alkylsulfonylaminophenyl,

genes are valuable intermediates that can be 3-methylsulfonyamino-phenyl, aminomethylphenyl, e.g.

Manner, e.g. as described below, in the above 2-aminomethylphenyl, thienyl, e.g. 2- or 3-thienyl, ami-

pharmacologically active compounds are converted to nomethylthienyl, e.g. 5-aminomethyl-2-thienyl, fuiyl, e.g.

that can. 2-fuyl, aminomethylfuyl, e.g. 5-aminomethyl-2-furyl, 1,4-

The invention particularly relates to a process for cyclohexadienyl, aminomethyl-1,4-cyclohexadienyl, e.g.

Preparation of compounds of formula VIII usable 65 2-aminomethyl-1,4-cyclohexadienyl, 1-cyclohexenyl or for the preparation of 2-penem compounds of formula I, aminomethyl-1-cyclohexenyl, e.g. 2-aminomethyl-1-cyclo-

wherein Rta is hydrogen or preferably one in a fer-hexenyl, in the above radicals being hydroxy and / mentally (i.e. naturally occurring) or bio-, semi-or or amino e.g. by acyl, such as optionally halogenated

7

624 390

Lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, can be protected, Rb for hydrogen and Rc for hydrogen, for amino, and also protected amino, such as acylamino, e.g. β-poly branched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino or 2-Ha-logen-lower alkoxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromo-ethoxycarbonylamino, or optionally lower alkoxy and / or nitro-substituted phenyl-lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamino, or for hydroxy, as well as protected hydroxy, such as acyloxy, e.g. β-poly branched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-gen-lower alkoxycarbonyl, such as 2,2,2-tichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, or for optionally, e.g. lower alkyl esterified, carboxyl or sulfo, or in which (2) RaCyan, 1-tetrazolyl, phenyloxy or 4-pyridylthio and Rb and R (. are hydrogen, or in which (3) Ra phenyl, 2-thienyl or 2- Fuiyl represent and Rb and Rc together syn-Niederalk-oxyimino, such as syn-methoxyimino, mean, R11 'is hydrogen, R2 primarily for hydroxy, furthermore for methoxy, a-polybranched lower alkoxy, for example tert-butyloxy, 2-halogen lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally diphenylmethoxy, for example substituted by lower alkoxy such as methoxy, for example diphenyl-methoxy or 4,4'-dimethoxydiphenylmethoxy, or 4-nitro benzyloxy, further tri-lower alkylsilyloxy, for example trimethylsilyloxy, and R3 is hydrogen, lower alkyl having up to 4 carbon atoms, such as methyl, lower alkoxy-lower alkyl having up to 4 carbon atoms, for example methoxymethyl, or lower alkanoyloxy lower alkyl having up to 4 carbon atoms, for example acetyloxymethyl, or phen yl- or benzyl, and salts, in particular pharmacologically usable, non-toxic salts, such as the alkali metal, e.g. Sodium, or alkaline earth metal, e.g. Calcium salts, or ammonium salts, including those with amines, of compounds of the formula I in which R2 is hydroxy.

The invention relates primarily to a process for the preparation of compounds of the formula VIII which can be used for the preparation of 6-acetylamino-2-R3-2-penam-3-carboxylic acid compounds, in which acetyl is substituted by the radicals Ra and Rb, where ( 1) Ra for phenyl or 1,4-cyclohexadienyl and Rb for hydrogen or optionally, for example protected amino as described above, or wherein (2) Ra is phenyloxy and Rb is hydrogen and R3 is hydrogen, methyl, methoxymethyl, acetyloxymethyl or phenyl, and esters, especially lower alkyl esters of such compounds, and the pharmacologically acceptable salts thereof .

The new compounds are prepared according to the invention by using an acylthio compound of the formula

R- "-H

R-

(VII)

cleaves the isopropylidene group by treating with ozone followed by a reducing agent.

Usually an ozone-oxygen mixture is used and the process is carried out in the presence of a solvent such as a lower alkanol, e.g. Methanol or ethanol, a lower alkanone, e.g. Acetone, an optionally halogenated 5 aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. a halogen-lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture, and preferably with cooling, e.g. at temperatures from about -90 ° C to about 0 ° C.

An intermediate ozonide is reductively cleaved, usually without being isolated, to a compound of formula VIII, using catalytically activated hydrogen, e.g. Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as nickel, furthermore palladium catalyst, preferably on a suitable support material, such as calcium carbonate or carbon, or chemical reducing agents, such as reducing heavy metals, including heavy metal alloys or amalgams, e.g. Zinc, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or an alcohol, e.g. Lower alkanol, reducing inorganic salts such as alkali metal iodides e.g. Sodium iodide, or alkali metal bisulfites, e.g. Sodium bisulfite, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, 25 or water, or reducing organic compounds, such as formic acid, are used. Reducing agents which can be easily converted into oxy compounds are advantageously used, the oxide formation being able to take place on account of an existing carbon-carbon double bond 30 or an existing oxide-forming hetero atom, such as sulfur, phosphorus or nitrogen atom. Such connections are e.g. suitably substituted ethene compounds (which are converted into ethyleneoxy compounds in the reaction), such as tetracyanethylene, in particular suitable sulfide compounds (which are converted into sulfoxide compounds in the reaction), such as di-lower alkyl sulfides, primarily dimethyl sulfide, suitable organic phosphorus compounds such as a phosphine, which may contain optionally substituted aliphatic or aromatic hydrocarbon radicals as 40 substituents (and which is converted into a phosphine oxide in the reaction), such as tri-lower alkylphosphines, for example tri-n-butylphosphine, or triaiylphosphines, for example Triphenylphosphine, furthermore phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents (and are converted into phosphoric acid triesters in the reaction), such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethylphosphite, or phosphoric acid triamides, which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as hexa-lower alkylphosphoric triamides, for example Hexamethylphosphoric acid triamide, the latter preferably in the form of a methanol adduct, also suitable nitrogen bases (which are converted into the corresponding N-oxides in the reaction), such as heterocyclic nitrogen bases of aromatic character, e.g. Bases of the pyridine type and in particular pyridine itself. The cleavage of the usually non-isolated ozonide normally takes place under the conditions used for its production, i.e. in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating, preferably at temperatures from about -10 ° C. to about + 25 ° C., and the reaction is usually completed at room temperature.

65 In a starting material of the formula VII, the amino protective group RjA preferably denotes an acyl group Ac, in which free functional groups which may be present, e.g. Amino, hydroxy, carboxyl, or sulfo groups, in an

624390

8th

as is known, amino groups e.g. by the abovementioned acyl, trityl, silyl or stannyl, and by substituted thio or sulfonyl radicals, and hydroxyl, carboxy or sulfo groups, e.g. are protected by the above etherifying or esterifying groups, including silyl or stannyl groups, and Rjb is hydrogen.

In a starting material of the formula VII, R2A preferably represents an etherified hydroxyl group with the —C (= 0) grouping, which forms an esterified carboxyl group, which is easily cleavable, especially under mild conditions, with any functional groups present in a carboxyl protecting group R2A known way, e.g. can be protected as indicated above. A group R2A includes Lower alkoxy, especially o-poly branched lower alkoxy, e.g. Methoxy or tert-butyloxy, or 2-halo-alkoxy, e.g. 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, 2-lower alkylsulfonyl-lower alkoxy, e.g. 2-methyl-sulfonylethoxy, or an optionally substituted one such as lower alkoxy, e.g. 1-phenyl-lower alkoxy group containing methoxy or nitro, such as optionally e.g. substituted benzyloxy or diphenylmethoxy, e.g. Benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, further an organic silyloxy or stannyloxy group such as tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy.

In the starting material of formula VII, R3 is in particular one of the preferred, optionally substituted hydrocarbon radicals, functional groups usually being in a protected form.

In a compound of the formula VIII obtainable according to the invention, a group RjA, Rxb, R3 and R2A can be converted into another group R ^, Rjb, R3 and R2A in a manner known per se; see e.g. German Offenlegungsschrift No. 2 655 298.

The compounds of formula VIII obtainable according to the invention can be processed further as follows.

The compound of the formula VIII can then be sol-volysed into a compound of the formula

R

b /

0

II

■ C R "

(IX)

R,

R

b /

CH ^ X

0 == • C-

■ 4

be transferred. Solvolysis can be carried out as hydrolysis or preferably as alcoholysis, usually with a lower alkanol, e.g. Methanol or ethanol, and the alcoholysis preferably in the presence of water and an organic solvent such as a lower alkanoic acid lower alkyl ester, e.g. Ethyl acetate, if necessary, carried out with cooling or warming. The a-ketocarboxylic acid of the formula VIII need not necessarily be isolated. Do you e.g. the cleavage of the ozonide in the presence of a solvolysis agent, e.g. Water, through, a compound of formula IX can be obtained directly.

