JPH0314823B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is based on the general formula (In the formula, R ₁ means amino or protected amino) Thiazole acetic acid derivative (syn isomer)
The present invention also relates to reactive derivatives at the carboxy group thereof, which can be used in the acylation reaction of the amino group of cephalosporin compounds, and salts thereof. The object compound of this invention <> is novel and can be produced by the method shown in the following scheme. (In the formula, R ^1a is a protected amino, Z is a protected carboxy, and X and Y are each a halogen.) The obtained compounds <a> and <b> are converted into amino acids of a cephalosporin compound by a conventional method. This can lead to reactive derivatives at the carboxy group that can be used in acylation reactions of the group. It is to be understood that the target compounds represented by formulas <>, <a> and <b> include tautomers based on their thiazole groups. That is, in the target compound, the formula

[Formula] (in the formula, R ¹ has the same meaning as before) is its tautotropic structure

[Formula] (wherein R ^1b is imino or protected imino). That is, each of the above groups <A> and <B> is in a so-called tautomeric relationship as shown by the following balanced formula. (In the formula, R ¹ and R ^1b have the same meanings as before.) The tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds as described above is widely known in the literature, and the above isomers are in equilibrium. It is obvious to those skilled in the art that they are related and that they can be easily interchanged. Therefore, they should be recognized as belonging to the same category as the compounds themselves. Therefore, these tautomers are clearly included in the scope of the present invention in both the starting compound and the target compound. In the present specification and examples, starting compounds and target compounds containing such tautomers are referred to as one of them for convenience, i.e.

[Formula] Represented by <A>. Suitable salts of the target compound <> include acid addition salts such as organic acid salts (e.g. acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or inorganic acid salts (e.g. hydrochloric acid). metal salts (e.g. sodium salts, potassium salts, calcium salts, magnesium salts, etc.); ammonium salts; organic amine salts (e.g. triethylamine salts, dicyclohexylamine salts, etc.), etc. Can be mentioned. In the explanations before and after this specification, examples of various groups included within the scope of the present invention will be explained as follows. The term "lower" means having 1 to 6 carbon atoms unless otherwise specified. Examples of suitable protected amino groups include acylamino, or amino substituted with conventional protecting groups other than acyl, such as aryl(lower)alkyl (eg, benzyl, trityl, etc.). Suitable protected iminos include acyliminos or iminos substituted with conventional protecting groups other than acyl, such as aryl(lower)alkyl (eg, benzyl, trityl, etc.). Suitable acyl moieties in the terms "acylamino" and "acylimino" include carbamoyl, aliphatic acyl, acyl containing aromatic or heterocyclic groups. Suitable examples of the above acyl include lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), preferably having 1 to 4 carbon atoms,
More preferably one having 1 to 2 carbon atoms; 2 to 2 carbon atoms
7 lower alkoxycarbonyls (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isoproxycarbonyl, ptoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary benzyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, (indanecarbonyl, etc.); aryl (lower) alkanoyl (eg, phenyl acetyl, phenylpropionyl, etc.); aryl (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.); and the like. The above acyl moieties may contain one to three suitable substituents, such as halogen (e.g. chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy,
isopropoxy, etc.), lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (eg, vinyl, allyl, etc.), aryl (eg, phenyl, tolyl, etc.), and the like. Suitable examples of acylamino include lower alkanoylamino or halo(lower)alkanoylamino [more preferably trihalo(lower)alkanoylamino]. Suitable examples of reactive derivatives at the carboxy group of compound <> that can be used in the acylation reaction of the amino group of the cephalosporin compound include acid halides, acid anhydrides, active amides, and active esters, such as acid chlorides; Acid azide; substituted phosphoric acid (e.g. dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.),
