CS195289B2 - Method of preparing cephalosporin compounds - Google Patents

Description

The invention relates to a process for preparing esters of cephalosporin compounds containing a carboxyl group at the 3-position of the dihydrothiazine ring of the cephem cyclic system.

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

wherein X is alkyl of 1 to 6 carbon atoms,

R is hydrogen, benzhydryl or alkyl of 1 to 6 carbon atoms,

R 1 is a hydrogen atom or an acyl group of the formula wherein R 1 is aryl of the formula

R "(Y) _{m -} CH 2 - wherein R" is phenyl or substituted phenyl wherein the substituents are 1 to 3 halogen atoms, hydroxy, nitro or C 1 -C 4 alkyl,

Y is O or S and m is 0 or i, or R * represents a substituted arylalkyl of formula

H

E wherein R "'is R" as defined above, 2-thienyl or 3-ithienyl, E is hydroxy or hydroxy protected with C 1 -C 4 alkanoyl, carboxyl or carboxy protected with C 1 -C 6 alkyl, or amino protected with (C 1 -C 6) alkoxy, or R 'denotes heteroarylmethyl of the formula R "CH 2" wherein R "is 2-thienyl, 3-thienyl, 2-furyl or 3-furyl, and when R" is a hydrogen atom of a pharmaceutically acceptable non-toxic acid salt, characterized in that the compound of formula (II),

where R 1 is R 1 as defined above,

R 11 is a carboxyl protecting group α

Z ‘is a group of the general formula

COOA where A is an alkali metal atom, is reacted with a compound of formula

Wherein X is as defined in formula I and T is an iodine or bromine atom, in the presence of hexamethylphosphoric acid, and optionally reacting the corresponding 2-cephem derivatives with a percarboxylic acid to give the 3-cephem derivatives and the sulfoxide formed; optionally, the 7-acyl group is cleaved by reaction with phosphorus pentachloride and an alcohol and optionally re-acylated at the 7-position by reaction with a halide or an active ester of R'-CO 2 H where R * is as defined above, optionally deesterifying the 3-carboxylic acid ester and / or an ester of a 4-carboxylic acid in an acidic medium and the product is isolated, optionally in the form of a salt of a 4-carboxylic acid, a benzhydryl ester or an alkyl ester of 1 to 6 carbon atoms of 4-carbonyl acid.

A variety of cephalosporin series antibiotics are known. All of these antibiotics exhibit the same basic cyclic structure, containing a four-membered [beta] -lactam ring attached to a six-membered dihydrothiazine ring, and differ in structure and biological effects from one another. Structurally known cephalosporin antibiotics differ from each other in the type of 7-acylamidosubstituted and also in the type of substituent at the 3-position of the dihydrothiazine ring. Desacetoxycephalosporanic acid, for example cephaloxin, has a 3-methyl substituent. Many known cephalosporins have a substituted methyl group at the 3-position. The desacetylcephalosporins have a 3-hydroxymethyl substituent. 3-Alkylthiomethyl and 3-heteroarylthiomethylcephalosporins are also described. They have recently been certain

3-methoxymethylcephalosporins described in U.S. Pat. No. 3,665,003 and 3-bromomethylcephalosporins have been described in U.S. Pat. U.S. Patent Nos. 3,647,788, 3,668,203 and 3,637,678.

In addition to 3-methyl- or 3-substituted methylcephalosporins, 3-formyl-substituted cephalosporins have also been reported. U.S. Pat. No. 3,351,596 of 7. XI. 1967 discloses a Chamberlin process comprising reacting 3-hydroxymethyl-7-acylamino-3-cephem-4-carboxylic acid with a diazo compound to form a 3-formylcephalosporin ester, followed by reacting the ester with an oxidizing agent selected from the group consisting of manganese dioxide and chromium trioxide. A similar reaction is described in Belgian Patent No. 768653. The corresponding 3-formylcephalosporinsulfoxides are described in U.S. Pat. No. 5,638,949; 3,674,784.

Another group of cephalosporins differing in the substituent type at the 3-position is described in Dutch Published Application No. 72 06,931, which discloses certain 3-unsubstituted cephalosporins, as well as a process for their preparation by decarbonylation of the corresponding cephalosporins.

3-formyl compounds.

The terms used in the foregoing definitions of compounds have the following meanings:

The term "alkyl of 1 to 6 carbon atoms" includes methyl, ethyl, n-propyl, n-butyl, isobutyl, pentyl, n-hexyl, cyclohexyl and the like aliphatic hydrocarbon chains.

When in the above definition R 1 is substituted phenyl, R 1 can be a mono- or disubstituted halophenyl such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-chlorophenyl, 3-chlorophenyl, 3-chlorophenyl, - bromophenyl, 4-bromophenyl, 3,4-bromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like, mono- or dihydroxyphenyl such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl and the like; morionyltrophenyl such as 3- or 4-nitrophenyl, mono- or disubstituted alkylphenyl such as 4-methylphenyl,

2,4-dimethylphenyl, 2-methylphenyl, 4-isopropylphenyl, 4-ethylphenyl, 3-n-propylphenyl and the like. Also, R 1 is disubstituted phenyl, where the substituents may be different, for example 3-methyl-4-hydroxyphenyl, 3-chloro -4-hydroxyphenyl,

4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and disubstituted phenyl with various substituents.

The term "protected carboxy" refers to a carboxy group protected by one of the commonly used ester protecting groups for carboxyl groups that block or protect the carboxyl group during the course of the reaction at other functional sites of the compounds. Such protected carboxyl

The 198288 groups are used for ease of cleavage by hydrolysis or hydrogenolysis. to the corresponding carboxylic acid. Examples of carboxylic acid protecting groups are tert-butyl, benzyl, p-methoxybenzyl, C 2 -C 6 alkanoyloxymethyl, β-iodoethyl, p-nitrobenzyl, diphenylmethyl (benzhydryl], phenacyl, p-halophenacyl, 2,2-trichloroethyl and the like ester-forming moieties: The type of these ester-forming moieties is not critical as long as the ester formed is stable under the reaction conditions described below. A preferred carboxyl protecting group is benzhydryl, p-nitrobenzyl, tert-butyl. [Beta], [beta] -trichloroethyl, p-methoxybenzyl and [beta] -odoethyl, most preferably benzhydryl, p-methoxybenzyl and tert-butyl.

In the foregoing definitions, the protecting groups for the carboxy group are not exhaustively defined. The function of these groups is to protect the reactive functional groups during the preparation of the desired products and then cleave without disturbing the remaining molecule. Many of these protecting groups are well known in the literature, and the use of other groups such as those described in J. F. W. Mc, Omie, "Protective Groups in Qrganic Chemistry", Plenum Press, 1973, is also appropriate. .

O

Examples of acyl groups R 1 -C 2 are benzo-4-yl, 4-chlorobenzoyl, 4-methylbenzoyl, 3,4-dichlorobenzoyl, 3-bromobenzoyl, 4-nitrobenzoyl and the like.

