CS246079B2 - Method of 7-aminocephalosporane acid's derivatives production - Google Patents

Description

The present invention relates to a process for the preparation of 7-aminocephalosporanic acid derivatives of the following general formula I, which are used as starting materials for the production of valuable antibiotics.

The present invention provides a process for the preparation of aminocephalosporanic acid derivatives of formula (I).

which is optionally once or twice, equally or differently substituted with C1-6 alkyl, wherein the two ortho alkyl groups can also be closed to form an optionally methyl substituted di- to decamethylene ring in which one ring carbon atom is optionally replaced by an oxygen or sulfur atom and which further optionally also contains one or two double bonds, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 1 -C 6 alkoxy group, a halogen, a trifluoromethyl group or hydroxy, phenyl or benzyl,

A is furthermore a quinolinium group of the formula wherein

R 1 represents a hydrogen atom or a methoxy group,

A represents the pyridinium group ® I

or isoquinolinium group

each of which is also optionally once or twice, equally or differently substituted by C1-6 alkyl, C1-6 alkoxy, halogen, trifluoromethyl or hydroxy.

In particular, the present invention relates to a process for the preparation of compounds of formula I in which:

A represents a pyridinium group of the formula

optionally substituted once or twice equally or differently with an alkyl group having 1 to 6 carbon atoms, wherein the two ortho-alkyl groups may also be closed to form an optionally methyl-substituted di-to decamethylene ring in which there is one carbon atom the ring optionally replaced by an oxygen or sulfur atom and which further optionally contains one or two double bonds; (C 2 -C 6) alkenyl; (C 2 -C 6) alkenyl; (C 1 -C 6) alkoxy; halogen, trifluoromethyl or hydroxy; an isemyl-containing group or a 'benzyl' group, or

A is furthermore a "dhinolternary group" or a "chlorine-free" group, but are also optionally substituted once or twice, equally or differently, by a (C 1 -C 6) -alkyl group, a (C 1 -C 6) -alkoxy group, with a ihatogen, a trifluoromethyl group or a hydroxy group.

A methyl group such as a possible substituent for the di-tietamethylene ring mentioned in the meaning of the substituent A, in which one or more of the ring carbon atoms is optionally replaced by an oxygen or a sulfur atom and which also contains one or two double bonds, may occur on the rings fused to the pyridinium group, regardless of whether the ring in question is saturated, unsaturated or also interrupted by an oxygen or sulfur atom.

The ring not fused to the pyridinium group may contain two to ten ring members (di- to decamethylene), but preferably contains three to five ring members and thus is, for example, a cycloperrtene, cyclohexene or cycloheptene ring. If such an uncondensed cross has a double bond, the examples of such rings include a dehydrocyclopentadiene, dehydrocyclohexadiene or dehydrocycloheptadlene ring.

As the oxygen-containing condensate of the oxygen-containing knuckles and which contain one or two double bonds, it may be mentioned: fur, rpyrano, hydrofuro and dlhydarapyano; tandiated sulfur atoms having two or one double bond include, for example: thieno, thiopyrano, dihydrothieno and dihydropyrano. Of the non-fused rings containing one oxygen or sulfur atom, in particular those containing only one double bond are suitable for methyl substitution.

Particularly preferred are, for example, the following substituents:

A represents a quinolinium group or an isoquinolinium group, which in each case are also optionally mono- or di-substituted, as well as differently substituted by C1-C6-alkyl, such as methyl, ethyl, propyl, preferably methyl, methoxy. hydroxy, halogen or trifluoromethyl; furthermore represents a pyridinium group which is optionally mono- or di-substituted, for example by a C1 -C4 alkyl group, such as, in particular, methyl, ethyl, propyl, isopropyl, n-butyl, sec. butyl, tert-butyl, dimethyl, trimethyl, methyl and ethyl, methyl and propyl, methyl and isopropyl, ethyl and ethyl;

(C 3 -C 4) alkenyl, in particular allyl, 2-methylallyl and buten-3-yl;

a (C 3 -C 3) alkenyl group such as a propargyl group;

(C 1 -C 6) alkoxy group, such as especially C 1 -C 6 methyloxy, and shadows;

halogen, such as, in particular, Mlu, S, Cl, Cl, 3-bromo, 3-iodo;

hydroxy, especially 3-hydroxy;

trifluoromethyl, especially 3-trifluoromethyl;

phenyl and benzyl.

If A is a pyridinium group which is substituted by two alkyl groups closed to form a di- to decamethylene ring which is again substituted one or more times, preferably once, by a methyl group and optionally contains one or two double bonds, then they come particularly preferably consider the following non-condensed ring systems:

cyclobuteno, cyclopenteno, cyclohexeno, cyclohepteno, dehydrocyclopenteno, dehydrocyclohexeno and dehydrocyclohepteno.

In the above condensed ring systems, if one carbon atom is replaced by an oxygen or sulfur atom, in particular oxygen, the following ring systems are suitable, for example:

furo] 2,3-b] pyridine, furo] 3,2-b] pyridine, furo [2,3-c] pyridine, furo] 3,2-c] pyridine, thieno] 2,3-bj pyridine, thieno [3,2-b] pyridine, thieno] 2,3-c] pyridine, thieno] 3,2-c] pyridine, thieno] 3,4-b] pyridine, thieno ¹ ] 3,4-c] pyridine.

The process according to the invention for the preparation of the compounds of the formula I consists in reacting the compound of the formula II

for example, a formyl group or an acyl group generally known in the chemistry of cephalosporins and penicillins, or a salt thereof is treated with such a pyridinium, quinolinium or isoquinoline base to form the compound. of formula III

co ₂ (>') in which

A, R 1 and R ³ are as defined above, after which the acyl group is cleaved by chemical or enzymatic methods generally known in the chemistry of cephalosporins and penicillins to give a compound of formula I.

As R ² suitable acyloxy lower aliphatic carboxylic acids, preferably having from 1 to 4 carbon atoms, for example acetoxy or propionyloxy, and in particular an acetoxy group, which are optionally substituted, such as · chloroacetoxy or acetylacetoxyskupina. For R ² there may be other groups, such as carbamoyloxy.

