NO761353L - - Google Patents

Description

STATE OF THE ART

Known commercially applicable cephalosporins such as e.g. cephalexin, cephaloglycln, cephaloridine* cephalothin, cefazolin and cefapirin, are produced by a number of known methods which also include the production of a number of intermediate products for the respective cephalosporins.

Cephalosporin-C and desacetoxy-cephalosporin-C can be produced by fermentation processes. The aminoadipyl portion of these compounds is removed by various chemical processes to give 7-aminocephalosporanic acid (7-ftCA) resp. 7-aminodesacetoxycephalosporaic acid (7-ABCA). These basic compounds are then re-. acylated to introduce the appropriate group. In most cases, a further chemical modification of the molecule is necessary to obtain the desired antibiotic. The disadvantage of this method is the relatively great difficulties and consequent high costs in the production and isolation of cephalosporin-C and desacetoxy-cephalosporin-C. For this reason, alternative methods have been investigated. Another way of approaching the problem is to use the readily available, cheap, industrial penicillin-G and -V as starting materials. From penicillin-V can cephalexin, an industrial

important cephalosporin, is produced by a multi-step process

which is illustrative of this way of attacking the problem. Penicillin-V is converted to its sulfoxide, which is then rearranged under suitable conditions to the cephalosporin. The cephalosporin is then acylated to 7-ACDA or its ester, and reacylated by one of several described processes to cephalexin. The need to protect the amine and/or acid functions and later cancel

this protection in some of the aforementioned processes increases the necessary number of steps and thus the costs of the method.

A useful alternative method is to react the penicillin sulphoxide with a mercaptan, whereby an azetidinone disulphide is obtained. Analogous sulfenamides are obtained by heating the sulfoxide in the presence of a silylated amide, or by treating the unacidic azetidine disulfide with a suitable amine. These compounds yield upon chlorination

or broination using different reagents 2-chloro-or 2-bromo-methylpenam or 3-chloro- or 3-bromo-cepham, in that

the compounds can be converted into each other. These 3-chloro- or 3-bromo-cephams can also be prepared either by heating a penicillin sulphoxide in the presence of a chloride or bromide site, or from 3-hydroxycepham. The chloro- or bromocephams can be dehydrohalogenated to the respective cephems by methods described in the literature, and these cephems can in turn be deacylated by known methods to 7-ADCA and its derivatives, which are the starting materials for certain industrial cephalosporins.

When carrying out the dehydrohalogenation of the known 3-chloro- or 3-bromocephams, the biologically inactive A 2 -cephams are unfortunately also formed, and this will entail either conversion of the A 2 -cepham

3

to the active A -cephem by a series of reactions, whereby the costs of the desirable A 3 -cephems are increased or the A 2 /A 3 mixture must be separated, which will also result in a reduction in the yield.

It would therefore be very desirable to be able to produce

a halogenated cepham derivative which overcomes the disadvantages of the previously known 3-chloro- or 3-bromocephams.

BRIEF DESCRIPTION OF THE INVENTION

According to the present invention, new compounds have now been obtained, more specifically 3-iodocephamer or 2-iodomethyl-penamer which is derived from 1,2,4-dithiaz-3-enazetidinone (2),

thiazol^-enazetidinone (3), sym-azetidinone disulfide (4), unsym-azetidinone disulfide or azetlidinone sulfonamide (5) by a new method.

The new compounds according to the present invention

is 3-iodocephamer or 2-iodomethylpenamer according to the following general formula:

where R is benzyl, phenoxymethyl, 4-amino-4-carboxy-l-butyl or suitably protected derivatives thereof, α-aminobenzyl or protected derivatives thereof, lower alkyl, aryl or heteroaryl, R30-, R3S- or R<3>R< 4>N where R3

is lower alkyl, aryl or aryl lower alkyl and R<4> is

3

hydrogen or R,

2

R is hydrogen or methoxy, and

R^" is hydrogen or a cleavable radical, e.g. -C^OCH^,

lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, benzhydryl, phenacyl or trimethylsilyl.

As certain 3-halogenephams can easily be converted into 2-halomethylpenamers, it is intended that the described new 3-iodocephams 1 should also include their isomeric forms, which are the 2-iodomethylpenamens IA obtained according to the above scheme.

It is immaterial whether cephamene 1^ or penamene IA is used as starting materials. Furthermore, it is difficult to distinguish between the structures and stereochemistry of isomeric penamers and cephams. The stated structure for the 3-iodocephams 1. is mainly determined by the close similarity that these compounds' NMR spectra (obtained under the same conditions) show with the corresponding spectra for 3-chlorocepham and 3-bromocepham, respectively, and the difference from the spectra for 2- chloromethylpenam and 2-bromomethylpenam. However, it should be noted that the 3-iodocephams and the 2-iodomethylpenams must be considered synonymous.

In general, the new 3-iodocephamers 1 according to the present invention are prepared by iodination of either 1,2,4-dithiaz-3-enazetidinone (2^), thiazol-2-enazetidinone (3_), sym-azetidinone disulfide (_4 ) or unsym-azetidinone disulfide or azetidinone sulfenamide {5} in a suitable inert solvent and preferably in the presence of moisture. These different reactions are illustrated schematically in reaction diagram I,

1 2 In reaction diagram I, R, R and R mean the same as stated above, but X stands for S or NH, R 3 stands for lower alkyl, -(CH9) CCO-lower alkyl where n is 1, 2 or 3, phenyl, heteroaryl or the group

where R<4> is lower alkyl, phenyl, heteroaryl,

-O-lower alkyl, -O-phenyl, -S-lower alkyl, -S-phenyl or NHR,

and R and R are the same or different, but both selected from the group H, lower alkyl, phenyl and heteroaryl, while the group -X-R<3> together can also form a succinimido or phthalimido group.

Iodine can be used as an iodination agent, an iodination agent such as e.g. N-iodosuccinimide or sulfenyl iodides or mixtures thereof. Depending on the starting compound, the amount of iodine is at least one molar equivalent or at least one atomic equivalent. Starting from the unsym-azetidinone 5, iodine is the preferred iodination agent.

Sulphenyl iodides and iodine are preferably used as iodine producing agents, whereby almost quantitative yields of 3-iodocephamer 1 or 2-iodomethylpenamer IA are obtained. In certain cases, optimum yields are obtained in the presence of moisture. The sulphenyl iodide is best produced in situ by the action of iodine on a mercaptan such as a lower alkyl mercaptan, an aryl mercaptan such as e.g. phenyl mercaptan, a heteroaryl mercaptan such as 2-mercaptobenzothiazole, an aryl lower alkyl mercaptan such as benzylmercaptan, a disulphide such as bis-2-benzothiazole disulfide or benzyl disulfide,

a thiomide such as thioacetamide or thiobenzamide, thiourea or a thioacid such as e.g. thioacetic acid or thiobenzoic acid, in a suitable inert solvent such as e.g. carbon tetrachloride, methylene chloride or chloroform. With the azetidinones 2, 3_ or 4_ as starting compounds, the sulfur compound/iodine/water system is preferred, since under these conditions almost quantitative yields are obtained. Nevertheless, one must be aware that the nature of the R-group substituent and the nature of the sulfenyl compound will also affect the yield.

When R in the azetidinone 2 or 3_ is phenoxymethyl, there will e.g. almost quantitative yields are obtained by using certain sulphenyl iodides such as e.g. benzothiazole-2-sulphenyl iodide in the presence of moisture, while when R is phenoxy, lower yields of approx. 5 - 30% with the same sulfenyl iodides and otherwise the same conditions.

The stoichiometry is again important when better yields are desired. Thus, with a mercaptan, a thiamide or an acid (1.5 molar equivalents) or a disulfide (0.8 molar equivalents) and iodine (3 molar equivalents), compounds 2 or 3_ give almost quantitative yields of compound 1, while 3 molar equivalents of mercaptan and 6 molar equivalents of iodine are preferred with compound 4_.

Also when the unsym compounds 5_ are used as starting compounds, the reaction proceeds smoothly and with excellent yield at ambient temperature, and the stoichiometry does not seem to be important. Reactions with respectively one atomic equivalent and one molar equivalent of iodine thus mainly gave the same yield of over 90% and are thus preferred.

The iodination reaction is preferably carried out at room temperature and the reaction time is from 5 - 30 h. The moisture that is necessary in certain cases is preferably introduced by bubbling moist air through the reaction mixture while stirring, or by stirring the reaction mixture with water.

Dioxane, tetrahydrofuran, ethyl acetate, methylene chloride, acetonitrile and similar solvents can be used as suitable solvents.

The production of the 1,2,4-dithiaz-3-enazetidinones 2 is described in Norwegian patent application no. 75 2936. The production of the thiazole-2-enazetidinones 3_ is described in US-PS 3 594 389, while the sym-azetidinone disulfides 4_ are obtained from azetidinone disulfide as described in Tetra. Letters, 3001 (1973) T. Kamiya et al.

The unsym-azetidinone disulfides 5_ are obtained by heating a penicillin sulfoxide (either the a- or g-sulfoxide or a mixture thereof) with the formula left: with a mercaptan (Tetra. Letters, 3001 (1973) T. Kamiya et al.) or with a thioamide of the formula:

4 • '5 where R and R are as indicated above. The reaction is carried out in the presence of

of a suitable solvent, e.g. dioxane or toluene. Examples of suitable thioacids include thioacetamide, thiourea, thiocarbazide, thiocarbamate and dithiocarbamate.

In the case of the 1,2,4-dithiaz-3-enazetidinones 3_, it is not necessary to isolate the compounds 3, so that a simplification of the process is possible when proceeding from the penicillin sulfoxide thioamide.

With one atomic equivalent of iodine and under otherwise identical conditions, the 1,2,4-dithiaz-3-enazetidinones 2 or thiazole-2-enazetidinone 3 are converted in high yield to the acid azetidinone disulfides £. This method constitutes a new process for the preparation of the compounds 4_.

The 3-iodocephams were found to be stable and to be particularly suitable in certain reactions, besides having the obvious advantage of giving high yields (usually over 90%) and that the reaction conditions were simple. An attempt to produce the bromine compound by reacting the disulfide 5 (reaction diagram II) with bromine under controlled conditions was thus unsuccessful. The reaction with iodine, on the other hand, gave good yields of 3-iodocephamet 1 (reaction diagram II).

Another advantage of the use of 3-iodocephames is their rapid and easy dehydroiodination to the 3-cephemes in the presence of a base which

e.g. pyridine. For this reason, the yields at this stage are also high, and complications such as a possible simultaneous formation of the biologically inactive 2-cephem is reduced to a minimum and practically does not exist.

Illustrating the advantages of the use of 3-iodocepham are the processes indicated in reaction diagrams II and III, in which readily available, relatively cheap, industrial ampicillin and penicillin-V are conveniently converted into cephalexin and 7-phenoxyacetamido-3-methylcef-3- em-4-carboxylic acid.

As shown in reaction diagram I, ampicillin (6) was converted to ampicillin sulfoxide (7). On treatment with chloromethyl methyl ether and triethylamine in the presence of carbon dioxide, this compound gave the diprotected ampicillin sulfoxide 8 in one step. Heating the by-product Q with a mercaptan such as e.g. Benzothiazole-2-thiol in dioxane for 16 h gave an almost quantitative yield of the unsym-azetli-nondisulfide 5, which on iodination with iodine in methylene chloride gave the 3-iodocepham 1. Dehydroiodination of compound 1 with pyridine

followed by deprotection with acid (trifluoroacetic acid) gave cephalexin ,9, isolated as its trifluoroacetic acid salt. Free cephalexin could be obtained from the salt by neutralization or by using an ion exchange resin. Reaction diagram III shows a similar conversion of penicillin-V (10) to 7-phenoxyacetaraido-3-methylcef-3-em-4-carboxylic acid (12). Penicillin-V (10) was converted to penicillin-V-sulfoxide (11), which could be used as such or optionally converted to an ester such as e.g. the methoxy acid ethyl ester. The compound 11 was, by heating with a suitable mercaptan, e.g. benzothia-zoI-2-thiol; converted to uns<y>m-azetidlnon<d>lsulfide<e>5 in excellent yields. Iodination gave 3- jodcef amene 1_. In the case of the free acid, silylation was desirable for the iodination reaction of

regard to solubility, as the silyl group was removed during the processing process. Dehydroiodination of compound 1 gives compound 12.

The procedure can be further simplified by superimposing the reactions in the same container. It will be obvious to those skilled in the art that various other modifications of the method are possible for conversion of e.g. ampicillin to cephalexin, 6-AP& to 6-ADCA, carbencilillin, α-sulfobenzylpenicillin and 6-mandelamidopenicillin to the respective cephalosporins, and 6-methoxypenicillins to 7-methoxycephalosporins. Another advantage is that the new 3-iodocepharas and 2-iodomethylpenams can be converted into various 3-substituted cephams and 2-substituted methylpenams with side chains (e.g. D-phenylglycyl) which are known to give enhanced properties. These are compounds that are otherwise difficult to produce.

3-Iodocephamen has an antibiotic effect. 7-phenoxyacetamido-12 3-methyl-3-iodocepham-4-carboxylic acid (1) (R « $OCH2, R « H, R H) is thus active against Baeillus subtilis KCIB 8057. This acid also exhibits the following activity compared to 7- phenoxyaceta-mido-3-methylicef-3-em-4-carboxylic acid.

One must also be aware that the 3-iodocephams (1) are useful intermediates for the production of cephalosporins. When treated with bases such as e.g. pyridine and collidine, they undergo e.g. a facile dehydroiodination to give the cephemene. The cephems thus obtained can be deacylated by known methods to the 7-ADCA derivatives, and these compounds can in turn be converted into the industrially important cephalexin by methods described in the literature.

DETAILED EXPLANATION OF THE INVENTION

UNDER REFERENCE TO EXAMPLES.

The present invention will appear more clearly with reference to the following examples, which are only intended to illustrate the invention and not to define it.

Example 1

Preparation of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (1) (R (j>OCH2-/R<2>H, R1 = CH^) from methyl 6-phenoxythioacetamidoopenicillanate sulfoxide with isolation of connection 2

(R = <j)OCH2-f R<2>= H,<R1>= CH3)

A solution of pure methyl 6-phenoxythioacetamidopenicillanate sulfoxide (500 mg, 1.3 mmol) in toluene (125 mL) was heated (in an oil bath at 120°C) with stirring and reflux under a nitrogen atmosphere for 3.1/2 h in a flask fitted with a Dean-Stark trap. The toluene was removed in vacuo. An NMR spectrum (CDCl^) of the wax-like residue showed complete reaction and formation of methyl-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2(0)oet-2-ene-8- on-7-isopropenyl acetate ( 2) (R = <|>0CH2, R2 = H, R<1>= CH3) : 67.5 - 6.9(m, 5H, CgHg), 5.72(d with wings , 2H, 3-lactam protons),

The combined residue was dissolved in purified dioxane, after which iodine (365 mg, 1.43 mmol) was added. The mixture was stirred, and moist air obtained by bubbling air through water was then passed through the solution. After 16 h, the reaction mixture was concentrated to dryness, and an NMR spectrum was obtained on the residue. The dark brown residue could be partially purified by absorption in ethyl acetate or methylene chloride or chloroform, washing with anhydrous sodium thiosulfate and water, drying over magnesium sulfate with added decolorizing charcoal and concentration, and the result was a pale yellow thick oil. The NMR spectra of the crude material and the partially purified product showed the formation of about 35% iodocepham 1, which

could be recognized at the -CH2~S four-leaf clover point at approx. 63

the single point at approx. 62.2. The presence of the iodocephamet 1 was confirmed by a thin layer chromatogram with an authentic sample of the compound 1_ as a comparison.

Example 2

Preparation of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate 1, (R = <j>OCH2-, R<2>= H, R<1>= CH3) from methyl-6-phenoxythio -acetamidopenicillanate sulfoxide without isolation of compound 2

(R = (j)OCH2, R2 = H, R<1>CH3)

A solution of pure methyl-6-phenoxythioacetamidopenicilla-nate sulfoxide (2 g, 5.2 mmol) in dioxane (500 mL) was heated with stirring and reflux for 4 h in a nitrogen atmosphere in an oil bath at 120°C. (Previous experiments had shown that these conditions gave a quantitative yield of methyl-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate (2)). The reaction mixture was cooled to ambient temperature, iodine (1.52 g, 6 mmol) was added, and moist air was bubbled through the stirred solution at ambient temperature for 16 h. The reaction mixture was then transferred to dryness and the residue taken up in methylene chloride, washed with aqueous sodium thiosulfate and water and dried over magnesium sulfate with decolorizing charcoal. The NMR spectrum of the obtained foam indicated the presence of approx. 20% of the 3-iodocepham 1. ~" The crude product (1 g) was purified by gradient elution chromatography on silica (Mallenkrodt Sllicar CC-7) using ether:hexane = 3:1 -+ ether as eluents. The pure

3-Iodocepham (100 mg) was thus obtained as an amorphous, pale yellow solid and was identical (according to the IR and NMR spectra and TLC) to an authentic sample prepared in a different way (see Example 17).

The NMR spectrum (CDCl3): «7.85 6.92(m, 6H, QgHg and MH), 5.88 and

5.7(dd, 1.8, J ~ 4Hz, C?-H), 5.42(d, 1H, J,« 4Hz, Cg-H), 4.95(s, 1H, C4-H) , 4.7(S, 2H, -0-CH2-), 3.85(s, 3H, COOCH^), 2.98(ABq, 2H, J * 15Hz, C2-CH2), 2.22(s , 3H, Cg-CHj) is quite characteristic of these compounds.

In a similar way, using trimethylsilyl-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate, raethoxymethyl-3 -phenoxymethyl-4,5-dithia-2,7-diazabicyclo[ 4,2,0 ] oc t-2-en-8-one-7-isopropenyl-acetate, trichloroethyl-3-phenoxymethyl-4,5-dithia- 2,7-diazablcyclo14,2,0]oct-2-en-8-one-7-isopropeny1-acetate, trimethylsilyl-3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0] oct-2-ene-8-one-7-isopropeny1-acetate,

methoxymethyl-3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isoproperyl acetate,

methyl 3-raethylthio-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropeny1-acetate,

methoxyethyl-3-methylthio-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-ene-8-one-7-isopropeny1-acetate,

tri-ethylsilyl-3-methylthio-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropeny1-acetate,

benzyhydryl-3-phenylthio-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropeny1-acetate, methyl 3-phenylthio-4,5- dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropeny1-acetate,

methoxyethyl-3-phenylthio-4,5-dithia-2,7-diazabicyclo[ 4,2,0 ]oc t- 2-en-8~one-7<-isopropenyl-acetate, trimethylsly1-3-phenylthio-4, 5-dithia-2,7-diazabicyclo [4,2,0] oet-2-en-8-one-7-isopropenyl-acetate, trichloroethyl-3-benzyl-4,5-dithia-2,7-diazabicyclo[ 4,2,0]oct-2-en-8-one-7-isopropenyl-acetate,

to obtain the following compounds 7-phenoxyacetaraido-3-methyl-3-iodocepham-4-carboxylic acid,

methoxymethyl 1-7- f enoxyacetamido-3-iaety 1-3- iodocef am-4-carboxylate trichloroethy 1-7-phenoxyacetamido-3-methyl1-3- iodocefam-4-carboxylate, 7-phenoxyami&o-3-methyl-3- Iodocepham-4-carboxylic acid, Methoxymethyl-7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate, Methyl-7-methylthiocarbamido-3-methyl-3-iodocepham-4-carboxylate, Retboxyethyl-7-methyltlocarbamldo-3- raety1-3-iodocepham-4-carboxylate, 7-methylthiolcarbaraido-3-methyl-3-iodocepham-4-carboxylic acid, benzhydryl-7-phenylthiolcarbam±do-3-methyl-3-iodocepham-4-carboxylate, methyl-7- phenylthiocarbamido-3-methyl-3-iodocepham-4-carboxylate, methoxymethyl-7-phenyl thiolcarbamido-3-methyl 1-3-iodocepham-4-carboxylate,

7-phenylthiolcarbamldo-3-methyl 1-3-iodocepham-4-carboxylic acid, resp. trichloroethyl-7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate.

