CH624412A5 - Process for preparing ylid compounds - Google Patents

Abstract

Ylid compounds of the formula II <IMAGE> where X<+> is either a trisubstituted phosphonio group or a diesterified phosphono group together with a cation, are prepared by treating an alpha -hydroxycarboxylic acid compound of the formula XI <IMAGE> where Xo is a reactive esterified hydroxyl group, with a trisubstituted phosphine compound or with a phosphite compound. The meaning of the other symbols is given in Claim 1. The ylid compounds can be used as intermediates for preparing bicyclic thiaaza compounds.

Description

The present invention relates to a process for the preparation of new ylide compounds of the formula

Since the discovery of penicillin, numerous bi-cyclic thia-aza compounds with yS-lactam structure have become known, which mainly contain the penam or 3-cephem structure as a bicyclic structural element. In the Penam 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 The sulfur has been replaced by other atoms, such as oxygen or carbon, and in the 6a or 7a position substituents, e.g. B. Methoxy introduced.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 continually look for new, active compounds. The greater the structural difference from the previously known ring systems and their modifications, the greater their potential will be, 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.

The present invention has for its object to produce new intermediates which for the production of / j-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 do not have previous antibiotics with / j-lactam structure, can be used.

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:

10th

15

20th

25th

30th

35

(II)

wherein RiA represents an amino protective group and Rib represents hydrogen or an acyl radical Ac, or wherein RiA and Ri1 'together form a bivalent amino protective group, RüA represents a radical together with the carbonyl group -C (= OJ - forms a protected carboxyl group, and R3 represents hydrogen or is an organic radical connected via a carbon atom to the carbonyl group -C (= 0) -, and in which X © denotes either a triple-substituted phosphonio group or a double-esterified phosphono group together with a cation, and salts thereof.

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

The ylid compounds of the formula II can be used to prepare bicyclic thia-aza compounds, in particular 6-amino-2-penem-3-carboxylic acid compounds of the formula

40

45

C - R

3 (I),

50

wherein Ri-y represents hydrogen or an amino protecting group RiA and Rib represents hydrogen or an acyl radical Ac, or wherein Rta and Rib together form a divalent 55 amino protecting group, R »hydroxy or one together with the carbonyl grouping -C (= 0) - one protected carboxyl group-forming radical R »A, and Rs stands for hydrogen or an organic radical connected via a carbon atom to the ring carbon atom, 60 or 1-oxides thereof, and salts of such compounds with salt-forming groups, such as. B. is described in CH-PS No. 620.444.

An amino protecting group RiA is a group that can be replaced by hydrogen, 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 Rib, is primarily the acyl radical of an organic car-

624 412

4th

bonic acid, preferably with up to 18, and primarily with up to 10, carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid and is in particular for a N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound which is preferably pharmacologically active and can be prepared in a naturally occurring or in a bio-synthetic, semi-synthetic or totally synthetic manner tion contained 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 15

Ra-C (Rb) (Rc) -C (= 0) -

(IA),

20th

wherein (1) Ra is an optionally substituted carbocyclic aryl radical, e.g. B. corresponding phenyl, an optionally substituted, preferably unsaturated cycloaliphatic hydrocarbon radical, for. B. corresponding cyclo-hexadienyl or cyclohexenyl, or an optionally substituted heterocyclic aryl radical, for. B. corresponding thienyl or furyl, Rb hydrogen and Re represent hydrogen or optionally substituted, in particular protected hydroxy, amino, carboxyl or sulfo, or wherein (2) Ra cyan, etherified hydroxy or mercapto, such as optionally substituted phenyloxy, phenylthio or Pyridylthio, or an optionally substituted unsaturated heterocyclic radical linked via a ring nitrogen atom, see. B. corresponding tetrazolyl, and Rb and Rc are hydrogen, or wherein (3) R; l is an optionally substituted carbocyclic aryl radical, e.g. B. corresponding phenyl, or an optionally substituted heterocyclic aryl radical, for. B. corresponding thienyl, or 35 furyl, and Rb and Re 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 furyl -18 means in particular 2-fliryl, while pyridylthio z. B. • 1-pyridylthio, and tetrazolyl z. B. represent 1-tetrazolyl.

Substituents of a phenyl or phenyloxy group Ra can be present in any position and are u. 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, as well as a thienyl or furyl group Ra are? .. B. optionally substituted member alkyl, such as optionally substituted, in particular protected aminomethyl,

such a substituent, in particular optionally protected aminomethyl, is primarily in the 2-position 55 of a 1,4-cyclohexadienyl or 1-cyclohexenyl radical or in the 5-position of a 2-thienyl or 2-furyl radical.

Optionally protected aminomethyl is primarily aminomethyl, optionally substituted by lower alkyl, e.g. B. methylaminomethyl, where amino is fl0 if protected, while etherified hydroxy z. B. lower alkoxy, such as methoxy, and esterified hydroxy z. B. lower alkanoyloxy, such as acetyloxy, aroyloxy, e.g. B. benzoyloxy, carbamoyloxy or halogen, e.g. B. chlorine, and optionally substituted amino z. B. substituted by lower alkyl 6S amino, e.g. B. methylamino, or lower alkylsulfonylamino, e.g. B. Mettiylsulfonylamino.

Protected hydroxy, 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-Penem skeleton being destroyed or other undesirable side reactions take place.

Amino groups can e.g. B. be protected by acyl radicals, an acyl radical primarily by a reduction by z. B. when treated with a chemical reducing agent or with catalytically activated hydrogen, or by solvolysis, for. B. by treatment with a suitable acid, also by means of irradiation, cleavable acyl residues of a half-ester of carbonic acid, such as a, preferably branched on the first carbon atom of the esterifying group and / or by aryl, for. B. optionally, as by lower alkoxy, e.g. B. methoxy, and / or nitro substituted phenyl or biphenyl or by arylcarbonyl, in particular benzoyl, substituted lower alkoxycarbonyl radical, for. B. tert-butyloxycarbonyl, tert-pentyloxycarbonyl, diphenylmethoxycarbonyl, a-4-biphenylyl-a-methyl-ethoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxy-benzyloxycarbonyl or phenacyloxycarbonyl, or on the second carbon atom of the esterifying group halogen-substituted lower alkoxycarbonyl radical, e.g. B. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl (or a residue which can be converted into the latter, such as 2-chloro or 2-bromoethoxycarbonyl), furthermore polycyclic cycloalkoxycarbonyl, e.g. B. Adamantyloxycarbonyl.

An amino group may also be substituted by an arylmethyl, such as polyarylmethyl, e.g. By trityl, a 2-carbonyl-vinyl grouping, such as a 1-lower alkoxycarbonyl-l-pro-pen-2-yl group, e.g. B. l-methoxycarbonyl-l-propen-2-yl, an arylthio or aryl-lower alkylthio group, e.g. B. 2-nitro-phenylthio or pentachlorophenylthio, further tritylthio, or an arylsulfonyl group, further by an organic silyl or stannyl group, such as one by lower alkyl, halogen-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl, or optionally modified functional groups, such as lower alkoxy, e.g. B. methoxy, or halogen, e.g. B. chlorine, substituted silyl or stannyl group, primarily tri-lower alkylsilyl, e.g. B. trimethylsilyl, halogen-lower alkoxy-lower alkylsilyl, e.g. B. chloromethoxymethylsilyl, or tri-deralkylstannyl, such as tri-n-butylstannyl, to be protected.

Hydroxy protecting groups are e.g. B. acyl radicals, in particular one of the acyl radicals of carbonic acid semiesters mentioned in connection with a protected amino group,

or organic silyl or stannyl residues, furthermore easily removable 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residues, primarily 1-lower alkyl-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. B. 1-methoxy-ethyl, 1-ethoxy-ethyl, 1-methylthio-ethyl or 1-ethylthio-ethyl, or 2-oxa- or 2-thiacyclone-lower alkyl with 5-7 ring atoms, such as 2-tetrahydrofuryl or 2- Tetra-hydropyranyl or corresponding thia analogues, as well as easily removable, optionally substituted a-phenyl-lower alkyl radicals, such as optionally substituted benzyl or diphenyl-methyl, the substituents of the phenyl radicals being, for. B. halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.

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

5

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An amino protecting group RiA can e.g. B. can also be an amino group protected by the acyl radical of a carbonic acid half-ester, a 2-carbonyl-vinyl, arylthio or aryl-lower alkylthio or arylsulfonyl group, a triarylmethyl radical or an organic silyl or stannyl group, a 5 such protective group being analogous to that of a correspondingly protected group Amino group in an acyl radical of the formula IA can be.

O-substituted hydroxyimino is especially lower alkoxyimino, e.g. B. methoxyimino or ethoxyimino, further io phenyloxyimino or phenyl-lower alkoxyimino, z. B. benzyl-oxyimino, such groups are preferably in the syn form.

A protected carboxyl group of the formula -C (= 0) -RaA is primarily an esterified carboxyl group, in which 15 RäA represents a hydroxy group etherified by an organic radical or an organic sillyl or stannyl group. Organic radicals, also as substituents in organic silyl or stannyl groups, are aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or 20 araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and also heterocyclic or heterocyclic-aliphatic radicals, preferably with up to 18 Carbon atoms.

An etherified hydroxyl group R2A together with the carbonyl group forms a, preferably easily cleavable, e.g. B. reductive, such as hydrogenolytic, solvolytic, such as acidolytically or hydrolytically cleavable, or easily into another functionally modified carboxyl group, such as convertible into a hydrazinocarbonyl group, esterified 30 carboxyl group. Such a group R2A is e.g. B. 2-Halogen-lower alkoxy, wherein halogen preferably has an atomic weight of over 19, e.g. B. 2,2,2-trichloroethoxy or 2-iodoethoxy, further 2-chloroethoxy or 2-bromoethoxy, which can be easily converted into the latter, or 2-NiederaIkylsulfonylnieder- 35 alkoxy, z. B. 2-methylsulfonylethoxy, or R »A is one,

by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g. B. methyl and / or phenyl, polysubstituted or by a, electron-donating 40 substituents having, carbocyclic aryl group or a, oxygen or sulfur as a ring member having heterocyclic group of aromatic character, mono-substituted methoxy group, such as tert-lower alkoxy, z . B. tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, z. B. diphenylmethoxy or 4,4'-di-methoxydiphenylmethoxy, lower alkoxy-phenyl-lower alkoxy, e.g. B. lower alkoxybenzyloxy, such as methoxybenzyloxy (where methoxy is primarily in the 3-, 4- and / or 5-position), primarily 3- or 4-methoxybenzyloxy, 3,4-dimethoxy-50 benzyloxy, or especially nitrobenzyloxy , e.g. B. 4-nitrobenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy, or furfuryloxy, such as 2-furfuryloxy. R2A can also be 2-oxa- or 2-thia-cycloalkoxy or -cycloalkenyloxy with 5-7 ring members, such as 2-tetrahydrofuryoxy, 2-tetrahydro-55 pyranyloxy or 2,3-dihydro-2-pyranyloxy or a corresponding thia group, or arylcarbonylmethoxy , wherein aryl is in particular an optionally substituted phenyl group, for. B. phenacyloxy, or forms together with the -C (= 0) grouping an activated ester so group and is, for example, nitrophenyloxy, z. B. 4-nitro-phenyloxy or 2,4-dinitrophenyloxy. RaA can also unbranched lower alkoxy, e.g. B. be methoxy or ethoxy.

An organic silyloxy or organic stannyloxy <35 group R «A is in particular a hydrocarbon radical which is optionally substituted by 1 to 3, preferably having up to 18 carbon atoms, substituted silyloxy or

Stannyloxy group. It preferably contains substituted or unsubstituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl, which is optionally substituted, for example by lower alkoxy, such as methoxy, or by halogen, such as chlorine, and is the first Line tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, halogen-lower alkoxy-lower alkylsilyloxy, e.g. B. chloro-methoxy-methyl-silyloxy, or tri-lower alkyl-stannyloxy, e.g. B. Trin-n-butylstannyloxy.

The group RaA can also be an etherified hydroxy group which, together with the carbonyl grouping C (= 0), forms an esterified carboxyl group which is cleavable under physiological conditions, primarily an acyloxymethoxy group, in which acyl z. B. means the rest of an organic carboxylic acid, primarily an optionally substituted lower alkane arbonic acid, or wherein acyloxymethyl forms the rest of a lactone. Hydroxy groups etherified in this way are lower alkanoyloxy-methoxy, e.g. B. acetyloxymethyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially a-amino lower alkanoyloxymethoxy, e.g. B. Glycyloxyméthoxy, L-Valyloxymethoxy, L-Leucyloxyme-thoxy, further phthalidyloxy.

A together with a -C (= 0) grouping which forms an optionally substituted hydrazinocarbonyl radical R2A is e.g. B. Hydrazino or 2-NiederalkyIhydrazi-no, e.g. B. 2-methylhydrazino.

