IE45016B1 - 2-(2-amino-4-thiazolyl)-2-hydroxyiminoacedtic acid and substituted derivatives thereof useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolylacetamido-cephalosporanic acid, and processes for preparing them - Google Patents

Description

This invention relates to . 2-(2-amino-Auseful as intermediates thiazolyl)-2-hydrosyimino-acetic acid, and substituted derivatives thereof/ in the manufacture of antibiotic oxime derivatives of 7“ aminothiazolylacetamido-cephalosporanic acid and processes for preparing them. In particular, it concerns intermediates useful in the manufacture of certain derivatives of Jacetoxymethyl-7- C2-(2- amino-Φ-thi azolyl)-2~ imino- acetamido]*· ceph-3-em-A-carboxylic acid.

In our copending Application Ho. 45015 10 out of which this Application is divided, there are described and claimed 7-aminothiazolyl-acetamido-cephalosporanic acid oxime derivatives of the general formula]: NH-R (I) wherein R represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis, S' represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from and . to A carbon atoms,/a represents a hydrogen atom, an alkali metal atom, an equivalent of sn alkaline-earth metal atom, an equivalent of a magnesium atom or a substituted ammonium group, with the proviso that when R’ represents a group removable by - 2 45016 aoid. hydrolysis or by hydrogenolysis E represents the same J or a different group removable by aoid hydrolysis or by hydro- i genolysis, and that when E' represents a hydrogen atom E also represents a hydrogen atom, the compounds being in the form ί of the syn isomer, as indicated in the general formula.

The aforesaid Application also provides various processes for preparing compounds of general formula Z. Those com- ’ pounds of general formula I wherein E represents and S’ represents E’j, E^ being a group removable by aoid hydrolysis or by hydrogenolysis and E' being a group removable by acid ' f hydrolysis or by hydrogenolysis or a saturated or unsaturated j hydrocarbyl radical having from 1 to 4 carbon atoms, may be . prepared by a process in which 7-amino-cephalosp0ranic aoid. J 'synisomer is reacted with an appropriate aeid7of the general formula : j (wherein E^ and E’^ are as defined hereinbefore) or a functional derivative thereof to obtain the desired syn-isomer' of the general formula .· - 3 4501® wherein E^ and. E'^ are as defined, hereinbefore.

The compounds of general formula II and related compounds wherein R^ and/or E’^ represent hydrogen are new, and this invention provides these useful intermediates per se.

Accordingly, this invention provides the syn isomer compounds of the general formula.: wherein Rg represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis and E'g represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from 1 to 4- carbon atoms, with the proviso that E*g does not represent a hydrogen atom when Eg represents a group removable by acid hydrolysis or by hydro15 genolysis. - 4 *S0l6 Those compounds of general formula lib that also fall -OfgeneraJ.. formula, lib within general formula II - that is, the compounds/wherein E2 and E*2 do not represent hydrogen - may he prepared hy a process in which an appropriate syn isomer of the general formula : (wherein Ej and E'^ are as defined hereinbefore and alk represents an alkyl radical having from 1 to 4 carbon atoms) is treated first with a base end then with an aoid -to form the deBired product of general formula II. This invention extends to such a process.

The base, which is used to saponify the product of formula Ill^is preferably sodium hydroxide, but other bases such as potassium or barium hydroxide can also be UBed.

The acid whioh is used to isolate the acid of formula II is preferably dilute hydrochloric acid, but other acids such as acetic acid or formic acid can also be used.

The compounds of general formula III are in turn conveniently prepared by protecting the amino groups, and - 5 ^016 where appropriate the oxime groups as well, of the corresponding syn isomers -of the general formula : wherein R' and alk are as defined hereinbefore„ The appropriate compound of general formula IV is treated with a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to form the corresponding product of general formula III.

Naturally the process employs a compound capable of introducing the appropriate group R^ (and R’^ when R' in compound IV is hydrogen) into the compound III and the compound most conveniently employed will depend upon the nature of the group. However, such protecting groups and their introduction into molecules are well known to those skilled in the art. By way of illustration, the trityl group is preferably introduced using trityl chloride, most preferably used in the presence of triethylamine, or another tertiary amine base such as another trialkylamine, N-methylmorpholine or pyridine.

