DE2042169C2 - 3-bromomethyl cephalosporin sulfoxide ester and process for their preparation - Google Patents

Description

wherein R ^{1 is} a phenylacetamido, D, L-2-bromophenylacetamido, phenoxyacetamide, formamido, 2,2,2-trichloroethoxycarbonylamino or D-2-2 ', 2', 2'-trichloroethoxycarbonylamino - phenylacetamido group and R ² denotes an easily cleavable carboxyl protective group customary in the cephalosporin field, characterized in that a compound of the general formula is used

CH ₃

(D

COOR ²

at a temperature between -40 ° C and + 85 ° C in a hydrocarbon or chlorinated hydrocarbon in the presence of azobisisobutyronitrile or a peroxide or with irradiation with ultraviolet or visible light or with ^ rays with elemental bromine, an N-bromamide, N-bromimide or 1,3,5-tribromo-1,2,4-triazole.

2. The method according to claim 1, characterized in that the brominating agent used is N-bromosuccinimide used.

3. 2,2,2-TrichloroethylO-bromomethyl-T ^ -phenylacetamidocephO-em ^ -carboxylate-tß-oxide.

4. 2,2,2 - trichloroethyl - 3 - bromomethyl - Iß- formamidoceph-S-em ^ -carboxylate-ljÖ-oxide.

5. tert-Butyl-S-bromomethyl-T ^ -formamidoceph-S-em ^ -carboxylate-ljS-oxide.

6. 2,2,2-Trichloroethyl-3-bromomethyl- Iß- [O -2- (2,2,2-trichloroethoxycarbonylamino) -2-phenylacetamido] -ceph-3-em-4-carboxylate-L3-oxide.

7,2,2,2 - ^^ 10 ^ 111x1-3- ^ 01 ™ ^^! -? / - ^^
chlorethoxycarbonylamino) - ceph - 3 - em - 4 - carboxylate-lj8-oxide.

8. 2,2,2-trichloroethyl-3-bromomethyl-7 ./?- (DL-2-bromphenylaeetamido) - eeph - 3 = em · 4 · carboxylate \ β-οχ \ ά.

Chem. Soc. 1962, 84, 3400, and J. Chem. Soc. 1965, 5031) refers to the term "cephem" refers to the basic cepham structure with a double bond.

In US Pat. No. 3,275,626 a general Process for the production of antibiotic substances including cephalosporins described, that consists in the fact that a so-called penicillin sulfoxide under acidic conditions on a

ίο Temperature from about 100 ° C to about 175 ° C. This process converts esters of 6ß-acylamidopenicillanic acid 1-oxides into the analogous esters of 7j? -acylamido-3-methylceph-3-em-4-carboxylic acids. By appropriate choice of reaction conditions, the cephalosporin analogs can be obtained in high yields. Although some of these cephalosporin analogs have strong antibacterial properties, it is desirable that it be possible to convert the resulting cephalosporin analogs containing a 3-methyl group into related compounds containing a substituted 3 -Methyl group contain, to convert. Cephalosporin compounds containing 3-methyl groups can also be obtained by fully synthetic methods, and this also makes it possible to convert them in the same way.

Attempts that have been made to obtain esters of T ^ -acylamido-S-methylceph-S-em ^ -carboxylic acids halogenate, had little success. However, it has been found that the bromination of cephalosporin sulfoxide esters with a methyl group in the 3-position gives the corresponding 3-bromomethyl compounds.

The process according to the invention therefore relates to the production of 3-bromomethyl-cephalosporin sulfoxide esters the general formula

(ID

COOR ²

wherein R ^{1 is} a phenylacetamido, D, L-2-bromophenylacetamido, Phenoxyace.tamido, formamido, 2,2,2-trichloroethoxycarbonylamino or D-2-2 ', 2', 2'-trichloroethoxycarbonylamino - phenylacetamido - Group and R ² denote an easily cleavable carboxyl protective group which is customary in the cephalosporin field, and is characterized in that a compound of the general formula

(D

COOR ²

at a temperature between -40 ° C and + 85 ° C in The invention relates to 3-bromomethyl-cephalosporin- 65 a hydrocarbon or chlorinated hydrocarbon

sulfoxide esters and a process for their preparation. The compounds of this application are in general with reference to Cepham (cf. J. Am.

hydrogen in the presence of azobisisobutyric acid nitride! or a peroxide or under irradiation with ultra- "iolettem or visible light or with y-rays with

elemental bromine, an N-bromamide, N-bromimide or 1,3,5-tribromo-1,2,4-triazole

The acylamido group may not be the desired group in the final product, but this can be achieved by subsequent conversions, which are below to be discribed. It is not necessary that the first acyl group be completely inert as it is through these subsequent conversions can be split off.

Carboxyl blocking groups

There are cephalosporin compounds as an ester with an alcohol or a phenol, which are easily cleaved again at a later stage in the reaction sequence can be used, for example by hydrolysis or reduction. Esters are generally in the solvents for the bromination reactions more soluble than the free acids, and the bromination proceeds easier.

Alcohol and phenol groups which can be easily cleaved off include those which contain electron-withdrawing substituents, for example sulfo groups and esterified corboxyl groups; these groups can subsequently be split off again by alkaline reagents. Benzyl and o-Benzyloxyphenoxy ester groups can be removed again by hydrogenolysis or hydrogenation. A preferred method of removal includes cleavage by acids and groups passing through Acids that can be removed include: adamantyl, tert-butyl, benzylic acid, such as anisyl and the residues of alkanols, the electron donors contained in the α-position, such as Äcylc: - τ, alkoxy, benzoyloxy, substituted benzoyloxy, halogen, alkylthio, Phenyl, alkoxyphenyl, or aromatic heterocycles. It should be noted that some of these groups at the same time can be subject to bromination.

Alcohol residues, which can then easily be split off by reduction, are residues of 2,2,2-trihaloethanol, for example 2,2,2-trichloroethanol, p-nitrobenzyl alcohol or 4-pyridyl methanol. 2,2,2-Trihalogenäthylgruppen can expediently by Zinc / acetic acid, zinc / formic acid, zinc / lower alcohol or zinc / pyridine or can be removed by chromium-II-reagents. p-nitrobenzyl groups can suitably removed by hydrogenation.

If the esterification group is subsequently removed by an acid-catalyzed reaction, so this can be achieved by using formic acid or trifluoroacetic acid (for example together with anisole) or alternatively by using hydrochloric acid (for example as a mixture with acetic acid).

It is particularly preferred to add such compounds in the bromination process of the present invention use a 2,2,2-Trichloräthoxycarbonyl- or contain a tert-butoxycarbonyl group as an ester group.

Other ester groups which can be easily converted to the carboxyl groups include silyloxycarbonyl groups.

Although silyloxycarbonyl groups by reacting the carboxyl group with a silanol in some cases can be formed, it may be better to react the carboxyl group with a derivative of a silanol, for example the corresponding chloride or amine. This is how silyloxycarbonyl derivatives are formed, containing tetravalent silicon radicals, and the silylating agent is conveniently a halosilane or a Silazane of the formula:

RiSiX; RlSiX; RjSi · NR ₂ -; RtSi - NH • SiRj; R ⁴ Si • NH • COR ⁴ ; RjSi NH · CO · NH · SiRj; R ⁴ NH · CO · NR ⁴ - SiR ⁴ or R ⁴ C (OSiRj): NSiRj

in which X denotes a halogen atom and the various R ⁴ groups, which can be identical or different, denote: hydrogen atoms or alkyl groups, for example methyl, ethyl, n-propyl, isopropyl groups; Aryl groups, for example a phenyl group; or aralkyl groups, for example benzyl groups. Some of these compounds may not be particularly stable under the reaction conditions, especially when R ^{4 is} hydrogen for all R ⁴ groups. It is generally preferred that the R ⁴ - Groups are hydrocarbon groups, and preferably the hydrocarbon group should be methyl or phenyl, such as in hexamethyldisilazane (Me ₃ Si) ₂ NH. Examples of suitable silylating agents are:

^2d trimethylchlorosilane,

Hexamethyldisilaxfrfi, Triethylchlorosilane, Methyltrichlorosilane, Dimethyldichlorosilane, Triethylbromosilane, Tri-n-propylchlorosilane, Bromomethyl-dimethylchlorosilane, Tri-n-butylchloride, Methyl diethylchlorosilane, Dimethylethylchlorosilane, Phenyldimethylbromosilane, Benzylmethylethylchlorosilane, Phenylethylmethylchlorosilane, Triphenylchlorosilane, Tri-0-tolylchlorosilane, Tri-p-dimethylaminophenyl-chlorosilane, N-ethyltriethylsilylamine, Hexaethyldisilazane, Triphenylsilylamine, Tri-n-propylsilylamine, Tetraethyldimethyl disilazane, Tetramethyl diethyl disilazane, Tetramethyl-diphenyl-disilazane,

Hexaphenyldisilazane and ^{) (1} hexa-p-tolyl-disilazane.

If one prepares compounds of the formula I with silyloxycarbonyl groups on an industrial scale, it can be advantageous to use silyl chlorides, such as wise Me ₃ SiCl or Me ₂ SiCl ₂ together with a base such as diethylamine, triethylamine, dimethylaniline, quinoline, lutidine or pyridine to use. An advantage that comes from using Verbin fertilize the formula I, wherein the ester group is a SiIyI- oxycarbonyl group means occurs, consists in the process according to the invention in that the ester group is removed under mild conditions and therefore tends to be during the isolation or subsequent reaction stages is removed.

The silyloxycarbonyl group is easily converted into a carboxy group by using the derivative a Excess of a compound or compounds

sets that contain active hydrogen, for example Water, acidified or basic reacting water, alcohols and phenols.

Manufacturing
of the 1-oxides used as starting material

Compounds of the formula I can be prepared by oxidation of a compound of the general formula:

CH,

(HD

COOR ²

Bromination

IO

15th

wherein R ¹ and R ^{2 have} the meanings given above and the dashed lines between the 2-, 3- and 4-positions indicate that the compound can be an A ² - or. ^ - compound or a mixture thereof. This oxidation can be carried out as described by Cocker et al, J. Chem. Soc. 1965,5015. The cephalosporin compound (III) is mixed with the oxidizing agent in an amount such that there is about 1 atom of active oxygen per atom of dihydrothiazine sulfur. The oxidizing agent should preferably be one which is preferably 1 / f-oxide or a mixture of la- and l / - provides oxides, in which the l> S-oxide predominates. Suitable oxidizing agents include metaperiodic acid, peracetic acid, permonophthalic acid, and m-chloroperbenzoic acid. Care should be taken not to use an excess of oxidizing agent as this leads to the formation of 1,1-dioxide.

Compounds of the formula (I) can also be prepared by oxidation of a Ceph-2-em compound a ceph-3-em-l-oxide is formed, as described in the Dutch published patent application no. 69 10 830 is written.

The 1-oxide is advantageously formed at a temperature below +10 ⁰ C, the formation of SUI-fon to keep minimal.

The 1-oxide can be formed in solution in an organic solvent and then after purification be brominated in the resulting solution. Suitable solvents are later brominated in particular, chlorinated hydrocarbons are valuable.

The 1-oxides can be formed from a compound of the formula (ΠΙ) in which R ² = H, and the acid-1-oxide formed can be esterified. Alternatively, a preferred ester of formula (III) can be used for the oxidation step.

55

The bromination of the compounds of the general formula I can be carried out by bromine itself or an N-bromo amide or an N-bromimide can be carried out. The N-bromamide or N-bromimide can contain a cyclic system, wherein the amide or imide bond forms part of the cyclic system. Examples of such N-bromamides include N-bromocaprolactam and examples of such N-bromimides include the 1,3-dibromo-5,5-di-lower alkylhydantoins, for example

65

1,3-dibromo-5,5-dimethylhydantoin,

1,3-dibromo-5-ethyl -5-methylhydantoin,

!, S-dibromo-S-isopropyl-S-methylhydantoin,

N-bromosuccinimide, N-bromophthalimide,
N-bromoacetamide.

Other useful N-bromoamides include N-bromoamides of lower alkanecarboxylic acids; H. N-bromo lower alkanoamides, for example N-bromoacetamide. Another useful brominating agent is 1,3,5-tribromo-1,2,4-triazole. Particularly preferred brominating agents include N-bromosuccinimide and 5,5-dimethyl-1,3-dibromohydantoin, this is because they are readily available.

The various brominating agents require an initiation reaction in order for them to form bromine atoms and suitable ones Initiator systems include azobisisobutyronitrile, peroxides, e.g. benzoyl peroxide, irradiation with ultraviolet or visible light sources, for example mercury arc or tungsten lamps, or by y-rays emitted by Co ^ sources are emitted.

The brominating agent can be added as such or in suspension or in solution in a suitable solvent, ie a solvent in which the starting material dissolves and which is essentially inert under the reaction conditions, for example a hydrocarbon such as benzene or a halogenated hydrocarbon, especially a chlorinated hydrocarbon, for example chloroform, methylene chloride, 1,2-dichlorathane. The brominating agent is added to a solution or suspension of the cephalosporin compound (I) in a halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane or chlorobenzene or a hydrocarbon such as benzene. The bromination can be carried out at temperatures in the range of -40 to +85 ⁰ C, preferably from -20 to +85 ⁰ C, are. The course of the bromination can be followed by determining the consumption of brominating agent and by thin-layer chromatography. The progress of the reaction can also be followed by observing the ultraviolet absorption spectrum or the optical rotation.

The bromination is vorteilhafterwuise carried out by using N-bromosuccinimide as the brominating agent or a dibromohydantoin and the reaction initiated by ultraviolet irradiation at low temperatures, for example from -20 to +10 ⁰ C.

It has been found that the addition of small amounts, for example up to 5% by volume of water or an aqueous Solution or suspension of a weak base, such as an alkali metal or alkaline earth metal salt of a weak one Acid, for example sodium bicarbonate, sodium carbonate, sodium acetate or calcium carbonate, the bromination reaction has a beneficial effect. on in this way the initial times and the reaction times can be reduced, and / or the yield the 3-bromomethyl compound can be increased. The aqueous solution or suspension of the weak base advantageously has a pH of 7 to 11,

The bromination can be carried out in an inert atmosphere will.

The bromination reaction according to the invention can be carried out continuously.

The j-bromomethyl compounds obtained can into other 3-halomethyl compounds, namely the 3-chloro or 3-iodomethyl compounds are, for example, by reaction with a suitable alkali metal halide, for conversion

the bromomethyl compounds into other halomethyl compounds. Such reactions can occur which involve compounds that provide other halide ions.

After the reaction has ended, the 3-bromomethyl compound to be isolated. An advantageous method is that one the resulting reaction mixture with water to remove the by-products such as imides or amides from the brominating agent were formed, washes, and the product is then isolated, for example by concentrating the Solution followed by crystallization of the product or by chromatography. The aqueous solution that the Imide or amide containing it can then be treated with bromine after adding alkali to make the brominating agent to regenerate.

Important compounds of formula (II) include:

2,2,2-trichloroethyl-3-bromomethyl-7y8-phenylacet-

amidocephO-enM-carboxylate-Lfl-oxide, 2,2,2-trichloroethyl-3-bromomethyl-7> 5-formamido-

cephO-eirM-carboxylate-ljo-oxide, tert-butylO-bromomethyl ^ jJ-formamidoceph-

S-em ^ -carboxylate- Lff-oxide, 2,2,2-dichloroethyl-3-bromomethyl-7 / J-phenoxy-

acetamidocephO-em ^ -carboxylate-IjS-oxide, 2,2,2-trichloroethyl-3-bromomethyl-7 / HD-2- (2,2,2-trichloroethoxycarbonylamino) -2-phenylacet-

amido] -ceph-3-em-4-carboxylat-l./J-oxyd, p-MethoxybenzylO-bromomethyl-T / i-phcnylacet-

amidoceph-3-em-4-carboxylate-l ^ S-oxide, tert-butylO-bromomethyl-T ^ -phenylacetamido-

ceph-3-em-4-carboxy lat- lyff-oxide, 2,2,2-trichloroethyl-3-bromomethyl-7> (2,2,2-trichloroethoxycarbonylamino) -ceph-3-em-4-carb-

OxyJat-HJ-oxide,
tert-butyl-S-bromomethyl-T ^ -phenoxy-acetamido-

ceph-3-em-4-carboxylate-l / i-oxide and 2,2,2-trichloroethy! -3-bromomethyl-7 / J- (DL-2-bromo-2-phenylacetamido) -ceph-3-em-4-carboxy! At- Ij3-oxide.

If at any stage the product is a 7 / J acylamido compound which does not contain the desired acyl group, the 7 / J-acylamido compound N-deacylated, the corresponding 7 / S-amino compound and the latter can be acylated with a suitable acylating agent.

Suitable processes for the N-deacylation of cephalosporin derivatives with 7/8 acylamido groups are described in British patents 10 41 985 and 11! 9 806, in Belgian patent 719 712 and in South African patents 68/5048 and 68/5327. Another method of N-deacylation that can be used is acid catalysis. For example, N-Deformylierjng can a 7 / J-formamido group with mineral acid at a temperature of -15 to +100 ⁰ C, preferably +15 to 40 ° C is performed. A suitable reagent for N-deformylation is concentrated hydrochloric acid in methanol, dioxane or tetrahydrofuran. Alternatively, N-deformytation can be carried out using a Lewis acid in a lower alkanol or a lower alkanediol under essentially anhydrous conditions. N-deformylation under sentlichen in far "anhydrous conditions can be at a temperature of -40 to + 100 ⁰ C, advantageously at -20 to + 70 ⁰ C are performed.

The 7> amino compound can be used as an insoluble salt, for example as Hydrochloric) or as hydrogen ptoluenesulfonate, be separated, or it can be adjusted by adjusting the pH (for example to the isoelectric Point) or it can be extracted with a suitable solvent if necessary will. The 7 /? - amino compound can then be acylated again. The new acylation can be carried out with the acylating agent of choice. A wide variety of acylating agents door the use in the cephalosporin field are described in the literature.

The compounds prepared according to the invention are much easier to crystallize and more stable than analogues Compound, and it therefore arise for synthesis great advantages of cephalosporin compounds. Due to the connection that can be produced according to the invention gen results in an excellent alternative way to the previously known syntheses for the production of Compounds of formula VIII

R ¹⁰ CONH

(vim

where R ¹⁰ CO is an acyl group and Y is the radical of a nucleophile. The compounds of the formula VIII and their salts generally have bacterial activity.

According to J. Chem. Soc. 1966, p. 1151, although cephalosporin sulfoxides are not readily reducible, it has surprisingly been found that a direct reduction of the S-bromomethyl cephalosporin sulfoxide esters prepared according to the invention to 3-bromomethyl cephalosporins is possible. The intermediate products according to the invention thus make it possible to prepare compounds of the formula (VIII) from penicillin sulfoxide esters, since the direct conversion of ³ -3-methyl cephalosporins into ³ -3-substituted cephalosporins is possible. This can be illustrated in more detail in the following reaction scheme.

oxidation

COOR ²

Brokerage

nucleophilic reaction

COOR ²

reduction

reduction

nucleophilic reaction

Deacylation (if applicable)

The 1-sulfinyl group can be reduced by known methods. This can be achieved, for example, by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salts, which were produced in situ by reacting with an acetyl chloride in the case of an acetoxysulfonium salt, the editing for example by sodium dithionite or by iodide ions, such as a solution of potassium iodide in a water-miscible Solvent, for example acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide, is carried out. The reaction may be carried out at temperatures of -20 to +50 ⁰ C.

Alternatively, the reduction of the 1-sulfinyl group with phosphorus trichloride or tribromide in solvents such as methylene chloride, dimethylformamide or tetrahydrofuran are preferably carried out at a temperature of -20 to +50 ⁰ C.

From what has been said above, it follows that the ^ 4 ³ -Un saturation was not subject to isomerization during the sequence of reactions described. This is an important feature of the present invention.

Alternatively, compounds of the formula (Π) 65 also be reduced first and then reacted with a nucleophile.

Important compounds of the formula (VIII) which are prepared on the basis of the intermediates according to the invention can be include.

Cefaloram, Cefalotin, Cefaloridin,
Cefazolin, cefaloglycine,
7 / J- (D-2-amino-2-phenylacetamido) -3-methyl-

thiomethylceph-B-em ^ -carboxylic acid,
7> 8- (D-2-amino-2-phenylacetamido) -3-methoxy-

methylceph-3-em-4-carboxylic acid and

p./K

methyl] -4- (N-hydroxymethylcarbamoyl) -

pyridinium-4-carboxyIate,

The following preparation instructions and examples illustrate the invention. In the case of the manufacturing instructions and examples, if nothing else specified:

determines the ultraviolet (UV) spectra in ethanol solutions,

the infrared (IR) spectra measured in Nujol® as a film,

the proton magnetic resonance spectra (PMR) are determined at 60 or 100 MHz as 5 to 10% solutions in dimethyl sulfoxide-d ₆ The values of the coupling constants (J) are not assigned.

Il

net. The signals are displayed as singlets (s), doublets (d), double doublets (dd), triplets (t), AB-quartets (AB-q) or multiplets (m).

4. The optical rotation values are determined at 19 to 30 ⁰ C in concentrations in the range from 0.8 to 1.2% as solutions in Pimethylsulfoxyd,

5. The solvers were over anhydrous magnesium sulfate dried,

6. low-boiling petroleum ether was a fraction with a boiling point of 60 to 80 ⁰ C,

7. All types of silica gel G were obtained from Merck A. G., Darmstadt,

8. Methylene chloride was dried by replacing it with basic aluminum oxide (Woelm, activity I) headed; Ν, Ν-Dimethylformamide was obtained by distillation over acidic aluminum oxide (Woelm, Activity I) dried.

9. Paper electrophoresis was done on Whatman ™ No. 3 MM paper carried out at 30 v / cm in a pH 1.9 buffer containing formic acid (16.7 ml, 98%), acetic acid (84 ml), acetone (105 ml) and water (495 ml) or, where indicated, this buffer was diluted to pH 2.2 with 4 volumes of water. Spots were made with an ultraviolet lamp made visible.

The R _c values mean the rate of migration in relation to N- [7j3- (2-thienylacetamido) ceph-3-em-3-ylmethyl] pyridinium-4-carboxylate (cefaloridin), R _c 1.00 as standard; Vitamin B ₁₂ served as an uncharged marker.

The examples are divided into two parts:

Part A

He deals with the manufacture of the starting materials of formula I.

part B

It deals with the bromination of the compounds of the formula I, whereby compounds of the formula II are formed.

Part A
Method Al

Methyl-S-methyl-TjS-phenylacetamidoceph-S-em-4-carboxylate-1 / J-oxide

a) Methyl-S-methyl ^ jfJ-phenylacetamidoceph-3-em-4-carboxylate

A solution of methyl-ojS-phenylacetamidopenicillanate-ljS-oxide (29.15 g, 80 mmol) in dry dioxane (600 ml), the pyridine (1.26 g, 16 mmol) and 89% phosphoric acid (1.76 g , 16 mmol) was refluxed for 15.5 hours. The condensed vapors were dried by passing them through a bed of molecular sieves (Linde ^e 4A, 1.5 mm, 40 g) in dry dioxane (approx. 50 ml) before being returned to the reaction mixture, the volume of which remained constant at about 600 ml. The cooled reaction mixture was evaporated in vacuo and the residue dissolved in methylene chloride (500 ml) and then washed successively with water, 2N hydrochloric acid, water, 3% aqueous sodium hydrogen carbonate solution and water (200 ml of each), dried and evaporated, whereby a solid was obtained which was recrystallized from commercially available denatured alcohol, the title compound being obtained in the form of colorless prisms (18.3 g, 66%), melting point = 196-198 °, [a] _D = + 136 ° (Dioxane), / U.,. = 259 nm (e = 6550). Cooling the mother liquors provided more identical material (1.85 g, 6.7%). Recrystallization of a small portion of the above solid gave an analytical sample, mp = 196-198.5 °, v _max (CHBr ₃ ) 3410 (NH), 1775 (azetidin-2-one), 1720 and 1240 (CO ₂ CH ₃ ) and 1670 cm "'(CONH), r 0.98 (1H, d, J 8 Hz; NH), 2.73 (5H, s; C ₆ H ₅ ), 4.39 (1H, dd , J 4.5 and 8 Hz; C ₇ -H), 4.95 (1 H, d, J 4.5 Hz; C ₆ -H), 6.25 (3 H, s; CO ₂ CH ₃ ) , 6.37 and 6.69 (2 H, partially smeared, AB-q, J 18 Hz; C ₂ -CH ₂ ), 6.46 (2 H, s; C ₆ H ₅ CH ₁ ) and 7.96 (3 H, s; C ₃ -CH ₃ ).

b) Oxidation of methyl 3-methyl-7j8-phenylacetamidocephO-em ^ -carboxylate

(i) With peracetic acid

With stirring, a solution of methyl S-methyl ^ jS-phenylacetamidocephO-em ^ -carboxylate (6.93 g, 20 mmol) in methylene chloride (100 ml) with approx. 10% peracetic acid solution (38 ml, approx. 50 mmol) treated dropwise over 15 minutes. After stirring for an additional 15 minutes, the Mixture carefully treated with aqueous 3% sodium hydrogen carbonate solution (150 ml), whereby a colorless solid precipitated out as a precipitate. This was separated by filtration, in methylene chloride (600 ml) and added to the organic portion of the original filtrate. The aqueous part of the filtrate was back extracted with methylene chloride (150 ml), which was then combined with the above extracts. The combined organic extracts were with saturated aqueous sodium hydrogen carbonate solution (150 ml), saturated saline solution f00 ml) washed, dried and then evaporated, the methyl S-methyl ^ -phenylacetamidoceph-S-em-4-carboxylate-l> oxide obtained (5.65 g, 78%) in the form

4-, feather-like needles. Mp = 226 to 227 °, [a] _D = + 183 °, X _n , ^ 265 nm (c = 8150). Concentration of the mother liquors provided an additional batch of identical material (0.69 g, 10%). Thin layer chromatography and spectral analysis indicated that the above sulfoxide was a simple diastereoisomer, Rp = 0.45 (coated with silica gel, acetone to methylene chloride = 1: 4); v _{m (a} (CHBr ₃ ) 3310 (NH), 1780 (azetidin-2-one), 1728 (CO ₂ CH ₃ ), 1646 and 1540 (CONH) and 1030 cm " ¹ (SO), τ 1.71 ( 1H, d, J 8 Hz; NH), 2.67 (5 H, s; C ₆ H ₅ ), 4.20 (1H, dd, J 5 and 8 Hz; C ₇ -H), 5.10 (1H, d, J 5 Hz; C ₆ -H), 6.18 (3 H, s; CO ₂ CH ₃ ), approx. 6.3 (4 H, unresolved multiplet; C ₆ H ₅ CH ₂ - and C ₂ H ₂ ), 7.95 (3 H, s; C ₃ -CH ₃ ).

(ii) With iodobenzene dichloride

A solution of methylO-methyl ^ jß-phenylacetamidoceph-3-em-4-carboxylate (6.93 g, 20 mmol) in water to pyridine (1: 4, 100 ml) was at -10 ° in & 5 in the absence of light and stirred with a solution of iodobenzene dichloride (11.0 g, 40 mmol) in dry Pyridine (25 ml) was treated dropwise over 10 minutes. The mixture was added for an additional hour

stirred at this temperature, then poured into methylene chloride (200 ml) and treated with 2N hydrochloric acid (4 × 200 ml). Water (2 × 200 ml), 3% aqueous sodium hydrogen carbonate solution (2 × 200 ml) and water (2 × 200 ml). The dried extract was then concentrated, then stored in the refrigerator, giving three batches of cefalosporin-1 / α-oxide (total 2.27 g, 31.3%), in all respects with the material described in Ib (i) identical, colorless, feather-like needles, melting point = 226 to 227 °, k _max 265.5 nm (r = 8150); R _h = 0.45 (as in Ib (i)). Concentration of the filtrate provided a brown tar which, when treated with ether, gave almost white prisms (1.62 g), mp = 174 to 175 °, [a] _D = -70 ° (chloroform), thin layer chromatography ( TLC) showed the presence of two compounds (R _1. = 0.45 and 0.24), the less polar one corresponding in its migration speed to the known diastereoisomeric oxide. The mixture was taken up in methylene chloride / acetone (4: 1) (50 ml) and chromatographed on silica gel G (100 g) with the same solvent mixture. 50 ml fractions were removed, evaporated, checked by TLC and pooled accordingly. Fractions 3 to 11 (137 mg) were crystallized from ether, a very small amount of the known diastereoisomeric oxide being obtained (118 mg), mp = 222 to 223 °. /., "," 266 nm ( _f = 8500). Fractions 13 to 31 (832 mg) yielded methyl 3-methyl-7 / J-phenylacetamidoceph-3-em-4-carboxylate-soloxide (727 mg, 10%), m.p. = 184 bis, on treatment with ether 185 °. Recrystallization from acetone / low-boiling petroleum ether gave colorless prisms, melting point = 186 to 187 °, [a] _D = -159 °, A _ma , 265 nm (C = 5150). v, "_u> (CHBr ₁ ) 3440 (NH), 1788 (azetidin-2-one), 1728 (CO ₂ CH ₃ ), 1682 and 1515 (CONH) and 1050 cm" ¹ (SO); τ 2.75 (5 H, s; C ₆ H ₅ ), 4.42 (1 H. d, J 5 Hz and 8 Hz ^- C, -H), 5 28 (IH, d, J 5 Hz · CH), 5, 87 and 6.40 (2H, AB-q, Yl7Hz; 'ci-H,), 6.25 (3H.'S; Co ₂ CH ₁ ). 6.45 (2 H. s; QH ^ CH ₂ ) and 7.92 (3H, s; C ₁ -CH,).

Procedure A2

2,2,2-Trichlorethylene-3-methyl-7 /? -Phenylacetamidocepho-em-4-carboxylate-lß-oxide

(i) With peracetic acid

A solution of 2,2,2-trichloroethyl-3-methyl-7 ./?- phenylacetamidoceph-S-em ^ -carboxylate (8.36 g, 18 mmol) in methylene chloride (100 ml) was cooled to 5 ° and stirred while a solution of peracetic acid (10% w / v; 20 ml, 26 mmol) was added. The mixture was then stirred at room temperature for 10 minutes. Hydrogen peroxide (29% w / v, 4 ml, 3.6 mmol) was added and stirring was continued for 30 minutes. The solution was washed successively with water (2 x 50 ml), sodium bicarbonate solution (2 x 50 ml, 3%) and water, then dried and evaporated to leave a gel. Crystallization of the gel from methanol gave the title compound (2.8 g, 32%) in the form of colorless crystals, melting point = 199 to 199.5 °, [a] _D = + 97 ° (CHCl ₃ ), X _n ^ _x 269 nm (E ',) " = 165). A second batch of the title compound (0.82 g, 9.5%), melting point = 195 to 197 ° [a) _D = + 105 ° (CHCl ₃ ), i _max 269 nm (£ | * "= 161) was obtained if one stirred the mother liquors at room temperature overnight. The filtrate from the second batch was evaporated and the residue was chromatographed on silica gel (0.05-0.2 mm, 150 g) using mixtures of methylene chloride and acetone as the eluent. Gradient elution gave impure starting material (0.56 g, 7%), melting point - 147 to 157 °, [a] _D - 67.5 ° (CHCl,), K, _ax 260 nm (£ J \, = 124), followed by the title compound (2.29 g, 27.5%), m.p. = 190 to 198 °, [ah = + 5.05.5 ° (CHCl ₃ ), X _max 269 nm (E ', ^x _rm = 159), parts of which were recrystallized from methanol, leaving colorless

ίο received needles. Mp = 200.5 to 202 ° (decomposition), [a] _D = 108 ° (CHCl ₃ ), A """269 nm (c - 7450), v _max (CHBr ₃ ) 1800 (azetidin-2-one ), 1740 (CO ₂ R), 1680 and 1510 (CONH) and 1043 cm " ¹ (SO).

Further elution yielded the Ια-oxide (0.21 g, 2.5%),

ι-, m.p. = 168 to 178 °, [a] _D = -199 ° (CHCl ₃ ), X _max 269 nm (£ j ';"= 94), which was recrystallized from acetone to give colorless needles. Mp. = 181 to 189 ° (decomposition), [a] _D = "237 ° (CHCl ₃ ), k _max 269 nm (c = 4850), v, _mlv (CHBi ₃ ) 1780 (Acctiuifi-2-ΰΓι), 1725 (CO ₂ R),

: n 1670 and 1510 (CONH) and 1040 cm " ¹ .