A bivalent amino protecting group formed together by the residues RjA and Rib 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. B. the acyl residue of a lower alkane or lower alkenedicarboxylic acid, such as succinyl, or an o-arylene dicarboxylic acid, such as phthaloyl, or is furthermore the acyl residue of a preferably substituted in the "position, e.g. B. containing an aromatic or heterocyclic radical, a-aminoacetic acid, wherein the amino group via a, preferably substituted, for. B. two lower alkyl, such as methyl group containing methylene radical is connected to the nitrogen atom, for. B. a, especially in the 2-position, substituted, for. B. 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 radical, for. B. 4,4-Dimethyl-2-phenyl-l-oxo-3-aza-l, 4-butylene.

The radicals RiA and Ri1 'together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably having up to 18 carbon atoms.

An organic radical Rs connected via a carbon atom to the carbonyl group -C (= 0) - is primarily an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arali-phatic hydrocarbon radical, in particular optionally substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl , Phenyl, naphthyl or phenyl-lower alkyl. Substituents of such residues are e.g. B. optionally functionally modified, such as etherified or esterified hydroxy or mercapto groups, for. B. hydroxy, lower alkoxy, e.g. B. methoxy or ethoxy, lower alkanoyloxy, e.g. B. acetyloxy or propionyloxy, halogen, e.g. B. chlorine or bromine, or lower alkyl mercapto, e.g. B. methoxy, or optionally functionally modified carboxyl groups, such as carboxyl, Niederalkox.ycarbonyl, z. B. methoxycarbonyl or ethoxycarbonyl, carbamoyl or cyan.

A lower alkyl group Rs contains e.g. B. to 7, in particular up to 4 carbon atoms, and is u. a. Methyl, ethyl, propyl,

624 412

6

Isopropyl, butyl, isobutyl, tert-butyl or pentyl. Substituted lower alkyl is primarily substituted methyl, such as hydroxymethyl, lower alkoxymethyl, e.g. B. methoxymethyl, lower alkanoyloxymethyl, e.g. B. acetyloxymethyl or propionyloxymethyl, or halomethyl, e.g. B. chloromethyl or bromomethyl, lower alkoxycarbonylmethyl, e.g. B. methoxy-carbonylmethyl or ethoxycarbonylmethyl, or cyanomethyl.

A cycloalkyl radical Ra has, for. B. 3 to 7 carbon atoms and is z. B. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, while a cycloalkyl-lower alkyl radical R3 contains, for example, 4 to 7 carbon atoms and z. B. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

A phenyl, naphthyl, e.g. B. 1- or 2-naphthyl, or a phenyl-lower alkyl, e.g. B. benzyl or 1- or 2-phenyl-ethyl radical Ra can, preferably in the aromatic radical, for. B. by lower alkyl, such as methyl or ethyl, lower alkoxy, e.g. B. methoxy, or halogen, e.g. B. fluorine or chlorine may be substituted.

A radical Ra can also represent a carbon-bonded heterocyclic or heterocyclic-aliphatic radical, preferably an aromatic character, such as pyridyl, e.g. B. 2-, 3- or 4-pyridyl, thienyl, e.g. B. 2-thienyl, or furyl, e.g. B. 2-furyl, or corresponding pyridyl, thienyl or furyl-lower alkyl, especially methyl, represent.

The compounds of the formula II can be used for the preparation of 2-penem compounds of the formula I which have valuable pharmacological properties. Compounds of formula I, wherein z. B. Ria for a in pharmacologically active N-acyl derivatives of 6/3-amino-penam-3-carboxylic acid or 7 /? - amino-3-cephem-4-carboxylic acid compounds occurring acyl radical Ac and Rib for hydrogen; or wherein Ria and Ri1 'together preferably in the 2-position, e.g. B. by an aromatic or heterocyclic radical, and in the 4-position preferably, for. B. by 2 lower alkyl, such as methyl, substituted 1-oxo-3-aza-l, 4-butylene radical, Ra has the meaning given above, and R2 is hydroxyl or one together with the carbonyl group, preferably easily cleavable under physiological conditions, esterified carboxyl group-forming etherified hydroxyl group R »A means, where in an acyl radical Ac any functional groups such as amino, carboxy, hydroxy and / or sulfo, usually in free form, or pharmacologically acceptable salts of such compounds with salt-forming groups, inhibit, for example the growth of gram-positive germs, such as Staphylococcus aureus, and gram-negative germs, such as Escherichia coli, Klebsiella pneumonia or Salmonella typhimurium, being in vitro in dilutions up to about 0.5 mcg / ml and in vivo against gram-positive Bacteria, e.g. B. Staphylococcus aureus, (e.g. in mice) in doses of about 0.003 g / kg, and against gram-negative bacteria, e.g. B. Escherichia coli, (e.g. in mice) in doses of about 0.065 g / kg, are effective with low toxicity. These new compounds, especially the preferred ones, or their pharmacologically acceptable salts, can therefore, for. B. in the form of antibiotic preparations for the treatment of corresponding system infections, also as feed additives, for the preservation of food or as a disinfectant.

1-oxides of compounds of the formula I in which Ria, Ri'1-Ra and Ra have the meanings given in connection with the formula I, or compounds of the formula I in which Ra has the meaning given above, the radicals Ria and Rib for Are hydrogen, or Ria is an amino protective group and rib hydrogen which are different from an acyl radical which occurs in pharmacologically active N-acyl derivatives of 6β-amino-penami-3-carboxylic acid or 7 /? - amino-3-cephem-4-carboxylic acid compounds,

or Ri «and Rj1 'together one, preferably from one in the 2-position, e.g. B. by an aromatic or heterocyclic radical, and in the 4-position preferably, for. B. by 2 lower alkyl, such as methyl, substituted l-oxo-3-aza-l, 4-butylene radical represent different bivalent amino protective groups, and R »is hydroxy, or Ria and Rib have the meanings given above, Ra for one, together with the -C (== 0) grouping represents a, preferably easily cleavable, protected carboxyl group-forming radical RtA, such a protected carboxyl group being different from a physiologically cleavable carboxyl group, and Ra having the meanings given above, are valuable intermediates which in a simple manner, e.g. B. as described below, can be converted into the above-mentioned pharmacologically active compounds.

The invention relates in particular to a process for the preparation of ylide compounds of the formula II which can be used for the preparation of 2-penem compounds of the formula I, in which Ria is hydrogen or preferably one in a fermentative (ie naturally occurring) or bio-, semi-or Totally synthetic, in particular pharmacologically active, such as highly active N-acyl derivative of a 6 /? - Amino-no-penam-3-carboxylic acid or 7y5-Amino-3-cephem-4-car-bonic acid compound, such as one of the above-mentioned acyl residues Formula (IA) means, where in this Ra, Rb and Re primarily have the emphasized meanings, Rib represents hydrogen, or wherein Ria and Rib together preferably in the 2-position, for. B. by an aromatic or heterocyclic radical, such as phenyl, and in the 4-position preferably, for. B. by two lower alkyl, such as methyl, substituted l-oxo-3-aza-l, 4-butylene radical, R2 for hydroxyl, for an etherified by an organic radical or an organic silyl or stannyl group or for an optionally substituted hydrazino group RtA is, and Ra is hydrogen, optionally substituted by etherified or esterified hydroxy, such as lower alkoxy or lower alkanoyloxy, lower alkyl, or optionally substituted by lower alkyl, lower alkoxy or halogen, phenyl or phenyl-lower alkyl, and salts of such compounds with salt-forming groups.

Primarily in a 2-penem compound of the formula I or in a salt of such a compound having salt-forming groups Ria is hydrogen or an acyl radical of the formula IA, in which (1) R; l has primarily the meanings highlighted, and for example thienyl, furyl, cyclohexadienyl or cyclohexenyl which is optionally substituted by hydroxy, protected hydroxy, lower alkoxy, lower alkanoyloxy, carbamoyloxy, halogen, lower alkylsulfonylamino or aminomethyl, Rb is hydrogen and 1 R (. hydrogen, optionally protected hydroxy, optionally protected amino or optionally protected amino or optionally protected carboxyl or represents sulfo, or in which (2) cyano, 1-tetrazolyl, optionally substituted phenyloxy such as phenyl, or 4-pyridylthio and Rh and R (. represent hydrogen, or in which (3) R; l represents phenyl, thienyl or furyl and Rh and R (, together mean syn-lower alkoxyimino, Rib stands for hydrogen, R2 stands for hydroxy, optionally a-poly-gal weighted lower alkoxy, e.g. B. methoxy or tert-butyloxy, or 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-iodoethoxy or easily convertible into this 2-chloroethoxy or 2-bromoethoxy, also phenacyloxy, l-phenyl-lower alkoxy with 1-3, optionally substituted by lower alkoxy and / or nitro-substituted phenyl

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

624412

most, e.g. B. 4-methoxybenzyloxy, 4-nitrobenzyloxy, 2-nitro-4,5-dimethoxy-benzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g. B. acetyloxymethoxy or pivaloyloxymethoxy, a-amino-lower alkanoyloxymethoxy, e.g. B. Glycyloxymethoxy, 2- s phthalidyloxy, further tri-lower alkylsilyloxy, e.g. B. trimethyl-silyloxy, and Rj represents hydrogen, lower alkyl, e.g. B.

Methyl, lower alkoxy lower alkyl, e.g. B. methoxymethyl, lower alkanoyloxymethyl, e.g. B. acetyloxymethyl, or optionally substituted by lower alkyl, lower alkoxy or halogen io-substituted phenyl or phenyl-lower alkyl.

The invention relates primarily to a process for the preparation of ylide compounds of the formula II which can be used for the preparation of 2-penem compounds of the formula I in which Ria is hydrogen or in particular an acyl group of the formula IA in which (1) Ra is phenyl, hydroxy -phenyl, e.g. B. 3- or 4-hydroxyphenyl, lower alkylsulfonylaminophenyl, e.g. B. 3-methylsulfonylamino-phenyl, amino-methylphenyl, e.g. B. 2-aminomethylphenyl, thienyl, e.g. B. 2-or 3-thienyl, aminomethylthienyl, e.g. B. 5-aminomethyl-2-thienyl, furyl, e.g. B. 2-FuryI, aminomethylfuryl, e.g. B. 5-aminomethyl-2-furyl, 1,4-cyclohexadienyl, aminomethyl-1,4-cyclohexadienyl, e.g. B. 2-aminomethyl-l, 4-cyclohexadienyl, 1-cyclohexenyl or aminomethyl-l-cyclohexenyl, e.g. B. 2-aminomethyl-1-cyclohexenyl, wherein in the above 25 radicals hydroxy and / or amino z. B. by acyl, such as optionally halogenated lower alkoxycarbonyl, e.g. B. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, may be géschiitzt, Rb for hydrogen and Rc for hydrogen, for amino and protected amino, such as acylamino, for. B. /? - polybranched 30-branched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino or 2-halogeno-lower alkoxycarbonylamino, e.g. B. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy- and / or nitro-substituted phenyl-35- alkoxycarbonylamino, e.g. B. 4-methoxybenzyloxycarbonyl,

amino or diphenylmethoxycarbonylamino, or for Hydro-R xy, and also protected hydroxy, such as acyloxy, e.g. B. yî-poly- ■

branched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halogeno lower alkoxycarbonyloxy, such as 40 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, or for optionally,

e.g. B. is esterified with lower alkyl, carboxyl or sulfo,

or where (2) Ra is cyan, 1-tetrazolyl, phenyloxy or 4-pyridylthio and Rb and Rc are hydrogen, or where 45 rin (3) Ra are phenyl, 2-thienyl or 2-furyl and Rb and Rc together are syn- Lower alkoxyimino, such as syn-methoxy-imino, mean Rib means hydrogen, R2 primarily for hydroxy, furthermore for methoxy, a-polybranched lower alkoxy, e.g. B. tert-butyloxy, 2-halogeno lower alkoxy, e.g. B. 50 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g. B. by lower alkoxy, such as methoxy, substituted diphenylmethoxy, e.g. B. diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or 4-nitrobenzyloxy,

also tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy,

and Rs is hydrogen, lower alkyl having up to 4 carbon atoms, such as methyl, lower alkoxy lower alkyl having up to 4 carbon atoms, e.g. B. methoxymethyl, or lower alkanoyloxy lower alkyl having up to 4 carbon atoms, e.g. B. acetyloxymethyl, or phenyl or benzyl, and salts, in particular pharmacologically usable, non-toxic salts, such as the alkali metal, for. B. sodium, or alkaline earth metal, e.g. B. calcium salts, or ammonium salts,

incl. those with amines, of compounds of the formula I,

where Ra is hydroxy. 65

The invention relates primarily to a process for the preparation of ylide compounds of the formula II which can be used for the preparation of 6-acetylamino-2-Rs-2-penem-3-

carboxylic acid compounds in which acetyl is substituted by the radicals Rt. and Rb, where (1) Ra for phenyl or 1,4-cyclohexadienyl and Rb for hydrogen or optionally, for. B. as described above, protected amino, or where (2) Ra is phenyloxy and Rb is hydrogen, and Rs is hydrogen, methyl, methoxymethyl, acetyloxymethyl or plienyl, and esters, especially lower alkyl esters of such compounds, and the pharmacologically acceptable salts thereof.