In acyl groups R ³ CO-, R 3 is hydrogen or R ⁴ - (CH 2) _n - in which n = 0 or 1 and R 4 is C 1 -C 10 alkyl, preferably C 1 -C 4 alkyl carbon which is optionally mono- or polysubstituted, equally or differently substituted by an optionally substituted carbocyclic or heterocyclic aryl group such as a phenyl or thienyl group, optionally substituted with an aryl or heteroaryloxy group such as a phenyloxy group, optionally substituted with an aryl or heteroarylthio group such as phenylthio or imidazolylthio, C 3 -C 6 cycloalkyl or C 4 -C 6 cycloalkenyl, optionally substituted C 1 -C 6 alkyloxy, optionally substituted C 1 -C 6 alkylthio, cyano, halogen, trifluoromethyl, sulfo, hyd hydroxy, amino and carboxy are optionally also protected or blocked, for example a group of the formula ... in which:

R ¹ represents a hydrogen atom or a methoxy group,

R ² is a group displaceable by a pyridinium, quinolinium or isoquinolinium base which corresponds to residues A of formula I, and

R ³ CO represents an acyl group, for example 246079

Z — NH — CHfCH 2 -

C00H

Z —NH— € H (CH2) 5CO—

COOH wherein Z is an optionally-substituted arylcarbonyl group such as a phenylcarbonyl group or a heteroarylcarbonyl group such as a thien-2-ylcarbonyl group, an optionally substituted C 1 -C 4 alkyloxycarbonyl group or -CH = C (CO 2 C 2 H 5) 2, an optionally substituted C 1 -C 6 alkylsulfonyl group or an optionally substituted phenylsulfonyl group such as a 4-methylphenylsulfonyl group or a 4-chlorophenylsulfonyl group; or

R 4 represents an optionally substituted carbocyclic or heterocyclic aryl group such as phenyl, thienyl or furyl.

R ³ - represents - a group of formula below

R4 — c—

II

N

OR ⁵ in which

R 5 represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms and

R4 is as defined above, or

R ³ represents a 'group' of the formula R ⁶ CO-C-

II

N

OR ^5, in which

R6 denotes an alkyl group having 1 to 6 carbon atoms.

In particular, the starting compounds are those in which the acyl groups R ³ EO are represented by thienylacetyl or phenylacetyl, which are cleaved enzymatically by penicillin G amidohydrolase.

Furthermore, preparatively-readily available, and hence cheap, "starting" compounds in which R 5 CO— may be - are, for example, thienylacetyl, phenylacetyl, as well as phenoxyacetyl. Especially preferred are the residues of the natural product cefatosporin-C; as their 1 blocked and protected derivatives of the formula

Z is as defined above.

Thus, the starting-compounds are known from the literature- or can be readily prepared by procedures known in the literature;

The reaction of the compounds of formula (H) with spyridinium, quinolinium or isoctinolium bases corresponding to residues A in formula (P) can be carried out in water or in a mixture of water and an organic solvent which is readily miscible with water. such as acetone; doxoxane, acetonitrile, dimethylformamide; dimethylsulfoxide or ethanol.

The reaction temperature is - generally - in the range of about 10 ° C to about 1 ° C, preferably between 20 ° C and 80 ° C. The base is added in an amount ranging from about equimolar to about five times the equimolar amount.

The exchange of the R2 residue is facilitated by the presence of neutral salt ions in the reaction medium, preferably iodide and thiocyanate ions. In particular, the addition of about '0 to -About 30 equivalents of potassium iodide, sodium iodide, thiocyanate -draselného ¹ or thlokyanátu solution. The reaction is preferably carried out near a neutral point; preferably at a pH in the range of about 5 db to about 8.

The reaction can also be advantageously carried out in a nonaqueous solution in the presence of t-r-ialk-yl iodosilane, such as t-trimethyl iodoilane or triethyl iodosilane, wherein the trialkyl iodosilane aliphatic radicals contain from 1 to 4 carbon atoms.

The reaction of the compounds of formula (I) with pyridine bases is known. For example, fsrov. European Patent Specification No. 60 (44) discloses that 3-iodomethyl cellolosporin derivatives, for example, compounds of the formula I, in which A = J, react with pyridine bases to form the corresponding pyridine compounds.

Such iodoalkyl derivatives can generally be prepared from esters, for example oetates, by reaction with trimethyliodosilane (cf. J. Amer. Chem. Soc. 99, 968, 1977; Angew. Chemie 91, 648, 1979), i.e. reactions which was subsequently transferred to yefelosporins (cf. European Patent Publication No. 34,924, U.S. Patent No. 4,266,049, T ^ trahedron Letters 1981, 3,9'5, European Patent No. 70,706¼).

According to the two-step procedure described in the European-patent patent number

60'44, for example, the acetates - corresponding to formula II (R @ ² = OCOCH3) are converted - first to J-iodomethylderivatives; these are isolated and reacted with the desired pyridine bases. Chromatographic purification is required to isolate the reaction products, with the highest yield of pure reaction product being less than 10% of theory.

Also in the process of the variant described in European Patent No. 70,706, Example 5, wherein the 3-iodomethyiderivatives are not isolated, after reaction with pyridine, the desired compound is identified by chromatography only among many other compounds.

Surprisingly, the yields of the reaction products of formula I can be increased up to more than 10-fold if the nucleophilic exchange reaction is carried out from the beginning in the presence of an excess of pyridinium, quinolinium or isoquinolinium bases corresponding to residue A in formula I. up to 4 carbon atoms in the alkyl moieties, preferably trimethyl iodosilane, is added to the reaction mixture after the addition of the base.

The process is carried out by adding pyridine, quinolinium or isoquinolinium base corresponding to residue A to a solution or suspension of the compound of formula II in a suitable solvent, and then adding trimethyl iodosilane. Instead of trimethyl iodosilane, for example, a reaction mixture consisting of iodine and hexamethyldisilane, which has been previously reacted at temperatures between about 60 and 120 ° C in a manner known in the literature, can be used to produce trimethyl iodosilane.

Instead of trimethyl iodosilane, triethyl iodosilane, which is produced in a manner known from the literature, can also be used with the same good result. This reaction is carried out at temperatures between about -5 and + 100 ° C, preferably between +10 and +80 ° C.

Suitable inert aprotic solvents are, for example, chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, carbon tetrachloride or lower alkylnitriles such as acetonitrile or. propionitrile, or frigens; a particularly excellent solvent is methylene chloride.

The pyridinium, quinolinium or isoquinolinium base corresponding to residue A is added in at least a stoichiometric amount up to a twenty-fold excess, preferably it is operated so as to bind the released amount of hydrogen iodide and to have at least 1 mol, preferably 2 to 5 mol of base.

