IE50516B1 - A process for the manufacture of cephalosporin derivatives,intermediates and their preparation - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A process for the manufacture of acyl derivatives of general formula I see diagramm : EP0030294,P12,F1 in which R represents hydrogen or a readily hydrolyzable ester group, as well as of salts of these compounds and hydrates of these compounds or of their salts by reating a halide of general formula II see diagramm : EP0030294,P12,F2 in which R has the significance given above and Y represents a halogen atom, or a salt of this compound with thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of this salt, characterized in that X signifies one of the groups see diagramm : EP0030294,P13,F3 in which R' represents hydrogen or a readily hydrolysable ether group.

Description

The present invention relates to a process for the manufacture of acyl derivatives, more particularly, cephalosporin derivatives of the general formula I ,NΊ W H2N -X Sz CH3ON= C-CONH CH,—S—X (I) wherein R represents sable ester group and a hydrogen atom or a readily hydroly· X represents one of the groups h3c.

H ,/ N OR or (a) (b) 5051k wherein R' represents a hydrogen atom or a readily hydrolysable ether group, as well as salts and hydrates of these compounds and hydrates 5 of said salts.

Where R'in group (b) represents a hydrogen atom, this group is present in tautomeric equilibrium with group (a).

As readily hydrolysable ester groups denoted by R 10 in the compounds of formula I there are to be understood R-groups on the carboxyl function which are present in the form of a readily hydrolysable ester group. Examples of such ester groups, which can be of the conventional type, are lower alkanoyloxyalkyl groups (e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl group), lower alkoxycarbonyloxyalkyl groups the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl group, lactonyl groups (e.g. the phthalidyl and thlophthalidyl group), lower alkoxymethyl groups (e.g. the methoxymethyl group) and lower alkanoylaminomethyl groups (e.g. the acetamidomethyl group).

As readily hydrolysable ether groups denoted by R' in the compounds of formula I there are to be understood R1-groups on the enolic function of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group of formula (b) which are present in the form of a readily hydrolysable ether group. Such ether groups can be the same groups which have been mentioned earlier in connection with the readily hydrolysable ester groups. Examples of such ethers are thus, for example, the lower alkanoyloxyalkyl ethers (e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxymethyl and 1-pivaloyloxyethyl ether), the lower alkoxycarbonyloxyalkyl ethers (e.g. the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethy1 ether), the lactonyl ethers (e.g. the phthalidyl and thiophthalidyl ether), the lower alkoxymethyl ethers (e.g. the methoxymethyl ether) and the lower alkanoylaminomethyl ethers (e.g. acetamidomethyl ether).

Examples of salts of compounds of formula I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylethylenediamine, alkylamines or dialkylamines) and salts with amino acids (e.g. salts with arginine or lysine). The salts can be mono-salts or di-salts. The 5051b second salt formation can occur in compounds with the hydroxy moiety of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts such as sulphates, nitrates and phosphates, alkylsulphonates and monoarylsulphonates such as ethanesulphonates, toluene10 sulphonates and benzenesulphonates and other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.

The ccnpounds of formula I and their salts, readily hydrolysable ester and ether, can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initially anhydrous product.

The products in accordance with the present invention can be present in the syn-isomeric form (Z foim) 5051G or in the anti-isomeric form (E form) CH3O or as mixtures of these two forms. The syn-isomeric form is preferred, as are mixtures in which the syn-isomeric form predominates.

Preferred compounds are: (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-(Z-methoxy-iminoacetamido]-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-y1) thio]methyl_/-8-oxo-5-thia-l-azabicyclo[4.2.0]10 oct-2-ene-2-carboxylic acid and its salts as well as the corresponding hydrates. 5051k The present invention provides a process for the manufacture of an acyl derivative of the general formula I, wherein R and X have the significance given earlier, or a 5 salt or hydrate thereof or a hydrate of said salt, which process comprises reacting a halide of the general formula II 5051k wherein X and R have the significance given earlier and ϊ represents a halogen atom, or a salt thereof with thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of said salt.

