IE47362B1 - New oxime derivatives of 7-amino-thiazolyl-acetic acid,and processes for preparing them - Google Patents

Description

This invention relates to new oxime derivatives of amino-thiazolyl-acetic acid, and processes for preparing them.

In our Patent Specification No. 47361 , from which this Application is divided, there are described and claimed new oxime derivatives of 7-(amino-thiazolyl-acetamido)-cephalosporanic acid, of the general formula: (I) (wherein R^ represents a) a radical -COgR1^ in which R'^ represents an alkyl radical having from 1 to 3 carbon atoms, a hydroa-en atom, an alkali-metal atom, an ammonium group, a substituted ammonium group, an equivalent of an alkanneearth metal atom or an equivalent of a magnesium atom, b) a cyano radical, or c) a carbamoyl radical (-CONHg); A represents a hydrogen atom, an alkali-metal atom, an ammonium group, a substituted ammonium group, an equivalent of an alkaline-earth metal atom or an equivalent of a magnesium atom; and R’ and R, which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms, with the proviso that when Rj la20 represents a radical θθρ^'ΐ in which R'^ is other than, an alkyl group having from 1 to 3 carhon atoms, A represents the same substituent as R^) the derivatives of general formula I being syn isomers.

The derivatives of general formula I are syn isomers because the imino substituent -OC(R')(S)R^ is in the syn configuration, and the term syn isomer will be used hereinafter in relation to the derivatives of general formula I and their precursors to refer to any compound having a substituent of the imino group in the syn configuration.

The syn isomers of general formula I have very good antibiotic activity against both Gram positive and Gram negative bacteria, and accordingly are indicated for usa in medicine.

Preferred syn isomers of general formula I are those wherein R^ represents a radical CC^E'^ ar.d those wherein S' and R each represent a hydrogen atom.

When R'y represents an alkyl radical this may be a 20 methyl, ethyl, n-propyl or isopropyl radical. The ethyl radical in preferred.

When either of R1 and R represents an alkyl group this may be a methyl, ethyl, n-propyl or isopropyl radical. Other preferred syn isomers of general fornula I are those wherein each of R' and R represent a methyl radical.

It should he understood that the syn isomersof general 47363 formula I can exist either in the form indicated by general formula I as set out hereinbefore, or in the following tautomeric form: N-H Λ General fornula I should be construed as covering both 5 tautomeric forms, as should all other formulae appearing in this Specification in relation to which such tautomerism is possible.

Our co-pending Application Mo. 47361 also describes and claims a process for preparing the syn isomers of general formula I wherein A represents a hydrogen atom and R1·^ (where present) represents an alkyl radical having from 1 to 5 carbon atoms or a hydrogen atom, in which process a compound of the general formula: CH,-O-C-CK_ J- «ι O (II) - 3 47362 (wherein A represents a hydrogen atom or an ester-forming group removable hy acid hydrolysis or by hydrogenolysis) is reacted with a syn isomer of the general formula· CQ2.H R.' (Ill) ι O~Ci ft (wherein R^ represents a group removable hy acid hydrolysis or hy hydrogenolysis, or a chloroacetyl radical; R^ repress a) a group CC^R^ in which R^ represents an alkyl radical having from 1 to 3 carbon atoms or an ester-forming group removable by acid hydrolysis or hy hydrogenolysis, b) a cyano radical, or c) a carbamoyl radical; and R* and R are as defined hereinbefore), or a functional derivative thereof, to form a syn isomer of the general formula I'; (wherein R^, R^ and A are as just defined and R' and R are as defined hereinbefore) which syn isomer of general - 4 4 7 3 6 2 formula 1' is treated with one or more appropriate agents selected from acid hydrolysis agents, hydrogenolysis agents and thiourea so as to obtain the desired corresponding syn isomer falling within general formula I.

The remaining syn isomers of general formula I may be formed hy salification of syn isomers prepared as just described By the term group removable by acid hydrolysis or by hydrogenolysis if meant a group that may be removed by acid hydrolysis or by hydrogenolysis from the remainder of the molecule without otherwise affecting the structure of the molecule - apart from sometimes removing other groups present which are removable by acid hydrolysis or hy hydrogenolysis.

When R^ represents a group removable by acid hydrolysis or hy hydrogenolysis this is preferably a b-butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxycarbonyl or 2-tetrahydropyranyl group.

When R^ or A represents an ester-forming group removable by acid hydrolysis or by hydrogenolysis this is preferably a benzhydryl, t-butyl, benzyl, TJ-methoxybenzyl or trichloroethyl group.

The present invention is directed to compounds which are useful as being intermediates in the production of the derivatives of general formula I, and to the production of such compounds.

Accordingly, the invention provides a compound which is a syn isomer of the general formula: 47363 wherein Y represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms; wherein R4 represents a group removable by acid nydroiysis or by hydrogenolysis, or a chloroacetyl radical; and X represents a 1-methyl-l-methoxy-ethyl radical or a group R' R wherein represents: a) a group CO^R^ in which R5 represents an alkyl radical having from 1 to 4 carbon atoms or an ester-forming group removable by acid hydrolysis or by hydrogenolysis, b) a cyano radical, 7 j U 4 c) a carbamoyl radical, or d) a radical-COOH, and R' and R, which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms.

Since the principal use of the present compounds is as intermediates in the production of the derivatives of general formula I, the preferred values of the symbols in the present compounds are reflected in the values of the substituents of general formula I mentioned above as being preferred.

In one aspect, the present invention provides the syn isomers of general formula III as defined above.

The specific syn isomers of general formula III which have their preparation described in the Examples set out hereinafter are particularly preferred, and this applies above all to the following:2-(2-tritylamino-thiazol-4-yl)-2-(ethoxycarbonyl5 -methyl-oxyimino)-acetic acid, syn isomer; 2-(tert-butoxycarbonyl-methyl-oxyinino)-2-(2-tritylamino-thiazol-4-yl)-acetic ac.id, syn isomer; and 2-(2-tritylamino-thiazol-4-yl)-2-(El-tert-butoxyearbonyl-l-methyl-ethylj-oxyimino)-acetic acid, syn isomer.