O

Examples of acyl groups R'-C-, where R * is a group of formula R '- (Y) m-CH 2 - and m are 0, are phenylacetyl, 4-chlorophenylacetyl, 3-hydroxyphenylacetyl, 4-hydroxy-3-methylphenylacetyl, 4- bromophenylacetyl, 4-nitrophenylacetyl and the like, and a. when Y is 1 and Y are oxygen, the acyl groups are phenoxyacetyl, 3-hydroxyphenoxyacetyl, 4-chlorophenoxyacetyl, 3,4-dichlorophenoxyacetyl, 2-chlorophenoxyacetyl, 3,4-dimethylphenoxyacetyl, 4-isopropylphenoxyacetyl, 3-nitrophenoxyacetyl and the like substituted. phenoxyacetyl groups, and when m is 1 and Y is S, examples of phenylthioacetyl groups are phenylthioacetyl, 2,5-dichlorophenylthioacetyl, 3-chloro-4-fluorophenylthioacetyl, 3-bromophenylthioacetyl and similar acyl groups.

Examples of acyl groups wherein R 1 is substituted arylalkyl of the formula

H

E is hydroxy-substituted arylalkyl, such as 2-hydroxy-2-phenylacetyl,

or a 2-formyloxy-2-phenylacetyl group of the formula.

O

OCHO and the like wherein the phenyl ring is substituted such as 2-hydroxy-2- (3-chloro-4-hydroxyphenyl) acetyl, 2-formyloxy-2- (4-hydroxyphenyl) acetyl, 2-hydroxy -2- (3-bromophenyl) acetyl, -2-formyloxy-2- (3,5-dichloro-4-hydroxyphenyl) acetyl, 2-formyloxy-2- (3-chloro-4-methoxyphenyl) acetyl, 2-hydroxy -2- (3-chlorophenyl) acetyl and the like.

Examples of the acyl group wherein R 'is a carboxyl or alkoxycarbonylein substituted arylalkyl group are 2-phenyl-2-carboxyacetyl, 2-phenyl-2-tert-butoxycarbonylacetyl, 2- (4-chlorophenyl) -2-benzyloxycarbonylacetyl, 2- (3-nitrophenyl) -2-carboxyacetyl and the like.

When R 'is an amino substituted arylalkyl or a derivative thereof, acyl groups are then 2-amino-2-phenylacetyl, 2-phenyl-2-tert-butoxycarbonylamino) acetyl, 2- (4-hydroxyphenyl) -2-aminoacetyl and the like acyl groups ;

O:. ₍ '||'. Examples of acyl groups R '-C', wherein R 'is a heteroarylmethyl group of the formula; R''- CH 2 -, are 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl.

Examples of diesters of 7-acylaminocephem-3,4-dicarboxylic acid, which are available according to the above procedure:

benzhy dryl-7- (2-thiazolylacetamido) -3- (2-bromoethoxycarbonyl) -2-cephem-4-carboxamide,

4‘-Nitrobenzyl-7-phenoxyacetamido-3-methoxycarbonyl-3-cephem-4-carboxylate. .

-1-oxide, tert-butyl-7-acetamide O-3-ethoxycarbonyl-3-cephem-4-carboxylate, benzhy dryl-7-phenylacetamido-3- (2-bromopropoxycarbonyl) -3-cephem-4- carboxylate,

4 ‘-nitrile of 1-7- (3-thienylacetamido) -3- (3-bromopropoxycarbonyl) -2-cephem-4-carboxylate

4‘-Methoxybenzyl 7- (2-thienylacetamido) -3- (2-bromoethoxycarbonyl) -3-cephem-4-carboxylate

Β (5 ') (3'), 3-trichloroethyl 7- (4-chlorophenoxyacetamido) -3- (3-bromo-2-butoxycarbonyl) -2-cephem-4-carboxylate,

2 '-] ethyl-7- (3-furylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylate and tert-butyl 7- (2-thlenylacetamido) -3- (2-bromoethoxycarbonyl) -2-cephem- 4-carboxylate.

Compounds of formula I may be prepared from 3-carboxycephem-4-carboxylic acid intermediate as described by Shaw et al. (Tetrahedron Letters pp. 689-692 (1973)), wherein the sodium carboxylic acid is reacted with an alkyl iodide in hexamethylphosphoramide. (HMPA 1 at room temperature. The preparation of sodium salts of 7-acylamino-3'-carboxy-3- (or 2) -cephem-4-carboxylic acid esters is described below. These salts react with alkyl iodides or alkyl bromides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, isopropyl iodide and n-butyl iodide in HMPA at room temperature and after 24-48 hours the corresponding esters are obtained in high yield. Similarly, sodium salts of 7-acylamino-3-carboxylic acid esters react with acyloxyalkyl halides in an inert organic solvent such as ethyl acetate , acetone and dimethylformamide, to give the corresponding acyloxymethyl esters, such as acetoxymethyl or pivaloyloxymethyl ester. esters of the carboxyl groups in the C-3 position, for example, trichloroethyl, p-methoxyhenzylester or benzyl, can be prepared by conventional esterification methods and procedures are well described in the cephalosporin art, as well as in other areas of general organic chemistry.

The 7-methoxy compounds are prepared from the 7-methoxylated starting compounds, i.e. the corresponding 7-methoxy-3-carboxy-3-cephem-4-carboxylic acid esters.

Removal of the ¹ ester protecting group at the 4-position yields new active antibiotic compounds that can be used against infections caused by Gram-positive and Gram-negative microorganisms.

Cefem-3,4-dicarboxylic acid esters can be converted directly to biologically active compounds by: a) conversion to the 3-cef emderivative (if the diester is originally 2-cephem), b) cleavage of the ester group protecting the G-4-carboxylic acid group.

Rearrangement of 2-cefem-derlvats to the corresponding

The 3-cephem compound is carried out by an oxidoreduction method well known in the chemistry of cephalosporin. Generally, this process is carried out by first oxidizing the 2-cephem compound, for example m-chloroperbenzoic acid, to give the corresponding 3-cephem-1-oxide derivative, which is then reduced with a trivalent phosphorus compound such as phosphorous bromide or phosphorous chloride, preferably using dimethylformamide such as solvents.