The halide starting materials of formula II can be prepared, for example, by reacting a primary amine of the general formula (III) wherein X and R have the significance given earlier, 5051b with a halogenated carboxylic acid of the general formula IV CH3ON=C—COOH co nv) ( CH2Y wherein Y represents a halogen atom, or with a reactive derivative thereof. The halogenated carboxylic acid of formula IV is used either in free form in the presence of a condensing agent (e.g. a N,Ν'-disubstituted carbodiimide such as N,Ν'-dicyclohexylcarbodiimide or an azolide compound such as N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole) or in the form of an acid halide such as the acid chloride or bromide, in the form of an acid anhydride such as an acid anhydride with a carbonic acid monoester (e.g. with monomethyl carbonate or monoisopropyl carbonate) or in the form of an activated ester such as the g-nitrophenyl ester, 2,4-dinitrophenyl ester, N-hydroxy15 succinimide ester of N-hydroxyphthalimide ester. The reaction is generally carried out in an inert organic solvent, for example, a halogenated hydrocarbon such as chloroform, dichloromethane, carbon tetrachloride, an ether such as tetrahydrofuran, dioxan, dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction is preferably carried out at a temperature in the range of from -50°C to +40°C, especially at -1O°C to +10°C. Ο 5 1 fc> The halide starting materials of formula IX can also be prepared by halogenating a compound of the general formula V wherein X and R have the significance given earlier .

The compounds of formula V can be obtained by reacting a primary amine of formula III, as hereinbefore defined, with 3-oxo-2-methoxyiminobutyric acid or with a reactive derivative thereof. This reaction is carried out in essentially the same manner as described earlier in connection with the reaction of a primary amine of formula III with a halogenated carboxylic acid of formula IV or with a reactive derivative thereof. The halogenation of the reaction product (i.e. a compound of formula V) leads to a halide of formula II and is preferably carried out by treatment with the corresponding halogen or thionyl halide (e.g. with chlorine, bromine or sulphuryl chloride), preferably in an inert solvent such as a halogenated hydrocarbon (e.g. dichloro5051b methane, dichloroethane, chloroform, dichloroethylene or carbon tetrachloride), a lower alkanecarboxylic acid (e.g. acetic acid) or an aromatic hydrocarbon (e.g. benzene or toluene). The halogenation is generally carried out at a temperature between 0°C and 6O°C.

The intermediate compounds of formula II, described above, and their preparation from primary amines of formula III or from compounds of formula V also form part of the present invention.

The reaction of a halide of formula II or a salt thereof with thiourea in accordance with the present invention is preferably carried out in an inert solvent such as, for example, a lower alkanol (e.g. ethanol), a lower ketone (e.g acetone), an ether (e.g. tetrahydrofuran or dioxan), dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction is generally carried out at a temperature in the range of from 0°C to 60°C, preferably at room temperature. The chloride, bromide, fluoride or iodide can be used as the halide of formula II, 2o the chloride or the bromide being preferred. The free acid of formula II or a salt thereof can be used in the present process. As salts of the acids of formula II there come into consideration the same salts as mentioned earlier in connection with the salts of the compounds of formula I. 51b The manufacture of the salts and hydrates of the compounds of formula I or the hydrates of such salts can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol or acetone). When a second equivalent of base is used, salt formation also takes place on the tautomeric enol form which may be present (2,5-dihydro"6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), a di-salt being formed.

The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can also be carried out at a temperature slightly above or below room temperature, for example in the range of from 0°C to +50°C.

The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous product (compound of formula I or salt thereof) can be exposed to a moist atmosphere (e.g. at +10°C to +40°C).

A syn/anti mixture of a compound of formula I which may be obtained can be separated into the corresponding syn and 5051 anti forms in the customary manner; for example, by recrystallisation or by chromatographical methods using a suitable solvent or solvent mixture.

The compounds of formula I and their salts as well 5 as the hydrates of these compounds and salts possess antibiotic, especially bactericidal, activity. They have a broad spectrum of activity against gram-negative microorganisms, including β-lactamase-forming Staphylococci and various β-lactamase-forming gram-negative bacteria such as, 1q for example, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens and Proteus and Klebsiella species.

The compounds of formula I and their salts as well as the hydrates of these compounds and salts can be used for 2_5 the treatment and prophylaxis of infectious diseases. A daily dosage of 0.1 g to 2 g is envisaged for adults. The administration is preferably carried out by the parenteral route.