This invention also provides a process for preparing the syn isomers of general formula III, in which process a syn isomer of the general formula: (wherein R4 is as defined hereinbefore) is reacted in the p-esence of a hase with a compound of the general formula: R' I Hal— C-Η ι I > R” (wherein Hal represents a halogen atom, and R^, R* and.R are as defined hereinbefore) to obtain the desired syn - 3 47362 isomer of general formula III.

The base used in the reaction should be a strong base, and in a preferred method of carrying out this process the strong base used is potassium t-butylate, sodium hydride or an alcoholic potassium hydroxide solution.

The halide of general formula V is preferably the bromide but the chloride or the iodide can also be used.

The syn isomeisof general formula IV are described in Patent Specification Mo. 45015. Some of the compounds of general formula V are known, but those which are not known can be obtained by halogenation of the known compounds of the general formula: S' I H-C-R.

I 7 R (wherein R? represents either a group COgRg in which represents an alkyl radical or a hydrogen atom, or R? represents a nitrile radical and S' and R are as defined hereinbefore) using standard techniques for halogenation at the a position.

The compounds of general fornula V wherein R^ represents a carbamoyl group can be obtained by amidation of the corresponding acids.

Certain of the syn isomers of general fornula III, being the syn isomers of the general formula: (wherein R^, R' and R are as defined hereinbefore), may be prepared by an alternative, multi-step process in which a syn isomer of the general formula: (wherein R^ is as defined hereinbefore and alk represents an 5 alkyl radical having from 1 to a carbon atoms) is treated., in the presence of a base, with a compound of the genei’al formula: R' I Hal-C-CC~alk, (V) I d 1 R (wherein Hal, R' and R are as defined hereinbefore and alk^ represents an alkyl radical having from 1 to a carbon atoms) to obtain a syn isomer of the general formula: - IO 47362 (wherein R^, R', R, alk and. alkare as defined hereinbefore) which is thereafter treatod with a base and then with an acid to obtain a syn isomer of the general formula: f! \C-CO,H k” (wherein R^, R’, R and alk are as defined hereinbefore), an appropriate functional derivative of the formed syn isomer VIII is formed and then treated with ammonia to obtain a syn isomer of the general formula: (wherein R^, R', R and alk are as defined hereinbefore) and the formed syn isomer (IX) is treated with a base and then with an acid to obtain the desired syn isomer of steneral formula III'.

In a preferred method of carrying out the process described above the reaction of the compound of general formula V with the syn isomer of general formula VI is carried out in the presence of a base such as potassium carbonate. Other bases such as sodium hydroxide, potassium hydroxide or triethylamine may, however, be used.

The halide of general formula V* is preferably the bromide but the chloride or the iodide may be used.

The conversion of the syn isomer of general formula 111 into a syn isomer of general formula VIII is carried out 15 under mild conditions so as not to saponify the group CO-alk.

Thus, the base treatment may be effected in the presence of t. single jquivalent of a base such as sodium hydroxide, potassium hydroxide or barium hydroxide, and preferably th·: reactants are cooled in a bath of iced water for about one hour.

Following the treatment with base an acid is added, and this is preferably aqueous hydrochloric acid. However, dilute sulphuric acid or acetic acid may be used.

The functional derivative formed from the acid of 25 general formula VIII must be capable of reacting with ammonia to form the amide IX. The derivative is preferably a mixed 4 7 3 6 2 anhydr-iHe formed, for example, in situ by the action of isobutyi chloroformate. However, other reactive derivatives may be used such as the syrametrie anhydride formed, for example, by the action of a carbodiimide such as dicyclohexylcarbodiimide or the active esters formed, for example, with N-hydroxysuccinimide, n- or oynitrophenol, or 2,4-dinitrophenol.

Saponification and reacidification of the compound of general formula IX may be carried out under the usual conditions for such treatment. For example, sodium hydroxide may be used to effect the saponification and hydrochloric acid may then be used to acidify the product.

The starting materials of general formula VI are described in Patent Specification No. 45015.

The nitriles of general formula III - that is to say, the syn isomers of the general fornula: (wherein R^, R1 and R are as defined hereinbefore) - may also be prepared by an alternative, multi-stage process in which a syn isomer of general formula IV is treated, in the presence of a base, with two equivalents of a compound of the general formula: _ Hal - C - CN I R (X) (wherein Hal, R' and H are as defined hereinbefore) to obtain a syn isomer of the general formula: R.M (XI) (wherein R^, R' and R are as defined hereinbefore), which syn isomer of formula XI is treated with a base, and then with an acid to obtain the desired syn isomer of general formula III.

In a preferred method of carrying out the process for preparing the syn isomers III, the reaction of the conpound of formula X with the syn isomer of formula IV is carried out in the presence of potassium carbonate. However, other bases such as sodium hydroxide, potassium hydroxide or triethylamine may he used.

The saponification of the syn isomers of formula XI to obtain the syn isomers of formula III is carried out under the normal conditions for saponification followed by reacidification. For example, treatment with sodium hydroxide - 14 47362 followed by hydrochloric acid may be used.

The invention provides a further process for preparing the syn isomers of general formula III, in which a syn isomer of the general formula VI is reacted in the presence of a base with a compound of general formula V to obtain a syn isomer of the general formula: (wherein R^, Rj, R', R and alk are as defined hereinbefore) which syn isomer of formula XII is treated with a base and then with an acid to obtain a syn isomer of general formula III The condensation of the compound of formula V with the syn isomer of formula VI is preferably carried out in the presence of potassium carbonate. However, other bases such as sodium hydroxide, potassium hydroxide or triethylamine may be used.

The saponification of the syn isomer of formula XII to obtain the syn isomer of formula III is carried out in such a manner that if Rj represents a group CCpR^ this is not itself saponified. As the base, methanolic potassium hydroxide solution may for example be used, and reacidification may then be effected with hydrochloric acid.

~ Furthermore,our co-pending Application No. 47361 describes and claims the preparation of the syn isomers of general formula 1' by an alternative route which may involve the use of the syn isomers of the general formula: (wherein R^is as defined hereinbefore), as an intermediate or starting material.

The syn isomers of general formula XV are also believed to be novel, and accordingly this invention provides them per se. The preferred values of the substituent R^ in general formula XV are as set out hereinbefore in relation to general formulae 1' and III.

