4, 5-dimethoxy phenyl ester compound as well as preparation method and application thereof

Abstract

The invention provides a 4, 5-dimethoxy phenyl ester compound as well as a preparation method and application thereof, and belongs to the technical field of medical chemistry. The structural formula of the 4, 5-dimethoxy phenyl ester compound is as shown in formula 1. The compound prepared by the invention can obviously reduce the occurrence rate of ankylosing attack and has obvious anti-epileptic activity.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a 4,5-dimethoxyphenyl ester compound, a preparation method and an application thereof. Background Art

[0002] Epilepsy is a common neurological disorder characterized by spontaneous, recurrent seizures caused by abnormal discharges of brain neurons. The hallmarks of epilepsy are spontaneous, recurrent seizures characterized by convulsions, loss of consciousness, myoclonus, hypotonia, and prolonged muscle contractions. The pathogenesis of epilepsy includes: 1) ion channel dysfunction; 2) imbalanced neurotransmitter secretion; 3) irregular neuroglial systems; 4) neuroinflammation and oxidative stress; and 5) abnormal neural circuits. Globally, there are approximately 65 million epilepsy patients, including approximately 10 million in China. While surgery and diet can be used to treat epilepsy, medication remains the preferred treatment.

[0003] Most anti-epileptic drugs currently on the market and under development primarily target ion channels, exerting their pharmacological effects by reducing the excitability of the nervous system. Their mechanisms of action include: 1) Inhibition of voltage-gated sodium channels: Voltage-gated sodium channels are the primary ion channels responsible for the rapid depolarization of neuronal action potentials. Inhibition of sodium channel currents can inhibit the generation and transmission of action potentials. Representative drugs include carbamazepine and phenytoin. 2) Enhancement of GABAA receptor activity: GABAA receptors are activated by the endogenous neurotransmitter GABA, generating inhibitory Cl- currents. Enhancing GABAA receptor activity can lower cell membrane potential and reduce neuronal excitability, making them the target of benzodiazepine anti-epileptic drugs. 3) Activation of voltage-gated potassium channels: Opening of potassium channels allows a large outflow of potassium ions, lowering cell membrane potential. Retigabine, developed by GlaxoSmithKline, is the first potassium channel opener for the treatment of epilepsy. 4) Inhibition of ionotropic glutamate receptors: Glutamate is an important neurotransmitter in the central nervous system. Ionotropic glutamate receptors are coupled to cation channels and are divided into three types: NMDA, KA, and AMPA. Glutamate-mediated neuronal hyperexcitation plays a key role in inducing epileptic seizures, so inhibition of ionotropic glutamate receptors can treat epilepsy. Representative drugs include the NMDA receptor antagonist ketamine and the AMPA receptor antagonist perampanel. 5) Inhibition of voltage-gated calcium channels: Voltage-gated calcium channels can be divided into L-type, T-type, N-type, R-type, and P / Q-type calcium channels based on their activation voltage and current characteristics. The antiepileptic drugs gabapentin and pregabalin are N-type calcium channel inhibitors, and ethosuximide is a T-type calcium channel inhibitor.

[0004] In addition, the mechanism of action of antiepileptic drugs also includes regulating the release of neurotransmitters through presynaptic effects (representative drugs are levetiracetam and brivaracetam) and mechanism-targeted drugs, such as carbonic anhydrase (CA) inhibitors and rapamycin (mTOR) inhibitors.

[0005] Although a variety of anti-epileptic drugs have been approved for clinical use, 30% of patients still cannot effectively relieve their symptoms due to drug side effects, specific reactions or drug tolerance. Therefore, the development of safer and more effective anti-epileptic drugs is still of great significance.

[0006] Based on this, the present invention provides a 4,5-dimethoxyphenyl ester compound with novel structure and high anti-epileptic effect, so as to provide a better drug option for the treatment of epilepsy. Summary of the Invention

[0007] The purpose of the present invention is to provide a 4,5-dimethoxyphenyl ester compound and its preparation method and application, so as to solve the technical problem that the targets of anti-epileptic drugs in the prior art are concentrated on ion channels or neurotransmitter systems and lack the technical problem of multi-mechanism synergistic effects.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a 4,5-dimethoxyphenyl ester compound, the structural formula of the 4,5-dimethoxyphenyl ester compound is shown in Formula 1:

[0010]

[0011] Among them, R 1 Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkyl derivatives;

[0012] When R in Formula 1 2 and R 3 When the dashed line between is not present, R 2 、R 3 Each selected from hydrogen, C 1-6 Alkyl, and R 2 、R 3 Not simultaneously hydrogen;

[0013] When R in Formula 1 2 and R 3 When the dotted line between the two is a bond, R 2 、R 3 Independently selected from C 1-3 Alkylene.

[0014] Furthermore, the 4,5-dimethoxyphenyl ester compound is selected from the compounds having the following structures:

[0015]

[0016] The present invention provides a method for preparing a 4,5-dimethoxyphenyl ester compound, comprising the following steps:

[0017] 1) dissolving compound a in dichloromethane, cooling, adding a dichloromethane solution of boron tribromide to react, and obtaining compound b;

[0018] 2) Ethyltriphenylphosphine bromide was mixed in tetrahydrofuran, and after cooling, n-butyl lithium was added dropwise to carry out a primary reaction. After cooling again, a tetrahydrofuran solution of compound b was added dropwise to carry out a secondary reaction to obtain compound c;

[0019] 3) (4-bromobutyl)triphenylphosphonium bromide was mixed in tetrahydrofuran, and after cooling, potassium tert-butoxide solution was added dropwise to carry out a primary reaction, and after cooling again, a tetrahydrofuran solution of compound b was added dropwise to carry out a secondary reaction to obtain compound d;

[0020] 4) Compound b is mixed with tetrahydrofuran, cooled, and isopropylmagnesium bromide is added dropwise to carry out a primary reaction to obtain an alcohol intermediate, which is then dehydrated with toluene and anhydrous copper sulfate to obtain compound e;

[0021] 5) Compound c, a basic compound and an organic solvent are mixed, cooled, and then an acyl chloride is added to react to obtain compound 1-5.

