DK147338B - METHOD OF ANALOGUE FOR THE PREPARATION OF CEPHALOSPOR COMPOUNDS OR SALTS OR BIOLOGICAL ACCEPTABLE ESTERS THEREOF - Google Patents

Description

147338

The present invention relates to an analogous process for the preparation of cephalosporin compounds of formula I as set forth in the preamble of claim 1, wherein R, Ra and R5 have the same meanings stated, or salts or biologically acceptable esters thereof. The process according to the invention is characterized by the characterizing part of claim 1.

The cephalosporin compounds disclosed herein are named from the substance "cepham" in accordance with J. Amer. Chem. Soc., 1962, 84, 3400, and the term "cephem" refers to the basic cepham structure with one double bond.

2 147338

Many cephalosporin compounds having antibacterial activity are known and these compounds have Δ unsaturation and are generally substituted at the 3-position with a methyl group or substituted methyl group and in 7β-3ΐΐ11ΐΐ θη with an acylamido group. It is now generally recognized that the antibiotic properties of a given ceph-3-em-4-carboxylic acid are predominantly determined by the nature of both the 7β-acylamido group therein and of the substituent at the 3-position containing the compound. Extensive research has been done to find combinations of such groups that provide antibiotics with special properties.

Cephalosporin antibiotics are used extensively to treat diseases caused by pathogenic bacteria, both in humans and animals, for example, to treat diseases caused by bacteria resistant to other antibiotics such as penicillin compounds, and cephalosporin compounds are also used extensively to treat penicillin hypersensitivity patients. In many cases, it is desirable to use a cepah-losporin compound that exhibits activity both against gram-positive and gram-negative microorganisms, and extensive research programs have been directed to the development of improved broad-spectrum cephalosporin antibiotics.

The practical utilization of a considerable number of known or commercially known cephalosporin antibiotics is limited by their relatively high sensitivity to the β-lactamases produced by many bacteria. Therefore, a desirable property of a broad-spectrum cephalosporin antibiotic is that it must exhibit substantial resistance to β-lactamases, including those produced by gram-negative microorganisms.

A further difficulty of many cephalosporin antibiotics intended for therapeutic use is that they can undergo degradation in vivo. Thus, a significant number of known cephalosporin antibiotics have been found to have the disadvantage that, after administration, they are deactivated, often rapidly, by enzymes (e.g. esterases) present in the body.

Danish Patent Application No. 2373/72 discloses cephalosporin compounds of the general formula 3 147338 R2.C.CO.NH ___ / \

1 in VI

\ h3 / —Y ^ 0

COOH

2 where R i.a. may be hydrogen, phenyl, naphthyl, thienyl, furyl 3 or pyridyl; alkyl, alkenyl, propinyl, cycloalkyl and phenylalkyl; methyl, vinyl or C1-6 OCONHCCHgJjjjX »where X is hydrogen or halogen and m is a number from 1-4. Formula VI thus generically encompasses the compounds I prepared by the process of the present invention, but the earlier application does not disclose or imply any such compound. The narrowly defined N-substituted 3-carbamoyloxymethylcephalosporins with narrowly defined 7-side chain by the present process gave better antibiotic effect than the closest analogues specifically exemplified in application 2373/72.

The most closely related compound shown herein is that given in Example 53, (6R, 7R) -7- [2-phenyl-2-methoxyiminoacetamido] -3- (N-chloroethylcarbamoyloxymethyl) -ceph-3-em-4 carboxylic acid. Comparative biological study of this compound has been performed with compounds prepared according to Examples 1/2, 7 and 8 of this specification. The results are shown in the table below.