(ii) With m-chloroperbenzoic acid

A solution of 2,2,2-trichloroethyl-3-methyl-7 / 3-

: 5 phenylacetamidoceph ^ -cm ^ -carboxylate (18.56 g, 40 mmol) in methylene chloride (200 ml) was stirred at 0 to 10 °, and a solution of m-chloroperbenzoic acid (8.91 g, 85% pure, 44 mmol) in methylene chloride (150 ml) was added over a period of 5 minutes.

iii th added. Stirring was continued for 15 minutes and then the reaction solution was washed with sodium bicarbonate solution (3%, 4XlOOmI). The bicarbonate extracts were combined and extracted with methylene chloride (100 ml). The combined organic solutions

tj genes were dried and evaporated, whereby one a colorless solid was obtained which was determined by column chromatography to SUikage! (0.05 to 0.2 mm, 500 g) with a mixture of methylene chloride-acetone as eluent cleaned wu.de. The corresponding frac-

"I" ions were combined to give the l /? - oxide (16.32 g. 85%) as a white solid, mp = 193 to 200 °, \ a] _n = + 104 ° (CHCl ₃ ). /., "". 269 nm (C, = 154).

Production A3

2.2.2-Trichloroethyl-7j8-foIτnamido-3-methylceph-3 -e m-4-carb oxy lat- l /? - oxy d

a) 2,2.2-Trichloräthy! -7 /? - formamido-3-methyl-5Ii ceph ^ -em ^ -carboxylate

Acetic anhydride (8 ml) was added to a solution of 2,2 ^ -trichloroethyl-7 ^ -amino-3-methylceph-3-em-4-carboxylate (6.91 g, 20 mmol) in 98-100% formic acid (40 ml) was added and the orange solution became stored at room temperature for 35 minutes and then evaporated successively at 30 ° / 15 mm and 30 ° / l mm. The orange colored residue was dissolved in ether (200 ml) and the solution was sequentially with 2N hydrochloric acid, water and 5% aqueous sodium hydrogen carbonate solution (each 50 ml) and water (100 ml), dried and evaporated to give the title ester in the form a pale yellow foam was obtained (6.50 g, 87%),

b5 [a} _D = + 96 ° (CHCl ₃ ), / L ^ - 262 to 263 nm (Ef i = 152), v _max (CHBr ₃ ) 3400 (NH). 1786 (azetidin-2-one), 1740 (CO ₂ R) and 1700 and 1510 cm " ¹ (CONH), τ (CDCl ₃ ) 1.74 (CHO), 7.79 (C ₃ -CH ₃ ).

b) 2,2,2-TricWoräthyl-7> formamido-3-methylcepn-3-em-4-carboxylate-1 / f-oxide

(i) A suspension of 2,2,2-trichloroethyl-7j8-amino-S-methylceph-S-em ^ -carboxylate-hydrogen-p-toluenesulfonate (155.5 g, 0.3 mmol) in ethyl acetate (600 ml ) and water (600 ml) was stirred with sodium carbonate (36.0 g) IV for ₂ hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (230 ml). The combined organic layers were washed with water (600 ml), dried and evaporated to give a brown oil which was redissolved in ethyl formate (500 ml). The solution was heated to reflux for 1 hour then evaporated in vacuo. The brown oil was redissolved in ethyl acetate (600 ml) and washed successively with 2N hydrochloric acid (600 ml), water (600 ml), 3% sodium bicarbonate solution (600 ml), water (600 ml), dried and in vacuo evaporated to give a pale yellow foam (112.3 g). This foam was dissolved in methylene chloride (11), chilled in ice and stirred while adding peracetic acid (0.285 mol, 0.95 equiv.) Over 35 minutes. The mixture was then stirred for a further 30 minutes at room temperature, partial crystallization of the Prodötte occurred. Methylene chloride (11) was added and the solution was washed successively with water (800 ml) and 3% sodium bicarbonate solution (1 × 1500 ml, 1 × 800 ml), then dried and concentrated in vacuo to a volume of approx. 400 ml. Methanol (450 ml) was added and the solution was slowly cooled to 0 ° with stirring. The fine, off-white solid was collected and combined with two additional batches of material obtained by concentrating the mother liquors. The combined solids were washed with ether-methanol (19: 1, 750 ml) and dried at 40 ° in vacuo to give the title compound (9Ug, 78%). Mp. = 168 to 171 ° (decomposition), [a] _D = + 105 °, / U "269.5 nm (£} *". = 174). A small sample of this was recrystallized from ethanol, an analytical sample being obtained as hemi-ethanol solvate, melting point = 176 to 181 ° (decomposition), [o] _D = + 107 °, X _max 269 nm (c = 7740), v _m "(CHBr ₃ ) 3610 (ethanol), 3440 (NH), 1800 (azetidin-2-one), 1741 (CO ₂ R), 1698 and 1509 (CONH) and 1041 cm" ¹ (SO), r ( CDCl ₃ ) 1.74 (1H, s; CHO), 2.90 (1H, d, J 10 Hz; NH), 3.82 (IH, dd, J 10 and 4 Hz; C ₇ -H) , 4.99 and 5.16 (2H, AB-q, J 11 Hz; CO ₂ CH ₂ CCl ₃ ), 5.40 (1H, d, J 4 Hz; C ₆ -H), 6.28 and 6.69 (2H, Ab-q, J 18 Hz; C ₂ -H ₂ ), 7.74 (3 H, s; C ₃ -CH ₃ ). Typical signals at r6.34 and 8.76 showed the presence of half a mole of ethanol.

(ii) A solution of 2,2,2-trichloroethyl-7 / * -formamido-S-methylcephO-em ^ -carboxylate (6.43 g, 17.2 mmol) in methylene chloride (50 ml) was cooled at 0 ° , and peracetic acid (46.2% w / v, 2.98 ml, 1.05 equiv) was added dropwise with stirring over 10 minutes. The pale yellow solution was ^{stirred at 0 9} for 30 minutes, then warmed to room temperature and washed successively with water, 3% aqueous sodium hydrogen carbonate solution and water (50 ml each), dried and evaporated to give a yellow solid (5.79 g ) received. This solid was crystallized by trituration with warm ethanol (50 ml) to give the title compound as an ethanol solvate (4.67 g, 66%), mp = 178-183 ° (decomposition), [a] _D = + 110 ° , X _max 269 nm (f = 7450), the spectra were similar to that of the compound described under (i) above.

Production A4

tert-Butyl-TyS-formamido-S-methylceph ^ -em-4-carboxylate-18-oxide

a) tert-ButyWjS-aminoO-methylceph-S-em-4-carboxylate

A mixture of 7jS-amino-3-methylceph-3-em-4-carboxylic acid (16.09 g, 75.2 mmol), dioxane (100 ml), sulfuric acid (10 ml) and isobutylene (90 ml) were in

is shaken in a pressure vessel until a clear solution was obtained ( _2½ hours). The solution was cooled and poured into a mixture of aqueous sodium bicarbonate (600 ml), ice (100 g) and ethyl acetate (150 ml). The aqueous layer was used twice more

Ethyl acetate extracted and the extracts were washed with Washed with salt solution and dried. Evaporation left behind a gum, which was treated with petroleum ether (boiling point 40 to 60 °) was triturated, whereby almost white crystals were obtained (11.17 g, 55%). A sample was out

Recrystallized ether, the pure ester being obtained. Mp. = 126 °, [a] _D = + 107 ° (ethanol),> l _majt 271 nm (£ ». = 239).

b) tert-butyl ^ jS-formamido / methylceph-3-em-4-carboxylate

(i) A solution of tert-butyl-7j & -amino-3-methylceph-3-em-4-carboxy! at (2 g) in formic acid (20 ml) and acetic anhydride (3 ml) was at room temperature

) 5 temperature kept for 5 minutes. The solvents were removed in vacuo and the residue was dissolved in ether. The solution was washed with 2N hydrochloric acid and water and dried. Evaporation of the ether gave the amide (1.74 g) in the form of a colorless foam, [a] _D = 127 ° (CHCl ₃ ), X _max 266 nm (c = 6650), v _m “(CHBr ₃ ) 3430 (NH ), 1775 (ß- lactam), 1720 (CO ₂ R) and 1690 and 1508 cm " ¹ (CONH), r (CDCl ₃ ) 1.80 (HCO), 3.03 (NH, d, J 9 Hz) , 4.23 (C ₇ -H, 1H, dd, J 4.5 and 9 Hz), 5.9 (C ₆ -H, 1H, d, J 4.5 Hz), 6.49 and 6 , 88 (C ₂ -CH _2, 2H, AB q, J 18 Hz), 7.91 (C ₃ -CH _3), 8.48 (tert-butyl).

(ii) A solution of tert-butyl-β-amino-S-methylceph-3-em-4-carboxylate (0.100 g, 0.3 mmol) in ethyl formate (5 ml, 73 mmol) was heated to reflux for 45 minutes . The solvent was distilled off in vacuo and the residue was dissolved in ether. Removal of the ether in vacuo yielded the formamido derivative as a foam, [a] _D = + 127 ° (CHCl ₃ ), / L "266 nm (e = 6600), R _r = 0.4 (benzene to ethyl acetate = 2: 1 Merck Silica gel), and the PMR and IR spectra were similar to those of a sample prepared by the method described in A4 (b) (i).

c) tert-butyl-T / Mbrmamido-S-methylcephO-em-4-carboxylate-1.0-oxy d

A solution of tert-butyl-7jff-formamido-3-methylceph-3-em-4-carboxylate (2.38 g, 8 mmol) in methylene chloride (20 ml) was cooled in an ice-water bath and stirred while adding peracetic acid (40% w / v, 1.6Ci ml, 1.05 equiv.) dropwise over 2 minutes added. The mixture was left at 0 for 30 minutes

Stirred to 5 ° and then washed for 30 minutes at room temperature, with water, aqueous bicarbonate solution and water, dried (Na ₂ SO ₄ ) and evaporated to give a pale yellow gel that was triturated with acetone-ether, the l / MDxydester was obtained as a cream-colored solid (1.86 g, 74%), melting point = 163 to 165 ° (decomposition), [a) _D = + 182 ° (CHCl ₃ ), X _max 264 nm (c = 7850), v _max (CHBr ₃ ) 3390 (NH), 1796 (azetidin-2-one), 1720 (CO ₂ R), 1695 and 1508 (CONH) and 1040 cm " ¹ (SO). τ (CDCl ₃ , with

2 drops Me ₂ SO-d ₆ ) 1.68 (1 H, s; NHCHO), 7.83 (3 H, s; C ₃ -CH ₃ ), 8.42 (9 H, s; CO ₂ C ( CH ₃ ) ₃ ), 8.78 (0.125 mol diethyl ether). The material was used for the following experiments without further purification.

Manufacture A5

2,2,2'-trichloroethyl-3-methyl-7. £ -phenoxyacetamidocephJ-em ^ -carboxylate-ljS-oxide

A solution of 2,2,2-trichloroethyl-3-methyl-7 / & phenoxyacetamidocephO-em ^ -carboxylate (4.80 g, 10 mmol) in methylene chloride (50 ml) was mixed with peracetic acid (1.9 ml, containing 5.26 mmol of oxidizing agent per ml contained, 10 mmol) at 20 to 30 ° with stirring during

Treated 3 minutes. The solution was washed with water (2x20 ml) and dilute sodium bicarbonate solution (20 ml), dried and evaporated to give a white solid (5.075 g). This solid can be used in the subsequent reactions without further purification. Recrystallisate of this solid from a mixture of methanol (50 ml) and acetone (15 ml) gave the title compound in the form of colorless needles (3.10 g, 62.6%). Mp. = 172 to 177 °, [a] _D = + 65 ° (CHCl ₃ ), A _m " 269 nm (££" = 180) and 275 nm (E ', _m = 163); Inflection at 264 nm (E? _R " = 165).

A small part of this compound was recrystallized from methanol-acetone, an analytical sample being obtained, melting point = 173 to 178 °, [a] _D = + 66.7 ° (CHCl ₃ ), / l _m “ _t 269 nm ( c = 9075) and 275 nm (ε = 8250), inflection at 265 nm (ε = 8675), v _m " _r 3450 (NH), 1780 (azetidin-2-one), 1745 (CO ₂ R), 1700 ( CONH), 1030 cm " ¹ (SO), τ (CDCI ₃ ) 2.15 Π H, d, J 10 Hz; NH), 2.5 to 3.2 (5 H, m; C ₆ -H ₅ ) , 3.88 (1 H, dd, J 10 and 4.5 Hz; C ₇ -H), 4.93 and 5.18 (2 H, Ab-q, J 12 Hz; CH ₁ CCI ₃ ), 5.38 (3 H, broadened s; C ₆ H ₅ OCH ₂ and C ₆ -H), 6.29 and 6.79 (2 H, AB-q, J 19 Hz; C ₂ -H ₂ ), 7.78 ( 3 H, s; C ₃ -CH ₃ ).

Production A6

2,2,2-trichloroethyl-3-methyl-7> [D-2-

(2,2,2-trichlorethoxycarbonylamino) -2-phenyl-

acetamido] -ceph-3-em-4-carboxylal-l ^ -oxide

Persacetic acid (46.2% w / v, 1.73 ml, 1.05 equiv.) Was added dropwise over 5 minutes to a stirred solution of 2,2,2-thioloroethyl-3-methyl-7> 8- [ D-2-phenyl-2- (2,2,2-trichloroethoxycarbonylamino) -acetamido] -ceph-3-em-4-carboxylate (6.54 g, 10 mmoles) in methylene chloride (50 ml) added to 0 ° was cooled. The reaction mixture was stirred at 0 ° for 30 minutes, washed with water, 3% aqueous sodium hydrogen carbonate solution and water (50 ml each), dried and evaporated to give a yellow solid (6.58 g) which was washed with warm ethanol (50 ml) ml) was triturated, whereby the title ester-LÖ-oxide was obtained (5.78 g, 86%). Mp = 216.5 to 217.5 ° (decomposition), [a] _D = + 42 °, A _max 269 nm (ε = 7400), v _max (CHBr ₃ ) 3360 (NH), 1798 (azetidine-2 -on), 1734 (COiR), 1690 and 1500 (CONH) and 1048 cm " ¹ (SO) r 1.52.163 (each IH, d, J 8 Hz; NH) 2.6 (5H, m; C ₆ H ₅ ), 4.19 (IH, dd, J 9 and 5 Hz; C ₇ -H), 4.43 (IH, d, J 8 Hz; CHNH), 4.82.5.01 (2H, AB- q, J 12 Hz; CH ₂ CCl ₃ ), 5.12 (IH, d, J 5 Hz; C ₆ -H), 5.19 (2H, s; NHCO ₂ CH ₂ CCl ₃ ), 6.12, 6.42 (2H, AB-q, J 19 Hz; C ₂ -H ₂ ) and 7.90 (3H, s;

ίο C ₃ -CH ₃ ).

Production A7

p-Methoxybenzyl-methyl-T / I-phenylacetarnidoceph-3-em-4-carboxylate-1 /? - oxide

A solution of p-methoxybenzyl-3-methyl-7 / S4> henylacetamidoceph-i-em ^ -carboxylate (9.04 g, 20 mmol) and peracetic acid (50% w / v, 4.6 mL 1.5 equiv.) In Methylene chloride (200 ml) was stirred for 30 minutes. Saturated sodium hydrogen carbonate solution (150 ml) was then added and stirring was continued for 15 minutes. The organic phase was washed with 3% sodium hydrogen carbonate solution and saturated sodium chloride solution (200 ml each), dried and evaporated to about 75 ml, giving the title ester oxide (7.19 g, 77%). Mp. = 194 to 194.5 °, X _max 226.5 nm (£ ;; "= 372) and 266 nm (££" = 212), inflection at 279 nm (£ {* _n = 140). Evaporation of the filtrate gave a second batch (1.30 g, 14%). M.p. = 188-189 °. _mM 227 nm (£ {* "= 355) and 266 nm (£} *;" = 193), inflection at 279 nm (£, "*" = 133). A portion of the first batch (1.5 g) was recrystallized from methylene chloride to give colorless crystals (0.90 g). Mp = 194-195 °, [a] _D = 129 °, X _max 227 nm (c = 17,350) and 266 nm (c = 10,000), inflection at 279 nm (c = 6700), W 1775 (azetidine -2-on), 1728 and 1716 (CO ₂ R), 1652 and 1540 (CONH), 1236 (OMe) and 1032 cm "'(SO), τ 1.72 (IH, d, J 8 Hz; NH) , 2.63, 3.07 (4H, 2d, J 9 Hz; CH ₂ C ₆ H ₄ OCH ₃ ), 2.69 (5H, s; C ₆ H ₅ ), 4.25 (IH, dd, J ~ 8 Hz; C ₇ -H), 4.80 (2H, s; CH ₂ C ₆ H ₄ ), 5.16 (IH, d, J 5 Hz; C ₆ -H), 6.21, 6, 44 (2H, AB-q, J 18 Hz; C ₂ -H ₂ ), 6.24 (3H, s; OCH ₃ ), 6.30, 6.48 (2H, AB-q, J 14 Hz; C ₆ H ₅ CH ₂ ), 7.98 (3H, s; C ₃ CH ₃ ).

