DK155218B - THIAZOLYLIC ACETIC ACID COMPOUNDS USED AS INTERMEDIATES IN THE PRODUCTION OF CEPHEM COMPOUNDS - Google Patents

Description

DK 155218 B

in

The present invention relates to novel thiazolyl acetic acid compounds for use as intermediates in the preparation of cephem compounds of the general formula

H0N S

Yji. "

I] di)

Qr N \ ^ \ CH2R4 COOH

Wherein A is either -CH- or -C-, where R is an amino -12 II 5 R NR 35 or hydroxyl group, and R is optionally an alkyl which may be 4 substituted, protected hydroxyl group and R is hydrogen , an acetoxy group, a group -SR wherein R is a 5- or 6-membered heterocyclic ring containing 1 ring-10 nitrogen atom and optionally 1-3 additional ring heteroatoms selected from oxygen, sulfur and nitrogen and which may be substituted by alkyl, alkoxy, halogen, haloalkyl, amino, 4 mercapto, hydroxyl, carbamoyl or carboxyl, or R is carbamoyloxy or a group which may be substituted by alkyl, halogen, a carbamoyl group, carboxyalkyl, hydroxyalkyl or haloalkyl, or pharmaceutically acceptable salts or esters thereof *

The thiazolylacetic acid compounds of the invention are characterized in that they have the general formula

R1 S

N - A * -COOH

20

V

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2 in which R is an optionally protected amino group and A 'is-2' denotes either -CH- or -C- wherein R represents an optionally l2. «5

R NR

protected amino or hydroxyl group, and R 1 is as defined above, or are salts, esters or reactive derivatives thereof.

After extensive research, we have succeeded in synthesizing the thiazolylacetic acid compounds of formula (I) which are useful intermediates in the preparation of an acylation reaction of the cephem compounds of formula (II) which have 10 strong antibiotic effects against a wide variety of microorganisms, including both gram-positive and gram-negative bacteria, especially by oral administration. The cephem compounds (II) can be used as therapeutic agents for various bacterial infections in animals and humans, as can be seen in the description of Danish Patent Application No. 5488/75.

Compounds of formula

R \ S

We N-1-CHCOOH (XI) nh 2 wherein R 1 has the same meaning as above, or a salt or ester thereof can be prepared by reducing a compound of formula

R1 S

YJ

N-1-CCOOH (IV) I 5

NR

5 1 'wherein R and R have the same meanings as above, or 3

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a salt or ester thereof, whereupon removing the protecting group if necessary.

Compounds of formula I can be prepared by reacting a compound of formula 5 XCH 2 - C - A '- COOH (XII) at 0 wherein X is a halogen and A' is as defined above, or a salt or a ester thereof with a compound of the formula

S

12 H

R - C-NH 2 (XIII) 12 wherein R is a lower alkoxy group or an amino group which may be protected, and if necessary, the protecting group is removed.

Compounds of formula

R1 S

Y) N - CH-COOH (XIX)

OH

Wherein R is as defined below, or a salt or ester thereof may be prepared by reacting a compound of the formula

S

14 II

R - C - NH 2 (XVII) wherein R is an amino group which may be protected with 20 trihaloacetone in the presence of a base to form a compound of formula 4

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R1? S

N-II-CHO (XVIII) 14 wherein R has the same meaning as above, the compound (XVIII) undergoes an addition reaction with hydrogen cyanide and hydrolyses the product thus obtained, whereupon removing the protecting group if necessary.

In compounds (I), R is an amino or hydroxyl group or a protected amino or hydroxyl group. The protected amino group means an amino group protected with such readily removable protecting groups for amino groups commonly used in the peptide chemistry, e.g. an alkylcarbonyl group such as formyl, acetyl and propionyl, an alkoxycarbonyl group such as t-butoxycarbonyl, an alkoxyalkylcarbonyl group such as methoxyacetyl and methoxypropionyl, a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl, a substituted alkylcarbonyl, a substituted alkylcarbonyl group -carbonyl, dichloroethyl arbonyl, trichloromethylcarbonyl, trichlorethylcarbonyl and trichloropropylcarbonyl, an aralkyl oxycarbonyl group such as benzyloxycarbonyl, a substituted aralkyloxycarbonyl group such as p-nitrobenzyloxycarbonyl, or an amino group protected. The protected hydroxyl group means a hydroxyl group protected with an easily removable protecting group for hydroxyl groups. Such easily removable protecting groups for 25 hydroxyl groups are e.g. an acyl group such as formyl, acetyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl, ethoxycarbonyl, β, β, β-trichloroethoxycarbonyl, β, β, β-tribromethoxy carbonyl and p nitrophenoxycarbonyl, a relatively removable protecting group under relatively mild conditions, such as tetrahydropyranyl, tetrahydrothiofuranol and methoxytetrahydropyranyl.

5

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The invention also includes, as mentioned, reactive derivatives of the compounds (I). As reactive derivatives of compounds (I), e.g. acid halide, acid anhydride, mixed acid anhydride, cyclic carboxy anhydride, active amide or ester thereof are used.

The thiazolylacetic acid compounds (I) can exist as D and L isomers with respect to the α-carbon atom, and any of these isomers as well as a mixture thereof can be successfully used in the preparation of cephalosporins or penicillins having an asymmetry center in the a-position. The D isomers generally have a stronger antibiotic effect than the L isomers.

The compounds (I) can e.g. are prepared by the methods described above and they. 'can be used in the state in which they are obtained by these methods, or after removal of the protecting groups. These approaches are explained in more detail below.

Reduction of compounds (IV).

The reduction conditions used in the present reaction can be selected from the known reduction methods insofar as the compounds (IV) can be reduced to the compounds (XI), and preferably are catalytic reduction using catalysts such as Raney nickel, platinum oxide, palladium. carbon, ruthenium carbon, rhodium carbon, copper chromium oxide, reducing agents using nascent hydrogen obtained by the coexistence of metals such as sodium, sodium amalgam, aluminum amalgam, and e.g. water or alcohols, reducing agents using metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium borohydride, reducing agents which treat metals such as zinc, iron, solvents such as acetic anhydride, formic acid or aqueous mixtures. The reaction conditions, such as reaction temperature, pressure, solution,

Λ r __ * ____: i ΊΊ _____ _ ___, ___ _ · ». * __ i · -> ___i___ O _____j _ _O

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e the nature of the starting materials, the reducing agents, etc.

After the reduction reaction, the reaction mixture may be subjected to removal of the protecting group directly or, if necessary, from the desired compound (XI).

If necessary, the compounds thus obtained are subject to removal of the protecting group and / or conversion of the convertible group. Removal of the amino group protecting group can e.g. is carried out by acid treatment for e.g. t-butoxycarbonyl in a treatment with zinc and an acid for e.g. β, β, β-trichloroethoxycarbonyl by reduction for e.g. p-nitrobenzyloxycarbonyl. For example, the protecting group for the hydroxyl group is removed. by means of potassium hydrogen carbonate in aqueous methanol for e.g. formyl or trifluoroacetyl, by treatment with dilute hydrochloric acid for e.g. tetrahydropyranyl, by treatment with zinc and acid for β, β, β-trichloroethoxycarbonyl. For example, the ester residue in carboxylic acids is removed. by acid treatment for e.g. benzhydryl, p-methoxybenzyl, by treatment for e.g. β-methylsulfonylethyl, by treatment with water for e.g. trimethylsilyl, dimethylsilenyl, by treatment with zinc and acid for e.g. β, β, β-trichloroethyl and by reduction for e.g. p-nitrobenzyl.