Bacteria. Least inhibitory concentration, _yg / mi_

Compound of Example Compound, 9 Ί q of Example 53 ___________ in Ans. 2373/72 S. aureus 663 <0.125 0.25 <0.125 0.25 1.25 S. aureus 853 0.5 0.5 0.25 0.5 1.0 S. aureus 1414 0.25 0.5 0 0.25 1.0 E. coli TEM 4444 8 E. coli TEM + 4844 8 S. typhimurium 804 4844 16

Pr. mirabilis 431 44 4 88

Pr. morganii 235 <0.25 <0.125 <0.125 <0.125 4 H. influenzae 1184 1 1 <0.5 <0.5 16_ U7338 4

It is clearly seen from the table that the compounds prepared by the present process have a higher effect than the known, both against the gram-positive Staphylococcus aureus and all the gram-negative organisms, in particular Proteus morganii and Haemophilus influenzae.

Thus, the compounds prepared by the process of the invention have particularly good broad spectrum activity combined with the desirable properties described above for high stability to S-lactamase and good stability in vivo.

They are defined as having syn-form (the cis-isomeric form) with respect to the configuration of the group ORa relative to the carboxamido group. In this specification, the sync configuration is reproduced structurally as follows: R.C.CONH-

II

N

The sight configuration is attributed to the connections based on the work of Ahmad and Spencer printed in Can. J. Chem 1961, 39, 1340.

Salts which may be formed, where appropriate, by the compounds of the present invention include both salts with inorganic bases, e.g., alkali metal salts such as sodium and potassium salts, and alkaline earth metal salts, e.g., with calcium, as salts with organic bases, e.g., procaine, phenylethylbenzylamine. dibenzylethylene diamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine. The salts may also take the form of resinates formed, for example, with a polystyrene resin or cross-linked polystyrene-divinylbenzene copolymer resin containing amino groups or quaternary amino groups.

When R in the above Formula I is a furyl group, it may be fur-2-yl or fur-3-yl, and if it is a thienyl group, it may be thien-2-yl or thien-3-yl. Preferably, the group R is a fur 2-yl group.

5 147338

As mentioned above, the group Ra of formula I is an alkyl group of 1-4 carbon atoms, e.g., methyl or ethyl, an alkenyl group or alkynyl group of 2-4 carbon atoms, e.g., vinyl, allyl or propargyl, a cycloalkyl group of 3-7 carbon atoms, e.g., cyclopentyl , or a phenyl group.

The group Rs of formula I may, to the extent that the respective definitions allow it to be identical to or different from the group Ra. Thus, it may be an alkyl group having 1-4 carbon atoms, eg methyl or ethyl, an alkenyl group having 2-4 carbon atoms, eg vinyl or allyl, or a cycloalkyl group having 3-7 carbon atoms, eg cyclopentyl.

Preferably, the group R is a fur-2-yl group and the group Ra is a methyl group.

According to the invention, it is particularly suitable because of its broad-spectrum antibiotic properties, its stability in the presence of human serum, its high stability to β-lactamases produced by various organisms, and its resistance to the action of mammalian ester agar (6R, 7R) -7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-3-N-methylcarbamoylloxymethylceph-3-em-4-carboxylic acid (the syn isomer) of the formula

OH H

-C. CONH - h''2 N

IN! 'II

N X-N Λ-CILO.CO.NHCH- \ 0 y '* AND- υ i

3 COOH

optionally in the form of its sodium salt.

If in formula III or V is a carboxyl blocking group, it may be the residue of an ester-forming alcohol (aliphatic or araliphatic), phenol, silanol or stannanol, or a symmetrical or mixed anhydride group derived from an appropriate acid.

Salts with bases of compounds of general formula I may be formed, for example, by reacting the cephalosporic acid with sodium or potassium 2-ethylhexanoate. Biologically acceptable ester derivatives can be formed by conventional feeding agents.

6 147338

An acylating agent corresponding to the acid of general formula IV may be condensed with an amino compound of general formula III wherein R "is a hydrogen atom or a carboxyl blocking group, or a derivative thereof such as a salt such as a tosylate or a N-silyl derivative, the condensation possibly being is carried out in the presence of a condensing agent and, if necessary, is followed by removal of the carboxyl blocking group R1.

Compounds of general formula I can thus be prepared by using as an acylating agent an acid halide, in particular an acid chloride or bromide, corresponding to the acid level. Such acylations can be carried out at a temperature between -50 and + 50 ° C, preferably at -20 and + 30 ° C. The acylation can be carried out in aqueous or non-aqueous media.