[0022] or

[0023] Compound d, a basic compound, and an organic solvent are mixed, cooled, and then acyl chloride is added to react to obtain compound 7.

[0024] or,

[0025] Compound e, a basic compound, and an organic solvent are mixed, cooled, and then an acyl chloride is added to react to obtain compound 8;

[0026] 6) Mixing acetic anhydride and formic acid for a first reaction, and then adding compound c and sodium bicarbonate for a second reaction to obtain compound 6;

[0027] The structural formula of the compound a is:

[0028]

[0029] The structural formula of the compound b is:

[0030]

[0031] The structural formula of the compound c is:

[0032]

[0033] The structural formula of the compound d is:

[0034]

[0035] The structural formula of the compound e is:

[0036]

[0037] Further, in the step 1), the molar volume ratio of the compound a and dichloromethane is 140-160 mmol: 340-350 mL;

[0038] The molar volume ratio of boron tribromide and dichloromethane in the boron tribromide dichloromethane solution is 140-160 mmol: 150-160 mL;

[0039] The molar ratio of the compound a and boron tribromide is 140-160: 140-160;

[0040] In the step 1), the reaction temperature is 20-40℃.

[0041] Further, in the step 2), the amount ratio of ethyl triphenylphosphonium bromide, tetrahydrofuran and n-butyllithium is 280-295 mmol: 275 mL: 280-295 mmol;

[0042] The molar volume ratio of compound b and tetrahydrofuran in the tetrahydrofuran solution of the compound b is 130-140 mmol: 140-160 mL;

[0043] The molar ratio of ethyl triphenylphosphonium bromide and compound b is 280-295: 130-140;

[0044] In the step 2), the temperature of one reaction is 20-40℃, and the time of one reaction is 30-60 min; the temperature of two reactions is 20-40℃.

[0045] Further, in the step 3), the amount ratio of (4-bromobutyl) triphenylphosphonium bromide, tetrahydrofuran and potassium tert-butoxide solution is 8-10 mmol: 10-15 mL: 15-20 mmol;

[0046] The molar volume ratio of compound b and tetrahydrofuran in the tetrahydrofuran solution of the compound b is 5-6 mmol: 10-15 mL;

[0047] The molar ratio of (4-bromobutyl) triphenylphosphonium bromide and compound b is 8-10: 5-6;

[0048] In the step 3), the temperature of the primary reaction is 60-80°C, and the time of the primary reaction is 50-70 minutes; the temperature of the secondary reaction is 60-80°C.

[0049] Furthermore, in the step 4), the ratio of compound b, tetrahydrofuran and isopropylmagnesium bromide is 15-18 mmol: 60-70 mL: 40-50 mmol;

[0050] The alcohol intermediate, toluene and anhydrous copper sulfate are used in a ratio of 11-15 mmol: 40-60 mL: 15-25 mmol;

[0051] In the step 4), the temperature of the primary reaction is 20-40° C., the time of the primary reaction is 50-70 min; the temperature of the dehydration reaction is 100-120° C.

[0052] Furthermore, in step 5), the basic compound independently comprises 4-dimethylaminopyridine and / or triethylamine;

[0053] The acyl chlorides independently include one or more of acetyl chloride, propionyl chloride, isobutyryl chloride, 2-methylbutyryl chloride and 2-ethylbutyryl chloride;

[0054] The organic solvent independently comprises anhydrous dichloromethane and / or anhydrous tetrahydrofuran;

[0055] The ratio of compound c, alkaline compound, organic solvent and acyl chloride is 1-11 mmol: 2-21 mmol: 5-25 mL: 1.6-13 mmol;

[0056] The ratio of compound d, basic compound, organic solvent and acyl chloride is 1-2 mmol: 2-3 mmol: 5-10 mL: 1-3 mmol;

[0057] The ratio of compound e, alkaline compound, organic solvent and acyl chloride is 3-5 mmol: 8-11 mmol: 5-10 mL: 6-8 mmol;

[0058] In the step 5), the reaction temperature is 20-40°C.

[0059] Furthermore, in step 6), the molar ratio of acetic anhydride, formic acid, compound c and sodium bicarbonate is 32-33:41-42:4-5:8-9;

[0060] In step 6), the temperature of the first reaction is 50-70° C., the time of the first reaction is 0.5-2 h, the temperature of the second reaction is 20-40° C., and the time of the second reaction is 16-24 h;

[0061] The temperature of the cooling in the steps 1) to 5) is independently ≤-5℃.

[0062] The application also provides application of the 4,5-dimethoxyphenyl ester compound in preparation of an anti-epilepsy drug, wherein the anti-epilepsy drug comprises the 4,5-dimethoxyphenyl ester compound and stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable co-crystals thereof.

[0063] The application has the following beneficial effects:

[0064] The 4,5-dimethoxyphenyl ester compound prepared by the application has multiple anti-epilepsy mechanisms, can significantly reduce the incidence of convulsive seizures, and has significant anti-epilepsy activity. DETAILED DESCRIPTION

[0065] The application provides a 4,5-dimethoxyphenyl ester compound, and a structural formula of the 4,5-dimethoxyphenyl ester compound is shown as formula 1.