The latter is used with a glyoxylic acid compound of the formula OHC-C (= 0) -R2A (X) or a suitable derivative, such as a hydrate or hemiacetal, e.g. a hemiacetal with a lower alkanol, e.g. Methanol or ethanol, and thus receives an a-hydroxy-carboxylic acid compound of the formula wherein X0 is hydroxy, which is usually obtained as a mixture of the two isomers, but can also be isolated in the form of a pure isomer.

The addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring takes place at room temperature or, if necessary, with heating, e.g. up to about 100 ° C, in the absence of an actual condensing agent and / or without the formation of a salt. Using the hydrate of the glyoxylic acid compound, water 25 is formed which, if necessary, can be obtained by distillation, e.g. azeotrope, or by using a suitable dehydrating agent such as a molecular sieve. It is preferred to work in the presence of a suitable solvent, e.g. Dioxane, toluene, or dimethylform-30 amide, or mixture of solvents, if desired or necessary, in the atmosphere of an inert gas such as nitrogen.

In a compound of formula XI, the secondary hydroxy group is converted into a reactive esterified hydroxy group, especially in halogen, e.g. Chlorine or bromine, or 35 into an organic sulfonyloxy group such as lower alkylsulfonyloxy, e.g. Methylsulfonyloxy, or arylsulfonyloxy, e.g. 4-methylphenylsulfonyloxy converted; This gives compounds of the formula XI, in which X ,, is a reactive esterified hydroxyl group, in particular halogen or organic sulfonyloxy, which can be obtained in the form of a mixture of the isomers or in pure form.

The above reaction is carried out by treating with a suitable esterifying agent, e.g. a halogenating agent such as a thionyl halide, e.g. -chloride, 45 a phosphorus oxyhalide, especially -chloride, or a halogenophosphonium halide, such as triphenylphosphine dibromide or diiodide, and a suitable organic sulfonic acid halide, such as chloride, preferably in the presence of a basic, primarily an organic basic agent such as an aliphatic tertiary amine, e.g. Triethylamine, di-isopropylethylamine or polystyrene "Hunig base", or a heterocyclic base of the pyridine type, e.g. Pyridine or col-iodine.

It is preferred to work in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran, or a mixture of solvents, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.

In a compound of the formula XI thus obtainable, 60 a reactive esterified hydroxyl group X0 can be converted by another reactive hydroxyl group in a manner known per se. So you can e.g. replace a chlorine atom by treating the corresponding chlorine compound with a suitable bromine or iodine reagent, in particular with an inorganic bromide or iodide salt, such as lithium bromide, preferably in the presence of a suitable solvent, such as ether, for a bromine or iodine atom.

9

624 390

A compound of formula XI, wherein X0 represents a reactive esterified hydroxy group, is prepared by treating with a suitable phosphine compound, such as a tri-lower alkylphosphine, e.g. Tri-n-butylphosphine,

or a triaiyl phosphine, e.g. Triphenylphosphine, or with a suitable phosphite compound such as a tri-alkyl phosphite e.g. Triethyl phosphite, or an alkali metal dimethyl phosphite, is converted into the desired starting material of the formula II, it being possible, depending on the choice of the reagent, to obtain a compound of the formula IIA or IIB.

The above reaction is preferably carried out in the presence of a suitable inert solvent such as a hydrocarbon, e.g. Hexane, cyclohexane, benzene or toluene, or an ether, e.g. Dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture. If necessary, one works under cooling or at elevated temperature and / or in the atmosphere of an inert gas such as nitrogen.

The use of a phosphine compound is usually carried out in the presence of a basic agent, such as an organic base, e.g. of an amine, such as tri-ethylamine, diisopropyl-ethyl-amine or polystyrene “Hünig base”, and thus arrives directly at the phosphoranylide starting material of the formula IIA, which is formed from the corresponding phosphonium salt.

The raw materials of the formula obtained

Ri

R,

0 = 3 = 0-

where RiA, R ^, R2A and R3 have the meanings given above, and in which X® denotes either a triply substituted phosphonio group or a doubly esterified phosphono group together with a cation, can then be ring-closed in 6-amino-2-penem- 3-carboxylic acid compounds of the formula

_a

R,

as group X® are triphenylphosphonio on the one hand and diethylphosphono on the other hand together with an alkali metal, e.g. Sodium ion.

In phosphonium compounds of the formula II, which are also referred to in the 5 isomeric ylen form as phosphorane compounds, the negative charge is neutralized by the positively charged phosphonium group. In phosphono compounds of formula II, which can also be referred to as phosphonate compounds in their isomeric form, the io negative charge is neutralized by the cation of a strong base which, depending on the preparation of the phosphono starting material, e.g. an alkali metal, e.g. Sodium, lithium or potassium ion. The phosphonate starting materials are therefore used as salts in the reaction.

i5 Formula II shows the starting material in the form in which the ring closure takes place. Usually the corresponding phosphoranylidene compound of the formula

(II)

C - R,

be transferred.

Group X® in the starting material of the formula II is one of the phosphonio or phosphono groups customary in Wittig condensation reactions, in particular a tri-ayl, e.g. Triphenyl, or tri lower alkyl, e.g. Tributylphos-phoniogroup, or one by lower alkyl, e.g. Ethyl, doubly esterified phosphono group, the Symb'ol X® in the case of the phosphono group still the cation of a strong base, especially a suitable metal such as alkali metal, e.g. Lithium, sodium or potassium ion. Prefers

(HA)

where X1 is a trisubstituted, especially a tri-ayl, e.g. Triphenyl, or a tri lower alkyl, e.g. Tri-n-35-butyl-phosphoranylidene radical, or the corresponding phosphono compound of the formula

R,

R

\ b /

H

H

N.

\

0 = 1

■ C — R, Ii • 0

CH — X /

(IIB)

(I)

Cr wherein X2 for a phosphono, especially a dialkylphos phono, e.g. Diethylphosphono is used, wherein a phosphono starting material of formula IIB by Be-55 with a suitable basic reagent, such as an inorganic base, e.g. an alkali metal carbonate, such as sodium or potassium carbonate, or an organic base, such as a tri-lower alkylamine, e.g. Triethylamine, or a cyclic base of the amidine type, such as a corresponding dira azabicycloalkene compound, e.g. 1,5-diaza-bicyclo [5.4.0] -undec-5-ene, in the form suitable for ring closure, i.e. is converted into the compound of formula II.

The ring closure can occur spontaneously, i.e. during the preparation of the starting materials, or by heating, e.g. in a temperature range from about 30 ° C. to about 120 ° C., preferably from about 50 ° C. and about 100 ° C., suitable condensing agents or catalysts being used, if necessary, to accelerate the ring closure reaction.

624 390

10th

The reaction is preferably carried out in the presence of a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. Methylene chloride, an ether e.g. Diethyl ether, a lower alkylene glycol lower alkyl ether, e.g. Dimethoxyethane or diethylene glycol dimethyl ether, a cyclic ether, e.g. Dioxane or tetrahydrofuran, a carboxamide, e.g. Dimethylformamide, a di-lower alkyl sulfoxide, e.g. Dimethyl sulfoxide, or a lower alkanol, e.g. Methanol, ethanol or tert-butanol, or in a mixture thereof, preferably at an elevated temperature, such as at about 50 to 150 ° C, and, if necessary, in an inert gas, e.g. Argon or nitrogen atmosphere.

The starting materials of formula VII used according to the invention can e.g. are prepared as follows, the following variant having proven particularly suitable for compounds in which R3 is different from hydrogen:

A compound of the formula

R,

R

b /

0:

CH— C

R,

'CH,

which one e.g. by converting a 6-amino-2,2-dimethyl-penam-3-carboxylic acid compound, in which the amino and the carboxyl group are in protected form, into the corresponding 1-oxide and reacting the latter with a suitable mercapto compound Formula R0-SH (IV) can be obtained, and in which R0 is a radical bonded to the sulfur atom via a carbon atom, in particular a cyclic and primarily a heterocyclic radical, for example 2-Benzthia-zolyl is obtained by treating with a basic agent such as an organic base, e.g. an amine such as tri-lower alkylamine, e.g. Triethylamine, or an inorganic base in the isomeric compound of the formula

R,

R.

\

N.

H

i

1

0 =

-R

/ CH3

(V)

= C

A * CH3

transferred.

