DE3010531A1 - METHOD FOR CYCLIZING SULFIDES - Google Patents

Description

HOECHST AKTIENGESELLSCHAFT HOE 79 / F 3 ^ 7 Dr.KA / a

-I ·

Process for cyclizing sulphides

The present invention relates to a process for cyclizing organic compounds.

Many pharmaceutically active compounds contain ring structures The process according to the invention is suitable for the production of ring structures containing ß-lactam. Surprisingly, it has been found that certain mono-, di- or polythioazetidinone derivatives cyclize can be, wherein one in a relatively simple manner pharmaceutically active, ß-lactam-containing ring compounds receives.

The present invention accordingly provides a process for the desulfurization of organic sulfides with simultaneous ring closure, which is characterized in that one ß-lactam, one to the nitrogen atom an unsubstituted or substituted divalent organic radical bonded nucleophilic group and a contains dithio or polythio group bonded to the adjacent carbon atom, with a trivalent organophosphorus compound implements. The sulfide is preferably additionally - simultaneously or subsequently - still with a thiophilic compound of the structure given below.

The starting compound preferably has the following general formula I

(D

O · "Υ-Nuc

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wherein Nuc is a nucleophilic group, Z is an optionally substituted aromatic, heterocyclic radical with up to 15, preferably up to 9 carbon atoms and at least one ring nitrogen atom and optionally another heteroatom in the ring, through one of its ring carbon atoms, which in turn is through a double bond is connected to a ring nitrogen atom / with the

Thio group ~ / ~ S / -linked, or an acyl radical - - η

an organic carboxylic or thiocarboxylic acid, Y an optionally substituted divalent organic The remainder and η is an integer from 2 to 4 / preferably 2, where the ß-Lactam.ring is unsubstituted or can be further substituted.

Examples of nucleophilic groups that may be mentioned are the HO, HS, H ₃ N, O, S ^ or ^ HN groups, R'S groups, in which R "is a protective group, such as, for example, a group of the formula

^siRll 3 ^and SnR '^ 5 denotes, in which R ^J ' denotes straight-chain or branched, optionally substituted alkyl with up to 8 carbon atoms, such as, for example, methyl or η-butyl; or R ¹¹¹ HN and R '''ttP groups, where R ¹ "denotes an organic group, such as, for example, optionally substituted alkyl or aryl, such as, for example, lower alkyl, phenyl or aralkyl, for example benzyl.

A prerequisite for ring closure during desulfurization is of course that the divalent organic radical Y is so is such that the nucleophilic group is attached to the carbon atom to which the / S / Z group is bonded, so-

- - η

can approximate that a chemical bond is possible.

The nucleophilic group is preferably attached to the nitrogen atom of the β-lactam via a preferably substituted one Vinylidene or alkylene radical or a preferably sub-

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substituted aromatic radical bound.

The starting materials preferably have the following substructures of the formulas III or IV

Nuc

R ⁴ OOC R ~

wherein Nuc has the meaning given above, R. for a hydrogen atom or a carboxy protecting group and R ^ represents a hydrogen atom or an organic radical.Als

R OOC groups come, for example, esters of optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohols with up to 18 carbon atoms. Organic radicals in the meaning of R can be optionally substituted cycloaliphatic radicals, especially with 5 to 7 ring carbon atoms, or optionally substituted aryl, in particular phenyl or an optionally substituted straight-chain or branched aliphatic group, such as, for example, alkyl, alkenyl or alkynyl with up to 8, in particular up to 4 Carbon atoms.

A group in the meaning of R ₅ can be substituted one or more times, for example by halogen; Oxo; Hydroxy or mercapto; Alkoxy or alkylthio; Alkylcarbonyl; Carboxy, alkoxycarbonyl, or alkylthiocarbonyl; Alkanoyloxy or alkanoylthio; Carbamoyl or carbamoyloxy, which can be substituted one or two times on the nitrogen atom by alkyl or aryl, and the corresponding, optionally substituted groups in which the oxygen atom or both or one of the two oxygen atoms

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is (are) replaced by a sulfur atom; Nitro, Cyano or azido; Amido or imido; Imino, amino, mono- or dialkylamino, mono- or diarylamino and N, N-alkylarylamino; Acylamino; Sulfinyl, sulfonyl or sulfonamido; Cycloalkyl; Aryl, aryloxy, arylthio, aryloxycarbonyl, arylthiocarbonyl, arylcarbonyloxy, arylcarbonylthio , Aralkoxycarbonyl, aralkylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthio, aralkoxy and aralkylthio; aromatic or non-aromatic heterocyclic groups with, for example, one or more heteroatoms, e.g. with up to 4 identical or different heteroatoms, such as nitrogen, oxygen or sulfur atoms and with a total of up to 14 atoms and the corresponding aromatic or non-aromatic hetero-0 or hetero-S groups.