The new compounds of the formula II are prepared according to the invention by using an α-hydroxycarbonic acid compound of the formula

(XI),

CH <v * X,

R,

wherein Xo stands for a reactive esterified hydroxy group, treated with a triply substituted phosphine compound or a phosphite compound.

Usually the corresponding phosphoranylidene compound of the formula

R,

C R,

(IIA)

o = c - 4

wherein Xi for a trisubstituted, especially a triaryl, e.g. B. triphenyl, or a tri-lower alkyl, e.g. B. tri-n-butyl-phosphoranylidene radical, or the corresponding phosphono compound of the formula

55

60

(HB)

wherein Xa for a phosphono-, especially a dialkyl-phosphono-, e.g. B. Diethylphosphonogruppe prepared, wherein a phosphono compound of formula IIB by treatment with a suitable basic reagent, such as one

624 412

8th

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. B. triethylamine, or a cyclic base of the amidine type, such as a corresponding diazabicycloalkene compound, for. B. 1,5-diaza-bicyclo [5.4,0] -undec-5-ene, in the form suitable for ring closure, i.e. H. is converted into the compound of formula II.

A compound of formula XI, wherein Xo represents a reactive esterified hydroxy group, is treated by treatment with a suitable phosphine compound, such as a tri-lower alkylphosphine, e.g. B. tri-n-butyl-phosphine, or a triaryl-phosphine, e.g. B. triphenylphosphine, or with a suitable phosphite compound, such as a tri-lower alkylphosphite, e.g. B. triethyl phosphite, or an alkali metal dimmethyl phosphite, converted into the desired compound of formula II, whereby depending on the choice of the reagent, a compound of formula IIA or IIB can be obtained.

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

It works when using a TPhosphin compound usually in the presence of a basic agent, such as an organic base, for. B. an amine, such as triethylamine, diisopropyl-ethylamine or polystyrene- "Hü-nigbase", and thus arrives directly at the phosphoranylidene starting material of the formula IIA, which is formed from the corresponding phosphonium salt.

In a compound of the formula II obtained according to the invention, the amino protective group RiA preferably denotes an acyl group Ac, in which free functional groups which may be present, for. B. amino, hydroxy, carboxyl, or sulfo groups, in a conventional manner, amino groups such. B. by the abovementioned acyl, trityl, silyl or stannyl, and by substituted thio or sulfonyl radicals, and hydroxyl, carboxy or sulfo groups, for. B. are protected by the above etherifying or esterifying groups, including silyl or stannyl groups, and Rib hydrogen.

In a compound of the formula II obtained according to the invention, 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 RaA in a manner known per se, e.g. B. can be protected as indicated above. One group is RaA. a. Lower alkoxy, especially a-polybranched lower alkoxy, e.g. B. methoxy or tert-butyloxy, or 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, 2-lower alkylsulfonyl-lower alkoxy, e.g. B. 2-methylsulfonylethoxy,

or an optionally substituted such as lower alkoxy, e.g. B. methoxy, or nitro-containing 1-phenyl-lower alkoxy group, such as optionally, for. B. as indicated, substituted benzyloxy or diphenylmethoxy, e.g. B. benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g. B. Trimethylsilyloxy.

In a compound of formula II obtained according to the invention, Rs is in particular one of the preferred, optionally substituted hydrocarbon radicals, functional groups usually being in protected form.

The group X® in a compound of the formula II obtained according to the invention is one of the phosphonio or phosphonio groups customary in the Wittig condensation reaction, in particular a triaryl, for. B. triphenyl, or tri-lower alkyl, e.g. B. Tributylphosphoniogruppe, or one by lower alkyl, for. B. ethyl, doubly esterified Phos-phono group, the symbol X © in the case of the Phos-10 phono group still the cation of a strong base, especially a suitable metal such as alkali metal, e.g. B. lithium, sodium or potassium ion. Preferred as group X © are triphenylphosphonio on the one hand and diethylphosphono on the other hand together with an alkali metal, e.g. B. Sodium ion.

In phosphonium compounds of the formula II, which are also referred to in the 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 in their isomeric form as phosphonate compounds, the negative charge is neutralized by the cation of a strong base, which, depending on the manner in which the phosphono compound is prepared, is, for. B. an alkali metal, e.g. B. sodium, lithium or potassium ion.

In a ylide compound of the formula II obtained according to the invention, one group RiA, Rib, Rs and RgA can be converted into another group RiA, Rib, Rs and RaA in a manner known per se.

The compounds of the formula II obtained according to the invention can be ring-closed into the 6-amino-2-pe-nem-3-carboxylic acid compounds of the formula

15

20th

25th

30th

35

40

45

C - R,

(I),

wherein Ria, Rib, R2 and Rs have the meanings given above, are transferred.

The starting materials used according to the invention for the preparation of compounds of the formula II, or IIA or IIB, can, for. B. can be prepared as follows, the following variant having proven particularly suitable for compounds in which R3 is different from hydrogen: A compound of the formula

55

R,

60 R

b /

CH - C

65

'CH,

0 = C -

9

624 412

the one z. B. by converting a 6-amino-2,2-dimethyl-penam-3-carboxylic acid compound, in which the amino and carboxyl groups are in protected form, into the corresponding 1-oxide and reacting the latter with a suitable mercapto Compound of the formula Ro-SH (IV) 5 can be obtained, and wherein Ro is a radical connected via a carbon atom to the sulfur atom, in particular a cyclic and primarily a heterocyclic radical, e.g. B. 2-BenzthiazoIyI, is obtained by treatment with a basic agent such as an organic base, e.g. B. egg io amine such as tri-lower alkylamine, z. B. triethylamine, or an inorganic base in the isomeric compound of the formula, the isopropylidene group is cleaved by treatment with ozone, followed by a reducing agent, giving a-ketocarboxylic acid compounds of the formula

R,

R

«

\ b /

N.

H

i i

0 =

H

V

o II

c-

(VIII)

15

S R

/ CH3 (V)

0 = c R,

o — c-

transferred.

The dithio compound of the formula V obtainable in this way is treated with a reducing agent and reacted simultaneously or preferably subsequently with a reactive acylation derivative of an acid of the formula Rs-C (= 0) -0H (VI). As a reducing agent are primarily hydride reducing agents such as alkali metal borohydrides, for. As sodium borohydride, also phosphine compounds such as tri-aryl, z. B. triphenylphosphine, wherein the hydride reducing agents are preferably used 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. B. acetic acid. Suitable acylating agents are, in particular, anhydrides of the acid of the formula VI, such as symmetrical anhydrides, e.g. B. anhydrides of lower alkane carboxylic acids, such as acetic anhydride, or mixed anhydrides, preferably with hydrohalic acid, d. H. the corresponding acid halides, primarily acid chlorides or bromides.

In the acylthio compounds of the formula so obtainable

K

R

b /

receives. Usually one uses an ozone-oxygen-20 mixture and works in the presence of a solvent, such as a Ni'ederalkanols, for. B. methanol or ethanol,

a lower alkan, e.g. B. acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. A halogen lower alkane, 25 such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture, and preferably with cooling, e.g. B. at temperatures from about -90 ° C to about 0 ° C.

An ozonide obtained as an intermediate is, usually without being isolated, reductively cleaved to a compound of the formula VIII, with catalytically activated hydrogen, for. B. hydrogen in the presence of a heavy metal hydrogenation catalyst, such as nickel, further 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. B. zinc, in the presence of a hydrogen donor, such as an acid, e.g. B. acetic acid, or an alcohol, e.g. B. lower alkanol, reducing inorganic salts such as alkali metal iodides, e.g. B. sodium iodide, or alkali metal bisulfites, e.g. B. sodium bisulfite, in the presence of a hydrogen donor, such as an acid, e.g. B. acetic acid, or water,

or reducing organic compounds, such as formic acid, are used. Reducing agents which can be easily converted into oxide compounds are advantageously used, the oxide formation being able to take place on account of an existing carbon-carbon double bond or an existing oxide-forming hetero atom, such as sulfur, phosphorus or nitrogen atom. Such connections are e.g. B. suitably substituted Äthenver compounds (which are converted into ethyleneoxy compounds in the reaction), such as tetracyanoethylene, particularly suitable sulfide compounds (which are converted into sulfoxide compounds in the reaction), such as diniederalkyl sulfides, primarily dimethyl sulfide, suitable organic Phosphorus compounds, such as a phosphine, which may contain substituted or unsubstituted aliphatic or aromatic hydrocarbon radicals (and which (VII) 60 is converted into a phosphine oxide in the reaction), such as tri-lower alkylphosphines, e.g. B. tri-n-butylphosphine,

or triarylphosphines, e.g. B. triphenylphosphine, also phosphites, which contain optionally substituted aliphatic hydrocarbon radicals as substituents (and are converted in the reaction into phosphoric acid ter such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid). triamide, which given

30th

35

40

45

50

624 412

10th

if contain substituted aliphatic hydrocarbon radicals as substituents, such as Hexaniederalkyl-phosphorigsäure-triamide, z. B. Hexamethylphosphorigsäuretriamid, the latter preferably in the form of a methanol adduct, further suitable nitrogen bases (which are converted in the reaction into the corresponding N-oxides), such as heterocyclic nitrogen bases of aromatic character, z. B.

Bases of the pyridine type and in particular pyridine itself. The usually non-isolated ozonide is normally cleaved under the conditions used to prepare it, i.e. H. 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.

The compound of formula VIII can then be converted into a compound of formula by solvolysis

R,

R

b /

20th

(IX)

25th

be transferred. The solvolysis can be carried out as hydrolysis or, preferably, as alcoholysis, usually with a lower alkanol, e.g. As 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, for. B. ethyl acetate, if necessary, with cooling 35 or heating. The «ketocarboxylic acid of the formula VIII need not necessarily be isolated. Do you z. B. the cleavage of the ozonide in the presence of a solvolysis agent, such as. As water, through, a compound of formula IX can be obtained directly. 40

The latter is used with a glyoxylic acid compound of the formula 0HC-C (= 0) -R2A (X) or a suitable derivative, such as a hydrate or hemiacetal, e.g. B. a Halbacetalm.it a lower alkanol, e.g. B. methanol or ethanol, and thus receives a «-hydroxy-carboxylic acid 45- compound of the formula

R,

R

\ b /

N.

H 1

H

0

II c

■ R

3 '

50

\

(XI)

CHv ^ X

■ 4

55

60

where Xo 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 glyoyl ester compound to the nitrogen atom of the lactam ring takes place at room temperature or, if necessary, with heating, e.g. B. up to about 100 ° C,

65

in the absence of an actual condensing agent and / or without the formation of a salt. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, by distillation, e.g. B. azeotropic, or by using a suitable dehydrating agent, such as a molecular sieve, is removed. Is preferably carried out in the presence of a suitable solvent, such as. B. dioxane, toluene or dimethylforma-mid1, or solvent mixture, 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. B. chlorine or bromine,

or into an organic sulfonyloxy group such as lower alkyl sulfonyloxy, e.g. B. methylsulfonyloxy, or arylsulfonyloxy, e.g. B. 4-MethylphenylsuIfonyIoxy converted; This gives compounds of the formula XI in which Xo represents 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. B. a halogenating agent such as a thionyl halide, e.g. B. chloride, a phosphorus oxyhalide, especially chloride, or a halophosphonium 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. As triethylamine, diisopropylethylamine or polystyrene "Hunig base", or a heterocyclic base of the pyridine type, for. As pyridine or collodin used.

Preferably one works in the presence of a suitable solvent, e.g. B. dioxane or tetrahydrofuran, or a solvent mixture, 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, a reactive esterified hydroxyl group Xo can be converted by another reactive hydroxyl group in a manner known per se. So you can z. B. 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, by a bromine or iodine atom.

In connection with the present description, organic radicals designated “lower”, unless expressly defined, contain 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:

i) A solution of 0.452 g of 2- (4 /? - acetylthio-2-oxo-3-phenyloxyacetyIamino-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 of "polystyrene-Hunig base" (sub-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), where

11

624 412

when using a 1: 1 mixture of benzene and ethyl acetate. This gives the pure and amorphous 2- (4 ^ -acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidi-nyl) -2-triphenylphosphoranylidene-acetic acid tert-butyl ester, thin layer chromatography (silica gel): Rf = 0.21 (benzene / 5 ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98 //, 3.31, «, 3.40 //, 5.68 //, 5.92 / 2, 6.11 / 1, 6.20 // (Shoulder), 6.28 // (shoulder), 6.34 / t (shoulder), 6.60 //, 6.72 //, 6.98 / u, 7.07 / j. (Shoulder) and 7.35 fi. io

The compound obtained can be processed further as follows:

A solution of 0.05 g of 2- (4 /? - acetylthio-2-oxo-3 / J-phenyIoxyacetyIammo-l-azetinyI) -2-triphenyIphosphoranyIi-denacetic acid tert-butyl ester in 50 ml of toluene is for 15 10 hours heated at 70 °, 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 20 0.025 cm thick), using a 1: 1 mixture of benzene and Ethyl acetate used. The pure amorphous 2-methyl-6-phenyloxyacetylamino-2-penem-3-carboxylic acid tert-butyl ester of the formula is thus obtained

25th

Q-O-CV

• ch.