Other compounds capable of introducing groups removable by acid hydrolysis or' hy hydrogenolysis which may be used include t-butyl chloroformate (conveniently prepared in situ) or t-butyl azidoformate» trichloro- 6 43016 ethyl or benzyl chloroformate, the mixed, formyl-acetic anhydride (prepared in situ), benzyl or dibenzyl halides and particularly the chlorides, phthalic anhydride or Scarbethoxy-phthalimide.

Certain of the compounds of general formula 111, namely those wherein EJ represents a saturated or uasaturated hydrocarbyl radical having from 1 to 4 carbon atqm.s, may be prepared by a prooess in which an appropriate syn isomer of the general formula : (IV) (wherein alk is as defined hereinbefore) is treated with an equivalent of a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to obtain the corresponding product of general formula : (v) (wherein Rj and alk are as defined hereinbefore) which is then treated with a hydrocarbylating agent to obtain the syii isomers . . . desired?product of the general formula ! 0Rb (Ilia) (wherein and. alk are as defined hereinbefore, and Eb represents a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms.

The compound capable of introducing a group removable 5 by acid hydrolysis or by hydrogenolysis is chosen.to introduce the desired protecting group, as explained above, end again is preferably trityl chloride. The formation of the product V using trityl chloride is preferably carried out in the presence of a base such as triethylamine.

Other bases such as other trialkylamines, H-uethyl-morpholine or pyridine can also be used.

Other compounds capable of introducing groups removable by acid hydrolysis or hydrogenolysis, such as t-butyl chloroformate or azidoformate, trichloroethyl or dibenzyl chloroformate, the mixed formyl acetic anhydride (prepared in situ), benzyl or dibenzyl halides (preferably the chlorides), phthalic anhydride or N-carbethoxy-phthalimide can also be used.

The hydrocarbylating agent which is used in the final 43016 step of preparing the products of formula IIIa is preferably an alkyl halide such as an alkyl iodide or an alkyl sulphate.

The compounds of general formula IV, and thus including 5 the compounds of general formula IV, may be prepared by any of the processes described in ova aforementioned Application No. -45015 Thus the compounds of general formula IV may be prepared by reacting thiourea with an appropriate compound of the general formula: X-OH -^-OOgaik N καλλα*0Ε' (VII') (wherein X represents a chlorine atom and E'^ represents a hydrogen atom, a group removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, or X represents a bromine atom and E'^ represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms) which process is characterised in that a) the reaction is carried out in an aqueous solvent; or b) the reaction is carried out at ambient temperature in the presence of a substantially stoichiometric amount of thiourea and with a reaction time of from 1 to 3 hours; or c) the reaction is carried out observing both of conditions a) and b).

The compounds of general formula VII' wherein X represents a bromine atom and E'fc represents a hydrogen atom may be obtained by treatment of the products of formula: - 9 (VIII) C-C0oalk ί 2 L with a brominating agent.

The brominating agent is preferably bromine itself.

The compounds of formula VII* wherein X represents a chlorine atom which are not known may be prepared from 5 ethyl-Y-chloro-a-oximinoacetylacetate (described in tf. of Medicinal Chemistry 1975, Vol. 16, no. 9). The compounds of general formula VII' wherein X represents a chlorine atom and R'k represents a group removable by acid hydrolysis or hy hydrogenolysis may be obtained by standard protecting reactions using funtional derivatives of the removable groups.

The compounds of general formula VII' wherein X represents a chlorine atom and represents a saturated or unsaturated hydrocarbyl· radical having from 1 to 4 carbon atoms may he obtained hy reacting ethyl-Y-ebloro-a-oximinoacetylacetate with an appropriate alkyl halide or sulphate.

Naturally, to obtain the desired substituent alk in the oompound of general formula VII1 appropriate saponification and re-esterification or transesterification may be used.

The compounds of general formulae III and IV as defined 20 herein are themselves new, and this invention extends to these new intermediates per se.