The dithio compound of the formula V obtainable in this way is treated with a reducing agent and, at the same time or preferably subsequently, reacted with a reactive acylation derivative of an acid of the formula R3-C (- 0) -0H (VI). Suitable reducing agents are primarily hydride reducing agents, such as alkali metal borohydrides, e.g. Sodium borohydride, also phosphine compounds, such as triaiyl,

e.g. Triphenylphosphine, preferably using the hydride reducing agents in the presence of suitable diluents, such as dimethylformamide, and in the absence of the acylating agent, which is usually used subsequently, while the phosphine reducing agents are preferably used in the presence of the acylating agent and suitable diluents, e.g. Acetic acid. Suitable acylating agents are in particular anhydrides of the acid of formula VI, such as symmetrical anhydrides, e.g. Anio-hydrides of lower alkanecarboxylic acids such as acetic anhydride or mixed anhydrides, preferably with hydrohalic acid, i.e. the corresponding acid halides, primarily acid chlorides or bromides.

In connection with the present description i5 contain, unless expressly defined, organic radicals designated “lower” up to 7, preferably up to 4 carbon atoms; Acyl residues contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

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

example 1

e) A solution of 0.24 g of 2- (4ß-acetylthio-3-oxo-3ß - phenyloxyacetyIamino-l-azetidinyl) -2- (2-propylidene) -acetic acid-

25 acid-4-nitrobenzyl ester in 20 ml of methyl acetate is cooled to -78 ° and a mixture of ozone and oxygen is passed so that 0.1 mmol ozone get into the mixture per minute. After the introduction of 1.5 equivalents of ozone, the supply of the gas mixture is interrupted and the mixture is left to stand at -78 ° for 15 minutes. The excess ozone is expelled by introducing nitrogen and the reaction mixture is treated with 1 ml of dimethyl sulfide. The mixture is left to stand in a closed vessel for 16 hours at room temperature. The volatile parts are evaporated under reduced pressure and the crystalline residue is recrystallized from a mixture of methylene chloride and diethyl ether. The almost colorless 2- (4ß-acetylthio-2-oxo-3ß-phenyloxy-acetylamino-l-azetidi-nyl) -2-oxo-acetic acid 4-nitrobenzyl ester melts at 154 to 40 156 °; [a] D20 = -13 ° ± 1 ° (c = 0.984% in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95 [i, 3.20-2.45 [i, 5.48 | x, 5.69 jx, 5.87 jji, 6.25 p., 6.58 n, 6.71 p ,, 6.95-7.08 [i, 7.25 yy, and 7.45 | i.

The compound obtained can be further processed as follows:

f) A solution of 2.78 g of crude 2- (4β-acetylthio-2-oxo - 3ß-phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid-4 - nitrobenzyl ester in 55 ml of methyl acetate is mixed with 500 ml of methanol and diluted 11 ml of water; one leaves

5o rend 18 hours at room temperature and evaporate under reduced pressure. The residue is chromatographed on 300 g of silica gel, the oxalic acid monomethyl mono-4-nitrobenzyl ester and other impurities 55 being washed out with a 4: 1 mixture of benzene and ethyl acetate. The 4β-acetylthio-3ß-phenyloxyacetylamino-azetidin-2-one is eluted with a 1: 1 mixture of benzene and ethyl acetate. The product is recrystallized from a mixture of methylene chloride and diethyl ether, mp 137.5-138.5 °; Thin layer chromatography (silica gel): 60 Rf = 0.20 (benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 n, 3.28-3.40 ji, 5.61 [i, 5.92 (j, 6.27 (x, 6.60 n, 6.71 ji , 6.97 jx and 7.08 (shoulder).

g) A solution of 0.294 g of 4β-acetylthio-3ß-phenyloxy-65 acetylamino-azetidin-2-one and 0.495 g of G lyoxylate tert-bu-

tylester hydrate in 10 ml toluene and 2.5 ml dimethylformamide is in the presence of sodium aluminum silicate molecular sieves (Union Carbide type A3; pore diameter 3Â;

11

624 390

fourth at 250 ° and under a pressure of 0.01 mm Hg) stirred for one hour at room temperature and then filtered. The filtrate is taken to dryness under reduced pressure. Toluene is added to the residue and evaporated again under high vacuum; this process is repeated several times. A mixture of the two isomers of 2- (4ß-acetylthio-2-oxo-3ß-phenyloxyacetylamino-- l-azetidinyl) -2-hydroxyacetic acid tert-butyl ester is obtained, thin layer chromatogram (silica gel): Rf ~ 0.25 (ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.85-3.15 p,

2.97 (i, 3.30-3.50 p, 5.61 | x, 5.75 (x, 5.90 p, 6.25 fi, 6.60 p., 6.70 p,

6.98 p., 7.07 p. (Shoulder) and 7.32 p. The product is used in the next step without cleaning.

h) A mixture of 0.455 g of the crude 2- (4ß-acetylthio - 2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) -2-hydroxy-escetic acid tert-butyl ester in 15 ml of dioxane is mixed with 0, 3 g of thionyl chloride and 1 g of polystyrene "Hunig base" [prepared by heating a mixture of 100 g of chloromethyl polystyrene (J. Am. Chem. Soc., Vol. 85, p. 2149 <1963>), 500 ml of benzene , 200 ml of methanol and 100 ml of diisopropylamine at 150 ° while shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3: 1 mixture of dioxane and triethylamine, 1000 ml of methanol, 1000 ml of dioxane and 1000 ml of methanol and drying for 16 Hours at 100 ° / 10 mm Hg; the product neutralizes 3.34 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water and is suspended in dioxane for 30 minutes before use] and the reaction mixture is stirred for 3 hours at room temperature, then filtered. The filtrate is evaporated under reduced pressure. This gives the amorphous, almost pure 2- (4β-acetylthio-2-oxo-3ß-phenyloxy-acetylamino-l-azetidinyl) -2-chloroacetic acid tert-butyl ester, which is probably present as a mixture of the two isomers; Thin layer chromatogram (silica gel): Rf = 0.52 (ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 p, 3.25 to 3.50 p, 5.59 p, 5.74 p, 5.89 p, 6.25 p, 6.60 p, 6, 71 p, 6.96 p, 7.32 p and 7.60 p. The product is processed without further cleaning.

i) A solution of 0.452 g of 2- (4β-acetylthio-2-oxo-3-phenyloxyacetylamino-l-azetidinyl) -2-chloroacetic acid tert-butyl ester and 0.393 g of triphenylphosphine in 15 ml of dioxane is present in the presence of 1.0 g polystyrene "Hünig base" (suspended in dioxane for 30 minutes before use) heated under a nitrogen atmosphere at 50 ° for 18 hours, then filtered and the filtrate evaporated under reduced pressure. The residue is subjected to preparative thin layer chromatography (silica gel plates 20 cm long, 20 cm wide and 0.15 cm thick) using a 1: 1 mixture of benzene and ethyl acetate. This gives the pure and amorphous 2- (4β-acetylthio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylidene-acetic acid tert-butyl ester, thin layer chromatography (silica gel): Rf = 0 , 21 (1: 1 benzene / ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98 p, 3.31 p, 3.40 p, 5.68 p, 5.92 p, 6.11 p, 6.20 p (shoulder), 6.28 p (shoulder), 6.34 p (shoulder), 6.60 p, 6.72 p, 6.98 p, 7.07 p (shoulder) and 7.35 p.

A solution of 0.05 g2- (4ß-acetylthio-2-oxo-3ß-phenyl-oxyacetylamino-l-azetinyl) -2-triphenylphosphoranylidene - acetic acid tert-butyl ester in 50 ml of toluene is at 70 ° for 10 hours warmed, slowly passing argon through the solution. The solvent is evaporated under reduced pressure and the residue is subjected to preparative layer chromatography on silica gel (Merck, analytical; three plates 20 cm long, 20 cm wide and 0.025 cm thick), using a 1: 1 mixture of benzene and es

ethyl acetate used. This gives the pure amorphous 2-methyl-6β-phenyloxyacetylamino-2-penem-3-carboxylic acid tert-butyl ester of the formula

CH-

C (CHß) 3

Rf = 0.53; Ultraviolet absorption spectrum (in ethanol): 15 \ nax = 305 mp, 275 mp, 268 mp and 263 mp; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98 p, 3.32 p, 3.41 p, 3.45 p (shoulder), 5.57 p, 5.90 p, 6.27 p, 6.60 p, 6.71 p, 6.97-7.08 p and 7.33 p; [afc20 = + 202 ° ± 1 ° (c = 0.567 in chloroform).