(ch3) 3

30th

35

Rf = 0.53; Ultraviolet absorption spectrum (in ethanol):

l max = 305 m / i, 275 m fi, 268 m / u and 263 m fi; Infrared absorption spectrum (in methylene chloride): characteristic 40 bands at 2.98fi, 3.32 / z, 3.41 //, 3.45 // (shoulder), 5.57fi, 5.90 fi, 6.21 fi, 6 , 60 / 1,6,71 / z, 6.97-7.08 // and 7.33 //: [a] D20 = + 202 ° ± 1 ° (c = 0.567 in chloroform).

The starting material can be produced as follows:

a) A solution of 36.6 g of 6 /? - phenyloxyacetylamino-45 penam-3-carboxylic acid l / 3-oxide, 11.1 ml of triethylamine and

23.8 g of 4-nitrobenzyl bromide and 200 ml of dimethylformamide are stirred for 4 hours at room temperature under nitrogen. 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 6 /? - phenyloxyacetylamino-penam-3-carboxylic acid-4-nitrobenzyl ester-lyS-oxide melts at 179-180 °.

b) A solution of 5.01 g of 6/3-phenyloxyacetylamino-penam-3-carboxylic acid-4-nitrobenzyl ester-l /? - oxide and 1.67 g of 2-mercaptobenzothiazole in 110 ml of dry toluene is refluxed in for 4 hours cooked in a nitrogen atmosphere. 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- [4 /? - (2-Benzthiazo-lyl-dithio) -3 / 3-phenyloxy-acetylamino-2-oxo-l-azetidinyl is thus obtained ] -2- (l-propen-2-yl) 4-nitrobenzyl acetate, mp 138-141 °.

c) 9.9 g of 2- [4β- (2-benzothiazolyldithio) -3 / ü-phenylox, yacetyIamino-2-oxo-l-azetidin.yl] -2- (l-propen-2-yl ) -

50

55

60

65

4-nitrobenzyl acetate in 200 ml of warm ethylene glycol dimethyl ether, add 5 ml of triethylamine and the solution is stirred for 75 minutes at room temperature. The solvent is evaporated off under reduced pressure; one. adds toluene and evaporates again under reduced pressure. The crude product is chromatographed on silica gel washed with hydrochloric acid; solvent toluene / ethyl acetate 3: 2. The 2- [4y3- (2-benzothiazolyldithio) -2 obtained as an almost white, crystalline foam -oxo-3 /? - phenyloxyacetylamino-l-azetidinyl] -2- (2-propylidene) _- acetic acid E8-4-nitrobenzyl ester is recrystallized from a mixture of methylene chloride and diethyl ether and the product is despite the melting point range of 105-115 ° It. Thin layer chromatography (silica gel; toluene / ethyl acetate 60:40) homogeneous; [a] D20 = -15 ° ± 1 ° (c = 0.908% in chloroform); ultraviolet absorption spectrum (in ethanol) ": Ima3t = 268 m fi (s = 24200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92fi, 5.61 fi, 5.78 // and 5.90fi.

d) A solution of 0.076 g of sodium borohydride in 10 ml of dimethylformamide is added under a nitrogen atmosphere and with cooling in a methanol / ice bath with a solution of 0.897 g of 2- [4 /? - (2-benzothiazolyldithio) - 2-oxo-3/3-phenyloxy-acetylamino-l-azetidinyl] -2- (2iTpropyliden) -acetic acid 4-nitrobenzyl ester in 14 ml of dimethylformamide and added dropwise over a period of 10 minutes. Then 7 ml of freshly distilled acetic acid bromide are added. The reaction mixture is stirred at 0 ° for 60 minutes, diluted with 350 ml of benzene and washed several times with 100 ml of water. It is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column of 50 g of silica gel, using benzene as the solvent. The fractions with benzene and a 9: 1 mixture of benzene and ethyl acetate are discarded; the desired 2- (4 /? - ethylthio-2-oxo-3 / J-phenyl-oxyacetyIamino-l-azetidinyl) -2- (2-propylidene) -acetic acid 4-nitrobenzyl ester is mixed with a 4: 1 mixture of Washed out benzene and ethyl acetate, subjecting the crude product to preparative thin layer chromatography (silica gel) and using a 2: 1 mixture of benzene and ethyl acetate. The product is obtained in an amorphous form; Thin layer chromatography (silica gel):

Rf = 0.45 (1: 1 benzene / ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95 / 1, 3.30 //, 3.35-3, -55 //, 5.63 //; 5.80 // (shoulder), 5.89fi, 6.15fi, 6.25 //, 6.3V, Wt, 6.97 //, 7.08, «, 7.18 //, 17.32 // and 7.43 //.

e) A solution of 0.24 g of 2- (4 /? - acetylthio-3-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -2- (2-propylidene) -acetic acid-4-nitrobenzyl ester in 20 ml of methyl acetate is cooled to -78 ° and a mixture of ozone and oxygen is passed through in such a way that 0.1 mmol of ozone per minute get into the mixture. After the introduction of 1.5 equivalents of ozone, the supply of the gas mixture is interrupted and the mixture is left at -78 ° for 15 minutes. The excess ozone is expelled by introducing nitrogen and the reaction mixture is treated with 1 ml of dimethyl sulphide. Allow to stand in a closed vessel for 16 hours at room temperature. The volatile components are evaporated under reduced pressure and the crystalline residue is recrystallized from a mixture of methylene chloride and diethyl ether. The almost colorless 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetyl-amino-l-azetidinyl) -2-oxo-acetic acid-4-nitrobenzyl ester melts at 154-156 °; Md20 = -13 ° ± 1 ° (c = 0.984 ° / o in chloroform); Infrared absorption spectrum (in methylene

624 412

12

io

15

chloride): characteristic bands at 2.95 p, 3.20-3.45, «, 5.48fi, 5.69p, 5,% l (i, 6.25 (i, 6.58p, 6.11 / 2, 6.95-1.08p, 1.25 / x and 7.45p.

f) A solution of 2.78 g of crude 2- (4 /? - AcetyIthio-2-oxo-3 / i-phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid-4-nitrobenzyl ester in 55 ml of methyl acetate is mixed with 500 diluted ml of methanol and 11 ml of water; the mixture is left to stand at room temperature for 18 hours and evaporated under reduced pressure. The residue is chromatographed on 300 g of silica gel, the oxalic acid monomethylmono-4-nitrobenzyl ester and other impurities being washed out with a 4: 1 mixture of benzene and ethyl acetate. The 4 /? - AcetyIthio-3 /? - phenyloxy-acetylamino-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): Rf = 0.20 (benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96p, 3.28-3.40p, 5.61p, 5.92p, 6.27p, 20 6.60 «, 6.71p, 6.97p and 7 , 08p (shoulder).

g) A solution of 0.294 g of 4 /? - AcetyIthio-3 / J-phenyloxy-acetylamino-azetidin-2-one and 0.495 g of tert-butyl ester of glyoxylic acid in 10 ml of toluene and 2.5 ml of dimethylform 25 amide is activated in the presence of sodium aluminum silicate molecular sieves (Union Carbide Type A3; pore diameter 3Â; activated at 250 ° and under a pressure of 0.01

mm Hg) stirred for one hour at room temperature and then filtered. The filtrate is reduced under 30

Pressure taken to dryness. 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- (4/3-acetylthio-2-oxo-3β-phenyloxyacetylamino-l-azetidinyl) -2-hydroxyacetic acid 35 tert-butyl ester, 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 ", 1.97p, 3.30-3.50p, 5.61p, 5.75p, 5.90p, 6.25p, 6, 60p, 6.70p, 6.98p, 7.07p (shoulder) and 1.32p. The 40 product is used in the next step without cleaning.

h) A mixture of 0.455 g of the crude 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -2-hydroxyacetic acid tert-butyl ester in 15 ml of dioxane is treated with 0 , 3 g of 45 thionyl chloride and 1 g of "polystyro-Hunig base" [prepared by heating a mixture of 100 g of chloromethylpolystyrene (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, 100 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 at room temperature for 3 hours, then filtered. The filtrate is evaporated under reduced pressure. This gives the amorphous, almost pure 2- (4β- ^ acetylthio ~ 2-oxo-3 / j-phenyIoxyacetylamino-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 2.96p, 3.25-3.50p, 5.95p, 5.14p, 5.89p, 6.25p, 6.60p, 6.71p, 6.96p, 7 , 32p and 7.60p. The product is processed without further cleaning.

50

55

65

Example 2:

c) A solution of 1.03 g of the crude 2- (4 / J-acetylthio-2-oxo-3 /? - phenyloxyacetyIamino-l-azetidinyl) -2-chloroacetic acid, methyl ester and 0.786 g of triphenylphosphine in 30 ml of absolute Dioxane is stirred under a nitrogen atmosphere in the presence of 2.0 g of "polystyrene base" at 50 ° for 18 hours and then filtered. The filter residue is washed with dioxane and the filtrate is evaporated. The residue is chromatographed on 30 g of silica gel, initially using a 4: 1 mixture of benzene and ethyl acetate as the mobile phase and removing 50 ml fractions. In the first fractions, the excess triphenylphosphine and then impurities are washed out. The amorphous methyl 2- (4 /? - acetylthio-2-oxo-3 /? - phenyl-oxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylidene is washed out with a 1: 1 mixture of benzene and ethyl acetate, [ a] D20 = -29 ° ± 1 ° (c = 0.774 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96p, 3.31p, 3.40p, 5.67p, 5.90p, 6.09p (shoulder), 6.19p, 6.25p (shoulder), 6, 26p (shoulder), 6.60p, 6.71 p and 6.97p.

The compound obtained can be processed further as follows:

A solution of 0.587 g of 2- (4ß-acetylthio-2-oxo-3Jö-phenyloxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylenidacetic acid methyl ester in 250 ml of toluene is heated under an argon atmosphere at 80 ° for 46 hours. The solvent is evaporated; the residue is chromatographed on 140 g of silica gel (acid-treated), using a 4: 1 mixture of benzene and ethyl acetate. The amorphous 2-methyl-6/3-phenyloxyacetyIamino-2-penem-3-carboxylic acid methyl ester is obtained in several fractions; Ultraviolet absorption spectrum (in ethanol): Amax at 306rn ", 275mp, 268m ;," and 262mp \ Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.91p, 3.32p, 3.43p, 5.56p, 5.85-5 , 90p, 6.21p, 6.60p, 6.10p, 6.91p and 7.08 / «.

The starting material can be produced as follows:

a) A solution of 0.588 g of 4 /? - acetylthio-3 /? - phenyloxy-acetylamino-azetidin-2-one and 0.636 g of glyoxylic acid methyl ester hydrate (bp. 55-62 ° / 35 mm Hg; prepared by treating Tartaric acid dimethyl ester in benzene with lead tetraacetate) in 20 ml of toluene and 5 ml of dimethylformamide is stirred in the presence of molecular sieves (see Example 1) for 90 minutes at room temperature, then filtered. It is washed with toluene and the filtrate is evaporated under reduced pressure. This gives the amorphous methyl 2- (4ß-acetylthio-2-oxo-3 /? - phenyloxyacety] amjno-l-azetidinyl) -2-hydroxy-acetic acid, infrared absorption spectrum (in methylene chloride): characteristic bands at 2.83p, 2.95p, 3.28-3.40p, 5.60p, 5.11p, 5.88p, 5.96p (shoulder), 6.24p, 6.21p (shoulder), 6.58m and 6.70p. The product is processed without cleaning.

b) A suspension of 2 g «polystyrene Hunig base»

(see Example 1) in 20 ml of absolute dioxane is stirred under a nitrogen atmosphere for 30 minutes and then with 1.08 g of crude 2- (4 / J-acetylthio-2-oxo-3 / J-phenyloxy-acetyIamino-1-azetidinyl ) -2-hydroxy-acetic acid methyl ester treated, followed by about 0.6 g of thionyl chloride in 10 ml of dioxane. The mixture is stirred at room temperature for 3 hours, then filtered and the filter residue washed with dioxane. The filtrate is evaporated under reduced pressure. The 2- (4 / f-acetythio-2-oxo-3/3-phenyloxyacetylamino-l-azetidinyl) -2-chloroacetic acid re-methyl ester is obtained in this way, thin layer chromatogram (silica gel): Rf ~ 0.4 and 0 , 44 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): character

13

624 412

Ristic bands at 2.95ß, 3.30 /;, 3.42, «, 5.59ß, 5.70,«, 5.89ß, 6.15ß, 6.19 ^ t (shoulder), 6.61 ß and 6.70, «. The product is processed without cleaning.