Production A8

tert.-ButyW-methyl ^. / T-phenylacetamidoceph-
το 3-em-4-carboxylate-L # oxide

Phenylacetyl chloride (0.58 ml, 1.1 equiv.) Was added to a stirred solution of tert-butyl 7 ^ -amino-3-methylcephO-enM-carboxylate (1.08 g, 4 mmol) in dimethylacetamide (2.5 ml) and acetonitrile (10 ml). The mixture was stirred at about 25 ° for 45 minutes, and then the acetonitrile was im Vacuum removed. Water (50 ml) and ethyl acetate (150 ml) were added and then the organic Phase washed with water, 3% sodium hydrogen carbonate solution and water (50 ml each), dried and evaporated. The remaining colorless oil was dissolved in methylene chloride (10 ml) and dissolved in chilled in an ice bath while peracetic acid (40%

b5 w / v, 1.16 ml, 1.1 equiv) added dropwise. The solution was stirred at about 20 ° 30 minutes, then Saturated sodium bicarbonate solution (20 ml) was added. The organic phase was washed with water (50 ml)

washed, dried and evaporated to give a colorless gelatinous solid. Thin-layer chromatography (acetone-methylene chloride, 1: 4), Rf = 0.49, 0.80. The solid was purified by chromatography on silica gel G (50 g). Elutioo with acetone-methylene chloride (1: 9) gave a pale yellow solid which was recrystallized from acetone / low-boiling petroleum ether, boiling point 40 to 60 ° (1: 1.10 ml) to obtain the tert-butyl-3-methyl-7j? -phenylacetamidoceph-S-em ^ -carboxylate-lJ-dioxide (0.17 g, 11%). Mp. = 87 to 88 °, [a] _D = + 36.5 °, X _n ^ 259 nm (c = 8150), v _mox (CHBr ₃ ) 3410 (NH), 1798 (azetidin-2-one), 1714 (CO ₂ R) and 1680 and 1510 cm " ¹ (CONH), τ (CDCl ₃ ) 2.66 (5H, s; C ₆ H ₅ ), 3.06 (IH, d, J 10.5 Hz; NH), 3.90 (IH, dd, J 10.5 Hz; C ₇ -H), 5.19 (IH, d, J 5 Hz; C ₆ H), 6.09, 6.55 (2H, AB-q, J 18 Hz; C ₁ H ₂ ), 6.34 (2H, s; C ₆ H ₅ CH ₂ ), 7.94 (3H, s; C ₃ -CH ₃ ), 8.49 (9H , s; CO ₂ C (CH ₃ ) ₃ ).

Further elution with acetone-methylene chloride (1: 9) yielded a colorless gelatinous solid which was dissolved in acetone (10 ml) and reprecipitated by adding low-boiling petroleum ether (boiling point = 40 to 60 °, 10 ml), whereby one the title ester IjB oxide was obtained (1.04 g, 67%). Mp = 181 to 182 ° (decomposition), Ia] ₀ = + 164 °, X _max 265 nm (c = 7900), v _mBX (CHBr ₃ ) 3390 (NH), 1790 (azetidin-2-one), 1716 (CO ₂ R), 1678 and 1510 (CONH) and 1050Cm " ¹ (SO), r (CDCl ₃ plus 3 drops of Me ₂ SO-d ₆ ) 2.68 (5H, s; C ₆ H ₅ ), 4, 12 (IH, dd, J 9.5.4.5 Hz; C ₇ -H), 5.34 (IH, d, J 4.5 Hz; C ₆ -H), 6.37 (2H, s; T ₆ H ₅ CH ₂ ), 6.56 (2H, s; C ₂ -H ₂ ), 7.91 (3H, s; C ₃ -CH ₃ ), 8.47 (9H ₁ .s; CO ₂ C 'CH ₃ ) ₃ ).

Production A9

2,2,2-trichloroethyl-3-methyl-

7jff- (2,2,2-trichloroethoxycarbonylamino) -

ceph-3-em-4-carboxylate-l / k) xyd

a) 2,2,2-trichloroethyl-3-methyl-

7X2,2,2-trichlorethoxycarbonylamino) -ceph-

3-em-4-carboxylate

2,2,2-trichloroethyl chloroformate (3.15 ml, 22 mmol) were added to a suspension of 2,2,2-trichloroethyl-7 / I-aminoO-methylceph-S-em ^ -carboxylate hydrogen ptoluenesulfonate ( 10.36 g, 20 mmol) in a mixture of dimethylacetamide (25 ml) and acetonitrile (100 ml). The mixture was stirred at about 25 ° for 30 minutes, the acetonitrile was evaporated and ethyl acetate (80 ml) was added. The solution was washed with saturated sodium hydrogen carbonate solution (80 ml), dried and evaporated to an oil which could not be crystallized. The oil was taken up in chloroform (50 ml), washed with water (3 x 50 ml) and evaporated again to give an orange colored foam which on trituration with methanol (20 ml) gave the title ester as an off-white solid, X _max 262 nm (E ¹ ^ _n = 113.5). Crystallization from ethanol provided the analytical sample, melting point - 179 to 181.5 °, [a] _D - + 70 °, X _mar 262 nm (c = 6000), v _m "(CHBr ₃ ) 3410 (NH), 1780 (Azetidin-2-one), 1740 and 1520 (NHCO ₂ R) and 1740 cm " ¹ (CO ₂ R), T (CDCl ₃ ) 3.98 (IH, d, J 9.5 Hz; NH), 4 , 34 (IH, dd, J 9.5 Hz; C ₇ -H), 4.91 (IH, d, J 5 Hz; C ₆ -H), 4.91, 5.08 (2H, AB-q , J 12 Hz; CO ₂ CH ₂ CCl ₃ ), 5.17 (2H, s; NHCOjCH ₂ CCI ₃ ), 6.34, 6.73 (2H, AB-q, J 18 Hz; C ₂ -H ₂ ), 7.74 (3H, s; C ₃ -CH ₃ ).

b) 2 ^, 2-trichloroethyl-3-methyl-

7X2 ^^ - trichlorethoxycarbonylamino) -ceph-

3-em-4-carboxylate-1> oxide

Peracetic acid (40% wt., 2.0 ml, 1.5 equiv.) Was added to a stirred solution over 15 minutes of 2 ^^ - trichloroethyl-3-methyl-7jS- (2 ^ -irichlorethoxycarbonylamino) -ceplt-3-em-4-carboxylate (5, ^ 4 g, 10.07 mmol) in methylene chloride (50 ml) in a

ίο Ice bath has been cooled, given. A colorless solid withdrew from the solution. The cooled mixture was stirred for 30 minutes and then the solid became filtered off, washed with water and dried to give the title ester-lj8-oxide (3.285 g, 61%).

is [a] _D = + 66 °, X _n ^ 269 nm (£ {* "= 135). The filtrate and washing waters were combined, and the organic phase was washed with water (2X25 ml), 4% sodium hydrogen carbonate solution (20 ml) and water (15 ml), dried and evaporated.

The solid which remained for 2 s was triturated with methanol, giving a less pure second batch of the ester isocyanate (1.60 g, 30%), melting point = 205 to 207.5 °, [a] _D = + 57 °, X _max 269 nm (£ {* "= 135). Parts of the first batch were recrystallized from boiling methanol, an analytical sample being obtained. Mp = 201 to 202 ° (decomposition), [a] _D = + 71 °, A _m «269 nm (c = 7500), w 3396 ( NH), 1772 and 1764 (azetidin-2-one), 1750 (CO ₂ R), 1730 and 1516 (NHCO ₂ R) and 1050 cm ' ¹ (SO), r 2.50 (IH, d, J 9 Hz ; NH), 4.26 (IH, dd, J

JO 9.5 Hz; C ₇ -H), 4.75, 4.87 (2H, AB-q, J 12 Hz; CO ₂ CH ₂ CCl ₃ ), 4.96 (IH, d, J 5 Hz; C ₆ -H) , 5.05 (2H, s; NHCO ₂ CH ₂ CCl ₃ ), 6.12 (2H, s; C ₂ -H), 7.84 (3H, s; C ₃ -CH ₃ ).

Production of AlO

tert-Butyl ^ -methyl-T ^ -phenoxyaoc-ianiidoceph-3-em-4-carboxylate-ljSoxyd

a) tert-Butyl-S-methyl-Tß-phenoxyacetamidoceph-3-em-4-carboxylate

A solution of ethylene oxide (12 ml) in dry methylene chloride (30 ml) was added to a solution of tert-butyl-TyS-amino-S-methylceph-S-em ^ -carboxylate (52 g, 0.193 mol) in dry methylene chloride (200 ml) which was cooled in an ice-water bath. A solution of freshly distilled phenoxyacetyl chloride (33.2 g, 0.194 mol) in dry methylene chloride (25 ml) was added over 2 minutes with stirring. The mixture was stirred for 2 hours, washed with 3% sodium hydrogen carbonate solution (2 X 70 ml), water, normal hydrochloric acid and brine (70 ml each), dried and evaporated to give a foam. This foam was redissolved in methylene chloride (200 ml) and part (3 ml) of the solution was evaporated again to give a white foam (1.13 g), [a] _D = + 107 °, X _max 268, 5 nm (e = 7850), 274.5 nm (c = 7000), inflection at 264 nm (c = 7500), v _max (CHBr ₃ ) 3417 (NH), 1786 (azetidin-2-one), 1718 ( CO ₂ R) and 1697 and 1530 cm " ¹ (CONH), rO.99 (IH, d, J 8.5 Hz; NH), 2.5 to 3.2 (5H, m; C ₆ H ₅ OCH ₂ ), 4.34 (IH, dd, J 8.5, 5 Hz; C ₇ -H), 4.91 (IH, d, J 5 Hz; C ₆ -H), 5.38 (2H, s; C ₆ H ₅ OCH ₂ ), 6,38,6,66 (2H, AB-q, J 18 Hz; C ₂ -H ₂ ), 8.01 (3H, s; C ₃ -Ch ₁ ), 8, 52 (9H, s; CO ₂ C (CH ₃ ) ₃ ).

b) tert-Butyl-S-methyl-Tβ-phenoxyacetamidoceph-3-em-4-carboxylate-1-> S-oxide

The remainder of the methylene chloride solution of tert-butyl-S-methyl-T ^ -phenoxyacetamidoceph-S-em- ^ caboxylate from (a) was stirred and cooled to -5 °, and then peracetic acid (38.6% W / V, 34.4 m !, 0.190 mol) was added, the temperature being kept below 5 °. Thin layer chromatography (acetone-methylene chloride, 1: 4) showed that the oxidation was incomplete, so parts (5X1 ml) of peracetic acid were added and stirring was continued until thin layer chromatography showed that only traces of unreacted sulfide remained. The reaction mixture was washed with 3% sodium hydrogen carbonate solution (3XlOOmI) and brine (100 ml), dried and evaporated to give a gel. This gel was dissolved in 1,2-dichloroethane (500 ml), and the solution was "uf about 2 rnl ^ * S! N ° edHrn ^r ft * and dsnn again to 500 rnl with dry 1,2-dichloroethane verdürat. A portion (62.2 ml) of this solution was used for Example BIO (i), the remainder was evaporated to give a gel which was triturated with methanol to low boiling petroleum ether (3: 2) and cooled. The colorless crystalline solid was separated off and washed with low-boiling petroleum ether, giving the title ester oxide (41.54 g). Mp = 116 to 120 °, with softening at 99 to 100 °, [a] _D = + 55.5 °, X _max 262.5 nm (E '* _m = 204) and 267 nm (£ {* "= 207), inflection at 273 nm (£ {* "= 165), thin layer chromatography (acetone-methylene chloride, 1: 4), R ₁ - = 0.44, with faint spots at R _f = 0.26, 0.65. Evaporation of the filtrate and trituration with low-boiling methanol petroleum gave a second batch (7.71 g). Mp. = 95 to 96 °, [a) _D = 71 °, A _moJ 263 nm (£ »" = 211) and 267 nm (E ', ^% _cm = 212), inflection at 273 nm (Ef _cm = 169) . The mother liquors were chromatographed on silica gel G (350 g) with acetone-methylene chloride (1: 4) as eluent to give unreacted starting material (3.31 g), which Titelester- \ ß oxide (12.65 g). Mp. = 92 to 95 °, [a] _D = + 73 °, X _m " 263 nm (£ {*" = 202) and 267.5 nm (£ | * "= 205), inflection at 273 nm (£ ',) "= 165) and tert-butyl-3-methyl- lß -pheüoxyacetamidoceph -3-eiTi-4-carboxylate -Xa oxide was obtained in the form of a pale yellow foam which was recrystallized from acetone to give a colorless crystalline Solid obtained (1.33 g), m.p. = 95 to 110 °, [a] _D = -125 °, X _max 263 nm (c = 6500) and 268 nm {ε = 6700), inflection at 274.5 nm (ε = 5450), v _mat 3252 and 3210 (NH), 1760 (azetidine-2-oii), 1716 (CO ₂ R), 1700 and 1540 (CONH) and 1024 cm " ¹ (SO), τ 0.71 (IH, d, J 9Hz; NH), 2.5-3.1 (6H, m; C ₆ H ₅ OCH ₂ ), 4.34 (1H, dd, J 9.4.5 Hz; C ₇ H ), 5.22 (1H, d, J 4.5 Hz; C ₆ -H), 5.38 (2H, s; C ₆ H ₂ OCH ₂ ), 5.86, 6.42 (2H, AB- q, J 17 Hz; C ₂ -H ₂ ), 7.98 (3H, s; C ₃ -CH ₃ ), 8.50 (9H, s; CO ₂ C (CH ₃ ) ₃ ), 7.90 ( approx. 0.3 M acetone).

A small part of the chromatographed 1 / M oxide was recrystallized from low-boiling methanol petroleum, giving a compound which melted at 84 to 91 ° and showed the following analytical values: [a] _D = + 78 °, X _max 263 nm (c = 9150) and 267.5 (c = 9250), inflection at 273 nm (c = 7350), v _max 3375 and 328G (NH), 1765 (azetidin-2-one), 17) 5 (CO ₂ R), 1660, 1670 and 1520 (CONH) and 1045 cm " ¹ (SO), τ 1.88 (IH, d, '10 Hz; NH), 2.5 to 3.1 (5H, m; C ₆ H ₅ OCH ₃ ), 4.03 (IH, dd, J 10.5 Hz; C ₇ -H), 5.06 (IH, d, J 5 Hz; C ₆ -H), 5.32 (2H, s; C ₆ H ₅ OCH ₂ ), 6.15, 6.39 (2H, AB-q, J 19 Hz; C ₂ -H ₂ ), 7.99 (3H, s; C ₃ -CH ₃ ), 8.49 (9H, s; CO ₂ C (CH ₃ ) ₃ ).

Manufacturing All

TyS-Formamido-S-methylceph-S-em ^ carboxylic acid] j8-oxide

T / f-Amino-S-methylceph-S-em ^ -carboxylic acid (21.4 g,

ίο 0.1 mol) was added to a mixture of formic acid (98 to 100%, 50 ml) and acetic anhydride (13 ml) with stirring. The black reaction mixture was stirred at 20 ° for 1 hour and then cooled to about 5 °, then peracetic acid (43.7% w / v, 17.4 ml, 0.1 mol) was added over 15 minutes. Towards the end of the addition, a pale brown solid had separated out. The reaction mixture was diluted with water (50 ml) and stirred for a further 10 minutes, and then the solid was filtered off, washed with water (30 ml), dried (10.63 g) and crystallized from boiling water (120 ml) , whereby the title acid was obtained (6.18 g, 24%), melting point = 165 to 168 °, resolidification and melting at 185 to 193 °, [a] ² _D ⁵ = + 293 ° (c = 1.13,

H ₂ O), [α] $ = + 211 ° (c = 1.09, Me ₂ SO), i _max (pH 6 phosphate) 255 nm (E '* _m = 329, ε = 8500), v "" (Nujol) 3300 (NH), 3620 and approx. 2600 (OH, monomeric and dimer), 1770 (azetidin-2-one), approx. 1760 and 1720 (CO ₂ H, monomeric and dimer), 1660 and 1535 (CONH ) and

jo 990 cm " ¹ (SO), τ (D ₂ O, NaHCO ₃ ) 1.80 (1 proton singlet, CHO), 4.12 (1 proton double, J 5 Hz; C ₇ -H), 5.14 (1 proton doublet, J 5 Hz; C ₆ -H), 6.36 (2 proton singlet; C ₂ -H ₂ ), 8.04 (3 proton singlet; C ₃ - CH ₃ ) .

J5 The compound was likely a hydrate.

