CA2183869A1 - Method of preparing 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridones - Google Patents
Method of preparing 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridonesInfo
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- CA2183869A1 CA2183869A1 CA002183869A CA2183869A CA2183869A1 CA 2183869 A1 CA2183869 A1 CA 2183869A1 CA 002183869 A CA002183869 A CA 002183869A CA 2183869 A CA2183869 A CA 2183869A CA 2183869 A1 CA2183869 A1 CA 2183869A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a process for the preparation of 1-hydroxypyridones of the formula I (I) <IMG> in which R is a phenyl radical or phenoxy radical which can be substituted as indicated in claim 1, from the corresponding pyrones with hydroxylamine or a hydroxylammonium salt.
Description
^ 21~386~
Process for the preparation of 6-aryloxymethyl-l-hydroxy-4-methyl-2-pyridones The present invention relates to a process for the preparation of 1-hydroxypyridones of the formula I
c~3 ~ 0 ~ ~ (I) in which R is a substituted or unsubstituted phenyl radical or phenoxy radical.
Various 1-hydroxypyridones are useful biological active compounds, for example 6-cyclohexyl-1-hydroxy-4-methyl-2-pyridone (ciclopirox) is used as an active compound in pharmaceuticals for the treatment of fungal infections.
1-Hydroxypyridones of the formula I, which are described in EP-B-241 918, also have very good antimycotic pro-perties and are of interest for use in pharmaceuticals, for example 6-((4-(4-chlorophenoxy)phenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone.
The last stage of the synthesis of the compounds of the formula I comprise6 the reaction of the pyrones of the formula II
(II) ~ O
R ~
which are also described in EP-B-241 918 and US-A-4 797 409, with hydroxylamine or a hydroxylammonium salt in the presence of a base. The known processes for carrying out this reaction, however, have disadvantages 2183g6~
~0 95/23136 PC'r/EP95/00220 which are an obstacle to transfer to the industrial scale.
EP-B-241 918 describes proces~e~ in which pyrones of the formula II are reacted with hydroxylammonium chloride in 2-aminopyridine or with hydroxylammonium sulfate in the presence of sodium carbonate in toluene. During the work-up, however, methylene chloride is employed. The use of this readily volatile chlorinated hydrocarbon in an industrial process is impossible for ecological reasons or would reguire extraordinary expense for the treatment of the waste air and of the waste water. Moreover, the yield of 45% for the preparation of 6-((4-(4-chloro-phenoxy)phenoxy)methyl)-l-hydroxy-4-methyl-2-pyridone indicated there i8 unsatisfactory for an industrial process. Other syntheses of 1-hydroxy-2-pyridones described in the literature (see, for example, DE-B-22 14 608 or Arzneim.-Forsch./Drug Res. 31(II), pp.
1311 - 1316 (1981)) also have industrial disadvantages of this type or prove unsuitable for the compounds of the formula I.
The process for the preparation of l-hydroxy-2-pyridones described in US-A-4 916 228 does without ecologically dubious auxiliaries. Isolation is carried out, however, in the form of the ethanolamine salts, for whose prepara-tion the l-hydroxypyridone must be present in ~olution.
The use of this process is described for the preparation of l-hydroxy-4-methyl-2-pyridones which carry a cyclo-hexyl radical or a 2,4,4-trimethylpentyl radical in the 6-position. On account of the other solubility properties of the compounds of the formula I which carry the aromatic biphenylyloxymethyl radical or the phenoxy-phenoxymethyl radical in the 6-position, the process of US-A-4 916 228, however, proves unutilizable for these.
Moreover, the conversion of the ethanolamine salts into the free l-hydroxypyridones would be associated with an additional working step.
- ~ ~18~86~
Process for the preparation of 6-aryloxymethyl-l-hydroxy-4-methyl-2-pyridones The present invention relates to a process for the preparation of 1-hydroxypyridones of the formula I
c~3 ~ 0 ~ ~ (I) in which R is a substituted or unsubstituted phenyl radical or phenoxy radical.
Various 1-hydroxypyridones are useful biological active compounds, for example 6-cyclohexyl-1-hydroxy-4-methyl-2-pyridone (ciclopirox) is used as an active compound in pharmaceuticals for the treatment of fungal infections.
1-Hydroxypyridones of the formula I, which are described in EP-B-241 918, also have very good antimycotic pro-perties and are of interest for use in pharmaceuticals, for example 6-((4-(4-chlorophenoxy)phenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone.
The last stage of the synthesis of the compounds of the formula I comprise6 the reaction of the pyrones of the formula II
(II) ~ O
R ~
which are also described in EP-B-241 918 and US-A-4 797 409, with hydroxylamine or a hydroxylammonium salt in the presence of a base. The known processes for carrying out this reaction, however, have disadvantages 2183g6~
~0 95/23136 PC'r/EP95/00220 which are an obstacle to transfer to the industrial scale.
EP-B-241 918 describes proces~e~ in which pyrones of the formula II are reacted with hydroxylammonium chloride in 2-aminopyridine or with hydroxylammonium sulfate in the presence of sodium carbonate in toluene. During the work-up, however, methylene chloride is employed. The use of this readily volatile chlorinated hydrocarbon in an industrial process is impossible for ecological reasons or would reguire extraordinary expense for the treatment of the waste air and of the waste water. Moreover, the yield of 45% for the preparation of 6-((4-(4-chloro-phenoxy)phenoxy)methyl)-l-hydroxy-4-methyl-2-pyridone indicated there i8 unsatisfactory for an industrial process. Other syntheses of 1-hydroxy-2-pyridones described in the literature (see, for example, DE-B-22 14 608 or Arzneim.-Forsch./Drug Res. 31(II), pp.
1311 - 1316 (1981)) also have industrial disadvantages of this type or prove unsuitable for the compounds of the formula I.
The process for the preparation of l-hydroxy-2-pyridones described in US-A-4 916 228 does without ecologically dubious auxiliaries. Isolation is carried out, however, in the form of the ethanolamine salts, for whose prepara-tion the l-hydroxypyridone must be present in ~olution.
The use of this process is described for the preparation of l-hydroxy-4-methyl-2-pyridones which carry a cyclo-hexyl radical or a 2,4,4-trimethylpentyl radical in the 6-position. On account of the other solubility properties of the compounds of the formula I which carry the aromatic biphenylyloxymethyl radical or the phenoxy-phenoxymethyl radical in the 6-position, the process of US-A-4 916 228, however, proves unutilizable for these.