The methyl 2- (4/5-acetylthio-2-oxo-3 / j-phenyloxyacetylamino-l-azetidinyl) -2-hydroxyacetate can also be prepared as follows:

d) A solution of 18.5 g of penicillin VI-oxide in tetra-hydrofuran is cooled to 0 ° and 160 ml of a solution of diazomethane in diethyl ether are added dropwise until no starting material thin-layer chromatography 10 (system: acetic acid / toluene / water 5: 5 : 1) can be determined. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in hot ethyl acetate. Diethyl ether is slowly added with stirring and the mixture is left to stand at 0 ° for 3 days until the precipitate has completely precipitated. This gives the crystalline penicillin V-methyl-ester-1-oxide, mp 135-137 °; Ultraviolet absorption spectrum (in ethanol). Amax at 260mß («= 1000), 267mi« (e = 1300) and 273m, «(e = 1100); Infrared absorption spectrum (in 20 methylene chloride): characteristic bands at 5.55fi, 5.1 ß, 5.9fi and 8.25ß.

e) A solution of 9.5 g of penicillin V-methyl ester l-oxide in 300 ml of benzene is mixed with 37.5 ml of acetic anhydride and 12.5 ml of trimethyl phosphite and heated at a bath temperature of 100 ° for 23 hours. After cooling, the solvent and excess of the reagents are removed under reduced pressure and the residue is dried twice with toluene. The residue is chromatographed on 300 g of silica gel,

using a 7: 1 mixture of toluene and ethyl acetate (10 fractions of 300 ml each) and a 4: 1 mixture of toluene and ethyl acetate (10 fractions of 300 ml each). First, impurities, then the 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azeti-35 dinyl) -2- (l-propen-2-yl) -acetic acid methyl ester as colorless and solid but non-crystalline product washed out: thin layer chromatogram (silica gel): RF = 0.4 (system ^ toluene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.55 / j, 40 5.65 (1, 5.85fi and 6.65 (i.

A solution of 4.04 g of methyl 2- (4 / J-acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyI) -2- (l-propen-2-yl) -acetic acid in 80 ml of dry Methylene chloride is mixed with 0.8 ml of triethylamine at room temperature. The reaction mixture is stirred for 70 minutes and then washed with dilute hydrochloric acid and a dilute aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. This gives the methyl 2- (4/8-acetyl-50 thio-2-oxo-3/5-phenyloxyacetylamino-l-azetidinyl) -2- (2-propylidene) as a colorless amorphous product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65fi, 5.15 (i (shoulder), 5.85, «and 8.15 ^.

g) A solution of 4 g of 2- (4 / J-acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -2- (2-propylidene) acetic acid methyl ester in 100 ml of methanol is added -20 ° cooled and passed through the solution for 100 minutes an ozone-oxygen mixture (total 3 equivalents of ozone). ^ The white crystalline precipitate is dissolved in 300 ml of methylene chloride and the solution is washed with 100 ml of a 10% aqueous sodium bisulfite solution. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized by adding methanol at 0 °. This gives methyl 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -2-oxo-acetic acid, mp 142-145 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.45, «, 5.70,« and 5.85 ß.

h) A solution of 0.380 g of 2- (4 /? - acetylthio-2-'oxo-3 /? - phenyloxyacetylamJino-l ^ azetidinyi) -2-oxo-acetic acid methyl ester in 10 ml of dry tetrahydrofuran (distilled over lithium aluminum hydride ) is cooled in an ice bath and treated with 1.5 ml of a 1 molar solution of diborane in tetrahydrofuran. The mixture is stirred for 60 minutes while cooling to 0 °, then diluted with ice-cooled methylene chloride and the organic phase is separated off, which is washed with a 25% aqueous ammonium chloride solution and with water. It is dried over sodium sulfate and evaporated under reduced pressure. This gives the 2- (4 /? - acetylthioi2-oxo-3 / J-phenyloxyacetylamino-l-acetidinyl) -2-hydroxyacetic acid methyl ester.

. K>

Example 3

Eiri'é solution of 0.027 g of the mixture of the two isomers of 2-chloro-2- [4 / H4-nitro-benzoyl) thio-2-oxo-3/9-phenyloxyacetylamino-l-azetidinyl] acetic acid tert. -butyl-esters. 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, using 5 fractions of ml of a 5: 1 and 7 fractions of 1 ml of a 2: 1 mixture of ethyl acetate and toluene. This gives 2- [4 / î- (4-nitro-benzoyl) thio-2-oxo-3 /? - phenylpyacetylamino-l-azetidinyl] -2-triphenylphosphoranylid; tert-butyl en-acetic acid as a pure amorphous product, infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.9, 5.95, 6.55, 1, 45 and 11.8 / 1.

The compound obtained can be processed further as follows:

A solution of 0.022 g of 2- [4 /? - (4-nitro-benzoyl) thio-2-oxo-3 /? Phenyloxyacetylamino-l-azetidinyl] -2-triphenyl-phos-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) -6 /? - phenyloxyacetylamino-2-penem-3-carboxylate is obtained as a residue after evaporation of the filtrate, infrared absorption spectrum (in methylene chloride): characteristic bands at 5.55 (i, 5.9 (i, 6.25 (i, 6.6 (1,7,45, «. and 8.1 ß.

The starting material can be produced as follows:

a) A solution of 38.5 g of penicillin V-methyl ester l-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 filtrate is evaporated to a volume of 400 ml and kept at -20 ° for 2 days. The methyl 2- [4 /? - (2-benzothiazolyldithio) -2-oxo-3 /? - phenyloxyacetylamino-no-l-azetidinyl] -2- (l-propen-2-yl) is called as obtained crystalline product, mp 135-137 ° after recrystallization from ethyl acetate, ultraviolet absorption spectrum (in ethanol): Amilx = 243 mß (f = 9300), 268 m //

624 412

14

(e = 13700) and 275 (e = 13000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.6 [i, 5.75p, 5.9p, 8.15, "and 9.95 ^.

b) A solution of 26.5 g of 2- [4 /? - (2-benzothiazolyldithio) -2-oxo-3/5-phenyloxyacetylamino-l-azetidinyl] -2- (l-propen-2-yl) -acetic acid methyl ester in 400 ml of methylene chloride is mixed with 4 ml of triethylenamine 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 toluene and ethyl acetate as the mobile phase; 14 fractions of 500 ml each are removed. The methyl 2- [4 /? - (2-benzthiazolyldithio) -2-oxo-3 /? - phenyloxyaoetylamino-l-azetidinyl] -2- (2-propylidene) acetic acid is thus obtained as a pale yellow, non-crystalline product which can be crystallized from ethyl acetate, mp 179-182 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.6 / u ,, 5.75p, 5.9p, 8.15 ^ 1 and 9.9 / t.

c) A solution of 0.106 g2- [4 /? - (2-benzthiazolyldithio) -

2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl] -2- (2-propyli-den) -acetic acid methyl ester in 5 ml dry dimethylformamide is cooled to -20 ° and with a solution of 0.01 g sodium borohydride in 1 ml of dimethylformamide added; the solution is prepared by stirring the mixture at room temperature for 10 minutes. 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. It is diluted with 70 ml of benzene, filtered and washed three times with 10 ml of water each. 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 0 ° for one hour. The insoluble material is filtered off and the filtrate is chromatographed on 5 g of silica gel, washing with a 7: 1 and 3 ^ mixture of toluene and ethyl acetate. The 2- [4 /? - (4-nitrobenzoyl) thio-2-oxo-3 /? - phenyloxy-acetylamino-1-azetidinyl] -2- (2-propylidene) acetic acid methyl ester is obtained as colorless Foam crystallizing from methanol, mp 132-134 °; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65 p, 5.8p, 5.95 p, 6.55p, 1.4p and 11.8 p.

d) A solution of 1.8 g of 2- [4 / 3- (4-nitro-benzoyl) thio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl] -2- (2-propylidene) Methyl acetate in 20 ml of ethyl acetate is filtered through a glass filter and the filtrate is treated with ozone (0.33 mmol / minute) at -20 ° for 45 minutes. The mixture is then diluted with 100 ml of ethyl acetate, washed with 40 ml of a 10% aqueous sodium hydrogen sulfite solution and twice with 25 ml of a dilute aqueous sodium chloride solution, and the organic phase is dried with sodium sulfate. The solvent is evaporated off under reduced pressure and the residue is recrystallized from cold methanol. This gives the methyl 2- [4 /? - (4-nitrobenzoyl) thio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl] -2-oxoacetate, mp 130-133 ° ; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.5p, 5.7p, 5.98p, 6.55p, 7.45p and 11.8 ^.

e) A solution of 0.48 g of methyl 2- [4 / 5- (4-nitro-benzoyl) -thio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl] -2-oxoacetic acid in 0 , 4 ml of ethyl acetate with

Dilute 20 ml of a 98: 2 mixture of methanol and water and leave to stand for 16 hours at room temperature. It is evaporated under reduced pressure, the residue is taken to dryness again with 5 ml of methanol and then crystallized from an ethyl acetate-benzene mixture. The 4 /? - (4-nitro-benzoyl) thio-3/3-phenyloxyacetylamino-azetidin-2-one is thus obtained. F. 152-155 °; Infrared absorption spectrum (potassium bromide): characteristic bands at 5.65p, 6.0p, 6.55p, 1.4p and 11.8 / t. A further amount of the desired product can be isolated from the mother liquor by means of chromatography on silica gel and using 4: 1 and 3: 1 mixtures of toluene and ethyl acetate as mobile phases.

f) A solution of 0.08 g of 4 / 5- (4-nitro-benzoyl) -thio-3 / J-phenyloxyacetylamino-azetidin-2-one and 0.2 g of tert-butyl glyoxylic acid in 1 ml of dry dimethylformamide and

2 ml of toluene are mixed with 2 g of molecular sieve and 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- [4y9- (4-nitro-benzoyl) thio-2-oxo-3/3-phenyloxyacetylamino-l-azetidynyl] acetic acid as an amorphous foam. Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.6p, 5.1p, 5.9p, 6.5p, 1.4p and 11.75 ^.

g) The tert-butyl 2-hydroxy-2- [4 / H4-nitro-benzoyl) thio-2-oxo-3ß-phenyloxyacetylammo-l-azetidinyl] acetic acid obtainable by the above process is dried in 2 ml Dissolved tetrahydrofuran and stirred at 0 °, then with

16 pl thionyl chloride and 32 p \ triethylamine were added. The reaction mixture is stirred at 0 ° for 30 minutes, then diluted with toluene and washed with dilute nitric acid and water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. This gives the mixture of the two isomers of 2-chloro-2- [4 /? - (4-nitro-benzoyl) thio-2-oxo-3y5-phenyl-oxyacetylamino-l-azetidinyl] acetic acid tert. -butyl ester, which can be purified by chromatography on 3.5 g of silica gel using 30 ml of a 4: 1 mixture of toluene and ethyl acetate, and that is obtained as an amorphous product.

Example 4:

f) A mixture of 1.4 g of 2- (4 /? - acetylthio-2-oxo-3 / î-phenyloxyacetylamino-l-azetidinyl) -2-chloroacetic acid, 4-nitro-benzyl ester, 0.785 g of triphenylphosphine and 1 , 8 g of "polystyrene Hunig base" in 20 ml of dioxane is heated under a nitrogen atmosphere at 50 ° for 17 hours and then filtered. It is washed with dioxane, the filtrate is evaporated under reduced pressure and the residue is chromatographed on 30 g of silica gel. It is first washed out with a mixture of benzene and ethyl acetate and the 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylidene-acetic acid-4-nitro-benzyl ester is eluted with a 1: 1 mixture of benzene and ethyl acetate, which is obtained as an amorphous product, thin layer chromatogram (silica gel): Rf = 0.20 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98 u, 3.33p, 3.42p, 5.66p, 5.90p, 6.09p (shoulder), 6.15 ^, 6.24p, 651p, 6 , 11p, 6.98p, 1.08p (shoulder), 1.11p (shoulder) and 7.44 / i.

The compound obtained can be processed further as follows:

A solution of 0.209 g of 2- (4 / J-acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -2-triphenylphosphorany-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

15

624 412

4-nitrobenzide liden-acetic acid in 210 ml of toluene is held at 80 ° for 4-22 days, a stream of argon being passed through the reaction mixture. Then this is evaporated under reduced pressure and the residue is chromatographed on 30 g of silica gel, a 4: 1 mixture of benzene and ethyl acetate being used as the mobile phase and fractions of 50 ml each being removed. After two fractions that are discarded, the amorphous 2-methyl-6 /? - phenyloxyacetylamino-2-penem-

3-carboxylic acid 4-nitrobenzyl ester with fractions 3 and 10

4 eluted, infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 / u, 3.31 / t, 3.45 / t, 5.54 //, 5.86-5.91 / ^, 6.30 ( i, 6.58 //, 6.72 / t, 6.95 (i, 7.08 // (shoulder), 7.43 // and 7.66 / 1.

