阅读说明：本技术 一种3,5-二甲氧基,4-烷基苯甲醇的工业化制备方法 (Industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol ) 是由 王海 李健雄 于 2020-12-31 设计创作，主要内容包括：本发明公开了一种3,5-二甲氧基,4-烷基苯甲醇的工业化制备方法,属于有机合成技术领域。该方法选用异丙基氯或异丙醇对甲苯磺酸酯、异丙醇对甲苯磺酸酯在盐酸三乙胺离子液体的溶剂兼催化剂的作用下直接付克烷基化上异丙基；反应完后用有机溶剂,如甲基叔丁基醚直接萃取分液,离子液体可重复套用；选用硼氢化钠直接在四氢呋喃水溶液中温和(0-30℃条件下,且无需加催化剂)还原上一步的异丙基酯化物与咪唑交换得到的酰基咪唑,还原完成直接倒入1-6mol/L强碱溶液中淬灭,分离有机相,从而安全环保地获得3,5-二甲氧基-4-异丙基苯甲醇。本发明操作方便,安全,大大减少了环境污染问题,适合工业化生产。(The invention discloses an industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol, belonging to the technical field of organic synthesis. Isopropyl chloride or isopropanol-p-toluenesulfonate and isopropanol-p-toluenesulfonate are directly subjected to parkinsonation and isopropyl alkylation under the action of a solvent of triethylamine hydrochloride ionic liquid and a catalyst; after the reaction is finished, organic solvent such as methyl tert-butyl ether is used for directly extracting and separating liquid, and the ionic liquid can be repeatedly used; sodium borohydride is directly used for reducing the acyl imidazole obtained by exchanging the isopropyl ester and imidazole in the last step in tetrahydrofuran aqueous solution under mild conditions (0-30 ℃ without adding a catalyst), the reduction is finished and directly poured into 1-6mol/L strong base solution for quenching, and an organic phase is separated, so that the 3, 5-dimethoxy-4-isopropyl benzyl alcohol is obtained safely and environmentally. The method is convenient and safe to operate, greatly reduces the problem of environmental pollution, and is suitable for industrial production.)

1. An industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol is characterized by comprising the following steps:

(1) carrying out Friedel-crafts alkylation reaction on 3, 5-dimethyl methyl benzoate and an alkylating agent in ionic liquid at the temperature of 10-25 ℃, separating the ionic liquid after the reaction is finished to obtain 4-alkyl-3, 5 dimethoxy-methyl benzoate, wherein the alkylating agent is alkyl halide with 1-6 carbon atoms or corresponding sulfonate, and the mass ratio of the 3, 5-dimethyl methyl benzoate to the alkylating agent is 1: 2-4;

(2) performing amine ester exchange reaction on 4-alkyl-3, 5 dimethoxy-methyl benzoate and imidazole in a solvent A at the temperature of 60-80 ℃ to obtain 4-alkyl-3, 5 dimethoxy-benzoylimidazole, wherein the mass ratio of the 4-alkyl-3, 5 dimethoxy-methyl benzoate to the imidazole is 1: 0.5-1.2;

(3) carrying out reduction reaction on 4-alkyl-3, 5 dimethoxy-benzoyl imidazole and a reducing agent in a solvent B at the temperature of 0-30 ℃, adding alkali liquor to quench after the reaction is finished to obtain 4-isopropyl-3, 5 dimethoxy benzyl alcohol, wherein the mass ratio of the 4-alkyl-3, 5 dimethoxy-benzoyl imidazole to the reducing agent is 1: 0.2-0.5, the solvent B is selected from tetrahydrofuran, methyltetrahydrofuran, glycol dimethyl ether, dioxane or a mixed solvent of the solvent B and water, and the reducing agent is selected from sodium borohydride or potassium borohydride.

2. The industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in step (1), the ionic liquid is separated by methyl tert-butyl ether, and the separated liquid is washed with water and dried by spin-drying to obtain 4-alkyl-3, 5 dimethoxy-methyl benzoate.

3. The industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in step (1), the ionic liquid is triethylamine hydrochloride-aluminum trichloride ionic liquid, and the molar ratio of triethylamine hydrochloride to aluminum trichloride is 1:1-3, wherein the mass ratio of the methyl 3, 5-dimethylbenzoate to the ionic liquid is 1: 2-5.

4. The industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in step (1), the alkylating agent is selected from the group consisting of isopropyl chloride, isopropyl bromide, isopropyl alcohol p-toluenesulfonate, isopropyl alcohol methanesulfonate, ethanol p-toluenesulfonate, ethanol methanesulfonate and 1-chlorohexane.

5. The industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in the step (1), the alkylating agent is isopropyl chloride.

6. The industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in the step (2), the solvent A is selected from toluene or xylene.

7. The industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in the step (2), the solvent A is toluene.

8. The industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol according to claim 1, wherein in the step (3), the solvent B is a mixed solvent of tetrahydrofuran and water, and the volume ratio of tetrahydrofuran to water is 8-12: 1.

9. the industrial production method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein in step (3), the alkali solution is 1 to 6mol/L sodium hydroxide alkali solution.

10. The industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol as claimed in claim 1, wherein the method comprises:

(1) performing Friedel-crafts alkylation reaction on 3, 5-dimethyl methyl benzoate and isopropyl chloride in ionic liquid at the temperature of 10-25 ℃, adding methyl tert-butyl ether after the reaction is finished, separating liquid, washing with water and spin-drying to obtain 4-isopropyl-3, 5-dimethoxy-methyl benzoate, wherein the ionic liquid is triethylamine hydrochloride-aluminum trichloride ionic liquid, and the molar ratio of the triethylamine hydrochloride to the aluminum trichloride is 1:1-3, wherein the mass ratio of the methyl 3, 5-dimethylbenzoate to the ionic liquid to the isopropyl chloride is 1: 2-5: 2-4;

(2) performing amine ester exchange reaction on 4-isopropyl-3, 5-dimethoxy-benzoic acid methyl ester and imidazole in toluene at the temperature of 60-80 ℃, cooling and crystallizing after the reaction is finished, and filtering to obtain 4-isopropyl-3, 5-dimethoxy-benzoylimidazole, wherein the mass ratio of the 4-isopropyl-3, 5-dimethoxy-benzoic acid methyl ester to the imidazole is 1: 0.5-1.2;

(3) carrying out reduction reaction on 4-isopropyl-3, 5-dimethoxy-benzoyl imidazole and sodium borohydride in a mixed solvent of tetrahydrofuran and water at 0-30 ℃, pouring into 1-6mol/L sodium hydroxide alkali liquor for quenching after the reaction is finished, standing for layering, taking an organic phase, and carrying out spin drying and recrystallization to obtain 4-isopropyl-3, 5-dimethoxy benzyl alcohol, wherein the mass ratio of the 4-isopropyl-3, 5-dimethoxy-benzoyl imidazole to the sodium borohydride is 1: 0.2-0.5.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to an industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol.

Background

Benemimod is an aromatic receptor modulator (Masutake Furue, et al. int J Mol Sci.2019,20(21): 5424), and is also the first aromatic receptor modulator drug. The aromatic hydrocarbon receptor is a ligand-activated transcription factor, and is involved in biological processes such as cell proliferation and differentiation, immunoregulation and the occurrence of inflammatory responses (Huyuqing and Zhang Jian. skin science bulletin, 2019,36(1): 26). The iguratimod inhibits inflammation induction, blocks an IL-23/IL-17 axis of an inflammation pathway and breaks an inflammation maintenance cycle by regulating an aromatic hydrocarbon receptor, so that the obvious curative effect on psoriasis is achieved. The benvitimod is also a tyrosine protein kinase inhibitor, belongs to a stilbene compound and has the chemical name of E-4-isopropyl-3, 5-dihydroxy-stilbene.

Chem.org.57: 4040-. WO9503695 discloses the extraction of benvitimod from the genus rhabdoid, intended for the development of antifungal drugs. Later researches show that the benvitimod can be used for treating various autoimmune diseases, such as psoriasis, eczema and other allergic diseases (patent number: ZL00816755.9, application date: 12/6/2000, hydroxystilbene, stilbene derivatives and analogues thereof for resisting inflammation, treating psoriasis and inhibiting protein kinase) and the medicine is firstly marketed in China in 2019 for treating adult psoriasis vulgaris with light to moderate stability locally. The benvitimod is a non-hormone micromolecule natural compound, has a simple molecular structure, can be obtained by a chemical synthesis method, and has a wide market prospect. The structural formula of the benvitimod is as follows:

the key intermediate is 3,5 dimethoxy-4-isopropyl benzyl alcohol, and the structural formula is as follows:

the synthesis of 3,5 dimethoxy-4-isopropylbenzyl alcohol is reported and disclosed at present as follows:

the catalyst is prepared by taking 3, 5-dimethyl methyl benzoate as an initial raw material, alkylating with concentrated sulfuric acid isopropanol and reducing.

The Friedel-crafts alkylation reaction related to the route takes isopropanol as an alkylating reagent and concentrated sulfuric acid as a catalyst; sodium borohydride is used as a reaction reagent in the reduction reaction, and Lewis acid such as boron trifluoride ethyl ether or iodine, aluminum trichloride and the like is used as a catalyst; the concentrated sulfuric acid Friedel-crafts reaction has more waste water and liquid, a large amount of carbide and sulfonated impurities, low yield and qualification after being refined for many times; in the reduction reaction, the Lewis acid catalyst boron trifluoride diethyl etherate is toxic and can react with an oxidant to generate toxic and corrosive smoke with water and vapor, and the reduction by using iodine, aluminum trichloride and other Lewis acids as catalysts relates to no water and no oxygen, and the amplification industrialization is difficult to operate. If the lithium aluminum hydride is reduced, the lithium aluminum hydride can be directly obtained, but the lithium aluminum hydride is more expensive, flammable and explosive, and difficult to operate in amplification. And the reaction temperature is relatively high.

Disclosure of Invention

In order to solve the problems, the invention discloses an industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol, which comprises the following reaction flow:

the method comprises the following steps:

(1) carrying out Friedel-crafts alkylation reaction on 3, 5-dimethyl methyl benzoate and an alkylating agent in ionic liquid at the temperature of 10-25 ℃, and separating the ionic liquid to obtain 4-alkyl-3, 5 dimethoxy-methyl benzoate after the reaction is finished. Wherein the alkylating agent is alkyl halide with 1-6 carbon atoms or corresponding sulfonate (specifically p-toluenesulfonate or isopropylmethanesulfonate), and the mass ratio of the methyl 3, 5-dimethylbenzoate to the alkylating agent is 1: 2-4.

(2) In a solvent A, 4-alkyl-3, 5 dimethoxy-methyl benzoate and imidazole are subjected to amine ester exchange reaction at the temperature of 60-80 ℃ to obtain 4-alkyl-3, 5 dimethoxy-benzoyl imidazole. Wherein the mass ratio of the 4-alkyl-3, 5 dimethoxy-benzoic acid methyl ester to the imidazole is 1: 0.5-1.2. Wherein, benzene ring has the function of electron absorption, if ester is directly reduced, very harsh reaction conditions (such as catalyst and the like under anhydrous and anaerobic conditions) are required, and hydrogen can be generated in the reaction process, which is not beneficial to industrial preparation; whereas the products of the amine transesterification of other organic amines with 4-alkyl-3, 5 dimethoxy-benzoic acid methyl ester cannot be reduced. In addition, the method can carry out reduction reaction in a mixed solvent of water and other solvents, has low requirements relative to the conventional reduction reaction conditions, can improve the solubility of reactants, and can reduce the using amount of the solvents.

