CH619231A5 - Process for the preparation of iodinated derivatives of cepham and of penam - Google Patents

Abstract

The new compounds corresponding to the formula I <IMAGE> in which the meaning of the symbols is given in Claim 1, and their isomers, are obtained by treatment of a corresponding 1,2,4-dithiaz-3-eneazetidinone or of a corresponding thiazol-2-eneazetidinone or of a corresponding disulphide of sym- or asym-azetidinone with an iodinating agent or iodine. These compounds have an antibiotic activity and are additionally used for the preparation of penicillins and of cephalosporins.

Description

The present invention relates to the preparation of new compounds, 3-iodocephames or 2-iodomethylpenames, obtained from 1,2,4-dithiaz-3-ene-azetidinones II of thiazol-2-ene-50 azetidinones III, disulfides of symmetrical azetidinone IVa or asymmetric azetidinone disulfides IVb.

The new compounds are 3-iodocephams or 2-iodo-methylpenames corresponding to the general formula

RCONH-i

'', C00R1

RC0NH-,

[I]

[IA]

619,231

4

in which R denotes a benzyl, phenoxymethyl, 4-amino-4-carboxyl-1-butyl, a-aminobenzyl radical, these radicals optionally carrying protective groups, a lower alkyl, aryl or heteroaryl radical, the radicals R30—, R3S -, R3R4N— where R3 is a lower alkyl, phenyl or phenyl- (lower alkyl) radical and R4 is hydrogen or R3;

R1 is hydrogen or a radical - CH2OCH3, a lower alkyl radical, 2,2,2-trichlorethyl, benzyl, p-nitrobenzyl, benzhydryl, phenacyl or trimethylsilyl, and

R2 is hydrogen or a methoxy radical. .

As starting materials for the preparation of other compounds, the cephalas I or the penises IA obtained can be used interchangeably. In addition, it is difficult to distinguish between the structures and stereochemistry of the isomeric stem and stem. The structure assigned to the 3-iodocephams I results mainly from the close resemblance existing between the NMR spectra of these compounds (obtained under identical conditions) and the corresponding spectra of 3-chlorocephame and of 3-bromocephame, and from the difference that they present with the spectra of 2-chloro-methylpenam and 2-bromomethylpenam. It should be noted however that the terms 3-iodocephame and 2-iodomethylpenam should be considered as synonyms.

The new compounds of formulas I and IA are prepared by iodizing with iodine or an iodination agent, namely 1,2,4-dithiaz-3-ene-azetidinones II, thiazol-2-ene-azetidinones III, symmetrical azetidinone disulfides IVa or asymmetric azetidinone disulfides IVb in a suitable inert solvent and, for the first two cases, in the presence of moisture. These various reactions are represented by diagram I.

/ See next page)

In Scheme I, the meanings of R, R1 and R2 are those previously indicated. X denotes S; R5 represents lower alkyl, a radical - (CH2) „COO— (lower alkyl) where n is a

/ R6

integer from 1 to 3, phenyl, heteroaryl or the group - C

NR7

where R6 denotes a lower alkyl, phenyl, heteroaryl radical,

- O— (lower alkyl), —O — phenyl, —S— (lower alkyl),

- S — phenyl or NHR8, and R7 and R8 may be the same or different and are both chosen from the radicals H, lower alkyl, phenyl or heteroaryl.

As iodination agent, N-iodosuccinimido or sulfenyl iodides, or mixtures with iodine can be used, for example. Depending on the starting compound, the amount of iodine is at least 1 molar Eq or at least 1 atomic Eq. When starting from asymmetric azetidinones IVb, iodine is the preferred agent.

As compounds giving rise to iodine, sulfenyl iodides and iodine are preferably used, and almost quantitative yields of 3-iodocephams I or 2-iodomethylpenames IA are thus obtained. In some cases, the best yields are obtained in the presence of moisture. To prepare the sulfenyl iodur, it is best to react the iodine in situ on a mercaptan such as a (lower alkyl) mercaptan, an arylmercaptan such as phenylmercaptan, a heteroarylmercaptan such as 2-mercaptobenzothiazole, an aryl (lower alkyl) mercaptan such as benzylmercaptan or a disulfide such as bis-2-benzothiazole disulfide or benzyl disulfide, a thioamide such as thioacetamide or thiobenzamide, a thiourea or a thioacid such as acid thioacetic or thiobenzoic acid, in a suitable inert solvent such as carbon tetrachloride, methylene chloride or chloroform. This is how the system comprising a sulfur, iodine and water compound is preferred when starting from azetidinones II, III, or IVa, because under these conditions almost quantitative yields are obtained. However, it should be taken into account that the nature of the substituent group R and that of the sulfenyl compound influence the yield.

Thus, when R is a phenoxymethyl group in azetidinones II or in, almost quantitative yields can be obtained by using certain sulfenyl iodides such as benzothiazole-2-sulfenyl iodide in the presence of moisture, while when R is a phenoxy group, low yields are generally obtained, of the order of 5 to 30%, with these same sulfenyl iodides and under otherwise identical conditions.

Stoichiometry is also important when you want to get better yields. Thus, the compounds II or III treated with a mercaptan, a thioamide or an acid (1.5 mol Eq) or a disulfide (0.8 mol Eq) and iodine (3 mol Eq) give almost quantitative yields of compound I, while with compound IVa, it is preferable to have 3 molar Eq of mercaptan and 6 molar Eq of iodine.

Likewise, when asymmetric IVb compounds are used as starting compounds, the reaction is carried out regularly and with excellent yields at room temperature, and stoichiometry appears to be of no importance. Thus, the reactions using an atomic equivalent or a molar equivalent of iodine give practically the same yields greater than 90%, and are therefore preferred.

The iodization reaction is preferably carried out at room temperature, and the reaction time is generally from 5 to 30 h. The humidity which is necessary in some cases is preferably introduced by bubbling air through the reaction mixture while stirring, or by stirring the reaction mixture with water.

As suitable solvents, dioxane, tetrahydrofuran, ethyl acetate, methylene chloride, acetonitrile and the like can be used.

The preparation of 1,2,4-dithiaz-3-ene-azetidinones II is described in Swiss Patent No. 612438.

The preparation of thiazol-2-ene-azetidinones III is described in US Patent No. 3,594,389, of July 10, 1971, while the symmetrical azetidinone disulfides IVa are obtained from azetidinone disulfide, as it has been described in "Tetra. Letters ”, 3001 (1973) by T. Kamiya et al.

The asymmetric azetidinone disulfides IVb can be obtained by heating a penicillin sulfoxide (the sulfoxides a or ß, or a mixture of the two) corresponding to the formula:

R2 H O

RCONH

with a mercaptan ("Tetra. Letters", 3001 (1973), T. Kamiya et al.) or with a thioamide of formula

S

R4 — C — NHR5 where R4 and R5 are as previously defined. The reaction is generally carried out in the presence of a suitable solvent such as dioxane or toluene. Examples of suitable thioamides include thioacetamide, thiourea, thiosemicarbazide, thiocarbamate and dithiocarbamate.

With an atomic equivalent of iodine and operating under otherwise identical conditions, it is possible to transform 1,2,4-dithiaz-3-ene-azetidinones II, or thiazol-2-ene-azetidinone III into disulfides of symmetrical azetidinone IVa with high yields. This procedure constitutes a new process for preparing the IVa compounds.

5

10

15

20

25

30

35

40

45

50

55

60

65

H ~ COORJ

R2 H

, a-r

X

II

COOR "

IVa

I „(l at eq.)

h2 °

ilr.0

COOR

II

R2 H

RCONH.

S — X-

<r

C1 mole eq,)

H COOR1

IVb

V

2

RZ H

RCONH-

.NOT

'TT

1

COOR

I (1_mole eq.)

o

R2 H ^

RCONH ^ - - CH2I

NOT

CH

3

ir "COOR1

IA.

619,231

The compounds I and IA obtained are stable and, in addition to the obvious advantage of high yields (usually greater than 90%) and simple operating conditions, they have been found to be particularly suitable for certain reactions. Thus, an attempt to prepare the brominated compound by reacting the disulfide IVb (Diagram No. H) with the bromine under determined conditions was unsuccessful. On the other hand, the reaction with iodine gave good yields of 3-iodocephaly I (diagram II).

Another advantage of using 3-iodocephams is their quick and easy dehydration, in the presence of a base such as pyridine, to give 3-cephem. As a result, the yields are also high at this stage, and complications such as the possible simultaneous formation of biologically inactive 2-cephem are minimized and almost nonexistent.

As examples of the benefits of using the compounds

I and IA obtained, we will quote the processes summarized in the diagrams

II and III, in which the commercial ampicillin and penicillin V (relatively inexpensive and readily available products) are conveniently transformed into cephalexin and 7-phenoxy-acetamido-3-methylceph-3-th-4- acid carboxylic, respectively.

As shown in diagram II, ampicillin 6 is transformed into ampicillin sulfoxide 7. This compound, treated with chloro-methylmethyl ether and triethylamine in the presence of carbon dioxide, gives the diprotected ampicillin sulfoxide 8, one operation. By heating compound 8 with a mercaptan such as benzo-thiazole-2-thiol in dioxane for 16 h, an almost quantitative yield of asymmetric azetidinone disulfide 5 is obtained, which, by iodination with iodine in chloride of methylene, gives 3-iodocephame I. By deiodhydration of I with pyridine, then elimination of the protective groups by an acid (trifluoroacetic acid), we can obtain cephalexin 9, which we can isolate in the form of its trifluoroacetate. Free cephalexin can be obtained from the salt by neutralization or by using an ion exchange resin.

Scheme III gives an example of an analogous transformation of penicillin V, 10, into 7-phenoxyacetamido-3-methyl-ceph-3-th-4-carboxylic acid, 12; penicillin V, 10, is transformed into penicillin sulfoxide V, 11, which can be used as it is or transformed if desired into an ester such as the methoxy-methyl ester. By heating with an appropriate mercaptan, such as

6

benzothiazole-2-thiol, compound 11 can be transformed into asymmetric azetidinone disulfides IVb, with excellent yield. Iodization gives the 3-iodocephams I. In the case of free acid, silylation is desirable for the ioda-tion reaction, for reasons of solubility, the silyl group being eliminated during the preparation operations. . Dehydration of I gives compound 12.