The syn isomers of general formula XV may he prepared by a process in which isopropenyl methyl ether of the formula: K2C = C /0CH5 CH, is reacted with a syn isomer of general formula IV to obtain the desired syn isomer of general formula XV.

The reaction of the isopropenyl nethyl ether with a syn isomer of formula IV is advantageously carried out in the presence of an acid - for example, in the presence of o-toluene sulphonic acid. It is also possible to employ the syn isomer of formula IV in the form of a salt with a mineral acid, such as a hydrochloride, and in this case the presence of an acid is not advantageous. The free amine of formula XV may he obtained hy neutralisation of the product of the reaction with a base such as pyridine.

The syn isomers of general formula 1' per se are claimed in our co-pending Application No. 47361 Xn another aspect, the present invention provides the syn isomers of the general formula: (XX) wherein represents a group removable by acid hydrolysis 15 or by hydrogenolysis, or a chloroacetyl radical; alk represents an alkyl radical having from 1 to 4 carbon atons; and Rg represents a) a group CO2R5 in which Rs represents an alkyl radical having from 1 to 4 carbon atoms or an ester-forming group removable by acid hydrolysis or by hydrogenolysis, b) a cyano radical, c) a carbamoyl radical or d) a radical-fOOH; and R' and R, which may be the same or different,each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms.

The principal use of the isomers of general formula XX, like those of general formula III, is of course in the preparation of the syn isomers of general formula I, and thus the preferred values of the substituents in general formula XX are reflected in the values of the substituents of general formulae I and III mentioned above as being preferred In one embodiment o± the invention, the syn isomers are those of general formula VII.

Additionally or alternatively, in another and sometimes overlapping embodiment of the invention, the syn isomers are those of general formula XX wherein Rg represents cyano or CO2Rg, and Rg is preferably an ethyl, benzhydryl, t-butyl, benzyl, ρ-methoxybenzyl or trichloroethyl radical.

In a further embodiment of the invention, the syn isomers are those of general formula VIII.

In a still further embodiment of the invention, the syn isomers are those of general formula IX.

In the syn isomers of general formula XX, R' and R are preferably hydrogen or methyl, and R^ is preferably a t^-butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxycarbonyl or 2-tetrahydropyranyl group.

The specific syn isomers of general formula XX which have their preparation described in the Examples set out hereinafter are particularly preferred, that is to say the following:Ethyl 2-(2-tritylamino-thiazol-4-yl)-2-ethoxycarbonyl-methyl-oxyimino)-acetate, syn isomer.

Ethyl 2-(2-tritylamino-thiazol-4-yl)-2-(carboxy-methyl-oxyimino)-acetate, syn isomer.

Ethyl 2-(2-tritylamino-thiazol-4-yl)-2-(carbamoy1-methyl-oxyiminc)-acetate, syn isomer.

Ethyl 2-(2-tritylamino-thiazol-4-yl)2-(Ci-tert20 -butoxycarbonyl-l-methyl-ethyil -oxyimino)-acetate, syn isomer.

This invention also provide:, a process fur preparing the syn isomers of general formula XX, in which process a syn isomer of general formula VI is treated, in the presence· of a base, with a compound of general formula V to obtain a syn isomer of general formula VII, which thereafter may be treated with a base and then with an acid to obtain a syn isomer of general formula VIII, after which an appropriate functional derivative of the formed syn isomer VIII may be formed and then treated with ammonia to obtain a syn isomer of general formula IX. Further details of this process are described above. The formed syn isomer IX may be treated with a base and then with an acid to obtain the desired syn isomer of general formula III' as described above.

The invention also provides another process for 10 preparing the syn isomers of general formula XX, in which a syn isomer of general formula VI is reacted in the presence of a base with a compound of general formula V to obtain a syn isomer of general formula XX.

The syn isomer of formula XX may be treated with a base and then with an acid to obtain a syn isomer of general formula III.

The condensation of the compound of formula V with the syn isomer of formula VI is preferably carried out in the presence of potassium carbonate. However, other bases such as sodium hydroxide, potassium hydroxide or triethylamine may be used.

The saponification of the syn isomer of formula XX to obtain the syn isomer of formula III is carried out in such a manner that if Rg represents a group COgR,. this is not itself saponified. As the base, methanolic potassium hydroxide solution may for example be used, and reacidification may then be effected with hydrochloric acid. 7362 In order that the invention may be well understood, the following Examples are given, though only by way of illustration.

Example 1: g-Cg-tritvlanino-thiszoW-yl )-2-( ethoxycarbonvl-methy2-oxyisino)-acetic acid, syn isoner.

One introduces, under argon, 10.5 cm'’ of a molar solution of potassium tert-butylate in tetrahydrofuran and adds, over 10 minutes at 20°C, a suspension of 2.15 E 2-(2-tritylamino-thiazol-4-yl)-2-hydroxyimino-acetic acid, x 3 syn isomer, in 35 cur of dry tetrahydrofuran and 2.5 cnr of a 4M solution of water in tetrahydrofuran. The temperature rises to 27°C. One agitates for one hour and adds, drop hy drop, z 3 cm of a solution obtained by adding to 1.1 cm of ethyl bronoacetate a sufficient amount of tetrahydrofuran to make up to 10 cm Cne agitates for one hour and adds a further 1 cm- of a molar solution of potassium tert-butylate in tetrahydrofuran, agitates for a further hour, vacuum-filters the slight amount of insoluble matter, rinses with tetrahydrofuran, drives off z 3 the solvent, takes up with 50 cm' of ethyl acetate, 15 cm of normal hydrochloric acid and 15 cm' of water, agitates, decants, washes with water, re-extracts with ethyl acetate, z dries, concentrates to dryness, adds 20 cnr of ethyl acetate and the product crystallises out. One chills, vacuumfilters the crystals, rinses with a minimum of ethyl acetate and makes into a paste with ether, dries and obtains 1.3 g of pure product.

One concentrates the filtrate, takes up with ethyl acetate, breaks up, chills, vacuum-filters ..the crystals, rinses with ethyl acetate, makes into a paste with ether and obtains a second yield of 185 ng of pure product - that is in toto 1.485 ? ol product.

