阅读说明：本技术 一种吡啶酮乙醇胺盐的制备方法 (Preparation method of pyridone ethanolamine salt ) 是由 蔡建 陈晓辉 陈坤 薛天辉 于 2019-11-16 设计创作，主要内容包括：本发明公开了一种吡啶酮乙醇胺盐的制备方法,其包括傅克酰基化、闭环、羟胺化和成盐等反应步骤。所述制备方法能够以温和的条件来高效制备吡啶酮乙醇胺盐,其所消耗的反应物料较少,各步所得物的产率和纯度较高,无需复杂的提纯步骤。(The invention discloses a preparation method of pyridone ethanolamine salt, which comprises the reaction steps of Friedel-crafts acylation, ring closure, hydroxylamine amination, salt formation and the like. The preparation method can be used for efficiently preparing the pyridone ethanolamine salt under mild conditions, the consumed reaction materials are less, the yield and the purity of the product obtained in each step are higher, and complicated purification steps are not needed.)

1. A method for preparing a pyridone ethanolamine salt represented by the following chemical formula 1:

the preparation method is characterized by comprising the following steps:

(1)

mixing anhydrous aluminum trichloride, anhydrous stannic chloride and the compound 2, adding the compound 1, and reacting at 35-45 ℃ for 5-7 hours to prepare a compound 3;

(2)

heating and refluxing the compound 3 in a 10% concentration sulfuric acid aqueous solution for 5 to 7 hours to prepare a compound 4;

(3)

reacting the compound 4 with hydroxylamine hydrochloride in the presence of 4-dimethylaminopyridine at 35 to 45 ℃ for 8 to 12 hours to prepare a compound 5; and

(4)

reacting said compound 5 with ethanolamine to prepare said pyridone ethanolamine salt.

2. The production method according to claim 1, wherein in the step (1), the molar ratio of the compound 2 to the anhydrous aluminum trichloride is from 1:0.9 to 1: 1.2.

3. The production method according to claim 1, wherein in the step (1), the molar ratio of anhydrous aluminum trichloride to anhydrous tin tetrachloride is 1:0.2 to 1: 0.4.

4. The method according to claim 1, wherein in step (1), the molar ratio of compound 2 to compound 1 is 1:1 to 1: 1.2.

5. The production method according to claim 1, wherein in step (3), the molar ratio of the compound 4 to hydroxylamine hydrochloride is 1:1 to 1: 4.

6. The method according to claim 1, wherein in the step (3), the molar ratio of the compound 4 to 4-dimethylaminopyridine is 1:0.01 to 1: 0.5.

7. The method according to claim 1, wherein in the step (4), the molar ratio of the compound 5 to the ethanolamine is 1:1 to 1: 1.5.

8. The production method according to claim 1, wherein in the step (4), the compound 5 and ethanolamine are heated to 35 to 45 ℃ and cooled to sufficiently precipitate crystals when crystal formation is observed.

Technical Field

The invention relates to the field of chemical synthesis, and in particular relates to a preparation method of pyridone ethanolamine salt.

Background

Pyridone ethanolamine salt, chemical name: 1-hydroxy-4-methyl-6- (2,4,4, trimethylpentyl) -2-pyridone ethanolammonium salt, english name: octopirox Piroctone amine (Octopirox for short), molecular formula: c₁₄H₂₃NO₂·C₂H₇NO, molecular weight: 298.43, white or light yellow crystalline powder, with very slight characteristic odor, is a compound formed by combining hydroxyl of 1-hydroxy-4-methyl-6- (2,4,4, trimethylpentyl) -2-pyridone with amine group of ethanolamine, and has the following structural formula:

the pyridone ethanolamine salt is a novel anti-dandruff and antipruritic, has broad-spectrum killing and inhibiting effects on fungi and mould, has good treatment effect on tinea pedis and tinea manuum, can be used as a preservative in cosmetics, and can be used as a bactericide in perfumed soaps. The anti-dandruff mechanism is capable of killing and inhibiting abnormal reproduction of malassezia furfur which causes excessive dandruff and scalp itch, and has the functions of resisting oxidation and decomposing oxides, so that external factors generated by dandruff can be fundamentally blocked, the aim of radically treating dandruff is fulfilled, and itching is effectively relieved. Under the condition of the same amount or less addition amount, the anti-dandruff and anti-itching effect is obviously better than that of other anti-dandruff and anti-itching agents.

In addition, the pyridone ethanolamine salt has excellent solubility and compounding performance, and cannot generate precipitation or layering phenomenon when being mixed with other cosmetic raw materials; has extremely low irritation, does not cause the problems of alopecia, hair breakage and the like, and has better safety than similar dandruff-removing and itching-relieving products. Therefore, the pyridone ethanolamine salt is a multifunctional anti-dandruff itching-relieving bactericide and is widely applied to hair care products, bath foam, cosmetics and washing products.

The existing preparation method of the pyridone ethanolamine salt mainly comprises reactions such as Friedel-crafts acylation, ring closure, hydroxylamine amination and salt formation, and has the problems of excessive raw material investment, low yield of each step, low purity, complex purification operation and the like, and corresponding improvement is needed.

Disclosure of Invention

[ problem ] to

In view of the disadvantages of the prior art, it is an object of the present invention to provide a process for the preparation of ethanolamines of pyridones, which enables very high purity products to be obtained in high yields and without the need for complex purification steps.