20 The starting material can be produced as follows:

a) A solution of 36.6 g of 6ß-phenyloxyacetylamino-penam-3-carboxylic acid-l-oxide, 11.1 ml of triethylamine and 23.8 g of 4-nitrobenzyl bromide in 200 ml of dimethylformamide is under nitrogen for 4 hours at room temperature

25 stirred. The reaction solution is then introduced into 1500 ml of ice water, the precipitate is filtered off, dried and recrystallized twice from a mixture of ethyl acetate and methylene chloride. The colorless, crystalline 6β-phenyloxyacetylamino-penam-3-carboxylic acid 4-nitrobenzyl ester 30-Lß-oxide melts at 179-180 °.

b) A solution of 5.01 g of 6β-phenyloxyacetylamino-penam-3-carboxylic acid-4-nitrobenzyl ester-Lß-oxide and 1.67 g of 2-mercapto-benzothiazole in 110 ml of dry toluene is refluxed in a for 4 hours Nitrogen atmo-

35 sphere cooked. The solution is concentrated by distillation to a volume of about 25 ml and diluted with about 100 ml of diethyl ether. The precipitated product is recrystallized from a mixture of methylene chloride and diethyl ether, and the 2- [4β- (2-Benzthiazolyl-di-40 thio) -3ß-phenyloxyacetylamino-2-oxol-azetidinyl] -2- ( 1-propen-2-yl) 4-nitrobenzyl acetate, mp 138-141 °.

c) 9.9 g of 2- [4β- (2-benzothiazolyldithio) -3ß-phe-nyloxyacetylamino-2-oxo-l-azetidinyl] -2- (l-propen-2-yl) -es- 4-nitrobenzyl acetate in 200 ml of warm ethylene glycol

45 dimethyl ether, 5 ml of triethylamine are added and the solution is stirred for 75 minutes at room temperature. The solvent is evaporated off under reduced pressure; toluene is added and the mixture is evaporated again under reduced pressure. The crude product is chromatographed on hydrochloric acid-washed Sili-50 cagel; Solvent toluene / ethyl acetate 3: 2. The almost white, crystalline foam obtained 2- [4ß- (2-B enzthiazolyldithio) -2-oxo-3ß-phenyloxy-acetylamino-l-azetidinyl] -2- (2-propylidene) -acetic acid-4-nitro -benzyl ester is recrystallized from a mixture of methylene chloride and 55 diethyl ether. Despite the melting point range of 105-115 ° according to thin layer chromatography (silica gel; toluene / ethyl acetate 60:40), the product is homogeneous; [<x] D20 = -15 ° ± 1 ° (c = 0.908% in chloroform); ultra violet absorption spectrum (in ethanol): = 268 mp 60 (e = 24 200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92 p, 5.61 p, 5.78 p and 5.90 p.

d) A solution of 0.076 g of sodium borohydride in 10 ml of dimethylformamide is under a nitrogen atmosphere and

65 with cooling in a methanol / ice bath with a solution of 0.897 g2- [4ß- (2-benzthiazolyldithio) -2-oxo-3ß-phenyl-oxyacetylamino-l-azetidinyl] -2- (2-propylidene) 4-nitrobenzyl acetate in 14 ml of dimethylformamide dropwise

624 390 12

and offset over a period of 10 minutes. Then 273m | x (e = 1100); infrared absorption spectrum (inMethylene

7 ml of freshly distilled acetic acid bromide are added. The chloride): characteristic bands at 5.55 p, 5.7 p, 5.9 p and

Reaction mixture is stirred at 0 ° for 60 minutes, 8.25 p.

Diluted with 350 ml of benzene and washed several times with 100 ml each e) A solution of 9.5 g of penicillin V-methyl ester 1-oxide water. It is dried over sodium sulfate and mixed in 300 ml of benzene, 37.5 ml of acetic anhydride and the solvent is evaporated under reduced pressure. The 12.5 ml of trimethyl phosphite are added and, with a bath temperature residue, the mixture is heated at 100 ° for 23 hours on a column of 50 g of silica gel. After cooling, graphed using benzene as solvent. The solvent and the excess of the rea- The fractions are removed under reduced pressure with benzene and a 9: 1 mixture of benghens and the re-zol and ethyl acetate are discarded; the ge io was taken to dryness twice with toluene. The undesired 2- (4ß-acetylthio-2-oxo-3ß-phenyloxyacetylamino- stand is chromatographed on 300 g of silica gel, using a 4-nitrobenzyl ester -l-azetidinyl) -2- (propylidene) a 7: 1 mixture of toluene and ethyl acetate (10 is washed out with a 4: 1 mixture of benzene and ethyl acetate fractions of 300 ml each) and a 4: 1 mixture of toluene and ester, the crude product of the preparative ethyl acetate (10 fractions to 300 ml each), subjected to thin-layer chromatography (silica gel) and 15 First, impurities, then the 2- (4ß-acetylthio-a 2: 1 mixture of benzene and ethyl acetate - 2-oxo-3ß-phenyloxyacetylamino- l -azetidinyl) -2- (1-propene-det. The product is obtained in amorphous form; thin -2-yl) -acetic acid methyl ester as colorless and solid, but layer chromatography (silica gel): Rf = 0.45 (benzene / Washed out vinegar- non-crystalline product; thin-layer chromic acid ethyl ester 1: 1); Infrared absorption spectrum (in methyl- togram (silica gel): Rf 0.4 (system: toluene / ethyl acetate-lenchloride): characteristic bands at 2.95 p, 3.30 p, 3.35 20 ester 1: 1); Infrared absorption spectrum (in methylene chloride): up to 3.55 yes, 5.63 p, 5.80 p (shoulder), 5.89 yes, 6.15 p 6.25 jx, 6.31 p, characteristic bands at 5.55 p, 5.65 p, 5.85 [i and 6.65 p. 6.45 p, 6.97 p, 7.08 p, 7.18 p, 7.32 p and 7.43 p. A solution of 4.04 g of 2- (4ß-acetylthio-2-oxo-3ß-phenyl-

oxyacetylamino- l-azetidinyl) -2- (l-propen-2-yl) -acetic acid-

Example 2 -methyl ester in 80 ml of dry methylene chloride is added to g) a solution of 4 g of 2- (4β-acetylthio-2-oxo-3ß-phe- 25 room temperature with 0.8 ml of triethylamine. The reacyloxyacetylamino-l- azetidinyl) -2- (2-propylidene) -acetic acid ion mixture is stirred for 70 minutes and then with methyl ester in 100 ml of methanol is cooled to -20 ° and dilute hydrochloric acid and a dilute aqueous Na solution through the solution for 100 minutes washed an ozone-oxygen-trium chloride solution. The organic phase is passed through a mixture (a total of 3 equivalents of ozone). The white precipitate is dried over sodium sulfate and crystalline precipitate is dissolved in 300 ml of methylene chloride and evaporated. The 2- (4β-acetylthio-2-oxo-3ß) and the solution are thus washed with 100 ml of a 10% aqueous sodium phenyloxyacetylamino-l-azetidinyl) -2- (2-propylidene) -acetic acid hydrogen sulfite solution . The organic phase becomes methyl acid ester as a colorless armorphic product; Infrared-dried over sodium sulfate and under reduced pressure sorption spectrum (in methylene chloride): characteristic Ban-evaporated. The residue is obtained by adding methades at 5.65 p, 5.75 p (shoulder), 5.85 p and 8.15 p.

noi crystallized at 0 °. The 2- (4β-acetylthio-2- 35

-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid- Example 3

re-methyl ester, mp 142-145 °; Infrared absorption spectrum (in d) A solution of 1.8 g2- [4ß- (4-nitro-benzoyl) thio-2-

Methylene chloride): characteristic bands at 5.45 p, 5.70 p -oxo-3ß-phenyloxyacetylamino-l-azetidinyl] -2- (2-propyl-

and 5.85 p. iden) -acetic acid methyl ester in 20 ml of ethyl acetate

The compound obtained can be processed further as follows 40 is filtered through a glass filter, and the filtrate at -20 °

be treated with ozone (0.33 mmol / minute) for 45 minutes

h) A solution of 0.380 g of 2- (4ß-acetylthio-2-oxo-3ß- delt. Then diluted with 100 ml of ethyl acetate, -phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid-washed with 40 ml a 10% aqueous sodium hydrogen ethyl ester in 10 ml dry tetrahydrofuran (over lithium sulfite solution and distilled twice with 25 ml each of a dilute aqueous aluminum hydride) is cooled in an ice bath, the sodium chloride solution is dried, and the organic phase and with 1, 5 ml of a 1 molar solution of diborane in tetrahedral sodium sulfate. The solvent is evaporated and treated under hydrofuran. The mixture is stirred for 60 minutes under reduced pressure and the residue is crystallized from cold cooling to 0 ° and then diluted with ice-cooled methylene methanol. The 2- [4β- (4-nitro-benzoyl) chloride is thus obtained and the organic phase is separated off using a 25% - -thio-2-oxo-3β-phenyloxyacetylamino-l-azetidinyl] -2-oxo -a-aqueous ammonium chloride solution and with water, methyl acetate, mp 130-133 °; Infrared absorption spec will wash. It is dried over sodium sulfate and triturated (in methylene chloride): characteristic bands at 5.5 p, evaporated under reduced pressure. The 2- (4β- 5.7 p, 5.9 p, 6.55 p, 7.45 p and 11.8 p are thus obtained.