One obtains an. analytical sample by taking close to reflux 3.14 g of product obtained as indicated above in 30 cnr of ethyl acetate. The dissolution is partial. Cne cools in iced water, vacuum-filters the crystals, rinses, makes into a paste with ether ana dries and obtains 2.77 g of purified product.

Analysis : ^28^2^5 ^3®' Calculated: C% 65.23 H% 4.89 K% 8.15 S£ 6.22 Found 65-1 4.9 8.0 6.1 N.M.R. = (CDClj, 90 MHz) 6.76 p.p.m. (proton of the thiazole ring) 7.28 p.p.m. (trityl group).

The 2-(2-t ritylaaino-thiazo1-4-yl)-2-hydroxyimino-acetic acid, syn isomer used at the start of Example 1 was prepared as follows: (A) Ethyl 2-(2-amino-thiazoi-4-yl)-2-hydrcxyimino-acetate, syn isomer. x Cne dissolves 0.8 g of thiourea in 2.4 cnr of ethanol and 4.8 cnr of water. One adds, over five minutes, the solution of 2 g of ethyl 4-chloro-2-hydroxyimino-5~oxo-butanoate and agitates for one hour at ambient temperature. One drives off the major part of the ethanol under partial vacuum and neutralises to pH 6 by adding solid sodium acid carbonate. One chills, vacuum-filters, washes with water and dries under vacuum at 40°C. One obtains 1.3? g of expected product.

M.Pt. » 2?2°C.

Analysis: C^KqO^N^S.

Calculated: C% 39.06 K% a.21 Ν*ί ie.52 S% la.9 Found : 38.9 a.4 19.7 14.6 (B) Ethyl 2-(2-tritylamino-thiazol-a-yl’i-2-hydroxyinino acetate, syn isomer.

One introduces 43.2 g of ethyl 2-(?-amino-thiazol-a-yl)-2-hydroxyimino acetate, syn isomer, prepared in Stage (A) x above into 120 cm' of dry dimethyl formamide. o 3 One cools to -35 c and introduces 32 cnr of triethylamine then, over 30 minutes and in portions, 60 g of trityl chloride. One allows the temperature to rise and observes total dissolution, then heating up to 3θ°0. After one hour x one pours on to 1.2 1 of iced water containing 40 cm of 22°Be hydrochloric acid.

One agitates in a hath of iced water, vacuum-filters, rinses with normal hydrochloric acid and makes into a paste with ether.

One obtains 69.3 g of hydrochloride.

The free base is obtained by dissolving the product in five volumes of methanol to which is added 120% triethylamine, then by precipitating gently with five volumes of water.

Analysis: 1/4 HgC Calculated: 0% 67.6 H/ 5*1 N% 9.1 S% 6.9 Found : 67.5 5·1 h.R 6.8 (C) 2-(2-tritylamino-thiazol-a-yi)-2-hydroxyimino-acetic acid, _ 24 7 3 6 2 syn isomer.

One introduces 11.5 g of product obtained in Stage (B) above into 50 cnr of dioxan and 25 cnr of 2N sodium hydroxide. One agitates for one hour in a water bath at 50°C. One chills for 10 minutes, vacuum-filters, rinses with 5θ°'ί anueous dioxan, with a mixture of dioxan and ether (1:1) and with ether. One obtains after drying 11.05 g of sodium salt. The corresponding acid is obtained by taking up the salt in aqueous methanol in the presence of hydrochloric acid.

Example - 2: 2-(tert-butoxvcarbonyl-methyl-oxyirino^-2-(2-tritylamino-thiazol-4-yl)-aeetic acid, syn isomer. a) One mixes, under argon, 8.59 g of 2-hydroxyimir.o-2-(2-tritylamino-thiazol-a-yl1-acetic acid in 10 cm-* 5 of z dioxan, containing 4 moles of water per litre, and 80 cnr of dioxan and agitates for fifteen minutes.

S) One prepares separately a solution of 5-1521 £ of z potassium tert-butylate in 40 cm' of dioxan, agitates at ambient temperature under argon for ten minutes and obtains a homogeneous suspension. One then introduces, at 25°C-25°C over fifteen minutes, the suspension prepared in a) above, z cooling slightly and rinsing with 25 cm- of dioxan.

One aritates for one hour at 23°C-?5°C· One then introduces, over fifteen minutes at 28°C-?9°C, a solution Z of 4.919 g of tert-butyl bromo-acetate in 15 cm- of dioxan. One aaitates for one hour at 26°0-Ύ°0, then adds with an interval of 10 minutes first 0.4?l g of potassium tert25 47362 butylate, then a solution of ϋ.772 p of tert-butyl broaoace-'-ate in 2 cm^ of dioxan. One agitates for 4-5 minutes at 25°C under argon, brings to pH 6 with 0.5 car of acetic acid, then distils to dryness and obtains 1Q.4. g of a resin.

One takes up the resin with ICC cm^ of methylene chloride and ICO cm' of water, then acidifies to pH 2-3 with cm' of normal hydrochloric acid. One decants, washes with distilled water, filters, re-extracts with methylene chloride, dries, rinses with methylene chloride and distils to dryness under vacuum. One obtains 12.? g of product, z One takes up with 31 cm' of ethyl ace. ate, initiates crystallisation and agitates for one aour at ambient temperature, then two hours at between 0°G and +5°0. One vacuum-filters and rinses at this temperature with ethyl acetate. One dries under vacuum and obtains 5-04. g of expected product.

The product is purified in the following manner: 3.273 £ are dissolved in 60 cm^ of methylethyl ketone saturated with water at reflux. One adds 0.33 g of active 20 charcoal with heating, vacuum-filters and rinses twice with cm' of boiling methyl ethyl ketone saturated with water. x One concentrates the filtrate under vacuum recovering 36 cnr of solvent. The product crystallises out. One chills for one hour at between C°C and +5°C under agitation, vacuum25 filters and rinses with nethyl ethyl ketone saturated with water. One dries under vacuum and obtains 2.68 g of pure expected, product.

M.Pt. = 19O°G.

Analysis : C^qH^qOjNjS.

Calculated: Ci 66.28 IF.' 5-58 N5- 7.75 S% 5-9 5 Found : 66.5 5-7 7-7 5-6 NMR (CBClj, 60 KHz) 1.46 p.p.m. (proton of the tert-butyl) 6.8 p.p.m. (proton of the thiazole ring).

Example 5-~ 2-(cyqnomethyl-oxyimino'>-?-(2-tritylan:ino-thiazol-a-ylj-acetic acid., syn isomer.

.Stage A: Cyanomethyl S-Xcv^pmeth^-oxyisinoTz-ziZriTl-Zlx. anino-thiazol-&-yl)-3cet3te,_syn_isomer· One mixes, under inert atmosphere, 12.Q p of 2-hydroxyiminc-2-(2-tritylaminothiazol-4-yl)-acetic acid, syn isomer, z 9.12 g of neutral potassium carbonate, 6C ca' of dry dimethyl z formamide and 7-6 cm of chloracetonitrile. One agitates. After it has solidified, one leaves for 65 hours in an z enclosed atmosphere. One pours on to a mixture of 750 cm' z z of water, 150 cm' of normal hydrochloric acid and 150 cm' of ethyl acetate, agitates, vacuum-filters the insoluble matter, rinses with ethyl acetate and with water and decants, x One washes with ICO cm' of water, re-extracts with three times ICO cm^ of ethyl acetate, dries the organic phase, vacuum-filters, rinses, concentrates to dryness and obtains a residue which one chromatographs on a column of silica, eluting with ether. One drives off the ether and obtains 8.69 g of expected product in the form of oil.

NMR: CDClj 60 MHz Proton of the thiazole : 6.8 p.p.m.

Proton of the trityl : 7.57 p.p.m.

Stage. B: _2-£cyarwme.thyl^oxyhrAn£)^2^(2-Xr/tyl£m2ji£~th^a_zo.l-4-yl)-acetic aeid, syn isomer.

One places 8.69 ε of product obtained in Stage A in cm* of dioxan. One cools in an ice bath and adds, over twenty minutes, drop by drop, 17.1 cm^ of normal sodium hydroxide. One leaves to heat up spontaneously and adds .5 cm* of 2N hydrochloric acid then drives off the dioxan and almost all the water. x One adds 20 cm- of water and ?0 cm- of ether, agitates for fifteen minutes, vacuum-filters the crystals, rinses with water and with ether, dries and obtains 4.32 g of expected product. M.Ft. with decomposition about 180°G.

KKR : CDOlj 60 KHz 4.7 p.p.m. : OCH,, CN 6.7 p.p.m. : proton of the tniazole 7.34 p.p.m. : proton of the trityl.

Example 4: 2-(2-tritylamino-thiazol-4-yl)-2-(carbamoyl-methyl20 -oxyimino)-acetic acid, syn isomer.

Stage A: Ethyl 2.~£2yt_”itylas.ino-tiii_az£)y_4-jyl) Under argon, one places 9·θ8 g of ethyl 2-(2-tritylamino-thiazol-4-yl)-2-hydroxyimino-acetate hydrochloride in 25 cn? of dry dimethyl formamide and adds 8.28 g of pure potassium carbonate. One agitates the medium for fifteen minutes, then cools for ten minutes in a bath of methanol and x ice, then adds, drop by drop over five minutes, 11.2 cm of 7 3 6 2 ethyl hromoacetate and leaves to heat up spontaneously under agitation and under an inert atmosphere. Cne then pours into a mixture of 400 cm^ of water and 80 cm^ of ethyl acetate, agitates, decants, washes twice with 80 cnr of water, and x χ re-extracts with 80 cm' and 50 cm' of ethyl acetate. Cne dries the organic phase, vacuum-filters, rinses and concentrates to dryness.

One takes up with ether and agitates, and the expected product crystallises out. One vacuum-filters, rinses with 10 ether, dries and isolates 7-54 g of expected product.

M.Pt. = 154°0.

NMR: CBClj ; 60 MHz O-CK--GO. 4-.75 p.p.m. 6·55 p.p.m. *2 2 proton of the thiazole ring.

Analysis Calculated Found C3CK29°5N3S C% 66.28 Η5ό 5.38 N% 7.73 S& 5.90 66.1 5-4 7.5 5-9 Stage B: Ethyl 2-(2-tritylamino-thiazol-4-yl)-2-(carboxy-methyl-oxyiminoi-acetate, syn isomer.

One mixes, under an inert atmosphere and in a hath of χ iced water, 4.077g of product obtained in Stage A in 11.3 cm' of dioxan. After cooling, one introduces, over twenty minutes, 8.25 cm^ of a normal solution of sodium hydroxide.

One leaves the medium in the cold for one hour, drives off 0 3 the dioxan at 25 G, then adds 9-75 cm of a normal solution X of hydrochloric acid. One adds 40 cm' of ethyl acetate, agitates, washes and re-extracts with ethyl acetate. One - 29 47362 dries the organic pha=se on magnesium sulphate, vacuum filters, drives off the solvents, takes up with ether, initiates crystallisation, agitates for half an hour the crystals formed, vacuum-filters, rinses with ether, dries and obtains 5.462 g of expected product. K.Pt. = 200°C.

The pure product for analysis is ohtained as follows: x One dissolves 400 mg of product obtained in 1 cm of dioxan, dilutes with 1C cnr' of isopropyl ether, agitates, allows to crystallise in a hath of iced water, vacuum10 filters, rinses with a solution of isopropyl ether containing 10¾ of dioxan, finishes hy making into a paste with isopropyl ether and isolates 520 mg of purified product.

NMR: 60 KHz CDClj 4.71 p.p.m. : -G-CHyCO15 6.46 p.p.m. : proton of the thiazole ring.

Stage C: Ethyl, 2-^22;t£ityj.amino-thia.z£l-4-yl)-2-c^rbamoylme_thyl-oxyimin£)-2a£eia^.ej. £/£ isomer.

Under an inert atmosphere and in a hath of methanol and dry ice one introduces a mixture of 3*609 g of ethyl 2-(220 -tritylamino-thiazo1-4-yl)-2-(carhoxy-methyl-oxyimino)-acetic X acid, syn isomer prepared in Stage B in 28 cnr of dry x x tetrahydrofuran, 21 cnr of dry methylenechloride and 0.77 cm' of pure N-methyl morpholine.