Those compounds of general formula lib wherein Rg and/or R'g represent(s) a hydrogen atom may he prepared by subjecting the corresponding compounds of general formula II wherein - 10 X ! ^SOis j E^ and/or E·^ represent(s) a group removable by acid ί hydrolysis or by hydrogenolysis to acid hydrolysis or hydrogenolysis, as appropriate, so as to form the desired compound of general formula lib.

The following Examples are now given, though only by way of illustration, to show certain preferred aspects of the invention.

Example 1: 2-(2-tritylamino-4-thiazolyl)-2-methoxy imino5 acetic acid Stage As Ethyl 2-(2-amino-4-fhiazoIyl)-2-aethoxyiminoacetate g of ethyl γ-chloro-a-methoxyimino-acetylacetate, cm^ of absolute ethanol and 0.42 g of crushed thiourea are placed together, the whole is agitated at ambient temperature for about two hours. It is diluted with 60 cm'’ of ether, the hydrochloride obtained crystallises out, the whole is agitated, vacuum-filtered., washed and dried. 685 mg oi x hydrochloride are obtained, and dissolved in 4 cm of water at 50°0. Potassium acetate is added until pH 6 is attained, - 12 and the amine released crystallises out. The whole is cooled and vacuum-filtered, the residue being washed with water and dried, and 270 mg of the desired product are obtained.

M.Pt. » 161°C. The product obtained has the syn configuration.

HMR (CDClj 60MHZ) p.p.m. : 4 (N-OCHj), 6.7 (proton of the thiazole ring).

Stage B s Ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxy10 imino-acetate 4.6 g of the product prepared according to the previous o X stage are dissolved at JO C in 92 cur of methylene chloride.

The solution is cooled to -1O°C, 2.9 cm^ of triethylamine are added, the whole is cooled to ~35°C, 6.1 g of trityl chloride are added over fifteen minutes, and the reaction mixture is left to return to ambient temperature, in all taking two hours thirty minutes. It is washed with water, then with 0.5N hydrochloric acid and with sodium acetate in water. It is dried, concentrated, taken up with ether, concentrated again, then dissolved in methanol; water and ether are added. Crystallisation is allowed to taka place, and the crystals are vacuum-filtered, then washed with ether. 6.15 g of the expected product are obtained. M.Pt. « 120°C.

The product obtained has the syn configuration.

Stage C : 2-(2-tritylamino-4-thia8olyl)-2-methoxyimiao- Ϊ ——————j il - .13acetic acid 7.01 g oi ester obtained in Stage B are dissolved in cm^ of dioxane 0 The solution is taken to 110°C in an oil bath and 9 cs? of 211 sodium hydroxide solution are added over five minutes, then the whole is left for thirty minutes at reflux under agitation. The sodium salt crystallises out.

The whole is cooled, vacuum-filtered, washed with dioxane, then with ether, and a first yield of 5-767 g of salt is obtained. The mother solution is concentrated and a second yield of 1.017 g is obtained to give 6.784 g of salt in all. z 3.06 g of salt are placed in 65 cm of methylene ? chloride and 6.5 cm^ of 2N hydrochloric acid, and the whole is washed with water, dried end concentrated to dryness to obtain the free acid quantitatively.

The product ‘obtained has the syn configuration.

NMR (DMSO, 60MHZ) p.p.m. : 3.68 (N-OCHj 6.6 (proton of the thiazole ring).