These processes can be further simplified by carrying out the reactions successively in the same container. Those skilled in the art will readily appreciate that various other variations of these methods are possible, for example for the transformation of ampicillin to cephalexin; 6-APA to 6-ADCA; carbenicillin, α-sulfobenzylpenicillin and 6-mandelamidopenicillin to the corresponding cephalosporins; and 6-methoxyphenicillins to 7-methoxycephalosporins. Another advantage is that the new 3-iodocephams and 2-iodomethylpenames can be transformed into various 3-substituted cephams and 2-substituted methyl-penams with side chains (such as D-phenylglycyl) which are known to confer increased activity, 20 compounds that are difficult to prepare otherwise.

The 3-iodocephams exhibit antibiotic activity.

Thus, 7-phenoxyacetamido-3-methyl-3-iodo-cephame-4-carboxylic acid, I (R = tpOCH2, R1 = H, R2 = H) is active against Bacillus subtilis NCIB 8057. This acid also has the following activity with respect to 7-phenoxyacetamido-3-methyl-ceph-3-th-4-carboxylic acid:

(MIC in g / ml) Staphylococcus S. lutea aureus

30

7-phenoxyacetamido-3-methyl-

ceph-3-th-4-carboxylic 0.254 1.01

iodocephamic acid carboxylic 0.254 0.507

It should be noted that the 3-iodocephams I are useful intermediates for the preparation of cephalosporins. For example, by treatment with bases such as pyridine and collidine, they easily dehydrate into cephemas. The cephemas thus obtained can be deacetylated by methods known as the derivatives of 7-ADCA and these compounds can in turn be transformed, by methods described in the literature, into cephalexin, an industrially important compound.

Diagram II:

Transformation of ampicillin into cephaloxin

And oN / C02 / ClCfl ^ OCH.,

so iJiÇHCONÏI

ampicillin 6

he h.

protected ampicillin

CÜOCH,; OCi [COOCII ^ OOh.,

V

IIS H / at

COOK

a c neONi r y s - s —r ampicillin sulfoxide I | '11

65 [[[f

COOCH0CC [[0H CG0CHo0Cri,

A ó Ò y asymmetric azetidinone disulfide IVb

7

619,231

V '

V

3

Diagram III:

9 ^ iì ''

I desacetoxycephalosporin V

1.2

COOII

Transformation of penicillin V into deacetoxycephalosporin V

$ 0 cu0comi ^

/ d

The following nonlimiting examples are given by way of illustration of the invention.

KX

o conit

30

penicillin V 10

(O)

V

35

40

<»0CHoC0NU

O

V

$ OCtI COîïH

4-1

Example 1:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = <pOCH2, R2 = H, R1 = CH 3) from methyl 6-phenoxythioacetamidopenicillinate sulfoxide with isolation of II (R = (pOCH2, R2 = H, R '= CH3) A solution of pure methyl 6-phenoxythioacetamidopenicillanate sulfoxide (500 mg, 1.3 mmol) in toluene (125 ml) is heated in an oil bath at 120 ° C., with stirring under reflux, under nitrogen, in a flask fitted with a Dean-Starte trap, for 3 V 2 h. The toluene is removed in vacuo. The NMR spectrum (CDCl 3) of the waxy residue shows a complete reaction and the formation of methyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate, II (R = cpOCH2, R2 = H, R1 = CH3): S 7.5 to 6.9 (m, 5H, C6H5); 5.72 (d with wings, 2H, ß-lactam protons); 5.19 and 5, 08 (ds, 2H, - ^ JCH2); 4.95 (s, 1H, CHCOOCH3); 4.87 (s, 2H, -OCH2-); 3.8 (s, 3H, COOCH3); 1.90 ( s, 3H, - <CH3).

Dissolve all of the residue in purified dioxane and add iodine (365 mg, 1.43 mmol), stir the mixture and pass through the solution moist air obtained by bubbling l air in water. After 16 h, the reaction mixture is concentrated to dryness and an NMR spectrum is carried out on the residue. The dark brown residue can be partially purified by taking it up with ethyl acetate or methylene chloride or chloroform, washing it with an aqueous solution of sodium thiosulfate and with water, drying it over sodium sulfate. magnesium with bleaching carbon and concentrating it, which gives a thick pale yellow oil. The NMR spectra of the crude product and the partially purified product show the formation of approximately 35% of frod iodocepham. r <r \ n \ I, which we identify by the quartet — CH2 —S — at around 83 and by C.GJIi (COOoî [,; OClL,) “o ie singlet *“ 5pH3 at around S 2.2 . The presence of iodocephaly I

is confirmed by thin layer chromatography performed using an authentic sample of I as a reference.

N, r- sv /

! I y penicillin sulfoxide 45

A— n ^ A 11

COOÎI (C00c: K2f'Cu3)

asymmetric azetidinone disulfide IVb

1. silylation

2. I2

3. desilylation

Example 2:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I, (R = <pOCH2, R2 = H, R1 = CH3) from methyl 6-phenoxythioacetamidopenicillinate sulfoxide without isolation of II (R = <pOCH2, R2 = H, R1 —CH3)

619,231

8

Is heated under reflux, with stirring, in a nitrogen atmosphere, in an oil bath at 120 ° C for 4 h a solution of sulfoxide

Pure methyl 6-phenoxythioacetamidopenicillinate (2.5 g,

2 mmol) in dioxane (500 ml). Previous experiments have shown that these conditions make it possible to obtain a quantitative yield of 3-phenoxymethyl-4,5-dithia-2,7-diazabi-cyclo- (4,2,0) -oct-2-en-8- methyl one-7-isopropenylacetate II. The reaction mixture is cooled to room temperature, iodine (1.52 g, 6 mmol) is added and humid air is bubbled through the stirred solution at room temperature for 16 h. The reaction mixture is evaporated to dryness, the residue is taken up in methylene chloride, washed with an aqueous solution of sodium thiosulphate and with water, and dried over magnesium sulphate with added bleaching charcoal. The NMR spectrum of the foam obtained indicates the presence of approximately 20% of 3-iodocephame I.

The crude product (1 g) is purified by elution gradient chromatography on silica (CC-7 silicar from Mallenkrodt) using an ether / hexane mixture in a 3/1 ratio and then ether as eluents. Pure 3-iodocephame (100 mg) is thus obtained in the form of a pale yellow amorphous solid and is identical (IR spectra, NMR and thin layer chromatography) to an authentic sample prepared by the other route (see example 17 ). The NMR spectrum (CDCI3): 8 7.85 to 6.92 (m, 6H, C5H5 and NH); 5.88 and 5.7 (dd, 1H, J = 4 c / s, C7-H); 5.42 (d, 1H, J = 4 c / s, C6-H); 4.95 (s, 1H, C4-H); 4.7 (s, 2H, - O — CH2—); 3.85 (s, 3H, COOCH3); 2.98 (ABq, 2H, J = 15 c / s, C2 -CH2); 2.22 (s, 3H, C3-CH3) is very characteristic of these compounds.

By operating in the same way, and using the following products:

3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

trimethylsilyl one-7-isopropenylacetate, 3-phenoxymethyl-4,5-dithia-2,7-biazabicyclo- (4,2,0) -oct-2-ene-

Methoxymethyl 8-one-7-isopropenylacetate, 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-

Trichlorethyl 8-one-7-isopropenylacetate, 3-phenoxy-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-

Trimethylsilyl, 7-isopropenylacetate, 3-phenoxy-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-

Methoxymethyl 7-isopropenylacetate, 3-methylthio-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

methyl one-7-isopropenylacetate, 3-methylthio-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

methoxymethyl one-7-isopropenylacetate, 3-methylthio-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

trimethylsilyl, 3-phenylthio-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-, trimethylsilyl one-7-isopropenylacetate

benzyhydryl one-7-isopropenylacetate, 3-phenylthio-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

Methyl 7-isopropenylacetate, 3-phenylthio-4,5-dithia-2,7-diazabicyclo- (4,2-0) -oct-2-ene-8-

methoxymethyl one-7-isopropenylacetate, 3-phenylthio-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

trimethylsilyl, 3-benzyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-, trimethylsilyl one-7-isopropenylacetate

trichlorethyl isopropenylacetate,

it is possible to obtain the following compounds:

7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxy-acid,

7-phenoxyacetamido-3-methyl-3-iodocephame-4-methoxymethyl carboxylate,

Trichlorethyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

7-phenoxyamido-3-methyl-3-iodocephame-4-carboxylic acid, 7-phenoxyamido-3-methyl-3-iodocephame-4-carboxylate, 7-methylthiolcarbamido-3-methyl-3-iodocephame-4-carboxylate methyl,

7-methylthiolcarbamido-3-methyl-3-iodocephame-4-methoxymethyl carboxylate,

7-methylthiolcarbamido-3-methyl-3-iodocephame-4-carboxylic acid,

Benzhydryl 7-phenylthiolcarbamido-3-methyl-3-iodocephame-4-carboxylate, 7-phenylthiolcarbamido-3-methyl-3,3-iodocephame-4-

methyl carboxylate, 7-phenylthiolcarbamido-3-methyl-3-iodocepham-4-methoxymethyl carboxylate,

7-phenylthiolcarbamido-3-methyl-3-iodocephame-4-carbo-xylic acid, and

7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylatede trichloroethyl.

Example 3:

Preparation of 3-phenoxy-4,5-dithia-2,7-diaza-bicyclo- (4,2,0) -oct-2-en-8-one-7-isopropenylacetic acid II (R = (pO , R2 = H, R1 = H)

A solution of 6-phenoxythiocarbamidopenicillanic acid sulphoxide (15 g, 0.04 mole) is heated with stirring under reflux in an atmosphere of dry nitrogen, in an oil bath maintained at 130 ° C. for 4 h. purified dioxane (300 ml). The reaction mixture is concentrated in vacuo and dried under high vacuum. The yellowish brown solid thus obtained is dissolved in the minimum quantity of hot acetone, the solution is treated with bleaching charcoal and filtered. The filtrate is concentrated to approximately 1A of its volume and an amount of hexane is added which is just sufficient to induce crystallization. The mixture is cooled overnight to about -10 ° and the pale yellow crystals obtained are filtered off and dried. 10.5 g (75%) of 3-phenoxy-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7- are thus obtained isopropenylacetic, which can be purified by recrystallization from acetone / hexane. The compound is in the form of white crystals, mp = 146-148 °, decomposed. The analysis by high resolution mass spectrography gives a mass of 350.0404 for the related ion (calculated for Ci5Hi4N2S23204 .: 350.0396). The NMR spectrum (DMSOd "): 5 7.68 to 7.15 (m, 6H, CoHs and COOH); 5.87 and 5.53 (ABq, 2H, J = 5 c / s, ß-lactam protons condensed in eis); 5.2 (s, 2H, - ^ CH2); 4.85 (s, 1H, —CHCOOH); 1.89 (s, 3H, - ^ CH3 is in agreement with the assigned structure.

Example 4:

Preparation of methyl 3-phenoxy-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate II (R = q> 0, R2 = H, R '= CH3)

3-phenoxy-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetic acid (10.0 g, is dissolved

28.5 mmol) in tetrahydrofuran (250 ml) and the solution is cooled in an ice bath. Diazomethane in ether (100 ml, in excess) is added, and the solution is stirred in an ice bath for 0.5 h, then concentrated in vacuo. The residue is taken up in the minimum amount of ether, and cooled in a dry ice / acetone bath while adding an equal volume of hexane. The white precipitate obtained is filtered off and dried, which gives 7.0 g of the product, mp = 79-82 ° C. A further 1.5 g of product is obtained from the mother liquor after concentration and repetition of the precipitation in ether / hexane. The two crops of crystals are combined (8.5 g, 81%), because they are identical (NMR spectra and thin layer chromatography). The NMR spectrum (CDCI3): 87.6 to 7.1 (m, 5H, C6H5); 5.7 and 5.48 (ABq, 2H, J = 4 c / s, ß-lactam protons condensed in eis); 5.22 and 5.12 (d, s, 2H, - <CH2) 5.0 (s, 1H, CHCOOCH3); 3.8 (s, 3H, COOCH3) and 1.97 (s, 3H, "- ^ 3H3) is in agreement with the assigned structure. Analysis by high resolution mass spectrography gives a mass of 364.0565 for the related ion (calculated for Ci6Hi6NS23204: 364.0552).

5

10

15

20

25

30

35

40

45

50

55

60

65

9

619,231

Example 5:

Methyl 7-Phenoxyamido-3-methyl-3-iodocephame-4-carboxylate I (R = ipO, R2 = H, R1 = CH3), using methylene chloride

Dissolve methyl 3-phenoxy-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate (2.0 g, 0.005 mole ) in purified methylene chloride (50 ml) and iodine (1.4 g, 0.0055 mole) is added. The reaction mixture is stirred at room temperature for 20 h, it is concentrated, the residue is taken up in dioxane and it is reacted with humid air for 16 h, then it is concentrated and redissolved in chloride methylene. The solution obtained is extracted with an aqueous solution of sodium thiosulfate (2 times) and with water (2 times). The organic phase is dried over magnesium sulphate and bleaching charcoal, filtered and concentrated. 1.9 g of a yellow foam are obtained in which the NMR spectrum indicates the presence of approximately 22% of 3-iodocephame I. This is confirmed by thin layer chromatography using as reference an authentic sample of 1 prepared by the other route (see example 34).

Example 6:

Methyl 7-Phenoxyamido-3-methyl-3-iodocephame-4-carboxylate I (R = <p O, R2 = H, R1 = CH3), using ethyl acetate

When purified ethyl acetate is used as solvent under the same conditions as in Example 5, the NMR spectrum shows that a yield of 3-iodocephalus of 30% is obtained.

Example 7:

Methyl 7-Phenoxyamido-3-methyl-3-iodocephame-4-carboxylate I (R = (p O, R2 = H, R3 = CH3) using dioxane When using purified dioxane as solvent under the same conditions that in Example 5, a yield of 3-iodocephalus, estimated from the NMR spectrum, of 25% is obtained.

Example 8:

Methyl 7-Phenoxyamido-3-methyl-3-iodocephame-4-carboxylate I (R = ip O, R2 = H, R3 = CH3), using tetrahydrofuran

When purified tetrahydrofuran is used as solvent under the same conditions as in Example 5, a 3-iodocephalic yield, estimated from the NMR spectrum, of 12.5% is obtained.

Example 9:

Sym- {3-phenoxyacetamidoazetidinone-1-methyl isopropenylacetate) -4-disulfide IVa (R = ip OCH2, R2 = H, R1 = CH3) from 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo - (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate methyl II (R— (pOCH2, R2 — H, R1 = CH3)

Methyl 6-phenoxythioacetamido-penicillinate sulfoxide (1.0 g, 2.6 mmol) is converted into 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct- 2-ene-8-one-7-isopropenyl-methyl acetate II (R = <p OCH2, R2 = H, R1 == CH3) as described in Example 1. The entire residue obtained is dissolved thermolysis in toluene in purified dioxane (500 ml), iodine (330 mg, 1.3 mmol) is added and air is bubbled through the stirred solution at room temperature for 20 h . The solution is concentrated, the residue is dissolved in methylene chloride, and the solution obtained is washed with an aqueous solution of sodium thiosulfate (2 times) and water (2 times), dried over magnesium sulfate and on charcoal, and we concentrate it. The yellow foam obtained weighs 0.9 g (94%). It is sym-azetidinone IVa (R = q> OCH2, R2 — H, R1 = CH3).

The NMR spectrum (CDCl3): 5 7.8 (d, 1H, NH), 7.5 to 6.95 (m, 5H, CgHs); 5.52-5.37 (m, 2H, β-lactam protons); 5.22 and 5.1 (brs, s, 2H, - <^ £ h2); 4.9 (s, 14, CHCOOCH3); 46 (s, 2H, -O-CH2); 3.75 (s, 3H, COOCH3); 1.91 (s, 3H, - <CH3 is in agreement with the assigned structure.

Example 10:

Methyl sym- (3-phenoxyacetamidoazetidinone-1-isopropenylacetate) -4-disulfide IIa (R = (pOCH2, R2 = H, R1 - CH3) from 3-phenoxymethyl-4-thia-2,6-diazabicyclo- ( 3,2,0) -hept-2-ene-7-one-6-isopropenylacetate methyl III (R = <pOCH2, R2 = H, R '= CH3)

When treating methyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-6-isopropenylacetate III (R = <pOCH2, R2 = H, R1 = CH3) (100 mg, 0.29 mmol) with an atomic equivalent (40 mg, 0.15 mmol) of iodine in dioxane (100 ml) in the same way as in Example 9 , the same product IVa is obtained (R = q> OCH2, R2 = H, R1 = CH3). The NMR spectrum is identical to that of the product of Example 9.

Example 11:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = <p OCH2, R2 = H, R '= CH3) from 3-phenoxy-methyl-4-thia-2,6- methyl diazabicyclo- (3,2,0) -hept-2-ene-7-one-6-isopropenylacetate III (R = q> OCH2, R2 = H, R1 = CH3)

When treating methyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-6-isopropenylacetate III (R = tpOCH2, R2 = H, R1 = CHs) by at least one molar equivalent of iodine in dioxane by the same process as that described in Example 1, the NMR spectrum of the product shows the presence of approximately 25% of 3-iodocephaly I .

Example 12:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = <pOCH2, R2 = H, R1 = CH3) from methyl 3-phenoxyacetamidoazetidinone-1-isopropenylacetate) -4-disulfide IVa (R = <pOCH2, R2 = H, R1 = CH3) When treating methyl sym- (3-phenoxyacetamidoazetidmone-1-iso-propenylacetate) -4-disulfide IVa (R = (pOCH2, R2 = H, R1 = CH3) by a molar equivalent of iodine in dioxane by the same process as in Example 1, the NMR spectrum of the product shows the presence of approximately 20% of 3-iodocephame I.

Example 13:

Methyl 7-phenoxyacetamido-3-methylceph-3-th-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-3-iodo-cephame-4-carboxylate I (R = <pOCH2, R2 = H, R] = CH3)

A solution of methyl 7-phenoxy-acetamido-3-methyl-3-iodocephame-4-carboxylate (250 mg, 0.5 mmol) in benzene (3 ml) containing pyridine (100 is heated under reflux for 1 hour). g, 1.25 mmol). By filtration and concentration, the methyl 7-phenoxyacetamido-3-methyl-3-ene-4-carboxylate and the starting compound are quantitatively obtained in the ratio, estimated from the NMR spectrum, of 3: L The cephem product has a characteristic NMR spectrum with signals at 8 7.8 to 6.9 (C6H6); 5.97 and 5.8 (dd, C7-H); 5.08 (d, C6-H); 4.61 (s, C-CH2); 3.88 (s, COOCH3); 3.4 (d, C2-CH2) and 2.2 (s, C3-CH3). Although most of these signals overlap with those of 3-iodocephaly, the cephem is easily identified by the doublet at 3.4 and the disappearance of the singlet C4-H (present in 3-iodocephaly) at 4.85.

Example 14:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = cp OCH2, R2 = H, R '= CH3) from 3-phenoxy-methyl-4,5-dithia-2, 7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-

5

10

15

20

25

30

35

40

45

50

55

60

65

619,231

10

methyl isopropenylacetate II (R = <pOCH2, R2 = H, R1 = CH3), using a sulfenyl iodide / iodine / water system. Stir with water (10 ml) at room temperature for 12 h, a mixture of methyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate (150 mg, 0.38 mmol ) thiourea (44 mg, 0.57 mmol) and iodine (290 mg, 1.14 mmol) in methylene chloride (10 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The NMR spectrum (CDCl3) of the product indicates the presence of more than 85% of 3-iodocephalus.