Example 3

Preparation of 3-phenoxy-4,5-dithia-2,7-diazabicyclo{4,2,O)oct-

; • ' 1 '2—1 1 ' ■ 2-en-8-one-7-isopropenylacetic acid ( 2) (R = $0, R = H, R H)

A solution of 6^-phenoxythiocarbamidopenicillanic acid sulfoxide (15 g, 0.04 mol) in purified dioxane (300 mL) was heated with stirring and reflux in a dry nitrogen atmosphere for 4 h in an oil bath maintained at 130°C. The reaction mixture was concentrated in vacuo and dried under high vacuum. The yellow-brown solid thus obtained was dissolved in the smallest possible amount of hot acetone, and the solution was treated with charcoal and filtered. The filtrate was concentrated to approx. 1/3 of its volume, and hexane sufficient to cause crystallization was added. The mixture was cooled overnight at approx. -10°C, and the resulting pale yellow crystals were isolated by filtration and drying to give 10.5 g (75%) of 3-phenoxy-4,5-dithia-2,7-diazabicyclo14,2,0 Joct-2- en-8-one-7-isopropenylacetic acid. The compound could be cleaned with wood

recrystallization from acetone/hexane. It was obtained as whites

crystals with a melting point of 146-148°. A high-resolution mass spectral analysis gave a mass of 350.0404 for the parent ion, while its calculated value for ci5Hi4&2S2 32 °4^ 350»u3s>6. NMR spectrum (DMSOdg) : 67.68 to 7.15(m, 6H, CgHg and COOH), 5.87 and 5.53(ABq, 2H, J «= 5Hz, ø-lactam protons cls-fused),

with the assumed spectrum.

Example 4

Preparation of methyl-3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-~ ' 2 1 2-en-8-one-7-isopropenyl acetate ( 2) , (R = <j>0, R = H, R = CU^)

3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0]oet-2-en-8-one-7-isopropenylacetic acid (10.0 g, 28.5 mmol) was dissolved in tetrahydrofuran (250 ml) and the solution cooled in an ice bath. Diazomethane in ether (100 mL, an excess) was added and the solution stirred in the ice bath for 0.5 h and then concentrated in vacuo. The residue was taken up in the smallest possible amount of ether and cooled in a dry ice/acetone bath, while an equal volume of hexane was added.

The resulting white precipitate was filtered off and dried to give

7.0 g of the product, m.p. 79-82°C. A further 1.5 g was obtained from the mother liquor after concentration and repetition of the ether/hexane precipitation. The two yields were combined (8.5 g, 81%), being the same (according to the NMR spectra and TLC). NMR spectrum (CDCl 3 ): 67.6 to 7.1(m, 5H, CgH 5 ), 5.7 and 5.48(ABq, 2H, J = 4Hz, γ-lactam protons

agreed with the assumed structure. A high-resolution mass spectral analysis gave a mass of 364.0565 for the parent ion, while the calculated value for C,C<H>,<C>N S^O. is 364.0552.

16 16 2 4

Example 5

Preparation of methyl-7-phenoxyamido-3-methyl-3-iodocepham-4-carboxy-

"2 1

let (1) (R = $0, R = H, R = CH3) using methylene chloride Methyl-3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-ene -

8-one-7-isopropenyl-acetate (2.0 g, 0.005 mol) was dissolved in purified methylene chloride (50 mL), and iodine (1.4 g, 0.0055 mol) was added.

The reaction mixture was stirred at room temperature for 20 h and concentrated, and the residue was taken up in dioxane and reacted with moist air for 16 h, to then be concentrated and redissolved in methylene chloride. The resulting solution was extracted with aqueous sodium thiosulfate (twice) and then with water (twice). The organic phase was dried with magnesium sulfate and charcoal, filtered and concentrated to give 1.9 g of a yellow foam whose NMR spectrum showed the presence of ca. 22% of the 3-iodocepham 1. This was confirmed by thin layer chromatography using an authentic sample of the compound 1_ prepared in a different way (see Example 34).

Example 6

Preparation of methyl 7-phenoxyamido-3-iaethyl-3-iodocepham-4-carboxylate (1) (R = $0-, R = H, R CH3) using ethyl acetate

By using purified ethyl acetate as solvent under the same conditions as in example 5, a 30% yield of 3-iodocepham was obtained, estimated from the NMR spectrum.

Example 7

Preparation of methyl 7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate (1) (R = <j>0-, R = H, R CE3) using dioxane

By using purified dioxane as solvent under the same conditions as in example 5, a 25% yield of 3-iodocepham was obtained, estimated from the NMR spectrum.

Example. 8

Preparation of methyl 7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate (1) (R ±= $0-, R » H, R CH3) using tetrahydrofuran

By using purified tetrahydrofuran as solvent under the same conditions as in example 5, a 12.5% yield of the 3-iodocepham was obtained, estimated from the NMR spectrum.

Example 9

Preparation of sym-(methyl-3-phenoxyacetamidoazetidinone-1-isopropenyl-acetate)-4-disulfide (4_) (R = <|)OCH2-, R<2>H, R1 = CH3) from methyl-3- phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate ( 2) (R = <|>OCH2-, R<2>= H, R<1>= CH3)

Methyl 6-phenoxythioacetamidopenicillanate sulfoxide (1.0 g, 2.6 mmol) was converted to methyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0oct-2-ene-8 -one-7-isopropenyl acetate (2_) (R = 2 1

<))0CH2-/R = H, R = CH^) as described in example 1. The total residue from the thermolysis in toluene was dissolved in purified dioxane (500 ml), iodine (330 mg, 1.3 mmol) was added , and moist air was bubbled through the stirred solution at ambient temperature for 20 h. The solution was concentrated, the residue was dissolved in methylene chloride, and the resulting solution was washed with anhydrous sodium thiosulfate (twice) and water (twice), dried over magnesium sulfate.and charcoal and concentrated. The resulting yellow foam weighed 0.9 g (94%) and was the sym-azetidinone 4_ (R = <J>0CH2-, R<2>= H, R<1>= CH3). NMR spectrum (CDCl 3 ) : 67.8(d, 1H, NH), 7.5

to 6.95(m,<5>H,<C>gH^), 5.52 to 5.37(m, 2H, β-lactam protons), 5.22

and 5,l(brs, s,

, 4.9 (s, 1H, CHCOOCH^ ) , 4.6 (s, 2H, -O-CH„ ) , 3.75 (s, 3H, COOCH 3 ), 1.91 (s, 3H,

) agreed with the assumed

structure.

Example 10

Preparation of sym-(methyl-3-phenoxyacetamidoazetidinone-1-iso-

2 T propenyl acetate)-4-disulfide (4_) (R = <J>0CH2-, R = H, R = CH3)

from methy1-3-phenoxymethyl-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-7-one-6-isopropenyl acetate (3) (R = <()0CH2-, R = H, R = CH3)

When treating methyl-3-phenoxymethyl-4-thia-2,6-diaza-bicyclol3/2,0]heot-2-en-7-one-6-isopropenyl acetate (3) (R =4>0CRo-*R = H, R CH^) {100 mg, 0.29 mmol) with one atomic equivalent (40 mg, 0.15 mmol) of iodine in dioxane (100 mL) in the same manner as described in Example 9, gave the same product 4_ ( R = 4>OCH 2 -, R 2 = H, R 1 <= CH^) obtained. The NMR spectrum was the same as that of the product in Example-9.

Example 11

Preparation of methyl-7-phenoxyacetamido-3-methyl-3-iodocepham-4-

- : • • ; o 9>carboxylate (1) (R » $OCH2-, R • H, Rx « CH3) from methyl-3- phenoxymethyl-4-thia-2,6-dlazabicyclo[3,2,0]hept-2-en-7-one-6-• . •—•—■ r-1—! 5 ■'. "'■ -t~—— isopropeny lactate (3) (R ■» $0CH2-, R «= H, R e=.CH3) In the treatment of methyl-3-phenoxymethyl-4-thia-2,6-diaza -bicyclo l3,2,0]hept-2-en-7-one-6-isopropenyl acetate (3) (R = $OCH_-, 2 1 R * H, R *= CH3) with at least one molecular equivalent of iodine in dioxane at it same method as described in example 1, the product's NMR spectrum showed that approx. 25% of the 3-iodocepham 1.

Example 12

Preparation of methyl-7-phenoxyacetamldo-3-methyl-iodocefara-4-

— — r 7 • •

carboxylate (1) (R <=» $0CH2-, R « H, Rx « CH3) from sym-(methyl-3-phenoxyacetamidoazetidinone-1-isopropenyl acetate)-4-disulfide (4) (R a ^0CH2-, R <2>H, R<1>CH3)

By treating sym-(methyl-3-phenoxyacetaraidoazetidinone-1-isopropenylacetate)-4-disulfide (4), (R $0CH3~, R2 = H, R1 « CH3) with one m oleqvvalent iodine in dioxane by the same procedure as described in example 1, the NMR spectrum of the product showed that approx. 20% of the iodine cepham 1.