Acylation with an acid halide can be carried out in the presence of an acid-binding agent, for example, a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bicarbonate or an oxyrane which serves to bind hydrogen halide released by the acylation reaction. Where an oxyran is used for this purpose, it is preferably a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The free acid form of a compound of general formula IV can itself be used as an acylating agent. Such acylations are conveniently carried out in the presence of, for example, carbodiimide such as N, Ν'-diethyl, -dipropyl or diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-dimethylaminopropylcarbodiimide; a carbonyl compound such as carbonyl diimidazole; or an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium-3'-sulfonate or N-t-butyl-5-methylisoxazolimium perchlorate. The condensation reaction is conveniently carried out in an anhydrous reaction medium such as methylene chloride, dimethylformamide or acetonitrile.

The acylation can also be performed with other amide-forming derivatives of the free acid IV such as a symmetrical anhydride or mixed anhydride, for example with pivalic acid or formed with a halogen formate such as a lower alkyl halide formate. The mixed or symmetrical anhydrides can be formed in situ. For example, a mixed anhydride can be formed by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed with the phosphoric acids (e.g. phosphoric acid or phosphoric acid), sulfuric acid or aliphatic or aromatic sulfonic acids, (e.g. p-toluenesulfonic acid).

The reaction of the 3-hydroxymethylcephalosporin V with an isocyanate of the general formula Rs.NCO (wherein R5 is as defined above) is preferably carried out in the presence of a tri-alkylamine having 1-4 carbon tooms in each alkyl group. The reaction can be carried out at a temperature in the range of -50 to + 105 ° C, conveniently at a temperature of 0 to 25 ° C. The reaction can be carried out in a substantially inactive organic solvent, for example, Ν, Ν-disubstituted amide, a halogenated hydrocarbon or an ether. Reactions of this type are described, for example, in U.S. Patent No. 3,355,452.

The 3-hydroxymethyl starting material for use in this process variant can be prepared, for example, in the ways described in British Patent No. 1,121,308 and Belgian Patent No. 783,449.

As indicated above, starting materials of the general formula III may be used in the form of acid addition salts, for example with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, toluene-p-sulfonic acid or methanesulfonic acid.

And possibly the blocking group as a substituent on the 4-carboxy group in compounds of the general formula III, V or VI is suitably a group which can be easily separated at a later stage of the reaction and is advantageously a group containing.

1-20 carbon atoms. Suitable blocked carboxyl groups are well known in the chemistry and a list of representative groups is included in our aforementioned Belgian Patent Specification No. 783 * 449.

Preferred blocked carboxyl groups are e.g. arylalkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxocarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group may later be removed by any of the relevant methods disclosed in the literature; for example, in many cases, acid or base catalyzed hydrolysis as well as enzymatically catalyzed hydrolysis can be used.

The antibiotically active compounds prepared by the method of the invention can be worked up for administration in any convenient manner in analogy with other antibiotics. Hereby, pharmaceutical compositions containing an antibiotic active compound of the general formula I or a non-toxic derivative thereof can be prepared, for example, a salt or a biologically acceptable ester, the preparation being processed for use in human and veterinary medicine. Such compositions may be reprocessed for practical use in a conventional manner by suitable pharmaceutical carriers or excipients.

Generally, the compositions may contain from 0.1% of the active material upwards, preferably 10-60% thereof, but depending on the intended mode of administration. Where the composition is in dosage units, each dose will preferably contain 50-1500 mg of the active substance. The dose used to treat adult humans will preferably be 500-4000 mg per day depending on the route of administration and the frequency of administration.

The compounds of the process according to the invention can be administered in combination with other, hence compatible drugs such as antibiotics, eg penicillins, other cephalosporins or tetracyclines.