Since, in addition to the R 2 to be exchanged in the starting compound of formula II, other functional groups present, such as amino, carboxy or amide groups, are also reacted with trimethyl iodosilane, trimethyl iodosilane is added in at least four to about twentyfold, preferably in five to tenfold excess.

The carboxyl functions and N-aminofunction in the compound of formula II can also be pre-silylated by treatment with a silylating agent such as bistrimethylsilylacetamide, bistrimethylsilyltrifluoroacetamide, trimethylchlorosilane, hexamethyldisilazane, bistrimethylsilylurea, and. either. in the absence or in the presence, preferably a pyridinium, quinolinium or isoquinolinium base of the desired group A, in the amount described above. Trimethyl iodosilane is then added in at least a stoichiometric amount or also in an excess, preferably in a 2 to 10-fold excess.

If functional groups such as hydroxy groups and the like are present in the pyridinium, quinolinium or isoquinolinium base corresponding to the residue A in formula I, these groups are preferably first silylated with the above-mentioned silylating agents and then used for the reaction.

The reaction products of formula III can be isolated, for example, by adding water or aqueous mineral acids, for example dilute hydrochloric acid, hydrobromic acid, hydroiodic acid or ¹ sulfuric acid, from the aqueous phase in a conventional manner, for example freeze-drying of the aqueous phase, chromatography and the like. polar reaction products from the aqueous solution in the form of a sparingly soluble salt such as hydroiodide.

In the compounds obtained. of formula III is then cleaved by the acyl group R @ ³ CO-- by generally known chemical species. processes, for example, by hydrolysis with dilute mineral acids such as hydrochloric acid or. sulfuric acid or via imide chlorides, or by enzymatic processes as described, for example, in DE-OS 3 019 838.

When. For example, using an imide chloride cleavage, the compound of formula III is reacted with, for example, phosphorus pentachloride, the resulting imide chloride is converted by addition of alcohol to an iminoether, which is then cleaved by hydrolysis or alcoholysis. The reaction was. preferably in the presence of a silylating agent such as trimethylchlorosilane. After hydrolysis of the reaction mixture by addition of water, the resulting compound of formula (I) is isolated from the aqueous phase in a conventional manner, for example by freeze-drying or chromatography on silica gel or the like. Preferably, the reaction products are isolated from the reaction solution directly in the form of sparingly soluble salts, for example in the form of hydrochloride or hydroiodide.

When enzymatic cleavage is used, it is cleaved, for example, in compounds of formula III in which R @ ³ CO is C6 H5 CH2 CO-- and

O

This reaction is carried out in a water solution at a temperature of from about 25 to 40 ° C, preferably at a temperature of from 35 to 37 ° C, and at a pH of about 25 to 40 ° C.

6.5 to 8.0, preferably at pH 7.2 to 7.8. The pH is kept constant by the addition of 1N sodium hydroxide solution. After completion of the reaction, the fixed enzyme was separated by filtration.

The reaction products of the formula I thus obtained are isolated from the aqueous phase in a customary manner, for example by freeze-drying, chromatography or precipitation as a sparingly soluble salt.

The compounds of formula (I) produced by the process of the invention are the starting materials for the production of a number of highly potent antibiotics of formula (III).

in which, for example

R ¹ is hydrogen or methoxy and

R ³ 'CO is especially 2- (aminoheterocyclyl) -2-oxyiminoacetyl, for example 2- (2-aminothiazolyl) -2-oxyiminoacetyl as described in DE-OS 31 18 732 and DE-OS 32 07 840, DE-OS 32 47 614 and DE-OS 32 47 613.

The following examples are intended to further illustrate the invention, but are not intended to limit the invention in any way.

Production of starting materials:

Example 1

3 - [(2,3-cyclopenteno-1-pyridinio) methyl] 7- (2-thienyl jacetamido) cef-3-em-4-carboxylate

Variant A):

A mixture of 150 g (0.36 mol) of 7- (2-thienylacetamido) -cephalosporanic acid sodium salt (Cephalothin), 680 g (7 mol) of potassium thiocyanate, 66.5 g (65 ml, 0.56 mol) of 2,3-cyclopentenopyridine, 150 ml of water and 30 g of 85% phosphoric acid are stirred for 4 hours at 66-68 [deg.] C. During this time the pH drops from 6.6 to pH 6.0 The yellow-colored thick liquid solution is diluted with 3 liters of water and four times The mixture is extracted with 400 ml of methylene chloride each time, while cooling and stirring, 110 ml of 18% hydrochloric acid are added dropwise over 5 minutes at 5 to 10 DEG C. to form a voluminous precipitate, and the reaction mixture is left on an ice bath for 2 hours. The mixture is then filtered, the filter residue is washed three times with 500 ml of water each time and dried under vacuum.

Yield:

130 g (0.245 mol) of pale yellow crystals (68% of theory) with a decomposition temperature of 156-158 ° C.

Analysis for

C22H21N3O4S2 X HSCN X H2O calculated:

% C, 51.86;% H, 4.54;% N, 10.52.

И Д 1 Q7Qr A ·

C 51.8%, H 4.3%, N 10.2%, S 18.0% calculated:

3.38% H2O;

found:

2.9% H2O.

IC spectrum (KBr technique):

1775 (lactam-CO)

040 cm ¹ (SCN) ¹ H-NMR spectrum (deuterated trifluoroacetic acid):

(5 = 1

2.3 to 2.8 (m, 2H, cyclopentene-H),

3.15 to 3.95 (m, 6H, 4 cyclopentene-H and SCH2),

4.06 (s, 2H, CH 2 CO),

5.2 to 6.2 (m, 4H, _CH2 Py and 2 lactam-H)

6.8 to 7.4 (m, 3H, thiophene),

7.65 to 8.70 ppm (m, 3H, Py).

Option b):

3.96 g (10 mmol) of 7 (2-thienylacetamido) -cephalosporanic acid are dissolved in 90 ml of methylene chloride and 10.2 g (10 ml, 86 mmol) of 2,3-cyclopentenopyridine are added. While stirring and cooling, 14 g (10 ml, 70 mmol) of trimethyl iodosilane are then added dropwise and the solution is heated at reflux for 2 hours. The reaction mixture is cooled to -15 ^DEG C., 25 ml of 2N hydrochloric acid solution are added and the organic phase is separated. The aqueous phase is adjusted ₍ by addition of sodium bicarbonate to pH 6.0) and chromatographed on silica gel (Grace, 0.1 mm) using 3: 1 acetone / water as the eluent. to give the title compound as a pale yellow amorphous solid.