It should be emphasized that this rearrangement can be carried out in any of several stages of the preparation process. of active compounds. Preferably, the conversion of the 2-cephem compound to the 3-cephem compound can be carried out at a stage where the 2-cephem compound has no free carboxyl or amino group. Thus, when applied to the preparation of particularly active compounds, the conversion of 2-cephem intermediates with an acylamino group (with each carboxyl or amino-protected optionally present in the acyl) in the C-7 position with the carboxy-protected ester in the 4-position and the ester in the C- 3. Although the order of rearrangement in the reaction sequences is not critical, then when conditions permit, it is experimentally preferable to carry out the rearrangement until the C-3 substitueht corresponds to the final product. ,

Cleavage of the ester moiety of the molecule at C-4 into the free 4-carboxyl group is carried out in a conventional manner, the use of specific methods depending on the presence of a particular ester protecting group. For example, benzhydryl, tert-butyl and p-methoxybenzyl groups are readily cleaved by reaction with an acid such as trifluoroacetic acid, usually in the presence of a carbonate stabilizer such as anisole. Deesterification of the N, N-triethyl and 2-iodoethyl esters is carried out by reaction with zinc and an acid such as formic, acetic or hydrochloric acid. The cleavage of the p-nitrobenzyl ester protecting group is usually carried out by hydrogenating the ester in the presence of palladium, rhodium and the like, in suspension or on a carrier such as barium sulfate, coal, alumina and the like. It should be noted that these methods can also be used to cleave protecting groups that may be present at any point in the cephem compound.

Cleavage of the ester protecting group of the carboxy group at the 4-position of the 3-cephemediester as defined above results in the formation of 7-acylamino-3-alkoxycarbonyl (or haloalkoxycarbonyl) -3-cephem-4-carboxylic acids, which are preferred anti-bacterial compounds of the invention.

Examples of such compounds are:

7- (2-thienylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid,

7-Phenylacetamido-3- (2-bromoethoxycarbonyl) -3-cephem-4-carboxylic acid,

7-phenoxyacetamldo-3- (2-iodoethoxycarbonyl) -3-cephem-4-carboxylic acid,

7- (2,5-dichlorophenylthioacetamido-3- (2-bromopropoxycarbonyl) -3-cephem-4-carboxylic acid),

7-chloroacetamido-3-ethoxycarbonyl-3-cephem-4-carboxylic acid,

193289

7-benzanildo-3-bromoethoxycarbonyl-3-cephem-4-carboxylic acid,

7- (3-thienylacetamido) -3- (2-iodopropoxycarbonyl) -3-cephem-4-carboxylic acid and

7- (2-thiazolylacetamido) -3-ethoxycarbonyl-3-cephem-4-carboxylic acid. '

The preparation of the starting material, a salt of 7-acylamino-4-alkoxycarbonyl-3-cephem-3-carboxylic acid, can be summarized as follows:

1. preparation of a 7-acylamino-3-formylcephem-4-carboxylic acid ester;

2. preparation of an acetal derivative of (cyclic or acyclic) -3-formyl functionality;

3. Conversion of acetal to the corresponding cephem-3,4-dl-carboxylic acid diester by reacting acetal with N-bronfsuiccinimide in the presence of a free radical initiator in an ethereal organic solvent at a temperature d d of 20 to 100 ° C;

4. deesterification of the ester function

3-carboxylic acid to give the corresponding cephem-3-carboxy-4-carboxylic ester;

5. Preparation of the 3-carboxylic acid salt.

The process for preparing 3-carboxycephemic compounds can be carried out using starting materials with a side chain preferred for the preparative process (due to availability or stability to reaction conditions ¹ and then this side chain can be replaced with other 7-acylamine side chains, preferred for maximum biological The intermediate in these transacylations is the corresponding 7-aminocephem derivatives.

The free acids form salts of carboxyl groups with either inorganic and organic bases. Pharmaceutically acceptable salts are formed by reaction of the free acids with bases such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium 2-ethylhexanoate, calcium carbonate, ethylaine, 2-hydroxyethylamine and the like. Preferred salts are alkali metal salts. A preferred base for forming the potassium salt is potassium 2-ethylhexanoate. Salts can be converted to the free acids by acidification. The free acids and their salts are considered equivalent.

Cephem antibiotics are relatively non-toxic compounds that are useful for combating infections in warm-blooded animals when administered parenterally at a pharmaceutically effective non-toxic dose. 3- (Substituted 3-carboethyl-3-cephem compounds) may be formulated into liquid pharmaceutical forms, for example, in water, isotonic saline, and the like, and administered by the intramuscular injection or intravenous route at a dose of 125 mg to 16 g per day depending body weight of patient, the disease and other factors relating to the patient. the. Infection can control the repeated administration of smaller doses to be 'tional cases, it is possible to apply more not toxic dose. the antibiotic ^compounds: can be used as free acid or as a non-toxic salts such as sodium or potassium salt.

A very preferred class of active compounds are those of the formula

COOH wherein R 1 is an acyl group of R‘-C— and R R3 is alkyl of 1 to 6 carbon atoms. A particularly preferred group of antibiotics is represented by the above formula wherein R 5 is alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms, and R 6 is

H ^;

R10-C- wherein R10 is phenyl or 4-hydroxyphenyl and E is hydroxy, formyloxy or carboxyl. Examples of such preferred compounds are:

7- (D-mandelamino) -3-methoxycarbonyl-3-cephem-4-carboxylic acid,

7- (2-phenyl-2-carboxyacetamido) -3-ethoxycarbonyl-3-cephem-4-carboxylic acid,

7- [D-2- (4-hydroxyphenyl) -2-formyloxyacetamido] -3-n-propoxycarbonyl-3-cephem-4-carboxylic acid,

7- [D-2- (4-hydroxyphenyl) -2-hydroxyacetamido] -3-methoxycarbonyl-3-cephem-4-carboxylic acid,

- (2-phenyl-2-carboxyacetamido) -3-cyclohexyloxycarbonyl-3-cephem-4-carboxylic acid,

7- [D- (2-phenyl-2-formyl-oxyacetamide) -3-isopropoxycarbonyl-3-cephem-4-carboxylic acid,

7- (2-phenyl-2-carboxyacetamido) -3-ethoxycarbonyl-3-cephem-4-carboxylic acid.

185288

A n ti microbi μ c te s y

Compounds of formula I have been tested for activity against some. microorganisms to determine the antimicrohial effect. Tests against the organism identified as X-12, a gram-positive organism of Bacillus subtilis and Serratia marcescens, a strain called X-99, a gram-negative organism, were used as tests;

Tests against X-12 were performed as sensitivity disc tests, where the compound dissolves, usually at a concentration of 1 mg / ml, and was applied to a 6.35 mm filter pa12 filter disc. The test results are given as the average of the zones in which the growth of the organism is inhibited,

Tests against 'X-99 have been performed to test that the test organism is grown in nutrient solutions containing low concentrations of the compound. The results are. listed as the lowest concentrations that inhibit the growth of the organism.