In order to demonstrate the antimicrobial activity of the compounds of formula I, the activity in vitro (minimum inhibitory concentration in pg/ml) was ascertained for (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido] -3-/-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl /-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-251b -carboxylic acid (denoted as A hereinafter). The results are compiled in the following Table: Test organisms A Haemophilus influenzae Strain 1 0.08 Strain 2 0.005 Strain 3 0.005 Strain 4 0.005 Strain 5 0.0025 Strain 6 0.0025 Strain 7 0.0025 Klebsiella pneumoniae 1.2 Escherichia coli Strain 1 0.02 Strain 2 0.6 Proteus mirabilis Strain 1 <0.01 Strain 2 <0.01 Proteus vulgaris <0.01 Proteus rettgeri <0.01 Staphylococcus aureus Strain ATCC 6538 2.5 Penicillin- -resistant strain 2.5 5051b Test organisms A Pseudomonas aeruginosa Strain 1 0.3 Strain 2 10 Strain 3 2.5 Strain 4 5 Strain 5 5 Strain 6 10 Strain 7 5 Serratia marcescens 0.08 The antibacterial activity in vivo was ascertained as follows: Groups of five mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. The test substance is administered subcutaneously in physiological sodium chloride solution three times (i.e. 1 hour, 2.5 hours and 4 hours) after the infection. The number of surviving animals is determined on the fourth day. Various dosages are administered and the dosage at which 50% of the experimental animals survive (Οϋ^θ, mg/kg) is determined by interpolation.

SOSlfc Test substance A CD5q, mg/kg 0.005 Toxicity Test substance A LD5Q, mg/kg i.v. 250-500 s.c. >4000 p.o. >5000 The compounds of formula I and their salts as well as the hydrates of said compounds and salts can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil's, polyalky leneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, 5051k dragees, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations can be sterilised and/or can contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers. They can also contain other therapeutically valuable substances. The compounds of formula I and their salts as well as the hydrates of such compounds and salts are preferably administered parenterally and for this purpose are preferably formulated as lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution.

The readily hydrolysable esters or ethers of formula I and their salts as well as hydrates of such salts can also be administered enterally. ί fe> The following Examples illustrate the present invention: Example 1 28.8 g of (6R,7R)-7-/ 4-bromo-2-[(Z)-methoxyimino]acetoacetamido_/-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thiolmethyl_/-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are dissolved in 400 ml of absolute ethanol. The solution is treated with 7.6 g of thiourea. After stirring for 15-20 minutes at 25°C, the product begins to crystallise from the orange solution as the hydrohromide. After stirring for 1.5 hours, the hydrohromide is filtered off under suction, washed successively with 200 ml of alcohol and 200 ml of low-boiling petroleum ether and dried at 35°-4O°C overnight in a high vacuum. 22g of almost colourless hydrobromide are obtained. This is dissolved, together with 15.7 g of sodium acetate trihydrate, in a mixture of 110 ml of water and 110 ml of acetone. 140 ml of acetone are added to the resulting solution until it is slightly turbid. Shortly thereafter the product begins to crystallise. The mixture is stirred for 30 minutes and 180 ml of acetone are added dropwise during a further 30 minutes, the crystallisation then being complete. The product is filtered off under suction, washed successively with 250 ml of 85% aqueous 5051 acetone, 250 ml of acetone and 250 ml of low-boiling petroleum ether and finally dried at 25 °C in vacuo.

There are obtained 19.6 g (59.3% of theory) of the almost colourless disodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl) -2-(Z-methoxyimino)acetamido]-3-/ [2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_7-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid which is recrystallised from water/acetone. There are obtained 25 17.3 g (52.3% of theory) of pure substance with [α]β = -150.8° (c = 1 in water). 1H-NMR spectrum in DMSO-dg (δ-values in ppm, s = singlet, d = doublet, q = quartet, b = broad; J = coupling constant in Hz; number of protons in parentheses): 3.47 (Ν-CHg) (s) (3), 3.49 (2-ch2) (AB-q/centering value; Jgem =·~Ί8 Hz) (2), 3.85 [=N-'0CiI3, (Z)] (s) (3), 4.37 O-CHg-S)(AB-q/centering value; Jgem = 12.5 Hz) (2), 5.04 (H-6) (d,JH_6,H_7 = 4.5 Hz) (1), 5.59 (H—7) (q, Jh_7jNH= 8 Hz,JH-7,H-6 = 4'5 Hz 6,75 (thiazolyl-H) (s) (1), 7.29 (-NH2) (b) (2), 9,52 (-C0-NH-) (d' JMH,H-7 = 8 HZ) {1)· The (6R,7R)-7-/ 4-bromo-2-[(Z)-methoxyimino]acetoacetamido_7-3-/-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_7-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows: 1 fe 592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. A solution of 290.6 g of sodium nitrite in 655 ml of water is added dropwise to this solution at 5°-10°C during 2.5 hours. The resulting yellow suspension is stirred at 20°C for 30 minutes, treated with 940 ml of water and stirred for a further 2 hours The mixture is treated with 900 ml of water and 900 g of ice and extracted three times in a stirring vessel with 1 litre of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 litre of water each time, then treated with 5 litres of water and the pH is adjusted to 6.8 with sodium hydrogen carbonate. After separating the agueous phase, it is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated at 40°C in vacuo. There is obtained (Z)-2-hydroxyimino-3-oxobutyric acid tert.butyl ester in the form of a yellow oil which is dried at 40°C in a high vacuum for a further 9 hours. The yield amounts to 626.65 g (89.2% of theory). 626.65 g of (Z)-2-hydroxyimino-3-oxobutyric acid tert.butyl ester are dissolved in 2.86 litres of acetone.