Production A12

a) 2,2,2-trichloroethyl-7 ./*- (DL-2-bromophenyl-

acetamidoJ-S-methylcephO-em ^ -carboxylate

2,2,2-TrichloräthyI-7 /? - arnino-3-methylceph-3-em-4-carboxylate (3.5 g, 10.1 mmol) and dic / clohexylarbodi-

4:> imide (2.5 g, 12.1 mmol) were dissolved in dry methylene chloride (40 ml) dissolved. A solution of DL-ar-bromophenylacetic acid (2.6 g, 12.1 mmol) in dry Methylene chloride (10 ml) was added slowly. The reaction mixture was for about 25 ° 2 hours

stirred in, then stirred at 5 ° overnight and then filtered, and the filtrate was evaporated to give a brown oil. The oil was dissolved in ethyl acetate (50 ml) and dissolved with dilute sodium bicarbonate solution (2 x 50 m!) And brine (50 ml)

and evaporated to give an oil which, upon dilution with ether (10 ml) and precipitation with low-boiling petroleum ether, gave the title compound as an α-Lm-colored solid (4.80 g, 88.5%). Mp. = 98 to 115 °, [ä \ _D = + 62 ° (CHCl ₃ ), v _may 3275 (NH),

bo 1766 (azetidin-2-one), 1730 (CO ₂ R) and 1660 and 1535 cm " ¹ (CONH), r (CDCl ₃ ) 2.3 to 2.3 (5H, m, C ₆ H.), 4.28 and 4.32 (IH, 2 superimposed dd, J 4.5 and 9 Hz; C ₇ -H, pair of diastereomers), 4.55 and 4.56 (IH, 2 s; PhCHBr, pair of diastereomers), 4, 99 (IH, d, J 4.5 Hz;

b5 C ₆ -H), 5.04 and 5.24 (2H, AB-q, J 12 Hz; CO ₂ CH ₂ CCl ₃ ), 6.48 and 6.77 and 6.48 and 6.80 (2H , 2 superimposed AB-q, J 19 Hz; C ₂ -H ₂ , pair of diastereomers), 7.80 (3H, s; C ₁ -CH ₃ ).

b) 2,2,2-Trichloroethyl-7> (DL-2-bromophenylacetamido) -3-methylceph-3-em-4-carboxylate-lj3-oxide

A solution of 2,2,2-trichloroethyl-7j8- (DL-2-brompheny / acetamido) -3-methylceph-3-em -4-carboxylate (1.542 g, 2.85 mmol) in methylene chloride (40 ml) was with peracetic acid (approx. 40% solution in acetic acid, 0.54 ml), reacted at approx. 25 ° with stirring for a few meows. Sodium bicarbonate (0.5 g) was added and stirring was continued for 5 minutes. The mixture was filtered and the filtrate was evaporated to leave the title compound as a colorless solid which could be used in the following steps without further purification. An analytical sample was obtained by crystallizing the crude solid from acetone. Mp. = 199 to 204 °, [a} " = + 110 °, X _max 267 nm (i = 8820), v _mj . _r 3356 (NH), 1755 (azetidin-2-one), 1725 (CU ₂ K), 1095, 1675 and 1515 (CONH), 1020 and 1045 (SO), r (CDCI, + traces Me ₂ SO-d ₆ ), 1.42 (IH. D, J 9 Hz; NH). 2.3 to 2.7 (5H, m; C ₆ H ₅ ), 4.21 (IH. Dd, J 4.5 and 9 Hz; C ₇ -H), 4.24 and 4.26 (1H, 2s; C ₆ H ₅ CHBr, pair of diastereomers), 4.93 and 5.18 (2H, AB-q, J 12.5 Hz; CO ₂ CHjCCl ₃ ), 5.12 (IH, d, J 4.5 Hz ; C ₆ -H), 6.2 and 6.64 (2H, AB-q, J 18 Hz; C ₂ -H ₂ ).

part B Example Bl

Bromination of methyl-3-methyl-7) 8-phenylacetate

amidocephO-em ^ -carboxylate-lje-oxide under

Production of methyl-3-bromomethyl-7) ß-phenyl-

acetamidoceph-3-em-4 -carboxylate-ljff-oxide

(i) Photoinitiates Brornisning with

N-bromosuccinimide in chloroform with heating

at reflux

A solution of methyl-S-methyl-Tß-phenylacetamidoceph-3-em-4-carboxylaH) 3-oxide (1.45 g, 4 mmol) and N-bromosuccinimide (1.25 g, 7 mmol) in dry, ethanol-free Chloroform (100 ml) was refluxed in an atmosphere of nitrogen and exposed to a tungsten lamp (1 X 100 watt bulb) for 1 hour. The reaction solution was evaporated to half its volume, then applied to eight preparative thin-layer plates (40 × 20 cm, which _{were coated with silica gel HF 254 + 366} and were 2 mm thick). The plates were eluted with methylene chloride-acetone (4: 1) and the Rp 0.4 bands were removed, combined and extracted with methylene chloride-acetone (1: 1.600 ml). Evaporation of the organic solution gave the title compound (423 g, 24%) as a solid which was pale off-white in color. Mp = 170 to 178 ° (decomposition), Ia] ₀ = + 50 °, X _max 280.5 nm (£ «_ = 209), v _max 1772 (azetidin-2-one), 1702 (CO ₂ CH ₃ ), 1640 and 1516 (CONH) and 1026 cm " ¹ (SO), τ 5.37 and 5.55 (2H, AB-q, J 5 Hz; CH ₂ Br). Portions of this product were further washed with cold Purified methylene chloride, giving a colorless solid, melting point = 193 to 194 ° (decomposition), [a] _D = + 60 °, A _mor 281 nm (ε = 9960).

Analysis: C ₁₇ H ₁₇ BrN ₂ O ₅ S (441.3)

Calculated:

C 46.3; H 3.9; Br 18.1; N 6.35; S 7.3%;

Found:

C 46.7; H 3.9; Br 18.0; N 5.6; S 7.4%.

The product gave (according to TLC) on spraying with ν pyridine, heating to 60 to 80 ° for 2 to 3 minutes, removing the excess pyridine by evaporation in vacuo and spraying with potassium iodoplatinum a pink-purple color.

i "(ii) bromination initiated by

Azobisisobutyronitrile in chloroform under Reflux heating

A solution of MethyW-methyl-T / J-phenylacetami-

i docephO-em ^ -carboxylate-ljS-oxide (150 mg, 0,43m mol), N-bromosuccinimide (80 mg, 0.45 mmol, 1.05 equiv.) And azobisisobutyronitrile (5 mg, 0.037 mmol) in dry, ethanol-free chloroform (15 ml) were in a Refluxed under a nitrogen atmosphere for 9.5 hours

- '»and then evaporated. The remaining orange colored oil was dissolved in methylene chloride-acetone (small volume, 4: 1) and applied to a column of silica gel G (10 g) with methylene chloride-acetone (4: 1) as Eluent chromatographies and fractions

2 ^r > divided into 10 ml. Fractions 10 and 11 were combined and evaporated to give the title compound (65 mg, 35%) as an almost colorless crystalline solid. Mp. 125 to 160 ° (decomposition), k "" 280 nm (E ',) _m = 154), by infrared and PMR spectroscopy

id and TLC it could be shown that the product was similar to that obtained from example B1 (i).

Example B2

r> bromination of 2,2,2-trichloroethyl-3-methyl-

Te-nhenylacetamidocenh-i-em ^ -carboxylate- V / 8-oxide with the production of 2,2,2-trichloro

ethyl / bromomethyl-T / i-phenylacetamidoceph-

3-em-4-carboxylate-Ij8-oxide

(i) Photoinitiated bromination with

N-bromosuccinimide in chloroform taking Reflux

A solution of 2,2,2-trichloroethyl-3-methyl-7j8-phenylacetamidoceph - 3 - em - 4 - carboxylate - \ ß- oxide (9.584 g, 20 mmol) in dry, ethanol-free chloroform (300 ml) was in a Refluxed nitrogen atmosphere and illuminated with fluorescent light

such a band light (8 X40 watt lamps) irradiate. N-Broinsuccinimid (890 mg, 5 mmol) was added and the mixture was heated at reflux for I ³ A hours, with further proportions of N-bromosuccinimide (6 x 890 mg) at intervals of 15 minutes, added became. The reaction mixture was then evaporated to give a brown gum. This gum was dissolved in methylene chloride-acetone (9: 1, 50 ml) and dissolved on silica gel G (0.05 to 0.2 mm, 400 g) with methylene chloride-acetone (9: 1) as the eluent medium chromatography. In this way, the 3-bromomethyl compound (2.35 g, 21%) was obtained as an off-white solid. Mp = 153 to 162 °, [a] _D = + 35 ° (r = 0.78), X _max 283 nm (££ _ = 159). The chromatography fractions that can be obtained immediately received from those who contained the above material, were triturated with acetone-ether (1: 1) to remove less polar contaminants. This delivered another amount of the 3-bromomethyl compound

- ¹ Il

(600 mg, 11%) as an off-white solid. Mp. = 144 to 157 °, [e] _B = + 31 °, X _max 283 nm (E \\ = 165) .. A small sample of this product was recrystallized from acetone-ether (2: 1), whereby the 3-bromomethyl compound obtained in the form of colorless crystals, m.p. = IbS up to 166 °, [O] ₀ = + 32 °, λ _ηαχ 284 nm (c = 9500), v _max 1784 (azetidin-2-one), 1783 (CO ₂ R), 1654 and 1526 (CONH) and 1036 cm ^H (SO), r 1.48 (IH, d, J 8 Hz; -NH), 2.72 (5H, s; C ₆ H ₅ ), 4 , 11 (IH, dd, J 4.5 and 8 Hz; C ₇ -H), 4.75 and 4.93 (2H, AB-q, J 12 Hz; CH ₂ CCl ₃ ), 5.00 (IH , d, J 4.5 Hz; C ₆ -H), 5.34 and 5.50 (2H, AB-q, J 10 Hz; CH ₂ Br), 5.97 and 6.22 (2H, AB- q, J 18 Hz; C ₂ -H ₂ ), 6.26 and 6.47 (2H, AB-q, J 14 Hz; C ₆ H ₅ CH ₂ ).

Analysis: C ₁₈ H ₁₆ BrCl ₃ N ₂ O ₅ S (558.7)

Calculated:

C 38.7; H 2.9; N 5.0; S 5.7%;

Total halogen content: 4.00 equiv. / Mole Found:

C 38.6; H 2.7; N 4.8; S 5.8% ;.

Total halogen content: 3.95 equiv. / Mol

(ii) Photoinitiated bromination with N-bromosuccinimide in chloroform at 15 °

A solution of 2,2,2-trichloroethyl-3-methyl-7> phel./lacetamidoceph-S-em^-carboxylat-ljS-oxyd (50 mg, 0.104 mmol) and N-bromosuccinimide (18.5 mg, 0.104 mmol) in dry, ethane-free chloroform (2.5 ml) was kept in a sealed tube at 15 ° and with a tungsten lamp (1 X 100 watt bulb) Illuminated for 22 hours. Investigation with thin layer chromatography indicated the presence of the title compound in the reaction mixture. The title compound was identified on the TLC plate by comparison the Rp values with a material obtained in B2 (i) above and by its characteristic pink color when sprayed with pyridine, heated to 60-80 ° for 5 minutes, the excess evaporated on pyridine and sprayed the plate with iodoplatinate reagent.

(iii) bromination with N-bromosuccinimide,

initiated by azobisisobutyronitrile in chloroform

with refluxing

A solution of 2J, 2-TricWoräthyl-3-methyl-7j8-phenylacetamidoceph-S-em ^ -carboxylate-l / S-oxide (102.5 mg, 0.214 mmol), N-bromosuccinimide (56 mg, 0.311 mmol) and Azobisisobutyronitrile (5 mg) in dry, ethanol-free chloroform (5 ml) was protected from light and heated to reflux. After 2 '/ ₂ hours, a further portion of N-bromosuccinimide (20 mg, 0.11 mmol) and then was heated further, had passed until a total of 4.5 hours since the beginning of the reaction. The solution was cooled and applied to a preparative thin-layer plate (20 × 20 cm, coated with silica gel HF _{254 + 366} , 2 mm thick). The plate was developed with methylene chloride-acetone (4: 1). The corresponding band was removed and extracted with methylene chloride-acetone (1: 1, 100 ml). Evaporation of the organic solution gave the title compound (36 mg, 30%), melting point = 144 ° to 149 °, U 283 nm (£ ί% = 151).

(iv) bromination with molecular bromine activated by light

A solution of 2,2,2-trichloroethyl-3-methyl-7> phenylacetamidocephO-em ^ -carboxylate-l ^ -oxide (500 mg, 1.04 mmol) in dry, ethanol-free chloroform (25 ml) was refluxed in heated in a nitrogen atmosphere and irradiated with tungsten light (ix 100 watt bulb). To the solution, which was heated to reflux, was added a solution of bromine (0.1 ml, 312 mg, 1.73 mmol) in dry, ethanol-free chloroform (10 ml) over a period of 70 minutes. After the reaction had taken place for 95 minutes, the solvent was evaporated and the remaining oil was purified by chromatography on silica gel G (0.05-0.2 mm, 50 g) using methylene chloride-acetone (9: 1) as the eluent. The appropriate fractions from the chromatography were combined, giving the 3-bromomethyl compound (198 mg, 34%) in the form of pale yellow crystals, melting point = 158 to 160 °, k _max 283 nm (E ',) _m = 171) . A small sample of this product was recrystallized from acetone-petroleum ether (bp = 60 to 80 °), whereby colorless needles were obtained, mp> ■ -, = 163 to 16S °, [a] _D = + 32 ° (c = 0.69), X _max 284 nm (f = 9500).

Analysis: C ₁₈ H ₁₆ BrCl ₃ N ₂ O ₅ S (558.7)

Calculated:
m C 38.7; H 2.9; N 5.0; S 5.7%;

Total halogen content: 4.00 equiv. / Mole Found:

C 39.7; H 2.9; N 4.9; S 5.7%;

Total halogen content: 3.92 equiv. / Mol

(v) Bromination with N-bromocaproiactam

A solution of 2,2,2-trichloroethyl-3-methyl-7-phenylacetamidoceph-S-em ^ -carboxylate-ljS-oxide (97 rag,

0.202 mmol) and N-bromocaprolactam (44 mg, 0.23 mmol) in dry, ethanol-free chloroform (5 ml) was heated to reflux in a nitrogen atmosphere and illuminated with a tungsten lamp (1X100 watt bulb) for 2 hours. The golden colored solution was then cooled and applied to a preparative thin layer plate (20X20 cm, coated with silica gel HF _{254 + 366} , 2 mm thick), and then the plate was eluted with methylene chloride-acetone (4: 1). The band with an Rf = 0.35 was removed and with

5½ methylene chloride-acetone (1: 1.250 ml) extracted. Evaporation of the filtrate gave starting material (21 mg, 22%) as a cream solid, X ^ _ax 269 nm (£ ",, = 159). The band with an R ₁ - = 0.5 gave when similar was treated that

3-Bromomethyl compound (17 mg, 15%) as an off-white solid, X _max 283 nm (£ ', * "= 153).

(vi) bromination with N-bromophthalimide

μ »A solution of 2,2,2-trichloroethyl-3-methyl-7 / J-phenylacetamidoceph-3-em-carboxylate-Le-oxide (102 mg, 0.21 mmol) and N-bromophthalimide (72 mg, 0.30 mmol) in dry, ethanol-free chloroform (5 ml) heated to reflux in a nitrogen atmosphere and

b5 illuminated with tungsten light (1X100 watt bulb) 5V for ₂ hours. The reaction mixture was cooled and applied to a preparative thin-layer plate (20X20 cm, coated with silica gel HF _{254 + 356} , 2 mm thick).

brought, and the plate was eluted with methylene chloride-acetone (4: 1). Working up the corresponding bands yielded starting material (63 mg. 50%, calculated on £ ■ ;;: ", values), X _{ma: i} 270 nm (E ', \, = 129) and the 3-bromomethyl compound (61 mg, 32.5%, calculated on £ ^. "Values), La.r 284 nm (E ',:" = 111). Both compounds were obtained as colorless solids contaminated with phthalimide.