The starting material can be produced as follows: 15

a) A solution of 3 g of L - (+) - tartaric acid and 5.6 ml of triethylamine in 20 ml of dimethylformamide is added dropwise with 8.64 g of 4-nitrobenzylbromide in 20 ml of dimethylformamide, with stirring at room temperature and shortly after the end Adding a precipitate first solves 20 and then a new one fails. This is filtered off and washed with benzene. The L - (+) - tartaric acid di-4-nitrobenzyl ester is thus obtained; F. 163-165 °; Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.91 fi, 3.29fi, 3.45-3.55 / t, 5.86ß, 6.21 / t, 6.51 //, 6.70 / t, 25th

6.96fi, 7.27 //, l, 40f_i (shoulder), 7.45 //, 1.80fi, 7.85 // (shoulder), 8.0-8.01 (1, 8.80 ( i, 9.25 (i and 10.07 //.

b) A solution of 3 g of L - (+) - tartaric acid di-4-nitro-benzyl ester in 60 ml of dioxane and 60 ml of benzene is mixed in 30 minutes with stirring and at room temperature in small portions of 30.16 g Lead tetraacetate added. After stirring for a further 90 minutes at room temperature, the precipitate is filtered off and washed with benzene. The filtrate is evaporated under reduced pressure, the residue is partitioned between methylene chloride 35 and an aqueous sodium hydrogen carbonate solution; the insoluble material is filtered off and discarded. The organic phase is dried and evaporated.

This gives the hydrate of the 4-nitrobenzyl ester of glyoxylic acid, infrared absorption spectrum (in methylene chloride): 40 characteristic bands at 2.90 //, 3.31 //, 3.44 //, 3.54 //, 3, ll (t, 5.16 (i (shoulder), 6.23 (i, 6.55 //, 7.44 / t, 7.61 / t, 7.80-8.45 (i (broad) and 8.80-9.30 // (broad).

c) In another approach using 2.8 g of L - (+) - tartaric acid di-4-nitrobenzyl ester, no precipitate forms after the residue has been partitioned between methylene chloride and an aqueous sodium hydrogen carbonate solution; the organic paste is separated and evaporated; a product is obtained which, according to the NMR spectrum, mainly consists of the ethyl hemiacetal of glyoxylic acid 50

4-nitrobenzyl ester. The ethanol required to form this product is most likely derived from the ethanol-stabilized methylene chloride.

d) A mixture of 0.588 g of 4 /? - acetylthio-3 /? - phenyloxy-5J acetylamino-azetidin-2-one and 0.765 g of the ethyl hemiacetal of the glyoxylic acid 4-nitrobenzyl ester in 20 ml of toluene and

5 ml of dimethylformamide is stirred in the presence of molecular sieves at room temperature for 2 hours, then filtered. It is washed with toluene and the filtrate is evaporated under reduced pressure, most recently under a high vacuum. The residue represents the amorphous 2- (4 / j-acetylthio-2-oxo-3/7-tphenyIoxyacetylam.ino-l-azetidinyl) -2-hydroxy-acetic acid 4-nitrobenzyl ester, thin layer chromatography (silica gel): Rf = 0.25 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.85 // (shoulder), 2.97 //, 3.33 //, 3.44, «(shoulder), 5.61 //, 5.72 / t , 5.90 //, 6.26 / t, 6.30 / t (shoulder), 6.55 (i, 6.10 (i, 6.97fi, 7.09 // (shoulder), 7.44 //, 7.80 / t (shoulder) and 8.0-8.34 // (wide); and is processed without cleaning.

e) A mixture of 1.39 g of 2- (4 /? - acetylthio-2-oxo-3 /? - phenyIoxyacetylamino-l-azetidinyI) -2-hydroxy-acetic acid-4-nitrobenzyl'ste? and 20 ml of dioxane stirred for 30 minutes at room temperature in the presence of 1.8 g of "polystyrene Hunig base" and then treated with a solution of 0.720 g of thionyl chloride in 12 ml of dioxane. The mixture is stirred for a further 5-2 hours and filtered; the filter residue is washed with dioxane and the filtrate is evaporated under reduced pressure. The residue gives the amorphous 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetyIamino-l-azetidi-. Nyl) -2-chloroacetic acid 4-nitrobenzyl ester, infrared absorption spectrum (in methylene chloride): characteristic bands at 2.91 (x, 3.32 //, 3.41 //, 5.60 //, 5.72 //, 5.90 //, 6.30 //, 6.35 // (shoulder ), 6.55p., 6.70 //, 6.95—7.10 // (wide) and 7.42 //; which is further processed without cleaning.

Example 5:

e) A mixture of 0.57 g of 2- (4 /? - acetylthio-2-oxo-3 /? - "phenyloxyacetylamino-l-azetidinyl) -2-chloroacetic acid allyl ester and 0.4 g of triphenylphosphine in 10 ml Dioxane is stirred under a nitrogen atmosphere in the presence of 1 g of polystyrene-Hunig base at 50 ° C. After 17 hours the mixture is filtered, the filter residue is washed with dioxane and the combined filtrates are evaporated. The syrupy residue is chromatographed on 20 g silica gel A 4: 1 mixture of benzene and ethyl acetate is used as the mobile phase and fractions of 25 ml are removed. In the first eight fractions, impurities are leached out, while with fractions 9 to 20 of the 2- (4 /? - acetylthio -2-oxo-3 /? - phenyloxyacetyl-amino-l-azetidinyl) -2-triphenylphosphoranylidtn-acetic acid allyl ester in the form of a colorless foam, "thin layer chromatogram (silica gel): Rf = 0.27 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at. 2.91 (1, 3.30-3.45 //, 5.66 //, 5.90 //, 6.08 // (shoulder), 6.15 (i, 6.23 (i (shoulder ), 6.58 //, 6.69 //, 6.95 //, 7.16 //, 7.40 //, 7.75-8.00 (i (broad), 8.10 / t , 8.26 //, 8.50 //, 8.85 //, 9.05 //, 9.25 // and 9.40 //. "

The compound obtained can be processed further as follows:

A solution of 0.150 g of 2- (4 /? - acetylthio-2-oxo-3ß- ■ phenyloxy acetylamino-l-azetidinyl) -2-triphenylphosphoranyliden-acetic acid allyl ester in 100 ml of toluene is at 80 ° for 2V2 days warmed in an argon atmosphere and then evaporated under reduced pressure. The syrupy residue is chromatographed on 15 g of acid-washed silica gel, a 4: 1 mixture of benzene and ethyl acetate being used as the mobile phase and fractions of 25 ml each being removed. The 2-methyl-6 / J-phenyl-acetylamino-2-penem-3-carboxylic acid alyl ester is washed out with fractions 2 and 3 and obtained as a colorless amorphous foam, thin layer chromatogram (silica gel): Rf = 0.48 (system: Ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 //, 3.40 //, 5.55 //, 5.86 // (broad), 6.25 //, 6.59fi, 6.69 ( t, l, 35fi and 7.65 //.

The starting material can be produced as follows:

a) A solution of 9.0 g of L - (+) - tartaric acid and 1.68 ml of triethylamine in 50 ml of dimethylformamide is mixed dropwise with 10.5 ml of allyl bromide, stirring the reaction mixture with cold water for a while. After the addition for 15 minutes, the mixture is stirred at room temperature for 2Va hours and then the

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30th

action mixture between benzene and water. The organic phase is dried over sodium sulfate and evaporated. The oily residue is distilled and the L - (+) - tartaric acid diallyl ester is distilled at a bath temperature of 140-150 ° and a pressure of 0.3 mm Hg, s infrared absorption spectrum (methylene chloride): characteristic bands at 2.86 °, 3.43 //, 5.75 / t, 7.25 «, 7.38ß, 7.75 / t (broad), 8.13 // (broad), 8.35 //, 8.93 // , 9.20 / «, 10.17ß (broad) and 10.62 // (broad).

b) A solution of 5.05 g L - (+) - tartaric acid diallyl ester M in 10 ml acetic acid and 25 ml water is treated dropwise with 6.2 g sodium periodate in 40 ml water; the addition takes 30 minutes, stirring and cooling in a water bath. After a further 30 minutes at room temperature, the reaction mixture is partitioned between ethyl acetate and water, the organic phase being washed with water and the aqueous phase with ethyl acetate. The combined organic solutions are evaporated; the residue is redissolved in ethyl acetate and filtered through a short column with neutral aluminum oxide, then evaporated. The residue is distilled in the presence of a few crystals of hydroquinone; the dihydrate of the glyoxylic acid allyl ester is distilled at a bath temperature of 110-130 ° and a pressure of 30-40 mm Hg; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.86ß (broad), 3.43 //, 3.55ß, 5.73 //, 6.25 //, 7.72-8.00 / t (broad), 8.24 // (broad), 9.13 / t (broad) 9.67 // (broad), 10.15 / t (broad) and 10.63, u (broad).

c) A solution of 0.294 g of 4 /? - acetylthio-3 /? - phenyIoxy-acetylamino-azetidin-2-one in 2.5 ml of dimethylformamide and 10 ml of toluene is mixed with 0.400 g of the hydrate of the glyoxylic acid allyl ester and the mixture at room temperature in the presence of molecular sieves under a nitrogen atmosphere. After 2-21 / »hours the mixture is filtered; and filter residue is washed with toluene. The combined 35 filtrates are evaporated under reduced pressure and finally under a high vacuum. The syrup-like 2- (4 /? - acetylthio-2-oxo-3-phenyloxyacetylamino-l-azetidinyl) -2-hydroxy-acetic acid allyl ester, thin layer chromatogram (silica gel): Rf = 0.26 (system: 40 ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88 //,

2.97 //, 3.45 //, 5.60 / i, 5.73 //, 5.90 //, 6.25 //, 6.30 / t (shoulder), 6.60 /; , 6.70 //, 6.98 //, 7.40 / t (wide), 7.75-8.00 // (wide), 8.10-8.30m (wide) and 8.55 / / .. 45

d) A suspension of 1 g of "polystyrene-Hunig base" in 5 ml of dioxane is stirred for 2 hours at room temperature and with a solution of 0.60 g of 2- (4 /? - acetylthio-2-oxo-3-phenyloxyacetylamino-l -azetidinyl) -2-hydroxy-acetic acid allyl ester in 5 ml of dioxane, followed by 0.22 ml of thionyl chloride. The mixture is stirred under a nitrogen atmosphere for 3 hours, then filtered and the filter residue is washed with dioxane. The combined filtrates are evaporated under reduced pressure and give the syrup-like 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetyl-amino-l-azetidinyl) -2-chloroacetic acid allyl ester, thin layer chromatogram (silica gel) : Rf = 0.53 (system: ethyl acetate / benzene 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 / t, 3.45 //, 5.58 / t 5.70 / t, 5.90 / t, 6.25 //, 6.30 / t ( Shoulder), 60 6.60 / ", 6.70 //, 6.96 / t, 7.35 / t (shoulder), 7.40 / t, 7.60 //, 7.80-8.00 / <(broad) and 8.10-8.30 // (broad).

Example 6:

g) A solution of the process described in Example 6f) from 0.295 g of 2-hydroxy-2- (4 /? - isóbutyrylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyi) acetic acid tert.-

butyl ester available 2-chloro-2- (4 /? - isobutyryIthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) acetic acid tert-butyl ester in 12 ml of dioxane is in the presence of 1 g «Poly -styrene-Hunig base »stirred for 30 minutes, then treated with 0.4 g triphenylphosphine 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 are washed out with benzene. The amorphous 2- (4 /? - isobutyrylthio-2-oxo-3/5-phenyloxyacetyl-amino-l-azetidinyl) -2-triphenylphosphoranylidene-acetic acid tert-butyl ester is mixed with a 1: 1 mixture of benzene and ethyl acetate eluted; Thin layer chromatogram (silica gel): Rf = 0.25 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 / t, 3.40 //, 5.65 //, 5.90 //, 6.10 / t, 6.18 / z, 6.25 / t (Shoulder), 6.59 //, 6.70 //, 6.96 / t, 7.33 / t, 7.75-8.12 // (broad), 8.02-8.14 // (wide) and 9.07 //.

The compound obtained can be processed further as follows:

A solution of 0.081 g of 2- (4 /? - isobutyrylthio-2-oxo-3y5-phenyloxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylidene-acetic acid tert-butyl ester in 40 ml of toluene is stirred under an argon atmosphere for 5- V2 heated at 70 °, then 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, tert-butyl 2-isopropyl-6 /? - phenyloxyacetylamino-2-penem-3-carboxylate of the formula h h

ü;> - <

ch,

50

55

65

ch-

0 = è-0-c (ch3) 3

as colorless syrup, Rf = 0.57 (system, benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.99 //, 3.40-3.50 //, 5.59 / t, 5.91 / t (broad), 6.26 / t, 6, 30 / t (shoulder), 6.35 // (shoulder), 6.60 / t, 6.70 / t, 7.34 «, 8.10-8.20 // (broad), 8.30 / / (Shoulder) and 8.70 //.