One observes dissolution, cools the medium in a bath 2$ at -20°C and adds, drop hy drop, C.91 cm^ of isobutyl chloroformate.

One agitates for 3 minutes at this tenperature, then 7 3 6 3 cools to ~35°C and adds excess gaseous ammonia. One agitates for 15 minutes at -30°C, then for one hour at ambient temperature. One concentrates to dryness, takes up with ethanol, agitates for 20 minutes, vacuum-filters the crystals formed, rinses with ethanol and dries.

One obtains 3.33 g of expected product. M.pt. = 180°0. NKB : CDClj 60 MHz 4.76 p.p.m. : 0-CH2-C02 6.63 p.p.m. : proton of the thiazole ring.

Analysis : C^H^O^S Calculated: C% 65.55 H£- 5.0? S% 6.25 Found : 65.5 5.1 6.3 Stage D: 2y£2-trityl amino-thi azol-A-^yl)-2-(jqarbamoyl-me th^l-oxyimino)-acetic acid, _syn isomer^ One introduces 3-5 B of product prepared in Stage C into 24 cm^ of dioxan and 6.8 cnT of 2N sodium hydroxide.

One agitates at ambient temperature and observes the dissolution, then the crystallisation of the sodium salt after forty-five minutes in contact. One leaves under agitation in an enclosed atmosphere for three hours and fifteen minutes.

One vacuum-filters the sodium salt, rinses with a mixture of dioxan and water (70:3θ)» then with ether, dries and isolates x 1.81 g of sodium salt. C-ne dissolves this salt m 5-3 cm of dimethyl sulphoxide, adds 5 cnr of a normal solution of hydrochloric acid and observes precipitation, then x crystallisation. One dilutes with 70 cnr of water, agitates for twenty minutes, vacuum-filters, rinses with water, dries and obtains 1.5 g of expected product. M.Pt.- 200°G.

NMR : CDClj 60 MHz 4.58 p.p.m. : -0-CH2-C0 6.66 p.p.m. : proton of the thiazole ring.

Example 5: ?-(2-trityla:nino-thiazol-4-yl)-2-(Cl-tert-butoxycarbonyl-l-methyl-ethyl]-oxyiaino)-acetic acid, syn isomer.

Stage A: Ethyl P-i.Rx.t.ritylamino^thiazol-a^yli-R-i £l-t£rt-_ -butoxycarbonyl-_l-me^hyl2ethyl2“£Xyimino2-a.c_etat£,_s^i_ isomer^ One mixes 9.8& ; of ethyl 2-(2-tritylamino-thiazol-4-yl) -2-hydroxyimino-acetate hydrochloride and 8.2S g of neutral x potassium carbonate in 25 cm' of ''ry dimethyl formamide.

Cne cools for ten minutes in a bath at -10°C and adds, over 15 three minutes, 19 cm^ of crude tert-butyl 2-bromo-2-methyl-propionate. One allows to heat up and agitates for sixteen hours. One observes solidification. One pours on to a z mixture of 400 cnr of distilled water and 200 cm' of ethyl acetate. One agitates, decants and washes with water, extracts twice with 100 cm^ of ethyl acetate, dries, vacuumfilters, concentrates, recovers an oil to which one adds 2aC cm' of petroleum ether, cools, initiates crystallisation, vacuum-filters at the end of half an hour and obtains 10.8 g of expected product.

M.Ft. = 1J4°C.

NMR : 60 MHz, COCl^ 6.71 p.p.m. : proton of the thiazole 7.28 p.p.m. : proton of the trityl.

Analysis : C^HjyO^N^S Calculated: C% 68.09 H<. 6.22 N% 7.01 S% 5.35 Found : 68.3 6-3 6.Q 5.3 Htage 13: R-^R-tritydamino-thiazol-^^yO-S^lXl-tjert-buto^^ carbonyl-l-methyl-ethylJ-oxyiminol-aeetic acid, syn isomer^ Cne mixes 1.2 g of product obtained in Stage A in z z cnr of IN methanolic potassium hydroxide and 4 cnr of methanol. One takes to reflux for two hours, cools and observes crystallisation of the starting product, of which one recovers 390 mg. One has therefore saponified 810 mg of product. One concentrates the filtrate to dryness and g * adds 1 cm' of dimethyl formamide and 2 cm' of a normal solution of hydrochloric acid (pH =2). Cne agitates, adds cm^ of water and some methylene chloride, agitates, decants, washes with water, re-extracts with methylene chloride, dries the organic phase, vacuum-filters and conentrates the filtrate z until an oil is obtained. One adds 4 cnr of chloroform and z dilutes with 30 cm of ether. One initiates crystallisation, vacuum-filters the crystals after a half hour's agitation, rinses with ether, dries and isolates 472 mg of expected product. M.Pt. = 190°C.

NMR : DMSO, 60 KHz 6.76 p.p.m. : proton of the thiazole 25 7-33 p.p.m. : proton of the trityl.

Example 6: 2-(2-tritylamino-thi3zol-4.-yI 7-3-( 1-methyl-l-aethoxy-ethypoxyimino'i-acetic acid, syn isomer.

One agitates for 20 minutes at ambient temperature 12.9 g of 2-hydroxyimino-2-(2-tritylaraino-thiazol-^-yl'>-acetic acid, syn isomer, in 120 cm' of methylene chloride and 12 cm' of 2-methoxy propene. One concentrates to dryness and agitates for a further 50 minutes in 60 cm^ of χ methylene chloride and 12 cm' of methoxy propene. One concentrates to dryness under reduced pressure to obtain the expected product. -0-0-0-C-0In the following claims, all formulae and substituents 10 therein are, unless otherwise indicated, as first defined.