Yield:

3.2 g (70.5% of theory)

IR spectrum (KBr technique):

1775 cm ^-1 (lactam-CO) / 1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ =

2.3 to 2.8 (m, 2H, cyclopentene-H),

3.1 to 3.95 (m, 6H, 4 cyclopentene-H and SCH2),

4.09 (s, 2H, CH 2 CO),

S =

5.2 to 6.25 (m, 4H, N-OH and 2 lactam-H),

6.8 to 7.4 (m, 3H, thiophene),

7.65 to 8.85 ppm (m, 3H, Py).

Example 2

3 - [(2,3-cyclopenteno-1-, pyridinio) methyl] -7-phenylacetamido-3-em-4-carboxylate

Variant A):

The procedure is analogous to Example 1a) using 14.4 g of 7-phenylacetamido-phosphoosporanic acid sodium salt, 68 g of potassium thiocyanate, 6.5 ml of 2,3-cyclopentenopyridine, 15 ml of water and 3.4 g of 85% phosphoric acid. The reaction mixture is then diluted with 120 ml of acetone and chromatographed over 500 g of silica gel (Grace, 0.1 mm) using 8: 1 acetone / water and then 2: 1 acetone / water as eluent. Fractions containing the product after freeze-drying yield

7.5 g (48% of theory) of a light gray amorphous solid.

IR spectrum (KBr technique):

770 cm @ ^-1 (lactam-CO) ¹ H-NMR spectrum (deuterated trifluoroacetic acid):

δ =

2.25 to 2.85 (m, 2H, cyclopentene-H),

3.1 to 3.75 (m, 6H, 4 cyclopentene-H and SCH2),

3.87 (s, 2H, CH 2 CO),

3.2 to 6.25 (m, 4H, CH2Py and 2 lactam-H),

7.38 (s, 5H, Ph);

7.6 to 8.7 ppm (m, 3H, Py).

Option b):

The procedure is analogous to Example 1b) using 3.9 g of 7-phenylacetamidocephalosporanic acid, 10 ml of 2,3-cyclopentopyridine and 10 ml of trimethyl iodosilane in 90 ml of methylene chloride. After hydrolysis, chromatography is carried out on silica gel using acetone / water (3: 1) as the eluent.

Yield:

2.4 g (53.5% of theory) of an amorphous solid.

The compound thus obtained is identical in all its properties to the compound prepared according to process 2a).

Example 3

3 - [(2,3-cyclopenteno-1-pyridinio) methyl] -7-phenoxyacetamidocapho-3-em-4-carboxylate

Variant A):

The procedure is analogous to Example 1 a) using 21.4 g of 7-phenoxyacetamidocephalosporanic acid sodium salt, 95 g of potassium thiocyanate, 9 ml of 2,3-cyclopentenopyridine and 1.5 g of 85% phosphoric acid in 21 ml of water. After dilution with acetone, chromatography is carried out on 600 g of silica gel using 8: 1 acetone / water as the eluent and then 2: 1 acetone / water as the eluent. Fractions containing the product were freeze-dried. 11.9 g (51% of theory) of a colorless amorphous solid are obtained.

IR spectrum (KBr technique):

770 cm ^-1 (lactam-CO) ¹ H-NMR spectrum (deuterated trifluoroacetic acid):

δ =

2.25 to 2.85 (m, 2H, cyclopentene-H),

3.15 to 3.9 (m, 6H, cyclopentene-H and SCH2),

4.81 (s, 2H, CH 2 CO), δ =

5.25 to 6.20 (m, 4H, N-N, and 2 lactam-H),

6.8 to 7.5 (m, 5 phenyl-H),

7.65 to 8.7 ppm (m, ZN, - Py).

Option b):

The procedure is analogous to Example 1b) using 2.5 g of 7-phenoxyacetamidocephalosporanic acid, 5 ml of 2,3-cyclopentenopyridine and 5 ml of trimethyl iodosilane in 45 ml of methylene chloride. After hydrolysis, the aqueous phase is chromatographed over silica gel using acetone / water (3: 1) as the eluent. The fractions containing the product, after freeze-drying, yield 1.8 g (61.5% of theory) of a brown solid. The compound thus obtained is identical in all its properties to the compound prepared according to Example 3a).

Example 4

7- (D-5-benzamido-5-carboxypentanamido) -3 - [(2,3-cyclopenteno-1-pyridinio) methyl] cef-3-em-4-carboxylate

Variant A):

5.2 g (10 mmol) of 7- (D-5-benzamido-5-carboxypentanamido) cephalosporanic acid, 11.9 g (11.7 ml, 0.1 mol) 2,3-cyclopentenopyridine, 66 g (0) (4 mol) of potassium iodide and 30 mg of ascorbic acid in 75 ml of water and 25 ml of acetone are heated at 66-68 ° C for 4 hours. After cooling, the reaction mixture is diluted with 500 ml of acetone and chromatographed over 300 g of silica gel. The acetone / water (7: 1) mixture was eluted with salt, the acetone / water (2: 1) mixture eluted the title compound. After freeze-drying the product containing fractions, 3.2 g (55% of theory) of a colorless amorphous solid are obtained.

IC spectrum (KBr technique):

1770 cm @ ^-1 (lactam-CO) ^X H-NMR spectrum (deuterated trifluoroacetic acid):

S =

1.8-3.9 (m, 15H, 6 cyclopentene-H,

SCH2 and pentane-H);

4.8 to 6.2 (m, 4H, N-N, and 2 lactam-H),

7.3 to 8.7 ppm (m, 8H, Py and phenyl).

Option b):

5.1 g (4 ml, 28 mmol) of trimethyl iodolane are added in one portion to the mixture consisting of 2.1 g (4 mmol) of 7- (D-5-benzamido-5-carboxypentanamido) cephalosporanic acid, 4.06 g ( 4 mL, 34 mmol) of 2,3-cyclopentenopyridine and 40 mL of methylene chloride. The reaction mixture was heated at reflux for 2 hours, then cooled by addition of 5 ml of 2N hydrochloric acid solution. The aqueous phase was separated, adjusted to pH = 6 by addition of sodium bicarbonate and chromatographed over 150 g of silica gel using acetone / water (5: 1) and then acetone / water (2: 1) as eluent. Product containing fractions gave, after freeze-drying, 1.9 g (47.5% of theory) of a pale yellow amorphous solid. The compound thus obtained is identical in all its properties to the compound described above.

