阅读说明：本技术 5-卤代邻藜芦醛的合成方法 (Synthesis method of 5-halogenated veratraldehyde ) 是由 陈芬儿 唐培� 李伟剑 蒋龙 于 2021-09-10 设计创作，主要内容包括：本发明属于有机化学领域,具体为一种5-卤代邻藜芦醛的合成方法,包括：用4-卤代愈创木酚为原料制得2-羟基-3-甲氧基-5-卤代扁桃酸；再用2-羟基-3-甲氧基-5-卤代扁桃酸制得5-卤代邻香兰素；再用5-卤代邻香兰素制得制得5-卤代邻藜芦醛。本发明的合成方法总收率在60％-70％之间,采用4-卤代愈创木酚为原料,克服了邻香兰素的来源受限,产能较低的问题。同时,本发明的5-卤代藜芦醛的合成方法,所使用的其他原料解释常见易得的原料,通过反应程序的优化,使反应条件温和,操作简便,化学收率高,成本低,非常适合工业化生产。(The invention belongs to the field of organic chemistry, and particularly relates to a method for synthesizing 5-halogenated veratraldehyde, which comprises the following steps: preparing 2-hydroxy-3-methoxy-5-halogenated mandelic acid from 4-halogenated guaiacol; then 2-hydroxy-3-methoxy-5-halogenated mandelic acid is used for preparing 5-halogenated o-vanillin; then 5-halogenated o-vanillin is used to prepare the 5-halogenated o veratraldehyde. The total yield of the synthetic method is 60-70%, 4-halogenated guaiacol is used as a raw material, and the problems of limited source and low productivity of o-vanillin are solved. Meanwhile, other raw materials used in the synthesis method of the 5-halogenated veratraldehyde explain common and easily-obtained raw materials, and the reaction condition is mild, the operation is simple and convenient, the chemical yield is high, the cost is low and the method is very suitable for industrial production through the optimization of a reaction program.)

1. A method for synthesizing 5-halogenated veratraldehyde, which is characterized by comprising the following steps:

preparing 2-hydroxy-3-methoxy-5-halogenated mandelic acid by using guaiacol as a raw material;

preparing 5-halogenated o-vanillin by using 2-hydroxy-3-methoxy-5-halogenated mandelic acid;

5-halogenated o-vanillin is prepared from the 5-halogenated o-vanillin.

2. The method for synthesizing 5-halogenated veratraldehyde according to claim 1, wherein the step of preparing 2-hydroxy-3-methoxy-5-halogenated mandelic acid from guaiacol comprises:

preparing 4-halogenated guaiacol by using guaiacol;

preparing 2-hydroxy-3-methoxy-5-halogenated mandelic acid by using 4-halogenated guaiacol as a raw material: 4-halogenated guaiacol and glyoxylic acid aqueous solution are subjected to electrophilic substitution reaction under the catalysis of inorganic base and the condition of adding alumina as an additive to prepare the 2-hydroxy-3-methoxy-5-halogenated mandelic acid.

3. The method of synthesizing 5-halogenated veratraldehyde according to claim 2, wherein the ratio of 4-halogenated guaiacol: inorganic base: alumina: the molar ratio of glyoxylic acid is 1.5-1.0: 3-1.5: 0.2-1.0: 1.0;

the inorganic alkali is sodium hydroxide or potassium hydroxide;

the alumina is neutral alumina or alkaline alumina;

the mass fraction of the glyoxylic acid aqueous solution is 40-50%.

4. The method for synthesizing 5-halogenated veratraldehyde according to claim 2, wherein the reaction temperature for preparing 2-hydroxy-3-methoxy-5-halogenated mandelic acid from 4-halogenated guaiacol is 25-100 ℃ and the reaction time is 6-24 hours.

5. The method for synthesizing 5-halogenated veratraldehyde according to claim 1, wherein the "preparing 5-halogenated o-vanillin with 2-hydroxy-3-methoxy-5-halogenated mandelic acid" specifically comprises:

oxidizing the 2-hydroxy-3-methoxy-5-halogenated mandelic acid by using metal inorganic salt in a mixed solvent of an organic solvent and water to perform decarboxylation oxidation to prepare the 5-halogenated o-vanillin.

6. The method of synthesizing 5-halo veratraldehyde according to claim 5, wherein the ratio of 2-hydroxy-3-methoxy-5-halo mandelic acid: the molar ratio of the metal inorganic salt is 1.0: 1.0 to 3.0;

the metal inorganic salt is any one of ferric chloride hydrate, cupric oxide, cuprous oxide or cupric hydroxide;

the organic solvent comprises one or two of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform or toluene;

the ratio of the organic solvent to the water is 5-1: 1.