The solution is cooled to 5°C and treated portionwise with 703.5 g of potassium carbonate. 322 ml of dimethyl sulphate are then added dropwise to the yellow suspension without cooling during 1 hour, whereby the temperature of the mixture should not rise above 25°C. The light beige 5051k suspension is stirred at 2O°-25°C for ca 4 hours until starting material can no longer be detected by thin-layer chromatography. The mixture is then poured into 7 litres of water and extracted three times with 1 litre of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 litre of water each time, dried over sodium sulphate and evaporated at 40°C in vacuo. The residual yellow oil is dried at 40°C in a high vacuum for a further 6 hours and subsequently distilled. There are obtained 577 g (85.6% of theory) of (Z)-2-methoxyimino-3-oxobutyric acid tert.butyl ester in the form of a yellow oil of boiling point 57°C/O.O2 mm Hg. ^H-NMR spectrum in CDClj (δ-values in ppm, s = singlet, number of protons in parentheses): 1.55 [-CiCH^J^] (s) (9), 2.36 (CH^-CO) (s) (3), 4.01 [= KK0CH3, (Z)] (s) (3). g of (Z)-2-methoxyimino-3-oxobutyric acid tert.butyl ester are dissolved in 400 ml of trifluoroacetic acid. The solution is left to stand at 25°C for 1 hour and then evaporated at 35°C in vacuo. The oily residue is crystallised from ether/petroleum ether. There are obtained 50 g (80.6% of theory) of yellowish water-soluble (Z)-2methoxyimino-3-oxobutyric acid of melting point 8O°-85°c. ^H-NMR spectrum in CDCl^ (δ-values in ppm, s = singlet, number of protons in parentheses): 2.43 (CH-j-CO) (3), 4.14 (= NX0CH3, (Z)] (s) (3), 10.47 (OH) (s) (1). lb 145 g of (Z)-2-methoxyimino-3-oxobutyric acid are dissolved in 1000 ml of alcohol-free and water-free dichloromethane. 10 ml of 30% hydrobromic acid in glacial acetic acid are added to the resulting solution. Then, a solution of 37.5 ml of bromine in 112.5 ml of dichloromethane is added dropwise during ca 2 hours, the temperature of the mixture being held at 2O°-25°C by slight cooling. Nitrogen is now blown through the mixture vigorously to remove hydrogen bromide. Subsequently, 250 g of ice, 250 ml of water and 2 litres of ether are added successively. The agueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. There are obtained 170 g of a brown oil which is crystallised from carbon tetrachloride. There are obtained 100 g (44.6% of theory) of almost colourless (Z)-4-bromo-2-methoxyimino-3-oxobutyric acid. ^H-NMR spectrum in CDCl^ (δ-values in ppm, s = singlet, number of protons in parentheses): 4.24 [= (Z) (s) (3), 4.41 (-CH2-) (s) (2), 11.00 (OH) (s) (1). 37.1 g of (7R)-7-amino-3-desacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-cephalosporanic acid are suspended in 800 ml of ethyl acetate and treated with 100 ml of Ν,Ο-bis-(trimethylsilyl)-acetamide. The mixture is stirred at 25°C for 30 minutes with the.exclusion of moisture, a light yellow solution resulting. This solution, cooled to -1Q°C, is added dropwise at -10°C to 0°C during 30 mintues to a solution of (Z)-4-bromo-2-methoxyimino-3-oxobutyric acid chloride, prepared from 22.4 g of (Z)-4-bromo-2-methoxyimino-3-oxobutyric acid in 300 ml of alcohol-free and water-free dichloromethane and .8 g of phosphorus pentachloride at 8°-l0°C. The mixture is stirred at 0°-5°C for 30 minutes and at 25°C for 1 hour. litre of ethyl acetate and 500 ml of water are added while stirring. The aqueous phase and the resinous intermediate layer are discarded. The organic phase is washed six times with 500 ml of water each time, dried over sodium sulphate and concentrated at 40°C in vacuo to a volume of 200 ml. The orange coloured concentrate is added dropwise while stirring to 1.8 litres of ether, the product separating in amorphous form. This product is filtered off under suction, washed successively with 1 litre of ether and 1 litre of low-boiling petroleum ether and dried at 35°C in vacuo overnight. There are obtained 37.2 g (64.4% of theory) of (6R,7R)-7-/—4-bromo-2-[(Z)-methoxyimino]acetoacetamido_7-3-/ [ (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_/-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of a beige amorphous product 1 with (a]D = -223.1° (c = 1 in methanol. H-NMR spectrum in DMSO-dg (δ-values in ppm, s = singlet, d = doublet, q = quartet, b = broad; J = coupling constant in Hz; number of protons in parentheses); 3.60 (N-CH^) (s) (3), 3.63 (2-CH2) (AB-q/centering value; Jgem= IS Hz) (2), 4.07 [= N 3, (Z)] (s) (3), 4.25 (3-CH2-S)(AB-q/centering value; Jgem= Hz) (2), 4.62 (Br-CH2-) (s) (2), 5.15 (H-6) (d,JH_6,H_7 = Hz) (1), 5.78 (H-7) (q,JH_7jNH = 8 Hz' JH-7,H-6 = 5 HZ> (1), 9.47 (NH) d,J.TO „ - = 8 Hz) (1), 11.12 (-COOH and -OH) Wtl / ti- I (b) (2).