[ solution ]

To achieve the above objects, one aspect of the present invention provides a method for preparing a pyridone ethanolamine salt represented by the following chemical formula 1:

wherein, the preparation method comprises the following steps:

(1)

mixing anhydrous aluminum trichloride, anhydrous stannic chloride and the compound 2, adding the compound 1, and reacting at 35-45 ℃ for 5-7 hours to prepare a compound 3;

(2)

heating and refluxing the compound 3 in a 10% concentration sulfuric acid aqueous solution for 5 to 7 hours to prepare a compound 4;

(3)

reacting the compound 4 with hydroxylamine hydrochloride in the presence of 4-dimethylaminopyridine at 35 to 45 ℃ for 8 to 12 hours to prepare a compound 5; and

(4)

reacting said compound 5 with ethanolamine to prepare said pyridone ethanolamine salt.

By the preparation method according to one embodiment of the invention, pyridone ethanolamine salt can be efficiently prepared under mild conditions, less reaction materials are consumed, the yield and purity of the product obtained in each step are high, and complicated purification steps are not required.

Further, in the step (1), the molar ratio of the compound 2 to the anhydrous aluminum trichloride may be 1:0.9 to 1:1.2, preferably 1: 1;

the molar ratio of anhydrous aluminum trichloride to anhydrous tin tetrachloride may be from 1:0.2 to 1:0.4, preferably 1: 0.3; and

the molar ratio of compound 2 to compound 1 may be 1:1 to 1:1.2, preferably 1: 1.1.

In the above step (1), compound 1 (methyl 3-methyl-2-butenoate) and compound 2(3,5, 5-trimethylhexanoyl chloride) are subjected to Friedel-Crafts acylation to prepare compound 3. Specifically, the reaction takes anhydrous aluminum trichloride and anhydrous stannic chloride as catalysts, wherein the anhydrous aluminum trichloride has strong activity, and when a compound 2 is added, the anhydrous aluminum trichloride is firstly complexed, the electron density of an acyl chloride group is changed to generate an acyl cation, and then the acyl cation is combined with the terminal carbon of a compound 1 under the catalysis of the anhydrous stannic chloride to remove hydrogen ions to generate a product compound 3. Wherein, because the compound 2 needs to be complexed with anhydrous aluminum trichloride to react, the molar weight of the compound 2 and the anhydrous aluminum trichloride are closer to each other, and then the acyl cation can react with the compound 1 in the presence of catalytic amount of anhydrous stannic chloride.

In addition, after the reaction is finished, hydrochloric acid can be added to quench anhydrous aluminum trichloride and anhydrous stannic chloride, meanwhile, an organic solvent is added to extract products, and then the products are separated by liquid separation.

Further, in the step (2), the compound 3 can be subjected to ring closure reaction by heating and refluxing with 10% sulfuric acid aqueous solution. Specifically, the compound 3 has both a ketocarbonyl group and a carbon-carbon double bond, the ketocarbonyl group is more likely to undergo enol tautomerism under heating, particularly, the enol-type double bond is also conjugated with another carbon-carbon double bond in a molecule, so that the stability of the enol-type isomer of the compound 3 is further increased, and a hydroxyl group of the generated enol-type isomer is further subjected to ester exchange reaction with an ester group of the molecule under the catalysis of sulfuric acid to form a ring, so that the compound 4 in a caprolactone form is generated. The method has simple conditions, and the obtained product has high purity and high yield.

Further, in the step (3), the molar ratio of the compound 4 to hydroxylamine hydrochloride may be 1:1 to 1:4, preferably 1: 2;

the molar ratio of compound 4 to 4-dimethylaminopyridine may be from 1:0.01 to 1:0.5, preferably 1: 0.1.

In the step (3), in the presence of a catalytic amount of 4-Dimethylaminopyridine (DMAP), the amino group of hydroxylamine hydrochloride attacks the caprolactone ring of compound 4 to cause aminolysis reaction and ring opening, thereby producing an amide compound, and then the nitrogen atom of the amide compound further replaces the hydroxyl group produced by the aminolysis reaction to cause the ring closure of the molecule again, thereby producing compound 5.

Further, in step (4), the molar ratio of the compound 5 to the ethanolamine may be 1:1 to 1:1.5, preferably 1: 1.2;

in the step (4), the compound 5 and ethanolamine are heated to 35 to 45 ℃ and cooled to sufficiently precipitate crystals when crystals are observed to be formed.

In the step (4), the N-hydroxyl group of the compound 5 has a certain acidity due to the electron-withdrawing property of the nitrogen atom, and thus can be bonded to the amine group of the basic ethanolamine to form a salt.

[ advantageous effects ]

In conclusion, the invention has the following beneficial effects:

the preparation method of the pyridone ethanolamine salt has simple process, the product prepared in each step has high yield and high purity, no complex purification step is needed, and the purity of the finally prepared pyridone ethanolamine salt can reach more than 99%.

Detailed Description

The present invention will be described in further detail with reference to examples.

Source of raw materials

3,5, 5-trimethylhexanoyl chloride, 98% pure, available from Sigma Aldrich;

methyl 3-methyl-2-butenoate, 97% pure, purchased from Sigma Aldrich;

anhydrous aluminum trichloride with the purity of 99 percent, which is purchased from chemical reagents of national drug group, Inc.;

anhydrous stannic chloride with purity of 99% and purchased from chemical reagents of national drug group, ltd;

4-dimethylaminopyridine with purity of 99% purchased from national pharmaceutical group chemical reagents, ltd;

ethanolamine, 99% pure, available from Sigma Aldrich (Sigma-Aldrich).

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