Example 13

Preparation of methyl 7-phenoxyacetamido-3-raethylceph-3-em-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-iodocepham-4-carboxylate (1) (R <J>OCH2~, R<2>= H, R<1>= CH3)

A solution of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (250 mg, 0.5 mmol) in benzene (3 mL) containing pyridine (100 mg, 1.25 mmol) was heated under reflux 1 1 h. Filtration and concentration gave a quantitative yield of methyl 7-phenoxyacetamido-3-methylcef-3-em-4-carboxylate and the starting compound in a ratio of 3x1, as estimated from the NMR spectrum. The prepared cepheme had a characteristic HMR spectrum with signals at «7.8 to 6.9(0^)j 5.97 and 5.8(dd, C?-H) s 5.08(d, Cg- H)} 4.61 (s, O-CH^-);

3.88(s, C00CH3)j 3.4(d, C2-CH2) and 2.2(s, C3-CH3). Although most of these signals overlap the signals for 3-iodocephem, the cephem can be easily identified from the double point at 3.4 bg the disappearance of the C4-H single point at 4.85 (present in 3-iodocef amet) ..

Example 14

Preparation of methyl-7-phenoxyacetamido-3-methyl-3-iodocefara-4-

- _ ,—

carboxylate (1) (R - $0CH2-, IT = H, R CH3) from methyl-3-phenoxymethyl-4,5-ditla-2,7-diazabicyclo[4,2,0]oct-2-ene-8 -one-7-isopropenyl acetate (2) (R $0CH2-, R<2>H, R CH3) using sulfenyl iodides/iodine/water

A mixture of methyl-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate (150 mg,

0.38 mmol), thiourea (44 mg, 0.57 mmol) and iodine (290 mg, 1>1 mmol)

in methylene chloride (10 ml) was stirred with water (10 ml) at ambient temperature for 12 h. The organic layer was dried over magnesium sulfate, filtered and concentrated. The t^-spectrum of the product (CDCl3) indicated the presence of over 85% 3-iodocepham.

Exactly similar reactions were carried out using the following mercaptans instead of thiourea with the following results:

Besides the above-mentioned mercaptans, other mercaptans such as e.g. methyl, ethyl, isopropyl, phenyl and benzyl mercaptans, thioamides such as benzamide-, N,N•-dimethylthiourea and N,N•-di-phenylthiourea, thioacids such as e.g. thioacetic acid and thiobenzoic acid and dlsulfides such as e.g. methyl-, benzyl-, t-butyl- and £-tol<y>logs are used. In a similar way, using thioform compounds such as those mentioned above and ethoxyethyl-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7 -isopropenyl acetate, trichloroethy1-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo{4,2,0]oct-2-en-8-one-7-isopropenyl acetate, benzyl-3-pheoxymethyl-4,5 -dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate,£-nitrobenzy1-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4 ,2,0]oct-2-ene-8-one-7-isopropenyl acetate, methoxymethyl-3-benzyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-ene-8 -one-7-Isopropenyl acetate, trichloroethy1-3-benzyl1-4,5-dithia-2,7-diazabicyclo[4,2,0)oct-2-en-8-one-7-isopropenyl acetate, benzyl-3-benzyl -4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate, benzhydryl-3~ben2yl-4,5-dithia-2,7-diazabicyclo [4,2,0]oct-2-en-8-one-7-isopropenyl acetate, and trichloroethyl-1-methoxy-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0] oct-2-en-8-one-7-isopropenyl acetate, possible to prepare the following compounds: methoxymethyl-7-phenoxyacetamido-3-me ty1-3-iodocepham-4-carboxylate, trichloroethyl 7-phenoxyacetamido-3-raety1-3-iodocepham-4-carboxylate, benzyl 7-phenoxyacetamido-3-methyl-3-je^cefara-4-carboxylate, £- nitrobenzy 1-7- f enoxyacetamido-3-methyl 1-3- iodocef am-4-carboxy lat,

methoxy acid ethyl-7-phenylacetaniido-3-iaethy 1-3-iodocefa ar-4-carboxylate, , trichloroethy i-7-phenylacetaiaido-3-iaety 1-3-iodocefa am-4-carboxylate, benzy1-7-phenylacetamido- 3-methyl-3-iodocepham-4-carboxylate, benzhydryl-7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate, resp. trichloroethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate.

Example 15

Preparation of methyl-7-feooxyacetamide6-3-methyl-3-iodocepham-4-

: •—2 :—=j— : ~~-carboxylate (1) (R $OCH"2, R » H, R CH3> from methyl-3-phenoxymethyl-4-thia-2,6-diazabicyclo(3, 2,0]hept-2-en-7-one-6-isopropenyl acetate (3$) (R = $OCH2#R = H, R = CB\j) using sulfenyl iodides/iodine/water.

To a stirred solution of methyl-3-phenoxymethyl-4-thia-2,6-diazabicyclo[3,2 ,0]hept-2-en~7-one-6-isopropenyl-acetate (100 mg, 0.28 mmol) in methylene chloride (15 mL) and the mixture stirred at ambient temperature for 15 min. Water (15 ml) was then added and the mixture stirred overnight at room temperature. The organic layer was separated, dried over Raagneslum sulfate, filtered and concentrated. The NMR spectrum of the residue showed the presence of approx. 00% of 3-iodocepham.

In a similar way using thio compounds such as e.g. thioacetamide, thioacetanilld, thiourea, K,EJ'-dimethylthiourea, N,»,-diphenylthiourea, t-butyl mercaptan, isopropyl mercaptan, thiophenol, p-chlorothiophenol, ethyl-2-mercaptoacetate, 2-mercaptobenzd-oxazole, 2-mercaptobenzimidazole, 2- mercaptotlazolene, triphenyl-methyl mercaptan, benzyl raercaptan, dimethyl disulphide, dibenzyl disulphide, di-t-butyl disulphide, di-£-tolyl disulphide, thio-acetic acid or thio-benzoic acid and the following compounds trichloroethy1-3-phenoxyethyl-4-thia-2,6-diazabicyclo [3;2,0]hept-2-en-7-one-6-isopropenyl acetate.

£-nitrobenzy 1-3-phenoxymethyl-4-thia-2,6-diazabicyclo 13,2,0]hept-2-en-7-one-6-isbpropenyl acetate, trichloroethyl-3-benzyl-4-thia-2 ,6-dlazabicyclo{3,2,0]hept-2-en-7-one-6-isoprbpenyl acetate, £-aitrobenzyl-3-beU3yl-4-thia-2,6-diazabicyclo[3,2,0]hept -2-en-7-one-6-isopropenyl acetate, resp.

trichloroethyl-1-methoxy-3-phenoxymethyl-4~thia-2,6-diazabicyclo[3,2,0]hept-2-en-7-one-6-isopropenyl acetate,

is it possible to obtain: trichlorethyl!-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate,£-nitrobenzyl-7-phenoxyacetamido-3-methyl1-3-iodocepham-4-carboxylate, trichloroethyl!-7- phenylacetamido-3-aretyl«r 3-iodocefam-4-carboxylate, £-nitrobenzyl 1-7-phenylacetamido-3-raethyl-3-iodocefam-4-carboxylate, and trichloroethyl-7-methoxy-7-phenoxyacetamido-3 -methyl-3-iodocepham-4-carboxylate.

Example 16

Preparation of methyl1-7-phenoxyacetamido-3-methyl1-3-iodcefam-4-

, ■ :21 ■ ~ . carboxylate (1) (R = $0CH2, R « H, R = CHj) from sym-(methyl-3-phenoxyacetaarldoazetidinone-1-isopropenylacetate)-4-disulfide (4) (R » $0CB2, R 2 83 H, R 1 C' H-" j) unde'<r>use of sulfenyl iodides/iod/water

2-Mercaptobenzothiazole (138 mg, 0.83 mmol) and iodine (427 mg, 1.68 mmol) were added to a stirred solution of sym-(methyl-3-phenoxyacetamidoacetidinone-1-isopropenylacetate)-4-disulfide ( 200 mg, 0.28 mmol) in methylene chloride (15 mL), and the mixture was stirred at room temperature. for 15 min. Water (15 mL) was then added and the reaction mixture was stirred overnight at room temperature. Both organic layers were separated, dried over magnesium sulfate, filtered and concentrated. The 13MR spectrum of the residue showed the presence of approx. 80% of the 3-iodocefaraet.

Similarly using any of the thio compounds thioacetamide, thioacetanilide, thiourea, H,N<*->dimethylthiourea, N,N'-diphenylthiourea, t-butyl mercaptan, isopropyl mercaptan, thiophenol, p_-chlorothiophenol, ethyl -2-mercaptoacetate, 2-mercaptobenzoxazole, 2-mercaptobenzimidazole, 2-mercaptothiazolene, triphenylmethyl mercaptan, benzyl mercaptan, dimethyl disulfide, dibenzyl disulfide, di-t-butyl disulfide, di-p-tolyl disulfide, thioacetic acid and thiobenzoic acid and the following compounds: sym-(benzhydryl-3 -phenoxyacetamidoazetidinone-1-isopropenyl acetate)-4-disulfate, sym-(methoxymethyl-3-phenoxyacetamidoazetidinone-1-isopropenyl-1-acetate)-4-disulfide, resp. sym-(benzyl-3-phenylacetamidoazetidinone-1-isopropenylacetate)-4-disulfide it is possible to obtain: benzhydryl-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate, methoxymethyl-7-phenoxyacetamido-3-methyl -3-iodocepham-4-carboxylate, and

benzyl 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate.