Identical reactions are carried out using the mercaptans below in place of thiourea, and the results indicated are obtained:

Sulfenyl iodide precursor

3-iodocephalic yield (%)

2-mercaptobenzothiazole

85

2-mercaptobenzimidazole

30

triphenylmethylmercaptan

30

p-chlorothiophenol

60

Ethyl 2-mercaptoacetate

30

2-mercaptothiazolene

75

thioacetamide

50

t-butylmercaptan

70

In addition to the above compounds, other mercaptans can also be used such as methyl-, ethyl-, isopropyl-, phenyl- and benzyl-mercaptans; thioamides such as benzamide, N, N'-dimethylthio-urea and N, N'-diphenylthio-urea; thio-acids such as thioacetic acid and thiobenzoic acid, and disulfides such as those of methyl, benzyl, t-butyl and p-tolyl.

By operating in the same way, with thio compounds, such as those described above and the compounds below: 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) - oct-2-ene-8-

methoxymethyl one-7-isopropenylacetate, 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

trichloroethyl one-7-isopropenylacetate, 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-

benzyl one-7-isopropenylacetate, 3-phenoxymethyl-4,5-dithia-2,7-diazabicyçlo- (4,2,0) -oct-2-ene-8-

p-nitrobenzyl one-7-isopropenylacetate, 3-benzyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-

methoxymethyl isopropenylacetate, 3-benzyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-

trichlorethyl isopropenylacetate, 3-benzyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-

benzyl isopropenylacetate, 3-benzyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-

benzhydryl isopropenylacetate, 1-methoxy-3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo-

(4,2,0) -oct-2-ene-8-one-7-isopropenylacetate of trichlorethyl, it is possible to prepare the following compounds: 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylated methoxymethyl, Trichlorethyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

Benzyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

P-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

Trichlorethyl 7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylated, 7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylate,

Benzyl 7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylate,

Benzhydryl 7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylate, and trichlorethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate.

Example 15:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = (f> OCH2, R2 = H, R1 = CHs) from 3-phenoxymethyl-4-thia-2,6-diazabicyclo - (3,2,0) -hept-2-ene-7-one-6-isopropenylacetate methyl III (R = <pOCH2, R2 = H, R1 = CH3), using a sulfenyl iodide / iodide / system water

To a stirred solution of methyl 3-phenoxymethyl-4-thia-2,6-diaza-bicyclo- (3,2,0) -hept-2-ene-7-one-6-isopropenylacetate (100 mg, 0, 28 mmol) in methylene chloride (15 ml), 2-mercaptobenzothiazole (70.2 mg, 0.42 mmol) and iodine (213 mg, 0.84 mmol) are added, and the mixture is stirred at room temperature for 15 min. Water (15 ml) is then added and the mixture is stirred overnight at room temperature. The organic layer is separated, dried over magnesium sulfate, filtered and concentrated. The NMR spectrum of the residue shows that the 3-iodocepham is formed with a yield of approximately 80%.

By operating in the same way, on thio compounds such as thioacetamide, thioacetanilide, thio-urea, N, N'-dimethyl-thio-urea, N, N'-diphenylthio-urea, t-butylmercaptan, isopropyl mercaptan, thiophenol, p-chlorothiophenol, ethyl 2-mercaptoacetate, 2-mercaptobenzoxazole,

2-mercaptobenzimidazole, 2-mercaptothiazolene, triphenyl-methylmercaptan, benzylmercaptan, dimethyl disulfide, dibenzyl disulfide, di-t-butyl disulfide, di-p-tolyl disulfide, thioacetic acid, thiobenzoic acid and the following compounds:

3-phenoxymethyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-

Trichlorethyl 6-isopropenylacetate, 3-phenoxymethyl-4-thia-2,6-dia2abicyclo- (3,2,0) -hept-2-ene-7-

p-nitrobenzyl, 3-benzyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-6-, 6-isopropenylacetate

trichlorethyl isopropenylacetate, 3-benzyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-6-p-nitrobenzyl isopropenylacetate, l-methoxy-3- phenylymethyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-6-isopropenylacetate of trichlorethyl,

it is possible to obtain the following compounds: trichlorethyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

P-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylatede trichlorethyl,

P-nitrobenzyl 7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylate, and trichlorethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate.

Example 16:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = qOCH2, R2 = H, R1 = CH3) from methyl sym- (3-phenoxyacetamidoazetidinone-1-isopropenylacetate) -4- disulfide IVa (R = <pOCH2, R2 = H, R1 = CH3), using a sulfenyl iodide / iodine / water system

To a stirred solution of methyl sym- (3-phenoxyacetamidoazetidinone-1-isopropenylacetate) -4-disulfide (200 mg, 0.28 mmol) in methylene chloride (15 ml), 2-mercaptobenzothiazole (138 mg) is added , 0.83 mmol) and iodine (427 mg, 1.68 mmol) and the mixture is stirred at room temperature for 15 min. Water (15 ml) is then added and the reaction mixture is stirred overnight at room temperature. We separate

5

10

15

20

25

30

35

40

45

50

55

60

65

11

619,231

the organic layer, dried over magnesium sulfate, filtered and concentrated. The NMR spectrum of the residue shows the presence of approximately 80% of 3-iodocephame.

In an analogous manner, using thio compounds such as thioacetamide, thiocetanilide, thio-urea, N, N'-dimethyl-thio-urea, N, N'-diphenylthio-urea, tert. butylmercaptan, isopropylmercaptan, thiophenol, p-chlorothiophenol, ethyl 2-mercaptoacetate, 2-mercaptobenzoxazole, 2-mercaptobenzimidazole, 2-mercaptothiazolene, tri-phenylmethylmercaptan, benzylmercaptan dibenzyl disulfide, di-tert.-benzyl disulfide, p-tolyl disulfide, thioacetic acid, thiobenzoic acid and the following compounds:

sym (benzhydryl-3-phenoxyacetamidoazetidinone-1-isopropenyl-

acetate) -4-disulfide, sym (methoxymethyl-3-phenoxyacetamidoazetidinone-1-iso-

propenylacetate) -4-disulfide, and sym (benzyl-3-pheny lacetamidoazetidinone-1 -isopropenyl-

acetate) -4-disulfide,

it is possible to obtain the following compounds: benzhydryl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

Benzyl 7-phenoxyacetamido-3-methyl-3-iodocephalic-4-carboxylate, and benzyl 7-phenylacetamido-3-methyl-3-iodocephalic-4-carboxylate.

Example 17:

7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = (p OCH2, R '= CH3, R2 = H) from 2-oxo-3- (2-phenoxy-acetamido) -4 - {benzothiazol-2-yl) dithio-a-isopropenylazetidine-1-methyl acetate IVb R = <pOCH2, R1 = CH3, R2 = H, X ~ R3 =

<X))

Stirred overnight (16 h) at room temperature, a mixture of 2-oxo-3- (2-phenoxyacetamido) -4- (benzothiazole-2-yl) -dithio-a-isopropenylazetidine-1-acetate (5.2 g, 0.01 mol) and iodine (3.0 g, 0.012 mol) in methylene chloride (200 ml). The dark red reaction mixture is washed with an aqueous sodium thiosulfate solution (2 times), then with water (2 times) and dried over magnesium sulfate with bleaching charcoal. The pale yellow filtrate is concentrated and a foam is obtained which is extracted with ether. The filtered ethereal solution gives a concentration of 4.8 g (97%) of methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate in the form of an almost white foam. The compound (2.8 g) is purified by gradient elution chromatography on silica gel (Mallinkrodt CC-7.150 g), using a hexane / ether mixture (2/1) and then ether as eluents. The compound (2 g) is isolated in the form of a light yellow amorphous solid, mp = 73-76 °. It becomes glassy and melts at 116-120 °. Exact analysis by high resolution mass spectography gives a peak of the related ion of 490.0069, while that calculated for C17Hi9N2OsI127S32 is 490.0060.

The NMR spectrum (CDCl3): 7.82 to 6.92 (m, protonsarylics and NH); 5.8 (q, C7-H); 5.42 (d, j = 4Hz, Cs-H); 4.95 (s, C4-H); 4.70 (s, -OCH2); 3.87 (s, -COOCH3); 2.98 (q, j = 15 Hz, C2-CH2); 2.22 (s, C3 — CH3) is compatible with the assigned structure.

Example 18:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = <pOCH2, R1 —CH3, R2 —H), using iodine (1 atomic Eq)

By reacting 2-oxo-3- (2-phenoxyacetamido) -4- (benzo-

thiazol-2-yl) dithio-a-isopropenylazetidine-1-methyl acetate (0.53 g, 0.001 mole) with iodine (0.13 g, 0.005 mole or 0.001 gram atom) in methylene chloride ( 25 ml) and by treating the product as described in Example 17, practically the same results are obtained. The products of Examples 17 and 18 are identical (NMR and IR spectra and thin layer chromatography).

Example 19:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = <pOCH2, R '= CH3, R2 = H), using N-iodosuccinimide

React 2-oxo-3- (2-phenoxyacetamido) -4- (benzothia-zole-2-yl) dithio-a-isopropenylazetidine-methyl acetate (200 mg, 0.38 mmol) -iodosuccinimide (94 mg, 0.416 mmol) in methylene chloride at room temperature. After 4 h, an NMR spectrum of the residue of an aliquot of the reaction mixture essentially shows the starting materials. After 3 days, however, the NMR spectrum shows the presence of approximately 28% of the 3-iodocephalus.

Example 20:

7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylic acid I (R = <pOCH2, R1 = H, R2 = H) from 2-oxo-3- (2-phenoxyacetamido) -4 acid - (benzothiazol-2-yl) -dithio-a.-isopropenylazetidine-l-acetic IVb (R = <pOCH2,

R '= H, R2 = H, X-R3 =

A 2-oxo-3- (2-phenoxy-acetamido) -4- (benzothiazol-2-yl) thio-a-isopropenyl-lazetidine-1-acetic acid (5.15 g, 10 mmol) mixture is stirred. methylene chloride (200 ml) and bistri-methylsilyltrifluoracetamide (2.5 g, 10 mmol) until complete dissolution (about 10 min), then iodine (1.5 g, 11.8 mmol) is added and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated and the residue is treated with ethyl acetate (50 ml). The slurry obtained is filtered to separate the bis-benzothiazoledisulfide, 1.4 g (85%). The filtrate is treated with methanol (3.0 g, 100 mmol) for 0.5 h, then it is successively extracted with an aqueous solution of sodium thiosulfate (2 x 30 ml), water (3 x 30 ml) and saturated brine, dried over magnesium sulfate, and the filtrate is concentrated. The residue (4.7 g, 99%) has IR spectroscopy (CHCl 3): 1770.1740 and 1690 cm-1; an NMR spectrum (CDCl3): 5 2.27 (s, 3H); 2.65 and 3.13 (ABd, 2H, J = 15 Hz); 4.65 (s, 2H); 4.90 (s, 1H); 5.38 (d, J = 4Hz, 1H); 5.70 (q, J = 4 and 10 Hz, 1H); 7.3 to 8.3 (m); 7.92 (d, J = 10Hz, 1H) and 10.2 (s, 1H) are in agreement with the assigned structure.

Likewise, using:

2-oxo-3- (2-phenylacetamido) -4- (benzothiazol-2-yl) dithio- acid

a-isopropenylazetidine-1-acetic acid and 2-oxo-3- (2-phenoxyamido) -4-benzothiazol-2-yl) dithio- acid

a-isopropenylazetidine-l-acetic,

we can get:

7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylic acid and 7-phenoxyamido-3-methyl-3-iodocephame-4-carboxylic acid. Example 21:

7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid, 12 and 7-phenoxyacetamido-3-methyl-3-cephem 7-phenoxyacetamido-3-methyl-3-iodo-cephalic acid is stirred 4-carboxylic (0.9 g, 1.9 mmol) and bistrimethyl-silyltrifluoracetamide (0.9 g, 3.5 mmol) in benzene (10 ml)

5

10

15

20

25

30

35

40

45

50

55

60

65

619231

12

until complete dissolution. Pyridine (0.5 g, 6.3 mmol) is added and the mixture obtained is heated under reflux for 1 h, then filtered. The filtrate is treated with methanol (0.3 g, 10 mmol) for 0.5 h, and the reaction mixture is successively extracted with water (4x5 ml) and saturated brine, dried over sulphate magnesium and it is concentrated. The IR and NMR spectra of the residue obtained (250 mg, 40%) correspond to 7-phenoxyacetamido-3-methyl-3-cephem.

The combined aqueous extracts of ethyl acetate (30 ml) are added, stirred and acidified to pH 1 with concentrated HCl. The ethyl acetate layer is extracted with saturated brine, dried over magnesium sulphate and concentrated, which gives 400 mg (60%) of 7-phenoxyacetamido-3-methyl-3-cephem acid. 4-carboxy-lique.

Example 22:

Methoxymethyl 6-phenoxyacetamidopenicillinate sulfoxide 11

Penicilin sulfoxide V (19.2 g, 0.05 mole) and triethanolamine (5.2 g, 0.052 mole) are stirred in methylene chloride (50 ml) until a pale yellow solution is obtained. . This solution is stirred in an ice bath while slowly adding chloromethyl methyl ether (4.5 g, 0.055 mole), keeping the temperature below 8 ° C. An exothermic reaction takes place, the color of the pale yellow reaction mixture becomes almost colorless, and a white solid (triethylamine hydrochloride) separates from the solution. After having stirred for approximately 2 h, the reaction mixture is extracted with cold water (2 x 25 ml), and the pale yellow organic layer is dried over magnesium sulphate, filtered and concentrated, which gives a thick pale yellow oil. Cold methanol (50 ml) is added and the mixture is stirred in an ice bath for 1 h, at the end of which a white solid has formed. By filtration and drying, 16.5 g (80%) of the desired ester are obtained, mp = 107-109 ° C, (oc) D = +192 (C = 1 in CHC13). From the mother liquor, a second harvest of 2.2 g is obtained, which represents a total of 18.7 g (91%) of methoxymethyl 6-phenoxy-acetamidopenicillinate sulfoxide. IR spectra (Nujol): 1790,1760,1700,1600 and 1590 (sh) cm "1 and the NMR spectrum (CDCls): 5 8.28 (d, 1H, J = 10.5Hz, NH); 7 , 42 to 6.83 (m, 5H, C6H5); 6.2 and 6.3 (dd, 1H, J = 4.5 Hz, C "-H); 5.47 and 5.28 (ABq, 2H , J = 6 Hz, COOCH2O, embarrassed rotation); 5.1 (d, 1H, J = 4.5 Hz, Cs-H); 4.71 (s, 1H, C3-H); 4.55 (s , 2H, -0-CH2-C0); 3.52 (s, 3H, - OCH3); 1.75 and 1.27 (ss, 6H, gern CH3) are in agreement with the assigned structure.

Example 23:

2-oxo-3- (2-phenoxyacetamido) -4- (benzothiazol-2-yl) -dithio-a.-isopropenylazetidine-1-methoxymethyl acetate IVb {R = (? OCH2, R1 = CH3OCH2, R2 = H, X-R3 =

A mixture of 2-mercaptobenzothiazole (3.68 g, 0.022 mol) and 6-phenoxyacetamidopenicillin methoxymethyl sulfoxide (8.48 g, 0.02 mol) is heated under reflux for 6 h in an oil bath at 120 °. ) in purified dioxane (100 ml). The reaction mixture is brought to dryness, the residue is taken up in chloroform, treated with bleaching charcoal, the filter and concentrated. Triturated with methanol / ether, filtered and dried, and 4.0 g of an electrified white powder, mp 121-123 °, are obtained. The IR spectrum (Nujol): 3400,1780,1750,1680, 1520 cm-1 and the NMR spectrum (CDCI3) & 8.0 to 6.8 (m, 9 aryl protons and - NH); 5.70

5.15 (m, protons of ß-lactam - and -COOCH2O-);

^ CH3

5.0 (s, CHCOÖ); 4.55 (s, OCH2CO); 3.43 (s, -CH2OCH3) and 2.0 (s, ^ CH3 are in agreement with the assigned structure.

Example 24:

7-Phenoxyacetamido-3-methyl-3-iodocephame-4-methoxymethyl carboxylate I (R = <pOCH2, R1 = CH3OCH2, R2 — H) from 2-oxo-3- (2-phenoxyacetamido) -4- ( benzothiazol-2-yl) -dithio-a-isopropenylazetidine-1-methoxymethyl acetate IVb (R = cpOCH2, R1 = CH3OCH2. R2 = H, X — R3 =

Stirred at room temperature for 3.5 h (time after which the reaction is found to be complete) a mixture of 2-oxo-3- (2-phenoxyacetamido) -4- (benzothiazol-2-yl) dithio- a-isopropenyl-azetidine-1-methoxymethyl acetate (0.4 g, 0.0007 mole) and iodine (0.18 g, 0.0007 mole) in methylene chloride. The reaction mixture is washed with an aqueous solution of sodium thiosulfate (2x10 ml) then with water (2 x 10 ml) and dried over magnesium sulfate. The filtered solution is concentrated and the residue is extracted with ether (to remove most of the insoluble benzothiazole). By concentration, the ether gives 0.34 g of the desired compound (96%). The NMR spectrum (CDCl3): 7.92 to 6.92 (m, aryl protons and —NH); 5.80 and 5.61 (dd, C7-H); 5.45 to 5.32 (m,

C6-H, and COOCH2O); 4.89 (s, C4-H); 4.62 (s, -0-CH2-CO); 3.52 (s, CH2OCH3); 2.92 (ABq, J = 15 Hz, C2-CH2); 2.22 (s, C3 — CH3) is in agreement with the assigned structure.

Example 25:

Methoxymethyl 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylate by dehydration of methoxymethyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate I (R = q> OCH2, R1 = CH3OCH2, R2 = H)

When dehydrated methoxymethyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate by the method of Example 13, 3-cephem is obtained with a yield estimated from the NMR spectrum of approximately 70%.

Example 26:

N-methoxymethyloxycarbonylampicillin sulfoxide 8 from ampicillin sulfoxide 7

A mixture of ampicillin sulfoxide (14.6 g, 0.004 mole) and triethylamine (9.7 g, 0.096 mole) is stirred in methylene chloride (125 ml) until completely dissolved (about 1 h). This solution is then stirred in an ice bath while slowly adding chloromethylmethyl ether (7.1 g, 0.088 mole) in the presence of a slow stream of carbon dioxide. The reaction mixture (containing solids) is stirred for an additional hour in the ice bath, and another hour at room temperature, still in the presence of the carbon dioxide stream. The reaction mixture is then strongly cooled and filtered. The solid obtained is washed with water (2 x 50 ml) then with ether and dried, which gives 8.7 g (43.7%) of methoxymethyl-N-methoxymethyl-carbamoylampicillin sulfoxide, Mp = 178-180 °. By recrystallization from methylene ether chloride, the PF rises to 186-187 °.

Centesimal composition for C2iH27N3S09:

Calculated: C 50.69 H 5.47 N8.44 S 6.45 Found: C 50.73 H 5.40 N8.17 S 6.50.

5

10

15

20

25

30

35

40

45

50

55

60

65

13

619,231

The IR spectrum (Nujol): 3350,1780,1740,1710,1700 (sh) 1675 (sh), 1660.1520 cm-1 and the NMR spectrum (DMSOdg):

8 8.22 (d, 2H, two -NH-), 7.45 (brs, 5H, C6H5); 6.0 and 5.85 (dd, J = 4Hz, Cs-H); 5.55 to 5.17 (m, 6H, C5-H, -CHCO, and two -OCH2O-); 4.52 (s, 1H, C3-H); 3.42 and 3.35 (ss, 6H, two —OCH3); 1.59 and 1.17 (ss, 6H, nemdimethyl) are in agreement with the assigned structure.

From the combined organic filtrates from this reaction, 6.5 g (33%) of a solid product are isolated. The IR and NMR spectra of this product correspond to the methoxymethyl-ampicillin sulfoxide.

Example 27:

2-Oxo-3- (v.-methoxymethyloxycarbonylaminophényU acetamido) -4- (benzothiazoyl-2-yl) dithio-ci.-isopropenylazetidine-1-methoxymethyl acetate IVb

(R = <p CH (NHCOOCH2OCH3), Ri = CH3OCH2, R2 = H, XR3

The mixture is heated under reflux for 16 h in an oil bath maintained at 130 ° C., a mixture of 2-mercaptobenzothiazole (0.22 g, 0.00125 mol) and methoxymethyl sulfoxide, N-methoxymethyloxycarbomylampicillin (0.6 g, 0.00125 mol) in purified dioxane (65 ml). The reaction mixture is brought to dryness. The product obtained (0.7 g, 93%) is separated from the unreacted product by extraction with an excess of ether, in which it dissolves. The product forms a glass at 60-65 ° and melts at approximately 120 ° C. The IR spectrum (Nujol) 3350 and 1790 at 1660 (multiplets) cm "1 and the NMR spectrum (CDCI3); 8 7.93 at 7 , 20 multiplets (br), aryl protons; 6.52 (d, NH); 5.6-4.9 (m, 10H); 3.39 (s, two -O-CH3); 1.90

/ CH2

(s, -) are in agreement with the assigned structure.

CH3 Example 28:

7-a .- (Methoxymethyloxycarbonylamino) phenylacetamido-3-methyl-3-iodicephame-4-methoxymethyl carboxylate I [R = <p CH {NHCOOCH2OCH3) R1 = CH3OCH2, R2 = H]

A mixture of 2-oxo-3- (a-methoxymethyloxycarbonylaminophenylacetamido) -4- (benzothiazol-2-yl) dithio-a-isopropenylazetidine-1-methoxymethyl acetate (700 mg, 1.12 mmol) is stirred at room temperature. and iodine (302 mg, 10.4 mmol) in methylene chloride (70 ml). The reaction is complete after approximately 3 h. The reaction mixture is washed with an aqueous solution of sodium thiosulfate (2 times), with water (2 times), and the organic layer is dried over magnesium sulfate. By concentration of the filtrate, 700 mg of a light brown foam is obtained, the NMR spectrum of which shows that it contains approximately 60% of the 3-iodocephalus characterized by the singlet C3-CH3 at 8 2.2 and the quartet AB at approximately 8 2.85.

Example 29:

7-a- (Methoxymethyloxycarbonylamino) phenylacetamido-3-methyl-3-cephem-4-methoxymethyl carboxylate and caphalexin 9

By heating the 7 - "- (methoxymethyloxycarbonylamino) -phenylacetamido-3-methyl-3-iodocephame-4-carboxylate with pyridine in benzene for 1 h, and treating the reaction mixture as described in example 13, 7-a- (methoxymethyloxycarbonylamino) -phenylacetamido-3-methyl-3-cephem-4-carboxylate of methoxymethyl is obtained, as shown by the NMR spectrum and thin layer chromatography using a reference sample prepared from cephalexin by the process described in Example 26.

The compound is easily transformed into cephalexin by treatment with aqueous acids such as hydrochloric acid, sulfuric acid, formic acid, methanesulfonic acid and tri-fluoracetic acid then adjustment of the pH to approximately 4.5 to precipitate cephalexin. A convenient purification technique consists in isolating a salt such as a cephalexin trifluoroacetate, by adding solvents such as ether to a solution of the compound which it is desired to isolate in the minimum amount of trifluoroacetic acid after complete dissolution.

Example 30:

6-Phenoxyamidopenicillamic acid sulfoxide A slurry of 6-phenoxyaminopenicillanic acid sulfoxide (23.3 g, 0.1 mole) in water (250 ml) is cooled to 0-5 ° C. the treatment with an aqueous solution of potassium hydroxide (2N) until a clear solution is obtained and the pH of the solution reaches 8. The solution obtained is diluted with tetrahydrofuran (250 ml). A solution of phenyl chloroformate (23.5 g, 0.15 mole) in tetrahydrofuran (100 ml) and an aqueous solution of potassium hydroxide (2N) are added separately at a rate such that the pH of the reaction mixture remains between 7.5 and 8.5. Once the addition is complete, and when the pH has stabilized at 8 for 15 min, the reaction mixture is concentrated to half its volume. The aqueous concentrate (pH 8.7) is extracted with ethyl acetate (which is discarded), then a layer of ethyl acetate (500 ml) is deposited over it and the pH of the mix 2 with an HCl solution (6N). The aqueous layer is further extracted with ethyl acetate (200 ml), and dried over magnesium sulfate, filtered and concentrated the extracts in combined ethyl acetate. The residue (23.65 g, 67%) has a PF of 158-167 ° (dec.); an IR spectrum (Nujol): 3400,1800,1750,1720 and 1530 cm-1; an NMR spectrum (DMSOde): 8 1.30 (s, 3H); 1.67 (s, 3H); 4.48 (s, 1H); 5.53 (d, J = 4.5 Hz, 1H); 5.80 (q, J = 4.5 and 9 Hz, 1H); 7.0 to 8.3 (m, 6H); and 8.1 (br, 0.1 H). A sample recrystallized from methanol melts at 175-177 ° (dec.).

Example 31:

Methyl 6-phenoxyamidopenicillanate sulfoxide A solution of 6-phenoxyamido-penicillanic acid sulfoxide (13.5 g) in tetrahydrofuran (200 ml) at 0-5 ° C is treated with a solution of diazomethane in ether until the nitrogen evolution ceases and the yellow color persists for 0.5 h. By concentration, the desired compound is obtained (14.0 g, 100%), mp = 50-70 °; IR spectrum (CHC13); 3400,1800,1750,1500 and 1480 cm-1; NMR spectrum (CDCl3): 8 1.20 (s, 3H); 1.73 (s, 3H); 3.87 (s, 3H); 4.72 (s, 1H); 5.13 (d, J = 4.5 Hz, 1H); 5.83 (q, J = 4.5 and 11 Hz, 1H); 6.80 (d, J = 11 Hz, 1H); and 7.1 to 7.7 (m, 5H).

Example 32:

2-Oxo-3- (phenoxyamido) -4- (benzothiazole-2-yl) dithio-a.-isopropenylazetidine-1-methyl acetate IVb (R = (? 0, R1 = CH3, X-R3 =

A solution of sulfoxide of

Methyl 6-phenoxyamidopenicillinate (11.0 g, 30 mmol) and 2-mercaptobenzothiazole (5.5 g, 33 mmol) in dioxane (180 ml). By concentration, a residue is obtained (16.1 g), part of which is chromatographed on Silicar CC-7 Mallinckrodt (300 g, passing through a sieve from 0.044 to 0.074 mm mesh size) using benzene / acetate mixtures ethyl. By elution with benzene / ethyl acetate mixtures 4/1 and 3/2, the compound is obtained

5

10

15

20

25

30

35

40

45

50

55

60

65

619,231

14

sought (9 g), of sufficient purity for further processing. The compound has an IR spectrum (CHCI3): 1780 and 1750 cm-1; NMR spectrum (CDCl3): 8 1.90 (s, 3H); 3.73 (s, 3H), 4.93 (s, 1H); 5.09 (brs, 1H); 5.20 (brs, 1H); 5.40 (q, J = 5 and 8 Hz, 1H); 5.58 (d, J = 5 Hz, 1H) and 6.9 to 8.1 (m).

Example 33

2-oxo-3- (phenoxiamido) -4- (benzothiazol-2-yl) dithio-a.-isopropenylazetidine-1-acetic acid IVb (R = (pO, R3 = iî, X-R3 =

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

Example 34:

Methyl 7-Phenoxyamido-3-methyl-3-iodocephame-4-carboxylate I (R = <pO, R '= CH3, R2 = H)

A mixture of 2-oxo-3- (phenoxyamido) -4- (benzothiazole-2-yl) dithio-a-iso-propenylazetidine-1-methyl acetate (0.52 g, is stirred at ambient temperature for 12 h. 0.001 mole) and iodine (0.25 g, 0.001 mole) in methylene chloride (25 ml). The reaction mixture is then washed with an aqueous solution of sodium thiosulfate (2 times) and with water (2 times) and dried over magnesium sulfate and over bleaching charcoal. The filtrate is concentrated in the form of a yellow foam (0.7 g). The foam is extracted with ether (3 times) and the ethereal solution is concentrated, which gives 0.4 g (85%) of the desired compound in the form of a light yellow foam. Purification is continued by gradient elution column chromatography using Mallinckrodt Silicar CC-7 with hexane / ether (2: 1) followed by ether. The compound is obtained in the form of a light yellow foam, NMR spectrum (CDCI3): 6 7.35 (br d, 5H, C6H5); 6.48 (d, 1H, -NH-, exchanged with D20); 5.62 and 5.4 (dd with a superimposed at 8 5.43.2H, protons of lactams (transforming into a quartet by exchange with D20); 4.95 (s, 1H, C4H); 3.83 (s, 3H, COOCH3); 3.02 (ABq, J = 15 Hz, 2H, C2-CH2); 2.22 (s, 3H, C3-3N3).

Similarly, using the following compounds: trichlorethyl-2-oxo-3- (2-phenoxyacetamido) -4- (benzo-thiazole-2-yl) dithio-a-isopropenylazetidine-1-trichlorethyl acetate,

trichlorethyl-2-oxo-3- (2-phenylacetamido) -4- (benzothiazole-2-yl) -

dichio-a-isopropenylazetidine-1-trichlorethyl acetate, methoxymethyl-2-oxo-3- (2-phenoxyamido) -4- (benzothiazol-2-yl) dithio-a-isopropenylazetidine-l-methoxymethyl-2-oxo acetate -3- (2-benzyloxyamido) -4- (benzothiazole-2-yl) dithio-a-isopropenylazetidine-1-benzyl acetate, 2-oxo-3- (2-trichlorethoxyamido) -4- (benzothiazole-2-yl ) dithio-

oc-isopropenylazetidine-1-trichlorethyl acetate, 2-oxo-3- (2-phenoxyacetamido) -4-acetimidoyldithio-a-iso-

methyl propenylazetidine-1-acetate, 2-oxo-3- (2-phenoxyacetamido) -4-N-phenylacetimidoyldithio-a-

methyl isopropenylazetidine-1-acetate, and 2-oxo-3- (2-phenoxyacetamido) -4-anilinothio-isopropenylazetidine-

1-methyl acetate,

it is possible to obtain the following compounds: trichlorethyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate,

Trichlorethyl 7-phenylacetamido-3-methyl-3-iodocephame-4-carboxylate,

7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylate, methoxymethyl, 7-benzyloxyamido-3-methyl-3-iodocepham-4-carboxylate,

Trichlorethyl 7-trichlorethoxyamido-3-methyl-3-iodocephame-4-carboxylate, and methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylated.

