CH636617A5 - Process for preparing cephalosporin analogues - Google Patents

Description

The present invention relates to a process for the preparation of analogues of cephalosporin of the formula 15

n h

îtr ° l

Uri-

15

20th

25th

characterized in that an amide, azide or hydrazide of the formula (15) is prepared and this is then hydrolyzed.

9. Process for the preparation of a compound of formula (17)

(17)

(15)

COX

wherein A is an acyl group, the COX of which is a carboxylic acid group or its salts, amides, imides, azides or hydrazides or an ester or tioester group or a metal oxycarbonyl group and Y is hydrogen or methoxy. The corresponding esters are also prepared, the 7-amino group of which is substituted.

The compounds produced according to the invention can be produced by means of the reactions mentioned below or by adapting suitable variations within the individual reactions mentioned.

So-called Oxadethiacephalosporine and Oxadethiapeni-cilline were developed by Christensen and Mitarb. (Journal of the American Chemical Society, Vol 96,7582 (1975)) and by Wolfe and co-workers. (Canadian Journal of Chemistry, Vol 52, 3996 (1974)) and in the authors of patents.

The acyl groups for A in formula (15) include e.g. Alk-oxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl, organic acyls such as alkanoyl, cycloalkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl or alkylphosphonyl. If possible, these groups may be interrupted in structure by a heteroatom, or they may be unsaturated or substituted, for example by halogen, e.g. Fluorine, chlorine or bromine, a nitrogen function, e.g. Amino, hydrazino, azido, alkylamino, arylamino, acylamino, alkylidenamino, acylimino, imino or nitro, oxygen function, e.g. Hydroxy, alkoxy, aralkoxy, aryîoxy, acyloxy or oxo, sulfur function, e.g. Mercapto, alkylthio, aralkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl or aryloxysulfinyl,

a carbon function, e.g. Alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl or cyano, or phosphorus function, e.g. Phosphoyl or phosphoric acid residue. A and B can together form a diacyl group of a polybasic acid, e.g. Phthalyl, pyridine-2,3-dicarbonyl, maleoyl or succinoyl.

Representative acyl groups for A in formula I above include the following groups:

1) a Ci-Cs-alkanoyl,

50 2) a C2-Cs-haloalkanoyl,

3) azidoacetyl,

4) cyanoacetyl,

5) Acyl groups of the formula

5S Ar-CQQ'-CO-

wherein Q and Q 'are each hydrogen or methyl and Ar is phenyl, dihydrophenyl or a monocyclic heterocyclic aromatic group with 1-4 heteroatoms and ^ which is represented by an inert group, e.g. Ci-C3-alkyl or alkoxy, chlorine, bromine, iodine, fluorine, trifluoromethyl, hydroxy, cyano, aminomethyl or nitro can be substituted;

6) Acyl groups of the formula

30th

35

45

65

Ar-G-CQQ'-CO-

wherein G is oxygen or sulfur and Ar, Q and Q 'have the above meaning;

7) Acyl groups of the formula

636617

Ar-CHT-CO-

in which Ar has the meaning given above and T represents i) amino, ammonio, amino protected by customary amino protecting groups, for example benzyloxycarbonyl, QC-i-alkoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, cyclopropylmethoxycarbonyl, methanesulfonylethoxycarbonyl, 2,2,2-triphen -Trichloräthoxycarbonyl, guanidylcarbamoyl, optionally substituted ureido-carbonyl, Ci to Cs alkanoyl, pyroncarbonyl, thiopyridone carbonyl, pyridoncarbonyl, homo- or heterocyclic monocyclic aromatic acyl, optionally substituted by hydroxy, Ci to C3 alkanoyloxyethyl, halogen, tri to C3-alkyl, Ci to C3-aminoalkyl or Ci to C3-hydroxyalkyl, or amino protected in the form of phthalimido or enamino, derived from acetoacetates, acetylacetone or acetoacet-amide; ii) hydroxy or Ci to C7 acyloxy, iii) carboxy or C2 to C7 alkoxycarbonyl, indanyloxycarbonyl, phenoxycarbonyl, or iv) azido, cyano, carbamoyl, alkoxysulfonyl, sulfo, aminosulfonyl or alkoxysulfonyl, or HT combined represents hydroxyimino the alkoxyimino;

8) C3 to Cs-2-Sydnon-3-alkanoyl;

9) (2- or 4-pyridon-l-yl) acetyl;

10) 5-aminoadipoyl, 5-aminodipoyl protected on the amino by Ci- to Cio-alkanoyl, Ci- to Cs-chloroalkanoyl or C2- to Ci0-alkoxycarbonyl, or 5-aminoadipoyl protected on the carboxy by benzhydryl, 2,2,2- Trichloroethyl, trialkylsilyl, Ci to Ca alkyl, nitrobenzyl or methoxybenzyl; and

11) Acyl groups of the formula

L-O-CO-

where L is an easily removable optionally substituted Ci to Cs hydrocarbon group, e.g. 2,2,2-trichloroethyl, isobornyl, tertiary butyl, 1-methylcyclohexyl, 2-alkoxy tertiary butyl, benzyl, p-nitrobenzyl or p-methoxybenzyl.