(3) And (3) carrying out reduction reaction on the 4-alkyl-3, 5 dimethoxy-benzoyl imidazole and a reducing agent in a solvent B at the temperature of 0-30 ℃, and adding alkali liquor to quench after the reaction is finished to obtain 4-isopropyl-3, 5 dimethoxy benzyl alcohol. Wherein the mass ratio of the 4-alkyl-3, 5 dimethoxy-benzoyl imidazole to the reducing agent is 1: 0.2-0.5, wherein the solvent B is selected from tetrahydrofuran, methyltetrahydrofuran, glycol dimethyl ether, dioxane and the like or a mixed solvent of the solvent B and water, and is preferably a mixed solvent of water and the solvent B; the reducing agent is selected from sodium borohydride, potassium borohydride and the like, and preferably sodium borohydride.

Wherein, in the step (1), the ionic liquid is separated by adopting methyl tert-butyl ether, and the 4-alkyl-3, 5 dimethoxy-methyl benzoate is obtained by liquid separation, water washing and spin drying.

Wherein, in the step (1), the ionic liquid is triethylamine hydrochloride-aluminum trichloride ionic liquid, and has a catalytic effect. The molar ratio of triethylamine hydrochloride to aluminum trichloride is 1:1-3 (specifically 1: 2), and the mass ratio of methyl 3, 5-dimethylbenzoate to ionic liquid is 1: 2-5.

Wherein, in the step (1), the alkylating reagent is selected from isopropyl chloride, isopropyl bromide, isopropanol-p-toluenesulfonate, isopropanol-methanesulfonate, ethanol-p-toluenesulfonate, ethanol-methanesulfonate or 1-chlorohexane, etc.

Preferably, in step (1), the alkylating agent is isopropyl chloride.

Wherein, in the step (2), the solvent A is selected from toluene or xylene.

Preferably, in step (2), the solvent a is toluene.

Preferably, in the step (3), the solvent B is a mixed solvent of tetrahydrofuran and water, and the volume ratio of the tetrahydrofuran to the water is 8-12: 1 (specifically, 10: 1 may be used).

Wherein, in the step (3), the alkali liquor is 1-6mol/L sodium hydroxide alkali liquor.

Preferably, the industrial preparation method of the 3, 5-dimethoxy, 4-alkyl benzyl alcohol disclosed by the invention comprises the following steps:

(1) carrying out Friedel-crafts alkylation reaction on 3, 5-dimethyl methyl benzoate and isopropyl chloride in ionic liquid at the temperature of 10-25 ℃, cooling to about 0 ℃ after the reaction is finished, adding methyl tert-butyl ether, separating liquid, washing with water, spin-drying and recrystallizing (methanol) to obtain 4-isopropyl-3, 5-dimethoxy-methyl benzoate. Wherein the ionic liquid is triethylamine hydrochloride-aluminum trichloride ionic liquid, and the molar ratio of the triethylamine hydrochloride to the aluminum trichloride is 1: the mass ratio of the 1-3, 3, 5-dimethyl methyl benzoate to the ionic liquid to the isopropyl chloride is 1: 2-5: 2-4.

(2) Performing amine ester exchange reaction between 4-isopropyl-3, 5 dimethoxy-methyl benzoate and imidazole in toluene at 60-80 deg.C, cooling for crystallization, and filtering to obtain 4-isopropyl-3, 5 dimethoxy-benzoylimidazole. Wherein the mass ratio of the 4-isopropyl-3, 5 dimethoxy-methyl benzoate to the imidazole is 1: 0.5-1.2.

(3) Carrying out reduction reaction on 4-isopropyl-3, 5 dimethoxy-benzoyl imidazole and sodium borohydride in a mixed solvent of tetrahydrofuran and water at 0-30 ℃, pouring into 1-6mol/L sodium hydroxide alkali liquor to quench after the reaction is finished, standing for layering, taking an organic phase, and carrying out spin drying and recrystallization (ethyl acetate) to obtain 4-isopropyl-3, 5 dimethoxy benzyl alcohol. Wherein the mass ratio of the 4-isopropyl-3, 5-dimethoxy-benzoyl imidazole to the sodium borohydride is 1: 0.2-0.5.

The invention develops an industrial preparation method of 3, 5-dimethoxy, 4-alkyl benzyl alcohol, isopropyl chloride or isopropanol p-toluenesulfonate, isopropanol p-toluenesulfonate and the like are selected to directly perform the para-alkylation on isopropyl under the action of a solvent of triethylamine hydrochloride ionic liquid and a catalyst; after the reaction is finished, organic solvent such as methyl tert-butyl ether is used for directly extracting and separating liquid, and the ionic liquid can be repeatedly used; sodium borohydride is directly used for reducing the acyl imidazole obtained by exchanging the isopropyl ester and imidazole in the last step in tetrahydrofuran aqueous solution under mild conditions (0-30 ℃ without adding a catalyst), the reduction is finished and directly poured into 1-6mol/L strong base solution for quenching, and an organic phase is separated, so that the 3, 5-dimethoxy-4-isopropyl benzyl alcohol is obtained safely and environmentally. The method is convenient and safe to operate, greatly reduces the problem of environmental pollution, and is suitable for industrial production.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.

EXAMPLE A preparation of methyl 4-isopropyl-3, 5 dimethoxy-benzoate

15kg of methyl 3, 5-dimethylbenzoate and 30kg of triethylamine hydrochloride aluminum trichloride ionic liquid are added into a 100L reaction kettle, 30L of 2-chloropropane is added at the low temperature of 0 ℃, the mixture is stirred at the room temperature for 8 hours, the temperature is reduced to 0 ℃, 50L of methyl tert-butyl ether is added into reaction liquid, liquid separation and water washing are carried out, so as to obtain white solid, 14.75kg of white solid product is obtained through recrystallization by using methanol, and the yield is 81%.

EXAMPLE preparation of methyl di-4-ethyl-3, 5 dimethoxy-benzoate

15kg of 3, 5-dimethyl methyl benzoate and 30kg of triethylamine hydrochloride aluminum trichloride ionic liquid are added into a 100L reaction kettle, 30L of ethyl alcohol methane benzene sulfonate is added at the low temperature of 0 ℃, the mixture is stirred for 8 hours at the room temperature, the temperature is reduced to 0 ℃, 50L of methyl tert-butyl ether is added into the reaction liquid, liquid separation and water washing and spin drying are carried out to obtain white solid, and the white solid product is recrystallized by methanol to obtain 13.1kg of white solid product with the yield of 76%.

EXAMPLE preparation of tris 4-hexyl-3, 5 dimethoxy-benzoic acid methyl ester

15kg of methyl 3, 5-dimethylbenzoate and 30kg of triethylamine hydrochloride aluminum trichloride ionic liquid are added into a 100L reaction kettle, 15L of 1-chlorohexane is added at the low temperature of 0 ℃, the mixture is stirred at the room temperature for 8 hours, the temperature is reduced to 0 ℃, 50L of methyl tert-butyl ether is added into the reaction liquid, liquid separation and water washing are carried out, so as to obtain white solid, 15.4kg of white solid product is obtained through recrystallization by using methanol, and the yield is 72%.

EXAMPLE preparation of tetrakis 4-isopropyl-3, 5 dimethoxy-benzoylimidazole

15kg of 4-isopropyl-3, 5-dimethoxy-benzoic acid methyl ester, 30L of toluene and 8.5kg of imidazole are added into a 100L reaction kettle, the temperature is slowly raised to 70-80 ℃, the mixture is stirred, the temperature is slowly reduced to 0 ℃ after no gas is discharged basically, the mixture is stirred and crystallized for more than 4 hours, and the white crystal 4-isopropyl-3, 5-dimethoxy-benzoyl imidazole 15.2kg is obtained after filtration, wherein the yield is 87%.

EXAMPLE five preparation of 4-isopropyl-3, 5 dimethoxy-benzyl alcohol

Adding 15.0 kg of 4-isopropyl-3, 5-dimethoxy-benzoylimidazole, 50L of tetrahydrofuran, 5L of water and 4kg of sodium borohydride into a 100L reaction kettle, stirring at room temperature for more than 6 hours, slowly pouring the mixture into 50L of 20% sodium hydroxide aqueous solution after the thin layer is completely monitored, separating the solution into two clear layers, carrying out organic phase separation, carrying out spin-drying to obtain a white solid, and recrystallizing with ethyl acetate to obtain 10.2kg of white crystals with the yield of 90%.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.