[0066]

[0067] R 1 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkyl derivatives;

[0068] When the dotted line between R 2 and R 3 in formula 1 is a bond, R 2 , R 3 are each selected from hydrogen, C 1-6 alkyl, and R 2 , R 3 are not hydrogen at the same time;

[0069] When the dotted line between R 2 and R 3 in formula 1 is a bond, R 2 , R 3 are independently selected from C 1-3 alkylene. In the application, the 4,5-dimethoxyphenyl ester compound is selected from the following compounds:

[0070]

[0071] The application provides a preparation method of a 4,5-dimethoxyphenyl ester compound, comprising the following steps:

[0072] 1) dissolving compound a in dichloromethane, and then adding a boron tribromide dichloromethane solution after cooling to react to obtain compound b;

[0073] 2) Ethyltriphenylphosphine bromide was mixed in tetrahydrofuran, and after cooling, n-butyl lithium was added dropwise to carry out a primary reaction. After cooling again, a tetrahydrofuran solution of compound b was added dropwise to carry out a secondary reaction to obtain compound c;

[0074] 3) (4-bromobutyl)triphenylphosphonium bromide was mixed in tetrahydrofuran, and after cooling, potassium tert-butoxide solution was added dropwise to carry out a primary reaction, and after cooling again, a tetrahydrofuran solution of compound b was added dropwise to carry out a secondary reaction to obtain compound d;

[0075] 4) Compound b is mixed with tetrahydrofuran, cooled, and isopropylmagnesium bromide is added dropwise to carry out a primary reaction to obtain an alcohol intermediate, which is then dehydrated with toluene and anhydrous copper sulfate to obtain compound e;

[0076] 5) Compound c, a basic compound and an organic solvent are mixed, cooled, and then an acyl chloride is added to react to obtain compound 1-5.

[0077] or

[0078] Compound d, a basic compound, and an organic solvent are mixed, cooled, and then acyl chloride is added to react to obtain compound 7.

[0079] or,

[0080] Compound e, a basic compound, and an organic solvent are mixed, cooled, and then an acyl chloride is added to react to obtain compound 8;

[0081] 6) Mixing acetic anhydride and formic acid for a first reaction, and then adding compound c and sodium bicarbonate for a second reaction to obtain compound 6;

[0082] The structural formula of the compound a is:

[0083]

[0084] The structural formula of the compound b is:

[0085]

[0086] The structural formula of the compound c is:

[0087]

[0088] The structural formula of the compound d is:

[0089]

[0090] The structural formula of the compound e is:

[0091]

[0092] In the present invention, in step 1), the molar volume ratio of compound a and dichloromethane is 140-160 mmol: 340-350 mL, preferably 142-158 mmol: 342-348 mL, and more preferably 145-155 mmol: 344-346 mL;

[0093] The molar volume ratio of boron tribromide to dichloromethane in the dichloromethane solution of boron tribromide is 140-160 mmol:150-160 mL, preferably 142-158 mmol:151-158 mL, and more preferably 145-155 mmol:153-156 mL;

[0094] The molar ratio of the compound a to boron tribromide is 140-160:140-160, preferably 142-158:142-158, and more preferably 145-155:145-155.

[0095] In the present invention, in step 1), the reaction temperature is 20-40°C, preferably 22-38°C, and more preferably 25-35°C.

[0096] In the present invention, in the step 2), the ratio of ethyltriphenylphosphine bromide, tetrahydrofuran and n-butyl lithium is 280-295 mmol: 275 mL: 280-295 mmol, preferably 283-293 mmol: 275 mL: 283-293 mmol, and more preferably 286-290 mmol: 275 mL: 286-290 mmol;

[0097] The molar volume ratio of compound b to tetrahydrofuran in the tetrahydrofuran solution of compound b is 130-140 mmol:140-160 mL, preferably 132-139 mmol:145-155 mL, and more preferably 134-137.5 mmol:150 mL;

[0098] The molar ratio of ethyltriphenylphosphonium bromide to compound b is 280-295:130-140, preferably 283-293:132-139, and more preferably 286-290:134-137.5.

[0099] In the present invention, in step 2), the temperature of the primary reaction is 20-40°C, preferably 22-38°C, more preferably 25-35°C; the time of the primary reaction is 30-60 min, preferably 35-55 min, more preferably 40-50 min; the temperature of the secondary reaction is 20-40°C, preferably 22-38°C, more preferably 25-35°C.

[0100] In the present invention, in step 3), the ratio of (4-bromobutyl)triphenylphosphine bromide, tetrahydrofuran and potassium tert-butoxide solution is 8-10 mmol:10-15 mL:15-20 mmol, preferably 8.1-9.0 mmol:11-14 mL:16-19 mmol, and more preferably 8.2-8.5 mmol:12-13 mL:17-18 mmol;

[0101] The molar volume ratio of compound b to tetrahydrofuran in the tetrahydrofuran solution of compound b is 5-6 mmol:10-15 mL, preferably 5.2-5.8 mmol:11-14 mL, and more preferably 5.4-5.6 mmol:12-13 mL;

[0102] The molar ratio of (4-bromobutyl)triphenylphosphonium bromide to compound b is 8-10:5-6, preferably 8.1-9.0:5.2-5.8, and more preferably 8.2-8.5:5.4-5.6;

[0103] In the present invention, in step 3), the temperature of the primary reaction is 60-80°C, preferably 65-75°C, and more preferably 70°C; the time of the primary reaction is 50-70 min, preferably 55-65 min, and more preferably 60 min; the temperature of the secondary reaction is 60-80°C, preferably 65-75°C, and more preferably 70°C.