The starting material can be obtained as follows: a) A mixture of 3.8 g of penicillin V-methyl ester l-oxide in 120 ml of benzene, 20 ml of isobutyric anhydride and 5 ml of trimethylphosphite is heated under reflux for 12 hours, then evaporated under reduced pressure . The syrup-like residue is chromatographed on 120 g of silica gel (column). Pre-wash with a 7: 1 mixture of benzene and ethyl acetate and elute the 2- (4 / msobutyrylthio-2-oxo-3 /? - phenyloxyacetylamino-l-. Azetidinyl) -2- (l-propen-2 -yl) -acetic acid tert-butyl ester with a 4: 1 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 / t, 3.32 / t, 3.41 //, 5.63 / t, 5.74 //, 5.91 //, 6.24 / t , 6.28 //, 6.60 //, 6.71 //, 6.97 //, 7.27 //, 7.35 // (shoulder), 7.53 //, 8.10 / / (broad), 8.28 //, (broad) and 8.50-8.60 / t.

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b) A solution of 0.100 g of tert-butyl 2- (4 / ï-isobutyrylthio-2-oxo-3 / J-phenyloxyacetylamino-l-azetidinyl) -2- (l-propen-2-yl) -acetate in 2 ml of methylene chloride and 0.03 ml of triethylamine are left 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. The 2- (4 /} - isobutyrylthio-2-oxo-3-phenyloxyacetylamino-l-azetidinyl) -2- (2-propylidene) -acetic acid & tert.-butyl ester is thus obtained as a colorless foam, Rf = 0.38 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97p, 3.32 / i, 3.41 / <, 5.64p, 5.81 / 1 (shoulder), 5.91 / i, 6.15 «, 6 , 25p, 6.29p (shoulder), 6.60p, 6.71 p, 6.97p, 7.24p, 7.34p, 8.16 / i (broad) and 8.12p.

c) A solution of 1.41 g of 2- (4 / msobutyrylthio-2-oxo-3-phenyloxyacetylamino-l-azetidinyl) -2- (2-prop.ylidene) acetic acid t-butyl ester in 32 ml Absolute methanol is cooled to -20 ° and treated with a mixture of ozone and oxygen (0.33 mmol ozone per minute) at this temperature for 32 minutes. After two more hours at -20 °, the crystalline material is filtered off and washed with a mixture of methanol and diethyl ether. This gives 2- (4 / j-isobutyrylthio-2-oxo-3 / J-phe-nyIoxyacetylamino-l-azetidinyl) -2-oxo-acetic acid tert-butyl ester, mp 112-114 ° after recrystallization from methanol: [a] D20 = -51 ° ± 1 ° (c = 1.015 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97p, 3.30p, 3.40p, 5.49p, 5.70p, 5.86p (broad), 6.25p, 6.29p (shoulder), 6.60p , 6.70p, 6.95p, 7.32p (wide), 8.20p (wide) and 8.50p.

d) A solution of 0.650 g of 2- (4 / Hsobutyrylthio-2-oxo-3 /? - phenyIoxyacetyIamino-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 2 V '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 4 / Msobutyrylthio-3 /) - phenyloxyacetylamino-azetidin-2-one is recrystallized from a mixture of methylene chloride and diethyl ether. F. 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 2.97p, 3.32p, 3.40p, 5.61p, 5.92p, 6.25p, 6.29p (shoulder), 6.60p, 6.70p, 6 , 97p, 7.08p (shoulder) and 8.10 / t (broad).

e) A mixture of 0.295 g of 4 / Hsobutyrylthio-3 /? - 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 in the presence of Molecular sieves stirred at room temperature. After 90 minutes the mixture is filtered, the filter residue is washed with toluene and the combined filtrates are evaporated, finally under high vacuum. This gives the syrup-like 2-hydroxy-2- (4 /? - isobutyryl-thio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) acetic acid tert-butyl ester, thin-layer chromatography (silica gel):

Rf = 0.32 (system: benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.86p, 2.97p, 3.40p, 3.45 ^ (shoulder), 5.61a, 5.76p, 5.91 p, 6.25p, 6.29p ( Shoulder), 6.60, «, 6.70p, 6.97p,

7.31 p, 7.75p (broad), 8.15p and 8.86p (broad); which is processed without cleaning.

f) A solution of 0.295 g of the crude 2-hydroxy-2- (4 / J-isobutyrylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -. acetic acid tert-butyl ester in 11 ml of dioxane is in The presence of Tg “polystyrene-Hunig base” was 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 2-1fa hours, filtered, washed with dioxane and the combined filtrates are evaporated, lastly under reduced pressure. This gives the 2-chloro-2- (4 /? - iso-butyrylthio-2- oxo-3 / j-phenyloxyacetylamino-l-azetidinyl) acetic acid tert-butyl ester, thin layer chromatogram (silica gel): Rf = 0.56 (system: ethyl acetate / benzene 1: 1), infrared absorption spectrum (in methylene chloride): characteristic bands in 2.97p, 3.40p, 3.50p, 5.58p, 5.71 p, 5.89p, 6.25p, 6.29p (shoulder), 6.60p, 6.70p, 6.89p, 6, 95p, 7.32p, 7.59'p, 7.75p (wide), 8.15 ^ (wide) and 8.70 / t; which is processed without cleaning.

Example 7:

e) A solution of the 2- (4β-acetylthio-2-oxo-3 /? - phenyl-oxyacetylamino-f-azetidiiiyl-2 ^ chloro-acetic acid-diphenyl-methyl ester) obtained in 75 ml of dioxane by the process described in Example 7d) 0.5 g of "polystyrene-Hunig base" is added and the mixture is stirred for 30 hours at room temperature, 0.4 g of triphenylphosphine is added, stirring is continued for 20 hours at 50 °, the filtrate is filtered and evaporated Chromatographed on silica gel (system: toluene / ethyl acetate 1: 1) and then purified by preparative layer chromatography, giving the oily 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetyIamino-l-azetidinyinyI) -2-triphenyIphos-phoranyliden-acetic acid-diphenylmethyl ester, thin layer chromatogram (silica gel): Rf = 0.28 (system: toluene / ethyl acetate 1: 1); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.9p, 3.45p, 5 , 7p, 5.95p, 6.04p, 6.2p, 6.3p, 6.65p, 6.75p, 7.0p, 8.15p,. 8.35p, 9.1 p, 9.34p and 9 , 56p.

The compound obtained can be processed further as follows:

A solution of 0.026 g of 2- (4 / j-acetylthio-2-oxo-3β-phenyloxyacetylamino-1 "azetidinyl) -2-triphenylphosphoranylidene-acetic acid diphenyl ester in 25 ml of toluene is heated at 80 ° for 48 hours. The solvent is then evaporated and the residue subjected to preparative layer chromatography (silica gel). This gives the 2-methyl-6 / j-phenyloxyacetylamino-2-penem-3-carboxylic acid diphenylmethyl ester, Rf = 0.59 (system: toluene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.0p, 5.58p, 5.9p, 6.3u, 6.65p, 6.73p, 8.2p, 8.65p and 9.3p.

The starting material can be produced as follows:

a) 4.2 g of L - (+) - tartaric acid are dissolved in 100 ml of warm absolute dioxane, the solution is mixed with a solution of 10.0 g of di-phenyldiazomethane in 100 ml of diethyl ether at room temperature and with stirring. The mixture is left to stand at room temperature for 16 hours, then the crystalline material is filtered off and the filtrate is concentrated to a small volume. The precipitate and the residue are dissolved in methylene chloride, the solution is washed twice with sodium hydrogen carbonate solution and once with water and evaporated. The residue is recrystallized from a mixture of methylene chloride and diethyl ether and gives the L - (-) - tartaric acid bis-diphenyl methyl ester, mp 115-117 °; [a] D20 = -16 ° ± 1 ° (c = 0.943 in chloroform); which is obtained as a hydrate.

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624 412

18th

b) A solution of 0.965 g of L - (-) - tartaric acid bis-diphenyl methyl ester hydrate in 10 ml of absolute benzene is mixed with 1.0 g of lead tetraacetate in 25 ml of benzene within 15 minutes. After 6 hours at room temperature, filter; the filtrate is washed with an aqueous sodium hydrogen carbonate 5 solution and a saturated sodium chloride solution in water and evaporated. The residue is taken up in diethyl ether, the solution is filtered; the filtrate is mixed with an aqueous sodium hydro-glyoxylic acid diphenylmethyl ester. 10th

c) A solution of 0.147 g of 4 / f? -acetylthio-3 /? - phenyloxy-acetylamino-azetidin-2-one in 5 ml of toluene and 1.5 ml of dimethylformamide is mixed with 0.402 g of diphenyl methyl ester of glyoxylic acid, and that Reaction mixture stirred at room temperature for 2-Vî hours in the presence of molecular • 15 seven. It is filtered, the filtrate is evaporated and the residue is dried under high vacuum. This gives the 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetyl-amino-l-azetidinyl) -2-hydroxy-acetic acid-diphenylmethyl ester, thin layer chromatogram (silica gel): Rf = 0.33 20 (system: toluene / ethyl acetate 1: 1); which is processed without cleaning.

d) A solution of the 2- (4/3-acetylthio-2-oxo-3/3-phenyloxyacetylamino-l-azetidinyl) -2-hydroxy-acetic acid-diphenylmethyI- 25 ester prepared in accordance with the above method in 5 ml of dioxane 0.5 g of «polystyrene Hunig base» and then 0.149 g of thionyl chloride are added. The reaction mixture is stirred for three hours at room temperature, then filtered and the filtrate evaporated. The crude 2- (4y? -Acetylthio-2-oxo-3 / 5-30 phenyloxyacetylamino-l-azetidinyl) -2-chloroacetic acid di-phenylmethyl ester is thus obtained; Thin layer chromatogram (silica gel):

Rf = 0.58 (system: toluene / ethyl acetate 1: 1); which is processed without cleaning.

35

Example 8:

f) A solution of 756 mg of 2- (4 /? - acetylthio-2-oxo-3 / J-phthalimido-l-azetidinyl) -2-chloroacetic acid tert-butyl ester in 21 ml of dioxane is mixed with 1 , 68 g of "polystyrene Hunig base" (neutralized 3.68 milliequivalents of hydrochloric acid per gram) stirred for 30 minutes. After addition of 766 mg triphenylphosphine, the mixture is stirred under nitrogen at 70 °. After 68 hours, the «polystyrene-Hunig base» is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo 45. 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 then elutes the amorphous 2- (4ß-acetyIthio-2-oxo-3 /? - phthaIimido-l-azetidinyI) -2-triphenyl- 50 phosphoranylidene-acetic acid tert.-butyl ester: thin layer chromatogram: Rf- Value = 0.32 (silica gel; benzene / ethyl acetate 1: 1); IR spectrum (in methylene chloride): characteristic absorption bands at 3.30; 3.40; 5.59; 5.65; 5.79; 5.90; 6.04-6.10; 6.13-6.20; 6.47; 7.22; 7.35; 7.80-8.05; 55 8.10 (broad); 8.85-9.05 (broad) / <.

The compound obtained can be processed further as follows:

A solution of 100 mg of 2- (4/5-acetylthio-2-oxo-3/3-eo phthalimido-l-azetidinyl) -2-triphenylphosphoranylidene acetic acid tert-butyl ester in 50 ml of absolute dioxane is in the presence 500 mg of «Polystyrene-Hunig 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 (2 kg of silica gel are stirred 3 times with 2 l of concentrated hydrochloric acid for 10 minutes, decanted, washed neutral with distilled water, washed with methanol and 60 hours at 120 ° activate), which is deactivated with 10% water, cleaned with benzene as the eluent. The 2-methyl-6 /? -Phthalimido-2-penem-3-carboxylic acid tert-butyl ester obtained crystallizes in the form of colorless needles from methylene chloride diethyl ether, mp. 179-181 °; UV spectrum (in 96% ethanol): 2max = 303m / t (s = 6370); IR spectrum (in methylene chloride): characteristic absorption bands at 3.30; 3.40; 5.55; 5.63; 5.74; 5.80; 6.25; 7.24; 7.33; 7.50 - 7.58; 7.80-8.05; 8.33; 8.70 fi.