Aromatic heterocyclic groups would be, for example, 1-methylimidazol-2-yl, 1,3-thiazol-2-yl, 1,3, 4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 1,3,4,5-tetrazol-2-yl, 2-quinolyl, 1-methylbenzimidazol-2-yl, Benzoxazol-2-yl or benzthiazol-2-yl and the corresponding 2-yl-oxy or 2-yl-thio groups.

Substitutable radicals in the meaning of R can be or be multiply substituted by the substituents described above. Preferred alkyl groups are those with up to 8, in particular with up to 4 carbon atoms are possible.

The term "lower" means here a molecule, a group or a radical with up to 8, in particular up to 4, carbon atoms. Unless otherwise noted _} halogen atoms are fluorine, chlorine, bromine or iodine atoms. The term "known" includes actual usage and literature, insofar as they belong to the state of the art.

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R stands in particular for methyl or substituted methyl, which is preferably replaced by one of the above groups may be substituted, for example for a mono- or polysubstituted methyl group, e.g.

Bromomethyl; etherified or esterified methyl, e.g. lower alkoxymethyl such as methoxymethyl, or lower alkanoyloxymethyl such as methylcarbonyloxyraethyl; methyl substituted by azido, nitrilo or thiocyanato; methylr substituted by the group -SHet wherein Het stands for an aromatic or non-aromatic heterocyclic group, especially an aromatic heterocyclic group as defined above, or by amino or mono- or di-lower alkylamino, Mono- or diarylamino or lower alkylarylamino or methyl substituted by acylamino.

As aromatic heterocyclic radicals Z are monocyclic or bicyclic, optionally for example by lower alkyl such as methyl or ethyl; lower alkoxy such as methoxy or ethoxy; Halogen, such as fluorine or chlorine or a radical substituted by aryl, such as phenyl.

For example, this would be monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic aromatic radicals, in particular monocyclic five-membered diazacyclic, oxazacyclic or thiazacyclic aromatic radicals and particularly preferably the corresponding benzdiazacyclic, benzoxazacyclic partial heterocyclic radicals with five-membered benzoxazacyclic radicals. Substitutable ring nitrogen atoms in radicals with the meaning of Z can be substituted, for example, by lower alkyl. Examples of such groups Z are 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2- yl, 1,3-oxazol-2 _r yl / -1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazole-2-yl, 2-quinolyl, 1-

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Methyl-benzimidazol-2-yl, benzoxazol-2-yl and especially benzthiazol-2-yl. Z can also represent pyridyl, an acyl radical of an organic carboxylic or thiocarboxylic acid, such as, for example, optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl with up to 18, preferably up to 10, carbon atoms, such as lower alkanoyl, e.g. acetyl or Propionyl; lower thioalkanoyl zJ *. Thioacetyl or thiopropionyl; Cycloalkanecarbonyl, wj.e, for example, cyclohexanecarbonyl; Cycloalkanethiocarbonyl, such as, for example, cyclohexanethiocarbonyl; Benzoyl; Thiobenzo / 1; Naphthylcarbonyl or naphthylthiocarbonyl; heterojyclic carbonyl or thiocarbonyl, such as, for example, 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoy], 2-, 3- or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl, 2 - or 3-thiofuroyl and corresponding substituted acyl or thioacyl / such as, for example, once or several times by lower alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy / such as methoxy, aryl, such as phenyl or by aryloxy, such as phenyloxy substituted acyl or thioacyl.

Z preferably denotes a group of the formulas

or

Trivalent organophore compounds are in particular those of the formula III

PR ¹ R ² R ³

12 3

wherein R, R or R, .die are the same or different

030041/0630 _{B. n} __

BATH ORIGINAL

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can, each for an optionally substituted hydrocarbon remainder, for example a straight or branched chain aliphatic group such as alkyl, an optionally substituted cycloaliphatic group such as cyclopentyl or cyclohexyl, optionally substituted Aryl, such as phenyl or for an optionally substituted hydrocarbon radical in which one or more Carbon atoms have been replaced by heteroatoms, in particular nitrogen, oxygen or sulfur atoms, such as, for example, alkoxy, amino or aromatic or non-aromatic heterocyclic groups. as Trivalent organophosphorus compounds are triphenylphosphine, tributylphosphine, tributylphosphine, trimethylphosphite or triethyl phosphite preferred.

As trivalent organophosphorus compounds of the formula III, preference is also given to those in which at least one

12 3
the radicals R, R and R represent an insoluble polymer which favors the removal after the reaction has ended. In general, one polymeric substituent will suffice.