Example 5

7- [D-5- (4-chlorobenzamido) -5-carboxypentanamido] -3 - [(2,3-cyclopenteno-1-pyridinlo) methyl] cef-3-em-4-carboxylate

Variant A):

In an analogous manner to that described in Example 4a), from 5.5 g (10 mmol) of 7- [D-5- (4-chloro-benzoyl) -5-carboxylic acid pentanamido) cephalosporanic acid, 11.9 g (0.1 mol)

2,3-cyclopentenepyridine, 66 g (0.4 mol) potassium iodide, 30 mg ascorbic acid in 100 ml acetone / water (3: 1) gave the title compound as an amorphous solid (48% yield) .

IR spectrum (KBr technique):

1770 cm ^-1 (lactam-CO) ⁴ H-NMR spectrum (deuterated trifluoroacetic acid):

=

1.9 to 2.9 (m, 8H, [alpha] 2/3 and 2 cyclopentene-H),

3.1 to 3.8 (m, 7H, 4 cyclopentene-H,

SCH2 and CH],

4.9 to 6.3 (m, 4H, N-OH and 2 lactam-H),

7.3 to 8.7 ppm (m, 7H, phenyl and Py).

Option b):

In an analogous manner to that in Example 4b), 2.2 g of 7- [D-5- (4-chlorobenzamido) -5-carboxypentanamido] cephalosporanic acid, 4.06 g of 2,3-cyclopentenopyridine and 5.1 g of trimethyl iodosilane were added in 40 ml. ml of methylene chloride gave the title compound as an amorphous solid after chromatography. Yield: 51%.

This compound is identical in all its properties to the compound described above.

In an analogous manner to that described in Example 4, variant a) (water exchange) or variant b) (triipethyl iodosilane procedure), the compounds described in the following examples 6 to 12 are obtained from the corresponding cephalosporin and 2,3-cyclopentenopyridine derivatives.

Example 6

7- (D-5-benzenesulfonamido) -5-carboxy pentanamido-3 - [(2,3-cyclopenteno-1-pyridinio) methyl] cef-3-em-4-carboxylate

Yield:

according to variant a): 45% of theory according to variant b): 52% of theory ¹ H-NMR spectrum (deuterated trifluoroacetic acid):

S =

1.6 to 4.4 (m, 15 H, 6 cyclopentene-H, pentane-H and SCH2),

5.15 to 6.2 (m, 4H, NH4 and 2 lactam-H);

7.4 to 8.65 ppm (m, 8H, phenyl and Py).

Example 7

7- [D-5- (4-methylbenzenesulfonamido) -5-carboxypentanamido] -3 - [(2,3-cyclopenteno-1-pyridinyl) methyl] cef-4-carboxylate

Yield according to variant a): 38% of theory

1 H-NMR spectrum (perdeuterated dimethylsulfoxide):

δ =

1.2 to 4.1 (m, 18 H at s 2.36 —N,

6-cyclopentene-H, 7-pentane-H and CH 2 S), δ =

4.8 to 5.7 (4H, CH2Py and 2 lactam-1),

7.2 to 9.4 ppm (9H, 3Py-H, 4 phenyl-H and

NH).

Example 8

7- [DD- (4-chlorobenzenesulfonamido) -5-5-carboxypentanamido] -3- (2,3-cyclopenteno-1-pyridinio) methylcef-3-em-4-carboxylate

Yield:

according to variant a): 48% of theory according to variant b): 55% of theory 1 H-NMR spectrum (deuterated trifluoroacetic acid):

δ =

1.6 to 4.4 (m, 15H, 6 cyclopentene-H,

7-pentane-1 and SCH2),

5.1 to 6.25 (m, 4β, CH2 and 2 lactam-1),

7.4 to 8.7 ppm (m, 7β, phenyl and Py).

Example 9

7-D-5-amino-5-carboxypentanamido-3--2,3-cyclo-openteno-1-pyridin-1-methylceph-3-em-4- (4-carboxylate)

Yield variant a): 19% of theory. ¹ H-NMR spectrum (deuterated water):

δ =

1.6 to 2.7 (m, 8И, (СИ2) 3 and 2 cyclopentene-I),

2.9 to 3.9 (m, 7И, 4 cyclopentene-1, SCH2 and СИ N),

5.9 to 5.95 (m, 4β, Ca№Py and 2 lactam-H),

7.6 to 8.7 ppm (m, 3И, Py),

Example 10

7- (D-5-tert-butyloxycarbonylamino-5-carboxypentanamide) -3- (2,3-cyclopenteno-1-pyridinio) methylcef-3-em-4-carboxylate

Yield according to variant a): 15% of the theory of the 1 H-NMR spectrum (peroxidated dimethylsulfoxide):

δ =

1.2 to 1.9 [m, 15 °, (CH 2) 3 and C (CH 3) 3],

1.9 to 2.4 (m, 2 cyclopentene-1),

2.7 to 4.0 (m, 7β, CHN, SCH2 and 4 cyclopentene-1),

4.8 to 5.7 (m, 4И, CH2Py and 2 lactam-1),

6.0 to 6.3 (NH),

7.7 to 8.9 (m, 3И, Py),

9.1 to 9.4 ppm (NH),

Example 11

7- [(D-5-carboxy-5- (2,2 - carbonyl dethoxy 1) vinylaminopentanamido] -3- ^ ^{.S-cyclopenten-l-pyridyl} O · nl) methylceph-3-em-C-carboxylate

Yield according to variant a): 14% of theory. ¹ H-NMR spectrum (perdeuterated dimethylsulfoxide):

δ =

1.0 to 1.4 (t, 6И, ethyl),

1.4 to 1.8 [m, 6И, (CH 2) 3],

1.9 to 2.4 (m, 2 cyclopentene-1),

2.8 to 4.3 (m, 11%, 4 cyclopentene-I,

CHNH, SCH2 and 4 ethyl),

4.7 to 5.7 (4И, CtoPy and 2 lactam-I),

7.6 to 9.8 ppm (6И, 3 Py-H, vinyl-1, 2 NH),

Example 12

7- (2-acetyl-2-syn-methoxyimmoacetamido) -4- (5-cyclopenteno-1-pyridinio) methylcef-3-em-4-carboxylate

Yield according to variant a): 18% of theory

4 H-NMR spectrum (trifluoroacetic acid, deuterated):

δ =

2.3 to 2.9 (m with s at 2.49, 5И, CH3CO and cyclopentene-I),

3.1 to 3.9 (m, 6И, SCH2 and 4 cyclopentene-I),

4.26 (s, 3И, N0CH3),

5.1 to 6.2 (m, 4И, CH2Py and 2 lactam-1),

7.6 to 8.7 ppm (m, 3И, Py),

In an analogous manner to that described in Example 4b) (trimethyl iodosilane procedure), the following compounds are obtained which correspond to the general formula:

C ₆ H _S CO 2 H-CH (С H g) 4 C о N ^н I

СООН о ^of COF in which A represents substithent 'indicated in the second column in Table 1.