Moreover, the conversion of the ethanolamine salts into the free l-hydroxypyridones would be associated with an additional working step.
- ~ ~18~86~
It i8 an object of the present invention to makeavailable an industrially simple and, in the ecological and economical re6pect, more favorable proces6 for the preparation of l-hydroxypyridones of the formula I.
Surprisingly, it has been found that this object is achieved by fir6t reacting the pyrone of the formula II
in a manner known per se with hydroxylamine or a hydroxylammonium salt in the presence of a base and then carrying out the isolation of the product from a mixture of water and water-miscible organic solvents in acidic medium. This is all the more surprising, as it is known from the literature (Arzneim.-Forsch./Drug Res. 31(II), 1311 - 1316 (1981)) that the reaction of pyrones with hydroxylamine does not proceed uniformly, but as by-products yields isoxazolineacetic acids which on acidifi-cation of the reaction mixture should at least precipi-tate from an aqueous system ~d, as in the crystalli-zation of the product from a system containing an organic solvent, it would rather be expected that relatively large amounts of 1-hydroxypyridone of the formula I would remain dissolved in the mother liquor and the yield would be decreased. Instead of this it is higher.
The present invention thus relates to a process for the preparation of 1-hydroxypyridones of the formula I
f~ ~N ~0 ~ O H
in which R is a phenyl radical or a phenoxy radical, where the phenyl radical and the phenoxy radical can also be substituted by one or more identical or different substituents selected from the group consisting of (C1-C~)-alkyl, halogen, trifluoromethyl, (C1-C~)-alkoxy and trifluoromethoxy, by reaction of pyrones of the formula W0 95/23136 2t 8~ g ~9 PCT/EP95/00220 II
~ 0 ~ ~II) in which R is defined as indicated for the formula I, with hydroxylamine or a hydroxylammonium salt in the presence of a base, which comprises carrying out the isolation of the product from a mixture of water and one or more water-miscible organic solvents and acidifying during the work-up.
(Cl-Ci)-alkyl substituents can be straight-chain or branched; the same applies to (Cl-C~)-alkoxy substituents.
Examples of (C,-C~)-alkyl groups which can occl~r as 6uch or in (Cl-C4)-alkoxy groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and tert-butyl.
Preferred alkyl groups are methyl and tert-butyl.
Preferred alkoxy groups are methoxy and tert-butoxy.
Examples of halogen are fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine, in particular chlorine, are preferred.
The radical R in the formula I can be in the 2-position, the 3-position or the 4-position. Preferably it is in the 3-position or the 4-position, particularly preferably in the 4-position. The phenyl radical and the phenoxy radical represented by R can be unsubstituted or mono- or polysubstituted. Preferably it is unsubstituted or mono-, di- or trisubstituted. Particularly preferably it is unsubstituted or mono- or disubstituted. The substituents can be in any desired poRitions.
Preferably, in the process according to the invention 1-hydroxypyridones of the formula I are prepared in which 218~86~
R is a phenoxy radical which can also be substituted by one or two identical or different substituents ~elected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy.
Particularly preferably, in the process according to the invention 1-hydroxypyridones of the formula I are pre-pared in which R is a phenoxy radical which is sub-stituted by one or two substituents selected from the group consisting of fluorine, chlorine and bromine.
Additionally preferably, the 1-hydroxypyridone of the formula I is prepared in which R is a chlorine-substitut-ed phenoxy radical, in particular a 4-chlorophenoxy radical in the 4-position. Other compounds which can be prepared by the process according to the invention are those of the formula I in which R is a phenyl radical in - the ~-position or a 4-trifluoromethylphenoxy radical in the 4-position.
The reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt in the presence of a base can be carried out with or without solvent.
Preferably, it is carried out in a solvent. Solvents which can be employed are, for example, esters, such as ethyl acetate or butyl acetate, ethers, such as dimethoxyethane, diethylene glycol dimethyl ether, dioxane or tetrahydrofuran, alcohols, such as methanol, ethanol, propanol, butanol or ethylene glycol monomethyl, -ethyl or -butyl ether, water, amides, such as dimethyl-formamide or N-methylpyrrolidone, or, for example, dimethyl sulfoxide. Preferred solvents are aliphatic or aromatic hydrocarbOns, such as, for example, hexane, heptane, benzine fractions, cyclohexane, methylcyclo-hexane, benzene, toluene, xylene, chlorobenzene or dichlorobenzene. Hydrocarbons selected from the series consisting of heptane, toluene, xylene, chlorobenzene and dichlorobenzene are particularly preferred. Solvents can be employed either on their own or as a mixture with one 218~869 ._ .
or more other solventæ. The reaction is very particularly preferably carried out in toluene.
Preferably, the conversion of the pyrone of the formula II into the 1-hydroxypyridone of the formula I is carried out by initially introducing the pyrone of the formula II
and, if appropriate, the solvent or a part of the solvent at the desired reaction temperature and then metering in the hydroxylamine or the hydroxylammonium salt and the base. Hydroxylamine is commercially available in the form of salts, e.g. as the hydrochloric, sulfuric, phosphoric or acetic acid salt. These salts can be metered in as such in solid or dissolved or suspended form, or in a separate step the hydroxylamine can be liberated from the salt using a base and metered in as such, preferably in the form of an optionally filtered solution. In particular when a ~droxylammonium salt is ~ployed in solid form, the addition to the pyrone of the formula II
is preferably carried out in several portions, particularly preferably at intervals which are æuited to the course of the reaction. The hydroxylamine or hydroxyl~mmonium salt is preferably employed in an amount from 1 to 10 mol per mole of the pyrone of the formula II, particularly preferably in an amount from 1.3 to 3 mol per mole of the pyrone. Hydroxyl~m~o~;um chloride or hydroxylammonium sulfate is preferably employed.