Finally, such trivalent organophosphorus compounds are also used of the formula III preferred, wherein at least

12 3
one of the radicals R, R and R represents a cationic or anionic group such as, for example, a quaternary ammonium group, a carboxylate or sulfate. The presence of a group provided with a charge promotes the isolation of the organophosphorus sulfide obtained, for example by separation or absorption on an insoluble ion exchange resin or by extraction into an aqueous solution at a suitable pH, if the organophosphorus sulfide is water-soluble.

Thiophiles are particularly suitable as thiophilic compounds Metal salts, such as, for example, thiophilic salts of an element of groups Ib, lib or VIII of the periodic table mentioned (see Advanced Inorganic Chemistry, F.A. Cotton

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and G. Wilkinson, Interscience), for example thiophi-Ie silver, copper, zinc, nickel, iron, cadmium, mercury or cobalt salts, silver and copper salts being preferred. Preferred thiophilic salts include (i) AgNO. ,, AgOSO ₀ CF ₀ , AgOSO ₂ Me, AgBF ₄ ^, AgPF ^, CuCl, CuBr, CuCl ₉ , CuBr ₃ , CuOSO ₂ Me, CuOSO ₂ CF ₃ , CuSO ., Cu (NO-J ₂ and the corresponding nickel, zinc, iron and cobalt salts or (ii) Ag ₂ CO, AgO, Cu (acac) ₂ , Cu (CO ₃ J ₂ , Cu ₂ CO ₃ , CuOR where R is alkyl or cycloalkyl, for example with up to 8 carbon atoms, preferably CH ₃ , C ₂ H _r or t-butyl, Silver acetate is particularly preferred.

The proton released in the course of the reaction with the thiophilic substance should expediently be removed by means of a base so that the reaction can proceed to the end. The base should preferably have a pK value of ^ 4. If metal salts with sufficient basicity are used, such as salts of group (ii) above, no further base need be added to the reaction mixture. If only weakly basic metal salts are used, such as salts of group (i) above, however, a further base with a pK value of ^ -4 should preferably be added. The term “thiophilic substance” used in this context denotes a thiophilic metal salt used alone or optionally in conjunction with a base.

Inorganic or organic, preferably organic, bases such as, if appropriate, lower alkyl can be used as bases or alkylamino-substituted pyridines, piperidines optionally substituted by lower alkyl, for example 2,2,6,6-tetramethylpiperidines or trisubstituted amines, such as triacylamines, e.g. triethylamine or ethyldiisopropylamine or N-alkylarylamines, e.g. 1,8-bis- (dimethylamine) -naphthalene or Ν, Ν-dimethylphenyl-

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axnin. As inorganic bases, metal hydrides such as e.g. sodium hydride or metal carbonates such as e.g. Sodium carbonate preferred.

According to a preferred embodiment of the invention Procedure, one sets the starting substance at the same time with the phosphine and a thiophilic substance, in particular a metal salt and, if necessary, a base to.

If disulfides are used as the starting substance, a monosulfide can form as an intermediate product. In the Implementation of disulfides used as starting substances with a phosphine alone, a mixture of monosulfide and the cyclic product is generally obtained. Puts this mixture or the isolated monosulfide with a thiophilic substance and, if necessary, a base, in order to obtain the desired cyclic Link.

The present invention accordingly also relates to a process for the desulfurization of organic sulfides with simultaneous ring closure, which is characterized in that a ß-lactam with a nucleophilic group bonded to the nitrogen atom via an optionally substituted, divalent organic radical and a nucleophilic group bonded to the adjacent carbon atom bound monothio group reacts with a thiophilic substance.
The monosulfide used as the starting compound preferably has the formula II

3 4

(H)

Y-Nuc

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■ 4Ί "

wherein Nuc and Z have the meanings given above and the ß-lactam ring, which is optionally in the 3-position can be substituted, and the preferred reactants have the meanings given above.

The process according to the invention is preferably carried out in the presence of a suitable, inert anhydrous solvent or diluent. Suitable solvents or thinners are all those which are inert towards the trivalent phosphorus compound, the sulfide and the end product. Examples of solvents and thinners are benzene, toluene, acetonitrile, ethyl acetate, dichloromethane, chloroform and dioxane. Mixtures of two or more solvents and thinners can of course also be used. The process may at a temperature of -40 to +80 ⁰ C, preferably from 0 to +20 ⁰ C is performed.

When using di- or polythio starting substances, preference is given to using the trivalent organophosphorus compound in x-1 equivalents, where χ is the total number of sulfur atoms contained in the di- or polythio part designated. It is preferred to use 1 to 2 equivalents of the thiophilic substance per equivalent of mono-, di- or polysulphide used as the starting substance.

When converting di- or polythio starting substances it is preferable to add both the trivalent organophosphorus compound and the thiophile to the reaction mixture Substance too.

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Al

The inventive method is particularly suitable for Conversion of substituted azetidinones into oxapenem or oxacephem ring systems or analogous compounds that have antibacterial properties. 5

The starting substances used in this case have the general formula V.