Claims (3)

1. CLAIMS 1. A compound which is a syn isomer of the general formula: 5 wherein Y represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms; wherein R 4 represents a group removable by acid hydrolysis or by hydrogenolysis, or a chloroacetyl radical; and X represents a1-methyl-l-methoxy-ethyl radical or a group R' 10 - C - % R wherein Rg represents: a) a group CO,,Rg in which R 5 represents an alkyl radical having from 1 to 4 carbon atoms or an ester-forming group removable by acid hydrolysis or by hydrogenolysis, b) a cyano radical, c) a carbamoyl radical, or d) a radical-COOH, 5 and R' and R, which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms.
2. 2. The syn isomers of the general formula: WH- R/, (HI) wherein R^ represents a group removable by acid 10 hydrolysis or by hydrogenolysis, or a chloroacetyl radical; R^ represents a) a group C0 2 Rg in which Rg represents an alkyl radical having from 1 to 3 carbon atoms or an ester-forming group removable by acid hydrolysis or by hydrogenolysis, b) a cyano radical, or 15 c) a carbamoyl radical; and R' and R, which may be the 47 3 6 same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms.
3. 3. A syn isomer as claimed in Claim 2, wherein R' and R each represent a hydrogen atom. 54. A syn isomer as claimed in Claim 2, wherein R' and R each represent a methyl group. 5. A syn isomer as claimed in any of Claims 2 to 4 wherein Rg represents COgR,.. 6. A syn isomer as claimed in Claim 5 wherein R g 10 represents an ethyl radical. 7. A syn isomer as claimed in Claim 5 wherein R 5 represent a benzhydryl, t-butyl, benzyl, p-methoxybenzyl or trichloroethyl radical. 8. A syn isomer as claimed in Claim 7, wherein R^ 15 represents a t-butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxy carbonyl or 2-tetrahydropyranyl group. 9. 2-(2-Tri tylamino-thiazol-4-yl)-2-(ethoxycarbony1-methyl-oxyimino)-acetic acid, syn isomer. 20 10· 2-(Tert-butoxyearbonyl-methyl-oxyimino)-2-(2-tritylamino-thiazol-4-yl)~acetic acid, syn isomer. 11. 2-(2-Tritylamino-thiazol-4-yl)-2-(C1-tert-butoxycarbonyl -l-methyl-ethyl]-oxyimino) -acetic acid, syn isomer. 47363 12. A process for preparing the syn isomers of general formula III, in which process a syn isomer of the general formula: is reacted in the presence of a base with a compound of 5 the general formula: R 1 Hal-C-R c 5 (V) R (wherein Hal represents a halogen atom) to obtain the desired syn isomer of general formula III. 13. A process as claimed in Claim 12, in which the base is potassium ^t-butylate, sodium hydride or an alcoholic 10 potassium hydroxide solution. 47363 14. A process as claimed in Claim 12 or Claim 13, in which the halide of general formula V is the bromide. 15. A process fcr preparing the syn isomers of general formula III wherein represents a carbamoyl radical, in 5 which process a syn isomer of the general formula: (wherein alk represents an alkyl radical having from 1 to 4 carbon atoms) is treated, in the presence of a base, with a compound of the general formula: H' I Eal-C-CO-alk, (V) I 2 1 H (wherein alk^ represents an alkyl radical having from 1 to 10 4- carbon atoms) to obtain a syn isomer of the general 39 47362 which is thereafter treated with ε base and then with an acid to obtain a syn isomer of the general formula: (VIII) β the formed syn isomer VIII then being converted into an appropriate functional derivative and treated with ammonia to obtain a syn isomer of the general formula: and the formed syn isomer IX is treated with a base and then with an acid to obtain the desired syn isomer of general 40 47363 16. A process as claimed in Claim 15, in which the reaction of the compound of eeneral formula V with the syn isomer of general formula VI is carried out in the presence of potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine. 17. A process as claimed in Claim Is or Claim 16, in which the halide of general formula V is the bromide. 18. A process as claimed in any of Claims 35 to 17, in which the syn isomer of general formula VII is reacted with a single equivalent of sodium hydroxide, potassium hydroxide or barium hydroxide, the reactants being cooled in a bath of iced water, and thereafter treated with aqueous hydrochloric acid, dilute sulphuric acid or acetic acid. 19. A process as claimed in any of Claims 15 to 13, in which the acid of general formula VIII is converted to a mixed anhydride, the symmetric anhydride or an active ester formed with N-hydroxysuccinimide, n- or o-nitrophenol or 2,4-dinitrophenol. 20. A process as claimed in any of Claims 15 to 19, in which the syn isomer of general formula IX is reacted with sodium hydroxide and then with hydrochloric acid. 21. A process for preparing the syn isomers of general formula III wherein R^ represents a cyano radical, in which process a syn isomer of general fornula IV is treated, in the presence of a base, with two equivalents of a compound of the general formula: 41 47362 (X) which syn then with formula: to obtain R' I Hal - C - CK ι fi· 1 (XI) isomer of formula XI is treated with a base and an acid to obtain the desired syn isomer of general CO2.H (III) -O-C-C.W P. 5 22. A process as claimed in Claim 21, in which the reaction of the compound of formula X with th .» syn isomer of formula IV is carried out in the presence of potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine. 23. A process as claimed in Claim 21 or Claim 22, in which 10 the saponification of the syn isomer of formula XI is effected with sodium hydroxide and then with hydrochloric acid. 24. A process for preparing the syn isomers of general fornula III, in which process a syn isomer of the general formula VI is reacted in the presence of a base with a comnound of general formula V to obtain a syn isoiner of the general formula: which syn isomer of formula XII is treated with a base and then with an acid to obtain the desired syn isomer of general formula III. 25· A process as claimed in Claim 24, in which the reaction of the compound of general formula V with the syn isomer of general formula VI is carried out in the presence of potassium carbonate, sodium hynroxide, potassium hydroxide or triethylamine. 