Suitable bases for the liberation of the hydroxylamine from its salt are inorganic and organic bases, for example secondary and tertiary amines, e.g. diisopropyl-amine, triethylamine, tributylamine, triethanolamine, or nitrogen heterocycles such as pyridine, quinoline or imidazole. Preferably, inorganic bases are employed, particularly preferably oxides, hydroxides, carbonates or hydrogen carbonates of the alkali metals or alkaline earth metals, but also, for example, acetates or basic phosphates of these metals. Examples of alkali metalæ and alkaline earth metals are, in particular, lithium, W0 95/23136 218;~869 PCT/EP95/00220 sodium, potassium, cesium, magnesium, calcium and barium, sodium and potassium being preferred. Very particularly preferably, the base employed in the process according to the invention is sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate. Bases can be employed either on their own or as a mixture with one or more other bases. The base is customarily employed in an amount equivalent to the amount of the hydroxylammonium salt employed, but an excess or a slight insufficiency of baRe can also be favorable. The ba~e can be employed in solid or dissolved or suspended form. If in the preferred embodiment of the proces~ according to the invention a hydroxylammonium salt as such is added to the pyrone of the formula II, the addition of the base is preferably carried out in parallel to this. If the hydroxylA ~;um salt is metered in in several portions, then the base is pref~rably also metered in in several portions. After completion of the addition of the hydroxylamine or of the hydroxyl~ - 'um salt and the base, the reaction mixture is subsequently stirred at the desired temperature until the desired degree of reaction is achieved. In general, approximately 4 to 14 hours are necessary for complete reaction.
The reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt is expediently carried out at temperatures below 120C. Preferably, it is carried out at 20 to 115C, particularly preferably at 20 to 100C, more preferably at 50 to 100C. The temper-ature can be altered while carrying out the reaction, e.g. increased during 6ubsequent stirring to complete the reaction.
The simple work-up is advantageous when working by the process according to the invention. If the conversion of the pyrone of the formula II to the 1-hydroxypyridone was carried out without solvent, after reaction is complete water and one or more water-miscible solvents are added.
W0 95/23136 218 3 8 6~ PCT/EP95/00220 _ -- 8 If the reaction of the pyrone with hydroxylamine or a hydroxylammonium salt is carried out in a solvent which is to be removed to isolate the product, the work-up of the reaction mixture can be carried out by first distil-ling off some or the entire amount of this solvent invacuo or at normal pressure and then treating the residue with water and one or more water-miscible organic 801-vents, or first water and/or a water-miscible organic solvent can be added to the reaction mixture, then the solvent to be removed can be distilled off, optionally as an azeotrope, and then the residue can subsequently also be treated with one or more water-miscible organic solvents and/or water. Preferably, first water is added to the reaction mixture, then the solvent to be removed is distilled off, optionally as an azeotrope with water and particularly favorably in a phase separator, and then the a~ueous residue_is treated with one or more water-miscible organic solvents. Dep~n~; n~ on the solubility ratios of the products and salts in the solvents used, it may also be favorable during the work-up to add a filtra-tion cut or a phase ~eparation. Solvent distilled off can be used for a subsequent batch of the reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt. In each case, a state of affairs is produced during the work-up in which the product of the reaction of the pyrone of the formula II with hydroxylamine or a hydroxylAmmo~;um salt is present in a mixture of water and one or more, preferably one, water-miæcible organic solvents.
The water-miscible organic solvents employed are pre-ferably those selected from the group consisting of the water-miscible alcohols, ethers, carboxylic acids and ketones. Examples of suitable solvents are methanol, ethanol, propanol, isopropanol, ethylene glycol, di- and triethylene glycol, propylene glycol, tetrahydrofuran, dioxane, ethylene glycol mono- and dimethyl ether, diethylene glycol mono- and dimethyl ether, formic~acid, W0 95/23136 2~838~ PCT/EP95/00220 g acetic acid and acetone. However, amides, such as formamide, dimethylformamide or N-methylpyrrolidone, or, for example, acetonitrile or dimethyl sulfoxide, are also suitable. Water-miscible organic solvents selected from the group consisting of methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, acetic acid and acetone are particularly preferably employed. Additionally preferably, methanol is employed as a water-miscible organic solvent. The ~uantitative ratios of the com-ponents of the mixture of water and one or more water-miscible organic solvents depend on the solubility properties of the respective substances.
The acidification of the reaction mixture obtained in the reaction of the pyrone of the formula II with hydroxyl-amine or a hydroxyl~mmo~ium salt can be carried outbefore or after addition of water and water-miscible organic solvents. If the pyrone was reacted in a solvent and this is to be removed to isolate the product by adding water and then distilling off this solvent, the acidification can be carried out before or after the addition of water, before or after the distillation or alternatively only after the addition of one or more water-miscible organic solvents. Preferably the acidifi-cation takes place when the product of the reaction of the pyrone is already present in the mixture of water and one or more water-miscible organic solvents intended for the isolation. Preferably, a pH of between 0 and 6, particularly preferably between 1 and 5, very particu-larly preferably between 2 and 4, is set during the work-up. Sulfuric acid, hydrochloric acid, phosphoric acid oracetic acid is preferably used for the acidification.
Suitable acids, however, are also, for example, nitric acid, formic acid, trifluoroacetic acid or methane-sulfonic acid. Mixtures of acid~ can also be used. The acids can be employed in pure form or in the form of solutions of any desired, in particular commercially available, concentrations.
2183~69 The l-hydroxypyridone of the formula I crystallizing out from the acidic mixture of water and one or more water-miscible organic solvents can be isolated in a customary manner by simple filtration or centrifugation and is customarily washed with water and/or a mixture of water and the water-miscible organic solvent(s) employed and/or with the organic solvent(s) employed and dried. Water-miscible organic solvents contained in the filtrate can be recovered by distillation and employed in a subsequent batch.
1-Hydroxypyridones of the formula I prepared by the process according to the invention are obtained in a particularly readily filterable form. They have a high purity such that when for certain intended uses further purification by recrystallization is necessary this is only associated with small losses. The l-hydroxypyridones of the formula I are obtained in distinctly higher yields by the process according to the invention than by the known processes, in the case of 6-((4-(4-chlorophenoxy)-phenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone, for example, in 54 to 66% compared with 45% by the process of EP-B-241 918. That these advantages are linked with the fact that - according to the invention - both a water-miscible organic solvent is used and the reaction mixture is acidified becomes clear when one of these conditions is not fulfilled. If 6-((4-(4-chlorophenoxy)phenoxy)-methyl-l-hydroxy-4-methyl-2-pyridone is prepared by the process according to the invention, however no organic solvent is added in this case, but a purely aqueous work-up is carried out, the precipitated product contains theisoxazolineacetic acid formed as a by-product, and the yield is only about 45%. Even if a water-miscible organic solvent is added, but the mixture is not rendered acidic, the yield is only 45%.
The following examples illustrate the invention.
21.8386g Examples 1 to 13: Preparation of 6-((4-(4-chlorophenoxy)-phenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone ExamPle 1 369.6 g (1.08 mol) of 6-((4-(4-chlorophenoxy)phenoxy)-methyl)-4-methyl-2-pyrone in 600 ml of toluene are initially placed in a 2 1 three-necked flask with a ~PG
stirrer and thermometer and the mixture is heated to 90C. A total of 114.6 g (1.08 mol) of sodium carbonate and 150 g (2.16 mol) of hydroxylammonium chloride are added at this temperature at intervals of 15 min each in 10 portions each. After stirring at 90C for 10 h, 900 ml of drin~ing water are added and toluene is distilled off in a phase separator. The aqueous residue is added to 3 1 of methanol, adjusted to pH 3 using 37% strength sulfuric acid, the mixture is brought to room temperature and the soli~ is filtered off. It ~8 washed with 300 ml of methanol and 300 ml of drinking water. The moist paste is stirred twice with 900 ml of drin~;ng water at 60C each time to remove residual salts, filtered off with suction and washed with 300 ml of water each time. Half of the moist product is dried.
Yield 107.7 g, corresponding to 55.8%. M.p. 168C.
The other half of the moist product is added to 450 ml of toluene, water is distilled off in a phase separator and the clear solution is cooled to 5C. The product which crystallizes out is filtered off with suction, washed with cold toluene and dried.
Yield 104.7 g, corresponding to 54.3%. M.p. 168C.
Example 2 The procedure is as in Example 1, but instead of 1.08 mol of sodium carbonate, 2.16 mol of NaOH powder are employed.
Yield 221.5 g, corresponding to 57.4%. M.p. 167C.
Examples 3 to 6 218386~
If the procedure is as in Example 1, but instead of sodium carbonate equivalent amounts of sodium hydrogen carbonate, potassium hydroxide, potassium hydrogen carbonate or potassium carbonate are employed, comparable results are obtained.
Examples 7 to 10 If the procedure is as in Example 1, but instead of methanol ethanol, ethylene glycol dimethyl ether or acetone is employed, comparable results are obtained.
Examples 11 and 12 If the procedure is as in Example 1, but instead of sulfuric acid hydrochloric acid or phosphoric acid is employed, comparable results are obtained.
Example 13 342.8 g (1 mol) of 6-((4-(4-chlorophenoxy)phenoxy)-methyl)-4-methyl-2-pyrone in 500 ml of toluene are initially introduced into a 2 l three-necked flask with a KPG stirrer, thermometer and reflux condenser, and the mixture is heated to 90C. In the course of nine hours, 76 g (l.9 mol) of sodium hydroxide flakes and 132.1 g (1.9 mol) of hydroxylammonium chloride are added in ten portions each at intervals of one hour in each case.
After stirring at 90C for four hours, 500 ml of water are added and toluene is distilled off in a phase separ-ator at normal pressure. The aqueous suspension is treated with 1.7 l of methanol and adjusted to pH 3 using 37% strength sulfuric acid. The mixture is brought to room temperature and the precipitate is filtered off with suction and washed with 300 ml of methanol and 300 ml of water. To remove residual salts, the moist paste is stirred at 60C two more times with 900 ml of drinking water in each case, filtered off with suction and washed with 300 ml of drinking water. The moist product is introduced into 800 ml of toluene, the mixture is dis-tilled in a phase separator until free of water and the 21~386~
clear solution is cooled to 5C. The product which crystallizes out is filtered off with suction, washed with cold toluene and dried.
Yield 235 g, corresponding to 65.6%; M.p. 167C.
ExamDle 14 Preparation of 6-((4-phenylphenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone 58.4 g (0.2 mol) of6-((4-phenylphenoxy)methyl)-4-methyl-2-pyrone are initially introduced in 200 ml of toluene and the mixture i8 heated to 90C. At intervals of one hour in each case, ten portions each of a total of 15.2 g (0.38 mol) of NaOH flakes and 26.4 g (0.38 mol) of hydroxylA~mo~;um chloride are introduced. After stirring at 90C for 3 hours, 200 ml of drinking water are added and~toluene is distilled off in a phase separator. The mixture is treated with 500 ml of methanol and adjusted to pH 3 using 37% strength sulfuric acid. After cooling to room temperature, the precipitate is filtered off with suction and washed twice with 20 ml of methanol each time and twice with 20 ml of drinking water each time. The moist product is extracted twice with stirring with 60 ml of drinking water at 60C each time and in each case filtered off with suction and washed with 20 ml of warm drinking water each time and dried. It is recrystallized from 215 ml of toluene, dried and extracted with stirring with 265 ml of methanol under reflux, and the solid is filtered off with suction, washed with 40 ml of methanol and dried. Yield 31.6 g, corresponding to 51.5%; M.p.
189-193C (Lit. EP-B-241918: 184C).
Example 15 Preparation of 6-((4-(4-trifluoromethylphenoxy)phenoxy)-methyl)-l-hydroxy-4-methyl-2-pyridone 26.5 g (70 mmol) of 6-((4-(4-trifluoromethylphenoxy)-phenoxy)methyl)-4-methyl-2-pyrone are heated to 90C in ~ 2183~9 ~o 95/23136 PCT/EP95/00220 140 ml of toluene and treated in eleven portions at intervals of one hour in each case with a total of 16.4 g (155 mmol) of sodium carbonate and 10.9 g (157 mmol) of hydroxyl~o~;um chloride. After stirring at 90C for 20 hours, 140 ml of dr;nk;ng water are added and toluene is distilled off in a phase separator. 560 ml of methanol is added to the aqueous suspension and it is adjusted to pH 3 using 37% strength sulfuric acid. After cooling to room temperature, the solid is filtered off with suction, washed twice with 56 ml of methanol each time and a total of 1130 ml of drinking water at 60C in portions and dried. It is recrystallized from 35 ml of toluene.
Yield 8.6 g, correspo~;n~ to 31.2%; M.p. 156-157C (Lit.
EP-B-241918: 149C).
Surprisingly, it has been found that this object is achieved by fir6t reacting the pyrone of the formula II
in a manner known per se with hydroxylamine or a hydroxylammonium salt in the presence of a base and then carrying out the isolation of the product from a mixture of water and water-miscible organic solvents in acidic medium. This is all the more surprising, as it is known from the literature (Arzneim.-Forsch./Drug Res. 31(II), 1311 - 1316 (1981)) that the reaction of pyrones with hydroxylamine does not proceed uniformly, but as by-products yields isoxazolineacetic acids which on acidifi-cation of the reaction mixture should at least precipi-tate from an aqueous system ~d, as in the crystalli-zation of the product from a system containing an organic solvent, it would rather be expected that relatively large amounts of 1-hydroxypyridone of the formula I would remain dissolved in the mother liquor and the yield would be decreased. Instead of this it is higher.
The present invention thus relates to a process for the preparation of 1-hydroxypyridones of the formula I
f~ ~N ~0 ~ O H
in which R is a phenyl radical or a phenoxy radical, where the phenyl radical and the phenoxy radical can also be substituted by one or more identical or different substituents selected from the group consisting of (C1-C~)-alkyl, halogen, trifluoromethyl, (C1-C~)-alkoxy and trifluoromethoxy, by reaction of pyrones of the formula W0 95/23136 2t 8~ g ~9 PCT/EP95/00220 II
~ 0 ~ ~II) in which R is defined as indicated for the formula I, with hydroxylamine or a hydroxylammonium salt in the presence of a base, which comprises carrying out the isolation of the product from a mixture of water and one or more water-miscible organic solvents and acidifying during the work-up.
(Cl-Ci)-alkyl substituents can be straight-chain or branched; the same applies to (Cl-C~)-alkoxy substituents.
Examples of (C,-C~)-alkyl groups which can occl~r as 6uch or in (Cl-C4)-alkoxy groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and tert-butyl.
Preferred alkyl groups are methyl and tert-butyl.
Preferred alkoxy groups are methoxy and tert-butoxy.
Examples of halogen are fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine, in particular chlorine, are preferred.
The radical R in the formula I can be in the 2-position, the 3-position or the 4-position. Preferably it is in the 3-position or the 4-position, particularly preferably in the 4-position. The phenyl radical and the phenoxy radical represented by R can be unsubstituted or mono- or polysubstituted. Preferably it is unsubstituted or mono-, di- or trisubstituted. Particularly preferably it is unsubstituted or mono- or disubstituted. The substituents can be in any desired poRitions.
Preferably, in the process according to the invention 1-hydroxypyridones of the formula I are prepared in which 218~86~
R is a phenoxy radical which can also be substituted by one or two identical or different substituents ~elected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy.
Particularly preferably, in the process according to the invention 1-hydroxypyridones of the formula I are pre-pared in which R is a phenoxy radical which is sub-stituted by one or two substituents selected from the group consisting of fluorine, chlorine and bromine.
Additionally preferably, the 1-hydroxypyridone of the formula I is prepared in which R is a chlorine-substitut-ed phenoxy radical, in particular a 4-chlorophenoxy radical in the 4-position. Other compounds which can be prepared by the process according to the invention are those of the formula I in which R is a phenyl radical in - the ~-position or a 4-trifluoromethylphenoxy radical in the 4-position.
The reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt in the presence of a base can be carried out with or without solvent.
Preferably, it is carried out in a solvent. Solvents which can be employed are, for example, esters, such as ethyl acetate or butyl acetate, ethers, such as dimethoxyethane, diethylene glycol dimethyl ether, dioxane or tetrahydrofuran, alcohols, such as methanol, ethanol, propanol, butanol or ethylene glycol monomethyl, -ethyl or -butyl ether, water, amides, such as dimethyl-formamide or N-methylpyrrolidone, or, for example, dimethyl sulfoxide. Preferred solvents are aliphatic or aromatic hydrocarbOns, such as, for example, hexane, heptane, benzine fractions, cyclohexane, methylcyclo-hexane, benzene, toluene, xylene, chlorobenzene or dichlorobenzene. Hydrocarbons selected from the series consisting of heptane, toluene, xylene, chlorobenzene and dichlorobenzene are particularly preferred. Solvents can be employed either on their own or as a mixture with one 218~869 ._ .
or more other solventæ. The reaction is very particularly preferably carried out in toluene.
Preferably, the conversion of the pyrone of the formula II into the 1-hydroxypyridone of the formula I is carried out by initially introducing the pyrone of the formula II
and, if appropriate, the solvent or a part of the solvent at the desired reaction temperature and then metering in the hydroxylamine or the hydroxylammonium salt and the base. Hydroxylamine is commercially available in the form of salts, e.g. as the hydrochloric, sulfuric, phosphoric or acetic acid salt. These salts can be metered in as such in solid or dissolved or suspended form, or in a separate step the hydroxylamine can be liberated from the salt using a base and metered in as such, preferably in the form of an optionally filtered solution. In particular when a ~droxylammonium salt is ~ployed in solid form, the addition to the pyrone of the formula II
is preferably carried out in several portions, particularly preferably at intervals which are æuited to the course of the reaction. The hydroxylamine or hydroxyl~mmonium salt is preferably employed in an amount from 1 to 10 mol per mole of the pyrone of the formula II, particularly preferably in an amount from 1.3 to 3 mol per mole of the pyrone. Hydroxyl~m~o~;um chloride or hydroxylammonium sulfate is preferably employed.
Suitable bases for the liberation of the hydroxylamine from its salt are inorganic and organic bases, for example secondary and tertiary amines, e.g. diisopropyl-amine, triethylamine, tributylamine, triethanolamine, or nitrogen heterocycles such as pyridine, quinoline or imidazole. Preferably, inorganic bases are employed, particularly preferably oxides, hydroxides, carbonates or hydrogen carbonates of the alkali metals or alkaline earth metals, but also, for example, acetates or basic phosphates of these metals. Examples of alkali metalæ and alkaline earth metals are, in particular, lithium, W0 95/23136 218;~869 PCT/EP95/00220 sodium, potassium, cesium, magnesium, calcium and barium, sodium and potassium being preferred. Very particularly preferably, the base employed in the process according to the invention is sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate. Bases can be employed either on their own or as a mixture with one or more other bases. The base is customarily employed in an amount equivalent to the amount of the hydroxylammonium salt employed, but an excess or a slight insufficiency of baRe can also be favorable. The ba~e can be employed in solid or dissolved or suspended form. If in the preferred embodiment of the proces~ according to the invention a hydroxylammonium salt as such is added to the pyrone of the formula II, the addition of the base is preferably carried out in parallel to this. If the hydroxylA ~;um salt is metered in in several portions, then the base is pref~rably also metered in in several portions. After completion of the addition of the hydroxylamine or of the hydroxyl~ - 'um salt and the base, the reaction mixture is subsequently stirred at the desired temperature until the desired degree of reaction is achieved. In general, approximately 4 to 14 hours are necessary for complete reaction.
The reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt is expediently carried out at temperatures below 120C. Preferably, it is carried out at 20 to 115C, particularly preferably at 20 to 100C, more preferably at 50 to 100C. The temper-ature can be altered while carrying out the reaction, e.g. increased during 6ubsequent stirring to complete the reaction.
The simple work-up is advantageous when working by the process according to the invention. If the conversion of the pyrone of the formula II to the 1-hydroxypyridone was carried out without solvent, after reaction is complete water and one or more water-miscible solvents are added.
W0 95/23136 218 3 8 6~ PCT/EP95/00220 _ -- 8 If the reaction of the pyrone with hydroxylamine or a hydroxylammonium salt is carried out in a solvent which is to be removed to isolate the product, the work-up of the reaction mixture can be carried out by first distil-ling off some or the entire amount of this solvent invacuo or at normal pressure and then treating the residue with water and one or more water-miscible organic 801-vents, or first water and/or a water-miscible organic solvent can be added to the reaction mixture, then the solvent to be removed can be distilled off, optionally as an azeotrope, and then the residue can subsequently also be treated with one or more water-miscible organic solvents and/or water. Preferably, first water is added to the reaction mixture, then the solvent to be removed is distilled off, optionally as an azeotrope with water and particularly favorably in a phase separator, and then the a~ueous residue_is treated with one or more water-miscible organic solvents. Dep~n~; n~ on the solubility ratios of the products and salts in the solvents used, it may also be favorable during the work-up to add a filtra-tion cut or a phase ~eparation. Solvent distilled off can be used for a subsequent batch of the reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt. In each case, a state of affairs is produced during the work-up in which the product of the reaction of the pyrone of the formula II with hydroxylamine or a hydroxylAmmo~;um salt is present in a mixture of water and one or more, preferably one, water-miæcible organic solvents.
The water-miscible organic solvents employed are pre-ferably those selected from the group consisting of the water-miscible alcohols, ethers, carboxylic acids and ketones. Examples of suitable solvents are methanol, ethanol, propanol, isopropanol, ethylene glycol, di- and triethylene glycol, propylene glycol, tetrahydrofuran, dioxane, ethylene glycol mono- and dimethyl ether, diethylene glycol mono- and dimethyl ether, formic~acid, W0 95/23136 2~838~ PCT/EP95/00220 g acetic acid and acetone. However, amides, such as formamide, dimethylformamide or N-methylpyrrolidone, or, for example, acetonitrile or dimethyl sulfoxide, are also suitable. Water-miscible organic solvents selected from the group consisting of methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, acetic acid and acetone are particularly preferably employed. Additionally preferably, methanol is employed as a water-miscible organic solvent. The ~uantitative ratios of the com-ponents of the mixture of water and one or more water-miscible organic solvents depend on the solubility properties of the respective substances.
The acidification of the reaction mixture obtained in the reaction of the pyrone of the formula II with hydroxyl-amine or a hydroxyl~mmo~ium salt can be carried outbefore or after addition of water and water-miscible organic solvents. If the pyrone was reacted in a solvent and this is to be removed to isolate the product by adding water and then distilling off this solvent, the acidification can be carried out before or after the addition of water, before or after the distillation or alternatively only after the addition of one or more water-miscible organic solvents. Preferably the acidifi-cation takes place when the product of the reaction of the pyrone is already present in the mixture of water and one or more water-miscible organic solvents intended for the isolation. Preferably, a pH of between 0 and 6, particularly preferably between 1 and 5, very particu-larly preferably between 2 and 4, is set during the work-up. Sulfuric acid, hydrochloric acid, phosphoric acid oracetic acid is preferably used for the acidification.
Suitable acids, however, are also, for example, nitric acid, formic acid, trifluoroacetic acid or methane-sulfonic acid. Mixtures of acid~ can also be used. The acids can be employed in pure form or in the form of solutions of any desired, in particular commercially available, concentrations.
2183~69 The l-hydroxypyridone of the formula I crystallizing out from the acidic mixture of water and one or more water-miscible organic solvents can be isolated in a customary manner by simple filtration or centrifugation and is customarily washed with water and/or a mixture of water and the water-miscible organic solvent(s) employed and/or with the organic solvent(s) employed and dried. Water-miscible organic solvents contained in the filtrate can be recovered by distillation and employed in a subsequent batch.
1-Hydroxypyridones of the formula I prepared by the process according to the invention are obtained in a particularly readily filterable form. They have a high purity such that when for certain intended uses further purification by recrystallization is necessary this is only associated with small losses. The l-hydroxypyridones of the formula I are obtained in distinctly higher yields by the process according to the invention than by the known processes, in the case of 6-((4-(4-chlorophenoxy)-phenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone, for example, in 54 to 66% compared with 45% by the process of EP-B-241 918. That these advantages are linked with the fact that - according to the invention - both a water-miscible organic solvent is used and the reaction mixture is acidified becomes clear when one of these conditions is not fulfilled. If 6-((4-(4-chlorophenoxy)phenoxy)-methyl-l-hydroxy-4-methyl-2-pyridone is prepared by the process according to the invention, however no organic solvent is added in this case, but a purely aqueous work-up is carried out, the precipitated product contains theisoxazolineacetic acid formed as a by-product, and the yield is only about 45%. Even if a water-miscible organic solvent is added, but the mixture is not rendered acidic, the yield is only 45%.
The following examples illustrate the invention.
21.8386g Examples 1 to 13: Preparation of 6-((4-(4-chlorophenoxy)-phenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone ExamPle 1 369.6 g (1.08 mol) of 6-((4-(4-chlorophenoxy)phenoxy)-methyl)-4-methyl-2-pyrone in 600 ml of toluene are initially placed in a 2 1 three-necked flask with a ~PG
stirrer and thermometer and the mixture is heated to 90C. A total of 114.6 g (1.08 mol) of sodium carbonate and 150 g (2.16 mol) of hydroxylammonium chloride are added at this temperature at intervals of 15 min each in 10 portions each. After stirring at 90C for 10 h, 900 ml of drin~ing water are added and toluene is distilled off in a phase separator. The aqueous residue is added to 3 1 of methanol, adjusted to pH 3 using 37% strength sulfuric acid, the mixture is brought to room temperature and the soli~ is filtered off. It ~8 washed with 300 ml of methanol and 300 ml of drinking water. The moist paste is stirred twice with 900 ml of drin~;ng water at 60C each time to remove residual salts, filtered off with suction and washed with 300 ml of water each time. Half of the moist product is dried.
Yield 107.7 g, corresponding to 55.8%. M.p. 168C.
The other half of the moist product is added to 450 ml of toluene, water is distilled off in a phase separator and the clear solution is cooled to 5C. The product which crystallizes out is filtered off with suction, washed with cold toluene and dried.
Yield 104.7 g, corresponding to 54.3%. M.p. 168C.
Example 2 The procedure is as in Example 1, but instead of 1.08 mol of sodium carbonate, 2.16 mol of NaOH powder are employed.
Yield 221.5 g, corresponding to 57.4%. M.p. 167C.
Examples 3 to 6 218386~
If the procedure is as in Example 1, but instead of sodium carbonate equivalent amounts of sodium hydrogen carbonate, potassium hydroxide, potassium hydrogen carbonate or potassium carbonate are employed, comparable results are obtained.
Examples 7 to 10 If the procedure is as in Example 1, but instead of methanol ethanol, ethylene glycol dimethyl ether or acetone is employed, comparable results are obtained.
Examples 11 and 12 If the procedure is as in Example 1, but instead of sulfuric acid hydrochloric acid or phosphoric acid is employed, comparable results are obtained.
Example 13 342.8 g (1 mol) of 6-((4-(4-chlorophenoxy)phenoxy)-methyl)-4-methyl-2-pyrone in 500 ml of toluene are initially introduced into a 2 l three-necked flask with a KPG stirrer, thermometer and reflux condenser, and the mixture is heated to 90C. In the course of nine hours, 76 g (l.9 mol) of sodium hydroxide flakes and 132.1 g (1.9 mol) of hydroxylammonium chloride are added in ten portions each at intervals of one hour in each case.
After stirring at 90C for four hours, 500 ml of water are added and toluene is distilled off in a phase separ-ator at normal pressure. The aqueous suspension is treated with 1.7 l of methanol and adjusted to pH 3 using 37% strength sulfuric acid. The mixture is brought to room temperature and the precipitate is filtered off with suction and washed with 300 ml of methanol and 300 ml of water. To remove residual salts, the moist paste is stirred at 60C two more times with 900 ml of drinking water in each case, filtered off with suction and washed with 300 ml of drinking water. The moist product is introduced into 800 ml of toluene, the mixture is dis-tilled in a phase separator until free of water and the 21~386~
clear solution is cooled to 5C. The product which crystallizes out is filtered off with suction, washed with cold toluene and dried.
Yield 235 g, corresponding to 65.6%; M.p. 167C.
ExamDle 14 Preparation of 6-((4-phenylphenoxy)methyl)-1-hydroxy-4-methyl-2-pyridone 58.4 g (0.2 mol) of6-((4-phenylphenoxy)methyl)-4-methyl-2-pyrone are initially introduced in 200 ml of toluene and the mixture i8 heated to 90C. At intervals of one hour in each case, ten portions each of a total of 15.2 g (0.38 mol) of NaOH flakes and 26.4 g (0.38 mol) of hydroxylA~mo~;um chloride are introduced. After stirring at 90C for 3 hours, 200 ml of drinking water are added and~toluene is distilled off in a phase separator. The mixture is treated with 500 ml of methanol and adjusted to pH 3 using 37% strength sulfuric acid. After cooling to room temperature, the precipitate is filtered off with suction and washed twice with 20 ml of methanol each time and twice with 20 ml of drinking water each time. The moist product is extracted twice with stirring with 60 ml of drinking water at 60C each time and in each case filtered off with suction and washed with 20 ml of warm drinking water each time and dried. It is recrystallized from 215 ml of toluene, dried and extracted with stirring with 265 ml of methanol under reflux, and the solid is filtered off with suction, washed with 40 ml of methanol and dried. Yield 31.6 g, corresponding to 51.5%; M.p.
189-193C (Lit. EP-B-241918: 184C).
Example 15 Preparation of 6-((4-(4-trifluoromethylphenoxy)phenoxy)-methyl)-l-hydroxy-4-methyl-2-pyridone 26.5 g (70 mmol) of 6-((4-(4-trifluoromethylphenoxy)-phenoxy)methyl)-4-methyl-2-pyrone are heated to 90C in ~ 2183~9 ~o 95/23136 PCT/EP95/00220 140 ml of toluene and treated in eleven portions at intervals of one hour in each case with a total of 16.4 g (155 mmol) of sodium carbonate and 10.9 g (157 mmol) of hydroxyl~o~;um chloride. After stirring at 90C for 20 hours, 140 ml of dr;nk;ng water are added and toluene is distilled off in a phase separator. 560 ml of methanol is added to the aqueous suspension and it is adjusted to pH 3 using 37% strength sulfuric acid. After cooling to room temperature, the solid is filtered off with suction, washed twice with 56 ml of methanol each time and a total of 1130 ml of drinking water at 60C in portions and dried. It is recrystallized from 35 ml of toluene.
Yield 8.6 g, correspo~;n~ to 31.2%; M.p. 156-157C (Lit.
EP-B-241918: 149C).
Claims (10)
1. A process for the preparation of 1-hydroxypyridones of the formula I
(I) in which R is a phenyl radical or a phenoxy radical, where the phenyl radical and the phenoxy radical can also be substituted by one or more identical or different substituents selected from the group consi 8 ting of (C1-C4)-alkyl, halogen, trifluoro-methyl, (C1-C4)-alkoxy and trifluoromethoxy, by reaction of pyrones of the formula II
(II) in which R is defined as indicated for the formula I, with hydroxylamine or a hydroxylammonium salt in the presence of a base, which comprises carrying out the isolation of the product from a mixture of water and one or more water-miscible organic solvents and acidifying during the work-up.
(I) in which R is a phenyl radical or a phenoxy radical, where the phenyl radical and the phenoxy radical can also be substituted by one or more identical or different substituents selected from the group consi 8 ting of (C1-C4)-alkyl, halogen, trifluoro-methyl, (C1-C4)-alkoxy and trifluoromethoxy, by reaction of pyrones of the formula II
(II) in which R is defined as indicated for the formula I, with hydroxylamine or a hydroxylammonium salt in the presence of a base, which comprises carrying out the isolation of the product from a mixture of water and one or more water-miscible organic solvents and acidifying during the work-up.
2. The process as claimed in claim 1, wherein R is a phenoxy radical which can also be substituted by one or two identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl and trifluoromethoxy.
3. The process as claimed in claim 1 and/or 2, wherein R is a 4-chlorophenoxy radical in the 4-position.
4. The process as claimed in one or more of claims 1 to 3, wherein the reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt is carried out in an aliphatic or aromatic hydrocarbon, preferably in a hydrocarbon selected from the group consisting of heptane, toluene, xylene, chloro-benzene and dichlorobenzene, particularly preferably in toluene.
5. The process as claimed in one or more of claims 1 to 4, wherein, as base, an oxide, hydroxide, carbonate or hydrogen carbonate of the alkali metals or alka-line earth metals or a mixture of these compounds is employed, preferably sodium hydroxide, sodium car-bonate, potassium hydroxide or potassium carbonate or a mixture of these compounds.
6. The process as claimed in one or more of claims 1 to 5, wherein the reaction of the pyrone of the formula II with hydroxylamine or a hydroxylammonium salt is carried out at 20 to 115°C, preferably at 20 to 100°C, particularly preferably at 50 to 100°C.
7. The process as claimed in one or more of claims 1 to 6, wherein the water-miscible organic solvent(s) are selected from the group consisting of the water-miscible alcohols, ethers, carboxylic acids and ketones, preferably from the group consisting of methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, acetic acid and acetone.
8. The process as claimed in one or more of claims 1 to 7, wherein, as water-miscible organic solvent, methanol is employed.
9. The process as claimed in one or more of claims 1 to 8, wherein during the work-up a pH of between 0 and 6, preferably between 1 and 5, particularly pre-ferably between 2 and 4, is set.
10. The process as claimed in one or more of claims 1 to 9, wherein, for acidification, sulfuric acid, hydro-chloric acid, phosphoric acid or acetic acid is used.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4405722A DE4405722A1 (en) | 1994-02-23 | 1994-02-23 | Process for the preparation of 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridones |
| DEP4405722.9 | 1994-02-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2183869A1 true CA2183869A1 (en) | 1995-08-31 |
Family
ID=6510929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002183869A Abandoned CA2183869A1 (en) | 1994-02-23 | 1995-01-21 | Method of preparing 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridones |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0746548B1 (en) |
| JP (1) | JPH09509185A (en) |
| KR (1) | KR970701176A (en) |
| CN (1) | CN1067056C (en) |
| AT (1) | ATE161529T1 (en) |
| AU (1) | AU680989B2 (en) |
| CA (1) | CA2183869A1 (en) |
| DE (2) | DE4405722A1 (en) |
| ES (1) | ES2111389T3 (en) |
| GR (1) | GR3025956T3 (en) |
| MX (1) | MX9603513A (en) |
| NZ (1) | NZ278082A (en) |
| WO (1) | WO1995023136A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4719863B2 (en) * | 2006-05-08 | 2011-07-06 | 国立大学法人大阪大学 | Novel fluorescent material, luminescent material, and fluorescent pigment comprising the fluorescent material |
| TWI518084B (en) * | 2009-03-26 | 2016-01-21 | 鹽野義製藥股份有限公司 | Process for pyrone and pyridone derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0241918B1 (en) * | 1986-04-18 | 1992-05-27 | Hoechst Aktiengesellschaft | 1-hydroxy-2-pyridinones, process for their preparation and medicines containing them, as well as intermediates formed by the preparation of 1-hydroxy-2-pyridinones |
-
1994
- 1994-02-23 DE DE4405722A patent/DE4405722A1/en not_active Withdrawn
-
1995
- 1995-01-21 NZ NZ278082A patent/NZ278082A/en unknown
- 1995-01-21 ES ES95905642T patent/ES2111389T3/en not_active Expired - Lifetime
- 1995-01-21 MX MX9603513A patent/MX9603513A/en unknown
- 1995-01-21 CA CA002183869A patent/CA2183869A1/en not_active Abandoned
- 1995-01-21 AT AT95905642T patent/ATE161529T1/en not_active IP Right Cessation
- 1995-01-21 CN CN95191775A patent/CN1067056C/en not_active Expired - Fee Related
- 1995-01-21 JP JP7522090A patent/JPH09509185A/en active Pending
- 1995-01-21 AU AU14172/95A patent/AU680989B2/en not_active Ceased
- 1995-01-21 KR KR1019960704627A patent/KR970701176A/en active IP Right Grant
- 1995-01-21 WO PCT/EP1995/000220 patent/WO1995023136A1/en active IP Right Grant
- 1995-01-21 DE DE59501170T patent/DE59501170D1/en not_active Expired - Fee Related
- 1995-01-21 EP EP95905642A patent/EP0746548B1/en not_active Expired - Lifetime
-
1998
- 1998-01-21 GR GR980400126T patent/GR3025956T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ278082A (en) | 1997-05-26 |
| MX9603513A (en) | 1997-05-31 |
| CN1141629A (en) | 1997-01-29 |
| WO1995023136A1 (en) | 1995-08-31 |
| DE4405722A1 (en) | 1995-08-24 |
| DE59501170D1 (en) | 1998-02-05 |
| EP0746548A1 (en) | 1996-12-11 |
| CN1067056C (en) | 2001-06-13 |
| GR3025956T3 (en) | 1998-04-30 |
| AU680989B2 (en) | 1997-08-14 |
| ES2111389T3 (en) | 1998-03-01 |
| KR970701176A (en) | 1997-03-17 |
| AU1417295A (en) | 1995-09-11 |
| ATE161529T1 (en) | 1998-01-15 |
| EP0746548B1 (en) | 1997-12-29 |
| JPH09509185A (en) | 1997-09-16 |
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