τϊ ⁶ \ r ~ ⁿ

(V)

Y-Nuc

wherein

Z, η and Nuc have the meanings given above, R _fi and R ₇ , which can be identical or different, each have a hydrogen or halogen atom or an optionally substituted aliphatic group and Y is a divalent group

organic group such as, for example, a group of the formulas R ⁴ OOC '^ R or R OOC' ^ R ⁵

wherein R and R have the meanings given above. The nucleophilic group should generally be 5 nen are in the cis position to the azetidinone ring so that the ring closure can take place.

The invention is illustrated in the following examples. The temperature is given in ⁰ C. and the amounts of solvent used for the chromatography are amounts by volume.

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- -1 Z -

example 1

2-methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem

A solution of 0.80 g of 4-nitrobenzyl-2- / 4R-benzthiazolyldithio-2-oxo-1-azetidinylV-S-hydroxycrotonate in dry chloroform is added to a stirred solution of 0.338 g of silver carbonate and 0.428 g of triphenylphosphine in 4 ml dripped dry chloroform. The mixture obtained is stirred for 1/2 hour at room temperature and then chromatographed directly (short-range close chromatography, Sicicagel H, methylene chloride / hexane) where 0.195 g (41% of theory) 2-methyl-3- (4-nitrobenzyloxycarbonyl) -oxapenem is obtained as a colorless, crystalline solid.

(T (CDCl ₃ ) 2.32 (3H, s, CH ₃ ) 3.42 (IH, dd J 17Hz J _trans IHz, 6-H) 3.86 (IH, dd J 17Hz J. 2.5 Hz, 6-H) 5.22

CXS

(IH, dd J 14Hz, -CH ₂ -) 5.50 (IH, d J 14Hz, -CH ₃ -) 5.93 ~ 1810, 1710, 1640 cm "'. Melting point 128.5-129 ° C. Example 2
2-methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem

A solution of 0.050 g of 4-nitrobenzyl-2- / 4 ~ R-benzthiazolyldithio-2-oxo-1-azetidiny] ./-3-hydroxycrotronate in 0.4 ml of deuterochloroform becomes a suspension of 0.024 g of silver oxide and 0.028 g of triphenylphosphine in 0.2 ml Deuterochloroform dripped.

After 10 minutes, the reaction mixture is centrifuged and the supernatant is examined by NMR spectroscopy, whereby 2-methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem as the main ingredient is proven.

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^J trans ^{lHz J} cis ² ' ^5Hz ' ⁵ " ^H)

•:. · ■ --- "5 Πι 1 Π ' ^

Example 3

0.0267 g of triphenylphosphine in 1 ml of deuterochloroform _r 0 is added to a stirred solution of 0.05 g of 4-nitrobenzyl-2- / 4R-benzthiazolyldithio-2-oxo-1 -azetidiny_l / -3-hydroxycrotonate and 0.0134 g Copper acetylacetonate in 0.4 ml of deuterochloroform. After 5 minutes, the solution obtained is centrifuged and examined by NMR spectroscopy, 2-methyl-3- (methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem being detected as the main component. Analysis by thin layer chromatography confirms this result.

Example 4

To a stirred solution of 0.028 g of triphenylphosphine and 0.0201 g of silver methanesulfonate in 0.3 ml of deuterochloroform a solution of 0.05 g of 4-nitrobenzy1-2- / 4R-benzthiazolyldithio-2-oxo-1-acetidinyl7 ~ 3- hydroxycrotonate and 10μ1 deuteropyridine in 0.5 ml deuterochloroform.

After 5 minutes, the precipitated solid is centrifuged off and the supernatant is examined by NMR spectroscopy, where 2-methyl-3- (4-nitrobenzyloxycarbonyl)! - oxapenem as Main component is detected. This result is also confirmed by the thin-layer chromatographic analysis confirmed.

Example 5

To a solution of 0.05 g of 4-nitrobenzyl-2- / 4R-benzthiazolyldithio-2-oxo-1-azetidiny] - / - 3-hydroxycrotonate a solution of 0.028 g of triphenylphosphine is added to 0.5 ml of Oeuterochloroform in 0.1 ml of deuterochloroform and shake at room temperature. The compounds were determined by NMR spectroscopy 2-methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem

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10531

and 4-nitrobenzyl-2- / 4S-benzthiazolyl-thio-2-oxo-1-azetidinyiy-3-hydroxycrotonate proven in a ratio of 1: 4.

Example 6

A solution of 0.075 g of 4-nitrobenzyl-2- / 4-pyridinedithio-2-oxo-1-azetidinyl ./- 3-hydroxycrotonate in 4 ml of dry methylene chloride is combined with 0.045 g of triphenylphosphine in 1 ml dry methylene chloride added. The resulting solution is stirred for 1.5 hours and evaporated in vacuo. By NMR spectroscopy 2-methyl-3- (4-nitrobenzylcarbonyl) -oxapenem and 4-p-mitrobenzyl-2- / ~ 4-pyridinthio-2-oxo-1-azetidinyl-7-3-hydroxycrotonate were found in the residue proven in a ratio of 1: 1.

The residue is poured onto 2 g of silica gel using mixtures of ethyl acetate and hexene as the eluent chromatographed, successively triphenylphosphine sulfide and 10 mg of 2-methyl-3- (4-nitrobenzyloxycarbonyl) -oxapenem as a colorless oil, which on prolonged standing crystallizes, receives.

810 cm " ^1. Melting point 12-5 ~ 129 ° C. Ος Example 7

2-methyl-3-p-nitrobenzyloxycarbony! Oxapenem

0.035 g of 4-p-nitrobenzyl-2- / 4'S-benzthiazolylthio-2-oxo-1-azetinyiy-3-hydroxycrotonate in 0.7 ml of CDCl ₃ are successively mixed with 6.4 μΐ pyridine and 0.025 g of silver methyl sulfonate and added for 20 minutes Stirred at room temperature. The reaction mixture is centrifuged and the supernatant is examined by NMR spectroscopy and thin-layer chromatography, with 2-Methy1-3- (4-nitrobenzyloxycarbonyl) -oxapenem being detected by both analyzes in comparison with a known sample.

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Example 8

χγοαΓίιοηγ! oxapenem

0.035 g of 4-nitrobenzyl-2- / 4S-benzthiazolylthio-2-oxo-1-azetidinyl / -3-hydroxycrotonate in 0.5 ml CDCl, are successively with 6.5 μΐ pyridine and 0.038 g silver trifluoromethyl sulfonate, with stirring, added at room temperature. The reaction mixture is centrifuged and the supernatant by NMR spectroscopy and thin layer chromatography investigated, whereby 2-methyl-3-nitrobenzyloxycarbonyloxapenem is detected.

Example 9
15th

2-methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem

33 mg of 4-nitrobenzyl-2- / 4S-benzthiazolylthio-2-oxo-1-azetidinyl 7-3-hydroxycrotonate in 0.5 ml of chloroform are at room temperature with excess sodium hydride and with 25 mg of silver trifluoromethyl sulfate are added and the mixture is stirred for 6 1/2 hours. The solid by-products are filtered off and the solvent evaporated to a crystalline solid which is according to thin-layer chromatography and NMR spectroscopic investigation of 2-methyl-3- (4-nitrobenzyloxycarbonyl) -oxapenem acts.

Example 10
2-methyl-3- (4-nitrobenzyloxycarbonyl) oxapenem

200 mg of 4-N ⁱ trobenzyl-2 / _{4S-benzthiazolylthio-2-oxo-1-azetidinyl:} 7 ~ 3-hydroxycrotonate 'in 5 ml of dry chloroform is added with stirring 47 mg of triethylamine. After 1 minute, 220 mg of freshly ground silver trifluoromethyl sulfonate are added at room temperature and the mixture is stirred for 15 minutes. The precipitated solid "is centrifuged off and

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-kl '

the remaining solution on a short distance silica gel column given. Rapid elution with dichloromethane / hexane gives 2-methyl-3- (4-nitrobenzyloxycarbonyl) -oxapenem-containing fractions which are combined and evaporated under reduced pressure, whereby 27 mg of the title compound are obtained as a white solid.

Example 11 2-methyloxapenem sodium salt

A solution of 0.10 g of 2-methyl-3- (4-nit ¹ "above zyloxycarbonyl) oxapenem in 7 ml of ethyl acetate is made with 0.10 g of palladium on carbon as the carrier material (10% by weight) and with a solution 0.027 g of sodium bicarbonate in 7 ml of water are added and the reaction mixture is hydrogenated until the reaction has ended, according to analysis by thin-layer chromatography, and becomes the aqueous solution

2.0 rait ethyl acetate washed and freeze-dried, whereby the 2-methyloxapenem sodium salt is obtained.

Example 12

6- (2-Hydroxy ^ -2-propyl) -2-methyl-3- (4-nitrobenzyloxycarbonyl) -oxapenem

CO ₂ CH ₅ ^ -NO ₂

206 mg of silver carbonate and 273 mg of tryphenylphosphine in 6 nil Chloroform are mixed with a solution of 563 mg of 4-nitro

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benzyl 2- / 4 (R) - (2-benzothiazolyldithio) -3- (2-hydroxy-2-propyl) -2-oxo-1-azGtidinyl / -3-hydroxycrotonate added in 7 ml of chloroform. The reaction mixture is stirred for 10 minutes, filtered through Hyflosupercel and added to Evaporated dry to leave a residue which can be dried over silica gel using hexane / ethyl acetate is chromatographed in a ratio of 2: 1 to 0: 1 as the eluent. This gives the title compound ajs colorless oil (145 mg, in 40% yield).