Example. 2 s 2-(2-tritylamino-4-thiazolyl)-2-(2~propenyloxyimino)-acetic acid Stage A : Ethyl 2-(2-*amino-4-thiazolyl)-2-(2-propenylosyimino)-acetate a) 9»7 e oi ethyl 2-hydroxyimino-4-chloro-acetylaoetate, 30 cs? of acetone and 9.15 cm^ of 3“i°dopropene are cooled in ice and 27«5 CIQ of 211 sodium hydroxide solution are added, - 14 ^S0i6 ι then the whole is left for en hour-and-a-half at ambient j temperature 5 b) 3-8 g of thiourea are added to the reaction mixture, I then this is maintained at 60°C for 15 minutes and then for ί 45 minutes at ambient temperature, the acetone is driven j off, methylene chloride is added, then water, then potassium ί ί carbonate, the whole is agitated, decanted, extracted with methylene chloride, dried and concentrated to dryness, 9.75 g of residue are obtained*which is chromatographed on silica, eluting with ether, 2.7 g of the product are isolated and , taken up with isopropyl ether, and the crystals are vacuumI filtered, rinsed and dried. 783 ag of the expected product are obtained. M.Pt. » 100°C. The product obtained has the j syn configuration. i Stage B : Ethyl 2-(2-tritylamino'-4-thiazolyl)-2-(2- 1 ; propeuyl-oxyimino)-acetate I I 511 mg of the product prepared in Stage A, 0.92 cnr of dimethyl-formamide, l.S cn? of methylene chloride and 0.29 cn? of triethylamine are mixed. The mixture is cooled to · -i5°c and 615 mg of trityl chloride are added. The whole is i left at ambient temperature for an hour-and-a-half, 2 cm? of IN hydrochloric acid then 5 cn? of water are added, the whole ia decanted, dried and concentrated to dryness, and 1.28 g of - ί the crude product are obtained. 1 The product obtained has the syn configuration. ϊ Stage Ο : 2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetic acid. 1.28 g of the product obtained in. Stage B, 6.2 cm^ of dioxane and 5 em^ of 2N sodium hydroxide are mixed and heated at 120°C. The whole is taken to reflux for one hour, the sodium salt crystallises out and is vacuum-filtered, rinsed with an ether/dioxane mixture, then dried. 805 mS of the product are isolated.

This is taken up in 10 cm^ of methylene chloride and 40 5 cm^ of HI hydrochloric acid and agitated to obtain a solution which is decanted, dried, concentrated to dryness, taken up with ether and vacuum-filtered. 715 mg of the expected product are obtained. M.Pfe. = 170°0.

The product obtained has the syn configuration.

Example 3 : 2“(2-tritylamino-4-thiazolyl)-2“(ethoxyimino)~ acetic acid Stage A s Ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate a) 19.4- g of ethyl γ-chloro-oc-oxyimino-acetoacetate 2° are placed in 60 cm^ of acetone and 14.3 cm5 of diethyl sulphate. The whole is cooled for 10 minutes in an ice bath and 55 of SH sodium hydroxide solution are added over 30 minutes, then the whole is agitated for 40 minutes; b) 7=8 g of thiourea are added to the reaction medium, a a οχ this is heated at 55°O f 6.9 g of potassium carbonate are added, and the whole is agitated, decanted, extracted with ethyl acetate, dried and concentrated to dryness. 17.4 g of residue are isolated end chromatographed on silica, eluting with ether.

The expected product is recovered, taken up with isopropyl ether, vacuum-filtered, rinsed and dried, and 2.8 g of the expected product are obtained. M.Pt. = 129°C. The product obtained has the syn configuration.

Stage B : Ethyl 2-(2-tritylsmiao-4-thiaaolyl)-2-ethoxyimino-acetats 3.16 g of the product obtained in Stage A, 6 cm? of dry dimethyl-formamide, 12 em^ of methylene chloride and 1.89 cm^ of triethylamine are placed under an inert gas.

The mixture is cooled to -15°C and 3.98 g of trityl chloride are slowly added. The whole is left to stand for half-anhour, the temperature is raised to +10°C, then the whole is maintained for three-and-a-half hours at ambient temperature 13 cm* of IK hydrochloric acid are added, and the whole is agitated, decanted, washed with IK hydrochloric acid, then with water. It is extracted with methylene chloride, dried and concentrated to dryness, and 7.89 g of crude residue are obtained.

The product obtained has the syn configuration. _ 17 ·Ol® Stage C : 2-(2-tritylamino-4-thiazolyl)-2-ethoxyiminoacetic acid.

A mixture of 7.89 g of the product obtained in Stage B, 40 cn? of dioxane and 19-5 cn? of 2N sodium hydroxide solution is heated at 110°C for one hour. The mixture is vacuum-filtered, r-insed with an ether/dioxane mixture, then with ether alone ^nd dried. 6.25 g of sodium salt are obtained and taken up in 60 cn? of methylene chloride and z 2G cm of IN hydrochloric acid, the two phases are agitated, 10 20 cn? of methanol are added, the whole is decanted, washed with water, extracted with a methylene chloride/methanol mixture, dried and concentrated, and 5»85 g of pure 2-(2tritylamino-4-thiazolyl)-2-ethoxyimino-acetic acid are isolated.

