CH615185A5 - Process for the preparation of novel cephalosporin analogues - Google Patents

Description

The invention relates to a process for the preparation of 30 new compounds of the formula I.

2nd

35

40

(I),

(HD,

C ^ CH2-CH = CH2

rls ^ \ Ii

R COOK

wherein

Z> S or> S- * 0 in the a or ß configuration;

R1 is a free or protected amino group;

R4 is hydrogen or a carboxyl protecting group;

45 R5 represents a hydrogen atom, an acyl group or a protected carboxyl group; and

R8 is hydrogen or a 7a lower alkyl or 7a lower alk

oxy grappe mean.

so The cephalo-sporin analogues mentioned in the present description are generally referred to with reference to "Cepham" (J.A.C. p. 84 (1962) 3400); the term "cephem" refers to the cephem skeleton with a double bond.

ss The new compounds are similar to those in «Cephalosporins and Penicillins-Chemistry and Biology, Ed. E. H.

Flynn, Academic Press, described valuable intermediates for the production of cephalosporin antibiotics. If, for example, compounds of the formula I, 60 in which R5 is hydrogen and Z> S, are treated with acid, followed by oxidation and reduction, then one takes place Rearrangement of the exocyclic double bond in the 2-position to the 3,4-position with a single carboxyl group in the 4-position, thereby producing active antibiotic compound 65 fertilizers.

If R5 is an acyl group or blocked carboxy group, this group can be removed during or before the introduction of the 3,4-double bond.

3rd

615185

The compounds of formula I are prepared according to the invention by using a compound of formula II

(II),

COOR

wherein X is halogen with the exception of fluorine, is subjected to an elimination reaction with elimination of hydrogen halide.

If Z is sulfur, the elimination of a halogen atom X can result in an episulphonium compound that can react rapidly with nucleophilic species that may be present. In order to prevent the formation of the episulphoium ion, it may be preferred to carry out the elimination on a compound in which Z has the meaning of SO.

The elimination of a halogen atom X can be carried out, for example, using an organic or inorganic base. Organic bases include tertiary bases, e.g. B. pyridine bases, triethylamine and other trialkylamines, l, 5-diazabicyclo- (4,3,0) -non-5-ene, 1,5-diazabicyclo- (5,40) -undec-5-ene and quaternary Ammonium bases, such as tetra-alkyl or aralkyl-trialkylammonium hydroxides, e.g. B. tetra-n-butylammonium hydroxide or N-benzyl-N, N, N-trimethylammonium hydroxide. The quaternary bases can be used in aqueous solution. Inorganic bases include, for example, alkaline earth metal and alkali metal hydroxides, alkoxides or carbonates. This elimination reaction is advantageously carried out in the presence of a water-miscible solvent, such as dimethylformamide, dioxane or tetrahydrofuran, but if desired, water-immiscible ethers and amides can be used as solvents. If the base is a liquid, e.g. B. pyridine, an additional solvent may not be necessary.

The elimination reaction can be carried out, for example, at a temperature of from -50 ° C. to the boiling point of the solvent used. The reaction is expediently carried out at room temperature for about 15 minutes. The course of the reaction can be followed by thin layer chromatography.

If one starts from a compound of the formula II in which R5 denotes a protected carboxyl group or an acyl group, it is necessary, if this group is to be retained in the end product, to carry out the elimination reaction under controlled or controlled conditions, since it is, for example, Use of excess base can lead to the protected carboxyl group or the acyl group being split off, as a result of which compounds of the formula I in which R5 is hydrogen are formed.

On the other hand, if, starting from compounds of the formula II in which R5 is a protected carboxyl group or an acyl group, a compound of the formula I in which R5 is hydrogen is to be prepared, the removal of R5 can be carried out by treatment with a base. In general, the base can be of the type specified above for the elimination of X. An acyl group can be removed particularly effectively by treatment with barium hydroxide. Blocked carboxyl groups, if these are esters, can also be cleaved by treatment with a nucleophile in an anhydrous aprotic solvent, for example an alkali metal halide, a thiol or an azide in tetrahydrofuran or dimethyl sulfoxide or hexamethylphosphoramide or dimethylformamide. Such removal can be done before, during or after the elimination or replacement or displacement of X. Such decarboalkoxylations can be carried out using quaternary ammonium hydroxides in aqueous or alcoholic solvents such as aqueous DMF.

If the compound of the formula I is to carry a 7a-alkoxy-substituted-dene, this can be present in the compound of the formula II is or after the elimination of HX, for example by treatment at low temperature with a tertiary alkyl hypochlorite in a solvent, such as a cyclic ether, e.g. B. tetrahydrofuran in the presence of a suitable lithium alkoxide. The compounds of the formulas I and II can have one or more asymmetric or geometrically isomeric centers and therefore exist in many cases in the form of geometric and / or chiral isomers, which can often be separated, for example by chromatography or crystallization.

The starting compounds of formula II can be prepared by using a compound of formula III

30th

R

(III),

wherein

R is hydrogen or an organic group having 1 to 20 carbon atoms; and

R9 and R10 either together form a carbon-nitrogen bond; or

R9 is hydrogen or an organic group of 1 to 20 carbon atoms; and

R10 is hydrogen or an amino protecting group, reacted with a molecular halogen with the exception of fluorine or a corresponding N-halogenamide in the presence of at least one equivalent of a protic solvent.

Halogen amides are preferably N-iodosuccinimide, N-bromoacetamide or N-bromosuccinimide. Water is preferably used as the protic solvent. In addition to the protic solvent, other solvents such as a dialkyl sulfoxide, e.g. B. dimethyl sulfoxide; an amide solvent, e.g. B. a dialkylamide solvent such as N, N-dimethylacetamide or N, N-dimethylformamide; a 65 lower alkanol, e.g. B. ethanol; a lower aliphatic nitrii, e.g. B. acetonitrile; a cyclic ether, e.g. B. tetrahydrofuran or dioxane; or a lower fatty acid, e.g. B. acetic acid. The temperature is expediently from -50 to

615185

4th

+ 150 ° C, preferably 0 to 120 ° C. The reaction is desirably carried out under acidic conditions and it is convenient to bring the medium to an apparent pH of about 3.0, e.g. by adding phosphoric acid, sulfuric acid or acetic acid. The course of the reaction can be followed by thin layer chromatography. If the molecular halogen used is iodine and there is a relatively high concentration of water, it may be desirable to carry out the reaction in the presence of potassium iodide to accelerate the dissolution of the iodine.

In thiazoline compounds of the formula III, R9 and R can each represent, for example, a methyl group.

If the compound of formula III is a compound in which R9 and R10 together form a carbon-nitrogen bond, e.g. B. a thiazoline, the use of an alcohol as a protic solvent generally leads to an imino ether group in the 7-position, which can be hydrolyzed in the aqueous work-up to the desired -NHCOR group; normally water gives the group -NHCOR directly. In certain cases, e.g. B. in the absence of water, such an imino ether can be cleaved to form a compound in which R1 has the meaning of NH2.

If the compound of formula III is a compound in which R9 and R10 have no carbon-nitrogen bond, i. H. is a thiazolidine, the starting product of the formula II is a Schiff base, which is normally hydrolyzed to form a corresponding compound in which R is a free amino group. It can be seen that the exact nature of groups R9 and R10 in thiazolidine compounds is not so important since these groups do not appear in the end product.