Example 17

Preparation of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (1) (R = <()OCH2, R1 = CH3, R<2>= H) from methyl 2-oxo-3- (2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetate (5) (R = <{>OCH2, R = CH3, R = H,

)

A mixture of methyl 2-oxo-3-(phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetate (5.2 g, 0.01 mol) and iodine (3.0 g, 0.012 mol) in methylene chloride (200 mL) was stirred overnight (16 h) at ambient temperature. The dark red reaction mixture was washed with aqueous sodium thiosulfate (twice) and water (twice) and dried over magnesium sulfate with decolorizing charcoal. The pale yellow filtrate was concentrated to a foam which was extracted with ether. The filtered ether solution gave 4.8 g (97%) of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate as an off-white foam. The compound (2.8 g) was purified by gradient elution chromatography on silica gel

(Mallinkrodt CC-7, 150 g) using hexether (2:1) + ether as eluent. The compound was isolated (2 g) as a pale amorphous yellow solid, m.p. 73-76°. At this temperature, the substance sinters or becomes a glass, which then melts at 116-120°. An accurate high-resolution mass spectral analysis yielded a measured strain peak of 490.0069, while the calculated value for

<C>1<7H>19N205I<127>S<32>is 490.0060.

NMR spectrum (CDCl 3 ) : 57.82 to 6.92(m, aryl protons and NH)j 5.8(q, C-<->H): 5.42(d, J= 4Hz, Cg-H) j 4.95(s, C4~H) j 4.70(s,

-OHCH 2 ): 3.87 (S, -COOCH 3 ); 2.98(q, J 15Bz, C2-Cg2); 2.22(s,

CD""CELj) agrees with the assumed structure.

Example 18

Preparation of methyl-7-phenoxyacetamido-3-methyl-3-iodoepham-

. ;r5 :— • 4-carboxylate (1) (R = $0CH2, R « CB3, R' = H) using iodine (one atomic equivalent).

When methyl 2-bxo-3-(2-phenoxyacetamido)-4-(benzothiazoIr2-yl)dithio-α-isopropenylazetidin-1-acetate (0.53 g, 0.001 mol) was reacted with iodine (0.13 g, 0.0005 mol or 0.001 g atom) in methylene chloride (25 ml) and the product worked up as described in example 17 * basically the same results were obtained there. The products from Examples 17 and 18 were the same (according to the NMR and IR spectra and TLC).

Example 19

Preparation of methyl-7-phenoxyacetamido-3-methyl-3-iodocepham-4-

1 1 1 2 ' ■ carboxylate (1) (R $0CH2-, R = CH3, R = H) using N-iodosuccinimide

Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenylazetidin-1-acetate (200 mg, 0.38 mmol) was reacted with N-iodosuccinimide (94 mg, 0.416 mmol) in methylene chloride at ambient temperature. After 4 h, an NMR spectrum of the residue from a portion of the reaction mixture showed mostly the starting materials. After 3 days, however, the NMR spectrum of the residue indicated the presence of approx. 38% of 3-iodocepham.

Example 20

Preparation of 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylic acid (1) (R = <{>0CH2, R1 = H, R<2>=. H) from 2-oxo-3-( 2-phenoxyaceta-mido)-4-(benzothiazol-2-yl)dithio-a-isopropenylazetidin-1-acetic acid

A slurry of 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)thio-α-isopropenylazetidin-1-acetic acid (5.15 g, 10 mmol) in methylene chloride (200 mL) and bis -trimethylsilyltrifluoroacetamide (2.5 g, 10 mmol) was stirred until dissolution was complete (ca. 10 min), after which iodine (1.5 g, 11.8 mmol) was added and the mixture stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue treated with ethyl acetate (50 mL). The resulting slurry was filtered to separate 1.4 g (85%) of bis-benzothiazole disulfide. The filtrate was treated with methanol (3.0 g, 100 mmol) for 0.5 h and then extracted in turn with 5% aqueous sodium thiosulfate (2 x 30 mL), water (3 x 30 mL) and saturated brine, dried over magnesium sulfate and concentrated. The residue (4.7 g, 99%) had the following IR spectrum (CHCl 3 ): 1770, 1740 and 1690 cm"<1> and NMR spectrum (CDCl 3 ): <52, 27 (s, 3H); 2.65 and 3.13(ABd, 2H, J = 15Hz); 4.65(s, 2H);

4.90(s, 1H); 5.38(d, J = 4Hz, 1H); 5.70(q, J = 4 and 10Hz, 1H);

7.3 to 8.3(m.), 7.92(d, J = 10HZ, 1H) and 10.2 (s, 1H). Both in accordance with the assumed structure.

It is in a similar way when using

2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetic acid, and

2-oxo-3-(2-phenoxyamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetic acid

possible to achieve

7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylic acid, resp. 7-Phenoxyamido-3-methyl-3-iodocepham-4-carboxylic acid.

Example 21

Preparation of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (12) and 7-phenoxyacetaraido-3-methyl--3-cephem

7-Phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylic acid

(0.9g, 1.9mmol) and bis-trimethylsilyltrifluoroacetamide (0.9g, 3.5mmol) in benzene (10 ral) were stirred until dissolution was complete. Pyridine (0.5 g, 6.3 mmol) was added and the resulting mixture was heated under reflux for 1 h and then filtered. The filtrate was treated with methanol (0.3 g, 10 mmol) for 0.5 h, and the reaction mixture was extracted successively with water (4 x 5 mL) and saturated brine, dried over magnesium sulfate and concentrated.

The infrared and NMR spectra of the resulting residue (250 mg, 40%) were consistent with those of 7-phenoxy-acetamido-3-methyl-3-cephem.

The combined aqueous extracts were layered with ethyl acetate (30 mL), stirred and acidified to a pH of 1 with concentrated hydrochloric acid. The ethyl acetate layer was extracted with saturated brine, dried over magnesium sulfate and concentrated to give 400 mg (60%) of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid.

Example 22

Preparation of methoxymethyl-6-phenoxyacetamidopenicillinate sulfoxide (11)

Pehicillin-V sulfoxide (19.2 g, 0.05 mmol) and triethylamine (5.2 g, 0.052 mmol) were stirred in methylene chloride (50 mL) until a pale yellow solution was obtained. This solution was stirred

in an ice bath while chloroethyl methyl ether (4.5 g, 0.055 mol) was added slowly while maintaining the temperature below 8°C. An exothermic reaction took place, and the color of the reaction mixture changed from pale yellow to almost colorless, and a white

substance (triethylamine hydrogen chloride) separated from the solution.

After stirring for approx. After 2 h, the reaction mixture was extracted with cold water (2 x 25 mL), and the pale yellow organic layer was dried over magnesium sulfate, filtered, and concentrated to give a thick, pale yellow oil. Cold methanol (50 ml) was added and the mixture stirred in an ice bath for 1 h. A white solid had then formed. Filtration and drying gave 16.5 g (80%) of the desired ester, m.p. 107-109°C, [αD] + 192 (c, 1 in CHCl 3 ). A further 2.2 g was obtained from the mother liquor, so that a total of 18.7 g (91%) of methoxymethyl-6-phenoxyacetamidopenicillinate sulfoxide was present. IR spectrum (Nujol): 1790, 1760, 1700, 1600 and ISgOfshJcirf1 and NMR spectrum (CDCl3): 68.28(d, 1H, J = 10.5Hz, -NH); 7.42 to 6.83(m, 5H, CgH5); 6.2 and 6.3(dd, 1H, J = 4.5Hz, Cg-H); 5.47 and 5.28(ABq, 2H, J = 6Hz, C00CH20-, restricted rotation); 5,l(d, 1H,

J = 4.5Hz, Cg-H); 4.71(s, 1H, C3~H); 4.55(s, 2H, -O-CH2-CO-); 3.52(s, 3H, -OCH 3 ): 1.75 and. 1.27 (ss, 6H, gem-CH3) agrees with the assumed structure therein.

Example 23

Preparation of methoxymethyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenylazetidine-1-acetate ( 5 ),

A mixture of 2-mercaptobenzothiazole (3.68 g, 0.022 mol)

and methoxymethyl-6-phenoxyacetamidopenicillinate sulfoxide (8.48 g, 0.02 mol) in purified dioxane (100 mL) was heated under reflux for 6 h in an oil bath maintained at 120°. The reaction mixture was transferred to the dry state, and the residue was taken up in chloroform, treated with decolorizing charcoal, filtered and concentrated. The residue was triturated with methanol ether, filtered and dried, and 4.0 g of an electrostatic white powder of melting point 121-123° was obtained. IR spectrum (Nujol): 3400, 1780, 1750, 1680, 1520 cm<-1> and NMR spectrum (CDC1.J : 68.0 to 6.85(m, 9-aryl protons and -NH);

5.70 to 5.15(m, 3-lactam protons,

CHCOO) ; 4.55(s, OCH 2 CO) ; 3.43(s, -CH2OCH3) and 2.0(s,

) our

in accordance with the assumed structure.

Example 24

Preparation of methoxymethyl-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (1) (R = <|>OCH2, R<1>= CH3OCH2, R<2>= H)

from methoxymethyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenylazetidine-1-acetate (5) (R = <(>OCH2, R1 =

A mixture of methoxymethyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidine-1-acetate (0.4 g, 0.0007 mol) and iodine ( 0.18 g, 0.0007 mol) in methylene chloride was stirred at ambient temperature for 3.5 h, at which time the reaction was found to be complete. The reaction mixture was washed with aqueous sodium thiosulfate (2 x 10 mL) and water (2 x 10 mL) and dried over magnesium sulfate. The filtered solution was concentrated and the residue extracted with ether (to remove most of the insoluble benzothiazole component). On concentration, the ether gave the desired compound in an amount of 0.34 g (96%). NMR spectrum (CDCl 3 ): <S 7.92 to 6.92 (m, aryl protons and -NH);

5.80 to 5.61(dd, C7"H); 5.45 to 5.32(m, C8-H and COOCH2O);

4.89(s, C4-H); 4.62(s, -0-CH2-CO): 3.52(s, CH2OCH3): 2.92(ABq, J = 15Hz, C2~CH2): 2.22(s, C3-CH3) is in conformity with the assumed structure.