7. the method for synthesizing 5-halogenated veratraldehyde according to claim 1, wherein the reaction temperature for preparing 5-halogenated o-vanillin from 2-hydroxy-3-methoxy-5-halogenated mandelic acid is 50-100 ℃ and the reaction time is 2-12 h.

8. The method for synthesizing 5-halogenated veratraldehyde according to claim 1, wherein the step of preparing 5-halogenated veratraldehyde from 5-halogenated o-vanillin comprises:

and carrying out methylation reaction on the 5-halogenated o-vanillin and a methylation reagent in the presence of an inorganic base and a phase-transfer catalyst in an organic solvent or in the absence of a solvent to obtain the 5-halogenated o-veratraldehyde.

9. The method of synthesizing 5-halo veratraldehyde according to claim 8, wherein the ratio of 5-halo-o-vanillin: inorganic base: phase transfer catalyst: the molar ratio of methylating agent is 1.0: 1.0-5.0: 0.1 to 1.0: 2.0 to 10;

the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide;

the phase-transfer catalyst is any one of tetrabutylammonium bromide, triethylbenzylammonium chloride, polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800;

the methylating agent is dimethyl sulfate or dimethyl carbonate.

10. The method for synthesizing 5-halogenated veratraldehyde according to claim 1, wherein the reaction temperature for preparing 5-halogenated veratraldehyde from 5-halogenated o-vanillin is 50-120 ℃ and the reaction time is 12-48 h.

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a synthesis method of 5-halogenated veratraldehyde.

Background

The veratraldehyde derivative is an important medical intermediate, can be used for synthesizing and preparing tetrahydropalmatine derivatives with central tranquilizing effect, berberine derivatives with antibacterial, antiarrhythmic, hypoglycemic effects and the like, plumbagic acid with phlegm eliminating and cough relieving effects, codeine analogues with cough relieving, sedative and analgesic effects and the like, and has wide application.

The veratraldehyde derivatives are mainly derived from chemical synthesis, and few reports are made on the preparation process at home and abroad. Kakde et al (org. Lett.2016,18,1752) reported a method for synthesizing 5-bromoveratraldehyde by brominating o-vanillin and then methylating to prepare 5-bromoveratraldehyde with a total yield of 80%.

Joshua et al (Synthetic Commun, 2008,38,434) reported another method for synthesizing 5-bromoveratraldehyde by first methylating o-vanillin and then brominating to produce 5-bromoveratraldehyde in an overall yield of 62%.

Patent publication No. CN101203500A discloses a method for synthesizing 5-chloro-o-veratraldehyde (see P138-139), which comprises preparing 5-chloro-o-veratraldehyde by using NCS chloro-o-vanillin and then carrying out methylation.

In the preparation method, firstly, the 5-halogenated o-veratraldehyde derivatives are all prepared from o-vanillin serving as a raw material, but the o-vanillin is a drug intermediate and can be used for synthesizing various drugs and spices. But because the o-vanillin is a byproduct for producing vanillin and ethyl vanillin, the o-vanillin source is limited, the productivity is low, and the price is high. Secondly, dimethyl sulfate with high toxicity is used in the methylation reaction in the preparation process, so that the labor protection cost is high.

Disclosure of Invention

In view of the above, the present invention provides a simple, efficient, and low-cost industrial synthesis method of 5-halogenated veratraldehyde.

The invention is realized by the following technical scheme:

a method for synthesizing 5-halogenated veratraldehyde (I), comprising:

preparing 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III) by using 4-halogenated guaiacol (II);

preparing 5-halogenated o-vanillin (IV) by using 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III);

5-halogenated o-vanillin (IV) is used to prepare 5-halogenated o-veratraldehyde (I).

The 4-halogenated guaiacol is prepared from guaiacol;

the synthesis process of the 5-halogenated veratraldehyde (I) is as follows:

wherein R is selected from Cl, Br and I halogen groups.

Further, the step of preparing the 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III) by using the 4-halogenated guaiacol (II) as a raw material specifically comprises the following steps:

4-halogenated guaiacol (II) and glyoxylic acid aqueous solution are subjected to electrophilic substitution reaction in a solvent under the catalysis of inorganic base and the condition of adding alumina as an additive to prepare 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III).

Preferably, in the electrophilic substitution reaction of the present invention:

the inorganic alkali is sodium hydroxide or potassium hydroxide; further preferred is sodium hydroxide.