[0104] In the present invention, in step 4), the ratio of compound b, tetrahydrofuran and isopropylmagnesium bromide is 15-18 mmol: 60-70 mL: 40-50 mmol, preferably 15.5-17.5 mmol: 62-68 mL: 42-48 mmol, and more preferably 16-17 mmol: 66 mL: 46 mmol;

[0105] The usage ratio of the alcohol intermediate, toluene and anhydrous copper sulfate is 11-15 mmol:40-60 mL:15-25 mmol, preferably 12-14 mmol:42-57 mL:18-22 mmol, and more preferably 13 mmol:45-55 mL:20 mmol.

[0106] In the present invention, in step 4), the temperature of the primary reaction is 20-40°C, preferably 25-35°C, more preferably 30°C; the time of the primary reaction is 50-70 min, preferably 55-65 min, more preferably 60 min; the temperature of the dehydration reaction is 100-120°C, preferably 105-115°C, more preferably 110°C.

[0107] In the present invention, in step 5), the basic compound independently comprises 4-dimethylaminopyridine and / or triethylamine, preferably triethylamine;

[0108] The acyl chlorides independently include one or more of acetyl chloride, propionyl chloride, isobutyryl chloride, 2-methylbutyryl chloride and 2-ethylbutyryl chloride, preferably one or more of acetyl chloride, propionyl chloride, isobutyryl chloride and 2-ethylbutyryl chloride, more preferably one or more of acetyl chloride, propionyl chloride and isobutyryl chloride;

[0109] The organic solvent independently comprises anhydrous dichloromethane and / or anhydrous tetrahydrofuran, preferably anhydrous dichloromethane.

[0110] In the present invention, in the step 5), the ratio of compound c, basic compound, organic solvent and acid chloride is 1-11 mmol: 2-21 mmol: 5-25 mL: 1.6-13 mmol, preferably 1.2-10.8 mmol: 2.5-20.8 mmol: 6-22 mL: 1.8-12.8 mmol, more preferably 1.5-10.6 mmol: 3-20.6 mmol: 8-20 mL: 2.0-12.6 mmol;

[0111] The usage ratio of the compound d, the basic compound, the organic solvent and the acid chloride is 1-2 mmol: 2-3 mmol: 5-10 mL: 1-3 mmol, preferably 1.2-1.8 mmol: 2.1-2.9 mmol: 6-9 mL: 1.2-2.2 mmol, more preferably 1.3-1.6 mmol: 2.2-2.8 mmol: 8 mL: 1.8-2.0 mmol;

[0112] The usage ratio of the compound e, the basic compound, the organic solvent and the acid chloride is 3-5 mmol: 8-11 mmol: 5-10 mL: 6-8 mmol, preferably 3.1-4.9 mmol: 8.5-10.5 mmol: 6-9 mL: 6.4-7.4 mmol, and more preferably 3.2-4.8 mmol: 9-10 mmol: 8 mL: 6.8-7.2 mmol.

[0113] In the present invention, in step 5), the reaction temperature is 20-40°C, preferably 22-38°C, and more preferably 25-35°C.

[0114] In the present invention, in step 6), the molar ratio of acetic anhydride, formic acid, compound c and sodium bicarbonate is 32-33:41-42:4-5:8-9, preferably 32.1-32.9:41.1-41.9:4.1-4.9, and more preferably 32.2-32.8:41.2-41.8:4.2-4.8:8.2-8.8.

[0115] In the present invention, in step 6), the temperature of the first reaction is 50-70°C, preferably 52-68°C, and more preferably 55-65°C; the time of the first reaction is 0.5-2h, preferably 0.7-1.8h, and more preferably 1-1.5h; the temperature of the second reaction is 20-40°C, preferably 22-38°C, and more preferably 25-35°C; the time of the second reaction is 16-24h, preferably 18-22h, and more preferably 20h.

[0116] In the present invention, in steps 1) to 5), the cooling temperature is independently ≤ 0°C, preferably ≤ -2°C, and more preferably ≤ -5°C.

[0117] In the present invention, in steps 1) to 5), after the reaction is completed, the reaction product is purified by column chromatography (petroleum ether / ethyl acetate = 6:1 to 3:1).

[0118] In the present invention, after each reaction is completed, the reaction is quenched with 150 mL of water and extracted;

[0119] The reagents used for the extraction are independently dichloromethane and / or ethyl acetate, preferably ethyl acetate; the number of extractions is independently 1 to 5 times, preferably 2 to 4 times, and more preferably 3 times; the volume of the extraction reagent is independently 3 to 7 mL, preferably 4 to 6 mL, and more preferably 5 mL.

[0120] In the present invention, the entire process is carried out under nitrogen protection.

[0121] The present invention also provides a use of the 4,5-dimethoxyphenyl ester compound in the preparation of an anti-epileptic drug. The anti-epileptic drug includes a 4,5-dimethoxyphenyl ester compound and its stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable cocrystals.