Use of the above procedures, which leads directly to compounds of formula II, wherein R1 is an amino group, allows selective, blocked amino groups to be introduced without the need to remove an existing blocking group.

If Z is to have the meaning of SO, the original cyclization product can be subjected to oxidation, as described, for example, by Cocker et al., J. Chem. Soc., 1965, 5015, using a peracid, such as peracetic acid, monoperphthalic acid, m - Chloroperbenzoic acid or metaperiodic acid. The oxidation is preferably carried out at a temperature not exceeding 10 ° C., an excess of oxidizing agent being avoided in order to minimize the formation of sulphone.

If a 7 a-alkoxy compound is desired, the alkoxy group can be introduced, for example, by the hypochlorite method described above.

Compounds of the formula III can be prepared, for example, by methods which are analogous to those described in Belgian patent 770 731, e.g. B. by reacting a compound of formula IV

'H

(iv)

COOR4 Y-C-CH2-CH = CH2 Rs

(V),

wherein Y is an eliminable substituent, such as a halogen atom, or a hydrocarbon sulfonyloxy group, e.g. B. represents a tosyloxy or mesyloxy group. Examples of suitable alkylation reagents include t-butyl-2-bromo-hex-4-enoate, t-butyl-2-bromopent-4-enoate and t-butyl-2-bromo-5-pheny! Pent-4-enoate. It is possible, through the alkylating agent initially used, only a part of the desired group

15

COOR4 -C-CH2-CH = CH2

20th

R5

with a suitable alkylating agent, e.g. B. a compound of formula V.

to introduce, the rest of the group being introduced in a subsequent reaction. For example, the compound of formula IV can originally be reacted with a bromalonate-25 diester, and the resulting product can then be reacted with an allylating agent such as allyl bromide. The alkylating or allylating agent may be a bromide, as in the specific examples mentioned above, another halide, e.g. B. a chloride or 30 iodide, or a reactive ester such as a hydrocarbon sulfonate ester, e.g. A tosylate or mesylate. The malonyl derivatives can be decarboalkoxylated before cyclization.

Preferred is the compound of formula IV, a compound in which R9 and R10 together form a carbon-nitrogen bond; the resulting thiazoline of formula III can then, if desired, be reduced to a thiazolidine.

The alkylation and allylation reactions are conveniently carried out in the presence of a base which is suitable for deprotonating the β-lactam nitrogen atom, for example an alkali metal carbonate, hydride, amide or silylamide, e.g. B. a sodium or potassium derivative. The solvent is preferably polar or can be, for example, a ketone, e.g. B. acetone or methyl ethyl ketone; a cyclic ether such as dioxane or tetrahydrofuran or an amide, imide or hydantoin solvent such as N, N-dimethylformamide or N, N-dimethylacetamide. If a carbonate base is used, some water is preferably present.

The compounds of formula III can have one or more asymmetric or geometric isomeric centers, and the compounds of formula III can thus exist as diastereoisomers and / or geometric isomers. It has been found that in general one diastereoisomer gives the cyclization reaction better than the other, and it is preferred to separate the isomers, e.g. B. by conventional decomposition techniques, and by a previous cyclization test to determine which is the preferred isomer. 60 The less potent isomer can usually be treated with a base, e.g. B. Potassium butoxide in aqueous t-butanol at 0 to 120 ° C, and solvents can often be chosen so that they bring about the selective crystallization of the desired isomer in order to achieve an essentially complete conversion of the desired isomer .

If the group R1 in one of the above formulas is a blocked amino group, this is expediently an acyl group

amido group RCONH, e.g. B. with 1 to 21 carbon atoms, in particular that of a penicillin obtained by a fermentation process, for. As phenylacetamido or phenoxy-acetamido, since compounds of the formula II can be derived from such a penicillins by a sequence of reactions.

If a 7β-acylamido compound which does not have the desired acyl group is obtained as the product of the formula I, the 7β-acylamido compound can be N-deacylated to form the corresponding 7β-amino compound and the latter can be acylated with a suitable acylating reagent.

Suitable methods for the N-deacylation of cephalosporo derivatives with 7β-acylamido groups are described, for example, in British Patents 1,041,985; 1,119,806; 1 227 014; 1,239,814; 1 244 191 and 1 241 655. Another method for N-deacylation that can be used is acid catalysis, e.g. B. a phenoxyacetyl group. For example, N-demformylation of a 7β-formamido group can be carried out using a mineral acid, as described in British Patent 1,290,327, or using a Lewis acid, as described in British Patent 1,321,265.

Alternatively, enzymatic N-deacylation methods can be used instead of chemical methods, and N-acyl groups can be exchanged by enzymatic treatment, for example as described in British Patents 1,313,990 and 1,324,159.

The 7 ß-amino compound can be used as an insoluble salt, e.g. B. a hydrochloride, or a hydrogen p-toluenesulfonate, or it can be precipitated by adjusting the pH (z. B. to an isoelectric point) and - if necessary - extracted with a suitable solvent. The 7β-amino compound can then be recycled. The renewed acylation can then be carried out with the desired acylating agent.

In addition, as noted above, the cleavage of a compound of Formula III can in some cases result in a 7β-amino compound of Formula II which, if desired, is acylated again. A variety of acylating agents for use in the cephalosporin field have been described in the literature.

If the 7β-acylamido group contains an amino group, it is generally necessary to protect it during the various reaction stages. The protective group is expediently a group which can be removed by hydrolysis without influencing the rest of the molecule, in particular the lactam and 7β-amido compounds. Such protecting groups are also suitable meanings for Ri0. The amine protecting group (s) and any carboxyl blocking group in the 4-CQQH position can be removed with the same reagent. An advantageous method is the removal of amine protecting groups and carboxyl blocking groups in the last stage of a preparative reaction sequence.

Amine protecting groups which are suitable as a substituent R10 or for protecting the 7β-amino group or an amino group in the 7β-acylamido chain can be mono- or divalent suitable groups, including acyl groups, for example low-alkanoyl, such as acetyl, substituted lower-rig-alkanoyl such as chloroacetyl, aryl-lower alkanoyl such as phenylacetyl and aroyl such as benzoyl or phthaloyl; lower alkoxycarbonyl such as isobutyloxycarbonyl or t-butyloxycarbonyl and substituted lower alkoxycarbonyl such as 2,2,2-tri-chloroethoxycarbonyl; Aryl-lower alkoxycarbonyl, such as benzyloxycarbonyl or diphenylmethoxycarbonyl; Cycloalkyloxycarbonyl, for example 1-adamantyloxycarbonyl; Sulfonyl, for example lower alkylsulfonyl, such as methanesulfonyl

615185

and arylsulfonyl such as p-toluenesulfonyl; Sulfenyl, for example o- or p-nitrophenylsulfonyl; Arylmethyl, for example trityl; Ylidene groups which have been formed by reaction with aldehydes and ketones which form ship's bases, for example benzaldehyde, salicylaldehyde or acetates-acetate; and divalent groups, so that the nitrogen atom forms part of a dihydropyridine ring, such protective groups being converted, for example, by reaction with formaldehyde and a β-keto ester, e.g. B. acetoacetic ester as described in Belgian patent 771 694 can be obtained. In general, such amine protecting groups can be removed in a conventional manner, depending on the group in question. The monovalent groups listed above are also suitable amine protecting groups for the nitrogen atom in the 4-position in thiazolidine derivatives of the formulas III and IV.