The aluminum oxide (Al)₂O₃) Neutral alumina or basic alumina; further preferred is basic alumina.

The mass fraction of the glyoxylic acid aqueous solution is 40-50%; further preferably 50%.

The solvent for the reaction is water.

Preferably, the 4-halogenated guaiacol (II): inorganic base: alumina: the molar ratio of glyoxylic acid is 1.5-1.0: 3-1.5: 0.2-1.0: 1.0; further preferably, the molar ratio is 1.1: 1.8: 0.4: 1.0.

preferably, the reaction temperature of the electrophilic substitution reaction is 25 ℃ to 100 ℃; the reaction time is 6-24 h.

Further preferably, the reaction temperature of the electrophilic substitution reaction is 55 ℃ to 65 ℃; the reaction time is 11-13 h, and 12h is optimal.

Further, the step of preparing 5-halogeno-o-vanillin (IV) from 2-hydroxy-3-methoxy-5-halogenomandelic acid (III) specifically comprises:

oxidizing the 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III) by using metal inorganic salt in a mixed solvent of an organic solvent and water to perform decarboxylation oxidation to prepare 5-halogenated o-vanillin (IV).

Preferably, in the decarboxylation oxidation reaction of the present invention:

the metal inorganic salt is any one of ferric chloride hydrate, cupric oxide, cuprous oxide or cupric hydroxide; further preferably, the metal inorganic salt is ferric chloride hexahydrate, and the oxidant is stable in chemical property, low in price and easy to obtain.

The 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III): the molar ratio of the metal inorganic salt is 1.0: 1.0 to 3.0; further preferably, the molar ratio is 1.0: 1.5.

the organic solvent comprises one or two of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform or toluene; when the organic solvent is a mixed reagent, the mixing proportion is that the volume ratio is 1: 0.1 to 0.9; further preferably, the organic solvent is toluene.

The ratio of the organic solvent to the water is 5-1: 1; further preferably, the ratio of organic solvent to water is 2: 1.

preferably, the reaction temperature of the decarboxylation oxidation reaction is 50-100 ℃; the reaction time is 2-12 h.

Further preferably, the reaction temperature of the decarboxylation oxidation reaction is 90 ℃; the reaction time is 4-5 h, and 4h is optimal.

Further, the step of preparing the 5-halogenated o-veratraldehyde (I) by using the 5-halogenated o-vanillin (IV) specifically comprises the following steps:

and (2) carrying out methylation reaction on the 5-halogenated o-vanillin (IV) and a methylation reagent in the presence of an inorganic base and a phase-transfer catalyst under the condition of an organic solvent or no solvent to prepare the 5-halogenated o-veratraldehyde (I).

Preferably, in the methylation reaction of the present invention

The inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide; further preferably, the inorganic base is potassium carbonate.

The phase-transfer catalyst is any one of tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride (TEBAC), polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800; further preferably, the phase transfer catalyst is tetrabutylammonium bromide (TBAB).

The methylating agent is dimethyl carbonate.

The 5-halo-o-vanillin (IV): inorganic base: phase transfer catalyst: the molar ratio of methylating agent is 1.0: 1.0-5.0: 0.1 to 1.0: 2.0 to 10; further preferably, the molar ratio is 1.0: 2.0: 0.5: 10.

the reaction may use a single organic solvent such as tetrahydrofuran, dichloromethane, chloroform or 1, 2-dichloroethane. It is preferable that the reaction is carried out without using an additional organic solvent and is carried out smoothly only by dispersing in the methylating agent.

Preferably, the reaction temperature of the methylation reaction is 50-120 ℃; the reaction time is 12-48 h.

Further preferably, the reaction temperature of the methylation reaction is 100-110 ℃, and is optimally selected to be 110 ℃; the reaction time is 23-25 h, and 24h is optimal.

The invention has the beneficial effects that:

the synthesis method of the 5-halogenated veratraldehyde adopts the 4-halogenated guaiacol as the raw material, and overcomes the problems of limited source and low productivity of o-vanillin.

The synthesis method of the 5-halogenated veratraldehyde does not adopt the synthesis principle of the reaction of o-vanillin and dimethyl sulfate, and in the methylation reaction, the good catalytic effect can be achieved without using dimethyl sulfate or even using an additional organic solvent for reaction, thereby avoiding toxic and harmful raw materials and reducing the labor protection cost.