Example

Table 1

Yield * 1 H-NMR spectrum (deuterium (%)) trifluoroacetic acid):

_____________________ δ (ppm)

1.7-3.9 (m, 9H, SCH2,7-pentane-H),

4.8 to 6.4 (m, 4H, CH2Py and 2 lactam-H),

7.4-9.2 (m, 10H, Py and phenyl).

1.7 to 3.9 (m, 9H, SCHa and 7 pentane-H),

4.8 to 6.3 (m, 4H, CH2-z and - 2 lactam-H),

7.3 to 8.6 (m, 10H, phenyl and quinoline),

8.9 to 9.4 (m, 2 quinoline-H-).

1.8 to 3.1 (m, 7H, pentane),

3.39 and 3.82 (AB, J = 19 Hz, SCH2),

4.8 to 6.3 (m, 4H, CH2Py and 2 lactam-H),

7.3 to 8.7 (m, 11H, phenyl 'and isoquinoline),

9.5 to 9.85 (m, 1 isoquinoline-H).

1.6 to 4.1 (m, 17H, 8 cyclohexene-H, 7-pentane-H and SCH2),

4.9 to 6.4 (m, 4H, CH2Py and 2 lactam-H),

7.3-9.0 (m, 8H, phenyl- and Py).

1.7-3.0 - (m, 7H, pentane),

2.76 (s, 3H, CH 3),

3.65 and 3.73 (AB, J = 19 Hz, SCH2),

4.7 to 6.3 (m, 4H, CH2Py and 2 lactam-H),

7.3 to 8.9 (m, 9H, phenyl and Py).

1.8 to 2.9 (m, 7 pentane-H),

3.42 and 3.76 (AB, J = 19 Hz, SCH2),

4.9 to 6.4 (m, 4H, CH2Py and 2 lactam-H),

7.3-9.25 (m, 14H, phenyl and Py).

4 E О 7 9

In an analogous manner to that described in Example 1b) (trimethyl iodosilane procedure), the following compounds are obtained which correspond to the general formula:

and wherein A is a substituent that is listed in the second column of Table 2.

Example

Table 2

Yield ¹ H-NMR (CDCl 3): ό (ppm)

2.66 (s, 3H, 2H),

3.40 and 3.72 (AB, J-19 (Iz, 2H,

SCH2),

4.06 (s, 2H, CH 2 CO),

5.05 to 6.40 (m, 4H, N-N, and 2 lactam-H),

6.8 to 7.4 (m, 3H, thiophene)

7.95 to 9.20 (m, 4H, Py).

3.38 and 3.72 (AB, J = 19 Hz,

SCH2),

4.10 (s, 2H, CH 2 CO),

4.9 to 6.3 (m, 4H, N-OH and 2 lactam-H),

6.9 to 7.3 (m, 3H, thiophene),

7.66 (s, 5H, Ph);

8.0 to 9.4 (m, 4H, Py).

1.7-2.4 (m, 4H, cyclohexene-H),

2.8 to 3.8 (m, 6H, 4-cyclohexene-H, SCH2),

4.05 (s, 2H, CH 2 CO),

5.15 to 6.25 (m, 4H, N-N, and lactam-H),

6.8 to 7.5 (m, 3H, thiophene),

7.6 to 8.8 (m, 3H, Py).

3.40 and 3.78 (AB, J = 19Hz, 2H,

SCH2),

4.08 (s, 2H, CH 2 CO),

5.15 to 6.35 (m, 4H, N-N, and lactam-H),

6.8 to 7.4 (m, 3H, thiophene),

7.9 to 8.8 (m, 6H, isoquinoline-H),

9.5 to 9.8 (m, 1 isoquinoline-H).

3.42 and 3.75 (AB, J = 19 Hz,

SCH2),

4.06 (s, 2H, CH 2 CO),

5.26 to 6.42 (m, 4H, CH2 Py and lactam-H),

6.8 to 7.4 (m, 3H, thiophene),

8.0-9.2 (m, 5H, Py).

In an analogous manner to that described in Example 1b) (trimethyl iodosilane procedure), the following compounds are obtained which correspond to the general formula:

and wherein R ¹ and R ² are the substituents listed in Table 3.

Table 3

Example R1 R ³ Yield (% of theory) 1 H-NMR spectrum (deuterated trifluoroacetic acid): <5 (ppm) 24 H ÍT “jj ⁿ W SCHj-CH ₃ 28 2.1 to 2.9 (m, 5H, CH5-sing at 2.33 and 2-cyclopentene-H), 3.1 to 3.9 (m, 6H, SCH2 and 4 cyclopentene-H), 4.03 (s, 2H, CH 2 CO), 5.15 to 6.25 (m, 4H, CH2Py and 2 lactam-H), 7.3 to 8.7 (m, 5H, Py and imidazole). 25 H CNCH2— 32 2.1 to 2.9 (m, 2 cyclopentene-H), 3.1 to 3.8 (m, 6H, SCH2 and 4 cyclopentene-H), 3.88 (s, 2H, CH 2 CO), 5.2 to 6.25 (m, 4H, CH2Py and 2 lactam-H), 7.65 to 8.7 (m, 3H, Py). 26 H N Ί II N ^x OCH ₃ M. ^Xs (THCCO 68 2.2 to 2.9 (m, 2 cyclopentene), 3.15 to 3.85 (m, 6H, SCH2 and 4 cyclopentene-H), 5.2 to 6.25 (m, 4H, CH2Py and 2 lactam-H), 6.60; 6.98 and 7.57 (one furan-H each), 7.6 to 8.7 (m, 3H, Py). 27 Mar: OCH3 65 2.2 to 2.9 (m, 2 cyclopentene-H),

2.9 to 3.8 (m, 6H, SCH2 and 4 cyclopentene-H),

3.70 (s, 3H, OCH 3),

4.10 (s, 2H, CH 2 CO),

5.25 to 6.20 (m, 4H, CH2Py and 2 lactam-H),

6.7 to 7.45 (m, 3 thiophene-H),

7.65 to 8.7 (m, 3H, Pyj).

Production of end products:

Example 1

7-Amino-3 - [(2,3-cyclopenteno-1-pyridinio) methyl] cef-3-em-4-carboxylate

(a) Chemical fission:

To a stirred suspension of 5.6 g (10.5 mmol) of the 3 - [(2,3-cyclopenteno-1-pyridinio) methyl] -7- (2-thienylacetamido) cef-3-em-4-carboxylate hydrothiocyanate salt ( Example 1) 5.6 ml (44 mmol) of N, N-dimethylaniline and 2.8 ml (22.2 mmol) of trimethylchlorosilane are added in 40 ml of absolute methylene chloride. A slight increase in temperature to 27 ° C resulted in a clear solution. After stirring at room temperature for 1 hour, the reaction mixture was cooled to -40 ° C, and 4.6 g (22.2 mmol) of phosphorus pentachloride was added all at once, bringing the temperature to -25 ° C.

The dark brown solution was stirred at -30 ° C for 1 hour and then poured into a solution of 9 mL of isobutanol in 18 mL of methylene chloride, which was cooled to -40 ° C. A precipitate formed. The mixture was left overnight in the refrigerator and then filtered and the residue washed with methylene chloride.

The wet crude product is immediately dissolved in 15 ml of methanol at -5 ° C and 80 ml of a 1: 1 mixture of methylene chloride and ether is added dropwise thereto, and after 2 hours of stirring at -10 ° C, the precipitate is filtered off, washed. acetone and dried under vacuum with phosphorus pentoxide.

Yield:

3.3 g (78% of theory) of a light brown, crystalline product.

Analysis for C16H17N3O3S. 2 HCl calculated:

C 47.41, H 4.97, Cl 17.49,

10.37% N;

finds no *

46.2% C, 5.6% H, 16.6% Cl, 9.8% N.

IR spectrum (KBr technique):

785 cm ^-1 (lactam-CO).

¹ H-NMR spectrum (deuterated trifluoroacetic acid):

δ =

2.55 to 2.95 (m, 2H, cyclopentene-H),

3.15 to 3.95 (m, 6H, 4 cyclopentene-H and SCH2),

5.53 (s, 2H, lactam-H),

5.55 and 6.03 (AB, J = 15 Hz, 2H, CH2Py),

7.65 to 8.70 ppm (m, 3H, Py).

(b) Enzymatic cleavage:

106 g (0.2 mol) of hydrothiocyanate salt of 3 - [(2,3-cyclopenteno-1-pyridinio) methyl] -7- (2-thienylacetamido) cef-3-em-4-carboxylate (Example 1) are suspended in 600 ml. A solution of 150 ml of Amberlite LA-2 (manufactured by Rohm and Haas) in 800 ml of ethyl acetate was added to the suspension, and the mixture was stirred in an ice bath for 2 hours.

The phases are separated and the aqueous phase is extracted twice with 50 ml of Amberlite LA-2 (in acetate form) in 150 ml of methyl isobutyl ketone and then washed four more times with 100 ml of methylene chloride each time. The aqueous phase is brought to a volume of 500 ml and adjusted to pH 7 with sodium bicarbonate (0.2 g). Then 100 g of the fixed penicillin G aminohydrolase enzyme are added and the mixture is stirred at 37 ° C and pH 7.1.

The pH is kept constant by dropwise addition of 1 N sodium hydroxide solution. After 2 hours 90% conversion is achieved (thin layer chromatography: silica gel plates, solvent system: acetone / water (5: 1). The fixed enzyme is filtered off, washed three times with 100 ml of water each time, the aqueous phases are treated with 2 N solution. hydrochloric acid to pH 6 and freeze-dried.

The amorphous lyophilisate is stirred in 250 ml of methanol, a small amount of insoluble material is filtered off, and 300 ml of 15% strength alcoholic hydrogen chloride are added to the filtrate, followed by 1 liter of ether. After 2 hours at 0 ° C, the precipitate was filtered off, washed with ether / methanol (4: 1) and dried in vacuo.

Yield:

g of a colorless product (75% of theory).

The compound thus obtained is identical in all its properties to the compound described in Example 1a above.

In analogy to Example 1 [method a): chemical cleavage; method b): enzymatic cleavage] from the corresponding 2-thienylacetamidocephalosporin derivatives the compounds of the general formula I are obtained, which are listed in the following Table 4.

24607 $

Table 4

Example

A Method Yield Ш-NMR spectrum (deuterium (% of trifluoroacetic acid): r) (δ) (ppm)

and 72 1.7-2.4 (m, 4H, cyclohexene- (b) Italy (69) -H), 2.7-3.95 (m, 6H, 4 cyclohexene-H and SCH2), 5.35 to 6.25 (m, 4H, NH4 - [alpha]) 2 lactam-H), 7.75 to 8.65 (m, 3H, Py). and 81 2.69 (s, 3H, SN), (b) (78) 3.66 (s, 2H, SCH 2), 5.25 to 6.39 (m, 4H, 2H and a) 2 lactam-H), 7.83 to 9.03 (m, 4 Py-H). and 77 3.4 to 3.9 (AV, 2H, SCH2), (b) (75) 5.2 to 6.4 (m, 4H, N-N, and 2 lactam-H), 7.9 to 8.8 (m, 5 quinoline-H1, 8.85 to 9.2 (m, 2 quinoline-H). and 80 3.5 to 4.0 (AV, 2H, SCH2), (b) (74) 5.1 to 6.6 (m, 4H, N-N, and 2 lactam-H), 7.9 to 8.8 (m, 6 isoquinoline-H), 9.8 to 9.95 (br s, 1 isoquinoline-H),

Example 6

7-Amino-3- (2,3-cyclopentene-1-pyridinio) methyl cef-3-em-4-carboxylate g (5.2 mmol) 7- (D-5-benzamido-5-carboxypentanamido) -3 (2,3-cyclopenteno-1-pyridinio) methylcef-3-em-4-carboxylate (cf. Example 4 - preparation of starting materials) were suspended in 20 ml of methylene chloride. After addition of 3.9 ml (31.2 mmol) of N, N-dimethylaniline and 3.9 ml (31.2 mmol) of trimethylchlorosilane, the reaction mixture was stirred at room temperature for 1 hour. The clear solution was cooled to -40 ° C and 6.2 g (30 mmol) of phosphorus pentachloride was added.

The solution was stirred at -30 ° C for 1 hour and then poured into a solution of 4.1 mL of isobutanol in 10 mL of methylene chloride, which was cooled to -40 ° C. The reaction mixture is left at 0 ° C for 1 hour and then the solvent is removed by rotary evaporation. The residue was dissolved in 5 g of ice water and the pH was adjusted to 6 by the addition of sodium bicarbonate. The solution was chromatographed over a silica gel column using acetone / water in a ratio of:

4 E 0 7 3

2: 1 as eluent. Fractions containing the product were freeze-dried.

Yield:

0.83 g (48%) ^* H-NMR spectrum (deuterated trifluoroacetic acid):

<5 =

2.2 to 2.9 (m, 2H, cyclopentene-H),

3.15 to 3.93 (m, 6H, 4 cyclopentene-H) and SCH2),

5.25 to 6.35 (m, 4H, CH2Py and 2 lactam-H),

7.65 to 8.0 (m, 1H, Py),

8.23 to 8.7 ppm (m, 2H, Py).

Example 7

The compound of Example 6 was prepared in Example 6 by the above procedure from the benzenesulfonamide derivatives shown in Examples 6, 7 and 8 (preparation of starting materials).

Yield:

% Of theory (using the compound of Example 6 - preparation of starting materials),% of the theory (using the compound of Example 7 - preparation of starting materials),% of the theory (using the compound of Example 8 - preparation of starting materials).

The compound obtained in all these cases is identical in all its properties to the compound described in Example 6.

Example 8

a) 3 - [(2,3-cyclopentyl-1-pyridinio) methyl] -7-formyl aminocef-3-em-4-carboxylate hydroiodide g (0.08 mol) was suspended in 400 ml of anhydrous 7-formylaminocephalosporanic acid. of absolute methylene chloride and then 46.8 ml (0.4 mol) of cyclopentenopyridine are added to the suspension at room temperature. Trimethyl iodosilane (45.6 ml, 0.32 mol) was added dropwise to the clear solution with stirring and moisture exclusion, and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled to 0 ° C, water (200 ml) was added and about 400 ml of saturated sodium bicarbonate solution (pH 6) was neutralized.

The phases are separated and the organic phase is then shaken into 80 ml of water. The combined aqueous phases are extracted three times with 200 ml of methylene chloride each time, separated, the methylene chloride residues are removed from the aqueous phase in vacuo and clarified with 4 g of activated carbon.

The filtered aqueous solution was adjusted to a pH of about 1.5 by the addition of 200 ml of a 1 N solution of hydroiodic acid and then concentrated in vacuo on a rotary evaporator to a volume of about 100 ml. The precipitate was filtered off, washed with acetone and dried under vacuum with phosphorus pentoxide.

Yield:

24.1 g (59.6% of theory).

Analysis for C17H17N3O4S. HJ. H2O (MW 505.3):

calculated:

C 40.41, H 3.99, J 25.11, N 8.32;

6.35% S, 3.56% H2O;

found:

C 40.1%, H 4.1%, J 23.7%, N 8.2%,

6.4% S, 4.2% H2O.

1 H-NMR spectrum (deuterated trifluoroacetic acid):

d =

2.3 to 2.8 (m, 2H, cyclopentene-H),

3.15 to 3.95 [m, 6H, 4 cyclopentene-1H) and SCH2],

5.25 to 6.30 (m, 4H, CH2Py and 2 lactam-H),

7.65 and 8.75 (m, 4H, HCO and 3 Py-H).

b) 7-amino-3 - [(2,3-cyclopenteno-1-pyridinio) methyl] cef-3-em-4-carboxylate

Dihydrochlorid:

20.2 g (0.04 mol) of the product obtained in step (a) are suspended in 200 ml of a 2 N hydrochloric acid solution. The suspension was heated to 60 ° C to give a clear solution which was left at this temperature for 5 minutes. The solution was then concentrated on a rotary evaporator to a volume of about 40 ml. After addition of 120 ml of acetone, the dihydrochloride of the title compound precipitates in crystalline form. This product is filtered off, washed with acetone and dried under vacuum with phosphorus pentoxide.

Yield:

15.4 g (86% of theory), decomposition at 167 ° C.

Analysis for C16H17N3O3S. 2 HCl. H2O (MW 422.4):

calculated:

45.5% C, 5.0% H, 16.8% Cl, 9.9% N,

4.3% H2O;

found:

44.0% C, 4.8% H, 15.2% Cl, 9.6% N,

3.3% H2O.

The NMR spectrum of this compound is in all

46 25 consistent with the NMR spectrum of the compound obtained according to Example 1a).

Monohydiodide and monohydrochloride:

0.422 g (1 mmol) of the above dihydrochloride is dissolved in 2 ml of water at room temperature. 84 mg of sodium bicarbonate as well as 0.05 ml (about 0.4 mmol) of 57% hydroiodic acid are then added. The monohydrojiodide is precipitated from the clear solution in crystalline form. This was filtered off, washed with a small amount of water and dried in vacuo with sulfuric acid.

Yield: 0.2 g.

Analysis for C16H17N3O3S. HJ. H2O (MW 477.3):

calculated:

H, 4.22; J, 26.59; N, 8.80.

Cl1 cl Ιθζβ? ΙΓΟ *

^40% 7 ° C, ^4% H 2 ^25% 0 J, ^8, 9% N

The monohydrochloride is obtained from the mother liquor by the addition of acetone until beginning crystallization. Recrystallization. from 200 ml of a 6: 1 mixture of acetone and water, 130 ml of pure monohydrate monohydrate are obtained.

Analysis for C16H17N3O3S. HCl. H2O (molecular weight 385.9):

calculated:

49.80% C, 5.22% H, 9.18% Cl,

N, 10.89; S, 8.31;

found:

50.1% C, 5.6% H, 8.8% Cl, 10.9% N,

8.9% S.

SUBJECT OF THE INVENTION

Claims (1)

A process for the preparation of 7-aminocephalosporanic acid derivatives of the formula I to 6 with carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoromethyl or hydroxy, phenyl or benzyl; which R ¹ represents a hydrogen atom or a methoxy group, A is pyridinium optionally substituted once or twice, equally or differently substituted with C 1 -C 6 alkyl; closed to form optionally a methyl-substituted di- to decamethylene ring in which one ring carbon atom is optionally replaced by an oxygen or sulfur atom and which further optionally also contains one or two double bonds, a C 2 -C 6 alkenyl group, an alkynyl group having 2 groups in each case also optionally once or twice, equally or differently substituted by a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen, a trifluoromethyl group or a hydroxy group, characterized in that of formula II R ³ CONH-4-CO OH (II) wherein R ¹ represents a hydrogen atom or a methoxy group,