J

W ⁷⁴⁵ ' ^{1805 cm}

1T (CDCl ₃ ) 1.78 and 1.86 (6H, s + s, (CH ₃ J ₃ ), 2.26 (3H, s, CH ₃ ), 3.45

(- "0.2H, d J 3Hz, 6-H), 3.63 (~ Ό.8Η, dJ« O.5Hz, 6-H), 5.26 (2H, m, CH ₂ ),

5.82 ("0.8H, d J ^ O.5Hz, 5-H), 5.93 (MD.2H, d J 3Hz, 5-H), 7.3-8.3 (4H, m, p-CgH ,.); Spectrum from approach 5/145.

Example 13

2-methyl-6 (S) - (phenylhydroxymethyl) -3- (4-nitrobenzyloxy- 20

carbonyl) oxapenem

A solution of 201 mg of 4-nitrobenzyl-2- / 4 (R) (2-benzothiazolyldithio) -2-oxo-3- (phenylhydroxymethyl) -1- is added dropwise azetidinyl / ^ 3-hydroxycrotonate in 5 ml dichloromethane 52 mg silver carbonate and 86 mg tripheny! Phosphine in 5 ml Dichloromethane. The reaction mixture is stirred for 10 minutes, filtered through Hyflosupercel and in vacuo to Evaporated dry, leaving the residue,

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which is chromatographed on silica gel using dichloromethane as the eluant. Receives 98 mg of the above 5 (R) -oxapenemester in 72% yield .

₃₎ 2-28 (3H, s, CH _3), 2.8 (lH, br, S, OH), 4.00 ⁽¹ H, dd J 0.5 Hz

J 5Hz), 5.27 (3H, m, 8-H and CH ₉ ), 2.8 (1 H, d J 0.5Hz, 5-H), 7.3-8.2 (9H, m, aromatic). 'max = 1805 cm "" ¹

Example 14

2-methyl-6 (R) - (1-hydroxyethyl) -3-pivaloyloxymethyloxycarbonyl) -oxapenem

CH,
HO— \ aS-S - '

IN

.CH

⁰ ^ = V) H

CO ₂ CH ₂ OCOC (CH ₃ ) 3 CO ₂ CH ₂ OCOC (CH ₃ ) 3

A solution of 170 mg of pivaloyloxymethyl-2 - /? (R) - (2-benzothiazolyldithio) -2-OXO-3- (1-hydroxyethyl) is added dropwise ) -i-azetidinyiy-3-hydroxycrotonate in 3 ml of dichloromethane 67 mg of silver carbonate and 86 mg of triphenylphosphine in 3 ml of dichloromethane, stirred for 10 minutes, filtered through Hyflosupercel, evaporate (250 mg, yellow oil) and chromatograph the residue rapidly over silica gel first using dichloromethane and then ethyl acetate / dichloromethane as an eluent in proportion

1: 2. This gives 31 mg of the above oxapenemester in 29% yield as a yellow oil.
^ (CDCl ₃ ) 1807, 1754 cm " ¹

cP (CDCl-) 1.22 (9H, s, C (CH-),), 1.40 (3H, d J 6Hz, CHj, 2.28 (3H, s, CH ₃ ), 3.73 (IH, dd J <1Hz J 5Hz, 6-H), 4.23 (1H, m, 8-H), 5.2 pH, broad, OH), 5.87 (3H, m, 5-H and

03004170630

CH ₉ ).

Example 15

2-methyl-6 (R) - (2-hydroxy-2-propyl) -S-pi oxycarbonyl) -oxapenem

A solution of 155 mg of pivaloyloxymethyl-2- / 4 "(R) is added dropwise - (2-benzthiazolyldithio) -3 (S) - (2-hydroxy-2-propyl) 2-oxo-1-azetidinyl./-3-hydroxycrotonate in 3 ml of dichloromethane to 44 mg of silver carbonate and 74 mg of triphenylphosphine in 4 ml of dichloromethane, stirred for 10 minutes, the mixture filtered through Hyflosupercel and evaporated in the. vacuum to dryness, leaving a residue that can only be removed over silica gel with the use of dichloromethane and then chromatographed on dichloromethane / ethyl acetate in a ratio of 2: 1 as the eluent. Included 22 mg of the above predominantly 5 (R) -oxapenemester are obtained in 23% yield as an oil.