9 147338

Some examples serve to elucidate the method of the invention. Melting points were determined on a Kofler block in Examples 1-6; in Examples 7-13, the melting points in open-ended capillary tubes were determined on a Mettler apparatus and they have the shape (M ^) where x is the heating rate in ° C per minute. minute and γ are the insertion temperature. Optical rotations were measured in the temperature range of 18-24 ° C. Ultraviolet spectra were measured in pH 6 phosphate buffer. The structures of the compounds are also confirmed by infrared and proton magnetic resonance spectroscopy.

Example 1 (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-3-N-phenylcarbamoylloxymethylceph-3-em-4-carboxylic acid syn isomer

A solution of 1.00 g of the syn isomer of (6R, 7R) -7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-3-hydroxymethylceph-3-em-carboxylic acid in 20 ml of Ν, Ν -dimethylformamide (purified by filtration through basic alumina) is cooled to 5 ° C and treated with 0.73 ml of triethylamine and 2.85 ml of phenyl isocvanate. The reaction mixture was stirred for 1 hour at 5 ° C, then the ice bath was removed and stirring was continued for 1 1/2 hours at ca. 20 ° C. The solution was partitioned between 100 ml of 3% aqueous sodium bicarbonate and 10 ml of ethyl acetate. The layers were separated and the aqueous solution was washed with 3x100 ml of ethyl acetate and then covered with 100 ml of ethyl acetate and acidified to pH 1.89 with concentrated hydrochloric acid.

The layers were separated and the aqueous layer extracted with an additional 4x100 ml of ethyl acetate. The combined organic extracts were washed with 5x150 ml of water and 100 ml of saturated sodium chloride solution and dried over MgSO 4, then the solvent was removed in vacuo to give a yellow foam which was triturated with 50 ml of ether to give 905 mg of the title compound with ctp = +270 (c = 1 in DMSO), Amax (pH 6) 255 nm (ε = 23,500) and 270 nm (ε = 19,500).

10

Example 2 147338

Sodium (6R, 7R) -7- [2- (2- (2-yl) -2-methoxyiminoacetamido7-3-N-methylcarb anoyloxymethylceph-3-em-4-carboxylate, syn isomer)

Treatment of 1,525 g of the syn isomer of (6R, 7R) -7- [1- (fur-2-yl) -2-methoxyiminoacetamide] -3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml of N, N-dimethylformamide with 1.12 ml of triethylamine and 2.0 ml of methyl isocyanate as described in Example 1 gave 0.803 g of the syn isomer of (6R, 7R) -7-, 2- (fPi'-2- yl) -2-methoxy-N-iminoacetamido7-3 metylkarbamoyloxymetylceph-3-em-4-carboxyl acid. A portion of it, namely 0.726 g, was dissolved in 2 ml of acetone and a solution of 1.66 mmol sodium DL-2-ethylhexanoate in 1.6 ml of acetone was added and the solution was left to refrigerate overnight. The product was filtered off washed with cooled acetone and dried in vacuo to give 282 mg of the title compound, ctp = + 59 ° (c = 1 in H 2 O), λ max (PH 6) 274 nm (ε = 17,600).

Example 3 (6R, 7R) -3- (N-Ethylcarbamoyloxymethyl) -7- [5- (fur-2-yl) -2-methoxy-iminoacetamido7-ceph-3-em-4-carboxylic acid, syn isomer

Reaction of 1.54 g (6R, 7R) -7-i-2- (fur-2-yl) -2-methoxy-iminoacetamido7-3-hydroxymethylceph-3-em-4-carboxylic acid (syn isomer) in 60 ml of Ν, Ν-dimethylformamide with 2.0 ml of ethyl isocyanate and 1.12 ml of triethylamine as in Example 1 gave 622 mg of the title compound at = + 68 ° (c = 1 in DMSO),

Amax (PH6) 273 um (ε = 16.350).

Example 4 (6R, 7R) -3- (N-t-Butylcarbamoyloxymethyl-7- / 2- (fur-2-yl) -2-methoxy-iminoacetamido7-ceph-3-em-4-carboxylic acid, syn isomer

Reaction of 2.00 g of the syn isomer of (6R, 7R) -7- 2- (fur-2-yl) -2-methoxyiminoacetamido7-3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml Ν, Ν-Dimethylformamide with 5.20 g of t-butyl isocyanate and 2.92 ml of triethylamine as in Example 1 gave 1.58 g of the title compound with aD = + 77 ° (c = 1 in DMSO), Amax (pH 6) 275 nm (ε = 16,400).

11

Example 5 147338 (6R, 7R) - 3- (N-Allylcarbamoyloxymethyl) -7β- (fur-2-yl) -2-methoxy-iminoacetamido'-7-ceph-3-emr-4-carboxylic acid, syn. isomer

Treatment of 2.00 g of the syn isomer of (6R, 7R) -7 (fur-2-yl) -2-methoxyiminoacetamido-3-hydroxymethyl ceph-3-em-4-carboxylic acid in 100 ml of N, N- dimethylformamide with 2.0 ml of triethylamine and 4.42 g of allylisocyanate as otherwise explained in Example 1 gave 1.63 g of the title compound with = + 32 ° (c = 1.1 in DMSO), Xmax (pH 6) 274 nm (ε = 13.100).

Example 6 (6R, 7R) -7- / gL (fur-2-yl) -2-methoxyiminoacetamido7-3-N-methylcarbamoylloxymethylceph-3-em-4-carboxylic acid, syn isomer

A suspension of 1.00 g of the syn isomer of (6R, 7R) -7- (fur-2-yl) -2-methoxyiminoacetamino / 3-hydroxymethyl ceph-3-em-4-carboxylic acid in 50 ml of dry dichloromethane was treated with 0.871 g of tri-n-butyltin oxide and stirred under nitrogen for 30 minutes. at 21 ° C, during which the suspension dissolved. 0.60 g (10.50 mmol) of methyl isocyanate was added and stirring was continued for an additional 3 hours. 30 ml of ethyl acetate and 30 ml of water were added and the dichloromethane was removed in vacuo. The volume of the ethyl acetate was approx. 30 ml and the pH of the solution was adjusted to 8.5 with aqueous sodium bicarbonate solution. The aqueous solution was washed with ethyl acetate (3 x 30 mL) and covered with additional ethyl acetate (30 mL), then adjusted to pH 1.9 with hydrochloric acid. The phases were separated and the aqueous phase was extracted with an additional 3 x 30 ml of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution and dried over magnesium sulfate, then the solvent was removed in vacuo to give the title carboxylic acid as a dirty white foam in an amount of 0.962 g; aD = + 47 ° (c = 0.57 in DMSO), λ max 273 nm (ε = 15.450) i

Example 7 (6R, 7R) -3-M-cyclohexylcar bamoyloxymethyl-7- / 2-iretroxyvinyl-2- (fur-2-yl) -acetamido7-ceph-3-em-4-carboxylic acid, synisomer

A suspension of 1.00 g of the syn isomer of (6R, 7R) -3-hydroxymethyl-7-i (β-methoxyimino-2- (fur-2-yl) -acetamido7-ceph-3-em 4-Carboxylic acid in 50 ml of dry benzene under nitrogen is treated with 0.870 g of tri-n-butyltin oxide and solution is stirred after stirring for 30 minutes, 1.318 g of cyclohexyl isocyanate and stirring are added for an additional 3 l / 2 hours during which period / became essentially complete.

Addition of 50 ml of water to the reaction mixture precipitated dicyclohexylurea which was filtered off. The benzene layer was separated and stirred and 50 ml of 0.1M hydrochloric acid was added to give a white gelatinous precipitate which was filtered off. The precipitate was dissolved in aqueous sodium bicarbonate solution extracted with 50 ml of ethyl acetate. The aqueous phase was acidified with 2M hydrochloric acid and extracted with 2 x 80 ml of ethyl acetate. The organic layer was washed with 2 x 150 ml of water, dried over magnesium sulfate and evaporated in vacuo to 396 mg of the title compound as a dirty-white solid, mp (m | q) 162 ° C, a 5 = + 38.0 ° (c = 1.03 in dioxane), Amax (pH 6 phosphate buffer) 274 nm (ε = 16,930).