[0122] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0123] Example 1

[0124] Under nitrogen protection, 153 mmol of compound a was dissolved in 346 mL of dichloromethane, cooled to -15 ° C, and then 153 mL of a dichloromethane solution of boron tribromide was added dropwise (the molar volume ratio of boron tribromide to dichloromethane in the dichloromethane solution of boron tribromide was 153 mmol:153 mL). After the addition was complete, the reaction was carried out at 30 ° C. After TLC monitoring of the complete reaction of the raw material, 100 mL of water was added at 0 ° C to quench the reaction, and the mixture was extracted with dichloromethane (3×100 mL). The organic phases were collected and combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 27.3 g of compound b with a yield of 97.9%;

[0125] The structural formula of the compound a is:

[0126]

[0127] The structural formula of the compound b is:

[0128]

[0129] Compound b was characterized and the results were: 1 HNMR (400MHz, CDCl3) δ11.40 (s, 1H), 9.71 (s, 1H), 6.91 (s, 1H), 6.48 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H);

[0130] Under nitrogen protection, 288.1 mmol of ethyltriphenylphosphonium bromide was mixed in 275 mL of tetrahydrofuran, cooled to -20°C, and then 288.1 mmol of n-butyl lithium was added dropwise. After the addition was complete, the temperature was raised to 30°C for a primary reaction. After 45 minutes of reaction, the temperature was again cooled to -20°C, and 150 mL of a tetrahydrofuran solution of compound b (the molar volume ratio of compound b to tetrahydrofuran was 137.2 mmol:150 mL) was added dropwise. After the addition was complete, the temperature was raised to 30°C for a secondary reaction. After TLC monitoring of the reaction of the raw material, 100 mL of water was added at 0°C to quench the reaction, and the pH was adjusted to 6 with hydrochloric acid. The mixture was extracted with ethyl acetate (3×100 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 17.7 g of compound c with a yield of 66.4%.

[0131] The structural formula of the compound c is:

[0132]

[0133] Compound c was characterized and the results were: 1HNMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 6.90 (s, 1H), 6.53 (dq, J=16.0, 1.6Hz, 1H), 6.4 3 (s, 1H), 6.13-6.00 (m, 1H), 3.679 (s, 3H), 3.676 (s, 3H), 1.81 (dd, J=6.8, 1.6Hz, 3H);

[0134] 13 CNMR (100MHz, DMSO-d6) δ148.6, 148.3, 142.0, 125.6, 121.9, 115.5, 110.1, 100.9, 56.2, 55.3, 18.6;

[0135] Under nitrogen protection, 1.54 mmol of compound c, 0.15 mmol of 4-dimethylaminopyridine, 3.08 mmol of triethylamine, and 8 mL of anhydrous dichloromethane were mixed and cooled to 0°C, followed by dropwise addition of 2.0 mmol of acetyl chloride. After the addition was complete, the mixture was reacted at 30°C. After TLC monitoring of the complete reaction of the raw material, 5 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (3×5 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain 300 mg of 4,5-dimethoxy-2-(E-propenyl)phenyl acetate, designated as compound 1, with a yield of 82.4%.

[0136] The structural formula of the compound 1 is:

[0137]

[0138] Compound 1 was characterized and the results were: 1 HNMR (400MHz, CDCl3) δ6.96 (s, 1H), 6.53 (s, 1H), 6.31 (dq, J=16.0, 1.6Hz, 1H), 6.1 6-6.06 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.32 (s, 3H), 1.87 (dd, J=6.4, 1.6Hz, 3H);

[0139] 13 CNMR (100MHz, CDCl3) δ169.7, 148.4, 147.0, 140.8, 126.2, 123.8, 122.1, 108.1, 105.9, 56.0, 55.9, 20.8, 18.7.

[0140] Example 2

[0141] Compared with Example 1, the difference is that in Example 2, under nitrogen protection, 10.3 mmol of compound c, 20.6 mmol of triethylamine and 20 mL of anhydrous tetrahydrofuran were mixed, cooled to -5°C, and 12.4 mmol of propionyl chloride was added dropwise. After the addition was complete, the reaction was carried out at 30°C. After TLC monitoring of the complete reaction of the raw material, 5 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3×5 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1), and then slurried with petroleum ether to obtain 2.0 g of 4,5-dimethoxy-2-(E-propenyl)phenyl propionate, recorded as compound 2, with a yield of 77.6%;

[0142] The structural formula of the compound 2 is:

[0143]

[0144] Compound 2 was characterized and the results were: 1 HNMR (400MHz, CDCl3) δ6.96 (s, 1H), 6.53 (s, 1H), 6.30 (dq, J=15.6, 1.6Hz, 1H), 6.16-6.06 (m, 1H), 3 .89 (s, 3H), 3.85 (s, 3H), 2.63 (q, J=7.6Hz, 2H), 1.87 (dd, J=6.4, 1.6Hz, 3H), 1.30 (t, J=7.6Hz, 3H);

[0145] 13 CNMR (100MHz, CDCl3) δ173.1, 148.4, 146.9, 140.9, 126.1, 123.9, 122.1, 108.1, 105.9, 56.0, 55.9, 27.5, 18.7, 9.1.