Example 2 Manufacture of dry ampoules for intramuscular administration: A lyophilisate of 1 g of the disodium salt of 10 (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_/-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is manufactured in the customary manner and filled into an ampoule. Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Claims (19)

1. CLAIMS:1. A process for the manufacture of an acyl derivative of the general formula I ch 2 — S—X (I) 5 wherein R represents a hydrogen atom or a readily hydrolysable ester group and X represents one of the groups N x 0 (a) ° (b) wherein R' represents a hydrogen atom or a readily hydrolysable ether group; or a salt or hydrate thereof or a hydrate 10 of said salt, which process comprises reacting a halide of the general formula XI wherein X and R have the significance given earlier in this claim and Y represents a halogen atom, 5 or a salt thereof with thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of said salt.

2. A process according to claim 1 wherein R and R' each represent a hydrogen atom. 10

3. A process according to claim 1 or 2, wherein Y represents a bromine atom.

4. A process according to any one of claims 1 to 3, wherein the halide starting compound of formula II is used in the syn form (Z form).

5. A process according to any one of claims 1 to 4 y wherein the halide of formula II has been prepared by reacting a primary amine of the general formula III 5 wherein X and R have the significance given in claim 1, with a halogenated carboxylic acid of the general formula IV CH 3 ON=C—COOH CO ί (IV) ch 2 y wherein Y represents a halogen atom, 10 or with a reactive derivative thereof.

6. A process according to claim 5, wherein R and R'each represent a hydrogen atom.

7. A process according to claim 5 or 6, wherein Y represents a bromine atom.

8. A process according to any one of claims 5 to 7, wherein the halogenated carboxylic acid of formula XV or the reactive 5 derivative thereof is used in the syn form (Z form).

9. A process according to any one of claims 5 to 8, wherein an acid chloride of the halogenated carboxylic acid of formula IV is used.

10. A process according to any one of claims 1 to 4, 10 wherein the halide of fonnula II has been prepared by halogenating a compound of the general formula V wherein X and R have the significance given in claim 1.

11. A process according to claim 10, wherein R and R' each represent a hydrogen atom.

12. A process according to claim 10 or 11, wherein the compound of formula V is used in the syn form (Z form). 5

13. A compound of the general formula IX wherein Y represents of the groups a halogen atom and X represents one (b) 10 and R and R' have the significance given in claim 1, or a salt thereof. 516

14. A compound in accordance with claim 13, wherein R and R' each represent a hydrogen atom.

15. A compound in accordance with claim 13 or 14, wherein Y represents a bromine atom.

16. (6R,7R) /~4-Bromo-2-[(Z)-methoxyiminolacetoacetamidoJ-2-£ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio] methyl J7-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid or a salt thereof.

17. A process according to claim 1 for the manufacture of an acyl derivative of the general formula (I) given and defined in claim 1 or a salt or hydrate thereof or a hydrate of said salt, substantially as hereinbefore described and exemplified.

18. An acyl derivative of the general formula (I) given and defined in claim 1 or a salt or hydrate thereof or a hydrate of said salt, whenever manufactured by a process claimed in a preceding claim.

19. A compound of the general formula (II) given and defined in claim 13 or a salt thereof, substantially as hereinbefore described and exemplified.