Example 35:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate, 1 (R = q> OCH2, R2 = H, R '= CH3) from 3-phenoxymethyl-4,5-dithia-2, Methyl 7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate, 2 (R = <pOCH2, R2 = H, R1 = CH3), using a disulfide system / iodine / water A mixture of 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct- is stirred at room temperature for 16 h with water (10 ml) Methyl 2-ene-8-one-7-isopropenylacetate (100 mg, 0.253 mol), dibenzyl disulfide (47 mg, 0.2 mmol) and iodine (193 mg, 0.76 mmol) in chloride methylene (10 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The NMR spectrum (CDCI3) of the product indicates that the product contains more than 85% of 3-iodocephame.

Identical reactions are carried out using dimethal disulfide, 2,2'-dithiobis (benzothiazole), in place of benzyl disulfide. In each case, the yield of 3-iodocephalus is estimated at more than 80%.

Example 36:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate, 1 (R = q> OCH2, R2 = H, R1 —CH3) from

Methyl 3-phenoxylmethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one-7-isopropenylacetate, 2 (R = <pOCH2, R2 = H , R1 = CH3), using thioacid / iodine / water systems. A mixture of 3-phenoxymethyl-4,5-dithiabicyclo- (4 ml) is stirred with water (10 ml) at room temperature for 16 h. , 2,0) -oct-2-ene-8-one-7-isopropenylacetate methyl (100 mg, 0.253 mmol), thiobenzoic acid (53 mg, 0.38 mmol) and iodine (193 mg, 0.76 mmol) in methylene chloride (10 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The NMR spectrum (CDC13) of the product shows that the product contains more than 85% of 3-iodocephame.

When the reaction is repeated in the same manner as above, but using thioacetic acid in place of thiobenzoic acid, low yields (about 20%) of 3-iodocephalus are obtained.

Example 37:

Methyl 7-Phenoxyacetamido-3-methylceph-3-ene-4-carboxylate from 7-phenoxyacetamido-3-methyl-3-iodocephame-

Methyl 4-carboxylate I (R = <pOCH2, R2 = H, R1 — CH3) using pyridine in benzene

A solution of methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate and pyridine in benzene is heated under reflux in an oil bath maintained at 90 °. The aliquots of the reaction mixture are removed periodically and the progress of the reaction is monitored by analysis of the NMR spectrum of the residue. The 3-iodocéphame contained in the mixture is characterized by the singlet C4-H at 8 4.9, by the doublet Cö-H at 8 5.38 and by the quartet C2-CH2 at 8 2.95; the ceph-3-th is characterized by its C6-H doublet at 8 5.05 and by its C2-CH2 doublet at 8 3.35. Any formation of ceph-2-th is easily detected by its singlet C3-CH3 at 8 1.92 and by its signal C2-H at 8 6.1. In all of the applicant's experiments using pyridine as a base, no formation of the ceph-2-th isomer was detected. The following table summarizes the results of experiments in which the relative amounts of pyridine were varied.

(Table at the top of the next column)

Example 38:

7-Phenoxyacetamido-3-methylceph-3-th-4-carboxylate from 7-phenoxyacetamido-3-methyl-3-iodo-

5

10

15

20

25

30

35

40

45

50

55

60

65

15

619,231

Table 1:

Dehydration of 3-iodocephalus using pyridine in benzene

No.

Molar ratio

Duration of reflux

Yield in

pyridine

(h)

ceph-3-th *

(Eq)

(%)

1

2.5

0.5

45

2

2.5

1.0

60

3

2.5

1.5

67

4

5

0.5

50

5

5

1.0

66

6

5

1.5

80

7

5

3.0

-100

8

10

0.5

60

9

10

1.0

-100

10

10

1.5

100

20

* No trace of the ceph-2-th isomer was detected in any of these experiments.

methyl cephame-4-carboxylate I (R = <pOCH2, R2 = H, 2s R1 —CHi) using pyridine alone

Methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate (100 mg) is dissolved in pyridine d5 (0.5 ml) and the reaction is monitored by periodically carrying out a spectrum on the sample. NMR. After 15 min at room temperature, the conversion rate to ceph-3-th is about 50%, and the reaction is complete after 2 h. The NMR spectrum does not change after a 24 h period, and here again no detectable amount of the ceph-2-th isomer is observed.

35

Example 39:

Methyl 7-Phenoxyacetamido-3-methylceph-3- (and 2-) th-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-3-iodo-phame-4-carboxylate I (R = ip OCH2, R2 = H, 40

R1 —CH3), using Hünig base, A mixture of 7-phenoxy-acetamido-3-methyl-3-iodocephame-4-carboxylate (200 mg, 0.395 mmol) and diisopropylethylamine (510 is heated under reflux for 1 h. mg, 3.5 mmol)

in benzene dö (1 ml). The reaction mixture is washed with hydrochloric acid (2N), then with water and dried. The NMR spectrum shows that the reaction was complete, but led to a mixture of approximately 40% ceph-2-th and 60% ceph-3-th.

Example 40: 50

Methyl 7-Phenoxyacetamido-3-methylceph-3- (and -2-) th-4-carboxylate from methyl 7-phenoxyacetamido-3-methyl-3-iodo-cephame-4-carboxylate I (R = ( $ OCH2, R2 = H, R1 = CH3) using DBU and DBN ss

A mixture of methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4- 'carboxylate (100 mg, 0.2 mmol) and 1.5-diaza-bicyclo is left at room temperature for 1.5 h. - (5,4,0) -undéc-5-ene (DBU, 300 mg, 2.0 mmol) in benzene dg (1 ml). The reaction mixture is washed with hydrochloric acid (2N), then with water and dried. The NMR spectrum shows that the reaction was carried out at approximately 75%, and led to a mixture of ceph-2-th and ceph-3-th.

When the DBU is replaced in the above reaction with 1,5-diazabicyclo- (4,3,0) -non-5-ene (DBN), the reaction time being 2 h at room temperature, the reaction is practically complete, the product being composed of a mixture of the isomers of ceph-2-th and ceph-3-th in a ratio of approximately 3: 7.

Example 41:

Methyl 6-phenoxyacetamido-2-methyl-2-iodomethylpenam-3-carboxylate IA (R = <p OCi / 2, R1 = CH3, R2 = H) and 7-phenoxyacetamido-3-methyl-3-iodocephame-4- methyl carboxylate I (R = cp OCH2, R1 = CH3, R2 = H) from 2-0x0-3- (2-phenoxyacetamido) -4- (benzothiazol-2-yl) -dithio-a.-isopropenylazetidine- 1-methyl acetate IVb (R = <pOCH2, R '= CH3, R2 = H, XR? =

~ - '<sX)>

Stirred at room temperature for 16 h a mixture of

2-oxo-3- (2-phenoxyacetamido) -4-benzothiazol-2-yl) methyl dithio-a-isopropenylazetidine-1-acetate (5.0 g, 9.5 mmol) and iodine (1.8 g, 14.2 mmol) in methylene chloride (100 ml). The reaction mixture is then quickly washed with an aqueous solution of sodium thiosulfate at 5% (2 times), the layer of methylene chloride is dried over magnesium sulfate, and it is brought to dryness, which gives 5.2 g of a yellow foam.

The product is chromatographed on a column of Mallicrodt Silicar CC-7 (350 g) using ether as eluent and collecting fractions of about 5 ml. Depending on their thin layer chromatogram, the appropriate fractions are combined.

Fractions 5 to 22 are combined and concentrated, giving 1.3 g of a yellow foam, the NMR spectrum of which indicates that it is composed of a mixture of benzothiazole disulfide,

3-iodocephame and 2-iodomethylpenam, characterized by its multiplet of ß-lactam at approximately 5.9 to 5.65, its singlet c3 - H to 5 4.9, its singlet - OCH2CO to 5 4.6, - CH2I at S 4.45, its singlet —COOCH2 at S 3.8 and its singlet - ch3— at S 1.6.

Combine the fractions 23 to 24 tonnes with the concentrates, which gives 1.2 g of a yellow foam consisting of 3-iodocephame and 2-iodomethylpenam, in the ratio of approximately 7: 3.

Fractions 35 to 65 are combined, and concentrated, to give 2.4 g of a pale yellow foam made up of 3-iodocephaly, with traces (about 5%) of 2-iodomethylpenam.

Example 42:

2-Oxo-3-phenoxyacetamido-4-acetimidoyldithio-a.-iso-propenylazetidine-1-methyl acetate IVb (R: (pOCH2CONH, R1 = CH3, R2 = H, R3 = CH3, R4 = H) and methylpenicillin V

The mixture is heated under reflux, with stirring for 5 h, in an oil bath at 120 ° C., a mixture of methylpenicillin V sulfoxide (0.38 g, 0.001 mole) and thioacetamide (0.08 g, 0.001 mole) in purified dioxane (25 ml). The clear reaction mixture is concentrated under vacuum, and a brown foam is obtained. The IR spectrum (chci3) shows intense and acute singlets at 1780,1745 and 1700 cm-1, with lower absorptions at 1600 and 3400 cm "1. The NMR spectrum (cdci3) indicates that it is '' a mixture containing as main product 2-oxo-3-phenoxyacetamido-4-acetimidoyldithio-a-isopropenylazetidine-methyl acetate, 5, characterized by signals at 5,22 and 5,1

^ CH2 ^ CHa / CH2

(-.), 2.55 (-) etl, 92 (-) among others,

CH3 NH ch3

and methylpenicillin V (in a proportion estimated at 20% and the presence of which is confirmed by thin layer chromatography), characterized by its gemdimethyl signals at 1.65 and 1.5. There are also traces of methyl 4-phenoxyacetamido-iso-thiazol-3-one-1-a-isopropenylacetate characterized by its signals at approximately 5 9.2 and 8.83.