The results of tests of typical compounds of formula I are as follows:

X-12

X-99

7- (2-thienylacetamido) -3-cephem-3,4-dibar- boxylic acid ..... 34 mm 7- (2-thienylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid 41 mm, ' methyl 7- (2-thienylacetamido) -3-carboxy-3-cephem-4-carboxylate 21 at 10 mg / ml; '' 1 ' 7- (2-thienylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid sodium salt « > 200 + µg / ml sodium salt of 7- (2-phenyl-2-formyloxyacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid idvojsodná salt of 7- (2-phenyl-2-karboxyacet- ^<* amido) -3-methoxycarbonyl-3 -4-carboxylic acid 33 mm, 16.5 1 7- [D- (2-phenyl-2-formyl-oxyacetamido)] - 3-methoxycarbonyl-3-cephem-4-carboxylic acid 40 Λ 7- (2-phenyl-2-formyloxyacetamido) -3- (4-nitrobenzyloxycarbonyl) -3-cephem-4-carboxylic acid 42 7 7- (2-phenyl-2-formyl-oxyacetamido) -3-chloro-3,4-dicarboxylic acid 130. 7- (2,5-dichlorophenylthioacetamido) -3-methoxycarbonyl-3-Cefem-4-carboxylic acid 41 '’ 22nd benzhydryl 7- [D- (2-phenyl-2-formyloxyacetamido)] -3-carboxy-3-cephem-4-carboxylate 21 at 5 mg / ml 7- (2-phenyl-2-karboxyacet amido) ^{-3-cephem-3,4-1} di'karboxylová acid 20 May 7- (2-thienylacetamido) -3- (2-bromoethoxycarbonyl) -3-cephem-4-carboxylic acid 31 7- [D- (2-phenyl-2-formyloxyacetamido)] -3- (2-bromoethoxycarbonyl) -3-cephem-4-carboxylic acid 39 3.5

193289

14

X-12 ¹ X-99,7- (2-Phenyl-2-carbonylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid

7- [D- (2-phenyl-2-aminoacetamido)] -3-methoxycarbonyl-3-cephem-4-carboxylic acid 7- (2-phenyl-2-formyloxyacetamido) -3- (4-nitrobenzyloxycarbonyl) sodium salt -3-chloro-4-carboxylic acid

7- (2-thienylacetamido) -3- (N, N-dimethylcarboxamide) -3-cephem-4-carboxylic acid

The invention is illustrated by the following examples. ’-.

P r a t a 1

Benzhydryl 7 - (2-thienylacetamido) -3-formyl-2-cephem-4-carboxylate

A solution of diphenyldiazomethane (19.4 g, 0.1 mol) was added dropwise to a suspension of 7- (2-thlenylaoetamido -) - 3-hydroxymethyl-2-cephem-4-carboxylic acid (23.6 g, 67 mmol) in 500 mL of ethyl acetate. ) in 50 ml of ethyl acetate. The reaction mixture was heated to reflux for 15 minutes, cooled to room temperature and evaporated to dryness in vacuo. The residue was washed with 1 L of ethyl ether / petroleum ether 1: 1 to give a pink solid: benzhydryl-7- (2-thienylacetamldo) -3-hydroxymethyl-2-cephem-4-carboxylate (33 g, yield 94.2%) ).

To a stirred solution of the benzhydryl ester in 1 liter of acetone was added dropwise 33.6 ml (76 mmol,

1.2 eq) of chromic acid. The reaction mixture was stirred at room temperature for 8 minutes. Isopropyl alcohol (35 mL) was then added and the mixture was stirred for an additional 5 minutes. The reaction mixture was concentrated in vacuo to a small volume and extracted with ethyl acetate (2 X 400 mL). The organic extracts were combined and washed successively with water (4X), sodium hydrogen carbonate solution, water, 1N hydrochloric acid, and brine, and then dried (Na 2 SO 4). Evaporation in vacuo to dryness afforded 31.3 g (95.4%) of crude benzhydryl-7- (2-thienylacetamido) -3-form of 1-2-methyl-4-carboxylate, which was purified by either crystallization from toluene ( 43% yield), or by chromatography; on silica gel (50 g) using a gradient. benzene-ethyl acetate (22 g, 62% yield). The product was recrystallized from methylene chloride / hexane to give. white needles (mp 149-150 ° C, IR (CHCl 3) 1785 (β-lactam C = O), 1680 (amide C = O) and 2830 cm ^-1 (forms 1 C = O), NMR (CDCl 3)

3.80 (s, 2, CH 2 sidechain), 5.12 (d, 1, J = 4.0 Hz, C 6 -H), 5.40 (q, 1, J = 4.0 and 8.0) Hz, C 2 -H), 5-, 51 (s, 1, C 4 -H) and 9.20 ppm (s, 1, CHO).

Analysis for C27H22N2O5S2:

Hg / ml mm Calcd: C 62.53, H 4.28, N 5.40;

Found: C 62.33, H 4.19, N 5.17.

Example 2

Benzhydryl-7- (2-thienylacetamido) -3- (1,3-dioxolan-2-yl) -2-cephem-4-carboxylate

Benzhydryl-7- (2-thienylacetamido) -3-? Ethyl 2-cephem-4-carboxylate (21.5 g, 41.5 mmol) was treated with 11.6 mL ethylene glycol (0.2 mol) and p-toluenesulfonic acid monohydrate (0.197). g, 1.04 mmol) in 500 mL of benzene. The mixture was heated to boiling for 10 hours using a Dean-Stark trap (1.5 mL of water was collected), cooled. and evaporated to dryness in vacuo. The product is taken up in ethyl acetate and washed successively with sodium bicarbonate solution (2x), water (2x) and brine, and then dried over sodium sulfate. Evaporation in vacuo to dryness gave the product which was chromatographed on 40 g of silica gel using a gradient of benzene and ethyl acetate. Crystallization of the purified product from melthylene chloride and hexane gave benzhydryl-7- (2-thienylacetamido) -3- (1,3-dioxolan-2-yl) -2-cep-4-carboxylate as colorless needles (15.07 g, 64.2%): mp 142-143 ° C, IR (CHCl 3) 1780 cm ^-1 (fact C = O), NMR (CDCl 3)

3.3-3.9 (m, 4, - CH2 --CH2 -),

3.83 (is, 2, CH2 side chain),

5.10 (d, 1, J = 4.0 Hz, C 6 -H),

5.17 fs, 1, acetal (CH),

5.21 (s, 1, C4-H) < a &gt;.

5.45 ppm (q, 1, J = 4.0 and 8.0 Hz, C2-H). Analysis for C29H26O6S2:

C 61.69, H 4.66, N 4.98 found C 61.69, H 4.43, N 5.10.