The carboxyl group of the starting compounds (IV) can be protected with a protecting group which can be removed under mild conditions which will not affect the thiazole ring, e.g. under acidic or alkaline conditions or reduction.

Therefore, the protecting groups may be selected from those of the carboxyl group commonly used in peptide synthesis. Examples are alkali metals such as sodium or potassium, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, substituted alkyl such as β-methylsulfonylethyl, trichlorethyl, diphenylmethyl, aryl such as phenyl, tolyl, substituted aryl such as p-tert-butylphenyl, p-nitrophenyl, aralkyl such as benzyl, phenethyl, tolubenzyl, substituted aralkyl such as p methoxybenzyl, p-nitrobenzyl. In this reaction, the starting compounds (IV) in which R ** is protected 7 appear

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hydroxyl, to give better results. The desired compounds (V) can be purified by purification methods known per se, such as solvent extraction, pH adjustment, crystallization, recrystallization, distillation, chromatography and ion exchange chromatography. The isolated compound (V) is a DL mixture and can be cleaved in the D-form and L-form by conversion to a suitable optically active, crystal-forming salt, e.g. with tartaric acid, mandelic acid, malic acid or camphor sulfonic acid.

Reaction of Compounds (XII) with (XIII).

In the starting compounds (XII), X means halogen such as chlorine, bromine, iodine or fluorine. When Y is hydrogen, Z means an amino group which may be protected where such group is exemplified above. Alternatively, Y and Z together represent a group of formula = NR, where such group is also illustrated above. The carboxyl group of the compounds (XII) may be similarly protected as mentioned above by the compounds (IV). In this reaction, it is desirable to react substantially equivalent moles of the starting compounds (XII) and (XIII). The reaction is generally carried out in a solvent and the solvent can be selected from organic solvents which do not interfere with the desired reaction. Suitable solvents are e.g. methanol, ethanol, propanol or tetrahydrofuran. The reaction is carried out smoothly at room temperature or under reflux conditions. The reaction is generally completed after one to several hours. The reaction is more easily performed by the addition of a base such as dimethylaniline or triethylamine. . After the reaction is completed, the removal or introduction of the protecting group can be carried out directly on the reaction mixture or, if desired, after isolation of the compound (XIV). The purification of the compounds (XIV) can be carried out by similar methods as mentioned above under a). When starting compounds (XIII) wherein R is a lower alkoxy group, the present reaction gives a compound (XIV) in which

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Reaction of the Compounds (XVII) and Trihalogen Acetone.

R 14 represents an amino group which may be protected as illustrated above and therefore examples of the compounds (XVII) are N- (trichloroethoxycarbonyl) thiourea, N- (t-butoxy-carbonyl) -thiourea and N- (benzyloxycarbonyl) - thiourea. As trihalogen acetone, e.g. 1,1,3-trichloroacetone or 1,1,3-tribromoacetone.

Advantageously, the reaction can be carried out in a solvent.

Any solvent capable of dissolving both starting materials may be used in so far as it does not interfere with the reaction; preferred examples are alcohols such as methanol, ethanol or propanol, ketones such as acetone or methyl ethyl ketone, ethers such as ether, tetrahydrofuran or dioxane, or mixtures thereof. This reaction takes place more smoothly in the presence of a base such as pyridine, picoline, quinoline, isoquinoline, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine, Ν, Ν-dimethylaniline or Ν, diet-diethylaniline. The reaction can proceed at room temperature and be accelerated by heating. Therefore, it is convenient to heat to about the boiling point of the solvent used. When appropriate conditions are selected in this reaction, in some cases an intermediate product, i.e. 4-brommethylthiazol.

The compounds thus obtained (XVIII) are subjected to addition with hydrogen cyanide to form so-called cyanhydrin compounds. To this end, cyanides, such as sodium cyanide or potassium cyanide, are generally reacted with the compounds (XVIII). The cyanhydrin compounds can be isolated as stable acyl derivatives by protection with a suitable protecting group, e.g. formyl or acetyl. An example of a suitable procedure is to react acetic anhydride with the cyanhydrin compounds in pyridine. The reaction to obtain the cyanhydrin compounds or their derivatives is preferably carried out in a solvent in the presence of a base. The solvent is desired to dissolve both the starting materials and the base, and is generally employed.

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des water or a mixture of water and an organic solvent miscible with water (e.g., methanol, ethanol, acetone, dimethylformamide). As a base, e.g. conveniently such a weak base as potassium dihydrogen phosphate, sodium hydrogen sulfite or triethylamine is used. The reaction is advantageously carried out during cooling or near room temperature to avoid unwanted side reactions. The reaction to obtain cyanhydrin compounds as α-acetoxy-acetonitrile derivatives is usually carried out by reaction with acetic anhydride with the first mentioned compounds in a solvent in the presence of a base.

In this reaction, any solvent which does not interfere with the reaction can be used, and in general, e.g. aprotic solvents such as chloroform, carbon tetrachloride, tetrahydrofuran, pyridine or dimethylformamide, or mixtures thereof. Any base can be used if it does not interfere with the reaction and preferred are organic tertiary bases such as pyridine, quinoline, isoquinoline, triethylamine or Ν, Ν-dimethylaniline. Among them, pyridine is most preferred because it also acts as a solvent. Acetic anhydride mentioned above is most preferred as an acylating agent, but other acylating agents including acetyl chloride may also be used. The reaction proceeds smoothly during cooling, but if desired it can be carried out at room temperature.

The cyanhydrin compounds thus obtained containing their acyl derivatives are subjected to hydrolysis to give the desired compounds (XIX). The hydrolysis is carried out in a solvent in the presence of an acid or base. As the solvent, methanol or ethanol is generally used. The reaction is advantageously carried out under cooling to near room temperature to avoid unwanted side reactions. In the reaction, inorganic acids such as hydrochloric acid or sulfuric acid are preferably used as acid and e.g. sodium hydroxide or potassium hydroxide as a base.

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10

Since the thus obtained α-hydroxyacetic acid derivatives (XIX) exist as a racemic mixture, it can be cleaved into optically active isomers, ie, D-form and L-form by processes known per se, e.g. by transferring them to 5 a suitable diastereomer.

The invention is further illustrated by the following examples.

Example 1.

A solution of 10.0 g of N- (β, β, β-trichloroethoxycarbonyl) -10 thiourea, 12.0 g of 1,1,3-tribromoacetone and 5.0 g of dimethylaniline in 100 ml of ethanol is heated under reflux for 2 hours. hours. After cooling, ethanol is removed under reduced pressure and the oily residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with water and dried over MgSO4.

The ethyl acetate is removed under reduced pressure and the oily residue is dissolved in a small amount of chloroform. From the solution, which is left to stand at room temperature, 2- (β, β, β-trichloroethoxycarbonyl) -amino-4-formylthiazole is obtained in crystalline form. 5.0 g. Melting point: 188-190 ° C.

Analysis for C

Calculated: C 27.69 H 1.66 N 9.23.

Found: C, 27.87; H, 1.69; N, 9.01.

NMR (ppm, 100 MHz, CDCl 3 -d 6 DMSO): 5.05 (2H, s, C

o Ό O Z

8.05 (1H, s, 5-H), 9.80 (1H, s, CHO).

Example 2.

To a mixture of 1.0 g of 2- (β, β, β-trichloroethoxycarbonyl) amino-4-formylthiazole, 0.87 g of KH 2 PO 4, 6 ml of water and 4 ml of dimethylformamide is added 0.33 g of KCN at room temperature and the mixture stir for 30 minutes. The reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with water and dried. Evaporation of the ethyl acetate gives α-hydroxy- [2- (β, β, β-trichloroethoxycarbonyl) -aminothiazole-11

DK 15521 8 B

NMR (ppm, 100 MHz, CDCl 3): 4.90 (2H, s, C 13 CCH 2 -), 5.70 (1H, s, -CHCN), 7.90 (1H, s, 5H).

Example 3

To a solution of 1.10 g of α-hydroxy- [2- (β, β, β-trichloro-5-ethoxycarbonyl) -aminothiazol-4-yl] -acetonitrile in 1 ml of pyridine is added 2.5 ml of acetic anhydride under ice-cooling. and the mixture is stirred for 1 hour. To the mixture is added ether and water, and the organic layer is washed with aqueous NaHCO 3 and with water in this order. Evaporation of the ether gives α-ethoxy- [2- (β, β, β-trichloroethoxycarbonyl) -amino-thiazol-4-yl] -acetonitrile. 1.3 g.

NMR (ppm, 100 MHz, CDCl 3): 2.20 (3H, S, COCH 3), 5.00 (2H, s, C 13 CCCH 2 -), 6.60 (1H, s,> CHCN), 7.30 (1H , s, 5-H).

Example 4.

In a solution of 1.30 g of α-acetoxy- [2- (β, β, β-trichloroethoxycarbonyl) -aminothiazol-4-yl] -acetonitrile in 10 ml of methanol, gaseous hydrogen chloride is bubbled for 10 minutes under ice-cooling. and the mixture is left at room temperature for 1 hour. After evaporation of the methanol, 40 ml of 50% aqueous methanol is added to the residue and stirred for 1 hour. To this reaction mixture is added 1.0 g of NaOH and stirred for 1 hour. The methanol is removed under reduced pressure and the residue is extracted with ethyl acetate after being acidified with 1 N HCl. The ethyl acetate layer is washed with water and dried. The ethyl acetate is removed under reduced pressure to give α-hydroxy- [2- (β, β, β-trichloroethoxycarbonyl) amino] thiazol-4-yl acetic acid. 0.996 g.

Mp. 135-136 ° C.

Analysis for CoH-O-N-SCl

o / D 2 J

Calculated: C 27.48 H 2.02 N 8.01.

Found: C 27.72 H 2.05 N 8.08.

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Example 5

To a solution of 21/43 g of ethyl α-ethoxyimino-β-οχο-γ-bromobutyrate in 80 ml of ethanol is added 8.81 g of methylthionocarbamate and the mixture is heated under reflux for 1.5 hours. After cooling, the ethanol is removed under reduced pressure and the oily residue is dissolved in chloroform. The chloroform solution is washed, dried and evaporated. The residue is purified by silica gel chromatography to give 11.9 g of ethyl α-ethoxyimino (2-hydroxythiazol-4-yl) acetate.

M.p. 54-55 ° C.

Analysis for C9H2O4N2S:

Calculated: C 44.25 H 4.95 N 11.47 Found: C 44.54 H 5.04 N 11.53.

NMR (ppm, 100 MHz, CDCl 3): 6.33 (1H, s, 5-H).

Example 6.

To a solution of 10 g of ethyl α-ethoxyimino (2-hydroxythiazol-4-yl) acetate in 30 ml of ethanol is added a solution of 11.47 g of Η0Η in 50 ml of water at room temperature and the mixture is stirred for 25 minutes. minutes. The reaction mixture is concentrated under reduced pressure and acidified with 10% aqueous HCl. The ethyl acetate extract of the reaction mixture is extracted with 10% 1 sec aqueous NaHCO 3. The aqueous layer is then acidified with 10% aqueous HCl and extracted with ethyl acetate. The ethyl acetate extract is washed, dried and evaporated to give a crystalline substance. Recrystallization of benzene ethanol gives α-ethoxyimino- (2-hydroxythiazol-4-yl) -acetic acid. 7.5 g. 131.5 ° C (dec).

Analysis for C

Calculated: C 38.88 H 3.72 N 12.95 Found: C 38.65 H 3.85 N 13.06.

NMR (ppm, 100 MHz, d -DMSO): 6.64 (1H, s, 5-H).

, 13

DK 155218B

Example 7

To a mixture of 1 g of α-ethoxyimino- (2-hydroxythiazol-4-yl) -acetic acid, 10 ml of 50% aqueous formic acid and 5 ml of methanol is gradually added 0.9 g of zinc dust under ice-cooling. The mixture is stirred for 1 hour at this state and then for 30 minutes at room temperature. The reaction mixture is filtered and the filtrate is passed through a column packed with ion exchange resin [Amberlite IR-120 (H)] and purified 2-hydroxy-thiazol-4-yl-glycine.

Analysis for C C-H₂O ^K₂S:

Calculated: N 16.08 Found: N 15.96.

NMR (ppm, 100 MHz, CF 3 OD): 5.56 (1H, s, 1 CH-C COH), 6.91 (1H, s, 5-H).

Example 8.

In a mixture of 40 ml of C. HCl and 100 ml of water, 8.8 g of ethyl a-oxyimino (2-aminothiazol-2-yl) acetate are dissolved under ice-cooling. A solution of 2.8 g NaNO 2 in 20 ml of water is added dropwise to this solution over a period of 20 minutes-20 hours. After stirring for 2.5 hours under ice-cooling, the reaction mixture is extracted with 200 ml of ethyl acetate. The extract is washed with water and dried, the ethyl acetate is distilled off, the resulting oil is purified by silica gel chromatography to give ethyl α-oxyimino (2-hydroxythiazol-4-yl) acetate.

NMR (ppm, 100 MHz, CDCl 3): 1.37 (3H, t, CH 2 CH 3), 4.36 (2H, q, CH 2 CH 3), 8.02 (1H, s, 5-H).

Example 9

To a solution of 1.3 g of ethyl α-oxyimino (2-hydroxythiazol-30-yl) acetate in 5 ml of ethanol is added under ice-cooling to 30 ml of 50% aqueous formic acid. Zinc dust (1.17 g) is gradually added to it.

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14

The reaction mixture is stirred for 2 hours under ice-cooling and filtered. The filtrate is evaporated under reduced pressure and the residue is poured into 10 ml of water. The water layer is neutralized with 10% aqueous NaHCO 3 and then extracted with ethyl acetate.

5 The extract is washed with water and dried. The ethyl acetate is distilled off, the resulting oil is purified by silica gel chromatography to give ethyl 2-hydroxythiazol-2-yl glycine.

NMR (ppm, 100 MHz, CDCl 3): 1.22 (3H, t, -CH 2 CH 3), 4.27 (2H, q, -CH 2 CH 3), 4.65 (1H, s, 1 CH-COOC 3), 77.14 (1H, s, 10 5-H).

The ester is acylated with β, β, β-trichloroethyl chloroformate in CH 2 Cl 2 in the presence of triethylamine to give ethyl α- (β, β, β-trichloroethoxy-carbonylamino) - (2-hydroxythiazol-4-yl) - acetate.

Analysis for c10H10O5N2SC13:

Calculated: N 7.41 Found: N 7.39.

NMR (ppm, 100 MHz, CDCl3: 1.26 (3H, t, -CH2CH3)) 4.22 (2H, q, -CH2CH3), 4.70 (2H, s, Cl3CCH2), 5.42 ~ T1H , d, 20 -CH-C00 C2 H + T, 7.24 (1H, s, 5-H).

Example 10.

To a solution of 1.93 g of ethyl α-oxyimino-3-oxo-γ-chloro-butyrate in 10 ml of ethanol is added 1.27 g of ethyl thionocarbamate and the mixture is heated at reflux for 2 hours. After cooling, the ethanol is evaporated, the residual oily substance is purified by silica gel chromatography to give ethyl α-oxoimino (2-hydroxythiazol-4-yl) acetate.

The ester is identical to the substance obtained in Example 8 in all respects.

Example 11.

To a solution of 2.65 g of ethyl-α-acetamido-3-oxo-Y-bromo-15

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butyrate in 10 ml of ethanol is added 1.09 g of methylthionocarbamate. The mixture is heated at reflux for 1.5 hours and concentrated under reduced pressure. The concentrate is dissolved in chloroform. The chloroform layer is washed, dried and concentrated to give ethyl α-acetamido (2-hydroxythiazol-4-yl) acetate as an oily material. This ester (2.0 g) is dissolved in 10 ml of methanol and a solution of 3.09 g of Ba (OH) 2 * 8 ^ 0 is added in 50 ml of water and the whole mixture is stirred at 70 ° C for 3 hours. After cooling, gaseous CO 2 is bubbled into the reaction mixture to precipitate BaCO 2. The thus-precipitated BaCO 2 is filtered off, the filtrate is passed through a column packed with ion exchange resin [Amberlitew IR-120 (H)] and purified 2-hydroxythiazol-4-yl glycine is obtained.

This substance is identical to the substance obtained in Example 2.5 in all respects.

Example 12.

To a solution of 2.2 g of ethyl α-methoxyimino-3-oxo “Y” bromo-butyrate in 40 ml of ethanol is added 1.22 g of dimethylaniline and 2.2 g of N- (β, β, β-trichloroethoxycarbonyl) - thiourea. The mixture is heated at reflux for 1.5 hours and concentrated under reduced pressure. The concentrate of the reaction mixture is recrystallized from ligroin to give ethyl α-methoxoxyimino- [2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl] acetate as crystals. 1.84 g. 125-128 ° C.

Analysis for cnHi2 ° 5N3SC13:

Calculated: C 32.65 H 2.99 N 10.38.

Found: C, 32.81; H, 3.14; N, 10.19.

NMR (ppm, 100 MHz, CDCl 3): 7.15 (1H, s, 5-H).

Example 13

To a solution of 8.1 g of ethyl α-methoxyimino- [2- (3,3,3-trichloroethoxycarbonylamino) -thiazol-4-yl] acetate in 50 ml of ethanol is added a solution of 11.2 g of Η0Η. a mixture

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16 at room temperature for 1 hour and then concentrated under reduced pressure. The residue is extracted with ethyl acetate.

The water layer is acidified with 10% aqueous HCl and the separated solid is isolated. Recrystallization of the aqueous methanol solid gives α-methoxyimino- [2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl] -acetic acid. 4.1 g. 162-163 ° C.

Analysis for C

Calculated: C, 28.70; H, 2.14; N, 11.16.

10 Found; C, 28.64; H, 2.11; N, 11.06.

NMR (ppm, 100 MHz, CDCl3 + dg-DMSO): 7.26 (1H, s, 5-H).

Example 14.

Ethyl 1-oc-methoxyimino- [2- ((3, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl] acetate (2.02 g) dissolved in 150 ml of ethanol containing 10% HCl is hydrogenated in the presence of 2.0 g of 5% Pd / carbon. After 240 ml of hydrogen is taken up, the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is washed with ether and suspended in 70 ml of ethyl acetate, to which 20 ml of 5% is added. s aqueous NaHCO 3.

The ethyl acetate layer is separated, washed, dried and evaporated to give [2- (B, β, .B-trichloroethoxycarbonylamino) -thiazol-4-yl] -glycine ethyl ester. 1.22 g.

Analysis for 0 0 12 12 4 4 ^ 3:

Calculated: C, 31.89; H, 3.21; N, 11.16.

Found: C, 31.91; H, 3.00; N, 10.63.

NMR (ppm, 100 MHz, CF 3 COOD): 5.82 (1H, s, X 1

Example 15

1) A solution of 19.3 g of ethyl α-oxyimino-B-oxo-γ-chloro-butyrate and 8.0 g of thiourea in 200 ml of ethanol is heated at reflux for 2 hours. The mixture is evaporated below

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17

The solution is washed twice with ether to remove unreacted butyrate and adjusted to pH 7.0-7 / 5 with NaHCO 3. Chloro-form extraction of the mixture gives ethyl α-oxyimino-2-amino-thiazol-4-yl acetate. 6/4 g. 137-138 ° C (dec.).

Analysis for C

Calculated: C, 39.06; H, 4.21; N, 19.52.

Found: C 39.64 H 4.09 N 19.62.

IR (nujol, cm 2): 3430 (C = NOH), 1710 (ester).

2) Ethyl α-oxyimino-2-aminothiazol-4-yl acetate (2.15 g) obtained as above is dissolved in a mixture of 20 ml of 50% aqueous formic acid and 10 ml of methanol. 1.5 g of zinc dust is added and the mixture is stirred for 3 hours under ice-cooling. The filtered reaction mixture is evaporated under reduced pressure and the concentrate is passed through a column packed with ion exchange resin [Amberlite IR-120 (H)]. The column is washed with water to remove formic acid and then eluted with 10% ammonia water to give 2-aminothiazol-4-yl glycine.

1.49 g. Recrystallization from aqueous ethanol gives pure substance m.p. 186-190 ° C (dec.).

Analysis for C ^H ^O 0N NS.1 / 2H₂O:

Calculated: C 32.96 H 4.43 N 23.06.

Found: C, 32.94; H, 4.61; N, 22.22.

NMR (ppm, 100 MHz, CF3 COD): 5.25 (1H, s, 1 CH-C00H), 6.75 (1H, s, 5-H). Violet color with ninhydrin reagent.

Example 16.

A solution of 19.3 g of thiourea and 53.5 g of ethyl α-oxy-imino-O-oxo-Y-chlorobutyrate in 300 ml of ethanol is stirred for 3 hours at room temperature and evaporated under reduced pressure.

Water (200 ml) is added to the residue and the aqueous solution obtained is washed twice with ether. 130 ml of 85% aqueous formic acid and 150 ml of ethanol are added. During ice-cooling casf f fie ffratri c 77 rr 71 nVcfrtw Ή i * 1 H orvn o hl nrr. r \ rr Aoir run - DK 155218 3

ICE

The filtered reaction mixture is passed through a column packed with ion exchange resin [Amberlite IR-120 (H)]. The column is washed with water and eluted with 10% ammonia water to give purified 2-aminothiazol-4-yl-glycine (27.5 g), which is identical to the substance obtained in Example 15, in all respects.

Example 17

Ethyl α-oxyimino-2-aminothiazole-4-yl acetate hydrochloride (503 mg) is dissolved in 10 ml of 50% aqueous formic acid and 5 ml of 10 ethanol. Zinc dust (300 mg) is added to this solution under ice-cooling and stirred for 3 hours. The reaction mixture is concentrated under reduced pressure below 30 ° C and the residue is adjusted to pH 7.5 by the addition of 1 N NaOH. Ethyl acetate extraction affords 2-aminothiazol-4-ylglycine ethyl ester. 130 mg.

NMR (ppm, 60 MHz, CF 3 OOD): 1.04 (3H, t, -CH 2 CH 3), 4.18 (2H, q, -CH 2 CH 3), 5.35 (1H, s, , 6790 (1H, S, 5-H). ~

Mass: m / e 201.0549 (theory: 201.0571).

Example 18.

To a solution of 26.6 g of ethyl α-acetamido-p-oxo-γ-bromo-butyrate in a mixture of 50 ml of ethanol and 20 ml of ether is added 9.14 g of thiourea and 15 ml of pyridine. The mixture is stirred for 1 hour at room temperature and then for 4 hours under reflux. The reaction mixture is evaporated under reduced pressure and 50 ml of ethyl acetate is added to the residue.

The mixture is extracted with 3 N HCl. The aqueous layer thus separated is adjusted to pH 10 by the addition of 1 N NaOH and extracted with ethyl acetate.

The ethyl acetate extract is washed, dried and concentrated. To the concentrate is added a small amount of chloroform to effect the crystallization of ethyl-α-acetamido-2-aminothiazole-19.

DK 15 5 218 B

4-yl acetate. 7.0 g. 161.1 ° C.

Analysis for C

Calculated: C 44.43 H 5.39 N 17.27.

Found: C, 44.46; H, 5.24; N, 16.99.

Example 19.

To a solution of 34.6 g of ethyl a-acetamido-p-oxo-Y-bromo-butyrate in a mixture of 50 ml of ethanol and 20 ml of ether is added 18.9 g of N-acetylthiourea and 15 ml of pyridine. The mixture is heated under reflux for 4 hours and concentrated under reduced pressure. The concentrate is extracted with ethyl acetate and the extract is washed with 5% aqueous NaHCO 3, then with water and dried. The oily substance obtained from the extract by removal of the solvent is purified by silica gel chromatography to give ethyl α-acetamido-2-15 acetamidothiazol-4-yl acetate. 4.46 g. M.p. 148.9 to 150 ° C.

Analysis for C ^H ^ jO-N NS. 1/4 ^ 0:

Calculated: C 45.59 H 5.39 N 14.50.

Found: C, 45.73; H, 5.40; N, 14.21.

Example 20

To a solution of 2.51 g of N- (β, β, β-trichloroethoxycarbonyl) thiourea and 2.66 g of ethyl-α-acetamido-β-οχο-γ-bromobutyrate in 50 ml of ethanol is added 1.8 g N, N-dimethylaniline. The mixture is stirred for 24 hours at room temperature and evaporated under reduced pressure. The residue is dissolved in 30 ml of chloroform and the solution is washed with 3N HCl, water and dried. The solid obtained by removal of the chloroform is purified by silica gel chromatography to give ethyl α-acetamido-2- (β, β, β-trichloroethoxycarbonylamino) thiazol-4-yl acetate. 1.43 g. 161.9 ° C.

20

DK 155218 B

Analysis for .1 / 21 ^0:

Calculated: C, 33.70; H, 3.54; N, 9.82.

Found: C 33.69 H 3.64 N 10.06.

NMR (ppm, 100 MHz, D 6 -DMSO): 1.15 (3H, t, -CH 2 CH 3), 4.09 (2H, g, -CH 2 CH 3), 1.88 (3H, s, COCH 3), 4, 96 (2h7, s, Cl3CCH2), 5.42 (1H, d7> CHCOOC2H5), 7.13 (1H, s, 5-H).

Example 21.

To a suspension of 100 mg of ethyl α-acetamido-2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl acetate in 5 ml of water 10 is added 2 ml of 1 N NaOH and the mixture is stirred for 2 hours at room temperature. The reaction mixture is washed with ethyl acetate, the water layer is adjusted to pH 2.0 with 1 N HCl and then extracted with ethyl acetate. The extract is washed, dried and evaporated to give N-acetyl-2- (β, β, β-trichloroethoxycarbonylamino) -15 thiazol-4-yl glycine. 65 mg. Mp. 158.0 ° C.

Analysis for C ^ qH ^ qO0N3SC13.1 / 2H₂O:

Calculated: C 30.05 H 2.77 N 10.51.

Found: C, 30.15; H, 2.52; N, 10.23.

NMR (ppm, 100 MHz, D 6 -DMSO): 1.89 (3H, s, C0CH2>, 4.97 (2H, s, C13CCH2)), 5.40 (1H, d,> CHC00H), 7.10 (1H, s, 5-H).

Example 22.

To a solution of 238 mg of ethyl α-oximino-β-oxo-γ-bromo-butyrate in 10 ml of ethanol is added 251 mg of N- (β, β, β-trichloroethoxycarbonyl) thiourea and the mixture is heated to reflux. for 6 hours. After cooling, 50 ml of chloroform is added, the organic solution is washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent and subsequent chromatographic purification on silica gel gives 164 mg of ethyl α-oximino-α- [2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl] acetate.

21

DK 155218 B

Analysis for C ^H ^N NO₂-SCl ^:

Calculated: C 30.74 H 2.58 N 10.75 Cl 27.23.

Found: C 30.95 H 2.51 N 10.75 Cl 27.02.

NMR (ppm, 100 MHz, CDCl3): 1.35 (3H, t, CH3CH2), 4.36 δ (2H, q, CH3CH2), 4.87 (2H, s, Cl3CCH2), 7794 (1H, s, thiazole ring proton).

Example 23

A solution of 2.0 g of ethyl α-oximino-α- [2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl] acetate in 50 ml of 10% HCl-ethanol is hydrogenated over 0.5 g of 5% palladium-on-charcoal while shaking. The reaction stops when 90 ml of hydrogen is taken up. An additional 1.5 g of the catalyst is added and 170 ml of hydrogen is taken up. Insoluble material is filtered off and the filtrate is concentrated under reduced pressure.

The residue is washed with ether and separated. The separated solid is dissolved in 5 ml of water, neutralized with 10% aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated.

The resulting residue is purified by chromatography on a silica gel column to give 560 mg of 2- (β, β, β-trichloroethoxy-carbonylamino) -thiazol-4-ylglycine ethyl ester.

Analysis for ^ (^ 12 ^ 3 ^ 4 ^^ 3:

Calculated: C, 31.89; H, 3.21; N, 11.16.

Found: C, 31.91; H, 3.00; N, 10.63.

NMR (ppm, 100 MHz, CF 3 CO 2 D): 1.37 (3H, t, CH 3 CH 2), 4.47 (2H, q, CH 2 CH 3), 4.98 (2H, s, C 13 CCH 2), 5.82 ° (1H, s, CH), 7.74 (1H, s, triazole ring proton).

Example 24.

To a solution of 3.40 g of 2- (β, β, β-trichloroethoxycarbonyl-22)

DK 1 552 18 B

amino) -thiazol-4-ylglycine ethyl ester in 50 ml of chloroform is gradually added 1.2 g of triethylamine and 2.50 g of β, β, β-trichloroethoxycarbonyl chloride with stirring at room temperature.

After 30 minutes of stirring, 100 ml of chloroform is added to the mixture, the obtained organic solution is washed with saturated aqueous NaCl solution, 1N hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, n-hexane is added to the residue and a crude product is obtained. The crude product is recrystallized from a mixture of ligroin and n-hexane to give 4.11 g of 2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl-N- (β, β, β-trichloroethoxycarbonyl) ) glycine ethyl ester. Yield 82%.

Analysis for C ^ HH ^ 3N₂O gsc: Calc'd: C, 28.28; H, 2.37; N, 7.61.

Found: C, 28.39; H, 2.38; N, 7.71.

NMR (ppm, 100 MHz, CDCl3): 1.21 (3H, t, CH3CH2), 4.60 (2H, q, CH3CH2), 4.83 and 4.86 (4H, two s, "cI3CCH2), 5.60 (1H, d, CH) T 6.98 (1H, s, thiazole ring proton), 7.38 (1H, 20 d, ct-NH).

Example 25

To a solution of 3.82 g of 2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl-N- (β, β, β-trichloroethoxycarbonyl) -glycine ethyl ester in 150 ml of ethanol is added a solution of 1 , 94 g of potassium hydroxide in 10 ml of water while stirring at room temperature. After stirring for 30 minutes, the solution is concentrated under reduced pressure and 50 ml of water is added to the residue. The aqueous solution is washed with ethyl acetate, adjusted to pH 2.0 with 1 N hydrochloric acid and extracted with two times 70 ml of ethyl acetate. The combined extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. n-Hexane is added to the residue and raw material is excreted. The crude material is recrystallized from a mixture of ethyl acetate οσ licroin # ocr to give 23

DK 155213 B

1.83 g of 2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl-N- (β, β, β-trichloroethoxycarbonyl) glycine. Yield 50%.

NMR (ppm, 100 MHz, CDCl 3): 4.80 (4H, s, Cl 3 Cl 2), 4.65 (1H, s, 2-NH), 5.48 (1H, broad d, CH), 6.14 ( 1H, broad d, 5 α-NH), 6.95 (1H, s, triazole ring proton).

Example 26

To a suspension of 3.46 g of 2-aminothiazol-4-yl glycine in 100 ml of Ν, Ν-dimethylacetamide is added dropwise 12.66 g of β, β, β-trichloroethoxycarbonyl chloride with stirring for 30 minutes at room temperature. After a further 30 minutes of stirring, 250 ml of ethyl acetate is added to the reaction mixture and the resulting solution is washed with 70 ml of 1 N hydrochloric acid.

The ethyl acetate is separated and extracted 3 times with 50 ml of 3% aqueous potassium hydroxide solution. The combined aqueous extracts are washed with ethyl acetate, adjusted to pH 2.0 with 1 N hydrochloric acid and extracted with 3x 100 ml of ethyl acetate. The combined extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. N-Hexane is added to the oily residue, and a crude material is precipitated. The crude material is separated and recrystallized from ethyl acetate and ligroin to give 510 mg of 2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-yl-N- (β, β, β-trichloroethoxycarbonyl) glycine. This product is identical to the compound obtained in Example 25 25 in all respects.

Example 27

To a solution of 18.7 g of ethyl-α-ethoxyimino-β-ο-butyrate in 100 ml of chloroform is added dropwise a solution of 15.9 g of bromine in 20 ml of chloroform under ice-cooling. The solution is stirred for 30 minutes at the same temperature and further for 1.5 hours at room temperature. The reaction mixture is washed with water, aqueous sodium bicarbonate solution and then with water in this order, whereupon the

DK 155218 B

dried over anhydrous magnesium sulfate. The solvent is evaporated from the dried solution and 250 ml of ethanol and 15.2 g of thiourea are added to the residue. The mixture thus obtained is refluxed for 2 hours and cooled, whereupon the solvent is distilled off under reduced pressure. To the residue is added 250 ml of water and a solid which is filtered off, washed with water and dried. 17.9 g of ethyl α-ethoxyimino-2-aminothiazol-4-yl acetate hydrobromide are obtained. Yield: 55%.

Analysis for C CH H ^^N NO₂SBr:

Calculated: C, 33.34; H, 4.35; N, 12.96.

Found: C, 32.52; H, 3.98; N, 12.92.

NMR (ppm, 100 MHz, dg-DMSO): 1.30 and 1.32 (6H, two t, CH 3 CH 2), 4.28 and 4.37 (4H, two q, CH 3 CH 2), 7.63 (1H, S, thiazole ring proton), 9.12 (2H, broad S, NH 2).

Example 28.

To a solution of 2.43 g of ethyl α-ethoxyimino-2-amino-thiazol-4-yl-acetate hydrobromide in 25 ml of anhydrous N, N-dimethylacetamide is added 1.43 g of chloroacetyl chloride under cooling and stirring. The solution is stirred for 30 minutes under ice-cooling and then for 30 minutes at room temperature. To the reaction mixture is added 150 ml of ethyl acetate and the mixture is washed repeatedly with saturated aqueous NaCl solution. The ethyl acetate layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. Water is added to the residue and a solid is precipitated.

The solid material is filtered off and dried. 1.90 g of ethyl α-ethoxyimino-2- (chloroacetamino) -thiazol-4-yl acetate are obtained.

Yield 79%.

NMR (ppm, 100 MHz, d 6 -DMSO): 1.24 and 1.27 (6H, two t, CH 3 CH 2), 4.22 (4H, two q, CH 3 CH 2), 4.30 (2H, S, C1CH2 CO), 7.99 (ΪΗ, S, thiazole ring proton).

25

DK 155218 B

Example 29.

1.06 g of ethyl α-ethoxyimino-2- (chloroacetylamino) thiazol-4-yl acetate are suspended in a solution of 0.94 g of potassium hydroxide in a mixture of 40 ml of ethanol and 2 ml of water and the suspension is stirred at room temperature so that a solution is formed and then stirred further for 45 minutes at room temperature. From the reaction solution, the ethanol is distilled off under reduced pressure, the residue is adjusted to pH 2.0 with 1 N hydrochloric acid under ice-cooling and 10 crystals are precipitated. The crystals are filtered off, washed with water and dried. 0.88 g of α-ethoxyimino-2- (chloroacetylamino) -thiazol-4-yl-acetic acid is obtained. Yield: 91%.

Analysis for CgHH ^ ^O₂SCl:

Calculated: C, 37.05; H, 3.45; N, 14.41.

Found: C, 37.17; H, 3.44; N, 14.09.

NMR (ppm 100 MHz, d 6 -DMSO): 1.28 (3H, t, CH 3 CH 2), 4.22 (2H, q, CH 3 CH 2), 4.32 (2H, S, CICH₂O), 8.00 ( IH, S, thiazole ring proton).

Example 30.

(1) To a solution of 5.03 g of N- (3,3,3-trichloroethoxycarbonyl) -thiourea and 5.32 g of ethyl-α-ethoxyimino-3-ω-γ-bromobutyrate in 50 ml of ethanol is added. 3.03 N, N-dimethylaniline and the mixture is heated for 2 hours in an 80 ° C water bath. The ethanol is distilled off from the reaction solution and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and then with water and dried, and the solvent is distilled off to give 7.85 g of ethyl α- (2-3,3,3-trichloroethoxycarbonylaminothiazol-4-yl) -a-ethoxy-iminoacetate as an oil. .

(2) To a solution of 2.00 g of ethyl α- (2-3,3,3-trichloroethoxycarbonylaminothiazol-4-yl) -α-ethoxyiminoacetate in 40 ml of methanol is added 20 ml of 1 N sodium hydroxide. The solution 26

DK 155218 B

Stir for 2 hours at 50 ° C and concentrate. To the concentrate is added 50 ml of water and the solution thus obtained is washed twice with ethyl acetate. The aqueous layer is adjusted to pH 2.0 with 3 N hydrochloric acid and a white solid is separated. The white solid is filtered off, washed with water and dried to give 1.40 g of α-ethoxyimino-2- (β, β, β-trichloroethoxycarbonylamino) -thiazol-4-ylacetic acid. Yield: 74.9%.

Analysis for 0, ΛΗη ._. Ν_0_801_: LO lvJ or o 10 Calculated: C 30.75 H 2.58 N 10.76.

Found: C 30.87 H 2.41 N 10.66.

NMR (ppm, 60 MHz, D 6 -DMSO): 1.13 (3H, t, CR 1 CR 2), 4.06 (2H, q, CH 3 CH 2), 4.90 (2H, S, Cl 3 CCH 2 O), 7.40 (1H, ~ S, thiazole ring proton).

Example 31.

To a solution of 27.3 g of ethyl α-methoxyimino-β-ω-butyrate in 120 ml of chloroform is added dropwise a solution of 25.3 g of bromine in 30 ml of chloroform over a period of 30 minutes. The solution is stirred for 1 hour at room temperature, washed with dilute aqueous sodium hydrogen carbonate solution and water and dried. From the dried solution, the solvent is distilled off and an oily crude product of ethyl α-methoxyimino-O-oxo-Y-bromobutyrate is obtained. The crude product is dissolved in 250 ml of ethanol and 24 g of thiourea is added and refluxed for 3 hours. After cooling, the precipitate is filtered off, washed with ethanol and then suspended in 300 ml of a mixture of ethyl acetate and tetrahydrofuran (1: 1). To the suspension is added 200 ml of 10% aqueous sodium bicarbonate solution and the mixture is shaken well. The organic layer is dried and the solvent is distilled off to give crystals which are washed with ether. 16.86 g of ethyl α-methoxyimino-α- (2-aminothiazol-4-yl) acetate are obtained. Mp. 112-113 ° C.

Analysis for CgHH₂ NN30O3S:

Dovnrmal ·. f Λ1 Q1 TI A ΆΔ 27

DK 155218 B

NMR (ppm, 60 MHz, CDCl 3): 4.04 (3H, S, OCH 3), 7.44 (1H, S, thiazole ring proton).

Example 32.

To a solution of 10 g of ethyl α-methoxyimino-α- (2-amino-5-thiazolo-4-yl) acetate in 100 ml of dimethyl acetamide is added dropwise 5.91 g of chloroacetyl chloride under ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture is poured into ice-water and the resulting solution is extracted with ethyl acetate. The organic layer is washed and dried to distill off on the solvent to give 12.66 g of ethyl α-methoxyimino-α- [2- (chloroacetamido) -thiazol-4-yl] acetate as crystals. Snip. 81-82 ° C.

Analysis for C 10 H 12 N 3 O 3 SCl:

Calculated: C, 39.29; H, 3.96.

Found: C, 38.74; H, 3.58.

NMR (ppm, 60 MHz, CDCl 3): 4.10 (3H, S, OCH 3), 4.24 (2H, S, C 1 CH 2 CO-), 7.94 (1H, S, thiazole ring proton).

Example 33

Ethyl α-methoxyimino-α- [2- (chloroacetamido) -thiazol-20-yl] acetate is added to a solution of 11.74 g of potassium hydroxide in a mixture of 25 ml of water and 500 ml. ethanol.

After stirring for 20 minutes at room temperature, the ethanol is distilled off under reduced pressure. The residue is added to water and the resulting solution is acidified by the addition of N hydrochloric acid, and the insoluble material is filtered off. 10.54 g of α-methoxyimino-α- [2- (chloroacetamido) -thiazol-4-yl] -acetic acid are obtained. Mp. 182-183 ° C.

Analysis for CgHgNgO3 SC1:

Calculated: C 34.60 H 2.90 N 15.13.

Found: C 34.53 H 3.00 N 14.80.

28

DK 155218 B

NMR (ppm, 60 MHz, d -DMSO): 4.00 (3H, S, OCH-), 4.38 b 6 (2H, S, C1CH2 CO), 8.00 (1H, S, thiazole ring proton).

Example 34.

A solution of 10.45 g of α-ethoxyimino-α- [2- (trichloroethoxy-carbonylamino) -thiazol-4-yl] -acetic acid ethyl ester in a mixture of 10% 1s hydrochloric acid and ethanol is catalytically hydrogenated over 8.0 g 5% palladium-on-charcoal at room temperature under atmospheric pressure. After uptake of two equivalents of hydrogen, the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. 7.43 g of α-amino-α- [2- (trichloroethoxycarbonylamino) -thiazol-4-yl] -acetic acid ethyl ester hydrochloride are obtained (yield: 72%). This product is suspended in ethyl acetate, the suspension is washed with saturated aqueous sodium hydrogen solution and with water and dried over anhydrous magnesium sulfate. The oily product obtained by distilling off the solvent is dissolved in 60 ml of Ν, Ν-dimethylformamide, and to the solution is added 4.2 g of tetramethylguanidine and then 3.94 g of t-butyloxycarbonyl azide and stirred for 15 hours at room temperature. .

The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid, then with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The oily product obtained by distilling off the solvent is purified by column chromatography on silica gel. There are obtained 4.06 g of α-t-butyl oxycarbonylamino-α- [2- (trichloroethoxycarbonylamino) -thiazol-4-yl] -acetic acid ethyl ester (yield: 46.5%). Mp. 94-95 ° C.

Analysis for C- HH ^N ^OSSCl ^:

Calculated: C, 37.79; H, 4.23; N, 8.81.

Found: C, 37.64; H, 4.28; N, 8.73.

Example 35.

To a solution of 2.80 g of α-t-butyloxycarbonylamino-α- [2- (trichloroethoxycarbonylamino) -thiazol-4-yl] -acetic acid

29; DK 155218 B

during cooling and stirring. The mixture is stirred for 1 hour and zinc dust is filtered off. The filtrate is poured into water and the resulting solution is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and then with water and dried over anhydrous magnesium sulfate. Distillation of the solvent gives 1.26 g (yield: 71.2%) of α-t-butyloxycarbonylamino-α- (2-aminothiazol-4-yl) -acetic acid ethyl ester as crystals. Mp. 143-144 ° C.

Analysis for C 19 H 19 N 3 O 4: 10 Calculated: C 47.83 H 6.35 N 13.95.

Found: C 47.79 H 6.27 N 13.70.

Example 36.

To a solution of 1.26 g of α-t-butyloxycarbonylamino-α- (2-aminothiazol-4-yl) -acetic acid ethyl ester in 5 ml of N, N-dimethylacetamide is added 708 mg of chloroacetyl chloride with stirring.

After stirring for an additional hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium hydrogen carbonate solution and then with water and dried over anhydrous magnesium sulfate. Distillation of the solvent gives 1.435 g of α-t-butyloxycarbonylamino-α- [2- (chloroacetamido) -thiazol-4-yl] -acetic acid ethyl ester as crystals (yield: 90.8%). Mp. 192-193 ° C.

Analysis for C 14 H 20 Cl 2 N 3 O 5 S: Calculated: C 44.50 H 5.34 N 11.12.

Found: C 44.87 H 5.55 N 10.94.

Example 37.

To a solution of 920 mg of at-butyloxycarbonylamino-α- [2- (chloroacetamido) -thiazol-4-yl] -acetic acid ethyl ester in 20 ml of ethanol is added 1.4 ml of an aqueous solution containing 681 mg of potassium hydroxide. and the mixture is stirred for 15 minutes at room temperature. The reaction solution 30

DK 1552 13 B

Concentrate to dryness under reduced pressure and dissolve the residue in water. The aqueous solution is adjusted to pH 2.0 with 1 N hydrochloric acid and extracted with ethyl acetate.

The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off and 690 mg of α-t-butyloxycarbonylamino-α- [2- (chloroacetamido) -thiazol-4-yl] -acetic acid are obtained as crystals (yield: 81%).

Mp. 169-170 ° C.

Analysis for C ^ CHigClN ^O₂S: 10 Calculated: C, 41.21; H, 4.61; N, 12.01.

Found: C, 41.40; H, 4.68; N, 11.74.

Example 38

To a solution of 11 g of 2-aminothiazol-4-ylglycine ethyl ester in 100 ml of dimethylacetamide is added dropwise 17 g of chloroacetyl chloride over 40 minutes under ice-cooling and the mixture is stirred at room temperature for approx. 16 hours. To the reaction mixture is added 200 ml of ice-water and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to give 14.8 g of 2-chloroacetamidothiazol-4-yl-N-chloroacetylglycine ethyl ester as o colorless crystals. Mp. 102.5-103.5 C.

NMR (ppm, 60 MHz, CDCl3): 4.16 (2H, S, ClCH2 O), 4.32 (2H, S, C1CH2 CO), 5.74 (1H, d, -CH-COOH), 7.14 (1H, S, thiazole-

^ I

ring proton). NH

Example 39.

To a solution of 3.54 g of 2-chloroacetamidothiazol-4-yl-N-chloroacetylglycine ethyl ester in 30 ml of ethanol is added dropwise a solution of 1.68 g of potassium hydroxide in 15 ml of water under ice-cooling and stirred for 15 minutes. .

The ethanol is distilled off under reduced pressure and the residue is acidified with 10% hydrochloric acid, then extracted with ethyl acetate. The ethyl acetate layer is washed with water and dry 31

DK 155218 B

acetamidothiazol-4-yl-N-chloroacetylglycine as colorless crystals. Mp. 184-186 ° C.

NMR (ppm, 60 MHz, d 6 -DMSO): 4.36 (2H, S, C 1 CH 2 CO), 4.58 (2H, S, CICH 2 CO), 5.66 (1H, d, -CH-C00), 7.40 (1H, S, thiazole ring proton). NH

Example 40.

To a suspension of 555.4 mg of α-methoxyimino-α- [2- (chloroacetamido) -thiazol-4-yl] -acetic acid in 5 ml of methylene chloride is added 416.3 mg of phosphorus pentachloride under ice-cooling. The resulting solution is stirred for 30 minutes and n-hexane is added thereto to precipitate 620 mg of α-methoxyimino-α- [2- (chloroacetamido) -thiazol-4-yl] -acetyl chloride hydrochloride.

Analysis for C 8 H 7 N 3 ° 3 SC 12 * HCl: Calculated: C 28.89 H 2.42 N 12.63.

Found: C 28.35 H 2.81 N 12.00.

Claims (5)

1. Thiazolylacetic acid compounds for use as intermediates in the preparation of cephem compounds of the general formula H0N s YJ! s, N - 1 -A-CONH- - / \ (II) or * \ ^> * CH 2 R 4 COOH 2 wherein A means either -CH- or -C-, where R is an amino- I 2 II 5 ΈΓ NR 3 or hydroxyl group and R 1 is optionally an alkyl which may be 4 substituted protected hydroxyl group and R is hydrogen, an acetoxy group, a group -SR wherein R is a 5- or 6-membered heterocyclic ring containing 1 ring nitrogen atom and optionally 1-3 additional ring heteroatoms selected from oxygen, sulfur and nitrogen and which may be substituted by alkyl, alkoxy, halogen, haloalkyl, amino, 4 mercapto, hydroxyl, carbamoyl or carboxyl, or R is carbamoyloxy or a group -N 2 which may be substituted by alkyl, halogen, a carbamoyl group, carboxyalkyl, hydroxyalkyl or haloalkyl, or pharmaceutically acceptable salts or esters thereof, characterized in that the thiazolylacetic acid compounds have the general formula DK 155218 B R1 S Yji N - A * COOH in which R is an optionally protected amino group and A 'means is either -CH- or -C- I 2 '5 R * NR 21 wherein R represents an optionally protected amino or hydroxyl group and R has the meaning given above, as well as salts, esters and reactive derivatives thereof. A compound according to claim 1, characterized in that A 'is -C-. Ils NR A compound according to claim 2, characterized in that it is in the form of the syn or anti-isomer. A compound according to claim 3, characterized in that R is a hydroxyl group. A compound according to claim 3, characterized in that R is a hydroxyl group protected by a lower alkyl group.