[0146] Example 3

[0147] Compared with Example 1, the difference in Example 3 is that in Example 3, 3.9 mmol of compound c, 7.7 mmol of triethylamine and 10 mL of anhydrous tetrahydrofuran are mixed under nitrogen protection, cooled to -5°C, and then 4.6 mmol of isobutyryl chloride is added dropwise. After the addition is complete, the reaction is carried out at 30°C. After TLC monitoring of the reaction of the raw materials, 5 mL of water is added to quench the reaction, and the mixture is extracted with ethyl acetate (3×5 mL). The organic phases are collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product is purified by column chromatography (petroleum ether / ethyl acetate / dichloromethane = 20:4:1) to obtain 950 mg of 2-methylpropionic acid-4,5-dimethoxy-2-(E-propenyl)phenyl ester, recorded as compound 3, with a yield of 92.2%;

[0148] The structural formula of the compound 3 is:

[0149]

[0150] Compound 3 was characterized and the results were: 1 HNMR (400MHz, CDCl3) δ6.96 (s, 1H), 6.50 (s, 1H), 6.31 (dq, J=15.6, 1.6Hz, 1H), 6.15-6.04 (m, 1H), 3 .89 (s, 3H), 3.85 (s, 3H), 2.91-2.79 (m, 1H), 1.86 (dd, J=6.4, 1.6Hz, 3H), 1.36 (s, 3H), 1.35 (s, 3H);

[0151] 13 CNMR (100MHz, CDCl3) δ175.7, 148.4, 146.9, 140.9, 126.0, 123.8, 122.2, 108.0, 105.8, 56.0, 55.9, 34.1, 19.0, 18.7.

[0152] Example 4

[0153] Compared with Example 1, the difference in Example 4 is that in Example 4, under nitrogen protection, 5.0 mmol of 2-methylbutyric acid was dissolved in 10 mL of anhydrous dichloromethane, cooled to -5°C, and then 15.0 mmol of oxalyl chloride was added dropwise. After the addition was complete, the reaction temperature was raised to 30°C, and after reacting for 1 hour, the excess oxalyl chloride and dichloromethane were removed by concentration to obtain 2-methylbutyryl chloride;

[0154] 3.9 mmol of compound c, 7.7 mmol of triethylamine, and 10 mL of anhydrous tetrahydrofuran were mixed and cooled to -5°C. After addition, 5.0 mmol of 2-methylbutyryl chloride was added dropwise. After completion of the addition, the mixture was reacted at 30°C. After TLC monitoring of the complete reaction of the starting material, 5 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (3×5 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate / dichloromethane = 20:4:1) to obtain 810 mg of 2-methylbutyric acid-4,5-dimethoxy-2-(E-propenyl)phenyl ester, designated as compound 4, with a yield of 74.6%.

[0155] The structural formula of the compound 4 is:

[0156]

[0157] Compound 4 was characterized and the results were: 1HNMR (400MHz, CDCl3) δ6.96 (s, 1H), 6.49 (s, 1H), 6.32 (dq, J=16.0, 1.6Hz, 1H), 6.15-6.04 (m, 1H), 3.89 (s, 3H), 3. 85 (s, 3H), 2.72-2.61 (m, 1H), 1.96-1.81 (m, 4H), 1.71-1.58 (m, 1H), 1.33 (d, J=6.8Hz, 3H), 1.05 (t, J=7.6Hz, 3H);

[0158] 13 CNMR (100MHz, CDCl3) δ175.3, 148.4, 146.9, 140.9, 126.0, 123.9, 122.2, 108.0, 105.9, 56.01, 55.95, 41.1, 26.7, 18.7, 16.7, 11.6.

[0159] Example 5

[0160] Compared with Example 1, the difference in Example 5 is that in Example 5, under nitrogen protection, 5.0 mmol of 2-ethylbutyric acid was dissolved in 10 mL of anhydrous dichloromethane, cooled to -5°C, and then 15.0 mmol of oxalyl chloride was added dropwise. After the addition was complete, the reaction temperature was raised to 30°C, and after reacting for 1 hour, the excess oxalyl chloride and dichloromethane were removed by concentration to obtain 2-ethylbutyryl chloride;

[0161] 3.9 mmol of compound c, 7.7 mmol of triethylamine, and 10 mL of anhydrous tetrahydrofuran were mixed and cooled to -5°C. 5.0 mmol of 2-ethylbutyryl chloride was added dropwise. After the addition was complete, the reaction was allowed to proceed at 30°C. After TLC monitoring of the complete reaction of the starting material, 5 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (3×5 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate / dichloromethane = 20:4:1) to obtain 1.0 g of 2-ethylbutyric acid-4,5-dimethoxy-2-(E-propenyl)phenyl ester, designated as compound 5, with a yield of 87.7%.

[0162] The structural formula of the compound 5 is:

[0163]

[0164] Compound 5 was characterized and the results were: 1HNMR (400MHz, CDCl3) δ6.96 (s, 1H), 6.48 (s, 1H), 6.35 (dq, J=16.0, 1.6Hz, 1H), 6.15-6.02 (m, 1H), 3.8 9(s, 3H), 3.85(s, 3H), 2.54-2.45(m, 1H), 1.92-1.76(m, 5H), 1.74-1.62(m, 2H), 1.05(t, J=7.6Hz, 6H);

[0165] 13 CNMR (100MHz, CDCl3) δ174.7, 148.4, 146.9, 141.0, 126.0, 124.1, 122.4, 108.1, 106.0, 56.03, 55.95, 48.9, 25.0, 18.6, 11.9.

[0166] Example 6

[0167] Compared with Example 1, the difference is that in Example 6, under nitrogen protection, 32.8 mmol acetic anhydride and 41.1 mmol formic acid were mixed and reacted at 60 ° C. for a first time, and after the reaction was cooled to room temperature for 1 hour, 4.1 mmol compound c and 8.2 mmol sodium bicarbonate were added and reacted for a second time at room temperature. After the reaction was carried out for 20 hours, 10 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3×10 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1), and then slurried with petroleum ether to obtain 530 mg of formic acid-4,5-dimethoxy-2-(E-propenyl)phenyl ester, recorded as compound 6, with a yield of 58.2%;

[0168] The structural formula of the compound 6 is:

[0169]

[0170] Compound 6 was characterized and the results were: 1 HNMR (400MHz, CDCl3) δ8.30 (s, 1H), 6.97 (s, 1H), 6.57 (s, 1H), 6.36 (dq, J=15.6, 1. 6Hz, 1H), 6.2-6.09 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.88 (dd, J=6.4, 1.6Hz, 3H);

[0171] 13CNMR (100MHz, CDCl3) δ159.8, 148.5, 147.4, 139.9, 126.9, 123.5, 122.1, 108.1, 105.5, 56.1, 56.0, 18.7;

[0172] Example 7

[0173] Compared with Example 1, the difference is that in Example 7, under nitrogen protection, 8.3 mmol (4-bromobutyl) triphenylphosphonium bromide was mixed in 12 mL of tetrahydrofuran, cooled to -10 ° C, and then 17 mmol of a tetrahydrofuran solution of potassium tert-butoxide (1 M) was added dropwise. After the addition was complete, the temperature was raised to 70 ° C for a reaction. After the reaction for 1 hour, the temperature was again cooled to -10 ° C, and 12 mL of a tetrahydrofuran solution of compound b was added dropwise (the molar volume ratio of compound b to tetrahydrofuran was 5.5 mmol: 12 mL ), after the addition was complete, the reaction temperature was raised to 70°C for a secondary reaction. After the reaction of the starting material was complete as monitored by TLC, 10 mL of water was added at 0°C to quench the reaction, and the pH was adjusted to 6 with hydrochloric acid. The mixture was extracted with ethyl acetate (3×10 mL), and the organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1 to 2:1), and then slurried with petroleum ether to obtain 370 mg of compound d, with a yield of 30.5%;

[0174] The structural formula of the compound d is:

[0175]

[0176] Compound d was characterized and the results were: 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),6.67(s,1H),6.44(s,1H),6.24-6.20(m,1H), 3.68(s,3H),3.64(s,3H),3.00-2.92(m,2H),2.83-2.75(m,2H),2.08-1.98(m,2H);

[0177] 13 C NMR (100MHz, DMSO-d6) δ148.2,147.9,141.5,139.3,115.7,115.0,111.3,100.8,56.1,55.3,32.1,32.0,17.8;

[0178] Under nitrogen protection, 1.4 mmol of compound d, 2.8 mmol of triethylamine, and 8 mL of anhydrous dichloromethane were mixed and cooled to -5°C, followed by the dropwise addition of 2.0 mmol of acetyl chloride. After the addition was complete, the reaction was carried out at 30°C. After TLC monitoring of the complete reaction of the raw material, 5 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3×5 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 330 mg of 4,5-dimethoxy-2-(cyclobutylidenemethyl)phenyl acetate, recorded as compound 7, with a yield of 89.9%.

[0179] The structural formula of the compound 7 is:

[0180]

[0181] Compound 7 was characterized and the results were: 1 H NMR(400MHz, CDCl3)δ6.85(s,1H),6.56(s,1H),5.99-5.95(m,1H),3.85(s,3H),3 .84(s,3H),3.07-2.98(m,2H),2.90-2.82(m,2H),2.32(s,3H),2.16-2.04(m,2H);

[0182] 13 C NMR (100MHz, CDCl3) δ169.7,147.5,146.6,144.4,140.8,122.1,113.5,109.6,105.9,55.92,55.90,32.6,32.4,20.8,18.1;

[0183] Example 8

[0184] Compared with Example 1, the difference in Example 8 is that in Example 8, under nitrogen protection, 16.5 mmol of compound b was mixed with 66 mL of tetrahydrofuran, cooled to -20°C, and then 46 mmol of a tetrahydrofuran solution (1 M) of isopropylmagnesium bromide was added dropwise. After the addition was complete, the reaction was carried out at 30°C. After TLC monitoring of the reaction of the raw materials, 20 mL of saturated ammonium chloride was added at 0°C to quench the reaction, and the mixture was extracted with ethyl acetate (3×15 mL). The organic phases were collected, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 3.2 g of alcohol, with a yield of 85.7%;

[0185] Under nitrogen protection, 13.3 mmol of alcohol was mixed in 50 mL of toluene, 19.9 mmol of anhydrous copper sulfate was added at room temperature, and then the reaction was carried out at 110°C. After TLC monitoring of the complete reaction of the raw material, it was cooled to room temperature, the insoluble solid was filtered off, the filtrate was concentrated to dryness, 10 mL of water was added, and extracted with ethyl acetate (3x10 mL), the organic phase was collected, then the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was dissolved in 2 mL of ethyl acetate, and then 1.8 g of compound e was obtained by adding petroleum ether to the slurry, with a yield of 65.0%;

[0186] The structural formula of the alcohol is:

[0187]

[0188] The structural formula of the compound e is:

[0189]

[0190] The compound e was characterized, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 6.17-6.14 (m, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H);

[0191] 13 C NMR (100 MHz, DMSO-d6) δ 149.5, 148.6, 141.5, 132.7, 121.2, 116.5, 115.1, 101.2, 56.9, 55.8, 26.9, 19.9;

[0192] Under nitrogen protection, 4.8 mmol of compound e, 9.6 mmol of triethylamine and 8 mL of anhydrous dichloromethane were mixed, cooled to -5°C, and then 7.2 mmol of acetyl chloride was added dropwise. After the addition was completed, the reaction was carried out at 30°C, and TLC monitoring of the complete reaction of the raw material was carried out. After the reaction was quenched by adding 5 mL of water, it was extracted with ethyl acetate (3x5 mL), the organic phase was collected, combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1), and then 443 mg of acetic acid-4,5-dimethoxy-2-(2-methylpropenyl) phenyl ester, denoted as compound 8, was obtained by adding petroleum ether to the slurry after dissolving the crude product in 2 mL of ethyl acetate, with a yield of 36.9%;

[0193] The structural formula of the compound 8 is:

[0194]

[0195] Compound 8 was characterized, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 6.73 (s, 1H), 6.58 (s, 1H), 6.02-5.99 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.25 (s, 3H), 1.87 (d, J = 1.6 Hz, 3H), 1.74 (d, J = 1.6 Hz, 3H);

[0196] 13 C NMR (100 MHz, CDCl3) δ 169.5, 147.8, 146.3, 141.7, 136.8, 123.0, 119.1, 112.8, 105.7, 56.1, 55.9, 26.1, 20.7, 19.4.