C onnection 3

Benzhydryl-7- (2-thienylacetamido) -3- (2-bromoethoxycarbonyl) -2-cephem-4-carboxylate

1S5289

Benzhydryl-7- (2-thienylacetamido) -3- (1,3-dioxolan-12-yl) -2-cephem-4-carboxylate (15.07 g, 25.8 mmol) was mixed with N-bromosuccinimide (5 , 25 g, 29.5 mmol) and azobisylbutyronitrile (36.5 mg, 0.25 mmol, 0.01 eq) in 1200 mL benzene. The mixture was heated to gentle boiling for 20 minutes, cooled and evaporated to dryness in vacuo to give a dark colored product. Chromatography on 30 g of silica gel with toluene / ethyl acetate gradient yielded 7.61 g (44.4%) of benzhydryl-7- (2-thienylacetiamido) -3- (2-bromoethoxycarbonyl) -2-cephem-4-carboxylate, m.p. 129-130 ° C, IR (CHCl 3) 1785 cm ^-1 (β-lactam, C = O), NMR (CDCl 3)

3.25 (t, 2, J = 6.0 Hz, CH2 Br),

3.83 (s, 2, CH 2 sidechain),

4.30 (t, 2, I = 6.0 Hz, O-CH 2 -),

4.95 (d, J, J = 4.0 Hz, Ce-H),

5.45 (q, 1, J = 4.0 and 8.0 Hz, C7-H),

5.50 (s, 1, C4-H);

7.80 ppm (s, 1, C 2 -H).

Analysis for CaHzsBf N2O6S2:

calculated calculated Preparation 4

H, 3.93; N, 4.37. C, 54.22; H, 3.90; N, 4.27

Benzhydryl-7- (2-thienylacetamido) -3- (2-iodoethoxycarbonyl) -2-cephem-4-carboxylate

Benzhydrylamine dry 1-7- (2-thIenylácetamldo) -3- (2-bromethoxykarbo ^| phenyl) -2-cephem-4-carboxylate (7.61 g, 12 mmol) was treated with sodium iodide (6.75 g, 45 meq) in 100 ml acetone. The reaction mixture was degassed and the lever heated to 35 ° C with stirring for 16 hours. The reaction mixture was then filtered and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water (3x), brine and dried over Na 2 SO 4. Evaporation in vacuo to dryness afforded 7.78 g (95.5%) of benzhydryl-7- (2-thienylacetamido) -3- (2-iodoethoxycarbonyl) -2-cephem-4-carboxylate:

IR (CHCl3) 1785 cm @ -1 ([beta] -lactam C = * 0], NMR (CDCl3)

2.96 (t, 2, J = 7.0 Hz, CH 2 I),

3.80 (s, 2, CH2 side chain),

4.24 (t, 2, J = 7.0 Hz, —OCH2—),

4.95 (d, 1, J = 4.0 Hz, C 6 -H),

5.24 (q, 1, J = 4,0 Hz, C7H, C4-H overlaid),

5.50 (s, 1.C 4 H) and, 7.80 ppm, (s, 1, C 2 -H).

Preparation 5

Benzhydryl-7- (2-thienylacetamido) -3-carboxy-2-cephem-4-carboxylate

Benzhydryl-7- (2-thienylacetamido) -3- (2-iodoethoxycarbonyl) -2-cephem-4-carboxylate (2.79 g, 4.05 mmol) was dissolved in a mixture of 8 mL glacial acetic acid and 48 mL dimethylformamide at 0 ° C and then treated with 2.79 g of zinc dust (10.5 eq.) for 1.5 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed successively with sodium bicarbonate solution (3 x], water, 1 N hydrochloric acid, brine) and then dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to afford 1.92 g (89%) of benzhydryl-7- ( 2 thiehylacetami ^| into) -3-carboxy-2-cephem-4-carboxylic carboxylate NMR (CDCl₃)

3.84 (s, side chain CH 2),

4.99 (d, 1, J = 4.0 Hz, Cs-H),

5.45 pm, C4-H and C7-H) a

7.80 ppm (b, C2-H).

Example 1

Benzhydryl-7- (2-thlenylacetamido) -3-18-propoxycarbonyl-2-ce-4-carboxylate

Isopropyl iodide (0.65 mL, 8.5 mmol) was added to a solution of berizhydryl-7- (2-thienyl-acetamldo) -3 ^, -capboxy-2-cephem-4-carboxylate sodium salt (0.725 g, 1.30 mmol) ) in 3.0 mL hexamethylphosphoramide (HMPA). The mixture was stirred at room temperature for 37 hours and then transferred to ethyl acetate with ethyl acetate. The solution was washed successively with 1N hydrochloric acid (3X) and brine (2X) and then dried over sodium sulphate. Evaporation in vacuo to dryness afforded the product which was chromatographed on 5 g of silica gel using a toluene / ethyl acetate gradient. There was thus obtained 522 g (70%) of the isopropyl ester as a white foam. IR (CHCl3) 1790 cm @ ^-1 ( ¹ H-lactam), NMR (CDCl3)

1,14 [two overlapped doublets, 6, —CH (CH3) 2],

3.84 (s, 2, CH2 side chain),

5.00 [mi 2, CeH and —CH (CH3) 2],

5.45 (q, 1.1, 4.0 and 8.0 Hz, C7-H),

5.55 (m, 1, C4 H),

6.9-7.5 (m, benzhydryl AzH and thlenyl) a

7.72 (m, 1, C 2 -H).

Example 2

Benzhydryl-7- (2-thienylacetamido) -3-isopropoxycarbonyl-3-cephem-4-carboxylate

A solution of m-Chloroperbenzoic acid (2.34 g, 11.5 mmol) in 40 mL of chloroform was added dropwise over 15 minutes to the cooled (ice bath for 10 minutes), stirred solution of benzhydryl-7- (2-thienylacetamido) -3-isopropyl. polycarbonyl-12-cephem-4-car-. boxylate (5.72 g, 10.25 mmol) in 250 mL of chloroform. After two hours, the reaction mixture was washed with sodium bicarbonate solution (3x), brine,

198289 dried over sodium sulphate and evaporated to dryness in vacuo to give the corresponding 3-oefemsulfoxide (thin layer chromatography - one spot). The product was dissolved in 100 ml of dimethylformamide (cooled in an ice bath) and then 1.37 was added. mL of phosphorous trichloride (15.7 mmol, 1.5 eq.) was removed from the ice bath and allowed to react at room temperature for 45 minutes. Ethyl acetate was added to the reaction mixture, and the resulting solution was washed successively with sodium bicarbonate solution (3x), water, (2x) and brine. After drying over anhydrous sodium sulfate, the solution was evaporated to dryness in vacuo. The crude product was chromatographed on 10 g silica gel using a toluene / ethyl acetate gradient. There was thus obtained benzhydryl-7- (2-thlenylacetamido) -3-isopropoxycarbonyl-3-cephem-4-carboxylate.

Example 3

7- (2-thienylacetamido) -3-isopropoxycarbonyl-3-cephem-4-carboxylic acid

To a cooled (5 ° C) suspension bezhydryl 7- (2-thienyl liacetamido) -3-isopropůxykarbonyl-3-cephem-4-carboxylate (0.316 g, 0.57 ^to 9 mmol) in 5 mL anisoiu 5.0 ml cold trifluoroacetic acid. The solid dissolved immediately and the resulting colorless solution was stirred under cooling for 10 minutes, then 50 ml of n-hepitan was added. The resulting solution was concentrated in vacuo to a small volume and a white solid precipitated. The solid was filtered off and dissolved in acetone. The acetone solution was evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate and extracted three times with cold sodium bicarbonate solution. The aqueous extracts were combined, overlaid with ethyl acetate, and acidified with 1 N hydrochloric acid. The organic phase was separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave 7- (2-thienylacetamido) -3-isopropoxycarbonyl-3-cephem-4-carboxylic acid; as a white solid. The product exhibits biological activity against both gram-positive and gram-negative organisms.

Example 4

Benzhydryl-7- (2-thienylacetamido) -3- (n-propoxycarbonyl) -2-cephem-4-carboxylate

Using the procedure described in Example i using 7- (2-thienylacetamido) -4-benzhydryloxycarbonyl-2-cephem-3-carboxylic acid sodium salt and n-propyl iodide, the title diester was obtained after silica gel chromatography. Yield: 75% IR (CHC) 1790 ^cm-1 (IJS-lactam C = 0) NMR (CDCl₃)

0.71 (m, 3, CH 3),

1.30 (m, 2, QCHaCl 2 CH 2),

3.71 (s, 2, side chain · - CH 2 -),

3.90 (m, 2, OCHOCH2CH3),

4.86 (d, 1, J = 4.0 Hz, Ce-H),

5.35 (q, 1, J = 4.0 Hz and 8, Q Hz, C7-H),

5.44 (d, 1, J = 1.0 Hz, C4-H);

7.65 ppm (d, 1, J = 1.0 Hz, C2-H). Example 5

Benzhydryl-7- (2-thienylacetamido) -3- (n-propoxycarbonyl) -3-cephem-4-carboxylate

To a cooled (5 ° C) stirred solution of 0.56-1 g of benzhydryl-7- (2-thienylacetamido) -3- (n-p-methoxycarbonyl) -2-cephem-4-carboxylate in 50 ml of chloroform was added a solution of 0.218 g of m-chloroperbenzoic acid in 2 mL of chloroform. After 12.5 hours, during which the mixture was allowed to warm to room temperature, the reaction mixture was washed with sodium bicarbonate solution (2X) and brine, and then dried over anhydrous sodium sulfate. Evaporation to dryness gave the product which was chromatographed on 5.0 g of silica gel. The purified product thus obtained is dissolved in 25 rolls of dimethylformamide. The solution was cooled in an ice bath and 0.214 ml of phosphorus trichloride was added. The reaction mixture was stirred without cooling for 1 hour and then transferred in ethyl acetate to a separatory funnel. The mixture was washed successively with sodium bicarbonate solution (3 times), water (4x) and brine (2 x), and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave the product which was chromatographed on 5.0 g of silica gel using a gradient of toluene and ethyl acetate. 0.328 g (58%) of benzhydryl-7- (2-thienylacetamido) -3- (m-propoxycarbonyl) -3-cephem-4-carboxylate is obtained in the form of a pale yellow solid IR (CHCl3) 1800 cm ^-1 ( [Beta] -lactam, C-O), NMR (CDCl3)

0.65 (m, 3, - 1 CH 2 CH 2 CH 3),

1.18 (m, 2, -OCH 3 CH 2 CH 3),. 3.68 (s, 2, side chain (CH2),

3.68 (m, 4, —OCH2 CH2 CH2 and C2-H),

4.85 (d, 1, I = 5.0 Hz, C 6 -H) a

5.82 ppm (q, 1, J = 5.0 and 9.0 Hz, C7-H). Example 6

7- (2-thienylacetamido) -3- (n-propoxycarbonyl) -3-cephem-4-carboxylic acid

Benzhydryl-7- ((2-thienylacetamido) -3- (n-propoxycarbonyl) -3-cephem-4-carboxylate) was de-esterified (65%) with a mixture of trifluoroacetic acid and aniso by the procedure of Example 3 to give the acid - The product shows biological activity against gram-positive and gram-negative organisms.

Example 7

Benzhydryl-7- (2-thienylacetamido) -3-methoxycarbonyl-2-cephem-4-carboxylate

NMR (CDCl3)

3.67 (s, CO 3 CH 3),

3.84 (s, CH2 side chain),

5.00 '(d, J = 4.0Hz, Ce-H),

5.00 (m, J = 4.0 and 8.0 Hz, C7-H),. 7.66 ppm (s, 1C 2 -H).

Example.

Benzhydryl-7- (2-thienylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylate

Mp 201 ° C (dec.), Methylene chloride-hexane, UV: λ _max 283 nm) (ε 13.6 x 10 ³ ), inflex 243 nm; IR (CHCl3) 1798 cm ^{@ -1} (n-lactam C = O), NMR DMSO-d6,

3.30 (s, 3, CO 2 CH 3),

3.74, 3.80 i (m, 4, CH2 side chain, C2-H),

5.25 (d, 1, J = 5.0 Hz, C 6 H).

5.90 (q, 1, J = 4.0 and 8.0 Hz, C7-H) a

7.0, 7.4 ppm (m, 13, benzhydryl ester _, thienyl).

Example 9

Methyl 7- (2-thienylacetamido) -3-benzhydryloxycarbonyl-2-cephem-4-carboxylate

NMR ^;

3.58 (s, 3, CO 2 CH 3),. .,

3.78 (s, 2, side chain CH 2),. 5.08 (d, 1, J = 4.0 Hz, C 6 H). .

5.42 i (s, 1, C4-H),

5.57 (q, 1, J = 4.0 and 8.0 Hz, C7-H) a

7.75 ppm (s, 1, C2-H). .

Example 10

Benzhydryl-7-amino-3-methoxycarbonyl-3-cephem-4-carboxylate

The same side chain cleavage procedure as described in Example 7 is followed. The corresponding 2-thienylacetamido compound is used as starting material. The product, the diester of the cephem compound, is isolated in 93% yield (one spot by thin layer chromatography). IC (CHCl 3) 1795 cm ^-1 (δ-lactam C = O), NMR (CDCl 3)

1.84 i (wide singlet, 2, NH2, exchangeable with D2O),

3.27 (S, 3, CO2CH 3),

3.41, 4.90 i (ABq, 2, J = 18.0 Hz, C2-H),

4.70 (d, 1, J = 5.0 Hz, iCe-H). 4.92 (d, 1, J = 5.0 Hz, C 7 -H),

7.11 (s, 1, benzhydryl CH);

7.4 ppm (s, 10, benzhydryl ArH).

Example 11

Benzhydryl-7- [D- (2-phenyl-2-formyl-acetamido)] -3-methoxycarbonyl-3-cephem-4-carboxylate

Carry out the same "deacylation procedure as described in. Example 8 only, benzhydryl 7-a ^mino-3-i methpxykarbonyl-3-cephem-4-carboxylate is used as starting material. Chromatography gave 0.211 g (61.2 percent) of product which crystallized from a mixture of methylene chloride and hexane as white needles (mp 207-208 ° C): IC (CHCl 3) 1800 cm ^-1 (O-lactam C = 0), NMR (acetone de)

3.34 (s, 3, OO 2 CH 3),

3.7 (m, Cz-H);

5.15 (d, 1, J = 5.0 Hz, C 6 H).

5.95 (q, J = 5.0 and 9.0 Hz, C7-H),

6.30 (s, 1, side CH chain);

7.10 (s, 1, benzhydryl CH),

7.5 (m, 10, benzhydryl ArH),

8.34 (S, 1, CHO);

8.43 ppm <(d, 1, J = 9.0 Hz, NH3).

Analysis for C CS3HHNeOeS: calcd.

H, 4.47; N, 4.78%

C 63.40, H 4.73, N 4.53%.

Example 12

7- [D- (2-phenyl-2-formyl-oxyacetamido) -1-. 3-Methoxycarbonyl-3-cephem-4-carboxylic acid

The same procedure as in Example 4 is followed. wherein the benzhydryl ester is desterified by reaction with trifluoroacetic acid in anisole. The product was crystallized from acetone, methylene chloride and hexane to give white crystals (mp 177-178 ° C).

Analysis for C18HteN2OflS:

calculated

IC 51, 43, H 3.84, N 6.66%, found

C 51.70, H 4.06, N 6.77.

Example 13

Benzhydryl-7 - [(2,5-dichlorophenylthlo) acetamido] -3-methoxycarbonyl-3-cephem-4-carboxylate

To a cooled (5 ° C), stirred solution of benzhydryl-7-amino-4-methoxycarbonyl-3-cephem-4-carboxylate (0.268 g, 0.632 mmol) in 30 mL of tetrahydrofuran was added 0.239 g (28.4 mol) of sodium bicarbonate. and 0.390 g (1.52 mmol) of 2,5-dichlorophenylthioacetic acid chloride, stirred for one hour under reflux, ethyl acetate was added and the solution was washed with water and brine and dried over anhydrous sodium sulfate. gradient of toluene and ethyl acetate gave 0.288 g (7.1%) of the title compound as a white solid, which crystallized from methylene chloride / hexane to give 173 mg of colorless crystals (mp 179-180 T). 1805 cm @ ^-1 , NMR (CDCl3, acetone d-6),

3.30 (s, CO 2 CH 3), .....

3.50, 3.85 (ABq, 2, J = 16 Hz, C2-H),

O

·. AND.' - 7 ’

3.93 (s, 2, S);

S — CH2 — C

5.15 i (d, J, 4.0 Hz, Ce-H),

5.85 ppm (q, 1 ', J = 4.0 and 8.0 Hz, C-H). Analysis for C30H24N2O6S2Cl2:

found

C 56.02, H 3.79, N 4.17., Calculated ·

C 55.99, H 3.76, N 4.35.

The corresponding 7 - [(2-, 5-dichlorophenylthio) acetamido] -3-methoxycarbonyl-3-cephem-4-carboxylic acid is prepared by cleavage of the benzhydryl ester with trifluoroacetic acid and ariisole as described in Example 4. The product shows antimicrobial activity.

Example 14

Benzhydryl-7- (2-phenyl-2-tert-butoxycarbonylacetamido) -3'-methoxycarbonyl-3-cephem-4-carboxylate

Following the procedure of Example 8, the acylation is acyl acyl is dl-2- (tert-butoxycarbanyl) -2-phenylacetyl chloride as the acylating agent. Chromatography of the reaction product gave the title diester (63.6%) which was crystallized from methylene chloride-hexane to give a white foam (mp 184-185 ° C): IR (CHCl 3) 1801 cm -1. ¹ (/ J-lactam C = 0) NMR (CDCl₃). 1.47. (s, 9, t-butyl),..

3.27 (s, 3, CO2CH3), [delta] 3.40, 3.80 '(ABq, 2, J = 18.0 Hz, Ca-H), 4.45, 4.50 i (2- s, 1, side chain CH),

4.93 and 4.96 (2-d, 1, j = 4.0 Hz, Ce-H),

5.87 (q, 1, J = 5.0 and 9.0 Hz, C7-H),

7.10 (s, 1, CH2),

7.4 (Ar and 7.25, 8.15 ppm (2-d, 1, J 1 = 9.0 Hz, NH).

For C35H34N2O8S: C, 65.41; H, 5.33; N, 4.36%. 22 found

C 65.26, H 5.55, N 4.19%.

Example 1 a d 15 '

7- (2-Phenyl-2-carboxyacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid disodium salt

Benzhydryl-7- (2-phenyl-2-tert-butoxycarbonylacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylate (0.257 g, 0.399 mmol) was dissolved in 40 mL of 97-100% formic acid and allowed to stand react for one hour at room temperature. The reaction mixture was evaporated to dryness to give a residue which was dissolved in ethyl acetate and extracted with sodium bicarbonate solution. The organic phase was separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation to dryness afforded 0.220 g of acid which was dissolved in 40 ml of ethanol and treated with 2 equivalents of sodium 2-ethylhexanoate. The solution was evaporated in vacuo until a precipitate formed. The solution was placed in the refrigerator overnight and then filtered to give 27 mg of the disodium salt: NMR (acetone-de) 3.75 (m, 5, CO2CH3, C2-H),

4.85 (2-s, 1, side chain CH],

5.17, 5.28. (12-d, 1, J = 5.0 Hz, C 6 -T) a

5.92 ppm (q, 1, J = 5.0 Hz and 9.0 Hz,

C7-H).

Note: doubling of some strips is caused by dl-mixture.

Example 16

Benzhydryl-7-D - [(2-phenyl-2-tert-butoxycarbonylamino) acetamido] -3-methoxycarbonyl-3-ether-4-carboxylate

To a cooled solution of (-, 20 ° C), a stirred solution of N-tert-butoxycarbonylphenylglycine (0.222 g, 0.882 mmol) in 30 mL of tetrahydrofuran was added N-methylmorpholine (0.089 g, 0.882 mmol) under argon. methyl chloroformate (0.097 g, 1.03 mmol). The mixture was allowed to react for 10 minutes at -20 ° C, then cooled to -30 ° C and a solution of benzhydryl-7-amino-3-methoxycarbonyl-3-cephem-4-carboxylate (0.312 g, 0.735 mmol) was added dropwise. ) in 8 ml tetrahydrofuran. The mixture was reacted for 30 minutes at -25 to ⁰ to -5 ° C. Cold ethyl acetate was then added, the mixture was washed with cold 1 N hydrochloric acid solution, cold sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. Evaporation and chromatography on silica gel using a toluene / ethyl acetate gradient afforded 0.305 g (63%) of the title compound: IR (OHCl 3) 1800 cm ^-1 (/ Haktam C = O), NMR (CDCl 3)

185289

1.42 '(s, 9, t-butyl),

3.25 (s, 3, CO 2 CH 3),

3.26, 3.75 (ABq, 2, J = 18.0 Hz, C-H),

4.85 (d, J, J = 5.0 Hz),

5.32 <(d, 1, J = 6.0 Hz, side chain CH and Ce-H) a

5.82 ppm (m, 2, C 7 -H and NH).