(vii) Photochemically initiated bromination
at 20 ° in 1,2-dichloroethane

A solution of 2,2,2-trichloroethyl-3-methyl-7> phenylacetamidoceph-S-em ^ -carboxylate-ljS-oxide (5 g, 10.4 mmol) in 1,2-dichloroethane (400 ml) was at Stirred at 20 ° under a dry nitrogen atmosphere with N-bromosuccinimide (2.80 mg, 15.7 mmol, 1.51 equiv.). The mixture was irradiated with a Hanovia 125 watt medium pressure mercury arc lamp using a Pyrexfilters *, where the temperature was maintained throughout the reaction at 20 ⁰ C. After 3 hours the solution was washed with water (2 x 100 ml) and the aqueous layers were washed together with 1,2-dichloroethane (50 ml). The purified organic layers were dried and evaporated to give a brown gum which was chromatographed on silica gel G (150-200 g) with methylene chloride-acetone (9: 1) as the solvent. The appropriate fractions were combined and evaporated, then triturated with methanol and evaporated again, whereby the title compound was obtained as an almost colorless solid (2.501 g, 43%), mp = 158 ° to 165 ° (decomposition). [a] _n = +3 \ °, X _max 282.5 nm (E ',) _m = 170). The fractions that were collected before those containing the title compound were evaporated and triturated with methanol to give a crude sample of 2,2,2-trichiorethyi-3-bromomethyl-7> e- (DL-2- bromo-2-phenylacetamido) -ceph-3-em-4-carboxylate-lj3-oxide was obtained in the form of a pale yellow solid (0.643 g), melting point = 183 to 186 °, [a] _D = + 15.9 ° , X _max 278.5 nm (E ',) " = 147), identified by TLC and PMR spectrum by comparison with an authentic sample.

Triturated methanol, giving a crude sample of 2,2,2-trichloroethyl-3-bromomethyl-7XDL-2-bromo-2-phenylacetamidol-ceph-i-em ^ -carboxylate-ljS-oxide (1.256 g). Mp = 180 to 186 ° (decomposition), [a] _D = 9.8 ° (r = 0.48), X _max 278.5 nm (E ',; _m = 139), identified with TLC and PMR by Comparison with an authentic sample.

(ix) Photochemically initiated bromination
at -20 ° in 1,2-dichloroethane

A solution of 2,2,2-trichloroethyl-3-methyl-7 / i-phenylacetamidoceph-S-em ^ -carboxylate-l / i-oxycl (5.0 g, 10.4 mmol) in 1,2-dichloroethane (400 ml) was stirred with N-bromosuccinimide (2.78 g, 15.6 mmol, 1.5 equiv.) At -20 ° under a dry nitrogen atmosphere. The mixture was _{illuminated for 3V for 2} hours with a 125 watt medium pressure mercury lamp, the temperature being kept at -20 ° all the time. The solution was then washed with water (2X200 ml) and the combined aqueous layers were washed with dichloroethane (50 ml). The combined organic layers were dried and evaporated to give an orange colored solid which was chromatographed on Kjeselgel G (250 g) with methylene chloride-acetone (9: 1) as the solvent. In this way, the title compound was obtained in two batches, both in the form of almost colorless solids, showing the following constants:

(i) (0.904 β. 15.5%), m.p. = 150 to 155 ° (decomposition), [oje = + 31.5 °, X _m × 282.5 nm (E ', \ = 165);

(ii) (2.306 g, 39.8%), m.p. = 156 to 168 ° (decomposition), [a] ₀ = 36.7 °, X _mx 282.5 nm (£! ^ = 168).

(viii) Photochemically initiated bromination
at 0 ° in 1,2-dichloroethane

A solution of 2,2 ^ -Trichloräthyl-3-methyl-7jS-phenylacetamidoceph-S-em ^ -carboxylate-ljS-oxide (5 g, 10.4 mmol) in 1,2-dichloroethane (400 ml) was at 0 ° Stirred with N-bromosuccinimide (2.80 g, 15.7 mmol, 1.51 equiv.) Under a dry nitrogen atmosphere. The mixture was illuminated for 1 hour with a 125 watt medium pressure mercury lamp using a Pyrex filter, keeping the temperature at 0 ° throughout the reaction. The solution was washed with water (2 × 100 ml) and the combined aqueous The layers were washed with 1,2-dichloroethane (50 ml), the combined organic layers were dried and evaporated to give a yellow oil which was soluble on silica gel G (160 g) with methylene chloride-acetone (9: 1) as a solvent. In this way the title compound was obtained in the form of an almost white solid (2.805 g, 48%), m.p. = 156 to 164 ° (decomposition), [a] _p = + 30 °, ^, "283 nm ( £} ^r ™ = 171.5) The fractions collected from those containing the title compound were pooled and the fractions eluted from those containing the titre compound were combined, evaporated with methanol triturated, the 2,2,2-trichloroethyl -3-bromomethyl-7> (DL-2-bromophenylacetamido) -ceph-3-em-4-carboxylate-ljS-oxide (0.751 g, 11.3%), melting point = 191 to 192 ° (decomposition;, [a] _D = + 5.1 °, X _max 281.5 nm (£; · „= 152).

(χ) Photochemically initiated bromination
with N-bromosuccinimide in benzene under

Reflux heating

A solution of 2,2,2-trichloroethyl-3-methyl-7jß-phenylacetamidocephO-em-1-carboxylate-Le-oxide (5 g, 10.4

so mmol) in benzene (500 ml) was stirred and refluxed in an "inert nitrogen atmosphere and with a fluorescent strip light (8X40 Watt lamps) irradiated. N-bromosuccinimide (3 g, 16.85 mmol) was added and the mixture turned 30% Heated to reflux for minutes and then evaporated. The remaining yellow gum was dissolved in methylene chloride-acetone (10: 1) and on silica gel G (0.05 to 0.2 mm, 150 g) with methylene chloride-acetone (10: 1) as the eluent. on

In this way, the 3-bromomethyl compound (2.40 g, 41%) was obtained in the form of a cream-colored solid, melting point = 150 to 155 °, [a] _D = + 31 °, ^, "283 nm (£"" = 164) The behavior of this product in thin-layer chromatography and its IR and PMR spectra

b5 were identical to that of an authentic sample of the Product.

The chromatographic fractions that mac before received those containing the 3-bromomethyl compound-

th, were combined and triturated with acetone-ether, the 2,2,2-trichlcrethyl-3-bromomethyl-7 /? - (DL ^ -bromophenylacetamidoJ-cepn-S-em ^ -cariioxylattff oxide obtained (380 mg ), in the form of a colorless solid. Mp. = 190 to 192 ° (decomposition), [a) _D = + 15.3 °, A _m "282 nm (£ {*. = 163), v _raav (CHBr ₃ ) 3350 (NH), 1798 (azetidin-2-one), 1735 (CO ₂ R), 1670 and 1510 (CONH), 1045 cm " ¹ (SO), r 1.09 (1 H, d, J 8 Hz; NH), 2.42 and 2.64 (5 H, two m; C ₆ H ₅ ), 4.00 (1 H, s; C ₆ H ₅ -CHBr-). 4.08 (1 H, dd, J 4.5 and 8 Hz; C ₇ -H), 4.75 and 4.93 (2 H, AB-q, J 12 Hz; -CH ₂ CCl ₃ ), 4.90 (1 H, d, J 4.5 Hz; C ₆ -H), 5.29.5.45 and 5.34 (two AB-q, 2 protons in total, created by the product being a mixture of diastereomers, J 12 Hz; -CH ₂ Br ), 5.85 and 6.10 (two AB-q, 2 protons in total, J 19 Hz; C ₂ -H ₂ ). Recrystallization of a small sample yielded an analytically pure sample, mp = 193 to 194 ° (decomposition) , [«] ,, - + 21.1 °, k _max 284 nrn {ε = 10 400).

Analysis: Ci ₈ H ₁₅ Br ₂ CI ₃ N ₂ O ₅ S (639.6)

Calculated:

C 33.9; H 2.4; N 4.4; S 5.0%;

Total halogen content: 5.00 equiv. / Mole of compound Found:

C 34.4; H 2.4; N 4.1: S 5.3%;

Total halogen content: 4.88 equiv / mole compound

Evaporation of the Mutteilf-ugen of the dibromo compound gave 2,2,2-trichloroethyl-2j3-bromo-3-methyl-Tjö-phenylacetamido-ceph-S-em ^ -carboxylate-ljS-oxide (1.33 g) in the form of a yellow Foam. [a] _D = -121 ° (CHCl ₃ ), X _max 289 nm (ε = 6590), v _max (CHBr ₃ ) 3350 (NH), 1798 (azetidin-2-one), 1735 (CO ₂ R), 1670 and 1510 (CONH), 1045 cm " ¹ (SO), r (CDCl ₃ ) 1.70 (5 H, s; C ₆ H ₅ -), 3.40 (1 H, d, J 10 Hz; NH ), 3.87 (1H, dd, J 10 and 4.5 Hz: C ₇ -H), 4.86 (1 H. d. J 4.5 Hz: CH), 4.91 (1 H, s; C ₂ -H), 5.01 and 5.16 (2 H, AB-q, J 12 Hz; CH ₂ CCl ₃ ), 6.37 (2 H, s; C ₆ H ₅ CH ₂ ), 7.70 ( 3 H, s; C ₃ - CH ₃ ). The crude foam showed a total halogen content of 4.0 equiv / mole of compound.

Example B3

Bromination of 2,2,2-trichloroethyl-7y? -Formamido-S-methylcephO-em-S-carboxylate-ljS-oxide (i)

with formation of 2,2,2-trichloroethyl-3-bromomethyl-TyS-foimamido-cephO-em ^ -carboxylate-l ^ S-oxide

(i) Photochemically initiated bromination
in chloroform with refluxing

A solution of 2,2,2-trichloroethyl-7jS-formamido-S-methylceph-S-em ^ -carboxylate-1ß-oxide-hemi-ethanol solvate (2.065 g, 5 mmol) in chloroform (200 ml) was washed with water (3 x 100 ml) to remove the ethanol, dried and concentrated to approx. 100 ml. N-bromosuccinimide (1.435 g, 7.5 mmol) was added, and the reaction mixture was heated to reflux for 30 minutes in a stream of nitrogen while it was exposed to an 8 X40 watt tungsten ribbon light. Then the TLC (acetori methylene chloride, 1: 4.2 x eluted) the presence of less polar compounds together with a trace of the starting material. The reaction mixture was mixed with water (2 × 100 ml and 1 × 50 ml) to remove the N-succinimide washed, dried and evaporated. The remaining foam was in the same volume Acetone-methylene chloride (1: 4) and dissolved on iueselgel G (TLC quality, 100 g) with acetone-methylene chloride (1: 4, 500 ml) and then acetone-methylene chloride (1: 2) as eluent chromatography. 25 ml fractions were collected and checked by TLC (Acetone-methylene chloride, 1: 4). The appropriate fractions were combined and evaporated, whereby an almost colorless solid (1.08 g) was obtained which was treated with a mixture of ether (40 ml) and Acetic (5 ml) to give the title compound

(0.95 g, 40%), melting point = 172 to 174 ° (decomposition), X _max 283 nm (£ j * "= 201), part (154 mg) of which was obtained from a mixture of warm chloroform (25 ml) and low-boiling petroleum ether (boiling point 40 to 60 °, 10 ml) recrystallized to give an analytical sample (121 mg). Mp. = 173 to 174 ° (decomposition), [a] _D = + 4.3 °, X _max 283 nm (c = 9980), v _max 3265 (NH), 1785 (azetidin-2-one), 1735, 1720 and 1240 (CO ₂ R), 1660 and 1530 (CONH) and 1030 err. " ¹ (S ^ O), r 1.58 (1H, d, J 9 Hz; NH), 1.84 (1H , s; CHO), 3.99 (1H, dd, J.

JO 9.5 Hz; C ₇ -H), 4.77 and 4.95 (2 H, AB-q, J 12 Hz; CO ₂ CH ₂ CCl ₃ ), 4.94 (1 H, d, J 5 Hz; C ₆ -H ), 5.33 and 5.47 (2 H, AB-q, J 10 Hz; C ₃ -CH ₂ Br), 5.93 and 6.20 (2 H, AB-q, J 18 Hz; C ₂ -H ₂ ).

₂ . Analysis: C _n II ₁₀ BrCl ₃ N ₂ O ₅ S (468.6)

Calculated:

C 28.2; H 2.15; N 6.0; S 6.8%;
Total halogen content: 4.00 equiv. / Mole of compound Found:
C 28.1; H 2.1; N 6.0; S 6.9%;

Total halogen content: 4.00 equiv / mole of compound

(ii) Photochemically initiated bromination
at 12 °

A solution of 2,2.2-trichloroethyl-7 # -formamido-S-methylceph - ^ - em ^ -carboxylate-l ^ -oxide (5 g, 12.85 mmol) in 1,2-dichloroethane (125 ml, which can be passed through dried by basic alumina) was cooled to 0 ° and under a nitrogen atmosphere stirred with N-bromosuccinimide (3.42 g, 19.25 mmol, 1.5 equiv.). The mixture was made with using a 125 watt medium pressure UV lamp a Pyrex filter * irradiated. The temperature of the reaction rose to 12 ° and was continued until completion the conversion as determined by TLC held there. The mixture was then made with water (3 x 50 ml) and the aqueous layers were washed with 1,2-dichloroethane (50 ml). the

organic splinters so combined were dried and concentrated to approximately 10 ml when crystallization started. The mixture was cooled overnight and then filtered. The solid was washed with a dichloroethane-ether mixture (1: 1.5 ml), then with ether and then dried in vacuo at 40 °. The title compound was obtained in the form of a colorless powder (3.23 g, 53.5%), melting point = 160 to 162 ° (decomposition), [a] _D = 4.1 °, X _max 282.5 nm (E. ',) _m = 196). The product was similar in its PMR spectrum and in its Rp values to that of Example B 3 (i).

(iii) Photochemically initiated bromination at 0 °

A solution of 2.2.2-TricMoräthyl-7, /? - forrnamido-3-methylceph-3-em-4-carboxylate-l> oxide (4.223 g, 10.83 mmol) in dry 1,2-dichloroethane (400 ml) was cooled at 0 ° under a dry nitrogen atmosphere and with N-bromosuccinimide (2.89 g, 16.28 mmol.

1.5 equiv.) Stirred. The temperature of the mixture was kept at 0 ° while it was irradiated with a 125 watt medium pressure UV lamp with a Pyrex filter. After 1 hour, the reaction solution was a) washed with water (3 * 100 ml), and the aqueous layers were washed with 1,2-dichloroethane (50 ml) The combined organic layers were dried and evaporated to give a slightly yellow sticky solid which was triturated with methanol (25 ml) and gave the title compound t »in The result was the form of a cream-colored solid (2.405 g, 47.5%), m.p. = 148 to 155 ° (decomposition), X _n ^ 283 nm (£ {* _cr , = 198). The filtrate from this was purified on silica gel G with methylene chloride -Acetone (1: 1) was chromatographed as a solvent, a further amount of the title compound being obtained in the form of a cream-colored solid (1.215 g, 23.9%), melting point = 132 to 140 ° (decomposition), X _max 283 nm (E ',) _m = 182) Both samples of the product were similar in their PMR spectrum and their Rp values to those in Example B 3 (i) describes samples.

(iv) Photochemically initiated bromination
at -20 °

25th

A solution of 2,2,2-trichloroethyl-7je-formamido-3-methyiceph-3-em-4-carboxylate-l-β-oxide (10 g, 25.7 mMc'O in dry 1,2-dichloroethane ( 400 ml) was cooled at -20 ° under a dry nitrogen atmosphere, N-bromosuccinimide (4.80 g, 27.0 mmol, 1.08 w equiv.) Was added to the solution and then stirred and the solution became Irradiated for 4 hours with a 125 watt medium pressure UV lamp with a Pyrex filter, the temperature being kept at -20 ° for the entire time c). The mixture was then warmed to 10 ° and treated with saline (3x50 ml) and the aqueous layer was extracted with 1,2-dichloroethane (50 ml). The combined organic layers were dried and concentrated to approximately 100 ml and then cooled. The title compound, which was obtained by filtration, was a colorless solid (8.446 g, 70%), m.p. = 160 to 165 ° (decomposition), [a] _D = + 4.7 °, X _may 282 nm {E ', \ = 194) The PMR spectrum of this product showed that it is 7% of the A Containing starting material, the presence of 4-, d) was confirmed by TLC analysis. The mother liquors from the product were chromatographed on silica gel G with methylene chloride-acetone (1: 1) as solvent, in this way a further amount of the title compound (0.785 g, 6.5%), melting point = 167> o to 170 was obtained ° (decomposition), [a] _D = + 3.3 °, X _mux 283 nm {Ε ', \ = 211). This sample of the product was similar in its PMR spectrum and Rp values to the sample obtained in Example B3 (i). The chromatography also gave an amount of the starting material (0.300 g, 3% material used), melting point = 168 to 170 ° (decomposition), X _max 269 nm (££ "= 184).