* J -1

* max 1805 cm

S (CDCl ₃ ) 1.22 (9H, bs, C (CH ₃ ) ₃ ), 1.38 and 1.41 (6H, s + s, (CHJ "C), 2.28 (3H, s, CHJ, 3.62 (iH, d J _{c c} 2Hz, 6-H),

J Δ 5 5.0

5.83 (3H, m, CH ₂ and 5-H).
Example 16

2-Methyl-6 (R) - (phenylhyd roxymethy l) ^ Sp ivaloylo xymethyl · - oxycarbonyl) -oxapenem

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A solution of 130 mg of pivaloyloxymethyl -2 ~ is added dropwise (4 (R) - (2 ~ benzthiazolyldithio) -3 (S) - (phenylhydroxynicthyl) 2-axo ~ 1-azetidinyl) -3-hydroxycrotonate in 2 ml Diehlormothan to 35 mg silver carbonate and 57 mg triphenylphosphine in 4 wl Dichloromethane, the reaction mixture is stirred for 10 minutes, filtered by Hyflosupercel and evaporates in a vacuum Dry up. The residue is then rapidly chromatographed over silica gel only using dichloromethane and then of dichloromethane / ethyl acetate in a ratio 2: 1 as eluent, with the predominantly 5 (R) -oxapenemester in 25% yield in an amount of Receives 21 mg as an oil.

1730, 1750, 1808 cm '

-1

0 (CDCl ₃ ) 1.12 (9H, s, C (CH ₃ J ₃ ), 2.15 (3H, S, CII ₃ ), 3.88 (1H, dd J _cc 0.5Hz, J, _o 5 Hz, 6-H), 5.04 (1H, d J _{0 a}

O ₁ D D, O ö, fc>

5Hz, 8-H), 5.63 (1H, d J _cc 0.5Hz, 5-H), 5.72 (211, s, CII ₀ ) 7.26 (5H, s, C.HJ

D D

BATHROOM 0R »© ^INAL

0300 417 06 3 0

Claims (1)