The product obtained has the sya configuration.

Example j : 2-(2-tritylamino-4-th.iazolyl)-2-is0propyloxyiaino-acetic acid Stage A s Ethyl 2-acetyl-2-isopropyloxyimino-acetate 39-8 g of ethyl 2-acetyl-2-hydroxyimino-aeetate are 20 placed in 200 cn? of pure acetone. The whole is cooled in. an ice hath and 52 g of potassium carbonate are added then, over half-an-hour, 25 ce? of 2-iodopropane. The whole is then agitated for 2 hours, 800 cn? of water and 500 on? of methylene chloride are added, the whole is agitated, _ Al&_ 43016 decanted, extracted with methylene chloride, dried, vacuumfiltered and concentrated, and 41.5 g of the expected product are isolated.

Stage B : Ethyl 4-bromo-2-isopropyloxyimino-aoetyl5 acetate The 41.5 g of the product obtained in the previous stage are placed in 190 cm^ of methylene chloride with traces of para-toluene-suluhonic acid. The whole is agitated and a solution of 11.9 cm^ of bromine in 50 cm^ of methylene chloride is introduced, over one hour, at ambient temperature. The whole is agitated., iced water is added, the whole is decanted, extracted with methylene chloride, washed with iced water, dried and concentrated, and 55 g of the expected derivative are isolated.

Stage 0 s Ethyl 2-(2-amino-4-thiazolyl)-2-isopropyloxyimino-acetate 14.9 g of thiourea are placed in 55 cm^ of ethanol and 105 cm^ of water and a solution of the 55 g df the product prepared in Stage B in 55 of ethanol is added over 40 minutes. The whole is agitated for two-and-a-half hours at ambient temperature, 220 cm^ of 10% sodium bicarbonate in water are added, the whole is agitated, vacuum-filtered, rinsed and dried, and 42,15 g of crude product are isolated and chromatographed on silica eluting with ether. The fractions rich, in the desired, product are recovered, then, concentrated, the‘crystals are taken up with isopropyl ether, vacuum-filtered and rinsed. 10.75 S of bhe desired product are obtained.

The product obtained has the syn configuration.

Stage I) : Ethyl 2-(2-tritylamino-4-thiazolyl)-2-isopropyloxyimino-acet ate and 15-2 g of trityl chloride are slowly added, the whole is agitated for two-and-a-half hours, 45 cm^ of normal hydrochloric acid are added, the whole is agitated, decanted, s washed with·40 cnr of water, extracted with methylene chloride, dried, vacuum-filtered and concentrated to dryness, and 27.7 g of the expected product are obtained.

The product obtained has the Byn configuration.

Stage E : 2-(2-tritylamino-4-thiazolyl)-2-isopropyloxyimino-acetic acid £0 A mixture of 27·7 S of the product obtained in Stage D, 150 om^ of dioxane and 65 cm^ of 2N sodium hydroxide are refluxed for two hours. The sodium salt crystallises, the mixture is cooled, vacuum-filtered, rinsed with a 1:1 ether/dioxane mixture and dried, and 16.85 g of crude sodium salt - 20 are obtained. 1J.9 g of this sodium salt are dissolved in .9 g of dimethyl-formamide, 100 cm^ of water and about $00 cm^ of methanol.· JO cm^ of 2N hydrochloric acid are added and th® methanol is driven off. The .remainder is diluted with water, vacuum-filtered, rinsed and dried. The 9.8 g of viscous product obtained are taken up in 220 cm^ of a 50:50 methylene chloride - methanol mixture, concentrated to dryness, taken up with ether and disintegrated. The formed crystals are vacuum-filtered, rinsed and dried. 4.9 g of the desired acid are obtained. M.Pt. r—·' 1?O°C.

An analytical sample ia obtained by dissolving 300 mg of crude product in 2 cm^ of methylene chloride and 1 cm^ of methanol, diluting this solution with water and methylene chloride. This solution is then agitated and the formed crystals are vacuum-filtered off, rinsed with methylene chloride and with water, then dried and 230 mg of pure product are isolated for analysis.