The starting material can be obtained as follows:

b) A solution of 2.5 g of methyl 2- (4/3-acetythio-3/3-phthalimi-do-2-oxo-l-azetidinyl) -2- (l-propen-2-yl) -acetate (R. Latrel, Liebigs Ann. 1974, 1937) in 60 ml of methylene chloride and 60 ml of methanol is passed through at 0 ° C. with a 0s / 02 mixture for 2 hours and 5 minutes (0.33 mM Os / min.). The reaction mixture is left to stand at -20 ° for 1 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- (4/5-acetylthio-2-oxo-3 /? - phthalimido-l-azetidinyl) -2-oxoacetate is used in the next step without purification.

c) A solution of 7.5 g of amorphous 2- (4 /? - acetylthio-2-oxo-3 / j-phthalimido-l-azetidinyl) -2-oxo-acetic acid methyl ester in a mixture of 85 ml of methyl acetate , 750 ml of 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, the 4 / J-acetyl-thio-3 / I-phthalimido-azetidin-2-one is obtained; F. 164-170 °; IR spectrum (methylene chloride): characteristic absorption bands at 2.97; 3.34; 3.41; 5.57; 5.65; 5.80; 5.90; 7.23; 7.85-8.05; 8.30; 8.95; 9.05 ji,

d) A solution of 1.45 g of 4ß-acetylthio-3 / j-phthalimido-azetidin-2-one and 2.475 g of tert-butyl ester of glyoxylic acid in 50 ml of toluene and 12 ml of dimethylformamide is mixed with freshly activated molecular sieve (see Example lf ) added and 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-3 /? - phthalimido-l-azetidinyl) -2-hydroxy- acetic acid tert-butyl ester. By crystallization from methylene chloride diethyl ether one of the epimers can be crystallized. Form of melting point 155-157 ° can be obtained. IR spectrum (in methylene chloride): characteristic absorption bands at 2.95-3.55 (broad); 5.60; 5.63 (sh); 5.89; 5.88 (sh); 7.23; 7.32; 7.80-8.05 (broad) fi.

e) A solution of 640 mg of the crystalline tert-butyl 2- (4 /? - AcetyI-thio-2-oxo-3 /} - phthalimklo-l-azetidinyl) -2-hydroxy-acetic acid in 13 ml Absolute dioxane is stirred at room temperature with 1.28 g «polystyrene-Hunig base» (see example 1h; neutralized 3.68 milliequivalents hydrochloric acid per gram) for 30 minutes, after which a solution of 533 mg thionyl chloride in 9 ml dioxane is added dropwise. The mixture is further stirred under nitrogen for 4 Vg hours at room temperature. The «polystyrene

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Hiinigbase »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- (4/5-acetylthio-2-oxo-3 / I-phthalimido-l ^ azetidinyl) -2-chloroacetic acid tert-butyl ester; Thin layer chromatogram: Rf value = 0.56 (Merck silica gel; benzene / ethyl acetate 1: 1); IR spectrum (in methylene chloride): characteristic absorption bands at 3.30; 3.40; 5.57; 5.63 (sh); 5.72 (sh); 5.78; 5.87 (sh); 7.20; 7.35; 7.58; 7.80-8.05; 8.70, «.

A similar mixture of epimers is obtained by starting from the non-crystalline mixture of epimers.

Example 9:

f) A solution of 1.5 g of crude 2- (4/5-acetylthio-3 / j-phenyloxyacetylamino-2-oxol-azetidinyl) -2-chloroacetic acid-15 acid p-methoxybenzyl ester and 786 mg triphenylphosphine in 20 ml of dioxane at 50 ° under nitrogen in the presence of 1.8 g of "polystyrene Hunig base" (neutralized 3.45 milliequivalents hydrochloric acid per gram), which was pretreated for 30 minutes in the same solvent, stirred for 16 hours. The «Polystyrene-Hunig base» is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together under reduced pressure. The syrupy residue is chromatographed on 30 g of silica gel. High-speed 2s de by-products are first eluted with benzene / ethyl acetate 4: 1. Benzene / ethyl acetate 1: 1 then elutes the 2- (4 /? - acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) -Ö-triphenylHphosphoranyliden-acetic acid-p-methoxy-benzyl, which for further purification 6 preparative silica gel thick-layer plates with benzene / ethyl acetate 1: 1 30 as eluent can be chromatographed. Rf = 0.24 (silica gel; benzene / ethyl acetate 1: 1); IR spectrum (in methylene chloride): characteristic absorption bands at 2.95; 3.30; 3.40; 3.55; 5.65; 5.90; 6.08 (sh); 6.13 (sh); 6.19; 6.21 (sh); 6.25 (sh); 6.60 6.70; 6.95; 7.85-8.00 (broad); 35 8.06; 8.53; 9.05 fi.

The compound obtained can be processed further as follows:

a) A solution of 85 mg of 2- (4 / j-acetylthio-2-oxo-3 /? - phenyloxyacetylamino-l-azetidinyl) - »2-triphenylphosphor- 40 anylidene-acetic acid-p-methoxybenzyl ester in 85 ml of toluene is during Heated under argon at 80 ° for 48 hours. The solvent is evaporated off under reduced pressure and the residue is chromatographed on 15 g of silica gel with benzene / ethyl acetate 4: 1. The 2-methyl-6 /? - phenyl-45 oxyacetylamino-2-penem-3-carboxylic acid p-methoxybenzyl ester is obtained, thin layer chromatogram: Rf value: 0.52 (silica gel; benzene / ethyl acetate 1: 1); UV spectrum (in 96% ethanol): Xmny = 305 rn «; 272 m / i; 267 mp; 260 m «; IR spectrum (in methylene chloride): characteristic absorption bands at 2.97; 3.30; 3.42; 3.57; 5.56; 5.85 (sh); 5.88;

6.20; 6.27; 6.60; 6.70; 6.96; 7.07 (sh); 7.30; 7.70; 8.07; 8.27; 8.51-8.60 (broad); 9.26; 9.69 fi.

The starting material can be obtained as follows:

b) A solution of 3 g of L - (+) - tartaric acid in 20 ml of dimethylformamide and 5.6 ml of triethylamine is treated dropwise with a solution of 8.04 g of p-methoxybenzyl bromide in 20 ml of dimethylformamide, the reaction mixture for 3 hours stirred at room temperature and partitioned between 300 ml of benzene and 100 ml of water. The organic phase is washed twice with 100 ml of water, dried over sodium sulfate and freed from the solvent in vacuo. The crude but crystalline di-p-methoxy-benzyl ester of L - (+) - tartaric acid obtained has a melting point of 98-100 °, Rf value = 0.34 (silica gel: ethyl acetate /

Benzene 1: 1); IR spectrum (in methyl en'chloride); Absorption bands at 2.88 '»3.30; 3.43; 3.58; 5.75; 6.21; 6.60; 6.85-7.10 "(wide); 8.08; 8.52; 8.95; 9.25; 9.69 fi.

c) To a solution of 4.6 g of the crude L - (+) - tartaric acid di-p-methoxybenzyl ester obtained in 150 ml of benzene, 5.2 g of lead tetraacetate are added in several portions within 20 minutes and the reaction mixture for 5 hours at room temperature touched. The precipitate is filtered off, washed with benzene and the filtrate and washing liquid are evaporated together in vacuo. The residue is dissolved in methylene chloride (made alcohol-free by filtering through aluminum oxide) and washed with 4% aqueous sodium hydrogen carbonate solution. The organic phase is evaporated under reduced pressure and gives a mixture of hydrated, hemihydrated and unhydrated glyoxylic acid p-methoxybenzyl ester. Rf = 0.25 (silica gel; ethyl acetate / benzene 1: 1); IR spectrum (in methylene chloride): absorption bands at 2.90; 3.30; 3.40; 3.57; 5.74 (broad); 6.20; 6.30; 6.60; 8.05; 8.50; 8.98-9.05 (sh); 9.14 (broad); 9.68 p.

d) A solution of 588 mg of 4β-acetylthio-3 / S-phenyl-oxyacetylamino-2-oxo-azetidine and 900 mg of the crude glyoxylic acid p-methoxybenzyl ester obtained in 30 ml of toluene and 5 ml of dimethylformamide is mixed with activated molecular sieves and Stirred for 3 hours at room temperature. The molecular sieves are filtered off, washed with toluene and the filtrates and washing liquid are evaporated together in vacuo. The amorphous, crude 2- (4/3-acetylthio-3 /? - phenyloxyacetylamino-2-oxo-l-azetidinyl) -2-hydroxy-acetic acid p-methoxybenzyl ester, Rf value =

~ 0.20, elongated stain, silica gel, benzene / ethyl acetate 1: 1).

e) A solution of 1.49 g of the crude 2- (4 /? - acetylthio-3 / 5'-phenyloxyacetylamino-2-oxo-l-azetidinyl) -2-hydroxy-acetic acid p-methoxybenzyl ester obtained in 20 ml of dioxane 1.8 g of “polystyrene Hunig base” (neutralized 3.45 milliequivalents of hydrochloric acid per gram) are added and the mixture is stirred at room temperature for 30 minutes. A solution of 720 ml of thionyl chloride in 12 ml of dioxane is added dropwise and the reaction mixture is stirred under nitrogen for 2.5 hours at room temperature. The «Polystyrene-Hunig base» is filtered off and washed with dioxane. The filtrate and washing liquid evaporated together in vacuo give the crude 2- (4y5-acetylthio-3 / i-phenyloxy-acetylamino-7-oxo-l-azetidinyl) -2-chloroacetic acid-p-methoxy-benzene ester; Rf value = 0.50 (silica gel; ethyl acetate / benzene 1: 1). '

M

Claims (11)

624 412 PATENT CLAIMS 1. Process for the preparation of ylide compounds of See formula aryl radical, or an optionally substituted heterocyclic aryl radical, and Rb and Re together preferably mean O-substituted hydroxyimino in the syn configuration. 2. The method according to claim 1, characterized in that an acyl radical RiA or Rib is a radical of the formula - c - I. R_ 0 II c - (IA) both 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 cyan, etherified hydroxy or mercapto, or an optionally substituted unsaturated heterocyclic radical linked via a ring nitrogen atom, and Rb and Rc are hydrogen, or in which (3) R is an optionally substituted carbocyclic R - 15 c - c - I. R (IA) 30th 35 40 45 50 55 60 65 means in which (1) Ra represents optionally substituted phenyl, optionally substituted cyclohexadienyl or cyclo-hexenyl, or optionally substituted thienyl or fu-ryl, Rb represents hydrogen and Rc represents hydrogen or optionally protected hydroxy, amino, carboxyl or sulfo, or in which (2) Ra is cyan, optionally substituted phenyloxy, phenylthio or pyridylthio, or optionally substituted tetrazolyl linked via a ring nitrogen atom, and Rb and Rc are hydrogen, or in which (3) Ra is optionally substituted phenyl, or optionally substituted thienyl or furyl, and Rb and R (together preferably denote O-substituted hydroxyimino in the syn configuration, 3rd 624 412 3. The method according to claim 2, characterized in that an acyl radical RiA or Rib is a radical of the formula (II) io in which RiA represents an amino protective group and Rib represents hydrogen or an acyl radical Ac, or in which RiA and Rib together form a divalent amino protective group, R2A represents a radical together with the carbonyl group -C (= protected carboxyl group) and R3 represents hydrogen or an organic radical connected via a carbon atom to the carbonyl group -C (= 0) -, and in which X® denotes either a trisubstituted phosphoniogroup or a doubly esterified phosphonogroup together with a cation, characterized in that an a-hydroxycarbon Acid compound of the formula 20th 25th R ' C - R- XI, CHa /% X, 0 = C R2 wherein Xo represents a reactive esterified hydroxy group, treated with a triply substituted phosphine compound or a phosphite compound. 4. The method according to claim 2, characterized in that RiA 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 optionally substituted by saturated aliphatic or aromatic hydrocarbon radicals or one by an unsaturated aliphatic Hydrocarbon radical, by means of a carbocyclic aryl group having electron-donating substituents or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, monosubstituted methoxy group, lower alkoxyphenyl-lower alkoxy, nitrobenzyloxy, furfuryloxy, 2-oxa-or 2-thia cycloalkoxy or cycloalkenyloxy with 5-7 ring members, or a corresponding thia group, or arylcarbonylmethoxy, in which aryl in particular represents an optionally substituted phenyl group, nitrophenyloxy, unbranched lower alkoxy, by 1 to 3 optionally substituted hydrocarbon residues, preferably with up to 18 carbon atoms, substituted silyloxy or stannyloxy, an acyloxymethoxy group, wherein acyl z. B. means the rest of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, means hydrazino or 2-lower alkylhydrazino. 6. The method according to claim 5, characterized in that R2a means tert-butyloxy, diphenylmethoxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy or methoxy. 7. The method according to claim 1, characterized in that Rs is hydrogen or optionally substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl or phenyl-lower alkyl. 8. The method according to claim 7, characterized in that Rs represents hydrogen, methyl, ethyl, 2-propyl, ace-toxymethyl, benzyl or phenyl. 9. The method according to claim 1, characterized in that X © represents triaryl or tri-lower alkylphosphonio. 10. The method according to claim 9, characterized in that X © represents triphenylphosphonio. 11. The method according to claim 1, characterized in that the 2 - (- 4/3-acetylthio-2-oxo-3 / j-phenyl-oxyacetylamino-l-azetidinyl) -2-triphenylphosphoranylidene-acetic acid tert-butyl ester manufactures.