Acetylthio-2-oxo-3β-phenyloxyacetylamino-l-azetidinyl) -2- The compound obtained can be further processed as follows:

-hydroxy-acetic acid methyl ester. be:

The starting material can be prepared as follows: ss e) A solution of 0.48 g of 2- [4ß- (4-nitro-benzoyl) -thio-

d) A solution of 18.5 g of penicillin V-1-oxide in tetra--2-oxo-3β-phenyloxyacetylamino-l-azetidinyl] -2-oxo-acetic hydrofuran is cooled to 0 ° and added dropwise with methyl acid ester in 0.4 ml of ethyl acetate, diluted with 160 ml of a solution of diazomethane in diethyl ether, 20 ml of a 98: 2 mixture of methanol and water is diluted until no starting material is left in thin layer chromatography and left to stand for 16 hours at room temperature, phish (system: acetic acid / Toluene / water 5: 5: 1) found »It is evaporated under reduced pressure, the residue can become. The reaction mixture is again evaporated under reduced pressure with 5 ml of methanol to dryness and the residue is dissolved in hot acetic acid and then from an ethyl acetate-benzene mixture of kri-acidic ethyl ester. Diethyl is slowly installed with stirring. The 4ß- (4-nitro-benzoyl) thio-3ß ether is thus added and the mixture is completely dissolved until -phenyloxyacetylamino-azetidin-2-òn, mp 152-155 °; Infrared trapping of the precipitation at 0 ° for 3 days allows 65 absorption spectrum (potassium bromide): characteristic bans. This gives the crystalline penicillin V-methyl ester 1-den at 5.65 p, 6.0 p, 6.55 p, 7.4 p and 11.8 p. From the mother oxide, mp 135-137 °; Ultraviolet absorption spectrum (in ethanol can be determined by chromatography on silica gel and under noi): \ nax at 260 mp (e = 1000), 267 mp (e = 1300) and use of 4: 1 and 3: 1 mixtures of toluene and It-

13

624 390

ethyl acetate can be isolated as mobile phases a further amount of the desired product.

f) A solution of 0.08 g of 4ß- (4-nitro-benzoyl) -thio-3ß - phenyloxyacetylamino-azetidin-2-one and 0.2 g of glyoxylic acid - tert-butyl ester in 1 ml of dry dimethylformamide and

2 ml of toluene are mixed with 2 g of molecular sieve and during

Stirred for 3 hours at room temperature. After filtering and washing with dry tetrahydrofuran and toluene, the filtrate is evaporated under high vacuum and the residue is taken to dryness a few times with toluene. This gives tert-butyl 2-hydroxy-2- [4β- (4-nitro-benzoyl) thio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl] acetic acid as an amorphous foam, infrared absorption spectrum ( in methylene chloride): characteristic bands at 5.6 | a, 5.7 yy., 5.9 p ,, 6.5 p, 7.4 | x and 11.75 fj ..

g) The 2-hydroxy - 2- [4β- (4-nitro-benzoyl) thio-2-oxo-3β-phenyloxyacetylamino-no-1-azetidinyl] acetic acid tert-butyl ester obtained by the above process is dissolved in 2 ml of dry tetrahydrofuran and stirred at 0 °, then 16 ml of thionyl chloride and 32 ml of triethylamine were added. The reaction mixture was stirred at 0 ° for 30 minutes, then diluted with toluene and washed with dilute nitric acid and water. The organic phase The mixture is dried over sodium sulfate and evaporated under reduced pressure to give a mixture of the two isomers of 2-chloro - 2- [4ß- (4-nitro-benzoyl) thio-2-oxo-3ß-phenyloxyacetylami-no- tert-Butyl 1-azetidinyl] acetic acid, which can be purified by chromatography on 3.5 silica gel using 30 ml of a 4: 1 mixture of toluene and ethyl acetate, and which is obtained as an amorphous product.

A solution of 0.027 g of the mixture of the two isomers of 2-chloro-2- [4ß- (4-nitro-benzoyl) thio-2-oxo-3ß-phenyl-oxyacetylamino-l-azetidinyl] -acetic acid tert.- butyl ester and 0.026 g triphenylphosphine in 0.5 ml dry tetrahydrofuran is kept under an argon atmosphere for 4 days at room temperature. 20 ml of ethyl acetate are added, the mixture is washed with 20 ml of a dilute aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and evaporated under reduced pressure. This gives an oily product which is chromatographed on 1 g of silica gel, 5 fractions of 1 ml of a 5: 1 and 7 fractions of 1 ml of a 2: 1 mixture of ethyl acetate and toluene being used. This gives 2- [4ß- (4-nitro-benzoyl) thio-2-oxo-3ß-phenyloxyacetylamino-no-1-azetidinyl] -2-triphenylphosphoranylidene-acetic acid - tert-butyl ester as a pure amorphous product, Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65 jx, 5.9 [i, 5.95 jx, 6.2 | i, 6.55 jj, 7.45 (i and 11.8 p ..

A solution of 0.022 g2- [4ß- (4-nitro-benzoyl) -thio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl] -2-triphenylphos-phoranylidene-acetic acid tert-butyl ester in 3 ml of dry toluene is held in a 55 ° warm bath for 17 hours, passing a stream of argon through the solution. The solution is then taken to dryness under reduced pressure and the residue is filtered through 0.6 g of silica gel in 10 ml of a 4: 1 mixture of toluene and ethyl acetate, then evaporated. The amorphous tert-butyl 2- (4-nitro-phenyl) -6ß-phenyloxyacetylamino-2-penem-3-carbonic acid is obtained as a residue after evaporation of the filtrate, infrared absorption spectrum (in methylene chloride): characteristic bands at 5 , 55 (i, 5.9 (x, 6.25 [i, 6.6 (i, 7.45 (i and 8.7 | i.

A solution of 0.02 g of tert-butyl 2- (4-nitro-phenyl) -6ß-phenyloxy-acetylamino-2-penem-3-carboxylate in 2 ml of dry methanol is mixed with 0.05 g of a 5% strength Palladium-on-carbon catalyst added and hydrogenated at 0 ° for 30 minutes. The reaction mixture is filtered and evaporated under reduced pressure. The 2- (4-aminophenyl) -6ß-phenyloxyacetylamino-2-penem-3-carbonic acid tert-butyl ester is thus obtained as a pale yellow, amorphous product, infrared absorption spectrum (in methylene chloride): cha-5 characteristic bands at 5.55 | i, 5.9 pt, 6.2 jx, 6.6 | i, 6.7 p and 8.65 [i.

The starting material can be obtained as follows:

a) A solution of 38.5 g of penicillin V-methyl ester 1-oxide in 1000 ml of toluene is mixed with 18.8 g of 2-mercapto-benzothiazole and the reaction mixture is heated at a bath temperature of 130 ° for 8 hours. After cooling, the solvent is removed under reduced pressure, the residue is dissolved in 600 ml of ethyl acetate at 60 °, and the solution is filtered through a warm glass filter. The Fil-15 tread is evaporated to a volume of 400 ml and kept at -20 ° for 2 days. The methyl 2- [4β- (2-benzothiazolyl-di-thio) -2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl] -2- (1-propen-2-yl) -acetate is obtained as a crystalline product , F. 135-137 ° after recrystallization from ethyl acetate, ultraviolet absorption spectrum (in ethanol): \ max = 243 mji (e = 9300), 268 m | i (e = 13 700) and 275 mji (e = 13 000 ); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.6 (i, 5.75 (i, 5.9 [i, 8.15 | i and 9.95 ji.