HOE 79 / F Patent claims: 1. Process for the desulfurization of organic sulfides with simultaneous ring closure, characterized / that one ß-lactam, one to the nitrogen atom nucleophilic group bonded via an unsubstituted or substituted divalent organic radical and contains a dithio or polythio group bonded to the adjacent carbon atom, with a trivalent one Organophosphorus compound converts. 2. The method according to claim 1, characterized in that the starting compound of the general formula I corresponds. T-Z ^ 0 Y-Nuc
20th wherein Nuc is a nucleophilic group, Z is an optionally substituted aromatic, heterocyclic Resc with up to 15 carbon atoms and at least one Ring nitrogen atom and optionally one more Heteroatom in the ring, which is represented by one of its ring carbon atoms, which in turn is linked by a double bond to a ring nitrogen atom with which Thio group - / s_ / is linked, or an acyl radical of an organic carboxylic or thiocarboxylic acid, Y an optionally substituted divalent organic radical and η an integer from 2 to 4 ' preferably 2, where the β-lactam ring can be unsubstituted or further substituted. 030041/0630 HOE 79 / F 3. The method according to claim 1, characterized in that the nucleophy group is a HO, HS, ^H 2 ^N ~ ' O -, S ~ - or H ^ N group, an R'S group, in which R ^{1 stands} for a protective group, an R '' ¹ HN or
an R ¹ ″ ISr group, in which R ^{111 is} an organic radical. 4. The method according to claim 3, characterized in that R ^{111 represents} optionally substituted alkyl or aryl. 5. The method according to claims 1-4, characterized in that the nucleophilic group has a
optionally substituted vinylene or allylene radical is bonded to the ß-lactam nitrogen atom, 6. The method according to claim 5, characterized in that the starting substance has the partial structural formulas III or IV owns \ _ / ^uc or 4 ' * 5 4 ROOC R R QOC wherein Nuc is given in claims 1 or 3 4th
Has meaning, R stands for a hydrogen atom or a protective group and R stands for an organic radical. 7. The method according to claim 6, characterized in that R is optionally substituted alkyl, alkenyl or alkynyl of up to 8 carbon atoms. 8. The method according to claim 7, characterized in that ifalls substitii 030041/0630 that R is optionally substituted alkyl, alkenyl HOE 79 / f 3 ^ 7 , j * or alkynyl of up to 4 carbon atoms. 9. The method according to claim 8, characterized in that that R is optionally substituted methyl. 10. The method according to claim 7, characterized in that 5 that an aliphatic group in the meaning of R is mono- or polysubstituted by halogen; Oxo, hydroxy or mercapto; Alkoxy or alkylthic; Alkylcarbonyl; Carboxy, alkoxycarbonyl, or alkylthiocarbonyl; Alkanoyloxy or alkanoylthio; Carhamoyl- or carbamoyloxy, one or the other on the nitrogen atom can be substituted twice by alkyl or aryl, as well as the corresponding, optionally substituted Groups in which the oxygen atom or both or one of the two oxygen atoms through a Sulfur atom is (are) replaced; Nitro, cyano or azido; Amido or imido; Imino, amino, mono- or Dialkylamino, mono- or diarylamino and N, N-alkylarylamino; Acylamino; Sulfinyl, sulfonyl or sulfonamido; Cyaloalkyl, aryl, aryloxy, arylthio, aryloxycarbonyl, arylthiocarbonyl, arylcarbonyloxy, arylcarbonylthio, Aralkoxycarbonyl, aralkylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthxo, aralkoxy and Aralkylthio; aromatic or non-aromatic heterocyclic groups, aromatic or non-aromatic Heterocycle O or heterocycle S groups. 11. The method according to claim 10, characterized in that R stands for one or more times by hauogen atoms substituted methyl, an esterified or etherified methyl group, one by a Het-S group, in which Het means an aromatic or non-aromatic heterocyclic group, substituted methyl group, or for one by amino, mono- or di-lower-alkylamino, Mono- or di-arylamino, lower alkylarylamino or acylamino substituted methyl group. 030041/0630 - ;. ■■ "30Ί0531 1 HOE 79 / F 3 ^ 7 12. The method according to claim 11, characterized in that 4th
that R stands for a carboxylic acid esterified by an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol having up to 18 carbon atoms. 13. The method according to claims 1 to 12, characterized characterized in that Z is pyridyl, for a monocyclic, five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic, oxatriazacyclic, diazacyclic, oxazacyclic or thiazacyclic aromatic radical or for a benzdiazacyclic, benzoxazacyclic or benzthiazacyclic Radical in which the heterocyclic part is aromatic and has five members, and one substitutable Ring nitrogen atom may optionally be substituted. 14. The method according to claim 13, characterized in that Z i-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methylbenzimidazol-2-yl, Benzoxazol-2-yl · benzthiazol-2-yl or 2-pyridyl means. 15. The method according to claims 1 to 12, characterized characterized in that Z is an acyl radical of an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18 carbon atoms. 16. The method according to claims 1 to 15, characterized in that the starting substance either simultaneously or in succession with a trivalent organophosphorus compound and a thiophilic substance either in situ or optionally after isolation of the desulfurized compounds obtained. 030041/0630 HOE 79 / F 17. The method according to claims 1 to 16, characterized characterized in that the trivalent organophosphorus compound corresponds to the formula III, UC III R ⁴ OOC R ⁵ 12 3
worm R, R or R, which can be identical or different, each represent an optionally substituted hydrocarbon radical or an optionally substituted hydrocarbon radical in which one or more carbon atoms have been replaced by heteroatoms. 18. The method according to claim 17, characterized in that that the trivalent organophosphorus compound is triphenylphosphine, tributylphosphine, trimethylphosphite or triethyl phosphite is used. 19. The method according to claim 17, characterized in that that in formula III at least one of the radicals. 12 3 R, R or R represents an insoluble polymer. 20. The method according to claim 17, characterized in that that in the formula III at least one of the radicals R, 2 3
R or R contains an anionic or cationic group. 21. Process for the desulphurisation of organic sulphides with simultaneous ring closure, characterized in that one ß-lactam, the one via an optionally substituted divalent organic radical nucleophilic group bonded to the nitrogen atom and one bonded to the adjacent carbon atom 030041/0630 HOE 79 / F 3 ^ 7 Contains monothxo group, reacts with a thiophilic substance. 22. The method according to claim 21, characterized in that the ß-lactam corresponds to the general formula Ia, S ^S ~ ^Z // ¹ V .0 Y-Nuc wherein Z, Y and Nuc are as defined in claims 2 to 15 5 have given meanings and where the ß-lactam ring can optionally be substituted in the 3-position. 23. The method according to claims 6 to 22, characterized in that that the thiophilic substance is thiophile silver, copper, zinc, nickel, iron, cadmium, Uses mercury or cobalt salts. 24. The method according to claim 23, characterized in that Ag_C0 ,, AgO, Cu (acac) _, Cu (CO) _, Cu ₂ CO ₃ or CuOR, where R is alkyl or cycloalkyl, is used as the thiophilic substance. 25. The method according to claim 23, characterized in that the thiophilic substance is salts of the group (i) AgNO ₃ , AgOSO ₂ CF ₃ , AgOSO ₃ Me, AgBF ₄ ", AgPFg", CuCl, CuBr, CuCl ₂ , CuBr ₃ , CuOSO ₂ Me, CuOSO ₂ CF ₃ , CuSO ,, Cu (NO ₃ ) ₂ or corresponding nickel, zinc, iron or cobalt salts and (ii) a base
begins. 030041/0630 HOE 79 / f "26. The method according to claim 25, characterized in that that the base is optionally by lower alkyl or alkylamino substituted pyridines · optionally lower alkyl substituted piperidines, trisubstituted amines, sodium hydride or sodium carbonate begins. 27. A β-lactam produced according to any one of claims 1 to 26. 030041/0830