If the aminoester is reacted with N-tert-butoxycarbonylphenyliglycine in the presence of a condensing agent (EEDQ), the above product is isolated in 42% yield.

Example 17

7-D- (2-Phenyl-2-aminoacetamido) -3-methoxycarbonyl-3-cephem-4-carboxylic acid

Benzhydryl-7-D - [(B-phenyl-S-tert-butoxycarbonylamino) Jacetamido] -3-methoxycarbonyl-3-cephem-4-carboxylate (0.168 g, 0.256 mmol) was dissolved in 95 mL of 97-100% formic acid and The mixture was stirred at room temperature for 30 minutes, evaporated in vacuo to dryness to give a product which was insoluble in CDCl 3 and acetone-de, dissolved in 3 mL cold trifluoroacetic acid, stirred in an ice bath for 10 minutes, diluted. The product is dissolved in acetonitrile 1 (9 ml), 1 ml of water is added and the pH is adjusted to 4.5 with dilute sodium hydroxide solution, and no precipitate is precipitated. which, after addition of 2 drops of water, 5 drops of acetonitrile, 4 drops of water and 4 ml of acetonitrile, crystallized.

Example 18

Benzhydryl-7-amino-3- (4-nitrobenzyloxycarbonyl) -3-cephem-4-carboxylate

Using the corresponding 7-thylacetamido compound as starting material, the amide side chain was cleaved as described in Example 7. The amino ester obtained as product was isolated in 85% yield.

IR (CHCl3) 1799 cm ^{@ -1} (n-lactam C1-10), NMR (CDCl3)

2.80 (broad stag, NH2),

3.74 (center ABq for C 2 H) a

4.85 ppm (m, 4, C 6 -H, C 7 -H and CH 2 ester). Example 19

Benzhydryl-7- [D- (2-phenyl-2-formyloxyacetamido)] - 3- (4-nitrobenzyloxycarbonyl) -3-cephem-4-carboxylate

To the cooled (5 ° C), stirred solution of benzhydryl-7-, amino-3- (4-nitrobenzyloxycarbonyl) -3-cephem-4-carboxylate (0.305 g,

Sodium bicarbonate (0.052 g, 0.514 mmol) was added in 25 .mu.l of tetrahydrofuran, followed by β-2-phenyl-2-formyloxyacetyl chloride (0.122 g, 0.615 mmol). The mixture was allowed to react with cooling for 30 minutes. Ethyl acetate was added, then the mixture was washed with cold water and brine and dried over anhydrous sodium sulfate. Evaporation to dryness and chromatography of the product on silica gel with a toluene / ethyl acetate gradient gave 0.183 g (48.4 percent) of the acylated benzhydryl ester:

IR (CHCl3) 1802 cm &lt; -1 & gt ^; ([beta] -lactam C1-10), NMR (CDCl3) i

3.37, 3.88 (ABq, 2, J ~ 18.0 Hz, C2-H),

4.67 and 4.85 (ABq, 2, J ~ 14.0 Hz; p-hitrobenzyl CH2),

4.88 (d, 1, J = 5.0 Hz, Ce-H),

5.75 (q, 1, J 1 = 5.0 and 9.0 Hz, C 7 -H),

6.18 (s, 1, side CH chain),

8.05 ppm (s, 1, CHO).

Example 20

7- [D- (2-phenyl-2-formyl-oxyacetamido)] -3- (4-nitrobenzyloxycarbonyl) -3-cephem-4-carboxylic acid

Following the procedure described in Example 4 wherein the benzhydryl group was removed by treatment with trifluoroacetic acid, the corresponding acid was obtained. The product crystallized from acetone / hexane to give 0.081g (65%) of tan crystals (m.p. 154-155 ° C). Analysis for C24H19N3O10Š:

calculated

,. C 53.24, H 3.54, δ 7.76%, found

C 53.28, H 3.68, N 7.47%.

Example 21

Benzhydryl-7- [D- (2-phenyl-2-formyloxyacetamido)] -3-carboxy-3-cephem-4-carboxylate

Benzhydryl-7- (D- (12-phenyl-2-formyl-oxyacetamido)) - 3- (4-nitrobenzyloxycarbonyl) -3-methyl-4-, carboxylate (0.224 g, 0.3 mmol) was dissolved in 5 mL methylene chloride and 40 ml of methanol. A re-reduced 5% Pd / / C catalyst (0.224 g) was added and hydrogenation was carried out at room temperature (50 psi hydrogen pressure) for two hours. Filtration of the reaction mixture and evaporation of the filtrate to dryness afforded the title compound (190 mg). The product exhibits antimicrohial activity on gram-positive and gram-negative microorganisms.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of cephalosporin compounds of formula I wherein X is alkyl of 1 to 6 carbon atoms, R is hydrogen, benzhydryl or alkyl of 1 to 6 carbon atoms, and R 1 is hydrogen or acyl of the formula R "CH 2", when R "" is 2-thienyl, 3-thienyl, 2-furyl or 3-furyl and, when R is hydrogen, a pharmaceutically acceptable non-toxic acid salt, characterized in that the compound of the formula II, wherein R 10 is R 1 as defined above, R 11 is a carboxyl protecting group, and Z 1 is a group of formula ¹ COOA wherein R 'denotes arylalkyl of the formula R' (YU-CH2-, wherein R 'is phenyl or substituted phenyl, wherein the substituents are 1 to 3 halogen atoms, hydroxyl, nitro or C1-C4 alkyl, Y is O or S and m is 0 or 1, or R 'is substituted arylalkyl of the formula H E where R "'isR" as defined in ¹ above, 2-thienyl or 3-thienyl, E is hydroxyl or hydroxyl protected by alkanoyl having from 1 to 4 carbon atoms, carboxyl or a' carboxyl group protected with an alkyl of 1 to 6 carbon atoms, an amino group or an amino group protected with C 1 -C 6 alkoxycarbonyl or R 'represents a heteroarylmethyl of the formula wherein A is an alkali metal atom, reacted with a compound of the formula X-T, wherein X is as defined in formula I, and T is an iodine or bromine atom, in the presence of hexamethylphosphoramide and optionally reacting the corresponding 2-cephem derivatives with percarboxylic acid to give 3-cephem derivatives and reduce the resulting sulfoxide with phosphorus halide and the 7-acyl group is cleaved by reaction with phosphorus pentachloride and an alcohol and optionally re-acylated at the 7-position by reaction with a halide or active ester of R'-CO 2 H, where R 'is as defined above, optionally de-esterifying the 3-carboxylic acid and / or ester The 4-carboxylic acid in an acid medium and the product is optionally isolated in the form of a 4-carboxylic acid, benzhydryl or C1-C6 alkyl ester of a 4-carboxylic acid.