Analysis: Calculated: C% 68.?? 5·34 H% 8.91 6.8 Pound: 68.6 5·5 8.8 θ·8 The product obtained hat the syn configuration.

Claims (17)

1. I. A compound of the general formulas (lib) wherein Eg represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis and E'g represents a hydrogen atom, a group removable by acid hydrolysis or by 5 hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, with the proviso that R'g does not represent a hydrogen atom when Eg represents a group removable by acid hydrolysis or by hydrogenolysis, in the form of the syn isomer. 10
2. 2. A compound as claimed in claim 1, being a syn isomer of the general formula: NH-R I CO 2 H N OR' (II) wherein E^ represents a group removable by acid hydrolysis or by hydrogenolysis and E'^ represents a group removable by acid hydrolysis or by hydrogenolysis or a saturated or 15 unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms. ·
3. 3. A process for preparing the compounds of general - 22 43016 formula II, as claimed in claim 2, in which process a syn isomer of the general formula: (III) (wherein and R'^ are as defined in claim 2 and alk represents an alkyl radical having from 1 to 4 carbon atoms) 5 is reacted first with a base and then with an acid to form a product of general formula II.
4. 4. A process as claimed in claim 3, in which the base is sodium hydroxide.
5. 5. · A process as claimed in claim 3 or claim 4, in which 10 the acid is dilute hydrochloric acid.
6. 6. A process as claimed in any of claims 3 to 5: ih which the compound of general formula III is prepared by treating the corresponding syn isomer of the general formula (IV) \ OR' (wherein R' represents a hydrogen atom, a group removable by 15 acid hydrolysis or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms and alk is as defined in claim 3) with a compound capable of introducing a group removable by acid hydrolysis - 23 or by hydrogenolysis to,form the desired product of general formula III.
7. 7. A process as claimed in claim 6, in which the compound of general formula IV is treated with trityl chloride in 5 the presence of a trialkylamine, N-methyl-morpholine. or pyridine.
8. 8. A process as claimed in any of claims 3 to 5, in whioh the compound of general formula III wherein represents a saturated or unsaturated hydrocarbyl radical having from 1 . 10 to 4 carbon atoms is prepared by a multi-step process in which an appropriate syn isomer cf the general formula: (IV) (wherein alk is as defined in claim 3) is treated with an equivalent of'a compound capable of introducing a group removable by acid hydrolysis or by hydrogenolysis to obtain 15 the corresponding product of general formula: NR·, -C0 2 alk (V) OH (wherein E^ is as defined in claim 2 and alk is as defined in claim 3) which is then treated with a hydrocarbylating agent to obtain the desired syn isomer of the general, formula: - 24 < * t1 4S01S NHR, 1 1 z COgcil k ORg (Ilia) wherein E^ is as defined in claim 1, alk is as defined in claim 3 and Hg represents a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms.
9. 9. A process as claimed In claim 8, in which the compound 5 of general formula IV is treated with trityl chloride in the presence of a trialkylamine, N-methyl-morpholine or pyridine.
10. 10. A process as claimed in claim 8 or claim 9, in which the hydrocarbylating agent is an alkyl halide or an alkyl 10 sulphate.
11. 11. A process as claimed in claim 3 and substantially as described herein with reference to any one of the Examples.
12. 12. A process for preparing a compound of general formula lib, as claimed in claim 1, wherein Hg and/or K'g represent(s) 15 a hydrogen atom, comprising subjecting a compound of general formula II claimed in claim 2 wherein and/or H 1 ^ represent(s) a group removable by acid hydrolysis or by hydrogenolysis to acid hydrolysis or hydrogenolysis, as appropriate, so as to form the corresponding compound of general formula lib. 20
13. 13. A process as claimed in claim 12 and substantially as described herein with reference to any one of the Examples,
14. 14. A compound of general formula lib as claimed in claim 1, whenever prepared by a process as claimed in any of claims 3 to 13. - 25 I
15. 15. · 2-(2-Tritylsmino-4-thiazolyl)-2-methoxyimino-acetic acid, syn isomer.
16. 16. A syn isomer of general formula III as defined in claim 3.
17. 17. A syn isomer of general formula IV as defined in claim 6.