Dialkyl phosphorous acid, sulfite, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.) mixed acid anhydrides with acids such as; symmetrical acid anhydrides; activated amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, or tetrazoles; or active esters (e.g. cyanomethyl esters, methoxymethyl esters,
Dimethyliminomethyl [<CH> ₃ N ⁺ ₂ = CH−] ester, vinyl ester, propargyl ester,
P-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester,
phenyl thioester, P-nitrophenyl thioester, P-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N-hydroxy compounds (e.g. N,N-dimethylhydroxyl) Amine, 4-hydroxy-2-(1H)-pyridone, N
-Hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H
- benzotriazole, etc.). Suitable protected carboxys include esterified carboxys, where the ester moiety includes lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.),
Here, the lower alkyl moiety preferably has 1 to 4 carbons; lower alkenyl esters (e.g. vinyl esters, allyl esters, etc.); lower alkynyl esters (e.g. ethynyl esters,
propynyl ester, etc.); mono (or di or tri)
Halo (lower) alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy (lower)
Alkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkanesulfonyl (lower) alkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester, etc.); aryl (lower) alkyl ester [ For example, phenyl (lower) alkyl esters, which may carry one or more suitable substituents (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenyl ester, trityl ester). , diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-
hydroxy-3,5-ditertiary butyl benzyl ester); aryl esters which may have one or more suitable substituents (e.g. phenyl ester, tolyl ester, tertiary butyl phenyl ester); , xylyl ester, mesityl ester, cumenyl ester, etc.). A preferable example of protected carboxy is a carbon number 2.
~7 lower alkoxycarbonyls (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably those having 2 to 5 carbon atoms can be mentioned. Preferred halogens are chlorine, bromine, fluorine and iodine. In the target compound explained and exemplified above,
Among preferred examples of R ¹ , particularly preferred are amino or acylamino [more preferably lower alkanoylamino or halo(lower)alkanoylamino (even more preferably trihalo(lower)alkanoylamino)]. The method for producing the object compound of this invention is as detailed below. Manufacturing method 1 Step 1 Compound <> can be manufactured by reacting compound <> with compound <>. The reaction is usually carried out in the presence of chlorine such as potassium carbonate.
It is carried out at room temperature in a solvent such as N,N-dimethylformamide or ethyl acetate. Step 2 Compound <> can be produced by subjecting compound <> to a halogenation reaction. Suitable halogenating agents include sulfuryl chloride and the like. The reaction is usually carried out in a solvent such as acetic acid at room temperature or under heating. Step 3 Compound <> can be produced by reacting compound <> with thiourea. This reaction is preferably carried out in the presence of a base such as sodium acetate, usually in a solvent such as water, alcohol (methanol, ethanol, etc.), tetrahydrofuran, or a mixed solvent thereof, at room temperature or under heating. Step 4 Target compound <a> can be produced by subjecting compound <> to an elimination reaction of the carboxy protecting group. A conventional hydrolysis reaction can be used as the elimination reaction of the carboxy protecting group in this reaction. This reaction is usually carried out at room temperature in the presence of a base such as sodium hydroxide, in a solvent such as water, alcohol (methanol, ethanol, etc.), tetrahydrofuran, etc., or a mixed solvent thereof. Production method 2 Target compound <b> can be produced by reacting compound <a> with an amino protecting agent. The amino protecting agent used in this reaction is a reagent commonly used when introducing an amino protecting group, and is preferably an acid anhydride (e.g. 2,2,2-
trifluoroacetic anhydride, formic acid acetic acid mixed acid anhydride, etc.). The reaction is preferably carried out in the presence of an amino activator such as bis(trimethylsilyl)acetamide.
It is generally carried out in a solvent such as ethyl acetate or acetic acid at room temperature. The object compound (I) of this invention has the general formula (In the formula, R ¹ has the same meaning as above, R ² means carboxy or protected carboxy, and R ³ means tetrazolyl having a lower alkenyl, respectively.) Intermediate for synthesizing the cephalic compound or its salts It is useful as This cephalometric compound (C) is produced by the following method. (In the formula, R ¹ , R ² , and R ³ each have the same meaning as before.) Compound (C) or a salt thereof is compound ()
Alternatively, it can be produced by reacting Compound (I) or a reactive derivative at its carboxy group or a salt thereof with a reactive derivative at its amino group or a salt thereof. Reactive derivatives at the amino group of compound () include Schiff base-type imino obtained by reacting compound () with a carbonyl compound such as acetoacetic acid, or an enamine-type compound that is a tautomer thereof; Silyl compounds obtained by reacting silyl compounds such as trimethylsilylacetamide and bis(trimethylsilyl)acetamide; derivatives obtained by reacting the compound () with phosphorus trichloride, phosgene, etc. are included. Suitable examples of reactive derivatives at the carboxy group of compound (I) include the aforementioned "reactive derivative at the carboxy group of compound (I) that can be used in the acylation reaction of the amino group of a cephalosporin compound". Reference may be made to the examples. Suitable salts of the compound () include acid addition salts such as organic acid salts (e.g. acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or inorganic acid salts (e.g. hydrochloride). ,
bromate, sulfate, phosphate, etc.); metallic (e.g., sodium salt, potassium salt, calcium salt, magnesium salt, etc.); ammonium salt; organic amine salt (e.g., triethylamine salt, dicyclohexylamine salt, etc.), etc. . Salts of compound (C) include commonly used non-toxic salts, such as metal salts [e.g., alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.)],
Inorganic salts such as ammonium salts, organic amine salts (e.g. trimethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), organic acid salts (e.g. acetate, maleate,
organic salts such as tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.),
Inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), amino acids (e.g. arginine,
Examples include salts with aspartic acid, glutamic acid, etc. The reaction can be carried out using conventional solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, or other organic solvents that do not adversely affect the progress of the reaction. It is generally carried out in the presence of , and these can also be used in combination. When compound (I) is reacted in the form of the free acid or its salts, the reaction is carried out using common condensing agents such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-
diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide; N,
N'-Diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(methylimidazole);Pentamethyleneketene-N-cyclohexylimine;Diphenylketene-N-cyclohexylimine;Ethoxyacetylene;1-alkoxy-1-chloroethylene; Trialkyl phosphorous acid; Ethyl polyphosphate; Isopropyl polyphosphate;
Phosphorus oxychloride; Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2
-Ethyl-5-(m-sulfophenyl)isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; with dimethylformamide and thionyl chloride, phosgene, phosphorus oxychloride It is preferable to carry out the reaction in the presence of a so-called Vilsmeier reagent obtained by the reaction of The reaction can also be carried out using organic or inorganic bases such as alkali metal hydrogen carbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N
-It can also be carried out in the presence of di(lower)alkylbenzylamine or the like. Reaction temperature is not limited;
Usually, the process proceeds to cooling or room temperature. In this reaction, the syn isomer of compound (I) is preferably reacted with compound () at around neutrality in the presence of the above-mentioned Vilsmeier reagent, so that the corresponding compound (C) is Syn isomers can be produced. When R ¹ is a protected amino in compound (C), the amino protecting group can be removed by a conventional method. The invention will now be explained by way of illustrative examples. Example 1 (1) A suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (50 g) and potassium carbonate (65.8 g) in N,N-dimethylformamide (150 ml) was poured under ice cooling. Cyclopentyl bromide (47.4 g) is added dropwise over 2-3 minutes while stirring. After stirring for 2 hours and 40 minutes at room temperature, the reaction mixture is poured into a mixture of methylene chloride (300 ml) and water (600 ml). Separate the organic layer,
The aqueous layer is further extracted twice with methylene chloride (200 ml), and all the organic layers are combined. Washed with brine, dried over magnesium sulfate, and evaporated to give 2-cyclopentyloxyimino-3-
An oil of ethyl oxobutyrate (syn isomer) (68.7 g) is obtained. IR (liquid film): 1740, 1670, 1495, 1430 cm ^-1 NMR (CC1 ₄ , δ): 1.32 (3H, t, J==7
Hz), 1.4-2.2 (8H, m), 2.33 (3H, s),
4.27 (2H, q, J = 7Hz), 4.87 (1H, m) (2) Add ethyl 2-cyclopentyloxyimino-3-oxobutyrate (syn isomer) (89 g) to acetic acid (89 ml) under ice cooling. , sulfuryl chloride (26.5 ml) was added dropwise over 10 minutes. 30~35℃
After stirring for 6 hours and 50 minutes, ice-cooled water (30 ml) was added to the reaction mixture. The resulting mixture was poured into water (500 ml) and diluted with methylene chloride (300 ml x 1 time,
Extract with 100ml x 1). Add the extract to saline solution,
Wash sequentially with dilute aqueous sodium bicarbonate solution and brine, and dry over magnesium sulfate. The molten soot was distilled off to obtain ethyl 2-cyclopentyloxyimino-3-oxo-4-chlorobutyrate (syn isomer) (69 g) as an oil. IR (liquid film): 1750, 1735, 1465, 1435, cm ^-1 NMR (CCI ₄ , δ): 1.33 (3H, t, J = 7
Hz), 1.3−2.4 (8H, m) 4.28 (2H, q, J=
7Hz), 4.46 (2H, s), 4.86 (1H, m) (3) Ethyl 2-cyclopentyloxyimino-3-oxo-4-chlorobutyrate (syn isomer)
(69.0 g), thiourea (20.1 g), sodium acetate trihydrate (35.9 g), ethanol (172 ml) and water (172 ml) were stirred at room temperature for 1 hour and 10 minutes. Ethanol is distilled off under reduced pressure, and the precipitated crystals are collected by filtration. The filtered crystals were washed with water and diisopropyl ether, dried, and
Obtain -cyclopentyloxyimino-2-(2-aminothiazol-4-yl)ethyl acetate (syn isomer) (37.5g) mp.134-136℃ IR (Nujol): 3490, 3450, 3250, 3120,
1735, 1540, 1460 cm ^-1 NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J
=7Hz), 1.62 (8H, broads), 4.27 (2H,
q, J=7Hz), 4.70 (1H, m), 6.85 (1H,
s), 7.20(2H,s) (4) 2-cyclopentyloxyimino-2-(2
-aminothiazol-4-yl)ethyl acetate (syn isomer) (37.4 g), 2N aqueous sodium hydroxide solution (132 ml), methanol (132 ml) and tetrahydrofuran (100 ml) at 35°C.
Stir for 6.5 hours. The reaction mixture is neutralized with 10% hydrochloric acid, methanol is distilled off under reduced pressure, water is added, and insoluble materials are filtered off. The filtrate was adjusted to pH 3.0 with 5% hydrochloric acid under ice cooling, and stirred for 30 minutes. The generated precipitate is collected by filtration, the residue is washed with water, and dried.
2-cyclopentyloxyimino-2-(2-
Aminothiazol-4-yl)acetic acid (syn isomer) (29.0 g) is obtained. mp. 186℃ (decomposition) IR (nujiol): 3330, 3120, 1635, 1450cm
^-1 NMR (DMSO-d ₆ ): 1.1-2.2 (8H, m), 4.68
(1H, m), 6.81 (1H, s), 7.18 (2H, broad s) (5) 2-cyclopentyloximino(2-aminothiazol-4-yl)acetic acid (syn isomer)
(8.5 g) in dry ethyl acetate (85.0 ml),
Add bis(trimethylsilyl)acetamide (13.5g) at 10°C and stir for 20 minutes. Mixture -
After cooling to 10°C and adding 2,2,2-trifluoroacetic anhydride (22.0 g) dropwise over 20 minutes, -
Stir at 5-0°C for 2 hours. The reaction mixture was reduced to −10
Cool to °C and add water (50ml) and ethyl acetate (100ml). The formed crystals are collected by filtration and dried to give 2-cyclopentyloxyimino-
2-[2-(2,2,2,-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (1.12 g) is obtained. IR (Nujiyor): 3200, 3130, 1720, 1590,
1580cm ^-1 NMR (DMSO−d ₆ , δ): 1.34−2.22 (8H,
m), 4.81 (1H, m), 7.71 (1H, s) The filtrate was diluted with saturated sodium bicarbonate solution to pH 1.5.
After adjusting the organic layer, the separated organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off and the residue was dissolved in diisopropyl ether and n-
The same compound (9.35g) was crystallized from hexane.
further obtain. Reference Example 1 A Vilsmeier reagent was prepared from dry dimethylformamide (2.6 g), phosphorous oxychloride (5.4 g) and dry ethyl acetate (10.4 ml) by a conventional method, and dry ethyl acetate (100 ml) was added to it, and further ℃2
-cyclopentyloxyimino-2-[2-(2,
2,2,-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (10.4 g) was added. This mixture was stirred at the same temperature for 30 minutes. The resulting product mixture was mixed with 7-amino-3(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (9.6 g) and trimethylsilylacetamide (24.8 g of dry ethyl acetate). (192 ml) solution at -10°C with stirring,
The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the ethyl acetate layer was separated and extracted with an aqueous sodium hydrogen carbonate solution (PH7.5). The aqueous layer was washed with twice the amount of ethyl acetate, ethyl acetate and tetradrofuran were added, and the pH was adjusted to 2.0 with 10% hydrochloric acid. The oil layer was separated, washed with water, dried over magnesium sulfate, treated with activated carbon, and evaporated to dryness. The residue was triturated in diethyl ether, the powder was filtered and washed with diethyl ether to give 7-[2-cyclopentyloxyimino-2-{2-(2,2,2
-trifluoroacetamido)thiazole-4-
yl}acedoamide]-3-(1-allyl-1H-
Tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (18.18g)
I got it. NMR (DMSO−d ₆ , δ): 1.28−2.26 (8H,
m), 3.73 (2H, m), 4.39 (2H, ABq, J=
14Hz), 4.77 (1H, m), 4.88-5.47 (5H.m),
5.70−6.52 (2H, m), 7.50 (1H, s), 9.67
(1H, d, J=8.0Hz) Reference example 2 7-[2-cyclopentyloxyimino-2-
{2-(2,2,2-trifluoroacetamide)
thiazol-4-yl}acedeamide]-3-(1
-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer (18.0 g) and tetrahydrofuran (36 ml),
Sodium acetate trihydrate (35.6g) in water (360ml)
After adding to the solution and stirring at room temperature for 18 hours, tetrahydrofuran was distilled off from the reaction mixture. residual liquid
The pH was adjusted to 3.0 with 15% hydrochloric acid, and the resulting precipitate was washed with water and dried to obtain crude 7-[2-cyclopentyloxyimino-2(2-(2-aminothiazole-
4-yl)acetamido]-3-(1-allyl-
1H-tetrazol-5-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer)
(20g) was obtained. This crude product was purified by column chromatography using aluminum oxide (60 ml) to give a concentration of 3 to 5%.
Purification was performed using an aqueous sodium acetate solution as an eluent to obtain the pure target substance (8.31 g). mp.140~145℃
(Disassembly). IR (nujiyor): 3300, 1770, 1660, 1620cm
^-1 NMR (DMSO−d ₆ , δ): 1.16−2.26 (8H,
m), 3.73, (2H, m), 4.41 (2H, ABq, J
= 14Hz), 4.68 (1H, m) 4.89-5.52 (5H,
m), 5.62-6.43 (2H, m), 6.73 (1H, s),
9.51 (1H, d, J = 8Hz).

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ means amino or protected amino) Thiazole acetic acid derivative (syn isomer)
and reactive derivatives at the carboxyl group thereof, which can be used in the acylation reaction of the amino group of cephalosporin compounds, and salts thereof. 2 2-cyclopentyloxyimino-2-(2
-aminothiazol-4-yl)acetic acid (syn isomer). 3. The compound according to claim 1, wherein R ¹ is acylamino. 4. The compound according to claim 3, wherein R ¹ is lower alkanoylamino or halo(lower)alkanoylamino. 5 2-cyclopentyloxyimino-2-[2
-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer).