HU207296B - Process for producing substituted 2-hydroxy-methyl-4-pyridone derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of a substituted 2- (hydroxymethyl) -4-pyridone derivative of the general formula (XVI) wherein Y is hydrogen, phthalimido or amino, R4 is a hydrogen atom or a cleavable group for protecting the hydroxyl group is preferred. benzhydryl, benzyl, trityl, triraethylsilyl, pmethoxybenzyl, p-nitrobenzyl or formyl; R5 is a cleavable group suitable for protecting the hydroxy group, preferably benzhydryl, benzyl, trityl, trimethylsilyl, ρ-methoxybenzyl, p-nitrobenzyl or formyl. The new compounds are intermediates in the synthesis of antibiotic cefem derivatives. (XIV) EN 207 296 B Scope of the description: 8 pages (including 4 sheets)

Description

This invention relates to novel 4-pyridone derivatives of general formula (XVI); in which Y is hydrogen, phthalimido or amino,

R ₄ is hydrogen or a cleavable group suitable for protecting a hydroxy group, preferably benzhydryl, benzyl, trityl, trimethylsilyl, pmethoxybenzyl, p-nitrobenzyl or formyl;

_R5 is suitable for protecting a hydroxyl group can be cleaved, preferably benzhydryl, benzyl, trityl, trimethylsilyl, ρ-methoxybenzyl, p-nitrobenzyl or formyl.

The novel compounds of formula (XVI) are preferred intermediates for the novel novel cephem carboxylic acid derivatives of formula (I) which are also valuable in

R 1 is vinyl, C 1 -C 4 alkanoyloxymethyl, -CH ₂ -A or -CH ₂ -SA, and

A is thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, triazinyl, triazolo-pyrimidinyl, pyridinium or cyclopentenopyridinium, these heterocyclic groups optionally having 1 to 4 carbon atoms, alkyl, carboxyl, , hydroxy, oxo or alkyl in the alkyl moiety substituted with C 1-4 -alkoxycarbonylmethyl and / or nitrogen atoms in C 1-4 -alkyl, hydroxy-C 1-4 -alkyl, carboxymethyl, di (C 1 -C 4 alkyl) amino (C 1 -C 3 alkyl) or an alkyl (C 1 -C 4) alkoxycarbonylmethyl group, respectively, or quaternized to prepare it. The preparation of compounds of formula (I) from compounds of formula (XVI) is the subject of a separate patent application.

Compounds of formula XVI as defined above are novel products not previously described in the literature. Analogous N-substituted 2-hydroxymethyl-4-hydroxy-4-pyridones have been described by LE Hare et al., J. Med. Chem. 17 (1), 1-5 (1974) as compounds having tyrosine hydroxylase inhibitory activity. The pyridone derivatives on the nitrogen atom do not contain a hydroxy group or a substituent attached to the nitrogen atom via an oxygen atom, but are in each case substituted by a mono- or diacylaminoalkyl group attached to the nitrogen atom via a carbon atom. There is no known literature on analogous derivatives substituted with an oxygen atom attached to the nitrogen atom.

The novel 4-pyridone derivatives of formula (XVI) as defined above are prepared according to the invention by:

- a cojic acid of formula (X) on the phenolic hydroxy group to form compounds of formula (XVI) wherein Y is hydrogen, that is to say, the narrower formula (XII) wherein R ₄ and R ₅ are as defined above, in the formula

_R5 is as defined above - is reacted with hydroxylamine and sodium acetate and, if desired, the N-hydroxy group of the resulting compound (XI) of the formula R ₄ is provided with a protective group;

(i) if desired, compounds of Formula containing phthalimide-2-yl group, i.e. the narrower (XIII), (XVI), where Y - wherein R ₄ and R ₅ are as defined above - to obtain a resultant, compound of formula (XVI) where Y is hydrogen - wherein R ₄ and R _s are as defined above - is reacted with N-hydroxyphthalimide;

(ii) optionally preparing a compound of formula (XVI) wherein Y is an amino group, i.e., a narrower compound of formula (XIV) wherein R ₄ and R ₅ are as defined above, wherein Y is phthalimide-2; reacting a compound of formula (XVI), wherein R ₄ and R ₅ are as defined above, with hydrazine.

In the practice of the above procedure, the phenolic hydroxy protected kojicic acid of formula (X) is treated with hydroxylamine hydrochloride in a suitable solvent, preferably water-diluted ethanol, at room temperature to 60 ° C. wherein R ₅ is as defined above, which is then optionally protected on the hydroxy group attached to the nitrogen atom with a protecting group as defined above for R ₄ , preferably benzhydryl. This yields a compound of formula (XVI) wherein Y is hydrogen, which is represented by formula (XII) in flow chart (A).

In the preparation of a compound of formula (XVI) wherein Y is a phthalimido group represented by formula (XIII) in Scheme (A), the compound of formula (XII) is reacted with N-hydroxyphthalimide in anhydrous solvent such as dioxane, tetrahydrofuran, formamide or dimethylacetamide, preferably in the presence of triphenylphosphine and azidocarboxylic acid diethyl ester, whereby the compound of formula XIII is obtained.

In the preparation of a compound of formula (XVI) wherein Y is an amino group represented by formula (XIV) in Scheme A, the phthalimide derivative of formula (XIII) thus obtained is reacted with hydrazine, preferably hydrazine hydrate; This reaction is carried out in a suitable solvent, preferably ethanol, at reflux temperature, to yield the amino derivative of formula (XIV): - where R ₄ and R ₅ are as defined above.

The protecting groups in the meaning of R ₄ and R ₅ are known, e.g. W. Green, from "Protective Groups in Organic Synthesis," (hydroxyl protecting groups, page 53).

The following examples illustrate a practical embodiment of the process of the invention:

HU 207 296 Β

Example 1

Preparation of 5- (benzhydryloxy) -2-hydroxymethyl-4-pyrone

The synthesis is illustrated in the flowchart 1-1. 14.2 g (0.1 mol) of coyic acid [2- (hydroxymethyl) -5-hydroxy-γ-pyrone] were added to 400 ml of ethanol, which was dissolved by heating to 60 ° C. The solution was cooled to room temperature, and 29.1 g (0.15 mol) of diphenyl diazomethane was added and the mixture was stirred at room temperature for eighteen hours. The reaction solution was evaporated to dryness and benzene (300 mL) was added and the insolubles were filtered off. Water (300 mL) was added to the filtrate, and the resulting precipitate was filtered off and washed with benzene; This gave 17.5 g (56.8%) of the title pyrone. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ (ppm):

4.33 (2H, s), 6.29 (1H, s), 6.49 (1H, s), 7.36 (10H, s), 7.44 (1H, s).

Example 2

Preparation of 1-hydroxy-2- (hydroxymethyl) -5- (benzhydryloxy) -4-pyridone

The synthesis is illustrated in the flowchart 1-2. 17.5 g (0.0568 mol) of the product obtained in Example 1 are added to and dissolved in 60 ml of ethanol and 60 ml of water, followed by addition of 39.5 g (0.568 mol) of hydroxylamine hydrochloride and Sodium acetate trihydrate (77.2 g, 0.568 mol) was added and the mixture was stirred at 60 ° C for eighteen hours. The resulting precipitate was filtered off and washed successively with water, then with ethanol, then with ethyl ether and then dried; This gave 8.1 g (44.0%) of the title pyridone derivative. NMR _(DMSO-d6) δ (ppm):

2.71 (2H, s), 6.65 (1H, s), 6.87 (1H, s), 7.26-7.63 (10H, m), 7.93 (1H, s).

Example 3 Preparation of 1,5-Di-benzhydryloxy-2-hydroxymethyl-4-pyridone

The synthesis is illustrated in flow charts 1-3. 8.1 g (0.0251 mol) of the product obtained in Example 2 are added to 125 ml of DMSO and dissolved therein by heating to -100 ° C. The solution was cooled to room temperature and 5.2 g (0.0375 mol) of potassium carbonate, 5.6 g (0.0375 mol) of sodium iodide and 6.7 ml (0.0375 mol) of benzhydryl chloride were added, followed by the mixture was stirred at room temperature for 18 hours with stirring. Ice water was added gradually to the reaction solution, the precipitate formed was filtered off and washed successively with water, then with ethyl ether / n-hexane (2: 1) and finally dried; 12.3 g (100%) of the title product are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ (ppm):

4.35 (2H, s), 5.96 (1H, s), 6.06 (1H, s), 6.55 (1H, s),

6.75 (1H, s), 7.26 (20H, s).

Example 4

Preparation of 2- (phthalimidoxymethyl) -1,5-di (benzhydryloxy) -4-pyridone

The synthesis is illustrated in flow charts 1-4. 12.3 g (0.0251 mol) of the product obtained in Example 3 are added to and dissolved in 125 ml of DMF, followed by 250 ml of anhydrous THF, 4.1 g (0.0251 mol) of N-. hydroxyphthalimide and 9.9 g (0.0376 mol) of triphenylphosphine. Subsequently, 5.8 ml (0.0377 mol) of diethyl diazodicarboxylate were added dropwise under ice-cooling. After stirring at constant temperature for 10 minutes, ethyl acetate (500 mL) and water (1500 mL) were added. The ethyl acetate layer was washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated to dryness. The residue was subjected to silica gel column chromatography (eluent: benzene: ethyl acetate = 4: 1); 8.0 g (50.2%) of the title product are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ (ppm):

4.97 (2H, s), 5.88 (1H, s); 6.26 (1H, s); 6.73 (1H, s), 6.84 (1H, s), 7.31 (10h, s), 7.44 (10H, s), 7.76 (4H, s).

Example 5

Preparation of 2- (Aminooxymethyl) -1,5-di (benzhydryloxy) -4-pyridone

The synthesis is illustrated in flow charts 1-5. 8.0 g (0.0126 mol) of the product obtained in Example 4 are suspended in 60 ml of ethanol and hydrazine monohydrate (0.629 g, 0.0126 mol) is added and the mixture is refluxed for one hour. The reaction solution is cooled to room temperature, the insolubles are filtered off and the filtrate is evaporated to dryness. The residue was suspended in chloroform (120 mL), the insolubles were filtered off and the filtrate was evaporated to dryness. The yield of 2- (aminooxymethyl) -1,5-di (benzhydryloxy) -4-pyridone (oil) was 90.5% based on the starting phthalimido derivative.

NMR (CDCl ₃ ): 2.6 (2H, broad, NH ₂ ), 4.32 (2H, s,

CH ₂ ), 5.93 (1H, s, CH), 6.02 (1H, s, CH), 6.40 (1H, s, CH), 6.76 (1H, s, CH), 7, 2-7.4 (20H, m, Phx4).

PATENT CLAIMS

Claims (4)

PATENT CLAIMS A process for the preparation of 4-pyridone derivatives of formula XVI wherein Y is hydrogen, phthalimido or amino; R ₄ is hydrogen or a cleavable group suitable for protecting a hydroxy group, preferably benzhydryl, benzyl, trityl, trimethylsilyl, pmethoxybenzyl, p-nitrobenzyl or formyl; R ₅ is a hydroxy protecting group can be cleaved, preferably benzhydryl, benzyl, trityl, trimethylsilyl, ρ-methoxybenzyl, p-nitrobenzyl or formyl preparation, characterized in that - for the preparation of compounds of formula (XVI) wherein Y is hydrogen, that is to say the more narrow formula (X), wherein R ₄ and R ₅ are as defined above, a coyic acid of formula (X) protected on the phenolic hydroxy group, in the formula HU 207 296 Β _R5 is as defined above - is reacted with hydroxylamine and sodium acetate and, if desired, the N-hydroxy group of the resulting compound (XI) of the formula R ₄ is provided with a protective group; and if desired, i) Y is compounds of Formula containing phthalimide-2-yl group, i.e. blonder circuit (XIII), (XVI) - wherein R ₄ and R _s are as defined above - to obtain a resultant Y reacting a compound of formula XVI wherein R ₄ and R ₅ are as defined above, with a hydrogen atom, with N-hydroxyphthalimide; ii) optionally converting the compounds of Formula where Y is an amino group, that is narrower (XIV), (XVI) - wherein R ₄ and R _s are as defined above - to obtain a resulting Y ftálimid2-yl A compound of formula XVI wherein R ₄ and R ₅ are as defined above is reacted with hydrazine. Step ii) of the process according to claim 1, characterized in that the compound of formula XVI wherein Y is hydrogen, wherein R ₄ and R ₅ are as defined above, in an aqueous alcoholic medium, preferably at 20 ° C and 60 ° C. Reaction temperature with hydrazine. 3. The process of claim 2 wherein the hydrogen is in the form of hydrazine hydrochloride. Step i) of the process according to claim 1, characterized in that the reaction is carried out in anhydrous organic solvent in the presence of triphenylphosphine and azidocarboxylic acid diethyl ester.