Specific acyl groups which may be present in acylamido groups R1 in the compounds of the formulas I and II are illustrated in the following list, which is not intended to be exhaustive. The list also serves to illustrate possible meanings for R and R9 when these are organic groups with 1 to 20 carbon atoms, since such groups can be regarded as residues of acyl groups RCO or R9CO.

(i) RuCnH2nCO- wherein Ru represents aryl (carbocyclic or heteroey-clic), cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl or a non-aromatic, heteroey-clic or mesoionic group, and n is the meaning of 0 or an integer from 1-4. Examples of these groups include phenylacetyl; Thien-2- and -3-acetyl, 3- and 4-isoxazolylacetyl, each substituted or unsubstituted; Pyridylacetyl, tetrazolylacetyl or a sydnone acetyl group. If n is different from 0, in particular if n has the meaning of 1, the a-carbon atom of the acyl group can be substituted by, for example, a hydroxy, esterified hydroxy (e.g. lower alkanoyloxy such as acetoxy), an amino -, blocked amino (e.g. amino, substituted by any of the blocking groups specified above), hydroxyimino, acyloxyimino (e.g. low alkanoyloxyimino) such as acetoxyimino or halo gene substituted low -Alkanoyloxyimino, such as mono- or dichloroacetoxyimino-) or etherified oxyimino- (e.g. low-rig-alkoxyimino-, such as methoxyimino- or t-butoxyimino-, low-cycloalkyloxyimino-, such as cyclopentyloxyimino- or aryloxyimino-, such as phenoxyimino- )group; Examples of a-substituted acyl groups of this type include 2-hydroxy-2-phenylacetyl, N-blocked 2-amino-2-phenylacetyl and 2- (fur-2-yl) -2-hydroxyiminoacetyl.

(ii) CnH2n + iCO- where n is 0 or an integer from 1-7. The alkyl group can be straight or branched and substituted by e.g. B. a halogen atom, a cyano group, a carboxy group, an alkoxycarbonyl group, a hydroxy group, a blocked amino group or a carboxycarbonyl group (-CO.COOH) or any of these groups wherein the functional group is blocked. Examples of such groups include formyl, glutaroyl, and N-blocked (e.g., N-ethoxycarbonyl) R-5-amino-5-carb-oxypentanoyl.

Rev

I.

(iii) RUZC — CO-

I.

RW

wherein Ru has the meaning defined under (i) and may additionally be benzyl, and Rv and Rw, which may be the same or different, each represent hydrogen, phenyl, benzyl, phenethyl or lower alkyl, and Z is an oxygen or

5

s

10th

is

20th

25th

30th

35

40

4s

50

55

60

65

615185

6

Is sulfur atom. Examples of this group include phenoxyacetyl or pyridylthioacetyl.

Another type of group R1 has the formula -NCH-NR7aR7b, wherein R7a and R7b, which may be the same or different, each represent a hydrocarbon group or hydrogen atom.

It can be seen that it is not necessary for an acyl amido group R1 in a compound of the formula II to be completely inert to the conditions of the various reactions since it can be replaced by a desired acylamido group using the above reactions.

If R5 in the formulas I to III is an acyl group, this is preferably the acyl radical of an aliphatic, aliphatic or aromatic acid which preferably contains 1 to 20 carbon atoms, for example a lower aliphatic acyl group, such as an acetyl group, or a monocyte group. cical aroyl group, such as a benzoyl group.

If R5 and -COOR4 in the formulas I to III are protected carboxyl groups, these expediently comprise ester groups which are formed with an alcohol (aliphatic or ariphatic), phenol, silanol or stannanol; or symmetrical or mixed anhydride groups. Such alcohols, phenols, silanols or stannanols which can be used to esterify a 4-carboxyl group preferably contain no more than 20 carbon atoms. Simple aliphatic or araliphatic alcohols or phenols can be used, e.g. B. alkanols or aralkanols, such as methanol, ethanol or benzyl alcohol. However, it may be appropriate to use groups that can easily be split in a subsequent stage of the reaction sequence.

Easily cleavable ester groups R5 and -COOR4, which may be present in the compounds of formulas I-III, include those given in the list below, which, however, is not intended to be an exhaustive list of possible ester groups.

(i) -COOCRaRbRc, wherein at least one of the radicals Ra, Rb and Rc is an electron donor, e.g. B. p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy or Fur-2-yl. The remaining groups Ril, Rhl and Rc can be hydrogen or organic substituting groups. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.

(ii) -COOCRaRbRc, wherein at least one of the groups Ra, Rb and Rc is an electron attractive group, e.g. B. ben-zoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitrophenyl or cyano. The remaining groups Ra, Rb and Rc can be hydrogen or organic substituent groups. Suitable esters of this type include benzoylmethoxycarbonyl, p-nitro-benzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl.

(iii) -COOCRaRbRc, wherein at least two of the radicals Ra, Rb and Rc are hydrocarbon radicals, such as alkyl, e.g. B. methyl or ethyl, or aryl, e.g. B. are phenyl, and the rest of Ra, Rb and Rc, if any, is hydrogen. Suitable esters of this type include t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenyl-methoxycarbonyl.

(iv) -COORd, wherein Rd is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl or tetrahydropyran-2-yl.

(v) Silyloxycarbonyl groups obtained by reacting a carboxyl group with a derivative of a silanol. The derivative of a silanol is expediently a halosilane or a silazane of the formula

(Re) 3SiD; (R *) 2SiD2; (Re) 3Si.N (R <=) 2; (R =) 3Si.NH.Si (R ^) 3;

(Re) 3Si.NH.CORe; (Re) 3Si.HN.CO.NH.Si (Re) 3; ReNH.CO. NRe.Si (Re) 3; or ReC [OSi (Re>]: NSi (Re) 3,

wherein D is a halogen and the different groups Re, which may be the same or different, are hydrogen atoms or alkyl, e.g. B. methyl, ethyl, n-propyl, iso-propyl; Aryl, e.g. B. phenyl; or aralkyl, e.g. B. benzyl groups. Preferred derivatives of silanol are silyl chlorides, such as trimethylchlorosilane and dimethyldichlorosilane.

If R8 is a lower alkyl or lower alkoxy group, the methyl and methoxy groups are preferred.

The following examples serve to illustrate the invention. All temperatures are given in ° C. Analytical thin layer chromatography, performed on Merck F254 silica gel precoated plates, was used to monitor reactions, the products being determined by UV absorption and staining with iodine vapor. The plates were developed in suitable mixtures of toluene and ethyl acetate. Column chromatography was performed on Merck 0.05 to 0.2 mm silica gel and preparative chromatography plates were performed on Merck silica gel PF254 + 366. The melting points were determined in open capillaries and are not corrected. NMR spectra were measured at 100 MHz. The signals for the coupling constants (given in Hz) were not determined and all integrals were satisfactory.

Preparation of the starting compounds A. t-Butyl- (2 ^, 1 'R, 5' R) -2- [3 '-Benzyl-4', 7 '-diaza-6'-oxo-2'-thiabicyclo- [3 , 2,0] -hept-3'-en-7'-yl] pent-4-enoate 0.22 g (1.0 mmol) (IR, 5R) -3-benzyl-4,7-diaza- 6-oxo-2-thiabicyclo- [3,2,0] -hept-3-ene, 4 ml of N, N-dimethylformamide and 1.2 ml of a 40% solution of N-benzyltrimethylam monium hydroxide in methanol (3 eq .) (Triton B) were at 20 ° C for 5 min. touched. 0.5 ml of t-butyl 2-bromopent-4-enoate was added and the mixture was stirred at 20 ° C. for 30 minutes. The solution was partitioned between 100 ml of ethyl acetate and 60 ml of water, and 2N-hydrochloric acid was added to pH 3. The aqueous layer was extracted with 2 X 50 ml of ethyl acetate and the combined organic layers were washed with 2 X 50 ml of water, the ethyl acetate was removed under reduced pressure and the resulting resinous product was chromatographed on 10 g of silica gel. Elution with a gradient of acetone (0 to 2%) in methylene chloride gave 0.18 g (49%) of the title compound as a semi-crystalline mixture of the diastereoisomers. The analytical sample was prepared by preparative thin layer chromatography; [a] ^ 1-53 °. (c 1,2 dioxane), vmax (CHBn) 1766 (β-lactam), 1728 (ester) and 923 cms. -1 ("CH2), x (CDCb) (indicates 1: 1 mixture of isomers) 2.70 (s; CöHs, 4.13 (d, J4 Hz; 5'-H), 4.40 (add m; 4-H), 4.41 (d, j4 Hz; l'-H); 4.88.4.94 and 4.96 (add. m; 5-H2), 5.69 and 5, 94 (2t, J7Hz; 2-H), 6.12 (s; CH2 CsHs), 7.36 and 7.50 (2t, J7Hz; 3-H2) and 8.57 and 8.59 (2s; t- Bu),

Analysis for C20H24N2O3S (372):

C H N S

Found 64.4% 6.5% 7.4% 8.6%

Calculated 64.5% 6.5% 7.5% 8.6%

By using sodium hydride as the base instead of N-benzyltrimethylammonium hydroxide, the yield rose to 76%.

B. t-Butyl- (2R, 4R, 6R, 7R) -2-iodomethyl-7-phenylacetamido-cepham-4-carboxylate 0.994 g (2.7 mmol) t-butyl- (2ç, l'R, 5 ' R) -2- [3'-benzyl-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

615185

4 ', 7'-diaza-6'-oxo-2'-thiabicyclo- [3,2,0] -hept-3'-en-7'-yl] pent-4-enoate were added with 0.68 g (2.67 mmol) iodine and 1.2 g of potassium iodide in 37 ml of dimethyl sulfoxide, which contained 10 ml of water (the pH was adjusted to 3 with phosphoric acid) and heated to 50 ° C. for 1.5 hours. The mixture was partitioned between 250 ml of ethyl acetate and 200 ml of dilute aqueous sodium thiosulfate solution. The ethyl acetate layer was washed with 2 X 50 ml of water and evaporated. The residue, dissolved in methylene chloride, was applied to a column of 50 g of silica gel, which was eluted with a gradient of acetone (0 to 10%) in methylene chloride. This gave 0.46 g (33%) of the title compound, which was further purified by crystallization from diethyl ether to form an analytical sample of F = 156-157 ° C (dec.); [a] i9 + 208 ° (c 0.86 dioxane), W (ethanol), 253 (e 930), 258.5 (s 930), 264, (e 775), Vmax (CHBn), 3390 (NH) , 1762 (β-lactam), 1728 (ester) and 1676 and 1502 cm-1 (amide), x (CDC13, 2.66 (S; CeHs), 3.60 (d, J9Hz; NH), 4.32 (d, d, J9.4Hz; 7-H), 4.73 (d, J4Hz; 6-H), 5.34 (dd, J6.2Hz; 4-H), 6.38 (S; OEfe- CsHs), 6.6 to 7.0 (addition; 2-H and 2-CH2I), 7.48 and 8.40 (addition m, 3-Ha), and 8.52 (S; t -Bu) /

Analysis for C20H25IN2O4S:

(516,397):

C H I N S

Found 46.5% 5.0% 24.0% 5.35% 6.6% Found: 46.5% 4.9% 24.6% 5.4% 6.2%

If the reaction was carried out in acetonitrile as solvent for 30 min, the yield could be increased to 47%.

C. Ethyl- (2 |, l'R, 5'R) -2- [3'-benzyl-4 ', 7'-diaza-6'-oxo-2'-thiabicyclo- [3,2,0] -hept-3'-en-7'-yl] pent-4-enoate

3.12 g (7.5 mmol) of diethyl- (l'-R, 5'R) -2-allyl-2- [3'-benzyl-4 ', 7'-diaza-6'-oxo-2' -thiabicyclo- [3,2,0] -hept-3'-en-7'-yl] -ma-lonat (Belgian patent 794 659) 75 ml of N, N-dimethylformamide and 5.0 ml of a 40% Solution of tetra-n-butylammonium hydroxide in water (7.5 mmol, 1 eq.) were stirred together at 20 ° C. for 1.25 hours. The mixture was partitioned between 1500 ml of ethyl acetate and 1000 ml of pH 3 water. The aqueous layer was extracted with 2X500 ml of ethyl acetate and the combined organic layers were washed with 2 X 500 ml of water. The ethyl acetate was removed under reduced pressure to give a resinous product which was purified by preparative thin layer chromatography. Elution with ethyl acetate: toluene = 4: 6 gave 0.96 g (30.7%) of the starting material and 1.025 g (39.7%) of the title compound. An analytical sample of the latter was obtained by further preparative thin layer chromatography; [a] î> 9 -66.1 ° (c = 0.7 dioxane), Vmax) (CHBn) 1760 (ß-lactam), 1730 (ester) and 920 cms.-1 (= CH2), x (CDCb ) 2.66 (SjCsHs), 4.01 (d, J5H; 5'-H), 4.13 (d, J5Hz; l'-H), 4.36 (addition; 4-H), 4.93 and 4.97 (2d, J17 and 10Hz; 5-H2), 5.54 addition; 2-H), 5.78 (q, J7Hz; CH2CH3), 6.09 (S; CH2 CeHs), 7.2 to 7.5 (addition; 3-H2) and 8.71 (t, J7Hz; CH2CH3).

Analysis for C18H20N2O3S, V2H2O (353.4):

C H N S

Found: 61.9% 5.9% 7.9% 9.1%

Calculated: 62.1% 5.9% 7.9% 9.1%

D. (2R, 6R, 7R) -4,4-diethoxycarbonyl-2-iodomethyl-7-phenylacetamidocepham 1.063 g (2.55 mmol) of diethyl- (l'R, 5'R) -2-allyl-2- [ 3'-ben-zyI-4 ', 7'-diaza-6'-oxo-2'-thiabicyclo [3,2,0] -hept-3'-en-7'-yl) malonate were obtained with 650 mg (2.55 mmol, 1 eq.) iodine in 37 ml dimethyl sulfoxide and 10 ml water containing 1.2 g potassium iodide, stirred at 50 ° C for 0.5 hours. The mixture was lowered to pH 3 by dropwise addition of phosphoric acid, and stirring was continued at 50 ° C for 2 hours. The mixture was partitioned between 800 ml of ethyl acetate and 800 ml of water. The organic layer was washed with 2 x 400 ml of water and the ethyl acetate was removed under reduced pressure to give a resinous product which was chromatographed on 30 g of silica gel. Elution with a gradient of ethanol (1 to 5%) in chloroform gave 1.00 g (68.6%) of the title compound. Further purification by preparative thin layer chromatography and elution with ethanol: chloroform = 2:98 gave 0.701 g (48.1%) of the title compound in the form of an isomer as a foam, [a] £ 9 + 239 ° (c = 0.7) , (Dioxane, ■ umax (CHBn), 3380 (NH), 1774 (ß-lactam), 1746 and 1738 (ester), and 1678 and 1502 cms. * 1 (amide), x (CDCb), 2.68 ( S; CeHs), 3.34 (d, J9Hz; NH), 4.24 (dd, J9.5Hz; 7-H), 4.63 (d, J5Hz; 6-H), 5.68 [q, J7Hz; (CH2CH3) 2], 6.39 (S; CHaCeHs), 6.72 (addition; CH2I), 7.02 (addition; 2-H), 7.26; and 8.04 ( m; 3-H2) and 8.69 [t, J7Hz; (CH2CH3) 2],

C21H25IN2O6S (560.41):

C H I N S

found 45.4% 4.6% 21.1% 4.2% 6.1%

calculated 45.0% 4.5% 21.1% 5.0% 5.7%

E. t-Butyl-2e, 4E, rR, 5'R) -2- [3'-benzyl-4 ', 7'-diaza-6'-oxo-2'-thiabicyclo- [3,2,0] -hept-3'-en-7'-yl] hex-4-enoate 2.40 g (11 mmol) (IR, 5R) -3-benzyl-4,7-diaza-6-oxo-2-thiabicyclo - [3,2,0] -hept-3-ene, 44 ml of N, N-dimethylformamide and 495 mg (as an oil dispersion, 11.8 mmol) of sodium hydride were stirred at 20 ° C. for 15 min. 4.4 ml (1.5 eq.) Of t-butyl-2-bromohex-4-enoate, prepared as described under I, were added and the mixture was stirred at 20 ° C. for 20 min. The mixture was poured into 1000 ml of ethyl acetate and 1000 ml of pH 3 water. The aqueous layer was extracted with 2 X 200 ml of ethyl acetate and the combined organic layers were washed with 2 X 200 ml of water. The ethyl acetate was removed under reduced pressure and the resulting resinous product was chromatographed on 100 g of silica gel. Elution with a gradient of acetone (0 to 10%) in methylene chloride gave 3.57 g (84%) of the title compound in the form of a resinous product (mixture of the Z and E isomers, [a] § $ 9-64, 9).

(c 0.147, dioxane), umax (CHBB) 1758 (β-lactam), 1722 (ester) and 964 cm-1 (ECH = CH), x (CDCb) showed (2R: 2S = 11: 9), 2, 68 (s; CeHs), 4.04 (d, J4Hz; 5'-H, 2S isomer), 4.10 (d, J4Hz; 5'H, 2R isomer), 4.14 (d, J4Hz; l'H-2S isomeres), 4.39 (d, J4Hz; l'-H, 2R isomer), 4.3 to 4.9 (add. m - CH = CH-CHs), 5 , 70 (t, J7Hz; CH-CChtBu, 2S isomer), 5.94 (t, J7Hz; CH-CC> 2tBu, 2R isomer), 6.01 and 6.22 (2d, branches, AB -Quartet.J16Hz; -CH2-C6H5, both isomers), 7.40 (t, J7Hz; -CH-CHz-CH 2R isomer, 7.50 (t, J7Hz; -CH-CH2-CH 2S isomer)) , 8.55 and 8.58 (s; t-Bu, both isomers).

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C21H26N2O3S (386.5):

C H N S

found 65.2% 6.8% 7.0% 8.4%

calculated 65.3% 6.8% 7.2% 8.3%

F. t-Butyl- (2 |, 4E, rR, 5'R) -2- [3'-benzyl-4 ', 7'-diaza-6'-oxo-2 "-thiabicyclo- [3,2, 0] -hept-3'-e 8-7'-yl] -5-phenylpent-4-enoate,

Separation into 2 R-2S isomers and conversion of the 2S isomer into the 2R isomer 2.18 g (10 mmol) (IR, 5R) -3-benzyl-4,7-diaza-6-oxo-2 -thia-bicyclo- [3,2,0] -hepte-3-3n, 40 ml of N, N-dimethylformamide and 0.45 g of a 57% dispersion in oil (1.1 eq) sodium hydride were 20 min at 20 ° C stirred. 4.5 ml (1.5 eq.) Of t-butyl-2-bromo-5-phenylpent-4-enoate were added and the mixture was stirred at 20 ° C. for 30 minutes. The solution was partitioned between 1000 ml of ethyl acetate and 1000 ml of pH 3 water. The organic layer was washed with 500 ml of water and 500 ml of saturated saline and then evaporated to dryness. The residue was chromatographed on 200 g of silica gel. Elution with acetone (0 to 25%) and methylene chloride gave 2.32 g (51.9%) of crude product as a semi-crystalline solid. A portion of this residue was recrystallized from ether, giving 0.228 g (5.1%) of the title compound as a 2R isomer of F = 74 to 80 ° C, [a]? | 9 - 66.1 °. (c 0.116, dioxane),

Âmax (ethanol), 343 nm (e 1.930), 293 nm (e 2.060), 283.5 nm (e 2.501) and 251.5 nm (e 17.150), Xmax (CHBr3), 1752 (ß-lactam), 1720 (CO2R) and 960 cm-1 (trans-CH = CH), t (CDCh), 2.68 (s; CeHf,), 3.49 (d, J15Hz; CH = CH), 3.94 (d, t, J15.6Hz: CH = CH), 4.04 (d, J4Hz; 5'-H), 4.11 (d, J4Hz; l'-H), 5.53 (t, J7Hz; -CH- C02tBu), 6.10 and 6.33 (2d,

Branches of the AB quartet J, 15Hz; CHaCeHs), 7.25 (t, J7Hz; -CH2-CH), 8.54 (s; t-Bu).

C26H28N2O3S (448.6):

C H N S

found 69.0% 6.5% 5.8% 7.0%

calculated 69.6% 6.3% 6.2% 7.15%

and 0.118 g (2.6%) of the title compound as the 2S isomer of F = 140 to 141 ° C [a] j | 9-130.0 °. (c 0.055, dioxane), Xmax (ethanol), 293 nm (e 986), 283.5 nm (e 1.410), and 251.5 nm (e 18.100), Vmax (CHBn) 1762 (β-lactam), 1728 (C02R), and 973 cnr1 (CH = CH),

t (CDCb), 2.62 (s; CeHs), 2.68 (mult; = CHCeHs), 3.44 (d, J16Hz; CH = CH), 3.86 (d, t, J16.6Hz; - CH = CH), 4.09 (d, J4Hz; 5'-H), 4.36 (d, J4Hz; l'-H), 5.86 (t, J7Hz; -CH-CO: tBu), 6 , 13 and 6.46 (2d, branches AB-quartet, J16Hz; CHbCsHs), 7.11 (t, J7Hz; -CH-CH2-CH) and 8.54 (s; t-Bu).

C2eH: sN203S (448.6):

C H N S

found 69.0% 6.3% 5.7% 6.9%

calculated 69.6% 6.3% 6.2% 7.15%

5.125 g (11.4 mmol) of the 2S isomer was suspended in 100 ml of almost boiling t-butanol and 0.5 ml of a 40% aqueous sodium hydroxide solution was added. The mixture was stirred at 23 ° C. for 30 minutes and then heated to 100 ° C. for 3 minutes. The resulting solution was allowed to cool to 25 ° C, the base was washed through

Addition of 2n-hydrochloric acid neutralized and the t-butanol was removed under reduced pressure. The residue was partitioned between 500 ml of ethyl acetate and 500 ml of water. The organic layer was washed with 2X250 ml water and evaporated to give an almost white solid. When rubbed with 100 ml of ether, the solid gave 3.3 g (64.5%) of the less crystalline 2R isomer and 1.83 g (35.5%) of the highly crystalline 2S isomer.

G. t-Butyl- (2ç, 4E, l'R, 5'R) -2- [3'-benzyl-4 \ 7'-diaza-6'-oxo-2'-thiabicyclo- [3,2, 0] -hept-3'-en-7 "-yl] -pent-4-enoate, separation of the isomers and conversion of the 2S isomer into the 2R isomer 29.5 g (79.4 mmol) of the mixture of isomers was recrystallized from diisopropyl ether and the supernatant liquid was decanted off, 12.84 g (43.4%) of the title compound in the form of the 2S isomer (crystalline) and 16.67 g (56.4%) of the title compound in the form of the 2R -Isomers (by evaporating the supernatant liquid) (not crystalline) were obtained.

12.4 g (33.3 mmol) of the 2S isomer were stirred with 100 ml of t-butanol and 1 ml of a 40% aqueous sodium hydroxide solution at 20 ° C. for 1 hour. The solution was adjusted to pH 7 by adding 2N hydrochloric acid. The solution was evaporated to dryness and the residue was partitioned between 1000 ml of ethyl acetate and 800 ml of water. The organic layer was removed and evaporated to dryness. The residue was recrystallized from diisopropyl ether to give 4.6 g (37.1%) of the crystalline 2S isomer of the title compound and 7.7 g (62%) of the non-crystalline 2R isomer of the title compound, the x (CDCb) Values showed 5.91 (t, J7.5 Hz; -CH-CChtBu) due to the presence of the 2S isomer and 5.65 (t, J7.5 Hz; -CH-CO02tBu) due to the presence of the 2R isomer.

H. t-Butyl- (4E) -2-bromo-5-phenylpent-4-enoate 80 ml (0.5 mol) of t-butylacetoacetate were mixed with 22.5 g of a 57% oily dispersion of sodium hydride, which was used once Washed petroleum ether (1.1 eq.) In 1100 ml of tetrahydrofuran at 20 ° C for 1.5 hours. 100 g (0.5 mol) of cinnamyl bromide was added and the mixture was stirred at 28 ° C to 30 ° C for 20 hours. The solvent was removed under reduced pressure and the residue was partitioned between 1500 ml of ethyl acetate and 1500 ml of pH 3 water. The aqueous layer was extracted with 2X500 ml of ethyl acetate and the combined organic phases were washed with 500 ml of water and 500 ml of saturated saline. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. 100 ml of benzene was added and the solution was evaporated to dryness to give crude t-butyl (4E) -2-acetyl-5-phenylpent-4-enoate. To a solution of the crude product obtained above in 1100 ml of tetrahydrofuran was added 22.5 g (1.1 eq.) Of a 57% dispersion of sodium hydride in oil, which was washed with petroleum ether. The mixture was stirred at 20 ° C for 2 hours. The mixture was cooled to -60 ° C and a solution of 26 ml bromine in 80 ml 1,2-dichloroethane was added. The mixture was stirred for 5 min at -60 ° C, then the solvent was removed under reduced pressure, and the residue was partitioned between 1000 ml of ethyl acetate and 1000 ml of pH 3 water. The organic phase was washed with 500 ml of water and 500 ml of brine, dried over anhydrous sodium sulfate and evaporated to give the crude t-butyl- (4E) -2-acetyl-2-bromo-5-phenylpent-4-enoate. This raw product

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was heated with 1000 ml of ethanol and 170 g (> / 2 mol) of barium hydroxydoxtahydrate in a ball mill for 4 hours at 30 ° C. The mixture was filtered through diatomaceous earth and the cake was washed with petroleum ether. The organic solution was partitioned between 1000 ml of petroleum ether and 800 ml of saturated saline. The saturated saline layer was extracted with 500 ml of petroleum ether, and the combined organic layers were washed with 2 X 500 ml of saturated saline, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was fractionally distilled to give 29 g (18.7%) of the title compound, bp 160 ° C./1 mm. umaX (CHBr3), 1725 and 1250 (ester), 1628 (Ph-CH = CH—), 1395 and 1370 (t-Bu), 964 (trans-CH = CH-) and 750 and 740 cm (CeHs), A (CDCb) 2.5 to 2.9 (s; CeHs), 3.49 (d, J16Hz; CeHsCH =), 3.93 (d, t, J16.6Hz, CH = CH), 5.82 (t , J7.5Hz; -CH-COOtBu), 6.9 to 7.3 (combined; = CH-CH2-) and 8.54 (s; tBu).

I. t-Butyl- (4E) -2-bromohex-4-enoate

98 ml (0.59 mol) of t-butyl acetoacetate, 1300 ml of tetrahydrofuran and 25 g (1 eq.) Of a 57% oily dispersion of sodium hydride, which was washed with petroleum ether, were stirred at 20 ° C. for 1 hour. 100 g of crotyl bromide (0.59 mol, commercially available 80% pure) was added and the mixture was stirred at 20 ° C. for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between 1000 ml of ethyl acetate and 1000 ml of pH 3 water. The aqueous layer was extracted with 2 X 500 ml of ethyl acetate and the combined organic layers were washed with 500 ml of water and 500 ml of saturated saline. The ethyl acetate was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in 100 ml of benzene and evaporated to give crude t-butyl- (4E) -2-acetyl-hex-4-enoate, x (CDCb), 4.1 to 4.9 (add. ; CH = CH), 6.64 (t, J7.5Hz; CH-COztBu), 7.3 to 7.7 (combined; CH2-CH =), 7.81 (s; CH3CO), 8 , 37 (d, J5Hz; CH3-CH =) and 8.53 (s; t-Bu).

The above crude product was stirred with 25 g (1 eq.) Of a 57% oil dispersion of sodium hydride, which was washed with petroleum ether, in 1300 ml of tetrahydrofuran at 20 ° C. for 1 hour. The mixture was cooled to -30 ° C. and a solution of 31 ml of bromine in 100 ml of 1,2-dichloroethane was added. The mixture was stirred at -30 ° C for 5 min. The solvent was removed under reduced pressure and the residue was partitioned between 1000 ml of ethyl acetate and 800 ml of water. The organic layer was washed with 500 ml of water and 500 ml of saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml of benzene, and the resulting solution was evaporated to give crude t-butyl (4E) -2-acetyl-2-bromohex-4-enoate.

A (CDCb) 4.1 to 4.9 (addition; CH = CH), 7.12 (d, J5Hz; = CH-CH2), 7.63 (s; CHaCO), 8.33 (d, J5Hz; CHsCH) and 8.52 (s; t-Bu).

The above crude product was treated with 1000 ml of ethanol and 200 g (0.6 mol) of barium hydroxide octahydrate in a ball mill at 25 ° C. for 3 hours. The mixture was filtered through diatomaceous earth and the cake washed with petroleum ether. The organic layer was washed with 500 ml of saturated saline, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was fractionally distilled to give 50 g (34%) of the title compound, bp 65-85 ° C / l mjn. x (CDCb) 4.1 to 5.0 (addition; CH = CH), 5.94 (t, J7Hz; CH2-CH), 733 (addition; CH2-CH), 8.35 ( d, J5Hz; CHa) and 8.53 (s; t-Bu).

J. t-Butyl- (2R, l'R, 3'ì;, 5'R) -2- (3'-benzyl-4 ', 7'-diaza-6'-oxo

2'-thiabicyclo- [3,2,0] -hept-7'-yl-pent-4-enoate 2 g (5.36 mmol) t-butyl- (2R, l'R, 5, R) -2 - (3'-benzyl-4 ', 7'-diaza-6'-oxo-2'-thiabicyclo- [3,2,0] -hept-3'-en-7'-yl) -pent-4- enoat (19a) were stirred with aluminum amalgam (made from 4 g of aluminum powder by treatment with mercury II chloride solution, followed by washing with water, ethanol and ether) in 150 ml of THF at 19 to 22 ° C. 2.5 ml of water was gradually added over 4 hours to maintain light foaming. The mixture was filtered through a plug of diatomaceous earth and evaporated to a partially crystalline oil. This was chromatographed on 100 g of silicon dioxide gel, the column being eluted with a gradient of acetone (0 to 10%) in methylene chloride, and 1.67 g (83%) of the title compound being obtained. An analytical sample was obtained by recrystallization from aqueous ethanol, F = 92-95 ° C, -90 °. (c 0.18, dioxane), Umax (CHBrc), 3430 (NH), 1750 (ß-lactam), 1720 (ester), 904 (= CH2) and 730 cm-1 (phenyl), x (CDCb), 2.76 (s; CeHs), 4.30 (addition; 4-H), 5.32 (d, J4 Hz) and 4.93 (veiled) (1'-H and 5'-H) 4 , 98 and 5.02 (2d, 5-H2), 5.34 (m; 3'-H), 5.77 (dd, J9, 6 Hz; 2-H), 6.62 (dd, J 14 , 4Hz) and 6.92 (dd, J14.7Hz) CH2 CeHs), 7.38 (add. 3-H2). 8.00 (broad s; NH), 8.60 (s; t-Bu).

C20H26N2O3S (374.4):

C H N S

found 64.0% 7.0% 7.25% 8.7%

calculated 64.2% 7.0% 7.5% 8.6%

K. t-Butyl-2R, 4R, 6R, 7R) -2-iodomethyl-7-phenylacetamido

cepham-4 'carboxylate 374 mg (1 mmol) t-butyl- (2R, l'R, 3'§, 5'R) -2- (3'-benzyl-4', 7'-diaza-6 ' -oxo-2'-thiabicyclo- [3,2,0] -hept-7'-yl) -pent-4-eonate were mixed with 1.75 ml of acetic acid, 1.75 ml of water and 7.4 ml of an ethanolic iodine solution containing 376 mg (1.5 mmol) of iodine was stirred at 23 ° C for 1.5 hours under nitrogen. The mixture was evaporated to an oil, dissolved in 50 ml of ethyl acetate and washed with aqueous sodium metabisulfite solution, pH 8 water and water and evaporated to a yellow, resinous product. This resinous product was dissolved in 7 ml of acrylonitrile and stirred at 0 ° C with 0.5 ml of pyridine and 0.5 ml of phenylacetyl chloride. After 10 minutes the mixture was warmed to 24 ° C. and stirred at this temperature for 1.5 hours. The mixture was evaporated, carefully pumped off and then partitioned between 70 ml of ethyl acetate and 70 ml of pH 8 water. The ethyl acetate solution was washed with water, evaporated to an oil and chromatographed on 25 g of silica gel. The column was operated with a gradient of acetone (0 to 10%) in methylene chloride, which eluted 260 mg of the crude product. This was dissolved in ether and gave a precipitate of white crystals of the title compound (52 mg, 10%) of F = 161-162.5 ° C (dec.). (Standard and mixed melting point = 161-162.5 ° C with decomposition); the thin layer chromatogram was the same as that of the standard; the IR and NMR spectra showed contamination with a closely related compound, possibly a 2-chloromethyl cephan.

L. t-butyl- (2R, 4R, 6R, 7R) -2-iodomethyl-7-phenoxyacetamido

cepham-4-carboxylate 561 mg (1.5 mmol) t-butyl- (2R, l'R, 3 '^, 5'R) -2- (3'-benzyl-4', 7'-diaza-6 '-oxo-2'-thiabicyclo- [3,2,0] -hept-7'-yl) pent-4-enoate were treated with 600 mg (1.5 eq.) iodine in 11 ml of ethanol, 2.7 ml acetic acid and 2.7 ml water 1.75 hours at 21 ° C and 0.75

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Stirred for hours at 50 "C. The mixture was evaporated to a resinous product, dissolved in 100 ml of ethyl acetate and washed successively with sodium metabisulfite solution, sodium bicarbonate solution and water. After drying over magnesium sulfate, the solution was evaporated to a resinous product. This was evaporated into 10 ml of 1,2-dichloroethane was dissolved and stirred with 225 mg (1.5 mmol) of phenoxyacetic acid and 310 mg (1.5 mmol) of DL-N, N'-dicyclohexylcarbodimide at 20 ° C. The mixture was passed through a column Filtered with 25 g silica gel and eluted with acetone (10%) in methylene chloride to give the crude product contaminated with a product, which is likely to be N, N-dicyclohexylurea, which was leached with ether to give 558 mg of a resinous product This was applied to preparative plates (4X20X20 cm) which were developed twice with 30% ethyl acetate in toluene to give 126 mg (16%) of the title compound as a foam.

+ 102 ° (c 0.14, dioxane), i) max (CHBn), 3670 (H2O). 3340 (NH), 1768 (ß-lactam), 1728 (ester), 1688 and 1520 (amide) and 751 cm-1 (phenyl), x (CDCb) 2.6 to 3.2 (add.; CeHs) , 3.08 (d, J 10 Hz; NH), 4.24 (dd, J 10.4 Hz; 7-H), 4.68 (d J 4 Hz; 6-H), 5.29 (dd , J 6.2Hz; 4-H), 5.46 (s; CH2O CeHs), 6.6 to 7.0 (combined; 2-H and 2-CH3), 7.40 and 8.30 ( Addition; 3-H2), 8.50 (s; t-Bu) and 8.2 to 3.9 (indicates some dicyclohexylurea - DCU),

C20H25IN2O5S (0.3MDCU (600.2):

C H I N S

found 48.2% 5.0% 21.1% 5.1% 6.4% calculated 47.9% 5.4% 21.1% 6.0% 5.4%

example 1

t-Butyl- (4R, 6R, 7R) -2-methylene-7-phenylacetamidocepham-4-carboxylate

0.40 g (0.775 mmol) of t-butyl (2R, 4R, 6R, 7R) -2-iodomethyl-7-phenylacetamido-cepham-4-carboxylate were mixed with 0.55 ml of a 40% tetra-n-butylammonium hydroxide solution in water (1 eq.) in 12 ml of N, N-dimethylformamide for 15 min at 20 ° C. The solution was adjusted to pH 4 with 2N hydrochloric acid. The N, N-dimethylformamide solution was distributed between 100 ml of ethyl acetate and 100 ml of water adjusted to pH 3 using 2N hydrochloric acid. The aqueous layer was extracted with 2 X 50 ml of ethyl acetate and the combined organic layers were washed with 2 X 50 ml of water. The ethyl acetate was removed under reduced pressure to give a yellow solid which was chromatographed on 15 g of silica gel. The mixture was eluted with a gradient of acetone (0 to 5%) in methylene chloride, giving 0.22 g (74%) of the title compound of F = 13 8-141 ° C.

[a] j, ° + 258 ° (c 0.6, dioxane), Âmax (ethanol) 244 nm (e 4,100), Vmax (CHBn) 3390 (NH), 1766 (ß-lactam), 1730 (ester) and 1678 and 1510 cm-1 (mid.), T (CDCb) 2.64 (S; CeHs), 3.54 (d,

J9Hz; NH), 4.38 (dd, J9.4Hz; 7-H), 4.54 and 4.63 (2S; 2- = CH2), 4.72 (d, J4Hz; 6-H), 5 , 35 (dd, J6.4Hz; 4-H), 6.34 (S; CH2 CeHs), 7.18 and 7.40 (AB part of ABX, Jab 15Hz, Jax 6Hz, Jbx 4Hz; 3-H2 ) and 8.52 (S; t-Bu),

C20H24N2O4S (388.476):

C H N S

found 61.65% 6.2% 7.05% 8.2%

calculated 61.8% 6.2% 7.2% 8.25%

Example 2

(6R, 7R) -4,4-diethoxycarbonyl-2-methylene-7-phenyl-acetamido-cepham and (4§, 6R, 7R) -4-ethoxycarbonyl-

2-methylene-7-phenylacetamidocepham 0.280 g (0.5 mole) (2R, 6R, 7R) -4,4-diethoxycarbonyl-2-iodomethyl-7-phenylacetamidocepham, 16 ml N, N-dimethylformamide and 0.34 ml of a 40% solution of tetra-n-butylammonium hydroxide in water (1 eq.) Were stirred together at 20 ° C. After 5 minutes a further amount of 0.14 ml of a 40% tetra-n-butylammonium hydroxide solution in water was added. The solution was then stirred at 20 ° C. for a further 40 min. The mixture was partitioned between 200 ml of ethyl acetate and 200 ml of pH 3 water. The ethyl acetate was washed with 2 X100 ml of water and then removed under reduced pressure to give a resinous product which was purified by preparative thin layer chromatography. Elution with ethyl acetate: toluene = 3: 7 gave 0.100 g (46.0%) of the 4,4-diethoxycarbonylcepham mentioned in the title in the form of a resinous product.

[a] g> + 329 ° (C 0.9, dioxane), umM (CHBr3) 3400 (NH), 1780 (β-lactam), 1756 and 1746 (ester) and 1684 and 1510 cm1 (amide), T ( CDCb) 2.66 (S; CeHs), 3.48 (d, J9Hz; NH), 4.32 (dd, J9.4Hz; 7-H), 4.54 and 4.62 (2S; 2 = CH2 ), 4.62 (d, J4Hz; 6-H), 5.68 and 5.72 [2q, J7Hz; (CH2CH3) 2], 6.36 (S; CH2C6H5), 6.96 and 7.12 (ABq, J14Hz; 3-H2) and 8.73 [t, J7Hz; (CH2CH3) 2],

C2iH24N20eS (432.5):

C H N S

found 58.6% 5.9% 6.4% 7.0%

calculated 58.3% 5.6% 6.5% 7.4%

and 0.033 g (18.0%) of the 4-ethoxycarbononyl cepham mentioned in the title.

[a] 25589 + 260.7 °, (c 0.13, dioxane), ti (ma> c) (CHBr3) 3390 (NH), 1770 (ß-lactam), 1740 (ester), 1678 and 1510 (amide ) and 912 cms.-1 (= CH2), t (CDCb) 2.63 (S; CeHs), 3.63 (d, J9Hz; NH), 4.36 (dd, J4.9Hz; 7-H) , 4.75 (d, J4Hz; 6-H), 4.57 and 4.62 (2S; 2 = CH2), 5.29 (dd, J6.4Hz; 4-H), 5.75 (q, J7Hz; CH2CH3), 6.32 (S; CH2C6H5), 7.26 (combined; 3-H2) and 3-H2) and 8.71 (t, J7Hz; CH2CH3).

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Claims (9)

615185 PATENT CLAIMS 1. Process for the preparation of new compounds of formula I. 2nd (I) 3 in which is Z> S or> S- »0 in the a or ß configuration; R1 is a free or protected amino group; R4 is hydrogen or a carboxyl protecting group; R5 represents a hydrogen atom, an acyl group or a protected carboxyl group; and 20 R8 is hydrogen or a 7a-lower alkyl or 7a-lower alkoxy group, characterized in that a compound of the formula II (II): COOR wherein X is halogen with the exception of fluorine, is subjected to an elimination reaction with elimination of hydrogen halide. 2. The method according to claim 1, characterized in that one starts from a compound of formula II, wherein Z> S ~ * 0. 3. The method according to claim 1, characterized in that one carries out the elimination reaction with the aid of a base. 4. The method according to claim 1, characterized in that one carries out the elimination reaction in the presence of a water-miscible solvent. 5. Application of the method according to claim 1 to starting compounds of the formula II, wherein Z> S is how you obtain it when you get a compound of formula III wherein R is hydrogen or an organic group having 1 to 20 carbon atoms; and R9 and R10 either together form a carbon-nitrogen bond; or R9 is hydrogen or an organic group of 1 to 20 carbon atoms; and R 1 denotes hydrogen or an amino protecting group, reacted with a molecular halogen with the exception of fluorine or a corresponding N-halogen amide in the presence of at least one equivalent of a protic solvent. 6. Application according to claim 5, characterized in that water is used as the protic solvent. 7. Application according to claim 5, characterized in that one carries out the reaction at a temperature of 0 to 120 ° C. 8. Application according to claim 5, characterized in that one carries out the reaction under acidic conditions. 9. Application according to claim 5, characterized in that one starts from a compound of formula III, wherein R9 and R10 together represent a carbon-nitrogen bond. 25th