Example 8 (6R, 7R) - 3-N-n-butylcarbamoyloxymethyl-7β-methoxyimino-2- (fur-2-yl) -acetamido7-ceph-3-em-4-carboxylic acid, syn isomer

A suspension of 2.00 g of the syn isomer of (6R, 7R) -3-hydroxymethyl-7β-methoxyimino-2- (fur-2-yl) -acetamido7-ceph-3-em-4 Carboxylic acid in dry benzene (under nitrogen) was treated with 1.74 g of tri-n-butyl tin oxide and solution was stirred after stirring for 1 hour. 2.08 g of n-butyl isocyanate was added and stirring was continued for an additional 4 hours. 100 ml of water was added to the reaction mixture and the stirred, separated benzene layer was treated with 100 ml of 0.1M hydrochloric acid to effect the deposition of a gelatinous precipitate; this was filtered off and dissolved in 100 ml of saturated aqueous sodium bicarbonate solution. After washing the aqueous solution with 2 x 100 ml of ethyl acetate, the aqueous phase was acidified with 2M hydrochloric acid under an ethyl acetate layer (100 ml). The organic phase was separated and the aqueous layer re-extracted with 100 ml of ethyl acetate. The combined organic extracts were washed with 2 x 200 ml of water, dried over magnesium sulfate and evaporated in vacuo to give the title compound as a pale yellow solid, m.p. (M + q) 149.6 ° C = +42, 6 ° (c = 1.03 in DMSO), Amax (pH 6 phosphate buffer) 274 nm (ε = 16.960),

Example 9 (6R, 7R) -7- Z 2 -methoxyimino-2- (thien-2-yl) -acetamino-3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid, syn isomer

A solution of 926 mg of the syn isomer of 2-methoxyimino-2- (thien-2-yl) -acetic acid in 30 ml of dry dichloromethane was cooled to ca. 0 ° C under dry nitrogen.

This solution was stirred at ca. 0 ° C with 0.7 ml of triethylamine, 0.43 ml of oxalyl chloride and 1 drop of dry N, N-dimethylformamide for 1 1/4 hour during which period a mild effervescence and decolorization occurred.

The solution was evaporated and dried in vacuo for 1/4 hour to give the corresponding acid chloride as dirty white crystals.

A solution of approx. 5 mmol of the acid chloride in 50 ml of dry acetone was added dropwise over 15 minutes. at about. To a solution of 862 mg (6R, 7R) -7-amino-3-N-methylcarbamoyloxymethyl-ceph-3-em-4-carboxylic acid and 756 mg of sodium bicarbonate in 60 ml of water, and the reaction mixture was stirred for a further 1 / 4 hours during which period the reaction "ended" (rated by tic).

The solution (at about pH 7) was washed with 3.x 100 ml of ethyl acetate and the combined washing liquids were back extracted with 2 x 50 ml of water.

147338 14

The aqueous phase was layered with 150 ml of ethyl acetate and acidified to pH 1.9 with concentrated hydrochloric acid. The aqueous phase was extracted with an additional 2 x 100 ml of ethyl acetate, then the organic extracts were combined, washed with 2 x 150 ml of water and 75 ml of saturated brine, and dried over magnesium sulfate and evaporated in vacuo to 1.503 g of semi-crystalline white solid. Trituration of the crude product with 30 ml of ether gave 863 mg of the title compound as a white solid, m.p. (m | 0) 144 ° C, α 2 = + 57.3 ° (c = 1.14 in DMSO) , Xmax (pH 6 phosphate buffer) 263 nm (ε = 16,300) with an inflection at 295 nm (ε = 10,650).

Example 10 (6R, 7R) -7β-ethoxyimino-2-phenylacetamido7-3-N-methylcarbamoyloxy-methylceph-3-em-4-carboxylic acid, syn isomer

This compound was prepared in a similar manner as described in Example 9, but with the difference that the acid chloride was prepared from 561 mg of the syn isomer of 2-ethoxyimino-2-phenyl acetic acid and that the crude acid chloride was isolated as a yellow crystalline solid.

Drop by dropwise addition of the acid chloride in 28 ml of dry acetone to a solution of 500 mg of (6R, 7R) -7-amino-3-N-methylcarbamoyl-oxymethylceph-3-em-4-carboxylic acid and 439 mg of NaOH. 35 ml water at approx. 10 ° C over 10 minutes and subsequent stirring at 5-10 ° C for 3 1/2 hours led to acylation of the amino compound, as evidenced by tic. The reaction mixture was then worked up in substantially the same manner as described in Example 9 to give 480 mg of the title compound as a white powder of melting point (MgO) 138 ° C, ό 2 = + 58.0 ° ( c = 1.0 in DMSO), λmax (pH 6 phosphate buffer) 259 nm (ε = 20,150).

Example 11 14-7338 (6R, 7R) -3-N-methylcarbamoyloxymethyl-7- [beta-phenoxyimino-2- »phenylacetamido7-ceph-3-em-4-carboxylic acid, syn isomer 700 mg of the acid chloride of 2-Phenoxyimino-2-phenylacetic acid (syn isomer) was prepared in the same manner as described in Example 9. The crude acid chloride was isolated as a light brown gum.

A solution of this crude acid chloride in 28 ml of dry acetone was added dropwise to a cooled solution of 500 mg (6R, 7R) - 7-amino-3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid, 35 ml of water and 439 mg of sodium bicarbonate over 10 minutes, and after tic examination, the reaction was complete after stirring for 3 hours at 5-10 ° C. The reaction mixture was then worked up in practically the same manner as described in Example 9, thereby yielding 453 mg of the title compound as a white powder of melting point (MgQ) 165 ° C, = + 78.8 ° (c = 1.23 in DMS0),

Xmax (pH 6 phosphate buffer) 260 nm (ε = 20,050) with inflections at 265.5 nm (e = 18,685) and 282 nm (ε = 13,300).

Example 12 (6R, 7R) -7- / 2-Cyclopentyloxyimino-2- (fur-2-yl) -acetamido7- 3-N-methyl-carbamoyloxymethylceph-3-em-4-carboxylic acid, syn isomer

The method used to prepare the acid chloride was the same as that used in Example 9 except that 556 mg of the syn isomer of 2-cyclopentyloxyimino-2- (fur-2-yl) -acetic acid was used as the starting acid. The acid chloride was then isolated as a crystalline solid

A solution of the above acid chloride in 25 ml of dry acetone was added dropwise at ca. 10 ° C to a solution of 500 mg (6R, 7R) -

7-Amino-3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid and 439 mg of sodium bicarbonate in 35 ml of water over a period of 10 minutes. After allowing the reaction to continue for 2 hours at 5-10 ° C

The reaction showed that the reaction was complete. The reaction mixture was worked up in substantially the same manner as described in Example 9, thereby yielding 608 mg of the title compound as a white powder of melting point (Mqq) 126 ° C, o 2 = + 6.8.5 ° (c = 1.06 in DMSO), λmax (pH 6 phosphate buffer) 276.5 nm (e = 19,400).

Example 13 (6R, 7R) -3-N-methylcarbamoyloxymethyl-7- / 5-methoxyimino-2- (fur-2-yl) -acetamido7-ceph-3-em-4-carboxylic acid, syn isomer

The preparation of the acid chloride was carried out in a similar manner to that described in Example 9, but with the exception that 282 mg of the synthesizer of 2-methoxyimino-2- (fur-2-yl) -acetic acid was used as starting material. The acid chloride was isolated as dirty white crystals.

A solution of approx. 1.67 mmol of the acid chloride in 17 ml of dry acetone was added dropwise at about 10 ° C to a solution of 287 mg (6R, 7R) -7-amino-3-N-methylcarbamoyloxymethyl ceph-3-em-4-carboxyl -acid and 252 mg of sodium hydr o gene carbonate in 20 ml of water over 15 min. The mixture was kept at 5 to 10 ° C for 1 hour after which the reaction was completed, as judged by tic. The mixture was worked up in a similar manner to that described in Example 9 to give 258 mg of the title compound as a solid having a melting point (Moq) 159 ° C, a 2 = + 58.9 ° (c = 1.08 in DMSO), \ max (pH 6 phosphate buffer) 273 nm (ε = 17,360) with inflections at 260.5 nm (ε = 15-300) and 285 nm (ε = 15.825).

Example 14 (R and S) -1-Acetoxyatyl- (6R, 7R) -3-N-methylcarbamoyloxymethyl-7- [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido3-ceph-3-em -4-Carboxylate A solution of 0.682 g (6R, 7R) -3-methylcarbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4 -carboxylic acid in 10 ml of N, N-dimethylformamide was successively treated at 0 ° C with 0.107 g of dry potassium carbonate and a solution of 0.286 g of (R, S) -1-acetoxyethyl bromide in 5 ml of Ν, Ν-dimethylformamide.

17 147338

The reaction mixture was stirred at 0 ° C for 50 minutes and partitioned between 40 ml of ethyl acetate and 40 ml of 2N hydrochloric acid. The aqueous phase was extracted with an additional 40 ml of ethyl acetate and the combined organic extracts were washed successively with 40 ml of water, 40 ml of aqueous sodium bicarbonate solution, 40 ml of water and 40 ml of saturated brine, dried over magnesium sulfate and evaporated to dryness in vacuo. Trituration of the residue, 0.63 g, with anhydrous ether gave 0.45 g of the title ester as a solid; [α] D = + 49.6 ° (c = 1.07 in DMSO); vmax (nujol) 3500-3100 (2 x NH), 1790 (β-lactam), 1766 (O.CO.CHg), 1725 (COOH), 1680 (O.CO.NHCH-j) and 1680 and 1534 cm 1 (CONH).

Preparation of a starting material (6R, 7R) -7-amino-3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid

A suspension of 1.029 g (6R, 7R) -7-amino-3-hydroxymethyl-ceph-3-em-4-carboxylic acid in 50 ml of dry dichloromethane was treated under nitrogen with 0.436 g of triethylamine and 1.25 g of tri-n-amine. butyl tin oxide and the mixture was stirred for 30 min. 0.570 g of methyl isocyanate was added in 5 ml of dry dichloromethane and the reaction was stirred at 22 ° C for 4 hours. The insoluble material was filtered off and 2 ml of water was added and the solution was cooled and the pH was adjusted to 3.1 with formic acid. The resulting suspension was stirred for 30 min. at about. 5 C and the precipitate was filtered off, washed with cold water and dried in vacuo to give 0.482 g of the title amino acid, = + 34 ° (c = 0.70 in DMSO), Xmax (pH 6 buffer) 263 nm (ε = 7.100), kinf 246 nm (ε = 6.300).

Claims (2)

147338 1. Analogous Process for Preparing Cephalosporin Compounds of the General Formula? ? S. R.jj.CONH_j_ / \ 1 _! _ N .J_CH_O.CO.NH.RS I xoRa / 2 COOH where R represents a furyl group, thienyl group or phenyl group, Ra represents an alkyl group of 1-4 carbon atoms, an alkenyl group or alkynyl group of 2-4 carbon atoms, a cycloalkyl-G group of 3-7 carbon atoms or a phenyl group and R is an alkyl group of 1-4 carbon atoms, an alkenyl group or alkynyl group of 2-4 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a benzyl group or a phenyl group, or salts or biologically acceptable esters thereof, the compound being a syn isomer optionally contains up to 10% of the anti-isomer, characterized in that: a) condensing a compound of the general formula h2n-i- ^ .... N ^^ jC ^ O.CO.NHR5 III COOR1 where R ^ · is a hydrogen atom or a carboxyl blocking group and R 5 has the meaning given above, or an acid addition salt or N-silyl derivative thereof with an acylating agent corresponding to the acid RCCOOH II IV