Example 25

Preparation of methoxymethyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate by dehydroiodination of methoxymethyl-7-phenoxyacetamido-3-methyl 1-3-iodocepham-4-carboxylate (1) (R = <j )OCH 2 , R 1 =

CH3OCH2, R2 = H)

By hydroiodination of methoxymethyl-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate by the method described in example 13, a yield of approx. 70% of the 3-cephem, estimated from the NMR spectrum.

Example 26

Preparation of methoxymethyl-N-metboxymethyloxycarbonylampicillin sulfoxide (8) from ampicillin sulfoxide (7)

A mixture of ampicillin sulfoxide (14.6 g, 0.004 mol) and triethylamine (9.7 g, 0.096 mol) in methylene chloride (125 mL) was stirred until complete dissolution (about 1 h). The resolution was

then stirred in an ice bath, at the same time as chloromethyl methyl ether

(7.1 g, 0.088 mol) was added slowly in the presence of a slow stream of carbon dioxide. The reaction mixture (containing solids) was stirred for a further 1/2 h in the ice bath and also 1 h at room temperature in the continued presence of the carbon dioxide stream.

The reaction mixture was then cooled well and filtered. The

the resulting solid was washed with water (2 x 50 mL) and with ether and then dried. 8.7 g (43.75) of the methoxymethyl-N-methoxymethylcarbamoylrapicillin sulfoxide were obtained, m.p. 178-180°. Recrystallization from methylene chloride/ether increased the melting point to 186-187°.

The IR spectrum (Nujol): 3350, 1780, 1740, 1710, 1700(sh) 1675(sh), 1660, 1520 cm""<1>and the NKR spectrum (DMCOdg): «8.22(d, 2H, to -NH-), 7.45(brs, 5H, CgH-)} 6.0 and 5.85(dd, J = 4Hz, Cg-H);

5.55 to 5.17(m, 6H, Cy-H, -CHCO and two -OCHjO-)j 4.52(s, 1H, C3-H)3.42 and 3.35(ss, 6H, two -OCH.3); 1.59 and 1.17 (ss, 6H, gem-dimethyl) are in agreement with the assumed structure.

From the combined organic filtrates from this reaction, 6.5 g (33%) of a solid was isolated. The IR spectrum and NJSR spectrum of this material were consistent with the material being methoxymethylampicillin sulfoxide.

Example 27

Preparation of methoxymethyl-2-oxo-3-(α-methoxymethyloxycarbonyl-amino-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetate (5) [R = $CH(NHCOOCH2OCH3) , R<1>= CH3OCH2,

A mixture of 2-mercaptobenzothiazole (0.22 g, 0.00125 mol) and methoxymethyl-N-methoxymethyloxycarbonylampicillin sulfoxide (0.6 g, 0.00125 mol) in purified dioxane (65 mL) was heated under reflux for 16 h in an oil bath which was maintained at 130°C. The reaction mixture was then transferred to the dry state. The product (0.7 g, 93%) was separated from unreacted material by extraction with an excess of ether, the product being soluble. The product forms a glass at 60-65° and melts at approx. 120°C. IR spectrum (Nujol): 3350 and 1790 to 1660 (multiple points) cm"<1> and NMR spectrum (CDCl 3 ): 67.93 to 7.20 (br multiple points, aryl protons); 6.52 (d, NH) ; 5.6 to 4.9(m, 10H): 3.39(s, two

corresponds to the assumed structure.

Example 28

Preparation of methoxymethyl-7-α-(methoxymethyloxycarbonylamino)-phenylacetamido-3-methyl 1-3-iodocepham-4-carboxylate (JL)

[R = <j)CH(NHCOOCH2OCH3) , R<1>= CH3OCH2, R<2>= H]

A mixture of methoxymethyl-2-oxo-3-(α-methoxymethyl-oxycarbonylamino-phenylacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenylazetidin-1-acetate (700 mg, 1.12 mmol) and iodine (302 mg, 10.4 mmol) in methylene chloride (70 mL) was stirred at ambient temperature. The reaction was found to be complete after approx. 3 h. The reaction mixture was washed with aqueous sodium thiosulfate (twice) and water (twice), and the organic layer was dried over magnesium. Concentration of the filtrate gave 700 mg of light brown foam whose NMR spectrum showed the presence of approx. 60% of the 3-iodocepham, which is characterized by the C3-OT3 single point at «2.2 and the C2~CH2AB four-leaf clover point at approx. “2.85.

Example 29

Preparation of raethoxymethyl-7-a-(methoxymethyloxycarbonylamino)

phenylacetamido-3-methyl-3-cephem-4-caxboxylate and cephalexin (9)

When methoxymethyl-7-α-(methoxymethyloxycarbonylamino)phenyl-acetamido-3-methyl-3-iodocepham-4-carboxylate is heated with pyridine in benzene for 1 h and the reaction is worked up as described in Example 13, the resulting product is methoxymethyl-7- o-(Methoxymethyloxycarbonylamino)phenylacetaraido-3-methyl-3-cephem-4-carboxylate, which is evident from the NMR spectrum and a thin-layer chromatogram using a reference sample prepared from cephalexin by the method described in Example 26 .

The compound was easily converted to cephalexin by treatment with aqueous acid such as hydrochloric acid, sulfuric acid, formic acid, methanesulfuric acid and trifluoroacetic acid, followed by setting the pH value to approx. 4.5 to precipitate the cephalexin. A convenient cleaning step is to isolate the salt, e.g. the cephalexin trifluoroacetate, by adding solvents such as e.g. ether, to a solution of the title compound in the smallest possible amount of trifluoroacetic acid after the solution is complete.

Example 30

Preparation of 6-phenoxyamidopenicillanic acid sulfoxide

A slurry of 6-aminepenicillanic acid-sulfoxide (23.3 g, 0.1 mol) in water (250 mL) was cooled to 0 to 5°C and then

treated with aqueous potassium hydroxide (2N) until a clear solution was obtained and the pH of the solution reached 8. The resulting solution was diluted with tetrahydrofuran (250 mL). A solution of phenylchloroformate (23.5 g, 0.15 mol) in tetrahydrofuran (100 mL) and an aqueous solution of potassium hydroxide (2N)

were added individually at such a rate that the pH value of the reaction mixture was maintained between 7.5 and 8.5. When the addition was complete and the pH had stabilized at 8 for 15 min, the reaction mixture was concentrated to half its volume. The aqueous concentrate (pH 8.7) was extracted with ethyl acetate (discarded) and layered with ethyl acetate (500 ml), and the pH of the mixture was lowered to 2 with aqueous hydrochloric acid (6N). The aqueous layer was further extracted with ethyl acetate (200 mL), and the combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated. The residue (23.65 g, 67%) had a melting point of 158-167° (decomp.), an IR spectrum (Nujol) of 3400, 1800, 1750, 1720 and 1530 cm"<1> and an NMR spectrum (DMSOdg) of 61.30(s, 3H) ; 1.67(s, 3H) ; 4.48(s, 1H) ; 5.53(d, J= 4.5Hz, 1H) ; 5.80( q, J = 4.5 and 9Hz, 1H); 7.0 to 8.3(m, 6H) and 8.1(br, s, 1H). A sample recrystallized from methanol had a melting point of 175-177°

(decomp.). •^

Example 31

Preparation of methyl 6-phenoxyamidopenicillanate sulfoxide

A solution of 6-phenoxyamidopenicillanic acid sulfoxide (13.5 g) in tetrahydrofuran (200 ml) at 0-5°C was treated with a solution of diazomethane in ether until the evolution of nitrogen ceased and the yellow color persisted for 0.5 h. Concentration gave the title compound (14.0 g, 100%), m.p. 50-70°; IR spectrum (CHCl 3 ): 3400, 1800, 1750, 1500 and 1480 cm"<1>; NMR spectrum (CDCl 3 ): 6.20 (s, 3H); 1.73 (s, 3H); 3.87 (s, 3H); 4.72 (s, 1H); 5.13(d, J = 4.5Hz, 1H); 5.83(q, J = 4.5 and 11HZ, 1H); 6.80 (d, J = 11Hz, 1H); and 7.1 to 7.7(m, 5H).

Example 32

Preparation of methyl-2-oxo-3-(phenoxyamido)-4-(benzothiazol-2-yl) dithio-α-isopropenylazetidin-1-acetate (5_)

A solution of methyl 6-phenoxyamidopenicillanate sulfoxide (11.0 g, 30 mmol) and 2-mercaptobenzothiazolium (5.5 g, 33 mmol)

in dioxane (180 ml) was heated under reflux for 6 h. Concentration gave a residue (16.1 g) of which a portion (13.6 g) was chromatographed on Mallinckrodt SilicarCC-7 (300 g, 200^-325 mesh)

using mixtures of benzene and ethyl acetate. Elution with mixtures of benzene and ethyl acetate in the ratios 4:1 and 3:2

gave the title compound (9 g) in sufficient purity

for further transformation. The compound had an IR spectrum

(CHCl 3 ) at 1780 and 1750 cm-1 and an NMR spectrum (CDC 3 ) of 61.90(s, 3H); 3.37(s, 3H) :, 4.93(s, -1H)j 5.07(brs, 1H) ; 5.20(brs, 1H); 5.40(q, J = 5 and 8Hz, 1H); 5.58(d, J = 5Hz, 1H) and 6.9 to 8.1(m).

Example 33

Preparation of 2-oxo-3-(phenoxyamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenylazetidin-1-acetic acid (5_)

This compound is obtained by heating 2-mercaptobenzothiazole with 6-phenoxyamidopenicillanic acid sulfoxide in dioxane for 6 h.