According to the synthesis method of the 5-halogenated veratraldehyde, the used other raw materials explain common and easily-obtained raw materials, and through optimization of a reaction program, the reaction condition is mild, the operation is simple and convenient, the chemical yield is high, the cost is low, and the synthesis method is very suitable for industrial production.

Detailed Description

In order to better explain the problems to be solved, the technical solutions adopted and the beneficial effects achieved by the technical solutions of the present invention, further description will be given with reference to specific embodiments. It should be noted that the technical solutions of the present invention include, but are not limited to, the following embodiments.

The specific techniques or conditions not specified in the examples of the present invention are performed according to the techniques or conditions described in the literature in the art or according to the product specification. The reagents or instruments used are not indicated by manufacturers, and are all conventional products which can be obtained by commercial purchase and the like.

The invention provides a synthetic method of 5-halogenated veratraldehyde (I). The method comprises the steps of carrying out electrophilic substitution reaction on 4-halogenated guaiacol (II) and glyoxylic acid aqueous solution in water as a solvent under the catalysis of inorganic base and the addition of alumina as an additive to prepare 2-hydroxy-3-methoxy-5-halogenated mandelic acid (III), carrying out decarboxylation oxidation in a mixed solvent of an organic solvent and water under the oxidation of metal inorganic salt to prepare 5-halogenated o-vanillin (IV), and finally carrying out methylation reaction with a methylation reagent under the participation of the inorganic base and a phase-transfer catalyst in the organic solvent or solvent-free condition to prepare the 5-halogenated o-veratraldehyde (I), wherein the total yield is between 60 and 70 percent. The synthetic route is as follows:

wherein R is selected from Cl, Br and I halogen groups.

Specifically, in the electrophilic substitution reaction of the present invention, the inorganic base is any one of sodium hydroxide or potassium hydroxide, and has a good catalytic effect. The alumina is neutral alumina or alkaline alumina. The alumina is cheap and easy to obtain, and can be used as a loading agent to promote homogeneous reaction in a water-used solvent. The mass fraction of the glyoxylic acid aqueous solution is any value between 40 and 50 percent, and the glyoxylic acid aqueous solution is also cheap and easy to obtain and has good reaction effect. Compound (II): inorganic base: alumina: the molar ratio of glyoxylic acid is 1.5-1.0: 3-1.5: 0.2-1.0: 1.0, and within this range, the reaction proceeded well. The solvent of the reaction is water, and the solvent is wide in source, economical and environment-friendly. The appropriate reaction temperature and reaction time are respectively 25-100 ℃ and 6-24 h.

In the decarboxylation oxidation reaction of the invention, the metal inorganic salt is any one of ferric chloride hydrate, cupric oxide, cuprous oxide or cupric hydroxide, and has good catalytic oxidation reaction effect. Compound (III): the molar ratio of the metal inorganic salt is 1.0: 1.0-3.0, and within the range of the material ratio, the reaction can be smoothly completed. The solvent for the reaction comprises at least one of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform and toluene, and can be a single solvent or a mixed reagent, and the volume ratio of the mixed reagent is 1: 0.1-0.9, and the solvents are wide in source, low in price, easy to obtain and convenient to recover. Meanwhile, the ratio of the organic solvent to the water is 5-1: 1, the reaction can be carried out well. The reaction temperature is controlled between 50 ℃ and 100 ℃. The reaction time is controlled to be 2-12 h, and the reaction is smoothly finished.

In the methylation reaction of the invention, the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide, and the methylation reaction can be well catalyzed. The phase-transfer catalyst is any one of tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride (TEBAC), polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800, and can promote the reaction to be well completed. The methylating agent is dimethyl sulfate or dimethyl carbonate, both of which can be used for methylation reaction. Compound (IV): inorganic base: phase transfer catalyst: the molar ratio of methylating agent is 1.0: 1.0-5.0: 0.1 to 1.0: 2.0-10, the reaction can be smoothly carried out. The reaction can be carried out using a single organic solvent such as tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane. The solvents are wide in source, cheap and easy to obtain, and convenient to recover. Meanwhile, the reaction can be carried out without an additional organic solvent, and the reaction can be carried out smoothly only by dispersing the organic solvent in a methylating agent. The reaction temperature is controlled between 50 ℃ and 120 ℃. The reaction time is controlled to be 12-48 h, and the reaction is smoothly finished.

Example 1

Preparation of 1.14-bromoguaiacol

Guaiacol (25g, 201mmol) was uniformly dispersed in 125mL of chloroform under the protection of argon, and the reaction mixture was pre-cooled at-5 ℃ for 10 minutes, and then a solution of bromine (10.3mL, 201mmol) in chloroform (75mL) was slowly added dropwise to the mixture to maintain the system as colorless as possible. After the dripping is finished, the reaction is moved to room temperature for 1 hour, and the reaction is detected by a TLC point plate. Using 150mL Sat. NaHSO₃(aq) quench reaction, separate in separatory funnel, aqueous layer extract 3 times with chloroform, combine organic phase, after one back wash with saturated salt solution, dry with anhydrous sodium sulfate and spin dry, get the light yellow crystal crude product. Reduced pressure distillation (97-100 deg.C/2 mmHg, lit.119-120 deg.C/5 mmHg) to obtain 4-bromoguaiacol (40g, 94%, mp 31-32 deg.C).

¹H NMR(400MHz,Chloroform-d)δ6.99(dd,J＝8.4,2.0Hz,1H),6.96(d,J＝2.0Hz,1H),6.80(d,J＝8.4Hz,1H),5.59(s,1H),3.87(s,3H)。

1.22 preparation of hydroxy-3-methoxy-5-bromomandelic acid

4-Bromoguaiacol (2g, 9.8mmol) was gradually added dropwise to a solution of sodium hydroxide (692mg, 17.3mmol) in water (12mL) under ice bath, to which was gradually added aluminum oxide powder (441.3mg, 4.33 mmol). After stirring for 5 minutes in an ice bath, an aqueous glyoxylic acid solution (50% by weight in H) was slowly added dropwise thereto₂O, 1.54g, 10.4mmol), and the pH value of the reaction solution is 9-10. Then the mixture is moved to 60 ℃ oil bath for reaction for 6 hoursThe reaction was monitored by TLC. After the reaction liquid is cooled to room temperature, the alumina powder is removed by suction filtration, and a small amount of 20% sodium hydroxide is used for washing a filter cake. Collecting the filtrate, adjusting the pH value of the filtrate to 3-4 by using concentrated hydrochloric acid, extracting a water layer for 4 times by using toluene, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, and then carrying out rotary drying on the organic phases, and recovering the raw material 4-bromoguaiacol (741mg, the conversion rate is 63%). The aqueous layer was then further adjusted to pH 1 with concentrated HCl, the aqueous layer was extracted 5 times with EA, the combined organic phases were dried over anhydrous sodium sulfate and spin dried, and the yellow solid product, 2-hydroxy-3-methoxy-5-bromomandelic acid (1.3g, 75%, decomp) was collected.>200℃)。

¹H NMR(400MHz,DMSO-d₆)δ12.44(br s,1H),9.11(br s,1H),7.05(d,J＝2.0Hz,1H),7.01(d,J＝2.0Hz,1H),5.80(br s,1H),5.25(s,1H),3.81(s,3H)。LC-MS(ESI)m/z calcd for[C₉H₈BrO₅]-276.0,found 276.0

Preparation of 32-hydroxy-3-methoxy-5-bromobenzaldehyde

Fully and uniformly mixing 25mL of aqueous solution of a crude product (5g, 18mmol) of 2-hydroxy-3-methoxy-5-bromomandelic acid with 100mL of toluene at room temperature, moving the mixture to a 90 ℃ oil bath for heating, slowly adding 20% of ferric trichloride aqueous solution (22mL,27mmol) into a reaction system, continuing to heat the mixture for reaction for 4 hours at the 90 ℃ oil bath after dripping is finished, and monitoring the reaction by TLC. Cooling the reaction solution to room temperature, adding appropriate amount of toluene to dilute the reaction solution, extracting the reaction solution with toluene in a separating funnel for 4 times, combining organic phases, washing the organic phases with water and saturated salt solution respectively, and washing with anhydrous Na₂SO₄After drying, spin-drying to obtain a pale yellow solid, 2-hydroxy-3-methoxy-5-bromobenzaldehyde (2.4g, 85%, mp ═ 115 ℃ C.). The pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted for 5 times by EA, the organic phases are combined and dried by anhydrous sodium sulfate, and then the 2-hydroxy-3-methoxy-5-bromomandelic acid (1.5g, the conversion rate is 70%) is recovered.

¹H NMR(400MHz,Chloroform-d)δ11.04(s,1H),9.85(s,1H),7.32(d,J＝2.0Hz,1H),7.18(d,J＝2.0Hz,1H),3.92(s,3H).。

Preparation of 42, 3-dimethoxy-5-bromobenzaldehyde

Sequentially adding 2 into the reaction kettleHydroxy-3-methoxy-5-bromobenzaldehyde (4g, 17.3mmol), 24.6mL dimethyl carbonate, tetrabutylammonium bromide (2.64g, 8.2mmol) and potassium carbonate (4.8g, 34.6mmol) were dispersed uniformly at room temperature, then warmed to 110 ℃ for 12 hours and monitored by TLC. Adding appropriate amount of water into the reaction system, extracting with diethyl ether in a separating funnel for 3 times, mixing organic phases, washing the organic phase with water and saturated salt solution once respectively, and passing through anhydrous Na₂SO₄Drying and spin-drying to obtain a brownish red solid crude product of 2, 3-dimethoxy-5-bromobenzaldehyde (4.038g, 98%, mp ═ 77-78 ℃).

¹H NMR(400MHz,Chloroform-d)δ10.34(s,1H),7.53(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),3.97(s,3H),3.91(s,3H)。

Preparation of 52-hydroxy-3-methoxy-5-bromomandelic acid

4-Bromoguaiacol (2g, 9.8mmol) was gradually added dropwise to a solution of potassium hydroxide (970mg, 17.3mmol) in water (12mL) under ice bath, to which alumina powder (1.059g, 4.33mmol) was gradually added. After stirring for 5 minutes in an ice bath, an aqueous solution of glyoxylic acid (50% wt% in H2O, 1.54g, 10.4mmol) was slowly added dropwise thereto, and the pH of the reaction mixture was 9 to 10. Then, the reaction mixture was transferred to an oil bath at 80 ℃ for 4 hours, and the reaction was monitored by TLC. After the reaction liquid is cooled to room temperature, the alumina powder is removed by suction filtration, and a small amount of 20% sodium hydroxide is used for washing a filter cake. Collecting the filtrate, adjusting the pH value of the filtrate to 3-4 by using concentrated hydrochloric acid, extracting a water layer for 4 times by using toluene, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, and then carrying out rotary drying on the organic phases, and recovering the raw material 4-bromoguaiacol (741mg, with the conversion rate of 60%). Then the water layer is continuously adjusted to pH value 1 by concentrated hydrochloric acid, the water layer is extracted 5 times by EA, the organic phases are combined and dried by anhydrous sodium sulfate and then are dried by rotation, and the yellow solid product 2-hydroxy-3-methoxy-5-bromine mandelic acid (1.2g, 70 percent) is collected.

Preparation of 62-hydroxy-3-methoxy-5-bromobenzaldehyde

Fully and uniformly mixing 25mL of aqueous solution of 2-hydroxy-3-methoxy-5-bromomandelic acid crude product (5g, 18mmol) and 100mL of toluene at room temperature, moving to a 90 ℃ oil bath for heating, slowly adding 20% ferric trichloride aqueous solution (44mL,54mmol) into the reaction system, continuing to heat the reaction system in the 100 ℃ oil bath for 12 hours after dripping, and monitoring by TLCAnd (5) detecting the reaction. Cooling the reaction solution to room temperature, adding appropriate amount of toluene to dilute the reaction solution, extracting the reaction solution with toluene in a separating funnel for 4 times, combining organic phases, washing the organic phases with water and saturated salt solution respectively, and washing with anhydrous Na₂SO₄After drying, spin-drying to obtain light yellow solid 2-hydroxy-3-methoxy-5-bromobenzaldehyde (2.5g, 90%). The pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted for 5 times by EA, the organic phases are combined and dried by anhydrous sodium sulfate, and then the 2-hydroxy-3-methoxy-5-bromomandelic acid (1.5g, the conversion rate is 76%) is recovered.

Preparation of 72, 3-dimethoxy-5-bromobenzaldehyde

2-hydroxy-3-methoxy-5-bromobenzaldehyde (4g, 17.3mmol), 24.6mL of dimethyl carbonate, polyethylene glycol 600(1.02g, 1.7mmol) and potassium carbonate (11.9g, 86.5mmol) were added in this order to disperse uniformly at room temperature, then the temperature was raised to 120 ℃ for reaction for 18 hours, and the reaction was monitored by TLC. Adding appropriate amount of water into the reaction system, extracting with diethyl ether in a separating funnel for 3 times, mixing organic phases, washing the organic phase with water and saturated salt solution once respectively, and passing through anhydrous Na₂SO₄Drying and spin-drying to obtain a brownish red solid crude product of 2, 3-dimethoxy-5-bromobenzaldehyde (3.7g, 90%, mp ═ 77-78 ℃).

Example 2

Preparation of 2.14-chloroguaiacol

Guaiacol (12.4g, 100mmol) was dispersed uniformly in 50mL chloroform under argon protection in a cold salt bath (-5 deg.C) and sulfuryl chloride (13mL, 160mmol) was slowly added dropwise thereto. After the addition, the reaction mixture was returned to 60 ℃ for 24 hours under reflux, and the reaction was monitored by TLC dot plate. In ice bath, 50mL Sat.Na is used₂S₂O₃The solution was quenched, separated in a separatory funnel, the aqueous layer was extracted 3 times with chloroform, the organic phases were combined, back washed once with saturated brine, dried over anhydrous sodium sulfate and spin dried to give 16.7g of crude brown yellow liquid. Reduced pressure distillation (82-90 deg.C/2 mmHg, lit.130 deg.C/7.5 mmHg) gave 4-chloroguaiacol as a pale yellow oily liquid (12.7g, 80%) with a content of 87% (GC-MS).

¹H NMR(400MHz,Chloroform-d)δ6.84(s,3H),5.61(s,1H),3.86(s,3H).

Preparation of 2.22-hydroxy-3-methoxy-5-chloromandelic acid

4-chloroguaiacol (10g, 63mmol) was gradually added dropwise to a 75mL aqueous solution containing sodium hydroxide (4.1g, 102mmol) under ice-cooling, and then alumina powder (2.57g, 25.2mmol) was gradually added thereto. After stirring for 5 minutes in an ice bath, an aqueous glyoxylic acid solution (50% by weight in H) was slowly added dropwise thereto₂O, 8.5g, 57mmol), the pH of the reaction solution is 9-10. Then, the reaction mixture was transferred to an oil bath at 60 ℃ for 6 hours, and the reaction was monitored by TLC. After the reaction liquid is cooled to room temperature, the alumina powder is removed by suction filtration, and a small amount of 20% sodium hydroxide is used for washing a filter cake. Collecting filtrate, adjusting pH of the filtrate to 3-4 with concentrated hydrochloric acid, extracting water layer with toluene for 4 times, mixing organic phases, drying with anhydrous sodium sulfate, and spin-drying to recover 4-chloroguaiacol (4.9g, conversion rate 51%). Then the pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted by EA for 5 times, the combined organic phases are dried by anhydrous sodium sulfate and then are dried by spinning, and the white solid product 2-hydroxy-3-methoxy-5-chloromandelic acid (5.7g, 86 percent, mp ═ 123-.

¹H NMR(400MHz,DMSO-d₆)δ6.94(d,J＝2.5Hz,1H),6.87(d,J＝2.5Hz,1H),5.25(s,1H),3.81(s,3H).LC-MS(ESI)m/z calcd for[C₉H₈ClO₅]-231.6,found231.6

Preparation of 32-hydroxy-3-methoxy-5-chlorobenzaldehyde

Fully and uniformly mixing 25mL of aqueous solution of 2-hydroxy-3-methoxy-5-chloromandelic acid crude product (5g, 21.5mmol) and 100mL of toluene at room temperature, moving the mixture to a 90 ℃ oil bath for heating, slowly adding 20% ferric trichloride aqueous solution (26mL,32.2mmol) into the reaction system, continuing to heat the mixture in the 90 ℃ oil bath for 4 hours after dripping is finished, and monitoring the reaction by TLC. Cooling the reaction solution to room temperature, adding appropriate amount of toluene to dilute the reaction solution, extracting the reaction solution with toluene in a separating funnel for 4 times, combining organic phases, washing the organic phases with water and saturated salt solution respectively, and washing with anhydrous Na₂SO₄After drying, the crude product was obtained as a pale green solid (2.4g, 86%, mp 92-96 ℃) and 82% (GC-MS) of 2-hydroxy-3-methoxy-5-chlorobenzaldehyde. The aqueous layer was further adjusted to pH 1 with concentrated HCl and the water extracted with EAThe layers are separated for 5 times, the combined organic phases are dried by anhydrous sodium sulfate and then are dried by spinning, and the raw material 2-hydroxy-3-methoxy-5-chloromandelic acid (1.5g, the conversion rate is 70%) is recovered.

¹H NMR(400MHz,Chloroform-d)δ10.97(s,1H),9.86(s,1H),7.17(d,J＝2.4Hz,1H),7.05(d,J＝2.4Hz,1H),3.92(s,3H).

Preparation of 42, 3-dimethoxy-5-chlorobenzaldehyde

2-hydroxy-3-methoxy-5-chlorobenzaldehyde (2.3g, 12.3mmol), 17.5mL dimethyl carbonate, tetrabutylammonium bromide (1.88g, 5.83mmol) and potassium carbonate (3.41g, 24.6mmol) were added in this order to disperse uniformly at room temperature, then the temperature was raised to 110 ℃ for 12 hours, and the reaction was monitored by TLC. Adding appropriate amount of water into the reaction system, extracting with diethyl ether in a separating funnel for 3 times, mixing organic phases, washing the organic phase with water and saturated salt solution once respectively, and passing through anhydrous Na₂SO₄After drying, spin-drying to give a brown solid crude 2, 3-dimethoxy-5-chlorobenzaldehyde (2.3g, 95%, mp ═ 80-84 ℃ C.), with a content of 96% (HPLC).

¹H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.38(d,J＝2.4Hz,1H),7.09(d,J＝2.4Hz,1H),3.97(s,3H),3.91(s,3H).

Preparation of 52-hydroxy-3-methoxy-5-chloromandelic acid

4-chloroguaiacol (10g, 63mmol) was gradually added dropwise to a 75mL aqueous solution containing potassium hydroxide (5.7g, 102mmol) under ice-cooling, and then aluminum oxide powder (3.2g, 31.5mmol) was gradually added thereto. After stirring for 5 minutes in an ice bath, an aqueous solution of glyoxylic acid (50% wt.% in H2O, 8.5g, 57mmol) was slowly added dropwise thereto at a pH of the reaction mixture of 9 to 10. Then, the reaction mixture was transferred to an oil bath at 80 ℃ for 12 hours, and the reaction was monitored by TLC. After the reaction liquid is cooled to room temperature, the alumina powder is removed by suction filtration, and a small amount of 20% sodium hydroxide is used for washing a filter cake. Collecting filtrate, adjusting pH of the filtrate to 3-4 with concentrated hydrochloric acid, extracting water layer with toluene for 4 times, mixing organic phases, drying with anhydrous sodium sulfate, and spin-drying to recover 4-chloroguaiacol (4.0g, conversion rate 60%). Then the pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted by EA for 5 times, the combined organic phases are dried by anhydrous sodium sulfate and then are dried by spinning, and the white solid product 2-hydroxy-3-methoxy-5-chloromandelic acid (5.5g, 83 percent, mp ═ 123-.

Preparation of 62-hydroxy-3-methoxy-5-chlorobenzaldehyde

Fully and uniformly mixing 25mL of aqueous solution of a 2-hydroxy-3-methoxy-5-chloromandelic acid crude product (5g, 21.5mmol) and 100mL of toluene at room temperature, moving the mixture to a 100 ℃ oil bath for heating, slowly adding 20% ferric trichloride aqueous solution (52mL,64.5mmol) into a reaction system, continuing to heat the mixture in the 120 ℃ oil bath for reaction for 8 hours after dripping is finished, and monitoring the reaction by TLC. Cooling the reaction solution to room temperature, adding appropriate amount of toluene to dilute the reaction solution, extracting the reaction solution with toluene in a separating funnel for 4 times, combining organic phases, washing the organic phases with water and saturated salt solution respectively, and washing with anhydrous Na₂SO₄After drying, the crude product was obtained as a pale green solid (2.4g, 86%, mp 92-96 ℃) and 82% (GC-MS) of 2-hydroxy-3-methoxy-5-chlorobenzaldehyde. The pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted for 5 times by EA, the organic phases are combined and dried by anhydrous sodium sulfate and then are spin-dried, and the raw material 2-hydroxy-3-methoxyl-5-chloromandelic acid (1.5g, the conversion rate is 70%) is recovered.

Preparation of 72, 3-dimethoxy-5-chlorobenzaldehyde

2-hydroxy-3-methoxy-5-chlorobenzaldehyde (2.3g, 12.3mmol), 17.5mL dimethyl carbonate, polyethylene glycol 600(3.49g, 5.83mmol) and potassium carbonate (8.4g, 61.5mmol) were added in sequence to the reaction vessel and dispersed uniformly at room temperature, then the temperature was raised to 120 ℃ for reaction for 18 hours, and the reaction was monitored by TLC. Adding appropriate amount of water into the reaction system, extracting with diethyl ether in a separating funnel for 3 times, mixing organic phases, washing the organic phase with water and saturated salt solution once respectively, and passing through anhydrous Na₂SO₄After drying, spin-drying gave a brown solid crude 2, 3-dimethoxy-5-chlorobenzaldehyde (2.17g, 90%, mp. 80-84 ℃).

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.