(v) bromination with photochemical initiation,
supplied by tungsten light

N-bromosuccinimide (6.05 g, 1.5 equiv.) Was added to a stirred solution of 2,2,2-trichloroethyl-7 /? - formamidoO-methylceph-S-enM-carboxylate-leoxide (8.86 g, 22.7 mmol) in dry 1.2-dichloroethane (400 ml) at 0 ° under a dry nitrogen atmosphere. The temperature was kept at 0 ± 5 °, and exposure was then carried out for 2 hours with six tungsten bulbs (150 watts), then with 3 tungsten bulbs for a further 2V for ₄ hours. The orange colored solution was washed with dilute sodium acetate solution (200 ml), water (200 ml), combined with the 1 ^ -dichloroethane (200 ml) used to wash the combined aqueous layers, dried and reduced to a small volume evaporated to give the title compound as an almost white solid (6.36 g, 60%), Λ _(ΜΧ 282 nm (£! * „= 204).

A solution of 2,2,2-trichloroethyl-7 ^ -formamido- "" - methylceph-3-em-4-carboxylate-lj & oxide (10.0 g,

25.6 mmol) in dry 1,2-dichloroethane (400 ml) was reacted with N-bromosuccinimide (6.84 g, 1.5 equiv.) Under a dry nitrogen atmosphere Hour at -10 ± 5 ° and then used for 4 hours at -20 °. The title compound was obtained as an almost white solid according to the procedure described in part a) (7.71 g, 64.4%), X _max 283 nm (£ {>", = 201).

A solution of 2,2,2-trichloroethyl-7> formamido-3-methylceph-3-em-4-carboxylaH £ oxide (8.86 g,

22.7 mmol) in dry 1,2-dichloroethane (400 ml) was mixed with 1,3-dibromo-5,5-dimethylhydantoin (4.87 g, 0.75 equiv.) In a dry nitrogen atmosphere using a tungsten light Initiation (3X150 Wattbimen) at 0 ° 1 _1/2 hours, then implemented at -20 ° for 5 hours. Isolation, as described in a), provided the title compound as an almost white solid (6.476 g, 61%), X _max 282.5 nm (E? „ -199).

A solution of 2,2,2-trichloroethyl-7j8-formamido-S-methylcephO-em ^ -carboxylate-IjiJ -oxide (442 g, 114 mmol) in 1,2-dichloroethane (250 ml) was with sodium acetate solution (15 ml , 4.25 molar) by adding glacial acetic acid, buffered to pH = 7. This two-phase solution was then mixed with l ^ -dibromo-5 ^ - dimethylhydantoin (2.74 g, 0.83 equiv.) In an atmosphere of dry nitrogen at 0 ° using tungsten light initiator (3 x 150 watts) during implemented l '/ ₂ hours. The title compound was isolated as described in a), giving an almost white solid (3.769 g, 70%), X _mox 282.5 nm (£ »» »= 196).

(vi) Bromination using a 125 watt medium pressure mercury lamp with Pyrex filter in 1,2-dichloroethane using a variety of brominating agents

Conc Vol. Of Mol-Xquivaleiu of Temp. Time (11) ') Fp. [οίο £ ', _rm at tration (I) 1,2-Di Brominating agents Hours. 282-3 nm ing / lOOml chlorine 7i Off ethane prey

300 1.5 N-bromosuccinimide

300 1.5 N-bromosuccinimide

+ 1 ml H ₂ O

3 '/ 2

I '/ 4

56.5 55

164-165 ° 169-171 °

+ 0.3 °
-3.5 °

201 194

continuation

Conc Vol. Of Mole equivalent of Temp. Time (itf) Fp. E ', * _m at tration (I) 1,2-Di Brominating agents Hours. 282-3 nm in g / 100 ml chlorine ri off ethane prey

c 2,300 1-5 N-bromoacetamide

d 2 300 1.5 N-bromocapro-

lactam

e 2 300 1.5 N-broraphtha imid

f 2 300 0.75 U-dibromo-5.5-

dimethylhydantoin

g 2 300 0.75 l, 3-dibromo-5.5-

dimethylhydantoin + 3 ml H ₂ O

h 2 250 0.75 U-dibromo-5,5-di-

methylhydantoin + Na ₂ CO ₃ (I equiv.) + 4 ml H ₂ O

i 2 250. 0.75 U-dibromo-5,5-di-

raethylhydantoin + 3 ml H ₂ O

j 2 300 0.75 U-dibromo-5-ethyl-

5-methylhydantoirr

k 2 300 0.75 l, 3-dibromo-5-iso-

propyl-5-methylhydantoin

I 2 250 1.5 bromine

r, 7 2 250 1.5 1,3,5-tribromo

1,2,4-triazole

-20 0

0 0

14 44.7 161-165 ° + 0.85 °

5 '/ 4 50.8 168.5-170.5 ° + 0.5 °

4 '/ 2 55.8 *) 162-164 ° + 1.6 °

I ³ A 55 168-170 ° -5.15 °

58

59.5

164-165 °

165-168 °

-17 I ¹ A 65.3 170-17Γ

-5.5 °

-9.6 °

-0.2 °

199 199

194

204

194

203

201

2 '/ 2 53 164-166 ° -2.7 ° 197

I ¹ A 50.8 167-170 ° -5.6 ° 201

4 012.6 ") 160-170 ° + 1.85 ° 212

3 035.5 °°) 161-164 ° + 1.5 ° 212

- Isolated after washing with water, by concentrating the solution. = Contaminated with phthalimide.

= 30% (1) was recovered although all Br _{2 was} consumed.

= 13% (1) was recovered.

- The product was determined by chromatography on silica gel! G isolated.

(vii) Bromination at -20 ° with photochemical initiation at 350 nm

N-bromosuccinimide (27.4 g, 1.5 equiv.) Was added to a stirred solution of ^^ - tricnloroethyl-T / I-formamido ^ -Methylceph-S-enM-carboxylate-ljS-oxide (40 g, 0.103 mol ) added in dry 1,2-dichloroethane (2 1) and cooled to -20 ° in an atmosphere of dry nitrogen. This mixture was passed at -20 ° for 9 hours through a Pyrex snake which surrounded a 40 watt UV tube with a peak at 350 nm. The dark orange colored reaction solution was washed with water (3X11), with the 1, 2-dichloroethane (11), which had been used to backwash the combined aqueous washing solutions, combined, dried and evaporated to a small volume, the title ester-1 /? - oxide being obtained in the form of an almost white solid (24, 46 g, 51%), mp = 160 to 162 °, [a] _D = -6 °, X _max 282 nm (E ', ^x _cm = 202).

Example B4

Bromination of tert-butyl-T ^ -formamido-S-methylcephO-em ^ -carboxylate-bS-oxide, under Production of tert-butyl-S-bromomethyl-TyS-formamidoceph-S-em ^ -carboxylate-ljS-oxide

(i) Photochemically initiated bromination with refluxing

A suspension of tert-butyl-7 / J-formamidoceph-3-em-carboxylate-L # oxide (314 g, 1 mmol) and N-bromosuccinimide (287 mg, 1.5 equiv.) In benzene (50 ml ) was heated at reflux for 30 minutes in a stream of dry oxygen-free nitrogen while irradiating with an 8X40 watt tungsten ribbon light. The benzene was removed in vacuo and the residue was dissolved in acetone-methylene chloride (1: 4, 5 ml) and chromatographed on silica gel G (TLC quality, 40 g) using acetone-methylene chloride (1: 4) as the eluent. Fractions of 10 ml were collected and checked by TLC (acetone-methylene chloride, 1: 2). Fractions 29 to 45 were combined and evaporated to give a pale orange colored solid (171 mg), A _m "278.5 nm (££" = 208), which was dissolved in acetone (approx. 4 ml). Addition of low-boiling petroleum ether (boiling point = 40 to 60 °, approx. 5 ml) precipitated the bromine

ester as a cut colorless gelatinous solid from (117 mg, 30% X softens at approx. 175 °, decomposes at approx. 200 °, [from - + 264 °, X ^ 278 nm {ε - 10 150), ν. «, 3320 (NHX 1770 (azetidin-2-one), 1716 (CO ₂ R), 1682 and 1526 (CONH) and 1021 cm " ¹ (S-OX r 1.64 (IH, d, J 9 Hz; NH), 1.82 (IH, s; NHCHO), 4.03 (IH, dd, J 94 Hz; C ₇ -HX 5.01 (IH, d, J 5 Hz; C ₆ -H), 547.5.61 (2H, AB-q, J10 Hz; Cj-CH ₂ Br), 6.02, 6.30 (2H, AB-q, J 18 Hz; C ₂ -H ₂ X 840 (9H, s; CO ₂ C (CHj) ₃ ).

(ii) Photochemically initiated bromination at -20 °

A suspension of tert-butyl-7j8-formamido-3-methylcepb-3-em-4-carbo3cylate-lj8-oxide (7.55 g, 24 mmol) in dry 1,2-dichloroethane (420 ml) was at 25 ° stirred and then briefly heated to 60 ° in order to achieve complete solution. The solution was cooled to about 30 ° and N-bromosuccinimide (6.41 g, 36 mmol) was added. Silver sheet exposed with a Pyrex filter *, the temperature being kept in the range of -15 ° to -20 ° during the whole time. The solution was washed with 0.5 M aqueous sodium acetate solution (100 ml) and water (100 ml), dried and evaporated. The gelatinous solid that remained was dissolved in chloroform (approx. 50 ml) and chromatographed on a column (internal diameter 94 cm) of silica gel (0.05 to 0.2 mm, 200 g). Elution with CMoroform ethyl acetate (1: 1, 11) and ethyl acetate (100 ml) provided a yellow gum which was triturated with ether (20 ml), measuring jasated-butyl-2j? -Bromo-S-bromomethyl-T / S-fönnaoirtoceph -3 -em -4 -carboxylate oxide was obtained in the form of a weakly yellow solid (1.43 g, 13%), m.p. - 128 to 130 °, ^ 295 nm (ET, - 181), which was triturated with a mixture of ether (approx. 8 ml) and methanol (approx. 1 ml), an analytical sample being obtained as a colorless solid (115 mg), melting point -132 ° to 134 °, [a ) " - -232 °. X ^ ₁ , 295 nm (c - 8650), IW ₁ (CHBr ₃ ) 3400 (NH), 1810 (azetidine-2-οηχ 1730 (CO ₂ R), 1702 and 1512 (CONH) and 1060 cm "'(p -OX r 1.44 (IH, d, J 9 Hz; NH), 1.83 (IH, s; CHO), 333 (IH, s; C ₂ -H). 3.94 (IH, dd, J 94 Hz ; C ₇ -H), 449 (IH, d, J 5 Hz; C ₆ -H), 5.56 (2H, s; C ₃ -CH ₂ Br), 8.45 (9H, s; CO ₂ CMe ₃ ).

Analysis:

■ 5 Calculated:

C 33.1; H 3.4; Br 33.9; N 5.9; S 6.8%;

Found:

C 33.0; H 3.4; Br 32.9; N 6.1; S 6.6%.

Further elution with ethyl acetate (700 ml) and then with ethyl acetate-acetone (2: 1, 800 ml) gave first mixed fractions and then the title ester US oxide in the form of a pale orange colored solid (4.82 g, 51%) , M.p. -> 200 °, X ^ 278 nm (E ¹ T, - 252X part of it (300 mg) was triturated with warm isopropanol (5 ml) containing a few drops of methanol to give a colorless solid ( 207 mg), m.p. **> 200 °, [a] _D - + 25 °. -U, 278 nm (r - 9800), v »" (CHBr ₃ ) 3440 (NH). 1802 (azetidine-2- on), 1720 (CO ₂ R), 1695 and 1508 (CONH) and 1038 cm " ¹ (SO).

Analysis: C ₁₃ H ₁₇ BrN ₂ O ₅ S (3934)

Calculated:

C 39.7; H 4.4; Br 20.3; N 7.1; S 8.15%;

Found:

C 39.6; H 4.4; Br 19.8; N 7.1; S 7.9%.

Example B5 Bromiening of 2J ^ -Trichlorithyl-3-msthyl-

7jff-phenoxyaceUmidoceph-3 ~ em-4-carboxyiLt-

t / 8-oxide with the production of 2,2,2-trichloro

ethyl-S-bromomethyl-Tje-phenoxyacetamidoceph-

3- € m-4-carboxylaH / ^ oxide

(i) Bromiening at -10 to 0 °

A solution of 2,2,2-TrichloräthyI-3-methyl-7 / iphenoxyaceiamidoccph - 3 - em -4 - carboxylate - \ ß- oxide (3.26 g, 646 mmol) in 1,2-dichloroethane (150 nü, ge

2 » dries by passing through basic aluminum oxide) was stirred with N-bromosuccinimide (1.76 g. 9.9 mmol, 14 equiv) in an atmosphere of dry nitrogen and cooled to -10 ° silver arc lamp (125 watts) using a Pyrex filter irradiated for 1 hour 25 minutes between -10 and 0 °. The mixture was then made with Water (3X75 ml) ^ wash, and the aqueous Layers were backed with 1,2-DicbJorättun (75 ml)

The combined organic layers were dried and evaporated to give a yellow gum which was triturated with methanol to give the title compound as an almost colorless solid (2.12 g, 564%), mp -148-150 °, [ a) _D - -30.4 °,

J5 / L ^ r 275 nm (E ¹ T, - 161), inflection at 271 nm (£ | * "-145) and 280 nm (E'T" - 153). Chromatography of the mother liquors provided an additional amount of the title compound (0.20 g, 54%). Mp - 152 to 1554 °. [a] _D --364 °, K ^ 276 nm (E ¹ T, - 161), inflection at 272 nm (£ {!. - 146) and 281 nm (£ {%, - 159). I'-rocrystallization of a small amount of the title compound from methanol gave an analytical sample, mp - 157 to 161 °, [a] _D - 36 °, Λ «* 276 nm (t - 9850), inflection at 271 nm (c -8650) and 282 nm (c - 9450), v""3420 (NH), 1789 (Aze-

*> tidin-2-one). 1745 (COjR), 1702 and 1521 (CONH). 1024 cm "'; r 1.83 (IH, d, J 9 Hz; NH), 2.60 to 3.15 (5H, m, C ₆ H ₃ ), 3.86 (IH, dd, J 9 Hz and 5 Hz; C ₇ -H), 4.74 and 4.91 (2H, AB-q, J 12 Hz; CH ₂ CCl ₃ ), 4.88 (IH, d, J 5 Hz; C ₆ -H) . 5.31 (2H, s, C ₆ HjOCH _2), 5.40 (2H, s;

.o CH ₂ Br), 5.87 and 6.17 (2H, AB-q, J 18 Hz; C ₂ H ₂ ).

Analysis: C "H _i6 BrCl ₃ N ₂ O ₆ S (574.7)

Calculated: C 37.6; H 2.8; N 4.9; S 5.6%;

Total halogen content: 4 equiv. / Mol

Found:

C 37.4; H 2.8; N 4.8; S 5.6%;

Total halogen content: 3.91 equiv. / Mol

(ii) Bromiening at -20 °

2,2,2-Trichloroethyl-S-methyl-T ^ -phenoxyacetamidoceph-3-em-4-carboxylate-1) β-oxide (10.78 g, 21.76 mmol) b-, was, as in (i ), with the exception that the temperature was kept at -20 °, whereby the title compound (8.36 g. 69%) was obtained in a manner similar to (i).

Example B6 Bromination of 2,2,2-trichloroethyl-3-methyl

7> {D-2- (2,2,2-tricnloroethoxycarbonylamino) -

2-phenylacetamido] -ceph-3-em-4-carboxylate-

l ^ -oxide for the production of 2,2,2 -Trichloräthyl-

3-bromomethyl-7XD-2- (2 ^, 2-trichloroethoxycarbonylamino> 2-pneuylacetamido] -ceph-3-cm-4-carboxy lat-

N-bromosucoinimide (1.87 g, 1.4 equiv.) Was added to a solution of 2,2,2-trichloroethyl-3-methyl-7> [D-2-phenyl ^ - ^ J ^ -trichlorethoxycarbonylaminoJ-acetamido] -ceph-3-ene>4-carboxylate-l> oxide (5.03 g, 7 ^ mmol) in dry 1,2-dichloroethane (400 ml). The suspension was cooled to -30 ° under a dry nitrogen atmosphere and irradiated for 1 hour with a 125 watt medium-thickness mercury UV lamp with a Pyrex filter, the temperature being kept between -20 and -30 ° throughout . Thin layer chromatography (acetone-methylene chloride, 1:19) indicated. that hardly any reaction had taken place, and so the temperature was raised to 0 ° and the irradiation was continued for 2 hours. The reaction mixture was washed with water (2 × 200 ml) and evaporated to give an orange-colored foam which had been chromatographed on silica gel G (150 g) with acetone-methyl chloride (1:19) as the eluent. The appropriate fractions were combined and evaporated to give the title compound as a yellow solid (2.44 g, 434%). Mp - 172 to 174 °, [a] _D - -14 °, X ^ 282 nra (c - 9000), v ^ 3330 (NH), 1790 (azetidin 2-one), 1738 (CO ₂ RX 1706 and 1530 (NHCOjR), 1660 and 1530 (CONH) and 1040 cnT ¹ (SO), r 144 (two superimposed IH, d; NHX 2.6 (5H, m; C ₆ H ₃ ), 4.06 (IH, dd; J 84 Hz and 44 Hz; C ₇ -H), 4.44 (IH, d, J 8 Hz; CH-NH), 4.78 and 4.95 (2H, AB-q, J 12 Hz; CO ₂ CH ₃ Ca ₃ ), 5.04 (IH, d, J 4.5 Hz; C ₆ -H), 5.19 (2H, s; NHCO ₃ CH ₃ Ca ₃ ), 537, 543 (2H, AB- q, J 10 Hz; CH ₃ Br), 6.03, 6.29 (2H, AB-q, J 18 Hz; C ₃ -H ₃ ).