In the COX group, X can contain up to 20 C atoms and can be an oxygen function such as Ci to Cs alkoxy, e.g. Methoxy, ethoxy or t-butoxy, C7 to C2o aralkoxy, e.g. Benzyloxy, methoxybenzyloxy, nitro-benzyloxy, diphenylmethoxy or trityloxy, mono- or dicyclic aryloxy, e.g. Phenoxy, or naphthyloxy, or organometalloxy e.g. Trimethylstannyloxy or trimethylsilyloxy, or metal oxy of groups I, II or III in the periodic table, e.g. Sodium oxy, potassium oxy, or magnesium dioxide, or X can also be sulfur functions, such as those formed by thiolesters, nitrogen functions, such as those formed by amides, hydrazides, azides. These groups may, if possible, be interrupted by a heteroatom in the skeleton, or they may be unsaturated or substituted by a substituent, such as one listed above, e.g. the nitrogen, oxygen, sulfur, carbon or phosphorus functions or halogen. The groups X can further form the following groups: Ci to Cs haloalkyl esters, C2 to Cio acyl alkyl esters, C2 to Cs alkoxyalkyl or aminoalkyl esters, C2 to Cs acyloxy alkyl esters, ò to Cs carbalkoxy alkyl esters , Phenyl esters, C? - to C2o-aralkyl esters, esters with C2-to Cio-oxime, Ci- to Cs-N-alkoxyamide, imide with saccharin, imide with phthalimide, N, N'-diisobutylhydrazide, metal salts, Ci- to Cö -Alkylamine salts, dicyclohexylamine salts or analogues thereof with 2-15 C atoms, or equivalent groups in action to these groups, and which have been mentioned above, where specified numbers of carbon atoms also apply to groups X.

Antibacterially preferred groups X include those

which acyloxymethyl esters, phenacyl esters, benzaldoxime esters, the N, N-dimethylaminoethyl ester, alkali metal salts, alkaline earth metal salts and other groups which are equivalent in activity to these groups are able to form. Preferred groups X include benzhydryloxy, p-nitro-benzyloxy, p-methoxybenzyloxy, 2,2,2-trichloroethoxy and alkali metal oxy.

It has been shown that the compounds of the formulas (15), (16) and (17) produced according to the invention are very effective antibacterial substances against numerous bacteria and the corresponding 1-thia or natural cephalosporins. These compounds produced according to the invention can be useful as bactericides for controlling bacterial infections in humans or animals or for preventing the decomposition of perishable foods. For humans, the compounds can be administered at a dose of 0.1 -5 g / day / human. Administration can be oral or parenteral, in the form of any conventional type of pharmaceutical formulation, such as in admixture with suitable carriers, etc.

The new process for the preparation of the compound of formulas (15) and (16) is illustrated in Scheme I below. It should be noted that the sequence of the individual reactions can be changed advantageously and if possible.

It should be noted that the introduction of a propargyloxy group in the 2-position of the azetidine ring to form compound 8 of the reaction scheme leads primarily to the 2,3-cis isomer, in a ratio of up to about 2: 1 or more, in contrast to Cases where the 3-amino group is acylated and where the reaction gives only or mainly the isomer with the 2,3-trans configuration and thus leads to an ineffective end product 16 which has a 6ß-hydrogen. In the present process, the introduction of the propargyloxy group precedes the acylation of the amino group if the acylation step is provided. Among the methods for introducing a propargyloxy group to the 2-position of the azetidine ring to form a compound of Formula 8 in the reaction scheme, that using tin chloride is also superior to that using silver tetrafluoroborate from the standpoint of higher yields or improved proportions the desired isomer and cost-saving production.

The present invention relates to a process for the preparation of a compound of the formula (15)

CK

COX

where A, B, X and Y have the meaning given. This process is based on a compound of formula (7) from y

Shark

C = C-

cox

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

636 617

wherein shark is halogen and X and Y have the above meaning converted to the desired compound by a series of steps as set out in Reaction Scheme I above.

In some respects, the present process from compounds 8 to 10 is analogous to the Neyler and Mitarb method. the Beecham Group (Jornal of Chemical Society, 1973, 57); the present process for the preparation of compounds 10 to 15 is also somewhat analogous to processes described in British Patent Application No. 39614/75

was disclosed by the present applicants and the present method from compounds 12 to 15 is somewhat analogous to the Neyler and Mitarb method. the Beecham Group (Journal of Chemical Society, 1972, 229), provided that the references given above refer to the 1-thia instead of the 1-oxacephalosporins. The step of the present process from compounds 15-16 is a common process in the field of the present invention and here only relates to compounds (15) wherein X io is different from OH.

Scheme 1

HOCfeC ^ CH Cl receptor

■>

CF ^ CHCH

cox

Acyclization

>

- ■ N,

H

O ^ (9)

r

_N-

, 0ch2c ~ ch

Hydrate

CH.

-c = c

CH "

cox

a.

-n.

H

0 = (10)

r

_N ^ _

OCH ^ COCH ^

ch tQcH3

cox

Oxidative cleavage

-n,

H

>

rf

(11)

0choc0cii "

2 y

~ ^ C = 0

dox

reduction

~~ n, h

0 = ^ (12)

r ch2c0ch3

-choh iox

Halogenize

>

H

0- (13)

r

.0ch2c0ch3

"^ CHlIal I

cox

Wittig.