25 b) A solution of 26.5 g of 2- [4ß- (2-benzothiazolyldithio) - 2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl] -2- (l-propen - 2-yl) - methyl acetate in 400 ml of methylene chloride is mixed with 4 ml of triethylamine at room temperature and the mixture is stirred at room temperature for 40 minutes, then with 200 ml of 1-n. Hydrochloric acid and washed with a dilute aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and then evaporated under reduced pressure. The non-crystalline residue is chromatographed on 500 g of silica gel with a 3: 1 mixture of 35 toluene and ethyl acetate as the mobile phase; 14 fractions of 500 ml each are removed. This gives the 2- [4ß- (2-benzthiazolyldithio) -2-oxo-3ß - phenyloxyacetylamino-l-azetidinyl] -2- (2-propylidene) acetic acid methyl ester as a pale yellow, not -crystalline product, which can be crystallized from ethyl acetate, mp 179-182 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.6 (i, 5.75 ji, 5.9 pt, 8.15 (i and 9.9 | x.

c) A solution of 0.106 g of 2- [4β- (2-benzothiazolyldithio) -45 -2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl] -2- (2-propyl-. iden) -acetic acid methyl ester in 5 ml of dry dimethylformamide is cooled to −20 ° and a solution of 0.01 g of sodium borohydride in 1 ml of dimethylformamide is added; the solution is prepared by stirring the mixture for 10 minutes at room temperature. The reaction mixture is stirred at -20 ° for 30 minutes, then 0.207 g of 4-nitro-benzoyl chloride in 0.5 ml of dimethylformamide are added. It is washed with a further 0.5 ml of dimethylformamide, then the mixture is stirred at room temperature for 40 minutes. 55 Dilute with 70 ml of benzene, filter and wash three times with 10 ml of water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in 20 ml of a toluene-ethyl acetate mixture and kept at 60 ° for one hour. The insoluble material is filtered off and the filtrate is washed on 5 g of silica gel chromatography, washing with a 7: 1 and a 3: 1 mixture of toluene and ethyl acetate. This gives the methyl 2- [4β- (4-nitro-benzoyl) -thio-2-oxo-3β-phenyloxyacetylamino-1-azetidinyl] -65 -2- (2-propylidene) -acetate as a colorless foam crystallized from methanol, mp 132-134 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65 fi, 5.8 jj, 5.95 jx, 6.55 | x, 7.4 n and 11.8 | x.

624 390

14

Example 4

c) A solution of 1.41 g of 2- (4ß-isobutyrylthio-2-oxo-3 - phenyIoxyacetylamino-l-azetidinyl) -2- (2-propyIiden) -acetic acid-tert-butyl ester in 32 ml of absolute Methanol is cooled to -20 ° and treated at this temperature for 32 minutes with a mixture of ozone and oxygen (0.33 mmol ozone per minute). After two more hours at -20 °, the crystalline material is filtered off and washed with a mixture of methanol and diethyl ether. 2- (4ß-Isobutyrylthio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid tert-butyl ester, mp 112-114 °, is thus obtained

after recrystallization from methanol; [ab20 = -51 ° ± 1 ° (c = 1.015 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 | i, 3.30 ji, 3.40 jul, 5.49 | i, 5.70 [i, 5.86 (i (broad), 6.25 [ i, 6.29 p. (shoulder), 6.60 fx, 6.70 (i, 6.95 [i, 7.32 yes (broad), 8.20 | x (broad) and 8.50 | x .

The compound obtained can be processed further as follows:

d) A solution of 0.650 g of 2- (4ß-isobutyrylthio-2-oxo - 3ß-phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid - tert-butyl ester in 13 ml of methyl acetate, 100 ml of methanol and 13 ml Water is stirred at room temperature for 2½ hours, and the reaction mixture is then evaporated to a smaller volume. It is partitioned between methylene chloride and water, the organic phase is separated off, dried and evaporated under reduced pressure. The residue is chromatographed on 30 ml of silica gel, eluting with a 4: 1 mixture of benzene and ethyl acetate. The still impure 4ß-isobutyiylthio-3ß-phenyloxyacetyl-amino-azetidin-2-one is recrystallized from a mixture of methylene chloride and diethyl ether, mp 109-111 °; Thin layer chromatography (silica gel): Rf = 0.26 (system: ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 | i, 3.32 fx, 3.40 | x, 5.61 ji, 5.92 (i, 6.25 | x, 6.29 p, (shoulder) , 6.60 (i, 6.70 | x, 6.97 fi, 7.08 ji (shoulder) and 8.10 [i (broad).

e) A mixture of 0.295 g of 4ß-isobutyiylthio-3ß-phenyl-oxyacetylamino-azetidin-2-one and 0.420 g of the hydrate of tert-butyl glyoxylate in 10 ml of toluene and 2.5 ml of dimethylformamide is added in the presence of molecular sieves Room temperature stirred. After 90 minutes the mixture is filtered, the filter residue is washed with toluene and the combined filtrates are evaporated, finally under high vacuum. The syrup-like 2-hydroxy-2- (4ß-isobutyrylthio-2-oxo-3ß - phenyloxyacetylamino-l-azetidinyl) acetic acid tert-butyl ester, thin layer chromatogram (silica gel): Rf = 0.32 ( System: 1: 1 benzene / ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.86 (i, 2.97 [i, 3.40 px, 3.45 jx (shoulder), 5.61 jx, 5.76 | i, 5.91 | x , 6.25 [i, 6.29 pi (shoulder), 6.60 fx, 6.70 (i, 6.97 [x, 7.31 jx, 7.75 | x (broad), 8.15 pi and 8.86 (i (wide); processed without cleaning.

I) A solution of 0.295 g of the crude 2-hydroxy-2- (4ß-isobutyrylthio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) acetic acid tert-butyl ester in 11 ml of dioxane is in the presence of 1 g of polystyrene «Hünig base >> stirred for 30 minutes and then a solution of 0.25 ml of thionyl chloride in 2.5 ml of dioxane was added. The mixture is stirred at room temperature for 2Vi hours, filtered, washed with dioxane and the combined filtrates are evaporated, lastly under reduced pressure. This gives tert-butyl 2-chloro-2- (4ß-isobutyrylthio-2-oxo-3ß-phe-nyloxyacetylamino-I-azetidinyl) acetic acid, thin layer chromatogram (silica gel): Rf = 0.56 (system: Ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 pt, 3.40 pi, 3.50 pi, 5.58 pi, 5.71 pi, 5.89 p ^ 6.25 pt, 6.29 pi ( Shoulder), 6.60 pi, 6.70 p., 6.89 px, 6.95 pi, 7.32 [i, 7.59 pi, 7.75 | x (wide),

8.15 yes (broad) and 8.70 pt; which is processed without cleaning.

g) A solution of the 2-hydroxy-2- (4ß-isobutyrylthio-2-oxo-3ß-phenyloxy-5 acetylamino-l-azetidinyl) acetic acid tert-butyl ester obtainable by 0.295 g according to the above procedure Tert-Butyl 2- (4ß-isobutyrylthio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) acetic acid in 12 ml of dioxane is stirred for 30 minutes in the presence of 1 g of polystyrene "Hünig base", 0.4 g of triphenylphosphine-lo were then added and the reaction mixture was stirred under a nitrogen atmosphere at 50 ° for 16 hours. The mixture is filtered and the filtrate is evaporated; the syrup-like residue is chromatographed on 30 g of silica gel (column). The excess of triphenylphosphine and impurities i5 are washed out with benzene. The amorphous 2- (4ß-isobutyiylthio-2-oxo-3ß - phenyloxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylidene-acetic acid tert-butyl ester is eluted with a 1: 1 mixture of benzene and ethyl acetate; Thin layer chromatogram (silica gel): Rf = 0.25 (system: Ben-20 zol / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 pi, 3.40 pi, 5.65 pt, 5.90 pi, 6.10 pi, 6.18 pt, 6.25 pi (shoulder), 6.59 pt , 6.70 pi, 6.96 jx, 7.33 pi, 7.75-8.12 pi (broad), 8.02-8.14 jx (broad) and 9.07 pu A solution of 0.081 g 2 - (4ß-Isobutyrylthio-2-oxo-3ß-25 -phenyloxyacetylamino-l-azetidinyl) -2-triphenyIphosphor-anylidene-acetic acid tert.-butyl ester in 40 ml of toluene is under an argon atmosphere for 5Vi hours at 70 °, then during Heated at 80 ° for 6 days and at 100 ° for 2 days. The solvent is evaporated under reduced pressure and the residue is subjected to preparative chromatography (silica gel). In addition to a larger amount of starting material and a by-product, 2-isopropyl-6β-phenyloxyacetylamino-2-penem-3-carboxylic acid re-tert-butyl ester of the formula is obtained

40 0 = Jc

0-C (CH3> 3

as colorless syrup, Rf = 0.57 (system: benzene / 45-ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.99 pi, 3.40-3.50 [x,

5.59 (x, 5.91 pi (wide), 6.26 pi, 6.30 pi (shoulder), 6.35 pi (shoulder),

6.60 pL, 6.70 pt, 7.34 px, 8.10-8.20 pi (wide), 8.30 pi (shoulder) and 8.70 pi.

so The starting material can be obtained as follows:

a) A mixture of 3.8 g of penicillin V-methyl ester 1-oxide in 120 ml of benzene, 20 ml of isobutyric anhydride and 5 ml of tri-methylphosphite is heated under reflux for 12 hours, then evaporated under reduced pressure. The

55 syrup-like residues are chromatographed on 120 g of silica gel (column). Wash with a 7: 1 mixture of benzene and ethyl acetate and elute the 2- (4ß-isobutyral-thio-2-oxo-3ß-phenyloxyacetylamino-l-azetidinyl) -2- (1 - propen-2-yl ) tert-butyl acetic acid with a 4: 1 Ge-60 mixture of benzene and ethyl acetate; Thin layer chromatogram (silica gel): Rf = 0.43 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 pt., 3.32 p ^ 3.41 pi, 5.63 pL, 5.74 | x, 5.91jx, 6.24 | i, 6.28 px , 6.60 jx, 6.71 pi, 6.97 pi, 7.27 | x, 65 7.35 | i (shoulder), 7.53 pt, 8.10 pi (broad), 8.28 pt ( broad) and 8.50 to 8.60 pu b) A solution of 0.100 g of 2- (4ß-isobutyrylthio-2-oxo - 3ß-phenyloxyacetylamino-l-azetidinyl) -2- (l-propen-2-yl) -

15

624390

tert-butyl acetic acid in 2 ml of methylene chloride and 0.03 ml of triethylamine is left to stand under a nitrogen atmosphere at room temperature for 90 minutes,

then diluted with additional methylene chloride. It is washed with 4 ml of 1-n. Hydrochloric acid and 4 ml of a 10% aqueous sodium chloride solution; the organic solution is evaporated under reduced pressure and the residue is purified using preparative layer chromatography. This gives 2- (4ß-isobutyiylthio-2-oxo-3-phenyloxyacetylamino-1-azetidinyl) -2- (2-propylidene) acetic acid tert-butyl ester as a colorless foam, Rf = 0.38 (system : Benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 p., 3.32 p, 3.41 p, 5.64 p ,, 5.81 p (shoulder), 5.91 p, 6.15 p, 6, 25 p, 6.29 p (shoulder), 6.60 (i, 6.71 p, 6.97 p, 7.24 p, 7.34 p., 8.16 p (broad) and 8.12 p .

Example 5

b) A solution of 2.5 g of methyl 2- (4ß-acetylthio-3ß-phthalimi-do-2-oxol-azetidinyl) -2- (l-propen-2-yl) -acetic acid (R. Latrel, Liebigs Ann. 19 74, 1937) in 60 ml methylene chloride and 60 ml methanol is flowed through at 20 ° with a 03/02 mixture for 2 hours and 5 minutes (0.33 mM 03 / min.). The reaction mixture is left to stand at -20 ° for one hour, diluted with methylene chloride and shaken with 100 ml of 10% aqueous sodium bisulfite solution. The organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent under reduced pressure. The amorphous residue, containing the amorphous methyl 2- (4ß-acetylthio-2-oxo - 3ß-phthalimidol-azetidinyl) -2-oxoacetate, can be processed as follows without further purification:

c) A solution of 7.5 g of amorphous 2- (4ß-acetylthio-2 - oxo-3ß-phthalimido-l-azetidinyl) -2-oxo-acetic acid methyl ester in a mixture of 85 ml of methyl acetate, 750 ml Methanol and 16 ml of water are left to stand at room temperature for 18 hours. The reaction mixture obtained is concentrated under reduced pressure, 250 ml of methylene chloride are added to the residue, the aqueous phase is separated off and the organic phase is dried over sodium sulfate. After evaporation of the solvent in vacuo and crystallization of the residue from methylene chloride diethyl ether, 4ß-acetylthio-3ß-phthalimido-azetidin-2-one is obtained; Mp 164-170 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 p, 3.34 p, 3.41 p, 5.57 p, 5.65 p, 5.80 p, 5.90 p, 7.23 p, 7 , 85 to 8.05 p, 8.30 p, 8.95 p, 9.05 p.

d) A solution of 1.45 g of 4β-acetylthio-3ß-phthalimido-azetidin-2-one and 2.475 g of glyoxylic acid tert-butyl ester hydrate in 50 ml of toluene and 12 ml of dimethylformamide is mixed with freshly activated molecular sieves (see Example lf) was added and the mixture was stirred at room temperature under nitrogen for 90 minutes. The molecular sieve is filtered off, washed with toluene and the filtrate and washing liquid are evaporated in vacuo. The residue is chromatographed on silica gel with benzene / ethyl acetate 9: 1 and 4: 1 and gives a mixture of the two epimers 2- (4ß-acetylthio-2-oxo-3ß-phthalimido- 1-azetidi-nyl) -2-hydroxy- tert-butyl acetate. One of the epimers can be obtained in crystalline form from the melting point 155-157 ° by crystallization from methylene chloride diethyl ether. Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95-3.55 p (broad), 5.60 p ,, 5.63 p. (Shoulder), 5.79 p, 5.88 p (shoulder), 7.23 p, 7.32 p, 7.80-8.05 p, (broad).

e) A solution of 640 mg of the crystalline 2- (4β-acetyl-thio-2-oxo-3β-phthalimido-l-azetidinyl) -2-hydroxy-acetic acid re-tert-butyl ester in 13 ml of absolute dioxane is added Room temperature with 1.28 g of polystyrene "Hünig base" (see example 1h; neutralized 3.68 milliequivalents of hydrochloric acid per gram) for 30 minutes, after which a solution of 533 mg of thionyl chloride in 9 ml of dioxane is added dropwise. The mixture is further stirred under nitrogen for 4 1/2 hours at 5 room temperature. The polystyrene "Hünig base" is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together under reduced pressure. The residue contains a mixture of the two epimers 2- (4ß-acetylthio-2-oxo-3ß-phthalimido- 1-azetidinyl) -lo -2-chloroacetic acid tert-butyl ester; Thin layer chromatogram: Rf = 0.56 (Merck silica gel; benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.30 p, 3.40 p, 5.57 p, 5.63 p (shoulder), 5.72 p (shoulder), 5.78 p, 5.87 p ( Shoulder), 7.20 p, 7.35 p, 7.58 p, i5 7.80-8.05 p, 8.70 p.

A similar epimer mixture is obtained if one starts from the non-crystalline epimer mixture.

f) A solution of 756 mg2- (4ß-acetylthio-2-oxo-3ß - phthalimido-l-azetidinyl) -2-chloroacetic acid tert-butyl ester 20 in 21 ml of dioxane is mixed with 1.68 g at room temperature Polystyrene “Hünig base” (neutralizes 3.68 milliequivalents of hydrochloric acid per gram) stirred for 30 minutes. After adding 766 mg triphenylphosphine, the mixture is stirred under nitrogen at 70 °. After 68 hours, the polystyrene “Hünig-25 base” is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on 50 g of Merck silica gel with benzene / ethyl acetate 9: 1, with unreacted triphenylphosphine being eluted first. Benzene / ethyl acetate 4: 1 elu-30 iert then the amorphous 2- (4ß-acetylthio-2-oxo-3ß-phthalimido-l-azetidinyl) -2-triphenylphosphoranylidene acetic acid - tert-butyl ester; Thin layer chromatogram: Rf = 0.32 (silica gel; benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 35 3.30 p, 3.40 p, 5.59 p, 5.65 p, 5.79 p, 5.90 p, 6.04-6.10 p, 6 , 13 to 6.20 p, 6.47 p, 7.22 p, 7.35 p, 7.80-8.05 p, 8.10 p, (broad), 8.85 to 9.05 p. (wide).

A solution of 100 mg2- (4ß-acetylthio-2-oxo-3ß - phthalimido-l-azetidinyl) -2-triphenylphosphoranyliden-es-40-acetic acid tert-butyl ester in 50 ml absolute dioxane is in the presence of 500 mg polystyrene - «Hünig-Base» heated to reflux for 48 hours. The reaction mixture is concentrated in vacuo and the residue is chromatographed on 10 g of acid-washed silica gel (stir 2 kg of silica gel 45 three times with 21 concentrated hydrochloric acid for 10 minutes, decant, wash neutral with distilled water, wash with methanol and activate for 60 hours at 120 °), which is deactivated with 10%, cleaned with benzene as the eluent. The 2-methyl-6ß-phthalimido-2-penem-3-50-carboxylic acid tert-butyl ester obtained crystallizes in the form of colorless needles from methylene chloride diethyl ether, mp. 179-181 °; Ultraviolet absorption spectrum (in 96% ethanol): \ max = 303 mp (e = 6370); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.30 p, 3.40 p, 55 5.55 p, 5.63 p, 5.74 p, 5.80 p, 6.25 p, 7.24 p, 7.33 p, 7.50-7.58 p, 7.80-8.05 p., 8.33 p, 8.70 p.

Example 6

b) A solution of 0.627 g of 2- (2-oxo-3ß-phenylacetylami-60 no-4ß-tritylthio-l-azetidinyl) -2- (l-propen-2-ylidene) acetic acid re-methyl ester in 10 ml Methylene chloride is treated with an excess of ozone at -20 ° until a thin layer chromatogram (system: toluene / ethyl acetate 1: 1) means that no starting material is available. 65 The mixture is then diluted with 50 ml of methylene chloride, washed with 20 ml of a 10% aqueous sodium bisulfite solution and 20 ml of a dilute sodium chloride solution in water, dried over sodium sulfate and evaporated under reduced pressure

624 390

16

Pressure. This gives the amorphous 2-oxo-2- (2-oxo-3ß - phenyloxyacetylamino-4ß-tritylthio-l-azetidinyl) acetic acid - methyl ester; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.5 [i, 5.7 [i, 5.9 (i and 8.1 fi.

The compound obtained can be processed further as follows:

c) A solution of 0.580 g of 2-oxo-2- (2-oxo-3ß-phenyloxy-acetylamino-4ß-tritylthio-l-azetidinyl) acetic acid methyl ester in 2 ml of acetone is mixed with 100 ml of a 98: 2 mixture diluted by methanol and water and stirred for 20 hours at room temperature, then evaporated under reduced pressure. The residue is taken to dryness again with 20 ml of methanol and the oily product is chromatographed on 18 g of silica gel, the white, crystalline 3β-phenyloxyacetylamino-4β-tritylthio-azetidine being used with a 3: 1 mixture of toluene and ethyl acetate. 2-one eluted, mp 186 to 187 ° after recrystallization from a mixture of ethyl acetate and diethyl ether at 0 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95 n, 5.65 | i, 5.9 (jl, 6.25 | i, 6.6 [i, 6.7 n and 6.95 (i.

d) A solution of 0.051 g of 3β-phenyloxyacetylamino-4ß-tritylthio-azetidin-2-one in 2 ml of methanol, prepared in the 5 heat, is cooled in a centrifuging vessel to 0 ° so quickly that no crystallization occurs, and under Shake with a 0.1-n. Solution of silver nitrate in methanol added. A white colloidal precipitate forms immediately; the mixture is kept at 0 ° for a further 15 minutes and then centrifuged. The solution is discarded; the solid residue is washed with 2 ml of cold methanol and dissolved in 2 ml of dry dimethylformamide. A stream of hydrogen sulfide is passed through the solution at 0 ° until formation of silver sulfide can no longer be determined. It is filtered through cotton wool and the filtrate is evaporated under reduced pressure. The residue is taken to dryness again with toluene and gives the crystalline 4β-mercapto-3ß-phenyl-oxyacetylamino-azetidin-2-one, mp 116-118 ° after recrystallization from acetone; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65 n, 6.0 jj, 6.25 p, 6.50 (i, 6.7 (i, 7.25 p, and 8.05 (a ..

20th

Claims (10)

624390 2nd PATENT CLAIMS 1. Process for the preparation of ot-ketocarboxylic acid compounds of the formula R, 3. The method according to claim 2, characterized in that an acyl radical RjA or a radical of the formula (VIII), wherein RjA represents an amino protecting group and Rxb represents hydrogen or an acyl residue Ac, or wherein RjA and Rjb together form a bivalent amino protecting group, R2A means a residue forming a protected carboxyl group together with the carbonyl group -C (= O) -, and R3 represents hydrogen or is an organic radical connected via a carbon atom to the ring carbon atom, characterized in that in an acyl thio compound of the formula R (VII), R - C R CIA) means, in which (1) Ra represents an optionally substituted carbocyclic aryl residue, an optionally substituted, preferably unsaturated cycloaliphatic hydrocarbon residue, or an optionally substituted heterocyclic aryl residue, Rb hydrogen and Rc hydrogen or optionally substituted hydroxy, amino, carboxyl or sulfo, or wherein (2) Ra is cyano, etherified hydroxy or mercapto, or an optionally substituted unsaturated heterocyclic radical linked via a ring nitrogen atom, and Rb and Rc are hydrogen, or where (3) Ra is an optionally substituted carbocyclic alyl radical, or an optionally substituted one heterocyclic aiyl radical, and Rb and Rc together preferably mean O-substituted hydroxyimino in the syn configuration. R, R-a-? 0 II c (IA) R cleaves the 2-propylidene group by treatment with ozone followed by a reducing agent. 2. The method according to claim 1, characterized in that an acyl radical RjA or Rxb represents a radical of the formula in which (1) Ra optionally substituted phenyl, optionally substituted cyclohexadienyl or cyclo-hexenyl, or optionally substituted thienyl or fu-iyl, Rb hydrogen and Re represent hydrogen or optionally i5-protected hydroxy, amino, carboxyl or sulfo, or in which (2) Ra is cyano, optionally substituted phenyloxy, phenylthio or pyridylthio, or optionally substituted tetrazolyl linked via a ring nitrogen atom, and Rb and Rc are hydrogen , or wherein (3) Ra is optionally substituted phenyl, or optionally substituted thienyl or furyl, and Rb and Rc together preferably mean O-substituted hydroxyimino in the syn configuration. 4. The method according to claim 2, characterized in that RaA is phenyloxyacetyl. 5. The method according to claim 1, characterized in that R2a 2-halogeno-lower alkoxy, wherein halogen preferably has an atomic weight of more than 19, 2-lower alkylsulfonyl-lower alkoxy, one by optionally substituted 30 -tuated saturated aliphatic or aromatic hydrocarbon radicals, polysubstituted or one, by an unsaturated aliphatic hydrocarbon radical, by a carbocyclic aryl group having an electron-donating substituent, or a heterocyclic group of aromatic character, having oxygen or sulfur as a ring member, monosubstituted-lower-methoxy group -phenylnie-deralkoxy, nitrobenzyloxy, furfuryloxy, 2-oxa- or 2-thia-cycloalkoxy or -cycloalkenyloxy with 5-7 ring members, or a corresponding thia group, or arylcarbonylmethoxy, 40 in which aryl in particular represents an optionally substituted phenyl group, nitrophenyloxy, un branched lower alkoxy, with 1 to 3 optionally substituted hydrocarbon radicals, preferably with up to 18 carbon atoms, substituted silyloxy or stannyloxy, an acyloxymethoxy-45 group, in which acyl, for example is the balance of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, means hydrazino or 2-lower alkyl hydrazino. 6. The method according to claim 1 or 5, characterized ge-50 indicates that R2A tert-butyloxy, diphenylmethoxy, 4- Methoxybenzyloxy, 4-nitrobenzyloxy or methoxy means. 7. The method according to claim 1, characterized in that R3 is hydrogen or optionally substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, 55 represents naphthyl or phenyl-lower alkyl. 8. The method according to claim 7, characterized in that R3 represents hydrogen, methyl, ethyl, 2-propyl, aceto-xymethyl, benzyl or phenyl. 9. The method according to claim 1, characterized in 60 shows that the starting material of formula VII is treated in the presence of a solvent. 10. The method according to claim 1 or 9, characterized in that the 2- (4ß-acetylthio-2-oxo-3ß-phe-nyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid-4-nitrobene Produces 65 cyl esters. 3rd 624 390 Since the discovery of penicillin, numerous bicyclic thia-aza compounds with a β-lactam structure have become known which mainly contain the penam or 3-cephem structure as the bicyclic structural element. In the Pe-nam and 3-cephem compounds, in particular the substituents on the 6- and 7-amino groups as well as the substituents in the 2- and 3-positions were modified in large numbers. The sulfur has been replaced by other atoms such as oxygen or carbon, and substituents, e.g. Methoxy introduced. An overview of previous work is given by E.H. Flynn, "Cephalosporins and Penicillins", Academic Press, New York and London, 1972. Recent developments are from J. Cs. Jaszberenyi et al., Progr. Med. Chem., Vol. 12, 1975, 395-477, and P.G. Sammes, Chem. Rev. 1976, Vol. 76, No. 1, 113-155. The emergence of new pathogenic germs, which have become resistant to the antibiotics previously used, as well as the known allergy symptoms, force research to continuously search for new, active compounds. Their value will be greater, the more structurally they differ from the previously known ring systems and their modifications, since this increases the possibilities that the new compounds have the disadvantages mentioned to a lesser extent or not at all. However, there is always the risk that deviations from the Penam or 3-cephem ring system lead to the loss of antibiotic activity.