Analysis: C ₃₁ H ₁₁ BrO ₄ N ₃ O ₇ S (749.1)

Calculated:

C 33.7; H 2.4; N 5.6; S 4.3%;

Total halogen content: 7.0 equiv / mole of compound

Found:

C 34.45; H 2.6; N 5.1; S 4.3%;

Total halogen content: 6.8 equiv / mole of compound

The subsequent fractions were evaporated to give unreacted starting material (0.87 g, 17%), X ^ 2684 fm (£ {». - 103).

Example B7 Bromination of p-methoxybenzyl-3-methyl- T / S-phenylacetamidocephO-em ^ -carboxylal- Iß-oxide for the production of p-methoxybenzyl

4-carboxy lat- ljS-oxy d

A solution of p-methoxybenzyl-3-methyl-TyS-phenylacctamidoceph-3-em-4-carboxylal-0e-oxide (4.00 g, 8.55 mmol) in dry U-dichloroethane (400 ml) was heated to -20 ° under a dry nitrogen atmosphere cooled, N-bromosutcinimide (228 g, 1.5 equiv.) was added and the mixture became a 125 watt mite high pressure mercury lamp using a Pyrex filters * exposed for 2 hours, the temperature remaining at approx. -20 ° the whole time became. The fine precipitate that precipitated had, was collected by filtration (1.80 g), [a] _o - + 114 °, Λ «« (0.1 M pH 6 phosphate), 254 nm (Ε ¹ ,), = 193) and 309.5 nm {Ε ·, \. - 67), r 7.97 (s; C ₃ -CH ₃ ), and the filtrate was washed with water (3 x 200 ml), ro ^; t the dichloroethane (100 ml) that you wash out

used in the combined aqueous wash solutions , combined, dried, and evaporated to give a red-black semi-solid. Trituration with methanol gave the title ester-ijS-oxide in As an off-white solid (254 mg, 5.4%), m.p.

π 171 to 174 ° (decomposition), [a] _D - -28 ° (Me ₂ NCHO), X ₁ ^ _x (MeOH) 2254 nm (ε - 16,500) and 272.5 nm (ε = 9050), inflection at 277.5 nm (c-8500), τ 1.64 (1H, d, J 9 Hz; NH), 2.63, 3.05 (4H, 2d, J 9 Hz; CH ₃ C ₆ R ₁ OCHj ), 2.70 (5H, s; C ₆ H ₅ ), 4.16 (IH, dd, 1 9.5 Hz; C ₇ -H), 4.74 (2H, s; CH ₃ C ₆ H ₄ ), 5.08 (IH, d, J 5 Hz; C ₆ -H). 5.38.5.58 (2H, AB-q, J 11 Hz; C ₃ -CH ₂ Br), 6.06.631 (2H, AB-q, i 18 Hz; C ₃ -H ₃ ), 6.24 (3H, s; OCK ^ 6,36,6,40 (2H, AB-q, C ₆ HsCH ₃ ). Chromatography of the filtrate on silica gel G gave p-methoxybenzaldehyde, which was equal to the IR spectrum with that of an authentic one Sample and by conversion into its 2,4-Dinitrophcnyihjjdrazon, m.p. - 250 to 251 °, was identified.

A portion (500 mg) of the acids obtained above by filtering the reaction mixture was dissolved in tetrahydro-

ju furan (50 ml) suspended and n? it a solution of Diazomethane esterified in ether. The solvents were removed and the remaining colorless Solid was dissolved in methylene chloride (40 ml). The resulting solution was diluted with water (20 ml) and

j) 3% sodium hydrogen carbonate solution (2X15 ml) washed, dried and evaporated, and the residue was subjected to preparative layer chromatography on silica gel G with acetone-methylene chloride (1: 1) as the eluent. Elution the less polar band provided methyl-3-bromomethyi-7 /? - phe · nylacetamidocephO-em ^ -carboxylate (104 g, 8.8%), melting point - 193 to 194 °, [a] _D - + 59 °, i ""277.5 nm (£ {*" - 197), during elution of the stronger polar band methyl-3-methyl-T / f-phenylacetamidoceph-S-em ^ -carboxylate

(170 mg, 19.7%), melting point - 210 to 215 °, \ o) _D - + 185 °, X _max 265 nm (£ · »« - 219).

Example B8

ίο bromination of tert-butyl ^ -methyl-Tyi-phenylacetamidocephO-em ^ -carboxylaH / S-oxide for the production of te; t.-butyl-3-bromomethyl-7) 8-phenylacetamidocephO-em ^ -carboxylate-l / S-oxide

Eiae solution of tert-ButylO-methyl-Tys-phenylacetamidoeeph - 3 - em - 4 - carboxylate - \ ß-oxide (339 mg, 1 mmol) and N-Üromsuccinimid (287 mg, 1.5 equiv.) In benzene ( 50 ml) were heated under reflux for 1 hour in a stream of dry nitrogen,

μ) while m ^;> an 8X40 watt fluorescent strip light was exposed. The reaction mixture was filtered off from traces of insoluble material, and the benzene was evaporated. The residue was dried on silica gel G (50 g) with acetone-methylene chloride (1:12)

nt as eluent chromatography. The appropriate fractions, determined by TLC (acetone-methylene chloride, I: 8) were combined, evaporated, triturated with ether (approx. 2 ml), whereby the title

ester-L <J-oxide was obtained in the form of a colorless crystalline solid (134 mg, 29%). Mp. = 158 to 160 °, [a] _D = + 52 °, k _max 279 nm (c = 9300), v _M "3250 (NH), 1786 (azetidin-2-one), 1710 (CO ₂ R) 1673 and 1526 (CONH) and 1028 cm "'(SO), rl, 57 (1 H, d, J 8.5 Hz; NH), 2.62 (5H, s, C ₆ H _5), 4.12 (IH, dd, J8.5 Hz; C ₇ -H), 5.01 (IH, d, J 5 Hz; C ₆ -H), 5.32 (2H, AB-q, J 12 Hz; C ₃ CH ₂ Br), 6.18 (2H, broad s; C ₂ -H ₂ ), 6.34 (2H, s; C ₆ H ₅ CH ₂ ), 8.42 (9H, s; CO ₂ C (CHj ) ₃ ).

Analysis: C ₂₀ H ₂₃ BrN ₂ O ₅ S (483.4)

Calculated:

C 49.7; H 4.8; Br 16.5; N 5.8; S 6.6%;

Found:

C 49.5; H 4 8; Br 16.0; N 5.5; S 6.7%.

Example B9 Bromination of 2,2,2-trichlorethylene-3-methyl-

7./H2,2,2-Trichloräthoxycarbonylamino)-ceph-

3-em-4-carboxylate-L8-oxide with manufacture

of 2,2,2-trichloroethyl-3-bromomethyl-7X2,2,2-tri-

chlorethoxycarbonylamino) -ceph-3-em-4-carb-

oxylate-ljS-oxide

A solution of 2,2,2-trichloroethyl-3-methyl-7ff- (2,2,2-trichloroethoxycarbonylamino) -ceph-3-em -4 -carboxylate-l> oxide (3.83 g, 7.13 mmol ) and N-bromosuccinimide (1.78 g, 1.4 equiv.) in benzene (350 ml) was refluxed for 1 hour in a stream of dry nitrogen while irradiating with 8 x 40 watts of fluorescent light from a tape light. The benzene was removed in vacuo and the orange-colored foam that remained was chromatographed on silica gel G (150 g) with acetone-methylene chloride (1:25) as the eluent. The appropriate fractions as determined by TLC (Aceion-Meihyicnchlorid, 1:15) were combined and evaporated to give an off-white solid (1.54 g). Trituration with ether (approx. 20 ml) gave the title ester L8 oxide (1.43 g, 33%), melting point = 202-204 °, [a] _D = -4.9 °, X _max 282.5 nm (ε = 9600), v _max 3380 (NH), 1778 (azetidin-2-one), 1740 (CO ₂ R), 1730 and 1526 (NHCO ₂ R) and 1020 cm " ¹ (SO), r 2.33 (IH, d, J 9 Hz; NH), 4.22 (IH, dd, J 9.5 Hz; C ₇ -H), 4.78, 4.95 (2H, AB-q, J 12 Hz; CO ₁ CH ₂ CCl ₃ ), 4.92 (IH, d, J 5 Hz; C ₆ -H), 5.11 (2H, s; NHCO ₂ CH ₂ CCl ₃ ), 5.35, 5.49 ( 2H, AB-q, J 10 Hz; C ₃ -CH ₂ Br), 5.92, 6.17 (2H, AB-q, J 18 Hz; C ₂ -H ₂ ).

Analysis: C ₁₃ H ₁₁ BrCl ₆ N ₂ O ₆ S (616)

Calculated:

C 25.3; H 1.8; N 4.55; S 5.2%;

Total halogen content: 7 equiv. / Mol

Found:

C 25.6; H 2.0; N 4.3; S 5.2%;

Total halogen content: 6.86 equiv. / Mol Example BIO Bromination of tert-butyl-3-methyl-7j8-phenox> -

acetamidoceph-S-em ^ -carboxylate-ljS-oxide under

Use of tert-butyl-S-bromomethyl ^ jS-phen-

oxyacetamidoceph-3-em-4-carboxylate-Le-oxide

(i) Photochemically initiated bromination -20 ° in the presence of water

The solution of terL-Butyl-S-methyl-TyS-phenoxy-

acetamidoceph-3-em-4-carboxylate-Lff-oxide in 1,2-D Chlorethane (62.2 ml) from the preparation process AlO (b) was made up with dry 1,2-dichloroctane 300 ml diluted, cooled to 5 ° and stirred in an atmosphere of nitrogen. 1,3-dibromo-5,5-dimethylhydantoin (5.1 g, 17.85 mmol) and water (1 ml) were added added, and the stirred reaction mixture was cooled to -20 ° and for 1V: hours with a 125 watt mercury lamp using one;

irradiated in Pyrex filters *. The brown solution was mi Washed water (2 x 100 ml), dried and evaporated to give a foam which was washed with Ace clay was rubbed. The crystalline material was filtered off, washed with cold acetone-ether (1: 1)

ι) and dried, giving the Titclester-lß-oxyi (4.19 g, 35% from tert-butyl-7> amino-3-methyl cephO-em ^ -carboxylate), melting point = 130 to 133 ° (Decomposition), [a] _D - -26 °, X _max 275 nm (r - 11300), inflection at 264 nm (ε = 8700), 270 nm (r = 10350) and

-Ό 279.5 nm (ε = 10750), v _max 3357 (NH), 1794 (azetidin-2-one), 1720 (CO ₂ R), 1694 and 1516 (CONH) and 1004 cm " ¹ (SO), r 1.86 (IH, d, J 10.5 Hz; NH), 2.5 to 3.2 (5H, m; C ₆ H ₅ OCH ₂ ), 3.93 (IH, dd, J 10 Hz; C ₇ -H) 4.97 (IH, d, J 5 Hz; C ₆ -H), 5.32 (2H, s; C ₆ H ₅ OCH ₂ )

r »5.41, 5.57 (2H, AB-q, J 9.5 Hz; C ₃ -CH ₂ Br), 6.00, 6.2 (2H, AB-q, J 19 Hz; C ₂ -H ₂ ), 8.46 (9H, s; CO ₂ C (CHj) ₃ 7.91 (IH,. «; Ca 0.15 M acetone).

Analysis: C ₂₀ H ₂₃ BrN ₂ O ₆ S (499.4) in

Calculated:

C 48.1; H 4.6; Br 16.0; N 5.6; S 6.4%; Found:

C 48.2; H 4.7; Br 15.7; N 5.6; S 6.2%; ) -. C 48.4; H 4.8; N 5.7%.

The mother liquors - became gravelly! G (150 g chromatographed using acetone-methylene chloride (3:17 as the eluent, mar 4 (i received a second batch of the ester L3-oxide (1.04 g 9% as above), m.p. = 128 to 132 ° (decomposition), [a] _D = -28 °, X _max 275 nm (E ',) _m = 218).

4i (ii) Photochemically initiated bromination + 5 ° to -5 ° in the presence of aqueous sodium hydrogen carbonate

A solution of tert-butyl-3-methyl-7/3-phenoxy

so acetamidoceph-3-em-4-carboxylate-Le-oxide (5.0 g 11.9 mmol) in 1,2-dichloroethane (250 ml) was aulO cooled and 1,3-dibromo-5,5-dimethylhydantoin (2.48 g 8.65 mmol), sodium hydrogen carbonate (1.00 g, 11.5 mmol) and water (5 ml) were added. The GE

5ί stirred reaction mixture was exposed to light through three 150-watt tungsten bulbs in a nitrogen atmosphere for 75 minutes while the temperature was kept between +5 and -5 ³ . The solution was washed with water (2 X 125 ml) with the dichloi

bo ethane (125 ml), which is used to wash the combined eggs had used aqueous washing solutions, combined, dried and evaporated, giving a yellow Foam received. Triturate with low-boiling acetone and petroleum ether (approx. 1: 1) and store in the refrigerator

O5 cabinet delivered the title Eier-ljS-oxide in the form of a light beige solid (4.49 g, 76%), melting point = 126 to 130 °, [a] ,, = -57 ° ,,! "" 274.5 nm (£ *. = 197), r7.90 (3H | s; 0.5 M acetone).

Example BIl

Preparation of 2,2,2-trichloroethyl-3-bromomethyl-TyS-phenoxyacetamidocephO-em ^ -carboxylate-8-oxide (the product of Example B5) from the starting material of the preparation process A5

without isolating the intermediate product

1,2,2 -TrichloroethylO-methyl-T / i-phenoxyacetamidoteph-3-em-4-carboxylate (10.00 g, 20.8 mmol) was as oxidized in the manufacturing process A5, with the exception that the temperature was kept at 0 °, whereby crude product (10.4 g) was obtained, which in 1,2-Di chloroethane (400 ml) was dissolved and brominated as in Example B 5 (i), whereby the title compound was obtained (8.57 g, 71.8%), mp = 156-157 °, [a] _D = - 43.6 °, X _max = 275 nm (£ | ^% _t "= 164), inflections at 270 nm (E ',) _m = 146) and 280 nm (E',) _m = 158).

Example B12 2,2,2-trichloroethyl-3-bromomethyl-7j5- (DL-2-bromophenylacetamido) -ceph-3-em-4-carboxylate-] _v >? - oxide

N-bromosuccinimide (1.43 g, 8.04 mmol) was added to a stirred solution of 2,2,2-trichloroethyl-7 ^ 8- (DL-2-bromophenylacetarnido) -3-methylceph-4-carboxylate (3, 0 g, 5.36 mmol) in dry 1,2-dichloroethane (150 ml) at 0 ° in a dry nitrogen atmosphere. The reaction solution was irradiated with ultraviolet light (125 watt mercury lamp with a pyrex filter ·) at 0 ° l '/ ₄ hours. The solution was then washed with water (3 x 75 ml) and combined with the 1,2-dichloroethane (75 ml) used to backwash the combined aqueous layers, dried and evaporated, whereby an oily solid was obtained. Trituration of this solid with methanol gave the title compound in the form of a pale yellow solid (2.19 g), melting point = 187 to 189 °, [a] _D = + 19.1 °, X _max 278.5 nm (E ', \ " = 150). Comparison of the product with that obtained in Example B2 (x) by TLC and PMR methods showed that the two were essentially the same, except that the product obtained in this example was 5 to 10% of the 3-methyl-18-oxide analog used as starting material was contaminated.

Claims (1)

Patent claims: 1. Process for the preparation of 3-bromomethylcephalosporin sulfoxide esters the general formula (ID COOR ²