0)

"n"

H

0-

(14)

r

öch2c0ch3

-c = p-I ^ cox

636617

6

An object of the present invention is the preparation of cephalosporins which are analogous to those of the above formula I, in which A is phenylacetyl, D-mandeloyl, a-phenylmalonyl, Da- (3-methanesulfonyl-2-oxo-imidazo-lidin-l- yl) -carb-amido-a-phenylacetyl or 2-thienylacet-amido; B is hydrogen, X is hydroxy and Y is hydrogen, and the pharmaceutically acceptable salts and esters of these compounds, of the type of salts and esters mentioned above.

Among these cephalosporin analogs mentioned is the compound of the following formula

C / -H-CÏCONH

6 5 |

l t °

COOH 0 ^ J ^

CO OH

in the form of the free acid, the pharmaceutically acceptable salts and esters, especially the diphenyl methyl ester, particularly antibacterial.

The above-mentioned specific compound 7ß- (a-carb-oxyphenylacetamido) -3-methyl-l-oxadethia-3-cephem-4-car-bonic acid shows a strong antibacterial activity against gram-negative bacteria in experiments in vitro,

even with higher vaccine material larger than 108 and in particular to strains of Escherichia coli resistant to numerous penicillins and cephalosporins. Their remarkable character is also evident from their strong activity against enterobacteria, which almost all penicillins and cephalosporins are inactive at a concentration of 100 [i / ml.

The above-mentioned specific compound can be prepared by acylating 7-amino-3-methyl-l-oxa-dethia-3-cephem-4-carboxylic acid or its ester with a reactive derivative of a-phenylmalonic acid, whereupon the protective groups are removed if necessary and the connection is cleaned according to usual methods.

The compound of formula (15) wherein the acyl group is phenylacetyl is the corresponding 1-thia compound, i.e. superior to 7-phenylacetamidodeacetoxycephalosporanic acid, especially in its excess strength compared to typical gram-negative bacteria.

As mentioned above, the compounds produced according to the invention can be used to prevent or to inhibit the growth of bacteria in humans and animals. These substances can also be used to inhibit the decomposition of a perishable material or for the disinfection of a substance, an object or a building structure.

The preparation of compounds of the formulas (15) and (16) according to the reaction scheme given above is described below in the form of an example. In this example stands for A-NH-phenylacetamido, for X diphenyl-methoxy and for Y hydrogen. In the NMR data, the Hz values in parentheses are coupling constants.

example

Diphenylmethyl-a- [2ß- and 2a-chloro-3ß-amino-4-oxoaze-tidin-1 -yl] -a-isopropylidene acetate (7)

To a solution of 13.48 g (20 mmol) of crude toluene p-sulfonate salt of diphenylmethyl-a- [2ß-methylthio-3ß-amino-4-oxoazetidin-l-yl] -a-isopropylidene acetate in 100 ml Methylene chloride was added to 19.4 ml of a solution of 1.34 mol / liter chlorine in carbon tetrachloride, (36 mmol) at -78 ° C. The mixture was then stirred at -78 ° C for 20 minutes and then at 0 ° C for 20 minutes and evaporated under reduced pressure. The residue was then triturated three times in a mixture of ether and petroleum ether and evaporated to give 13.45 g of the toluene-p-sulfonate salt of diphenylmethyl-a- [2ß- and 2a-chloro-3ß-amino-4-oxoazetidine-1 -yl] -cc-isopropylidene-s acetate as a yellow foam.

The product was treated with an aqueous solution of sodium bicarbonate and extracted with dichloromethane to give 9.50 g of crude diphenylmethyl-ct- [2ß- and 2 <x-chloro-3ß-amino-4-oxoazetidin-l-yl ] -a-isopropylidene-10 acetate (7) as a tan-heavy syrup. From its NMR spectrum, the ratio of 2ß- and 2a-chloro-isomers was estimated to be about 4: 1. The separation of 2.50 g, which is part of the crude product by chromatography over 100 g of silica gel containing 10% water, gives 120 mg of a l from the 15 fraction eluted with a mixture of benzene and ethyl acetate (3: 1): l-mixture of 2a and 2β-chlorine isomers and 480 mg of pure 2ß-chlorine isomer. 2a chlorine isomer:

NMR: 8CDCb l, 98s3H, 2.25s3H, 2.83br-s2H, 4.33d (l, 2Hz) lH, 2o! 5.47d (l, 2Hz) lH, 6.90slH, 7.30sl0H (estimated from NMR of the mixture) 2ß-chlorine isomer:

IR: v ™ Cb 3425.3370, 1787.1730 cm- '.

NMR: 5CDCh l, 98s3H, 2.25s3H, 2.80br-s2H, 4.50d (4.0Hz) lH, 5.87d (4.0Hz) lH, 6.90slH, 7.30sl0H. 25 Diphenylmethyl-a- [2ß- and 2ct- (2-propynyloxy) -3ß-amino-4-oxoazetidin-1 -yl] -a-isopropylidene acetate (8).

(1) To a solution of 0.95 g of crude diphenylmethyl-ct- [2ß- and 2 <x-chloro-3ß-amino-4-oxoazetidin-l-yl] -a-isopropylidene acetate (7) in one A mixture of 3 ml of propargyl alcohol and 2 ml of tetrahydrofuran was added to 0.79 g (4 mmol) of silver tetrafluoroborate and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with 50 ml of benzene, cooled to 0 ° C and stirred with a mixture of 10 ml of a 5% aqueous sodium bicarbonate solution and 5 ml of saturated brine. The mixture was then filtered through a layer of Celite and the filtrate was separated. The benzene layer was then dried over sodium sulfate, concentrated under reduced pressure and a brown, heavy oil was obtained which, after purification by chromatography over 50 g of silica gel containing 10% water, 134 mg of a 2a-propynyloxy derivative and 134 mg of a 2ß-propy -nyloxy derivative, eluted from fractions with a mixture of benzene and ethyl acetate (1: 1). 45 2a-propynyloxy isomer:

IR: vZ ° '3400.3320.2115.1767.1772 cm-1.

NMR: 5CDCh l, 83br-s2H, l, 98s3H, 2.22s3H, 2.33t (2.5Hz) lH, 4.07d (2.5Hz) 2H, approx. 4.07dlH, 4.93d (l, 0Hz ) lH, 6.90slH, 7.32slOH.

so 2ß-propynyloxy isomer:

IR: v £ »ch 3410.3320.2115.1767.1720 cm- '.

NMR: 5CDCh l, 77br-s2H, 2.00s3H, 2.23s3H, 2.27t (2.5Hz) lH, 4.12d (2.5Hz) 2H, 4.23d (4.0Hz) lH, 5.27d (4Hz) 1H, 6.90s 1H, 7.32s 10H.

55 (2) To a solution of 0.95 g of crude diphenylmethyl-a- [2ß- and 2a-chloro-3ß-amino-4-oxoazetidin-l-yl] -a-isopropylidene acetate (7) in 5 ml Propargyl alcohol, 818 mg (6 mmol) of molten zinc chloride was added and the mixture was stirred at room temperature for 2 hours. 60 This reaction mixture was then mixed with 50 ml of benzene. thin, cooled to 0 ° C, shaken with 30 ml of 5% aqueous sodium bicarbonate solution and then stirred vigorously. The mixture was then filtered through a layer of Celite to remove the separated solids and the filtrate was separated for 6 seconds. The benzene layer was then dried over sodium sulfate and evaporated under reduced pressure, leaving a brown heavy oil. By cleaning the residue using chromato-

graphie over 50 g of silica gel containing 10% water, 107 mg of the starting material, 106 mg of 2cc-propynyl-oxy-isomer and 213 mg of 2ß-propynyloxy-isomer are obtained from the fraction eluted with a mixture of benzene and ethyl acetate (l: l ).

(3) Reaction (1) and (2) above can be carried out using sodium iodide, stannous chloride and silver perchlorate,

instead of zinc chloride and silver tetrafluoroborate.

Diphenylmethyl-a- [2ß- (2-propynyloxy) -3ß-phenylacet-amido-4-oxoazetidin-1-yl] -a-isopropylidene acetate (9).

To a solution of 2.039 g (5.04 mmol) of diphenylmethyl-a- [2ß- (2-propynyloxy) -3 ß-amino-4-oxoazetidin-1-yl] -a-iso-propylidene acetate (8) in 15 ml Methylene chloride was added 1.00 ml (7.56 mmol) phenylacetyl chloride and 0.61 ml (7.56 mmol) pyridine with stirring at 0 ° C. Stirring was continued at 0 ° C for 30 minutes, the mixture was then mixed with ice water and extracted with methylene chloride. The methylene chloride layer was washed with water and dried over sodium sulfate and evaporated under reduced pressure. After purification of the residue by chromatography over 100 g of silica gel containing 10% water and using a mixture of benzene and ethyl acetate (3: 1) as the eluent, 2.242 g (85.1%) of the above-mentioned product (9) are obtained as light yellow foam.

IR: v ™ ch3425,1680,1510,3310,2115,1773,1720 cm- '. NMR: 8CDCb l, 98s3H, 2.25s3H, 2.23t (2.5Hz), 3.58s2H, 3.95d (2.5Hz) 2H, 5.32-5.52m2H, 6.50d (10Hz) lH, 7.00slH, 7.35-7.40m 15H.

Diphenylmethyl-cc- [2ß-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-1 -yl] -a-isopropylidene acetate (10).

To a solution of 2.236 g (4.28 mmol) of diphenylmethyl-a- [2β- (2-propynyloxy) -3ß-phenylacetamido-4-oxoazetidin-1-yl] -a-isopropylidene acetate (9) in 20 ml of methanol was added 2 ml of water added. Then 0.8 ml of a saturated solution of mercurisulfate in 10% sulfuric acid was added to this solution and the mixture was treated under reflux for 30 min. The reaction mixture was then cooled, diluted with ethyl acetate and washed with water. The ethyl acetate layer was then dried over sodium sulfate and concentrated under reduced pressure. After purification of the residue by chromatography over 100 g of silica gel, which contains 10% water, and using a mixture of benzene and ethyl acetate (12: 1) as eluent, 1.547 g (66.9%) of the above-mentioned product (10) as a light yellow foam. IR: v ™ cl! 3425,1676,1510,1774, 1736 (shoulder), 1720 cm "1. NMR: 8CDCh 1.83s3H, 1.97s3H, 2.23s3H, 3.60s2H, 3.60 + 3.97q (8Hz) 2H, 5th , 03d (4Hz) lH, 5.27dd (4.8Hz) lH, 6.50d (8Hz) lH, 6.93slH, 7.30 + 7.33ml5H.

Diphenylmethyl-cc- [2ß-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-l-yl] gly oxalate (11).

Ozonized oxygen was added to a solution of 2.342 g (4.33 mmol) of diphenylmethyl-q- [2β-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-1-yl] -a-isopropylidene acetate (10) in 40 ml of methylene chloride for 25 min initiated at -78 ° C. The excess ozone was then purged with nitrogen gas and the mixture was blended with 3 ml of dimethyl sulfide and stirred at -78 ° C for 30 minutes and at room temperature for 30 minutes. The resulting reaction mixture was then mixed with three drops of acetic acid, washed with water, dried over sodium sulfate and evaporated under reduced pressure, and 2.312 g of the above-mentioned product (11) were obtained as a light yellow foam.

IR: v ™ cl) 3420.1680.1507.1822.1733.1707 cm "1.

NMR: 8CDCh l, 87s3H, 3.55s2H, 5.30-5.57m2H,

636 617

6.85d (8Hz) lH, 4.22s2H, 6.93slH, 7.22 + 7.30ml5H. Diphenylmethyl-a- [2ß-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-l-yl] glycolate (12).

2.50 g was added to a solution of 2.312 g of diphenylmethyl-a- [2ß-acet-onyloxy-3ß-phenylacetamido-4-oxoazetidin-l-yl] glyoxalate (11) in a mixture of 10 ml of methylene chloride and 10 ml of glacial acetic acid activated zinc powder was added with stirring and the mixture was then stirred for 3 hours at room temperature. This reaction mixture was then filtered through a layer of Celite, which layer was then washed with methylene chloride. The filtrate obtained was washed with water, dried over sodium sulfate and evaporated under reduced pressure, and 2.136 g of the above product (12) was obtained as a light yellow foam, as a mixture of epimers in the a-position. IR: v ™ cli3425.1675.1505.3350.1785.1740 cm "1.

Diphenylmethyl-a- [2ß-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-1 -yl] -a-chloroacetate (13).

To a solution of 2.136 g of diphenylmethyl-a- [2ß-aceto-nyloxy-3ß-phenylacetamido-4-oxoazetidin-l-yl] glycolate (12) in 20 ml of anhydrous methylene chloride was added 0.90 ml of thionyl chloride and 0, 33 ml of pyridine was added at 0 ° C. with stirring. After stirring for 1 h at 0 ° C, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was then washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 2.251 g of crude product (13) above as a brown foam of a mixture of epimers in the a-position.

IR: v ™ clj3430, 1680, 1510, 1795, 1752, 1740 (shoulder) cm "1.

Diphenylmethyl-a- [2ß-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-1-yl] -a-triphenylphosphoranylidene acetate (14).

To a solution of 2.251 g of diphenylmethyl-a- [2ß-acetonyloxy-3ß-phenylacetamido-4-oxoazetidin-l-yl] -a-chloroacetate (13) in 20 ml of anhydrous methylene chloride, 1.50 g of triphenylphosphine was added and the mixture was added treated under nitrogen at reflux for 4 h. The reaction mixture was then poured into ice water, mixed with 20 ml of 5% aqueous sodium bicarbonate solution and extracted with methylene chloride. The resulting organic layer was then washed with water, dried over sodium sulfate and evaporated under reduced pressure. Purification of the residue by chromatography over 100 g of silica gel containing 10% water and using a mixture of benzene and ethyl acetate (1: 2) as eluent gives 2.328 g of the above product (14) as a yellow foam.

IR: v ™ cll3433,1675,1507,1770, 1735, 1628 cm "1.

Diphenylmethyl-1-oxadethia-3-methyl-7-phenylaceta-mido-3-cephem-4-carboxylate (15)

A solution of 2.328 g of diphenylmethyl-a- [2β-aceto-nyloxy-3ß-phenylacetamido-4-oxoazetidin-1-yl] -a-triphenyl-phosphoranylidene acetate (14) in 30 ml of anhydrous dioxane was added under nitrogen for 65 h Treated reflux and then evaporated under reduced pressure to remove the dioxane. The residue was purified by chromatography over 150 g of silica gel containing 10% water and using a mixture of benzene and ethyl acetate (1: 1) as a developing solvent to give 1.103 g (74.7%) of the above product (15 ). After crystallizing this product from ether, pure colorless crystals of compound (15) with F = 106-107 ° C. are obtained.

IR: Vmax01 '3428,1679,1510,1792, 1721 cm "1.

7

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

636617

NMR: SCDCb l, 93s3H, 3.63s2H, 4.03s2H, 4.95d (4Hz) lH, 5.68dd (4.9Hz) lH, 6.67d (9Hz) lH, 6.92slH, 7.33 + 7 , 38ml5H. [afe5 -62.7 ± 1.9 ° (c = 0.533, CHC13).

UV: / ™ xCh 267.5 nm (s = 7760).

1-Oxadethia-3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid (16).

To a solution of 66 mg diphenylmethyl-1-oxadethia

3-methyl-7-phenylacetamido-3-cephem-4-carboxylate (15) in

3 ml of methylene chloride was added to 0.2 ml of anisole and 0.2 ml of tri-fluoroacetic acid with stirring at 0 ° C, and stirring of the mixture was continued at 0 ° C for 2 hours. This reaction mixture was then concentrated to dryness under reduced pressure and the residue was dissolved in 5% aqueous sodium bicarbonate solution and washed with ether. The aqueous layer was then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was then washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from a mixture of methylene chloride and petroleum ether gives 30 mg of the named product (16) as colorless crystals and with F = 180-182 ° C. (dec.). IR: 3404, 1778, 1650, 1536 cm "1.

Diphenylmethyl-1-oxadethia-7-amino-3-methyl-3-cephem-4-carboxylate (17).

To a solution of 600 mg (1.243 mmol) of diphenyl-methyl-l-oxadethia-7-phenylacetamido-3-methyl-3-cephem-

4-carboxylate (15) in 15 ml methylene chloride was added 518 mg (2.486 mmol) phosphorus pentachloride and 0.181 ml (2.486 mmol) pyridine at -20 ° C and the mixture was at 30 ° C for 30 min and then at room temperature for 45 min stirred. The solution thus obtained was then mixed with 10 ml of methanol, stirred for 30 min, diluted with water and stirred for 30 min at room temperature. The reaction mixture was then concentrated under reduced pressure, neutralized with 5% sodium bicarbonate solution in the presence of ice and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure, and a light yellow foam was finally obtained. After purification of the foam by chromatography over 50 g of silica gel containing 10% water and using a mixture of ethyl acetate and benzene (2: 1) as eluent, 367 mg of the above-mentioned product (17) are obtained as a colorless foam.

IR: v ™ a '3420.3350.1787, 1720 cm "1.

NMR: 8CDCb l, 75s2H, 2.02s3H, 4.33s2H, 4.48d (4Hz) lH,

5.00d (4Hz) 1H, 6.97s 1H, 7.40ml 0H.

Diphenylmethyl-1-oxadethia-7-N-tert-butoxycarbonyl-D-a-phenylclycinamido-3-methyl-3-cephem-4-carboxylate (18).

To a solution of 150 mg (0.412 mmol) of diphenylmethyl-1-oxadethia-7-amino-3-methyl-3-cephem-4-carboxylate (17) in a mixture of 8 ml of tetrahydrofuran and

4 ml of acetone was added to 155 mg (1.5x0.412 mmol) of N-tert-butoxycarbonyl-da-phenylglycine and 152 mg (1.5x0.412 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline added and the mixture was stirred at room temperature for 14 h. The reaction mixture was then diluted with ethyl acetate, washed with water, then with hydrochloric acid, with aqueous sodium bicarbonate solution and finally with water, dried over sodium sulfate and evaporated to give a light yellow foam. After purification of the foam by chromatography over 30 g of silica gel containing 10% water and using a mixture of benzene and ethyl acetate (2: 1), 248 mg of the above-mentioned product (18) are obtained.

IR: v ™ ch 3430, 1695, 1510, 1800, 1720 cm "1.

NMR: SCDCh l, 43s9H, l, 98s3H, 4.18s2H, 5.00d (4Hz) lH, 5.27d (7Hz) lH, 5.65q (4.8Hz) lH, 5.67d (7Hz) lH, 6 , 77d '(8Hz) lH, +7.4 aromatic H.

Trifluoroacetate of l-oxadethia-7-D-a-phenylglycine-amido-3-methyl-3-cephem-4-carboxylic acid (19).

To a solution of 246 mg of diphenylmethyl-1-oxadethia-7-N-tert-butoxycarbonyl-D-a-phenylglycinamido-3-methyl-

3-cephem-4-carboxylate (18) in 1.5 ml methylene chloride, 0.7 ml anisole and 1.5 ml trifluoroacetic acid were added and the mixture was stirred at 0 ° C for 80 min and then for 40 min at room temperature and under reduced pressure. The residue was treated with a mixture of ether and petroleum ether and 180 mg of the above-mentioned product (19) are obtained in the form of a light yellow powder; when the melting point is determined, decomposition takes place at 135 ° C.

IR: VSS 3410.1775, 1675.1527 cm "1.

NMR: 8D;, + DCI l, 97s3H, 4.33s2H, 5.10d (3.8Hz) lH, 5.32slH,

7.53s5H.

UV: 255 nm (= 7080).

Diphenylmethyl-1-oxadethia-7-D-mandelamido-3-methyl-3-cephem-4-carboxylate (20).

To a solution of 71.6 (0.196 mmol) of diphenylmethyl-1-oxadethia-7-amino-3-methyl-3-cephem-4-carboxylate (17) in 8 ml of ethyl acetate were successively added a solution of 100 mg of sodium bisulfite in 4 ml Water and then 52.5 mg (1.5 x 0.196 mmol) of mandelic acid-O-carboxyanhydride were added with vigorous stirring at 0 ° C. Stirring was continued for 1 h at room temperature and the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The light yellow powder thus obtained was purified by chromatography on 20 g of silica gel containing 10% water and using a mixture of benzene and ethyl acetate (1: 1), and 80.4 mg of the above-mentioned product (20) were obtained. IR: v ™ cll3425, 1695, 1510, 1797, 1727 cm "1.

NMR: 8CDCl1 l, 97s3H, 3.92br-slH, 4.20s2H, 5.00d (4Hz) lH, 5.13slH, 5.63q (4; 9Hz) lH, 6.98slH, up to 7.4 aromatic H.

1-Oxadethia-7-D-mandelamino-3-methyl-3-cephem-4-car-bonic acid (21).

To a solution of 78.4 mg of diphenylmethyl-1-oxadethia-7-D-mandelamino-3-methyl-3-cephem-4-carboxylate (20) in 2 ml of methylene chloride was added 0.3 ml of anisole and 0.3 ml of trifluoroacetic acid was added at 0 ° C and the mixture was stirred at 0 ° C for 30 min and then evaporated under reduced pressure. The residue was dissolved in an aqueous sodium bicarbonate solution and washed with ether. The aqueous layer was then acidified with hydrochloric acid and extracted with ethyl acetate. The extract solution was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was then ground in a mixture of ether and petroleum ether and 25 mg of the above-mentioned product (21) are obtained in the form of a light yellow powder with an F of about 120 to about 135 ° C.

IR: v ^ ax 3400.1781.1712.1673.1524 cm "1.

Compounds (17) and (19).

In a manner similar to that described above for preparations from (8) to (16), compounds (17) and (19) were protected, e.g. prepared with N-tertiary butoxycarbonate and O-formyl groups in the acyl groups.

7- [D-2- (3-Methylsulfonyl-2-oxoimidazolidin-l-yl) -carbon-amido-2-phenylacetamido] -3-methyl-l-oxadetia-3-cephem-

4-carboxylic acid (22).

8th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

To a solution of 63.5 g of trifluoroacetate of 7- (D-2-phenylglycinamido) -3-methyl-1-oxadethia-3-cephem-4-car-bonic acid (19) in a mixture of 0.8 ml of tetrahydrofuran and 0.2 ml of water were added 40 ml of triethylamine. The stirred mixture was then treated at 0 ° C. with 83 mg of 3-methyl-sulfonyl-2-oxoimidazolidine-carboxylic acid and 40 p.1 of triethylamine. The carboxylic acid mentioned is first activated with 0.6 μl, mol of phosgene in CCh. After stirring at room temperature for 15 min, the mixture was acidified with 2N hydrochloric acid and mixed with water and ethyl acetate. The formed ethyl acetate layer was then washed with water and extracted with aqueous sodium bicarbonate solution. The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer formed was then washed with water, dried over sodium sulfate and evaporated to remove the ethyl acetate. After the residue has been triturated in ether, 23 mg of the abovementioned compound (22) are obtained in the form of a light yellow powder and with an F of about 150-170 ° C.

IR: vS013325, 1787, 1730, 1678, 1527, 1168 cm-1.

Diphenylmethyl-7- (2-thienylacetamido) -3-methyl-1-oxa-dethia-3-cephem-4-carboxylate (23).

To a solution of 85.5 mg (0.235 mmol) of diphenyl-methyl-7-amino-3-methyl-1-oxadethia-3-cephem-4-carboxylate (17) in 3 ml of methylene chloride at 0 ° C was 56 , 5 mg (0.353 mmol) of 2-thienylacetyl chloride and 19 µl (0.353 mmol) of pyridine were added and the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under reduced pressure to remove ethyl acetate. After purification of the residue by chromatography over 20 g of silica gel containing 10% water and using a mixture of benzene and ethyl acetate (2: 1) as elution solvent, 111.9 mg of the above-mentioned compound (23) are obtained as a light yellow foam.

IR: v ™ ch3420, 1792, 1722, 1680, 1505 cm "1.

NMR: CDCh l, 95s3H, 3.83s2H, 4.13s2H, 4.97d (4Hz) lH, 5.67dd (4; 9Hz) 1H, 6.62d (9Hz) lH, 6.98s 1H, 6.9 -7.3ml3H.

7- (2-Thienylacetamido) -3-methyl-l-oxadethia-3-cephem-4-carboxylic acid (24).

0.3 ml of anisole was added to a solution of 110 mg of diphenylmethyl-7- (2-thienyl-acetamido) -3-methyl-1-oxadethia-3-cephem-4-carboxylate (23) in 3 ml of methylene chloride at 0 ° C and 0.3 ml of trifluoroacetic acid were added and the mixture was stirred at 0 ° C for 30 min. The reaction mixture was then evaporated to dryness under reduced pressure and ground in a mixture of methylene chloride, ether and petroleum ether; 51.5 mg of the above-mentioned compound (24) are obtained as a light yellow powder with F = 180-185 ° C. (with decomposition).

636617

IR: Vmai013320, 1775.1720.1655.1550 cm "1.

Diphenylmethyl-7ß- (a-diphenylmethoxycarbonyl-a-phe-nylacetamido) -3-methyl-l-oxadethia-3-cephem-4-carboxylate

(25).

To a solution of 85.6 mg (0.235 mmol) of diphenylmethyl-7-amino-3-methyl-1-oxadethia-3-cephem-4-carboxylate in a mixture of 6 ml of tetrahydrofuran and 3 ml of acetone was added 245 mg (0.705 mmol ) of the monobenzhydryl ester of a-phenylmalonic acid and 174 mg (0.705 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the mixture was stirred at room temperature for 4 h. The reaction mixture was then diluted with ethyl acetate, washed with water, diluted with hydrochloric acid, aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and concentrated, and finally 241 mg of a heavy syrup were obtained. After purification of the syrup by chromatography over 30 g of silica gel, which contained 10% water, using a mixture of ethyl acetate and benzene (1: 4) as the eluent and after trituration in a mixture of ether and petroleum ether, 102.6 mg are finally obtained (63%) of the above compound (25) as a colorless foam.

IR: v ™ cl! 3420.3350.1797.1725, 1680.1516 cm "1.

NMR: 5CDCI> l, 93s3H, 4.10s2H, 4.68s2H, 4.90d (4Hz) lH, 5.60q (4; 10Hz) lH, 6.85s2H, approx.7.25m.

7β- (a-Phenylmalonamido) -3-methyl-l-oxadethia-3-cephem-4-carboxylic acid (26).

0.2 ml was added to a solution of 100 mg of diphenylmethyl-7ß- (a-diphenyl-methoxycarbonyl-a-phenylacetamido) 3-methyl-1-oxadethia-3-cephem-4-carboxylate (25) in 3 ml of methylene chloride Anisole and 0.2 ml trifluoroacetic acid were added at 0 ° C and the mixture was stirred at 0 ° C for 2 h. Thereafter, the reaction mixture was concentrated under reduced pressure and the residue was treated in a mixture of ether and petroleum ether to obtain 46 mg (89%) of the above-mentioned compound

(26) as an almost colorless powder with F = 115-120 ° C.

IR: VS01 approx. 3400-2300, 1770, 1720, 1630, 1525 cm "1.

Sodium 7ß- (a-phenylmalonamido) -3-methyl-l-oxadethia-3-cephem-4-carboxylate.

The product (26) obtained above was dissolved in an aqueous solution of 0.001 N sodium bicarbonate and diluted with water; the result is a solution of the compound called sodium salt, which is suitable for antibacterial experiments in vitro on Mueller-Hinton agar plates. A strong antibacterial activity was also shown against gram-negative bacteria, including pseudo-monas strains, which show resistant properties against commonly available penicillins and cephalosporins.

9

5

10th

15

20th

25th

30th

35

40

45

50

B

Claims (10)

636 617 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula 15 (15) As2Î «J p-OCH2COCH3 (left) c = o I cox 10th Halogenation of the compound of formula (12) y in which A can be acyl, COX the free carboxylic acid group or its salts, amides, imides, hydrazides or an ester or thioester group and Y = hydrogen or methoxy, characterized by the following process steps: - reaction of the compound of formula (7) 15 20th , v "N« v ^ ^ OCH2COCH3 height iox RoÄ (12) 3rd 636617 cechconïï-6 51 r co oh ^ n, i co oh or a pharmaceutically acceptable salt or ester thereof. 3. The method according to claim 1, characterized in that X is characterized by X benzhydryloxy, p-nitrobenzyloxy, p- Is methoxybenzyloxy, 2,2,2-trichloroethoxy or alkali metaloxy. 4. The method according to claim 1 for the preparation of a compound wherein Y is methoxy. 60 5. The method according to claim 1 for the preparation of a compound in which A is phenylacetyl, D-mandeloyl, a-phenylmalonyl, Da- (3-methylsulfonyl-2-oxoimidazo-lidin-l-yl) -carbonamido-a-phenylacetyl or 2-thienyl- acetyl, Y is hydrogen, COX represents the free carboxylic acid group 65 or its pharmaceutically acceptable salts or an ester group. 6. The method according to claim 5 for the preparation of a compound of the formula 7. The method according to claim 1 for the preparation of a compound of formula (16) a-hn- \ (16) characterized in that an ester or tioester of the formula (15) is prepared and this is then saponified. (7) cox in which shark is halogen, with a compound of the formula HOCH2C = CH in the presence of a halide ion acceptor; Introduction of the acyl group A into the compound of the formula (8) - Ylid formation with a compound of formula (13) 25 y ^ och-coch h j v 30 0 ^ - ^ CHEal I. (13) cox - Intramolecular condensation of the phosphoranylidene of the formula 35 (14) h2n <^ och2c = ch cox J - hydration of the compound of formula (9) 8. The method according to claim 1 for the preparation of a compound of formula (16) a-hn y Cr -n (16) H. coo h Y .v / \ cox h. in which COX has the meaning given below, characterized in that, according to claim 1, a compound of the formula 15 in which COX denotes an ester group is prepared and then the acyl group A is split off. (8th) 40 0ch2c0ch ^ (14) * 0ch2c = ch cox - Oxidative cleavage of the compound of the formula "ï O' ^ 0CH2C0CK ^ i j -— c- <*** 3 ò0x j (9) (10) - Reduction of the compound of formula (11) and that optionally a free carboxylic acid obtained is converted into a pharmaceutically acceptable salt, so 2. Process according to claim 1, characterized in that the group X forms acyloxymethyl ester, phenacyl ester, benzaldoxime ester, N, N-dimethylaminoethyl ester, alkali metal salts and alkaline earth metal salts. 10. A process for the preparation of a compound of the formula 15, in which A is an acyl group and COX is an ester group, characterized in that a compound of the formula (17) is prepared according to claim 9 and another acyl group A is introduced into it.