25. A process as claimed in Claim 24 or Claim 25, in which the syn isomer of general formula XII is reacted with methanolic potassium hydroxide solution and then with hydrochloric acid. 27. A process for preparing a s/£n isomer of general formula III, which process is substantially as described herein with reference to any one of Examples 1 to 528. A syn isoiner of General formula III whenever prepa-ed - 47362 by a process claimed in any one of Claims 12 to 27. 30. The syn isomers of general formula XV wherein R ft represents a t-butoxycarbonyl, trityl, benzyl, benzhydryl, 5 trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxy carbonyl or 2-tetrahydropyranyl group. 31. A process for preparing the svn isomers of general formula XV, in which process isopropenyl methyl ether of the formula: h 2 c = C OCH, / > 10 is reacted with a syn isomer of general formula IV to obtain the desired syn isomer of general formula XV. 32. A process as claimed in Claim 31, in which the reaction is carried out in the presence of an acid. 33. A process as claimed in Claim 31, in which the syn 15 isomer of general formula IV is used in the form of a salt with a mineral acid, and the free amine of formula XV is obtained following the reaction with isopropenyl-methyl ether by neutralisation of the product with a base. - AA 34. A process for preparing a syn isomer of general formula XV, which process is substantially as described herein with reference to Example 6. 35. A syn isomer of general formula XV whenever prepared 5 by a process as claimed in any one of Claims 31 to 34. 36. The syn isomers of the general formula: H wherein R 4 represents a group removable by acid hydrolysis or by hydrogenolysis, or a chloroacetyl radical; alk represents an alkyl radical having from 1 to 4 carbon 10 atoms; and R^ represents: a) a group COpR'^ in which R 5 represents an alkyl radical having from 1 to 4 carbon atoms or an ester-forming group removable by acid hydrolysis or by hydrogenolysis, b) a cyano radical, c) a carbamoyl radical, or d) a radical-COOH; and R' and R, which may be the same or different, each represent a hydrogen atom or an alkyl radical having from 5 1 to 3 carbon atoms. 37. A syn isomer as claimed in Claim 36 of the general formula: B wherein alk^ is an alkyl radical having from 1 to 4 carbon atoms, and R 4 , alk, R' and R are as defined in Claim 36. 10 38. A syn isomer as claimed in Claim 36, wherein R 5 represents CO 2 R 5 , or a cyano radical. 39. A syn isomer as claimed in Claim 38, wherein R^ represents an alkyl radical having from 1 to 3 carbon atoms 40. A syn isomer as claimed in Claim 38, wherein R^ 15 represents a benzhydryl, t-butyl, benzyl, £-methoxybenzyl, trichloroethyl or ethyl radical. 41. A syn isomer as claimed in Claim 36 of the general formula: 47363 wherein R^, alk, R' and R are as defined in Claim 36. 42. A syn isomer as claimed in Claim 36 of the general formula: NHR, A N, CO 2 alk (Π) \ f O-C-CONH. wherein R^, alk, R' and R are as defined in Claim 36. 43. A syr. isomer as clained in any one of the Claims 36 to 42, wherein R' and R each represent a hydrogen atom. 44. A syn isomer as claimed in any one of Claims 36 to 42, 5 wherein R’ and R” each represent a methyl group. 45. A syn isomer as claimed in any one of the Claims 36 to 44, wherein R^ represents a t-butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxy-carbonyl or 2-tetrahydropyranyl 10 group. 46. Ethyl 2-(2-tritylamino-thiazol-4-yl)-2-(ethoxycarbonyl -methyl-oxyimino)-acetate, syn isomer. 47. Ethyl 2-(2-tritylaaino-thiazol-a-yl)-2-(carboxy-methyl-oxyimino)-acetate, syn isomer. 15 48· Ethyl 2-(2-tritylar.ino-thiazol-4-yl)-2-(carbanoylmethyl-oxyiair.o)-acetate, syn isomer. 49. Ethyl 2-(2-tritylaaino-thiazo1-4-71)-2-([l-tert-butox? r -carbonyl-1-methyl-ethylj-oxyimino)-acetate, syn isomer. 50. A process for preparing the syn isomers of general 20 formula XX as defined in Claim 36,in which process a syn 48 4 73 6 2 S' isomer of the general formula: wherein alk and. R, t are as defined in Claim36 is treated, in the presence of a hase, witn a compound of the general formula: R* Hal-C-CC^all^ (V) I R 5 wherein Hal represents a halogen atom, alk, is as defined in Claim37, and R' ar.d R” art as defined in Claim 3q to obtain a syn isomer of the general formula: 0-C-CQ o alk, I “ R which optionally is thereafter treated with a b.a6e and then with an acid to obtain a pyn isomer of the general formula: the formed syn isomer VIZI optionally then being converted into an appropriate functional derivative and treated with s ammonia to obtain a yn inoaer of the general formula: CC\alk (IX) O-c-ccrw-, 5!· A process as claimed in Claim in which the reaction of the compound of general formula V with the syn isomer of general formula VI is carried out ir, the presence of potassium carbonate, sodium hydroxide, 1.0 potassium hydroxide or triethylamine. 4. 7 3 6 2 52. A process as claimed in Claim 50 or Claim 51, in which the halide of general formula V* is the bromide. 53. A process as claimed in any one of Claires 50 to 52, in which the syn isomer of general formula Vll is reacted 5. With a single equiv ilent of sodium hydroxide, potassium hydroxide or hariur hydroxide, the reactants being cooled in a bath of iced ·.ater, anc thereafter treated with aqueous hydrochloric acid, dilute sulphuric acid or acetic acid. 6. 10 54. A process as claimed in any of Claims 50 to 53, in which the acid of -eneral formula VIII is converted to a mixed anhydride, tie symmetric anhyd'ide or an active ester formed with i-hydr ixysuccinimi. e, n- or o-nitrophenol or 2,4-cinitropher.il. 7. 15 55. A process for preparing the syn isomers of general formula XX , defined in Claim 3b,in which process a syn isomer of the general formula VI, defined in Claim 50, is reacted in the presence of a base with a compound of general formula: K’ I Hal-C-it (, 7) I Ii 8. 20 wherein S’, It and 3^ are as defined in Claim 36 and Hal represents a halogen atom, to obtain a syn isomer of the general formula: 47363 Ν II (XX) 50. A process as claimed in Claim 55, m which the reaction of the compound of general formula V with the «•yn isoner of general formula VI is carried out in the presence of potassium carbonate, sodium hydroxide, i, potassium hydroxide or triethylamine. 57. A process for preparing a syn-isomer of general formula XX, defined in Claim 36, which process is substantially as hereinbefore described with reference to Example 4 or Example 5. io 58. A syn isomer of general formula XX, defined in Claim 35 whenever prepared by a process claimed in any one of Claims 50 to 57.