65

619231

16

Example 43:

2-Oxo-3-phenoxyacetamido-4- (N-phenylacetimidoyl) dithio- (t-isopropenylazetidine-1-acetate IVb (R = q> OCH2CONH, R1 = CH3, R2 = H, R3 = CH3i R4 = cp)

The mixture is heated under reflux, with stirring, in an oil bath at 120 ° C for 5 h, a mixture of methylpenicillin V sulfoxide (0.38 g, 0.001 mole) and thioacetanilide (0.15 g, 0.001 mole)

in purified dioxane (25 ml). The clear reaction mixture gives, by concentration under vacuum, a brown foam. The NMR spectrum (CDCI3) indicates that the reaction is incomplete, since the product contains approximately 20% of methylpenicillin V sulfoxide, in addition to 2-oxo-3-phenoxyacetamido-4- (N-phenylacetamidoyl) -dithio-a- methyl isopropenylazetidine-1-acetate characterized by 8 5.7 to 5.3 (m, ß-lactam protons), 5.2 and 5.05

^ ch2

(- '), 4.92 (—CHCOOCH3), 4.5 (-O-CH2), 2.72 CH3

CHi

(- ^) etl, 92 (- ').

ch3 ch3

Similarly, using solvents such as toluene, dichloroethane, mesitylene, and thioamides such as thiobenzamide, N-methylthioacetamide, N-methylthio-

benzamide, N-phenylthiobenzamide, thionicotinamide, thio-isonicotinamide, 2-thiazolethioacetamide and 2-thiazole-thiobenzamide, and penicillin sulfoxides such as trichlorethylpenicillin V sulfoxide, methoxymethyl-penicillin sulfoxide of p-nitrobenzylpenicillin V, penicillin sulfoxide G, methoxymethylpenicillin G sulfoxide, trichlorethylpenicillin G sulfoxide, 6-phenoxy-amidopenicillin G sulfoxide, methoxymethyl-N- (methoxy-methyloxycarbonyl) sulfoxide of di (methoxymethyl) carbenicillin, and 6-thiene-2-ylacetamido-6-methoxypenicillin sulfoxide, various azetidinone disulfides of formula 5 are obtained.

Example 44:

Methyl 7-Phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate from 2-oxo-3-phenoxyacetamido-4- (amino-imidoyl) dithio-a-isopropenylazetidine-1-methyl acetate IVb (R = <pOCH2CONH, R '= CH3, R2 = H, R3 = NH2, R4 = H) All of the crude product obtained in Example 43 is dissolved in methylene chloride (5 ml) and stirred with l 'iodine (0.13 g, 0.00052 mole) at room temperature for 16 h. The reaction mixture is then concentrated, which gives a brown foam. The formation of methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate in this reaction is indicated by comparison of the NMR spectrum of the crude product with that of an authentic sample. Thin layer chromatography performed on an authentic sample of 3-iodocephalus confirms the presence of this compound in the reaction mixture.

R

Claims (9)

619,231 1. Process for the preparation of a new compound corresponding to formula I R [I] H [III] or its IA isomer RCONH / COOR1 in which R, R1 and R2 are as defined above, with at [IA] 20 at least one equivalent of iodine or of an iodination agent in the presence of moisture in an appropriate solvent. 2. Process for the preparation of a compound corresponding to formula I, characterized in that a thiazol-2-ene-azetidinone corresponding to formula III is treated in which X is S and R5 is lower alkyl, the radical - (CH2) „COO-lower alkyl where n is a number from 1 to 3, a phenyl, heteroaryl or R6 NR 619,231 where R6 is lower alkyl, phenyl, heteroaryl, —O — alkyl, —O — phenyl, —S — alkyl, —S — phenyl or NHR8, where R7 and R8 are the same or different and are both selected from the group comprising H, a lower alkyl radical and a phenyl or heteroaryl radical, with at least one equivalent of iodine or of an iodination agent in an appropriate solvent. 2 „.., 3. Process for the preparation of a compound corresponding to the formula -"> mule I, characterized in that a disulfide of symmetry is reacted azetidinone or an asymazetidinone disulfide corresponding to formulas IVa and IVb respectively [IVa] 30 ^ COOR in which R denotes a benzyl, phenoxymethyl, 4-amino-4-carboxyl-1-butyl, a-aminobenzyl radical, these radicals optionally bearing protective groups, a lower alkyl, aryl or heteroaryl radical, the radicals R30—, R3S -, R3R4N— where R3 is a lower alkyl, phenyl or phenyl- (lower alkyl) radical and R4 is hydrogen or R3; R1 is hydrogen or a radical - CH2OCH3, a lower alkyl radical, 2,2,2-trichlorethyl, benzyl, p-nitrobenzyl, benzhydryl, phenacyl or trimethylsilyl, and R2 is hydrogen or a methoxy radical, characterized in that a 1,2,4-dithiaz-3-ene-azetidinone corresponding to formula II is treated [II] R ' RCONI-L r \ l 'ICOOR and [IVb] 50 55 RCONH; X - IV '/ CO OR in which R, R1 and R2 are as defined above, with at least one equivalent of iodine or of an iodination agent in the presence of moisture in an appropriate solvent. 4. Method according to claim 1, characterized in that the starting l, 2,4-dithiaz-3-ene-azetidinone is 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2 , 0) -oct-2-ene-8-one-7-iso methyl propenylacetate and in that the iodocephame obtained is 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylated methyl. 5. Method according to claim 1, characterized in that the 1,2,4-dithiaz-3-ene-azetidinone is 3-phenoxy-4,5-dithiaz-2,7-diazabicyclo- (4,2,0 ) -oct-2-ene-8-one-7-isopropenylacetate methyl and in that the iodocephame obtained is methyl 7-phenoxyamido-3-methyl-3-iodocephame-4-carboxylate. 6. Method according to claim 2, characterized in that the thiazol-2-ene-azetidinone is 3-phenoxymethyl-4-thia-2,6-diaza-bicyclo- (3,2,0) -hept-2- methyl ene-7-one-6-isopropenylacetate and in that the iodocephame obtained is methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate. 7. Method according to claim 4, characterized in that reacts 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo- (4,2,0) -oct-2-ene-8-one -7-methyl isopropenylacetate with thiourea and iodine, which gives methyl 7-phenoxyacetamido-3-methyl-3-methyl-3-iodocephame-4-carboxylate. 8. Method according to claim 6, characterized in that reacts 3-phenoxymethyl-4-thia-2,6-diazabicyclo- (3,2,0) -hept-2-ene-7-one-6 -methyl isopropenylacetate with methyl 2-mercapto-benzothiazole and iodine to give methyl 7-phenoxyacetamido-3-methyl-3-iodocephame-4-carboxylate. 9. Method according to claim 3, characterized in that reacts 2-oxo-3- (2-phenoxyacetamido) -4- (benzothiazol-2-yl) -dithio-a-isopropenylazetidine-1-methyl acetate with iodine, which gives methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate. Commercial cephalosporins, such as cephalexin, cephaloglycin, cephaloridin, cephalotin, cephazo line and cephapirin are prepared by a number of different processes involving intermediates which differ from one cephalosporin to another . Cephalosporin C and deacetoxycephalosporin C can be prepared by fermentation processes. The aminoadipyl part of these compounds is eliminated by various chemical processes, which gives respectively 7-aminocephalo-sporanic acid (7-ACA) and 7-aminodeacetoxycephalospora- picnic (7-ACDA). These base compounds are then re-acetylated to introduce the appropriate group therein. In most cases, further chemical modification of the molecule is necessary to provide the desired antibiotic. The disadvantage of this route is the relative difficulty and, therefore, the high cost of the preparation and isolation of cephalosporin C and deacetoxycephalosporin C. Therefore, other processes. Another route uses commercial penicillins G and Y as starting materials, which are inexpensive and readily available. Cephalexin, which is an industrially important cephalosporin, is produced by a process in several stages starting from penicillin V which can be taken as an example of this access route. Penicillin V is transformed into its sulfoxide which rearranges to cephalosporin under appropriate conditions. i5 The cephalosporin is then deacetylated to 7-ADCA or its ester, and reacetylated to cephalexin by various methods which have been described. The need to protect the amine and / or acid functions and subsequently to remove the protecting groups during some of these operations adds to the number of steps required, and therefore increases the cost of this process. Another useful route is to react penicillin sulfoxide with a mercaptan, which leads to a disulfide - azetidinone. Analogous sulfenamides are obtained by heating the sulfoxide in the presence of a silylated amide, or by treating the asymmetric azetidinone disulfide with a suitable amine. By chlorination or bromination by various reagents, these compounds give 2-chloro- (or bromo) methylpenam or 3-chloro- (or bromo) cephames, the compounds being able to transform into each other. These 3-chloro- (or bromo) cephames are also prepared either by heating a penicillin sulfoxide in the presence of a chloride or a bromide, or from 3-hydroxycephame. The chloro- or bromocephames can be dehydrohalogenated to the respective cephemas by methods which are described in the literature, and these cephemas can in turn be deacetylated by known methods into 7-ADCA and its derivatives, which are the products of departure of certain commercial cephalosporins. Unfortunately, when the dehydrohalogenation of the known 3-chloro- and 3-bromocephams is carried out, the biologically inactive A2-cephems are also formed, and this implies either that the A2-cephem is transformed into the active A3-cephem by a series of reactions, which raises the cost of the desired A3-cephemas, that is to say that the mixture of A2- and A3- is separated, which also causes a reduction in the yield. Accordingly, it would be highly desirable to produce a halogenated cephalic derivative which does not have the disadvantages of the 3-chloro- or 3-bromocephames of the prior art.