Example 34

Preparation of methyl 7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate (1) (R = <j>0, R<1>= CH3, R<2>= H)

A mixture of methyl 2-oxo-3-(phenoxyamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetate (0.52 g, 0.001 mol) and iodine (0.25 g, 0.001 mol) in methylene chloride (25 mL) was stirred at ambient temperature for 12 h. The reaction mixture was then washed with aqueous sodium thiosulfate (twice) and water (twice) and dried over magnesium sulfate and decolorizing charcoal. The filtrate was concentrated to a yellow foam (0.7 g). The foam was extracted with ether (three times) and the ether solution concentrated to give 0.4 g (85%) of the title compound as a pale yellow precipitate. The compound was further purified by gradient elution column chromatography using Mallinckrodt Silicar CC-7 and hexane:ether (2:1) ether. The compound was obtained as a pale yellow foam with an rms spectrum (CDCl 3 ) of "7.35(br d, 5H, CgH-); 6.48(d, 1H, -HH-,replaced by t>20) in 5.62 and 5.4 (dd with a superimposed s at 65.43, 2H, β-lactam protons [the pattern changes to a four-leaf clover -point at D20 replacement])? 4.95(s, 1H, C4-H)» 3.83(s, 3H, CO0CH3); 3.02(ABq, J= 15Hz, 2H, C2-CH2)j 2.22(s, 3H, C3-C<H>3). In a similar way, when using trichloroethyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio -a-isopropenylazetidine-1-acetate, trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio- α-isopropenyl azetidine-1-acetate, methoxymethyl-2-oxo-3-(2-phenoxyamido)-4-(benzothiazol-2-yl)dithio- α-isopropenyl azetidine-1-acetate, benzyl-2-oxo-3-(2-benzyloxyamido)-4-(benzothiazol-2-yl)dithio- α-isopropenyl azetidine-1-acetate, trichloroethyl 1-2-oxo-3-(2-trichloroethoxyamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetldin-1-acetate, methyl-2-oxo-3-(2-phenoxyacetamido)-4-acetimidoyldithio-a-isopropenyazetidine-1-acetate, methyl-2-oxo-3-(2-phenoxyacetamido)-4-N-phenylacetimidoyldithio-a-isopropenyazetidine-1-acetate l-aeetat, and methyl-2-oxo-3-(2-phenoxyacetamido)-4-anilinthio-a- isopropeny 1<- azetidine-1-acetate possible to obtain the following compounds: trichloroethyl 1-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate,

trichloroethyl 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate, methoxymethyl-7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate, benzyl 7-benzyloxyamido-3-methyl-3-iodocepham- 4-carboxylate, trichloroethyl-7-trichloroethoxyamido^3-methyl-3-iodocepham-4-carboxylate, resp.

methyl 1-^ 7-f enoxyacetamido-3-methy 1-3-j odcef am-4-carboxy lat.

Example 35

Preparation of methyl-7-phenoxyacetamido-3-methyl-3-iodocefara-4- 2 1

carboxylate (1) (R — <*>OCH2-, R * H, R « CH3) from methyl-3-f exi6xymethyl-4,5-dithia-2,7-diazabicyclo 14.2 ,.0 ] oct-2 -en-8-one-7-isopropenyl acetate (2) (R =» $OCH2->R = H, R = CH3) using disulfides/iodine/water

A mixture of methy1-3-phenoxymethyl-4,5-dithia-2,7-diaza-blcyclo[4,2,0]oct~2-en-8-one-7-isopropenyl acetate (100 mg, 0.253 mmol) in benzyl disulfide (47 mg, 0.2 mmol) and iodine (193 mg, 0.76 mmol) in methylene chloride (10 mL) was stirred with water (10 mL) at ambient temperature for 16 h. The organic layer was dried over magnesium sulfate , filtered and concentrated. The NMR spectrum (CDCl 3 ) of

the product accounted for over 85% of the 3-iodocepham.

Exactly similar reactions were carried out using

dimethyl disulfide or 2,2'-dithiobis(benzothiazole) instead

dibenzyl disulfide. The dt yield of 3-iodocepham in both cases was estimated at over 80%.

Example 36

Preparation of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (1) (R « $0C_2-, R2 = H, R » CH3) from methyl 3-phenoxymethyl-4,5-dithia- 2,7-diazabicyclo[4,2,0}oct-2-en-8-one-7-isopropenyl acetate (2) (R $OCH2~, R H, R - CH3) using thioacids/iodine/water

A mixture of methy1-3-phenoxymethyl-4,5-dithia-2,7-diaza-bicyclo[4,2,0]oct-2-en-8-one-7-isopropenyl acetate (100 mg, 0.253 mmol), Thiobenzoic acid (53 mg, 0.38 mmol) and iodine (193 mg, 0.76 mmol) in methylene chloride (10 mL) were stirred with water (10 mL) at ambient temperature for 16 h. The organic layer was dried over magnesium sulfate, filtered and concentrated. The NMR spectrum of the product (CDCl 3 ) indicated over 85% of the 3-iodcefamet.

By repeating the above reaction using thioacetic acid © instead of thiobenzoic acid, low yields (about 20%) of the 3-iodocepham were obtained.

Example . 37

Preparation of methyl 1-7-phenoxyacetamido-3-methylcef-3-em-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (1) (R = 4>OCH2-, R2 = H, R<1>= CH3> using pyridine in benzene

A solution of methyl 7-phenoxyacetamido-3-methyl-3-iodoceph am-4-carboxylate and pyridine in benzene was heated at reflux in an oil bath maintained at 90°. Fractions of the reaction mixture were removed periodically and the progress of the reaction followed by analysis of the NMR spectrum of the residue. The 3-iodocepham in the mixture is characterized by the C2-H single point at 6 4.9, the Cg-H double point at 65.38 and the C2-CH2-quadruple point at 6 2.95. The cef-3-em is characterized by its Cg-H double point at 65.05 and its C2"CH2 double point at 63.35. Possibly produced cef-2-em is easily detected by its C3~CH3 single point at 61.92 and its C2-H signal at 66.1. In all the experiments with pyridine as base, no appreciable amounts of the cef-2-em isomer were produced. Table 1 shows the results of experiments where the relative amount of pyridine was varied .

Example 38

Preparation of methyl 1-7-phenoxyacetamido-3-methylcef-3-em-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-2 1

4-carboxylate (1) (R = <j>0CH2-, R = H, R = CH3) using pyridine alone

Methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (100 mg) was dissolved in pyridine d,-(0.5 ml) and the reaction monitored by performing an NMR spectrographic analysis on the period disk samples. After approx. 15 min at ambient temperature there was approx. 50% conversion to cef-3-em, and after 2 h the reaction was complete. The NMR spectrum did not change after a 24 hour period and again no appreciable amount of the cef-2-em isomer could be detected.

Example 39

Preparation of methyl 7-phenoxyacetamido-3-methylcef-3-(and -2-)em-4-carboxylate from methyl-7-phenoxyacetamido-3-ethyl-3-iodocepham-4-carboxylate (1) (R <j »OCH2-, R<2>H, R<1>CH3) using Hunig's base

A mixture of methyl 1-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (200 mg, 0.395 mmol) and diisopropylethylamine (510 mg, 3.95 mmol) in benzene dg (1 mL) was heated under back run for 1 h. The reaction mixture was washed with hydrochloric acid (2N) and water and dried. The NMR spectrum showed complete reaction,

but a mixture of approx. 40% of the cef-2-em compound and 60% of the cef-3-em compound.

Example 40

Preparation of methyl 7-phenoxyacetamido-3-methylcef-3-(and -2-)em-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-5 1 carboxylate (1) (R =QOCH^-, R = H, R = CH3) using DBU and DBN.

A mixture of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (100 mg, 0.2 mmol) and 1,5-diazabicyclo[5,4,0]undec-5-ene (DBU, 300 mg, 2.0 mmol) in benzene dg (1 mL) was left at ambient temperature for 1.5 h. The reaction mixture was washed

-with sodium chloride (2N) and water and dried. The NMR spectrum showed

about. 75% reaction with formation of a mixture of cef-2-em and cef-3-em.

Using 1,5-diazabicyclo[4,3,0]non-5-ene (DBN) instead of DBU in the above reaction, the reaction was substantially complete after a reaction time of 2 h at ambient temperature, and the product consisted of a mixture of cef -2-em and cef-3-em isomers, a ratio of approx. 3:7.

Example 41

Preparation of methyl 1-6-phenoxyacetamido-2-methyl-2-iodomethylpenam-3-carboxylate (IA) (R = <f>0CH2-, R1 = CH3, R2 = H) and methyl 7-phenoxyacetamido-3-methyl 1 -3-Iodocepham-4-carboxylate (1) (R = <{>0CH2-, R = CH3, R = H) from methyl-2-oxo-3-(2-phenoxyacetamido)-4-benzothiazol-2-yl ) dithio-α-isopropenylazetidine-1-acetate ( 5) (R = <J>OCH2,

A mixture of methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidine-1-acetate (5.0 g, 9.5 mmol) and iodine (1 .8 g, 14.2 mmol) in methylene chloride (100 mL) was stirred at ambient temperature for 16 h. The reaction mixture was then quickly washed (twice) with an aqueous sodium thiosulfate solution (5%), and the methylene chloride layer was dried over magnesium sulfate and evaporated to dryness to give 5.2 g of a yellow foam.

The material was chromatographed on a column of Mallinckrodt Silicar CC-7 (350 g) using ether as eluent, collecting fractions of approx. 5 ml. The appropriate fractions were combined according to their thin-layer chromatograms.

Fractions 5-22 were combined and concentrated to give 1.3 g of a yellow foam whose NMR spectrum indicated a mixture of benzothiazole disulphide, 3-iodocepham and 2-iodomethylpename, characterized by its B-lactara multiple point at ca. 55.9 - 5.65, C^-H singlet at 64.9, -OCHjCO singlet at 64.6, -CHjI

at 54.45, -COOCT2 single point at 63.8 and -CH^ single point at 61.6.

Fractions 23 to 34 were combined and concentrated to give 1.2 g of a yellow foam consisting of 3-iodocepham and 2-iodomethylpename in a ratio of ca. 7:3.

Fractions 35 to 65 were combined and concentrated to

give 2.4 g of a pale yellow foam consisting of 3-iodocephamet with traces (ca. 5%) of 2-iodomethylpenamet.

Example 42

Preparation of methyl-2-oxo-3-phenoxyacet3mido-4-acetimidoyl-dithio-α-isopropenylazetidine-1-acetate (5) (R « 4»OCH2CONH, R = CH3»

R<2>= H,R<3>= CH3,R<4>H) and methyl-penicillin-y

A mixture of methyl 1-penicillin-V-sulfoxide (0.38 g,

0.001 mol) and thioacetamide (0.08 g, 0.001 mol) in purified dioxane (25 mL) were heated under reflux with stirring for 5 h in an oil bath maintained at 120°C. The clear reaction mixture was concentrated under vacuum to a brown foam. The IR spectrum (CHC1',)

-1 showed strong, sharp single points at 1780, 1745 and . 1700 cm with weaker absorptions at 1600 and 3400 cm-1. The NMR spectrum (CDCl3) indicated a mixture containing methyl-2-oxo-3-phenoxyacetamido-4-acetyrflidoyldithio-α-isopropenylazetidine-1-acetate (5)

as the main product, characterized by wood signals including wood

and methylpenicillin-V (estimated at 20% and confirmed by thin layer chromatography), characterized by its gem-dimethyl signals at 61.65 and 1.5. In addition, there were trace amounts of methyl-4-phenoxyacetamido-isothiazol-3-one-1-a-isopropenyl acetate, characterized by its signals at approx. 69.2 and 8.83.

Example 43

Preparation of methyl 2-oxo-3-phenoxyacetamido-4-(N-phenyl-acetimidoyl)dithio-α-isopropenylazetidine-1-acetate (5) (R = <j>OCH2CONH,

R<1>CH3 , R<2>H, R<3>CH3, R<4><(,)

A mixture of methyl-penicillin-V-sulfoxide (0.38 g,

0.001 mol) and thioacetanilide (0.15 g, 0.001 mol) in purified dioxane

(25 ml) was heated under reflux with stirring for 5 h in an oil bath maintained at 120°C. The clear reaction mixture gave a brown foam on concentration under vacuum. The NMR spectrum

(CDC13) indicated that the reaction was incomplete and that there was

about. 20% methyl penicillin-V-sulfoxide together with methyl-2-oxo-3-phenoxyacetamido-4-(N-phenylacetimidoyl)dithio-a-isopropenylacetidine-1-acetate, which is characterized by 65.7 - 5.3 (m, 3-lactam protons),

Various azetidinone disulphides of the formula 5<_> are obtained in a similar way using solvents such as e.g. in toluene, dichloroethane or mesitylene, thioamides such as e.g. thiobenzamide, N-methylthioacetamide, N-methylthiobenzamide, JNt-phenylthiobenzamide, thionicotinamide, thioisonicotinamide, 2-thiazolthioacetamide and 2-thiazolthiobenzamide, and penicillin sulfoxides such as e.g. trichlorety 1-penicillin- V-sulfoxide, methoxymethyl-penicillin-V-sulfoxide, £-nitrobenzyl-penicillin-V-sulfoxide, penicillin-G-sulfoxide, methoxymethyl-1-penicillin-G-sulfoxide, trichlorethyl-penicillin-G-

sulfoxide, 6-phenoxyamidopenicillin sulfoxide, methoxymethyl-N-(methoxymethyloxycarbonyl)ampicillin sulfoxide, di(methoxyethyl)carbenicillin sulfoxide, and 6-thien-2-ylacetamido-6-methoxypenicillin sulfoxide.

Example 4 4

Preparation of methyl 7-phenoxyacetamido~3-methyl-3-iodocepham-4-carboxylate from methyl 2-oxo-3-phenoxyacetamido-4-(aminoimidoyl)-dithio-α-isopropenylazetidine-1-acetate (5) (R « $OCH2CONH,

R<1>CH3, R<2>H, R3 - NH-, R<4>H)

The total crude product obtained in Example 43 was dissolved in methylene chloride (5 mL) and stirred with iodine (0.13 g,

0.00052 mol) at ambient temperature for 16 h. The reaction mixture was then concentrated to give a brown foam. The formation of methyl 1-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate in this reaction was shown by comparison of the NMR spectrum of the crude product with that of an authentic sample. A thin layer chromatogram using an authentic sample of the 3-iodocepham confirmed its presence in the reaction mixture.

Example 45

Dehydroiodination of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate using pyridine in benzene

A solution of methyl 1-7-phenoxyacetamido-3-arethy1-3-iodocepham-4-carboxylate and pyridine in benzene was heated under reflux in an oil bath maintained at 90°. Periodic fractions of the reaction mixture were taken out and the progress of the reaction followed by analyzing the NMR spectrum of the residue. The 3-iodcef amet 1 mixture is characterized by the C^-H single point

at 64.9, a Cg-H double point at 65.38 and a C2-CH2 four-leaf clover point at 62.95. The cef-3 is characterized by its Cg-H double point at 65.05 and its C2-CH2 double point at 63.35. Any cef-2-em produced is easily detected using its

C3-CH3~ single point at 61.92 and its C2~H signal at 66.1. In all experiments using pyridine as the base, no appreciable amounts of the cef-2-em isomer were produced.

Claims (14)

1. Chemical compound which is suitable as an intermediate for the production of known penicillins and cephalosporins, characterized in that it has the following general formula: where R is benzyl, phenoxymethyl, 4-amino-4-carboxy-1-butyl or protected derivatives thereof, α-aminobenzyl or protected derivatives thereof, lower alkyl, aryl or heteroaryl, R<3>0-, R3S- or R3R4N- where R3 is lower alkyl, phenyl or phenyl lower alkyl and R<4> is hydrogen 3 or R , R1 is hydrogen or a cleavable radical such as e.g. -CH2OCH3, lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, benzhydryl, phenacyl or trimethylsilyl, and 2 R is hydrogen or methoxy. 2. Compound as stated in claim 1, characterized in that it is methyl 1-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate. 3. ' Compound as stated in claim 1, characterized in that it is methyl 7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate. 4. Compound as stated in claim 1, characterized in that it is 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylic acid. 5. Compound as stated in claim 1, characterized in that it is methoxymethyl-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate. 6. Compound as stated in claim 1, characterized in that it is methoxymethyl-7-a-(methoxymethyloxycarbonylamino)-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate. 7. Process for the production of a chemical compound which is suitable as an intermediate for the production of known penicillins and cephalosporins and which itself has an antibiotic effect and which has the following general formula: where R is benzyl, phenoxymethyl, 4-amino-4-carboxy-l- butyl or protected derivatives thereof, α-aminobenzyl or protected derivatives thereof, lower alkyl, aryl or heteroaryl, R30-, R3S- or R3R4N- where R3 is lower alkyl, phenyl or phenyl lower alkyl and R 4 is hydrogen, R<1> is hydrogen or a cleavable radical, and 2 R is hydrogen or methoxy, characterized by 1,2,4-dithiaz-3-ene-azetidinone (2) or a thiazol-2-ene-azetidinone (3) with the formula: wherein R, R 1 and R 2 are treated with more than one atomic equivalent of iodine or a sulfenyl iodide and iodine in the presence of moisture in a suitable solvent. 8. Process as stated in claim 7, characterized in that the 1,2,4-dithia-3-enazetidinone starting material is methyl 1-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0 ]oct-2-en-8-one-7-isopropenyl acetate, and that the iodocepham compound produced is methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate. 9. Process as stated in claim 7/characterized in that the 1,2,4-dithiaz-3-enazetidinone starting material is methyl-3-phenoxy-4,5-dithiaz-2,7-diazabicyclo[4,2,0]oct -2-en-8-one-7-isopropenyl acetate, and that the produced iodocepham compound is methyl 7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate. 10. Process as stated in claim 7, characterized in that the thiazol-2-enazetidinone is methyl 1-3-phenoxymethyl-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-7-one 6-isopropenyl acetate, and that the produced iodocepham compound is methyl 7-phenoxyacetamido-3-methyl-iodocepham-4-carboxylate. 11. Method as stated in claim 7, characterized in that methyl-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo [4,2,0]oct-2-en-8-one-7-isopropenyl acetate is reacted with thiourea and iodine to give methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate. 12. Method as stated in claim 7, characterized in that methyl-3-phenoxymethyl-4-thia-2,6-diazabicyclo-[3, 2,0]hept-2-en-7-one-6-isopropenyl acetate is reacted with 2 - mercaptobenzothiazole and iodine to give methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate. 13. Process for the production of a chemical compound which is suitable as an intermediate for the production of known penicillins and cephalosporins and which itself has an antibiotic effect, and which has the following general formula: where R is benzyl, phenoxymethyl, 4-amino-4-carboxy-1-butyl or protected derivatives thereof, α-aminobenzyl or . protected derivatives thereof, lower alkyl, aryl or heteroaryl, R<3>0-, R<3>0- or R3R4N- where R3 is loweralkyl, phenyl or phenylloweralkyl and R4 is hydrogen, R1 is hydrogen or a cleavable radical, and R 2 is hydrogen or methoxy, characterized in that a sym-azetidinone disulfide (2) or an unsym-azetidinone disulfide (4<_a>) with the formula where X is S or NH, R 5 is lower alkyl, - (CH 2 ) nC00 -lower alkyl where n is 1, 2 or 3, phenyl, heteroaryl or where R^ is lower alkyl, phenyl, heteroaryl, -O-alkyl, -O-phenyl, 8 7 8 -S-alkyl, -S-phenyl or NHR , wherein R and R may be the same or different and each is selected from the group consisting of of H, lower alkyl, phenyl and heteroaryl, while -X-R 5 together can also form a succinimido- or phthalimido radical, treated with iodine or an iodizing agent in a suitable solvent. 14. Process as stated in claim 13, characterized in that methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenylazetidin-1-acetate is reacted with iodine to give methyl 1-7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate.