Process for preparation of N-hydroxypyridone compounds

Abstract

The present invention relates to a process for preparing N-hydroxypyridone compounds (I) from pyrone compounds using a phase transfer catalyst. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for preparing N-hydroxypyridone compounds from pyrone compounds using a phase transfer catalyst. Background Art

[0002] Preservatives in cosmetic formulations and household formulations extend their shelf life, thus providing consumers with a higher cost performance. In addition, preservatives prevent consumers from spreading microorganisms in their homes or on themselves, thus providing health benefits. Antimicrobial active substances are well described in the art, and there are many available substances that provide excellent performance.

[0003] Piroctone Olamine, also known as (Clariant) and piroctone ethanolamine, is a compound used for the treatment of fungal infections. The chemical name of piroctone is the monoethanolamine salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone. Thus, piroctone is the ethanolamine salt of piroctone.

[0004] Piroctone ethanolamine is often used as a substitute for the commonly used compound zinc pyrithione in anti-dandruff shampoos.

[0005] GB1440975, EP0158481 and WO2006 / 081969 describe the use of piroctone ethanolamine as an anti-dandruff agent and / or as a preservative. DE4439029 and DE19517891 disclose methods for preparing piroctone ethanolamine. Summary of the Invention

[0006] Surprisingly, it has now been found that phase transfer catalysts can be used to prepare N-hydroxypyridone compounds from pyrone compounds in good yields.

[0007] The present invention relates to a method for preparing a compound of formula (I)

[0008]

[0009] wherein

[0010] R 1 is hydrogen, a straight-chain or branched C1-C 20 -alkyl, a straight-chain or branched C2-C 20 -alkenyl, a C3-C8-cycloalkyl, a cyclohexyl-(C1-C4)-alkyl, a benzyl or a benzyl substituted by 1 to 3 C1-C4-alkyls;

[0011] R 2is hydrogen, a straight-chain or branched C1-C5-alkyl group, a straight-chain or branched C2-C5-alkenyl group, a straight-chain or branched C2-C5-alkynyl group or a benzyl group, or R 2 may be combined with R 1 or R 3 and R 2 and R 1 or R 3 and the two carbon atoms to which they are attached together form a 5- or 6-membered carbon ring;

[0012] R 3 is hydrogen, a straight-chain or branched C1-C5-alkyl group or a phenyl group;

[0013] R 4 is hydrogen, a straight-chain or branched C1-C5-alkyl group, a straight-chain or branched C2-C5-alkenyl group, a straight-chain or branched C2-C5-alkynyl group, a methoxymethyl group, or a benzyl group;

[0014] Q + is H + 、Li + 、Na + 、K + 、 1 / 2Ca ++ 、 1 / 2Mg ++ 、 1 / 2Zn ++ 、1 / 3Al +++ 、NH4 + 、hydroxylamine, [NHR 5 R 6 R 7 + or a combination thereof;

[0015] R 5 、R 6 and R 7 are each independently hydrogen, a straight-chain or branched alkyl group having 1 to 22 carbon atoms, a straight-chain or branched, mono-unsaturated or poly-unsaturated alkenyl group having 2 to 22 carbon atoms, a C6-C 22 -alkylamidopropyl group, a straight-chain mono-hydroxyalkyl group having 2 to 10 carbon atoms or a straight-chain or branched di-hydroxyalkyl group having 3 to 10 carbon atoms, where at least one of the groups R 5 、R 6 and R 7 is not hydrogen;

[0016] The method comprises the step of reacting a compound of formula (II) with a hydroxylamine or hydroxylammonium compound in the presence of a phase transfer catalyst

[0017]

[0018] ​wherein

[0019] R 1 、R 2 、R 3 and R 4 are as defined in the compounds of formula (I).

[0020] Advantageously, the compounds of formula (I) can be used as phase transfer catalysts for the preparation of the compounds of formula (I). This facilitates the reaction and enables improved yields to be achieved.

[0021] The method of the present invention is a method for preparing a compound of formula (I)

[0022]

[0023] wherein

[0024] R 1 is hydrogen, straight-chain or branched C1-C 20 -alkyl, straight-chain or branched C2-C 20 -alkenyl, C3-C8-cycloalkyl, cyclohexyl-(C1-C4)-alkyl, benzyl or benzyl substituted with 1 to 3 C1-C4-alkyl groups;

[0025] R 2 is hydrogen, straight-chain or branched C1-C5-alkyl, straight-chain or branched C2-C5-alkenyl, straight-chain or branched C2-C5-alkynyl or benzyl, or R 2 can together with R 1 or R 3 and R 2 and R 1 or R 3 the two carbon atoms to which they are attached together form a 5- or 6-membered carbon ring;

[0026] R 3 is hydrogen, straight-chain or branched C1-C5-alkyl or phenyl;

[0027] R 4 is hydrogen, straight-chain or branched C1-C5-alkyl, straight-chain or branched C2-C5-alkenyl, straight-chain or branched C2-C5-alkynyl, methoxymethyl, or benzyl;

[0028] Q + is H + 、Li + 、Na + 、K + 、 1 / 2Ca ++ 、 1 / 2Mg ++ 、 1 / 2Zn ++ 、1 / 3Al+++ 、NH4 + 、hydroxylamine, [NHR 5 R 6 R 7 + or a combination thereof;

[0029] R 5 、R 6 and R 7 are each independently hydrogen, a straight-chain or branched-chain alkyl group having 1 to 22 carbon atoms, a straight-chain or branched-chain, mono-unsaturated or poly-unsaturated alkenyl group having 2 to 22 carbon atoms, a C6-C 22 -alkylamidopropyl group, a straight-chain monohydroxyalkyl group having 2 to 10 carbon atoms or a straight-chain or branched-chain dihydroxyalkyl group having 3 to 10 carbon atoms, where at least one of the groups R 5 、R 6 and R 7 is not hydrogen.

[0030] Preferably, the compound of formula (I) wherein

[0031] R 1 is hydrogen, a straight-chain or branched-chain C1-C 20 -alkyl group, a straight-chain or branched-chain C2-C6-alkenyl group, a C5-C7-cycloalkyl group, a cyclohexyl-(C1-C4)-alkyl group, a benzyl group or a benzyl group substituted with 1 to 3 methyl groups;

[0032] R 2 is hydrogen, a straight-chain or branched-chain C1-C4-alkyl group or a benzyl group, or R 2 can together with R 3 and the 2 carbon atoms to which R 2 and R 3 is attached form a 5- or 6-membered carbon ring;

[0033] R 3 is hydrogen, or a straight-chain or branched-chain C1-C4-alkyl group;

[0034] R 4 is hydrogen, a straight-chain or branched-chain C1-C4-alkyl group or a benzyl group;

[0035] Q + is H + 、Li + 、Na + 、K + 、 1 / 2Ca ++ 、 1 / 2Mg ++ 、 1 / 2Zn ++ 、NH4 + 、hydroxylamine, [NHR​5 R 6 R 7 + or a combination thereof;

[0036] R 5 、R 6 and R 7 are each independently hydrogen, a straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms, a straight-chain or branched-chain, mono-unsaturated or poly-unsaturated alkenyl group having 2 to 12 carbon atoms, a straight-chain monohydroxyalkyl group having 2 to 8 carbon atoms or a straight-chain or branched-chain dihydroxyalkyl group having 3 to 8 carbon atoms, provided that at least one of the groups R 5 、R 6 and R 7 is not hydrogen.

[0037] More preferably, the compound of formula (I) wherein

[0038] R 1 is hydrogen, a straight-chain or branched-chain C6-C 10 -alkyl or cyclohexyl;

[0039] R 2 is hydrogen;

[0040] R 3 is hydrogen or methyl;

[0041] R 4 is hydrogen;

[0042] Q + is H + 、Li + 、Na + 、K + 、 1 / 2Ca ++ 、 1 / 2Mg ++ 、 1 / 2Zn ++ 、NH4 + 、hydroxylammonium, [NHR 5 R 6 R 7 + or a combination thereof;

[0043] R 5 、R 6 and R 7 are each independently hydrogen, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, a straight-chain monohydroxyalkyl group having 2 to 6 carbon atoms or a straight-chain or branched-chain dihydroxyalkyl group having 3 to 6 carbon atoms, provided that at least one of the groups R 5 、R 6 and R 7 ​​At least one of them is not hydrogen.

[0044] More preferably, it is a compound of formula (I), wherein

[0045] R 1 is hydrogen, a straight-chain or branched C6-C 10 -alkyl or cyclohexyl;

[0046] R 2 is hydrogen;

[0047] R 3 is methyl;

[0048] R 4 is hydrogen;

[0049] Q + is H + 、Na + 、K + 、NH4 + 、hydroxylammonium, [NH3(CH2CH2OH)] + or a combination thereof.

[0050] More preferably, it is a compound of formula (I), wherein

[0051] R 1 is 2,4,4-trimethylpentyl;

[0052] R 2 is hydrogen;

[0053] R 3 is methyl;

[0054] R 4 is hydrogen;

[0055] Q + is H + 、Na + 、hydroxylammonium, [NH3(CH2CH2OH)] + or a combination thereof.

[0056] More preferably, it is a compound of formula (I), wherein

[0057] R 1 is 2,4,4-trimethylpentyl;

[0058] R 2 is hydrogen;

[0059] R 3 is methyl;

[0060] R 4 is hydrogen;

[0061] Q + is H+ , hydroxylamine, [NH3(CH2CH2OH)] + or a combination thereof.

[0062] Particularly preferred are the compounds of formula (I) in which

[0063] R 1 is 2,4,4 - trimethylpentyl;

[0064] R 2 is hydrogen;

[0065] R 3 is methyl;

[0066] R 4 is hydrogen;

[0067] Q + is H + , [NH3(CH2CH2OH)] + or a combination thereof.

[0068] In a preferred embodiment, the compound of formula (I) is selected from 1-hydroxy-6-methyl-pyridin-2-one, 1-hydroxy-4,6-dimethyl-pyridin-2-one, 1-hydroxy-3,4,6-trimethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-ethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-isopropyl-pyridin-2-one, 1-hydroxy-4-methyl-6-heptyl-pyridin-2-one, 1-hydroxy-4-methyl-6-undecyl-pyridin-2-one, 1-hydroxy-4-methyl-6-heptadecyl-pyridin-2-one, 1-hydroxy-4-ethyl-5,6-dimethyl-pyridin-2-one, 1-hydroxy-4,5-trimethylene-6-methyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-methyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-ethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-isobutenyl-pyridin-2-one, 1-hydroxy-4,6-dimethyl-5-benzyl-pyridin-2-one, 1-hydroxy-3-benzyl-4,6-dimethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-benzyl-pyridin-2-one, 1-hydroxy-3,4-dimethyl-6-(2,4-dimethylbenzyl)-pyridin-2-one, 1-hydroxy-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-ethyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-propyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-6-(2,4,4-trimethylpentyl)-pyridin-2-one, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-pyridin-2-one, 1-hydroxy-4-ethyl-6-(2,4,4-trimethylpentyl)-pyridin-2-one, 1-hydroxy-4-propyl-6-(2,4,4-trimethylpentyl)-pyridin-2-one and salts thereof. Preferably, the compound of formula (I) is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or a salt thereof. Particularly preferably, the compound of formula (I) is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone, or an ethanolamine salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone. In a particularly preferred embodiment, the compound of formula (I) is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone. In another particularly preferred embodiment, the compound of formula (I) is an ethanolamine salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone.

[0069] wherein Q + is not H +The compound of formula (I) can be converted into one in which Q + is H + by treatment with water and / or an acid such as hydrochloric acid or sulfuric acid. For example, a compound of formula (I) in which Q + is Na + , hydroxylamine or a combination thereof can be converted into one in which Q + is H + by treatment with water and / or an acid such as hydrochloric acid or sulfuric acid.

[0070] Wherein Q + is H + of the compound of formula (I) can be converted into one in which Q + is not H + by treatment with a base such as an amine. For example, a compound of formula (I) in which Q + is H + of the compound of formula (I) can be converted into one in which Q + is [NH3(CH2CH2OH)] + by treatment with monoethanolamine.

[0071] The method of the present invention comprises the step of reacting a compound of formula (II) with hydroxylamine or a hydroxylammonium compound in the presence of a phase transfer catalyst

[0072]

[0073] wherein

[0074] R 1 , R 2 , R 3 and R 4 are as defined in the compound of formula (I).

[0075] In a preferred compound of formula (II), R 1 , R 2 , R 3 and R 4 are as defined in the preferred compound of formula (I). In a more preferred compound of formula (II), R 1 , R 2 , R 3 and R 4 are as defined in the more preferred compound of formula (I). In an even more preferred compound of formula (II), R 1 , R 2 , R 3 and R 4 are as defined in the even more preferred compound of formula (I). In a particularly preferred compound of formula (II), R 1 , R2 , R 3 and R 4 as defined in the compounds of formula (I) which are particularly preferred.

[0076] React a compound of formula (II) with hydroxylamine or a hydroxylammonium compound. In one embodiment, a compound of formula (II) is reacted with hydroxylamine. Hydroxylamine can be used, for example, in the form of an aqueous solution. Hydroxylamine is commercially available, for example, as a 50% aqueous solution. In a preferred embodiment, a compound of formula (II) is reacted with a hydroxylammonium compound. Suitable hydroxylammonium compounds are known to those skilled in the art.

[0077] Preferred hydroxylammonium compounds are selected from hydroxylammonium sulfate, hydroxylammonium chloride, hydroxylammonium acetate, hydroxylammonium phosphate, hydroxylammonium nitrate, hydroxylammonium perchlorate, hydroxylammonium oxalate, hydroxylammonium bisulfate, hydroxylammonium 4-methylbenzenesulfonate, and hydroxylammonium bromide. More preferred hydroxylammonium compounds are selected from hydroxylammonium sulfate, hydroxylammonium chloride, and hydroxylammonium acetate. Even more preferred hydroxylammonium compounds are selected from hydroxylammonium sulfate and hydroxylammonium chloride. Particularly preferred hydroxylammonium compound is hydroxylammonium sulfate.

[0078] Preferably, the molar ratio of the compound of formula (II) to the hydroxylamine equivalent is from 1.0:1.0 to 1.0:6.0, more preferably from 1.0:1.5 to 1.0:6.0, more preferably from 1.0:2.0 to 1.0:4.0, more preferably from 1.0:2.0 to 1.0:3.5, even more preferably from 1.0:2.0 to 1.0:3.0, still more preferably from 1.0:2.5 to 1.0:3.5, particularly preferably from 1.0:2.5 to 1.0:3.0.

[0079] In a preferred embodiment, the molar ratio of the compound of formula (II) to the hydroxylammonium compound is from 1.0:0.5 to 1.0:3.0, more preferably from 1.0:0.8 to 1.0:3.0, more preferably from 1.0:1.0 to 1.0:2.0, more preferably from 1.0:1.0 to 1.0:1.8, even more preferably from 1.0:1.0 to 1.0:1.5, still more preferably from 1.0:1.2 to 1.0:1.8, particularly preferably from 1.0:1.2 to 1.0:1.5. For example, when hydroxylammonium sulfate is used as the hydroxylammonium compound, such a molar ratio is preferred.

[0080] In another preferred embodiment, the molar ratio of the compound of formula (II) to the hydroxylamine or hydroxylammonium compound is from 1.0:1.0 to 1.0:6.0, more preferably from 1.0:1.5 to 1.0:6.0, more preferably from 1.0:2.0 to 1.0:4.0, more preferably from 1.0:2.0 to 1.0:3.5, even more preferably from 1.0:2.0 to 1.0:3.0, still more preferably from 1.0:2.5 to 1.0:3.5, particularly preferably from 1.0:2.5 to 1.0:3.0. For example, when hydroxylammonium chloride or hydroxylammonium acetate is used as the hydroxylammonium compound, such molar ratios are preferred.

[0081] React the compound of formula (II) with the hydroxylamine or hydroxylammonium compound in the presence of a phase transfer catalyst.

[0082] Preferably, the phase transfer catalyst is selected from monocarboxylic acids, salts of monocarboxylic acids, esters of monocarboxylic acids, dicarboxylic acids, salts of dicarboxylic acids, esters of dicarboxylic acids, tricarboxylic acids, salts of tricarboxylic acids, esters of tricarboxylic acids, hydroxamic acids, salts of hydroxamic acids, esters of hydroxamic acids, cyclic hydroxamic acids, salts of cyclic hydroxamic acids, esters of cyclic hydroxamic acids, and mixtures thereof. Preferably, the salt is a hydroxylammonium salt. Preferably, the ester is a methyl ester.

[0083] In a preferred embodiment, the phase transfer catalyst is selected from

[0084] the compound of formula (Ia)

[0085]

[0086] wherein

[0087] R 1 、R 2 、R 3 and R 4 are as defined in the compound of formula (I);

[0088] D + is H + 、Li + 、Na + 、K + 、 1 / 2Ca ++ 、 1 / 2Mg ++ 、 1 / 2Zn ++ 、1 / 3Al +++ 、NH4 + 、hydroxylammonium, [NH3(CH2CH2OH)] + or a combination thereof, and / or O - D + =O(C1-C4-alkyl);

[0089] Compound of formula (F)

[0090]

[0091] wherein

[0092] R 1 、R 2 、R 3 and R 4 are as defined in the compound of formula (I);

[0093] T + is H + 、Li + 、Na + 、K + 、 1 / 2Ca ++ 、 1 / 2Mg ++ 、 1 / 2Zn ++ 、1 / 3Al +++ 、NH4 + 、hydroxylammonium, [NH3(CH2CH2OH)] + or a combination thereof, and / or O - T + =O(C1-C4-alkyl); and mixtures thereof.

[0094] In the preferred compound of formula (Ia), R 1 、R 2 、R 3 and R 4 are as defined in the preferred compound of formula (I). In the more preferred compound of formula (Ia), R 1 、R 2 、R 3 and R 4 are as defined in the more preferred compound of formula (I). In the even more preferred compound of formula (Ia), R 1 、R 2 、R 3 and R 4 are as defined in the even more preferred compound of formula (I). In the particularly preferred compound of formula (Ia), R 1 、R 2 、R 3 and R 4 are as defined in the particularly preferred compound of formula (I).

[0095] Preferred is the compound of formula (Ia), wherein

[0096] D + is H +, Li + , Na + , K + , NH4 + , hydroxylamine, [NH3(CH2CH2OH)] + or a combination thereof, and / or O - D + =OCH3.

[0097] More preferably, the compound of formula (Ia), wherein

[0098] D + is H + , Na + , K + , hydroxylamine or a combination thereof.

[0099] Even more preferably, the compound of formula (Ia), wherein

[0100] D + is H + , Na + , hydroxylamine or a combination thereof.

[0101] Particularly preferably, the compound of formula (Ia), wherein

[0102] D + is H + , hydroxylamine or a combination thereof.

[0103] In the preferred compound of formula (F), R 1 , R 2 , R 3 and R 4 are as defined in the preferred compound of formula (I). In the more preferred compound of formula (F), R 1 , R 2 , R 3 and R 4 are as defined in the more preferred compound of formula (I). In the even more preferred compound of formula (F), R 1 , R 2 , R 3 and R 4 are as defined in the even more preferred compound of formula (I). In the particularly preferred compound of formula (F), R 1 , R 2 , R 3 and R 4 are as defined in the particularly preferred compound of formula (I).

[0104] Preferably, the compound of formula (F), wherein

[0105] T + is H + , Li+ , Na + , K + , NH4 + , hydroxylamine, [NH3(CH2CH2OH)] + or a combination thereof, and / or O - D + =OCH3.

[0106] More preferably, the compound of formula (F), wherein

[0107] T + is H + , Na + , K + , hydroxylamine or a combination thereof.

[0108] Even more preferably, the compound of formula (F), wherein

[0109] T + is H + , Na + , hydroxylamine or a combination thereof.

[0110] Particularly preferably, the compound of formula (F), wherein

[0111] T + is H + , hydroxylamine or a combination thereof.

[0112] The compound of formula (Ia) can be obtained in situ, for example, when carrying out the method of the present invention, for example, as a by-product or side product.

[0113] The compound of formula (F) can be obtained in situ, for example, when carrying out the method of the present invention, for example, as a by-product or side product.

[0114] In a preferred embodiment, the phase transfer catalyst is selected from benzoic acid, hydroxylammonium benzoate, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt, 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone hydroxylammonium salt, the compound of formula (III),

[0115]

[0116] the compound of formula (IV),

[0117]

[0118] Compounds of formula (V),

[0119]

[0120] and mixtures thereof.

[0121] The hydroxyammonium salt of benzoic acid can be obtained, for example, in situ from benzoic acid and hydroxylamine or a hydroxyammonium compound.

[0122] The hydroxyammonium salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone can be obtained, for example, in situ from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone and hydroxylamine or a hydroxyammonium compound.

[0123] The hydroxyammonium salt of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone can be obtained, for example, in situ from 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone and hydroxylamine or a hydroxyammonium compound.

[0124] Compounds of formula (III) can be obtained, for example, in situ when carrying out the process of the present invention, for example as an incidental or by-product.

[0125] Compounds of formula (IV) can be obtained, for example, in situ when carrying out the process of the present invention, for example as an incidental or by-product.

[0126] Compounds of formula (V) can be obtained, for example, in situ when carrying out the process of the present invention, for example as an incidental or by-product.

[0127] More preferably, the phase transfer catalyst is selected from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, the hydroxyammonium salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, the hydroxyammonium salt of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone,

[0128] compounds of formula (III),

[0129]

[0130] compounds of formula (IV),

[0131]

[0132] compounds of formula (V),

[0133]

[0134] and mixtures thereof.

[0135] More preferably, the phase transfer catalyst is selected from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt,

[0136] the compound of formula (III),

[0137]

[0138] the compound of formula (IV),

[0139]

[0140] the compound of formula (V),

[0141]

[0142] and mixtures thereof.

[0143] Particularly preferably, the phase transfer catalyst is selected from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt,

[0144] the compound of formula (III),

[0145]

[0146] the compound of formula (IV),

[0147]

[0148] and mixtures thereof.

[0149] In a preferred embodiment, the phase transfer catalyst is the compound of formula (I) as described herein. In a more preferred embodiment, the phase transfer catalyst is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or a salt thereof. In an even more preferred embodiment, the phase transfer catalyst is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt. In a particularly preferred embodiment, the phase transfer catalyst is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone. In another particularly preferred embodiment, the phase transfer catalyst is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt.

[0150] In a preferred embodiment, the phase transfer catalyst is a compound of formula (I) as described herein. In a preferred process of the invention in which the phase transfer catalyst is a compound of formula (I) as described herein, the compound of formula (I) is added as the phase transfer catalyst. Adding as the phase transfer catalyst means, for example, adding the phase transfer catalyst to the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound. This also applies to the preferred embodiments of the compounds of formula (I) as described herein.

[0151] In a preferred embodiment, the phase transfer catalyst is a compound of formula (Ia) as described herein. In a preferred process of the invention in which the phase transfer catalyst is a compound of formula (Ia) as described herein, the compound of formula (Ia) is added as the phase transfer catalyst. Adding as the phase transfer catalyst means, for example, adding the phase transfer catalyst to the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound. This also applies to the preferred embodiments of the compounds of formula (Ia) as described herein.

[0152] The prior art discloses processes in which a compound of formula (I) or (Ia) as described herein is a reaction product of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound. However, in the processes disclosed in the prior art, the compound of formula (I) or (Ia) is not added as a phase transfer catalyst. In the processes disclosed in the prior art, the compound of formula (I) or (Ia) is generated in situ as the reaction proceeds.

[0153] In a preferred embodiment, the phase transfer catalyst is a mixture of the following:

[0154] C1) A compound of formula (Ia) as described herein, and

[0155] C2) A compound of formula (F) as described herein or a salt thereof.

[0156] In another preferred embodiment, the phase transfer catalyst is a mixture of the following:

[0157] C1) A compound of formula (I) as described herein, and

[0158] C2) A compound of formula (III) as described herein or a salt thereof.

[0159] In a more preferred embodiment, the phase transfer catalyst is a mixture of the following:

[0160] C1) 1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or a salt thereof, and

[0161] C2) A compound of formula (III) as described herein or a salt thereof.

[0162] In a further more preferred embodiment, the phase transfer catalyst is a mixture of the following substances:

[0163] C1) 1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt, and

[0164] C2) A compound of formula (III) as described herein or a compound of formula (IV) as described herein.

[0165] In a particularly preferred embodiment, the phase transfer catalyst is a mixture of the following substances:

[0166] C1) 1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, and

[0167] C2) A compound of formula (III) as described herein.

[0168] In another particularly preferred embodiment, the phase transfer catalyst is a mixture of the following substances:

[0169] C1) 1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt, and

[0170] C2) A compound of formula (IV) as described herein.

[0171] Preferably, the weight ratio of C2 to C1 is from 1:1 to 1:20, more preferably from 1:2 to 1:15, still more preferably from 1:3 to 1:12, and particularly preferably from 1:5 to 1:10.

[0172] Preferably, the phase transfer catalyst is used in an amount of 0.1 to 30 mol%, more preferably 1 to 20 mol%, and particularly preferably 5 to 15 mol% based on the amount of the compound of formula (II).

[0173] Preferably, the phase transfer catalyst is used in an amount of 0.5 mg to 500 mg / 1 g of the reaction mixture.

[0174] In a preferred embodiment, the compound of formula (I), preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or a salt thereof, particularly preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt, is recycled from the previous method as described herein.

[0175] In a preferred embodiment, the phase transfer catalyst used in the reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound is at least a portion of the reaction mixture obtained from a prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound. Preferably, the reaction mixture is washed with water before use. In one embodiment, the reaction mixture is washed with water and / or an acid (such as hydrochloric acid or sulfuric acid) before use.

[0176] In a preferred embodiment, the reaction mixture obtained from the prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains, after washing with water, 16 to 65% by weight, preferably 22 to 55% by weight, more preferably 28 to 47% by weight, particularly preferably 33 to 41% by weight of the phase transfer catalyst, based on the total weight of the reaction mixture.

[0177] In a preferred embodiment, the reaction mixture obtained from the prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains

[0178] M1) a compound of formula (Ia) as described herein,

[0179] M2) a compound of formula (F) as described herein or a salt thereof, and

[0180] M3) optionally, a compound of formula (II) as described herein.

[0181] In another preferred embodiment, the reaction mixture obtained from the prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains

[0182] M1) a compound of formula (I) as described herein,

[0183] M2) a compound of formula (III) as described herein or a salt thereof, and

[0184] M3) optionally, a compound of formula (II) as described herein.

[0185] In a more preferred embodiment, the reaction mixture obtained from the prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains

[0186] M1) 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or a salt thereof,

[0187] M2) a compound of formula (III) as described herein or a salt thereof, and

[0188] M3) Optionally, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone.

[0189] In a still more preferred embodiment, the reaction mixture obtained by the said previous reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound comprises

[0190] M1) 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone hydroxylammonium salt,

[0191] M2) A compound of formula (III) as described herein or a compound of formula (IV) as described herein, and

[0192] M3) Optionally, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone.

[0193] In a particularly preferred embodiment, the reaction mixture obtained by the said previous reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound, after washing with water, comprises

[0194] M1) 15 to 50% by weight, preferably 20 to 45% by weight, more preferably 25 to 40% by weight, particularly preferably 30 to 36% by weight, based on the total weight of the reaction mixture, of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone hydroxylammonium salt,

[0195] M2) 1 to 15% by weight, preferably 2 to 10% by weight, more preferably 3 to 7% by weight, particularly preferably 3 to 5% by weight, based on the total weight of the reaction mixture, of a compound of formula (III) as described herein or a compound of formula (IV) as described herein, and

[0196] M3) Optionally, 0.1 to 10% by weight, preferably 0.3 to 5% by weight, more preferably 0.5 to 3% by weight, particularly preferably 0.7 to 2% by weight, based on the total weight of the reaction mixture, of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone.

[0197] Generally, the reaction mixture obtained by the said previous reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound comprises a solvent, particularly preferably heptane or toluene. Further examples of preferred solvents are described below.

[0198] The preferred embodiments of the said prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound correspond to the preferred embodiments described herein for the process of the present invention. The preferred embodiments of the process of the present invention described herein are also applicable to the said prior reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound.

[0199] In a preferred embodiment, at least a portion of the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound is used as a phase transfer catalyst in the next reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound. Preferably, the reaction mixture is washed with water before use. In one embodiment, the reaction mixture is washed with water and / or an acid (such as hydrochloric acid or sulfuric acid) before use.

[0200] In a preferred embodiment, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains, after washing with water, 16 to 65% by weight, preferably 22 to 55% by weight, more preferably 28 to 47% by weight, particularly preferably 33 to 41% by weight of the phase transfer catalyst, based on the total weight of the reaction mixture.

[0201] In a preferred embodiment, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains

[0202] M1) a compound of formula (Ia) as described herein,

[0203] M2) a compound of formula (F) as described herein or a salt thereof, and

[0204] M3) optionally, a compound of formula (II) as described herein.

[0205] In another preferred embodiment, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains

[0206] M1) a compound of formula (I) as described herein,

[0207] M2) a compound of formula (III) as described herein or a salt thereof, and

[0208] M3) optionally, a compound of formula (II) as described herein.

[0209] In a more preferred embodiment, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains

[0210] M1) 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or a salt thereof,

[0211] M2) A compound of formula (III) or a salt thereof as described herein, and

[0212] M3) Optionally, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone.

[0213] In a further more preferred embodiment, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound comprises

[0214] M1) 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone hydroxylammonium salt,

[0215] M2) A compound of formula (III) as described herein or a compound of formula (IV) as described herein, and

[0216] M3) Optionally, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone.

[0217] In a particularly preferred embodiment, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound, after washing with water, comprises

[0218] M1) 15 to 50% by weight, preferably 20 to 45% by weight, more preferably 25 to 40% by weight, particularly preferably 30 to 36% by weight, based on the total weight of the reaction mixture, of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone hydroxylammonium salt,

[0219] M2) 1 to 15% by weight, preferably 2 to 10% by weight, more preferably 3 to 7% by weight, particularly preferably 3 to 5% by weight, based on the total weight of the reaction mixture, of a compound of formula (III) as described herein or a compound of formula (IV) as described herein, and

[0220] M3) Optionally, 0.1 to 10% by weight, preferably 0.3 to 5% by weight, more preferably 0.5 to 3% by weight, particularly preferably 0.7 to 2% by weight, based on the total weight of the reaction mixture, of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone.

[0221] Typically, the reaction mixture obtained by the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound contains a solvent, particularly preferably heptane or toluene. Further examples of preferred solvents are described below.

[0222] A preferred embodiment of the next reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound corresponds to the preferred embodiments described herein for the process of the invention. The preferred embodiments of the process of the invention described herein are also applicable to the next reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound.

[0223] In a preferred embodiment, the reaction of a compound of formula (II) with a hydroxylamine or hydroxylammonium compound is carried out in the presence of a base.

[0224] In one embodiment, the compound of formula (II) reacts with hydroxylamine in the presence of a base. In another embodiment, the compound of formula (II) reacts with hydroxylamine in the absence of a base.

[0225] In a preferred embodiment, the compound of formula (II) reacts with a hydroxylammonium compound in the presence of a base.

[0226] Suitable bases are known to those skilled in the art. Examples of suitable bases are metal carbonates, metal hydrogencarbonates or metal hydroxides. Preferred bases are selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogencarbonates, alkaline earth metal hydrogencarbonates, alkali metal hydroxides, alkaline earth metal hydroxides and mixtures thereof. More preferred bases are selected from alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydroxides and mixtures thereof. Even more preferred bases are selected from alkali metal carbonates, alkali metal hydrogencarbonates and mixtures thereof. Particularly preferred bases are selected from alkali metal carbonates.

[0227] Examples of suitable bases are lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, cesium hydrogencarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium carbonate, magnesium carbonate, barium carbonate, nickel carbonate, zirconium carbonate, calcium hydroxide, magnesium hydroxide, barium hydroxide, nickel hydroxide or zirconium hydroxide. Preferred bases are selected from lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide and mixtures thereof. More preferred bases are selected from lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and mixtures thereof. Even more preferred bases are selected from lithium carbonate, sodium carbonate, potassium carbonate and mixtures thereof. Still more preferred bases are selected from sodium carbonate, sodium hydrogencarbonate and mixtures thereof. Particularly preferred base is sodium carbonate.

[0228] Preferably, the molar ratio of the base equivalent to the hydroxylamine equivalent is from 1.0:0.5 to 1.0:3.0, more preferably from 1.0:0.8 to 1.0:2.0, still more preferably from 1.0:1.0 to 1.0:1.5, still more preferably from 1.0:1.0 to 1.0:1.2, and particularly preferably from 1.0:1.0 to 1.0:1.1.

[0229] In a preferred embodiment, the molar ratio of the base to the hydroxylammonium compound is from 1.0:0.5 to 1.0:3.0, more preferably from 1.0:0.8 to 1.0:2.0, still more preferably from 1.0:1.0 to 1.0:1.5, still more preferably from 1.0:1.0 to 1.0:1.2, and particularly preferably from 1.0:1.0 to 1.0:1.1. For example, when using hydroxylammonium sulfate as the hydroxylammonium compound and an alkali metal carbonate (such as sodium carbonate) as the base, such a molar ratio is preferred.

[0230] In a preferred embodiment, the reaction of the compound of formula (II) with hydroxylamine or a hydroxylammonium compound is carried out in the presence of a solvent. Suitable solvents are known to those skilled in the art.

[0231] Preferred solvents are selected from organic solvents, water, and mixtures thereof. More preferred solvents are selected from heptane, hexane, cyclohexane, methylcyclohexane, dimethylcyclohexane, toluene, benzene, 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, tert-pentanol, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 2-aminopyridine, glycol monoethyl ether (such as ethylene glycol monoethyl ether), water, and mixtures thereof. Still more preferred solvents are selected from hexane, cyclohexane, methylcyclohexane, heptane, benzene, 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene, toluene, glycol monoethyl ether (such as ethylene glycol monoethyl ether), water, and mixtures thereof. Particularly preferred solvents are selected from heptane, toluene, water, and mixtures thereof.

[0232] In a preferred embodiment, the solvent comprises at least 80% by weight, preferably at least 90% by weight, more preferably at least 95% by weight, and particularly preferably at least 98% by weight of heptane or toluene based on the total weight of the solvent.

[0233] In a preferred embodiment, the solvent comprises

[0234] 80 to 100% by weight, preferably 90 to 100% by weight, more preferably 95 to 100% by weight, and particularly preferably 98 to 100% by weight of heptane or toluene based on the total weight of the solvent, and

[0235] 0 to 20% by weight, preferably 0 to 10% by weight, more preferably 0 to 5% by weight, and particularly preferably 0 to 2% by weight of water based on the total weight of the solvent.

[0236] In a preferred embodiment, the solvent comprises

[0237] 80 to 99.8% by weight, preferably 90 to 99.7% by weight, more preferably 95 to 99.6% by weight, particularly preferably 98 to 99.5% by weight of heptane or toluene, based on the total weight of the solvent, and

[0238] 0.2 to 20% by weight, preferably 0.3 to 10% by weight, more preferably 0.4 to 5% by weight, particularly preferably 0.5 to 2% by weight of water, based on the total weight of the solvent.

[0239] In a preferred embodiment, the solvent comprises at least 80% by weight, preferably at least 90% by weight, more preferably at least 95% by weight, particularly preferably at least 98% by weight of heptane, based on the total weight of the solvent.

[0240] In a preferred embodiment, the solvent comprises

[0241] 80 to 100% by weight, preferably 90 to 100% by weight, more preferably 95 to 100% by weight, particularly preferably 98 to 100% by weight of heptane, based on the total weight of the solvent, and

[0242] 0 to 20% by weight, preferably 0 to 10% by weight, more preferably 0 to 5% by weight, particularly preferably 0 to 2% by weight of water, based on the total weight of the solvent.

[0243] In a preferred embodiment, the solvent comprises

[0244] 80 to 99.8% by weight, preferably 90 to 99.7% by weight, more preferably 95 to 99.6% by weight, particularly preferably 98 to 99.5% by weight of heptane, based on the total weight of the solvent, and

[0245] 0.2 to 20% by weight, preferably 0.3 to 10% by weight, more preferably 0.4 to 5% by weight, particularly preferably 0.5 to 2% by weight of water, based on the total weight of the solvent.

[0246] In a preferred embodiment, the solvent comprises at least 80% by weight, preferably at least 90% by weight, more preferably at least 95% by weight, particularly preferably at least 98% by weight of toluene, based on the total weight of the solvent.

[0247] In a preferred embodiment, the solvent comprises

[0248] 80 to 100% by weight, preferably 90 to 100% by weight, more preferably 95 to 100% by weight, particularly preferably 98 to 100% by weight of toluene, based on the total weight of the solvent, and

[0249] Water in an amount of from 0 to 20% by weight, preferably from 0 to 10% by weight, more preferably from 0 to 5% by weight, particularly preferably from 0 to 2% by weight, based on the total weight of the solvent.

[0250] In a preferred embodiment, the solvent comprises

[0251] Toluene in an amount of from 80 to 99.8% by weight, preferably from 90 to 99.7% by weight, more preferably from 95 to 99.6% by weight, particularly preferably from 98 to 99.5% by weight, based on the total weight of the solvent, and

[0252] Water in an amount of from 0.2 to 20% by weight, preferably from 0.3 to 10% by weight, more preferably from 0.4 to 5% by weight, particularly preferably from 0.5 to 2% by weight, based on the total weight of the solvent.

[0253] In a preferred embodiment, the reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound is carried out at a temperature of from 60 to 120 °C, preferably from 70 to 110 °C, more preferably from 75 to 105 °C, particularly preferably from 75 to 85 °C, and also particularly preferably from 95 to 105 °C.

[0254] Preferably, the compound of formula (II) is reacted with a hydroxylamine or hydroxylammonium compound for at least 8 hours, more preferably at least 12 hours, even more preferably at least 16 hours, particularly preferably at least 20 hours. For example, the compound of formula (II) is reacted with a hydroxylamine or hydroxylammonium compound for from 8 to 36 hours, preferably from 12 to 32 hours, more preferably from 16 to 28 hours, particularly preferably from 20 to 24 hours.

[0255] The reaction of the compound of formula (II) with a hydroxylamine or hydroxylammonium compound can be worked up in a conventional manner, for example as described in the examples.

[0256] In a preferred embodiment, the method of the invention is a method for preparing a compound of formula (I)

[0257]

[0258] wherein

[0259] R 1 is 2,4,4 - trimethylpentyl;

[0260] R 2 is hydrogen;

[0261] R 3 is methyl;

[0262] R 4 is hydrogen;

[0263] Q + is H + [NH3(CH2CH2OH)] +or a combination thereof;

[0264] The method comprises the step of reacting a compound of formula (II) with hydroxylamine or a hydroxylammonium compound in the presence of a phase transfer catalyst

[0265]

[0266] wherein

[0267] R 1 、R 2 、R 3 and R 4 are as defined in the compound of formula (I);

[0268] wherein the phase transfer catalyst is selected from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt,

[0269] a compound of formula (III),

[0270]

[0271] a compound of formula (IV),

[0272]

[0273] and mixtures thereof.

[0274] In a preferred embodiment, the method of the present invention is a method for preparing a compound of formula (I)

[0275]

[0276] wherein

[0277] R 1 is 2,4,4-trimethylpentyl;

[0278] R 2 is hydrogen;

[0279] R 3 is methyl;

[0280] R 4 is hydrogen;

[0281] Q + is H + 、[NH3(CH2CH2OH)] + or a combination thereof;

[0282] The method comprises the step of reacting a compound of formula (II) with hydroxylamine or a hydroxylammonium compound in the presence of a phase transfer catalyst

[0283]

[0284] wherein

[0285] R 1 、R 2 、R 3 and R 4 are as defined in the compound of formula (I);

[0286] wherein the phase transfer catalyst is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt.

[0287] Optionally, the phase transfer catalyst used in the reaction of the compound of formula (II) with a hydroxylamine or a hydroxylammonium compound is at least a part of the reaction mixture obtained by a previous reaction of the compound of formula (II) with a hydroxylamine or a hydroxylammonium compound.

[0288] Optionally, at least a part of the reaction mixture obtained by the reaction of the compound of formula (II) with a hydroxylamine or a hydroxylammonium compound is used as the phase transfer catalyst in the next reaction of the compound of formula (II) with a hydroxylamine or a hydroxylammonium compound.

[0289] Optionally, the method further comprises treating the compound of formula (I) in which Q + is H + with monoethanolamine to obtain the compound of formula (I) in which Q + is [NH3(CH2CH2OH)] + . The treatment of the compound of formula (I) in which Q + is H + with monoethanolamine can be carried out in a solvent, which is preferably selected from ethyl acetate, methyl tert-butyl ether, ethanol, isopropanol and mixtures thereof, more preferably selected from ethyl acetate, methyl tert-butyl ether and mixtures thereof, and the solvent is particularly preferably ethyl acetate. The compound of formula (I) in which Q + is [NH3(CH2CH2OH)] + can be precipitated from the solvent.

[0290] In a preferred embodiment, the method of the present invention is a method for preparing a compound of formula (I)

[0291]

[0292] wherein

[0293] R 1 is 2,4,4-trimethylpentyl;

[0294] R 2 is hydrogen;

[0295] R 3 is methyl;

[0296] R 4 is hydrogen;

[0297] Q + is H + 、[NH3(CH2CH2OH)] + or a combination thereof;

[0298] The method comprises the following steps

[0299] i) Reacting a compound of formula (II) with hydroxylamine or a hydroxylammonium compound in the presence of a phase transfer catalyst

[0300]

[0301] wherein

[0302] R 1 、R 2 、R 3 and R 4 are as defined in the compound of formula (I);

[0303] wherein the phase transfer catalyst is selected from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt,

[0304] a compound of formula (III),

[0305]

[0306] a compound of formula (IV),

[0307]

[0308] and mixtures thereof;

[0309] to obtain a compound of formula (I) wherein Q + is H + ;

[0310] ii) Optionally, reacting a compound of formula (I) wherein Q + is H + with monoethanolamine to obtain a compound of formula (I) wherein Q + is [NH3(CH2CH2OH)] + .

[0311] In a preferred embodiment, the method of the present invention is a method for preparing a compound of formula (I)

[0312]

[0313] wherein

[0314] R 1 is 2,4,4-trimethylpentyl;

[0315] R 2 is hydrogen;

[0316] R 3 is methyl;

[0317] R 4 is hydrogen;

[0318] Q + is H + 、[NH3(CH2CH2OH)] + or a combination thereof;

[0319] The method comprises the following steps

[0320] i) reacting a compound of formula (II) with hydroxylamine or a hydroxylammonium compound in the presence of a phase transfer catalyst

[0321]

[0322] wherein

[0323] R 1 、R 2 、R 3 and R 4 are as defined in the compound of formula (I);

[0324] wherein the phase transfer catalyst is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt;

[0325] to obtain a compound of formula (I) wherein Q + is H + ;

[0326] ii) optionally, reacting a compound of formula (I) wherein Q + is H + with monoethanolamine to obtain a compound of formula (I) wherein Q + is [NH3(CH2CH2OH)] + .

[0327] The present invention also relates to the use of a compound of formula (I) of the present invention or a phase transfer catalyst as described herein as a phase transfer catalyst for the preparation of a compound of formula (I) of the present invention.

[0328] Preferred embodiments of the use of the present invention correspond to the preferred embodiments described herein for the method of the present invention. The preferred embodiments of the method of the present invention described herein are also applicable to the use of the present invention.

[0329] The compound of formula (I), in particular piroctone or piroctone ethanolamine salt, can be used as an anti-dandruff agent or a preservative. Preferably, dandruff is caused by dandruff-causing organisms, more preferably Malassezia species, particularly preferably Malassezia furfur and / or Malassezia globosa.

[0330] The compound of formula (I), in particular piroctone or piroctone ethanolamine salt, can be incorporated into a cosmetic composition. Preferably, the cosmetic composition is a hair care composition, a scalp care composition or a skin care composition. For example, the cosmetic composition can be selected from shampoos, conditioners, hair growth liquids, cream rinses, body washes, bubble baths, bath oils, facial cleansers, cleansing masks, cleansing milks, micellar waters, makeup removers, cleansing wipes, fragrances, soaps, shaving soaps, shaving foams, cleansing foams, masks, creams, hand creams and body lotions. In a preferred embodiment, the cosmetic composition is a shampoo composition or a conditioner composition. In a particularly preferred embodiment, the cosmetic composition is an anti-dandruff shampoo composition.

[0331] Preferably, the cosmetic composition comprises from 0.01 to 10% by weight, more preferably from 0.05 to 5% by weight, still more preferably from 0.1 to 2.0% by weight, particularly preferably from 0.1 to 1.0% by weight, for example from 0.1 to 0.5% by weight or from 0.5 to 1.0% by weight, of the compound of formula (I), in particular piroctone or piroctone ethanolamine salt, based on the total weight of the cosmetic composition.

[0332] The present invention is illustrated by the following examples, but is not limited thereby. Detailed Description

[0333] Examples

[0334] The phase transfer catalyst used

[0335] A) Piroctone (CAS: 50650-76-5) (237.34 g / mol), also known as:

[0336] -1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2-one

[0337] -1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone

[0338] -1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone

[0339] -2(1H)-Pyridinone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-

[0340] -1-Hydroxy-methyl-6-(2,4,4-trimethylpentyl)-2-(1H)-pyridone

[0341] B) A liquid phase transfer catalyst according to Example 1 or Example 2

[0342] Example 1: Synthesis of a Phase Transfer Catalyst / Heptyl Solvent System

[0343] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen attachment, a reflux condenser, and an internal thermometer, a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 255 g / 1.56 mol of hydroxylammonium sulfate, 160 g / 1.5 mol of sodium carbonate, 3 g / 0.17 mol of water, and 300 g of heptane was suspended under stirring (50 U / min). The reaction mixture was continuously heated to 70 to 75 °C over a period of 15 - 60 minutes and the stirring was increased to 300 rpm during this process. The start of the reaction could be observed at about 70 to 75 °C. This was indicated by visible foam formation and CO2 evolution. The intensity of CO2 evolution continuously increased and caused the reaction temperature to drop to about 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreased and the reaction temperature rose again. Once this point was reached, the reaction mixture was heated to the reflux temperature (about 80 - 82 °C). The reaction mixture was kept at reflux for 20 hours.

[0344] The reaction mixture was cooled to 60 °C. 615 grams of water at a temperature of 60 °C was added. The reaction mixture was stirred at 340 U / min for 1 hour. After this reaction time, the stirring was stopped. Phase separation subsequently occurred in the reactor. The aqueous phase was separated and the organic phase was divided into portions of 120 g.

[0345] Example 2: Synthesis of a Phase Transfer Catalyst / Tolyl Solvent System

[0346] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, a mixture of 320 g / 1.4 mol of pyranone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone), 255 g / 1.56 mol of hydroxylammonium sulfate, 160 g / 1.5 mol of sodium carbonate, 3 g / 0.17 mol of water, and 310 g of toluene was suspended under stirring (50 rpm). The reaction mixture was continuously heated to 70 to 75 °C over a period of 15 - 60 minutes and the stirring was increased to 300 rpm during this process. The start of the reaction could be observed at approximately 70 to 75 °C. This was indicated by visible foam formation and CO₂ evolution. The intensity of the CO₂ evolution continuously increased and triggered a decrease in the reaction temperature to approximately 60 - 70 °C. After complete release of the hydroxylamine, the CO₂ flow measurably decreased and the reaction temperature increased again. Once this point was reached, the reaction mixture was heated to the reflux temperature (approximately 98 - 103 °C). The reaction mixture was kept under reflux for 20 hours.

[0347] The reaction mixture was cooled to 60 °C. 615 g of water at a temperature of 60 °C was added. The reaction mixture was stirred at 340 rpm for 1 hour. After this reaction time, the stirring was stopped. Phase separation subsequently occurred in the reactor. The aqueous phase was separated and the organic phase was divided into portions of 120 g.

[0348] Example 3: Heptyl solvent system / Using piroctone as a phase transfer catalyst.

[0349] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, a mixture of 320 g / 1.4 mol of pyranone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone), 35 g / 0.15 mol of piroctone, 255 g / 1.56 mol of hydroxylammonium sulfate, 160 g / 1.5 mol of sodium carbonate, 3 g / 0.17 mol of water, and 300 g of heptane was suspended under stirring (50 rpm). The reaction mixture was continuously heated to 70 to 75 °C over a period of 15 - 60 minutes and the stirring was increased to 300 rpm during this process. The start of the reaction could be observed at approximately 70 to 75 °C. This was indicated by visible foam formation and CO₂ evolution. The intensity of the CO₂ evolution continuously increased and triggered a decrease in the reaction temperature to approximately 60 - 70 °C. After complete release of the hydroxylamine, the CO₂ flow measurably decreased and the reaction temperature increased again. Once this point was reached, the reaction mixture was heated to the reflux temperature (approximately 80 - 82 °C). The reaction mixture was kept under reflux for 20 hours.

[0350] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove the heptane by distillation.

[0351] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 88 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt using a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate in a vacuum drying oven (80 mbar) at 50 °C overnight.

[0352] Yield: 264.99 g / 57.4% piroctone ethanolamine salt (99.3%, by HPLC)

[0353] Example 4: Heptyl solvent system / using piroctone as a phase transfer catalyst.

[0354] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyranone), 35 g / 0.15 mol of piroctone, 305 g / 1.86 mol of hydroxylammonium sulfate, 190 g / 1.8 mol of sodium carbonate, 3 g / 0.17 mol of water, and 300 g of heptane under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of the CO2 evolution continuously increases and causes the reaction temperature to drop to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 80 - 82 °C). Maintain the reaction mixture at reflux for 20 hours.

[0355] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove the heptane by distillation.

[0356] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 110 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt with a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0357] Yield: 302.8 g / 65.6% piroctone ethanolamine salt (97.8%, by HPLC)

[0358] Example 5: Toluenyl solvent system / using piroctone as a phase transfer catalyst.

[0359] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 35 g / 0.15 mol of piroctone, 305 g / 1.86 mol of hydroxylammonium sulfate, 190 g / 1.8 mol of sodium carbonate, 3 g / 0.17 mol of water, and 300 g of toluene under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of the CO2 evolution continuously increases and causes the reaction temperature to drop to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 98 - 103 °C). Keep the reaction mixture under reflux for 20 hours.

[0360] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove toluene by distillation.

[0361] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 110 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt with a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0362] Yield: 313 g / 67.8% piroctone ethanolamine salt (98.9%, by HPLC)

[0363] Example 6: Toluenyl solvent system / using piroctone as a phase transfer catalyst.

[0364] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 35 g / 0.15 mol of piroctone, 255 g / 1.56 mol of hydroxylammonium sulfate, 160 g / 1.5 mol of sodium carbonate, 3 g / 0.17 mol of water, and 300 g of toluene under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of CO2 evolution continuously increases and causes the reaction temperature to drop to approximately 60 - 70 °C. After complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 98 - 103 °C). Keep the reaction mixture under reflux for 20 hours.

[0365] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove toluene by distillation.

[0366] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 88 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt with a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate in a vacuum drying oven (80 mbar) at 50 °C overnight.

[0367] Yield: 269.14 g / 58.3% piroctone ethanolamine salt (99.5%, by HPLC)

[0368] Example 7: Heptyl solvent system / liquid phase transfer catalyst.

[0369] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 120 g of the reaction solution obtained from Example 1, 305 g / 1.86 mol of hydroxylammonium sulfate, 190 g / 1.8 mol of sodium carbonate, and 300 g of heptane while stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of CO2 evolution continuously increases and causes the reaction temperature to drop to approximately 60 - 70 °C. After complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 80 - 82 °C). Maintain the reaction mixture at reflux for 20 hours.

[0370] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and take a 120 g sample of the reaction mixture as the liquid phase transfer catalyst for subsequent experiments. Treat the remaining reaction solution with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove the heptane by distillation.

[0371] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 98 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt with a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate in a vacuum drying oven (80 mbar) at 50 °C overnight.

[0372] Yield: 251 g / 60.3% piroctone ethanolamine salt (99.8%, by HPLC)

[0373] Example 8: Heptyl solvent system / liquid phase transfer catalyst.

[0374] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 120 g of the reaction solution obtained from Example 1, 256 g / 1.55 mol of hydroxylammonium sulfate, 160 g / 1.5 mol of sodium carbonate, and 300 g of heptane under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of the CO2 evolution continuously increases and causes the reaction temperature to decrease to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 80 - 82 °C). Keep the reaction mixture under reflux for 20 hours.

[0375] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and take a 120 g sample of the reaction mixture as the liquid phase transfer catalyst for subsequent experiments. Treat the remaining reaction solution with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove the heptane by distillation.

[0376] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 92 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt using a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0377] Yield: 240 g / 57.1% piroctone ethanolamine salt (99.6%, by HPLC)

[0378] Example 9: Heptyl solvent system / liquid phase transfer catalyst.

[0379] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 122 g of the reaction solution from Example 8, 305 g / 1.9 mol of hydroxylammonium sulfate, 190 g / 1.8 mol of sodium carbonate, and 310 g of heptane under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of the CO2 evolution continuously increases and causes the reaction temperature to drop to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 80 - 82 °C). Hold the reaction mixture at reflux for 20 hours.

[0380] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase. Treat the remaining reaction solution with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove heptane by distillation.

[0381] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 110 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt using a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0382] Yield: 297 g / 63.2% piroctone ethanolamine salt (98.9%, by HPLC)

[0383] Example 10: Tolyl solvent system / liquid phase transfer catalyst.

[0384] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 120 g of the reaction solution obtained from Example 2, 305 g / 1.86 mol of hydroxylammonium sulfate, 190 g / 1.8 mol of sodium carbonate, and 300 g of toluene under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of CO2 evolution continuously increases and causes the reaction temperature to decrease to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 98 - 103 °C). Maintain the reaction mixture at reflux for 20 hours.

[0385] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase, and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase, and take a 120 g sample of the reaction mixture as the liquid phase transfer catalyst for subsequent experiments. Treat the remaining reaction solution with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase, and remove heptane by distillation.

[0386] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 95 g of monoethanolamine and 4.5 g of water, and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt using a filter chute, and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0387] Yield: 265.6 g / 64.4% piroctone ethanolamine salt (99.7%, by HPLC)

[0388] Example 11: Tolyl solvent system / liquid phase transfer catalyst.

[0389] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 120 g of the reaction solution obtained from Example 10, 255 g / 1.56 mol of hydroxylammonium sulfate, 160 g / 1.5 mol of sodium carbonate, and 300 g of toluene under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of the CO2 evolution continuously increases and causes the reaction temperature to decrease to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases, and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 98 - 103 °C). Hold the reaction mixture at reflux for 20 hours.

[0390] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and take a 120 g sample of the reaction mixture as a liquid phase transfer catalyst for subsequent experiments. Treat the remaining reaction solution with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase and remove heptane by distillation.

[0391] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 95 g of monoethanolamine and 4.5 g of water and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt with a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0392] Yield: 243 g / 57.8% piroctone ethanolamine salt (99.8%, by HPLC)

[0393] Example 12: Tolyl solvent system / liquid phase transfer catalyst.

[0394] In a 2 L double-jacketed reactor equipped with an anchor stirrer, a Claisen adapter, a reflux condenser, and an internal thermometer, suspend a mixture of 320 g / 1.4 mol of pyrone (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyrone), 120 g of the reaction solution obtained from Example 2, 305 g / 1.86 mol of hydroxylammonium sulfate, 190 g / 1.8 mol of sodium carbonate, and 300 g of toluene under stirring (50 U / min). Continuously heat the reaction mixture to 70 to 75 °C over a period of 15 - 60 minutes and increase the stirring to 300 rpm during this process. The start of the reaction can be observed at approximately 70 to 75 °C. This is indicated by visible foam formation and CO2 evolution. The intensity of the CO2 evolution continuously increases and causes the reaction temperature to drop to approximately 60 - 70 °C. After the complete release of hydroxylamine, the CO2 flow measurably decreases and the reaction temperature rises again. Once this point is reached, heat the reaction mixture to the reflux temperature (approx. 98 - 103 °C). Keep the reaction mixture at reflux for 20 hours.

[0395] Cool the reaction mixture to 60 °C. Add 615 g of water at a temperature of 60 °C. Stir the reaction mixture at 340 U / min for 1 hour. After this reaction time, stop stirring. Phase separation subsequently occurs in the reactor. Separate the aqueous phase, and treat the organic phase with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase, and take a 120 g sample of the reaction mixture as the liquid phase transfer catalyst for subsequent experiments. Treat the remaining reaction solution with 8 g of sulfuric acid (48 - 50%). Stir the reaction mixture again at 340 U / min for 1 hour. Separate the aqueous phase, and remove heptane by distillation.

[0396] Absorb the organic residue in ethyl acetate (approx. 30 °C) to precipitate piroctone ethanolamine salt. Temper the organic phase in ethyl acetate to an internal temperature of 62 °C. In a dropping funnel, weigh 115 g of monoethanolamine and 4.5 g of water, and add them to the reaction solution within 10 minutes. The internal temperature should not rise above 65 °C during the addition. Continue stirring at 65 °C for 30 minutes. Then cool the reaction mixture to 0 °C. Piroctone ethanolamine salt precipitates as needle-shaped white crystals. Remove the piroctone ethanolamine salt with a filter chute and wash it portionwise with ice-cooled ethyl acetate. Dry the precipitate overnight at 50 °C in a vacuum drying oven (80 mbar).

[0397] Yield: 300 g of 65% piroctone ethanolamine salt (99.2%, by HPLC).

Claims

1. A method for preparing a compound of formula (I) wherein R 1 is hydrogen, a straight-chain or branched C1-C 20 -alkyl, a straight-chain or branched C2-C 20 -alkenyl, a C3-C8-cycloalkyl, a cyclohexyl-(C1-C4)-alkyl, benzyl or a benzyl substituted by 1 to 3 C1-C4-alkyl groups; R 2 is hydrogen, a straight-chain or branched C1-C5-alkyl, a straight-chain or branched C2-C5-alkenyl, a straight-chain or branched C2-C5-alkynyl or benzyl, or R 2 may be joined to R 1 or R 3 and together with R 2 and R 1 or R 3 the two carbon atoms to which they are attached together form a 5- or 6-membered carbocyclic ring; R 3 is hydrogen, a straight-chain or branched C1-C5-alkyl or phenyl; R 4 is hydrogen, a straight-chain or branched C1-C5-alkyl group, a straight-chain or branched C2-C5-alkenyl group, a straight-chain or branched C2-C5-alkynyl group, methoxymethyl, or benzyl; Q + is H + , Li + , Na + , K + , 1 / 2 Ca ++ , 1 / 2 Mg ++ , 1 / 2 Zn ++ , 1 / 3 Al +++ , NH4 + , hydroxylamine, [NHR 5 R 6 R 7 + or a combination thereof;​ R 5 、R 6 and R 7 are each independently hydrogen, a straight-chain or branched alkyl group having 1 to 22 carbon atoms, a straight-chain or branched mono-unsaturated or poly-unsaturated alkenyl group having 2 to 22 carbon atoms, a C6-C 22 -alkylamidopropyl group, a straight-chain monohydroxyalkyl group having 2 to 10 carbon atoms or a straight-chain or branched dihydroxyalkyl group having 3 to 10 carbon atoms, provided that at least one of the groups R 5 、R 6 and R 7 is not hydrogen; the method comprises the step of reacting a compound of formula (II) with hydroxylamine or a hydroxylammonium compound in the presence of a phase transfer catalyst wherein R 1 、R 2 、R 3 and R 4 as defined in the compounds of formula (I).

2. The method according to claim 1, wherein R 1 is hydrogen, a straight-chain or branched C1-C 20 -alkyl, a straight-chain or branched C2-C6-alkenyl, a C5-C7-cycloalkyl, a cyclohexyl-(C1-C4)-alkyl, benzyl or benzyl substituted by 1 to 3 methyl groups; R 2 is hydrogen, a straight-chain or branched C1-C4-alkyl or benzyl, or R 2 may together with R 3 and with R 2 and R 3 form a 5- or 6-membered carbocyclic ring together with the 2 carbon atoms to which they are attached; R 3 is hydrogen, or a straight-chain or branched C1-C4-alkyl group; R 4 is hydrogen, a straight-chain or branched C1-C4-alkyl, or benzyl; Q + is H + , Li + , Na + , K + , 1 / 2 Ca ++ , 1 / 2 Mg ++ , 1 / 2 Zn ++ , NH4 + , hydroxylamine, [NHR 5 R 6 R 7 + or a combination thereof;​ R 5 、R 6 and R 7 are each independently hydrogen, a straight-chain or branched alkyl group having 1 to 12 carbon atoms, a straight-chain or branched mono-unsaturated or poly-unsaturated alkenyl group having 2 to 12 carbon atoms, a straight-chain mono-hydroxyalkyl group having 2 to 8 carbon atoms or a straight-chain or branched di-hydroxyalkyl group having 3 to 8 carbon atoms, where at least one of the groups R 5 、R 6 and R 7 is not hydrogen.

3. The method according to claim 1 or 2, wherein the compound of formula (I) is selected from 1-hydroxy-6-methyl-pyridin-2-one, 1-hydroxy-4,6-dimethyl-pyridin-2-one, 1-hydroxy-3,4,6-trimethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-ethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-isopropyl-pyridin-2-one, 1-hydroxy-4-methyl-6-heptyl-pyridin-2-one, 1-hydroxy-4-methyl-6-undecyl-pyridin-2-one, 1-hydroxy-4-methyl-6-heptadecyl-pyridin-2-one, 1-hydroxy-4-ethyl-5,6-dimethyl-pyridin-2-one, 1-hydroxy-4,5-trimethylene-6-methyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-methyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-ethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-isobutenyl-pyridin-2-one, 1-hydroxy-4,6-dimethyl-5-benzyl-pyridin-2-one, 1-hydroxy-3-benzyl-4,6-dimethyl-pyridin-2-one, 1-hydroxy-4-methyl-6-benzyl-pyridin-2-one, 1-hydroxy-3,4-dimethyl-6-(2,4-dimethylbenzyl)-pyridin-2-one, 1-hydroxy-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-methyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-ethyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-4-propyl-6-cyclohexyl-pyridin-2-one, 1-hydroxy-6-(2,4,4-trimethylpentyl)-pyridin-2-one, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-pyridin-2-one, 1-hydroxy-4-ethyl-6-(2,4,4-trimethylpentyl)-pyridin-2-one, 1-hydroxy-4-propyl-6-(2,4,4-trimethylpentyl)-pyridin-2-one and salts thereof. Preferably, the compound of formula (I) is 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone or a salt thereof, particularly preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone, or the ethanolamine salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone.

4. The method according to any one of claims 1 to 3, wherein the phase transfer catalyst is selected from monocarboxylic acids, salts of monocarboxylic acids, esters of monocarboxylic acids, dicarboxylic acids, salts of dicarboxylic acids, esters of dicarboxylic acids, tricarboxylic acids, salts of tricarboxylic acids, esters of tricarboxylic acids, hydroxamic acids, salts of hydroxamic acids, esters of hydroxamic acids, cyclic hydroxamic acids, salts of cyclic hydroxamic acids, esters of cyclic hydroxamic acids, and mixtures thereof, wherein the salt is preferably a hydroxylammonium salt, and / or wherein the ester is preferably a methyl ester.

5. The method according to any one of claims 1 to 4, wherein the phase transfer catalyst is selected from compounds of formula (Ia) wherein R 1 、R 2 、R 3 and R 4 as defined in the compounds of formula (I); D + is H + , Li + , Na + , K + , 1 / 2 Ca ++ , 1 / 2 Mg ++ , 1 / 2 Zn ++ , 1 / 3 Al +++ , NH4 + , hydroxylamine, [NH3(CH2CH2OH)] + or a combination thereof, and / or O - D + = O(C1-C4-alkyl); compounds of formula (F) wherein R 1 、R 2 、R 3 and R 4 as defined in the compounds of formula (I); T + is H + , Li + , Na + , K + , 1 / 2 Ca ++ , 1 / 2 Mg ++ , 1 / 2 Zn ++ , 1 / 3 Al +++ , NH4 + , hydroxylamine, [NH3(CH2CH2OH)] + or a combination thereof, and / or O - T + = O(C1-C4-alkyl); and mixtures thereof.

6. The method according to any one of claims 1 to 5, wherein the phase transfer catalyst is selected from 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt, 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone hydroxylammonium salt, compounds of formula (III), compounds of formula (IV), compounds of formula (V), and mixtures thereof.

7. The method according to any one of claims 1 to 6, wherein the reaction of the compound of formula (II) with a hydroxylamine or a hydroxylammonium compound is carried out in the presence of a solvent, wherein the solvent is preferably selected from hexane, cyclohexane, methylcyclohexane, heptane, benzene, 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene, toluene, diethylene glycol monoethyl ether, water, and mixtures thereof, and the solvent is more preferably selected from heptane, toluene, water, and mixtures thereof.

8. The method according to any one of claims 1 to 7, wherein the reaction of the compound of formula (II) with a hydroxylamine or a hydroxylammonium compound is carried out in the presence of a base, wherein the base is preferably selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

9. The method according to any one of claims 1 to 8, wherein the molar ratio of the compound of formula (II) to the hydroxylamine equivalent is from 1.0:1.0 to 1.0:6.0, preferably from 1.0:1.5 to 1.0:6.0, more preferably from 1.0:2.0 to 1.0:4.0, more preferably from 1.0:2.0 to 1.0:3.5, still more preferably from 1.0:2.0 to 1.0:3.0, yet more preferably from 1.0:2.5 to 1.0:3.5, and particularly preferably from 1.0:2.5 to 1.0:3.

0.

10. The method according to any one of claims 1 to 9, wherein the phase transfer catalyst is used in an amount of 0.1 to 30 mol%, preferably 1 to 20 mol%, more preferably 5 to 15 mol%, based on the amount of the compound of formula (II).

11. The method according to any one of claims 1 to 10, wherein the reaction of the compound of formula (II) with hydroxylamine or a hydroxylammonium compound is carried out at a temperature of 60 to 120 °C, preferably 70 to 110 °C, more preferably 75 to 105 °C, particularly preferably 75 to 85 °C, and still particularly preferably 95 to 105 °C.

12. The method according to any one of claims 1 to 11, wherein the phase transfer catalyst is a compound of formula (I) as defined in any one of claims 1 to 3, and the phase transfer catalyst is preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or a salt thereof, particularly preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt.

13. The method according to claim 12, wherein the compound of formula (I), preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or a salt thereof, particularly preferably 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone hydroxylammonium salt, is recycled from a previous method as defined in any one of claims 1 to 12.

14. The method according to any one of claims 1 to 13, wherein the phase transfer catalyst used in the reaction of the compound of formula (II) with hydroxylamine or a hydroxylammonium compound is at least a part of the reaction mixture obtained from a previous reaction of the compound of formula (II) with hydroxylamine or a hydroxylammonium compound.

15. The method according to any one of claims 1 to 14, wherein at least a part of the reaction mixture obtained from the reaction of the compound of formula (II) with hydroxylamine or a hydroxylammonium compound is used as the phase transfer catalyst in the next reaction of the compound of formula (II) with hydroxylamine or a hydroxylammonium compound.

16. Use of a compound of formula (I) as defined in any one of claims 1 to 3 or a phase transfer catalyst as defined in any one of claims 4 to 6 as a phase transfer catalyst for the preparation of a compound of formula (I) as defined in any one of claims 1 to 3.

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