[0197] 100 mg of Compound 1, Compound 2, Compound 6 or Compound 7 was weighed into a beaker, 2.0 g of HS-15 and 8 mL of normal saline were added to obtain a mixture, the mixture was stirred at 65°C with a magnetic stirrer until completely dissolved, then cooled to room temperature, diluted to 10 mL, filtered with a 0.22 μm microporous filter, and a clear and uniform micellar solution of Compound 1, Compound 2, Compound 6 or Compound 7 was prepared;

[0198] 100 mg of Compound 3 and 1.5 g of HS-15 were weighed into a beaker, about 8 mL of normal saline was added, the mixture was stirred at 65°C with a magnetic stirrer until completely dissolved. Then cooled to room temperature, diluted to 10 mL, filtered with a 0.22 μm microporous filter, and a clear and uniform micellar solution of Compound 3 was prepared;

[0199] 100 mg of Compound 4, Compound 5 or Compound 8 and 1.0 g of HS-15 were weighed into a beaker, about 8 mL of normal saline was added, the mixture was stirred at 65°C with a magnetic stirrer until completely dissolved. Then cooled to room temperature, diluted to 10 mL, filtered with a 0.22 μm microporous filter, and a clear and uniform micellar solution of Compound 4, Compound 5 or Compound 8 was prepared;

[0200] The protective effect of the compounds 1-8 of the application on a pentylenetetrazole-induced mouse model of epilepsy was tested, and the test method was as follows:

[0201] Reagents and materials: SPF adult male KM mice, weighing 25-35 g, 10 mg / mL micellar solution of compounds 1-8;

[0202] Animal grouping: The test mice were randomly divided into 9 groups, with 10 mice in each group, namely normal saline group and compound 1-8 solution group. Each group was administrated by intraperitoneal injection.

[0203] Evaluation methods and results:

[0204] After a period of drug administration, each group received an intraperitoneal injection of 70 mg / kg pentylenetetrazol (PTZ) to induce epilepsy. The mice were observed for 30 minutes after model establishment, during which the Racine score and seizure latency (Racine score ≥ 1) were recorded. The Racine grading scale is 0 (normal non-epileptic activity), 1 (wet-dog shaking or scratching), 2 (head nodding or tail flicking), 3 (unilateral forelimb extension or unilateral limb clonus), 4 (multiple limb clonus or tonic), and 5 (falling and generalized tonic-clonic seizure). The clonic seizure rate (CSR) and tonic seizure rate (TSR) were calculated based on seizure severity. Racine scores of 1-3 were classified as clonic, and Racine scores of 4-5 were classified as tonic. If the mice did not experience a seizure within 30 minutes, the latency was calculated as 1800 seconds. The test results are shown in Table 1.

[0205] Table 1 Protective effects of compounds 1 to 8 of the present invention on epilepsy mouse model induced by pentylenetetrazol

[0206]

[0207] The incidence of spasticity was analyzed using the Fisher exact test, the latency was analyzed using one-way analysis of variance (ANOVA) and post hoc analysis (LSD or Dunnett's T3), and the Racine score was analyzed using the Mann-Whitney U test (non-parametric test). Compared with the model group, *P≤0.05, **P≤0.01, ***P≤0.001.

[0208] As shown in Table 1, compounds 1 to 8 can significantly prolong the latency period of epileptic seizures and significantly reduce the Racine score; compounds 1 to 8 can significantly reduce the incidence of tonic seizures; anti-epileptic tests show that compounds 1 to 8 have significant anti-epileptic activity.

[0209] The protective effect of compound 1 on the maximum electric shock model (MES) in mice was tested:

[0210] Reagents and materials: SPF adult male KM mice, weighing 25-35 g, 10 mg / mL solution of compound 1 and compound 8;

[0211] Animal grouping: The test mice were randomly divided into three groups, namely, normal saline group, compound 1 solution group and compound 8 solution group. Each group was medicated by intraperitoneal injection.

[0212] Evaluation methods and results

[0213] First, the physiological pharmacological electronic stimulator was set to a 20ms pulse width, a 10ms interval, a wave count of 100, a voltage of 200V, a current limit of 4mA, and a waveform of "positive pulse + interval + negative pulse." After a 5-minute pre-drug administration, the two alligator clips on the electrode output cable were soaked with saline and clamped onto the mouse's ears. The "Start" button was pressed and the mouse was observed to see if it experienced a tonic seizure with forelimb flexion and hindlimb extension. The test results are shown in Table 2.

[0214] Table 2 Protective effects of compounds 1 and 8 of the present invention on the maximum electric shock model (MES) in mice

[0215] Group (ip) Dosage (mg / kg) Total number of animals (n) Protection rate Model Group - 12 0％ Compound 1 130 12 100％*** Compound 8 120 12 91％***

[0216] The protection rate was evaluated using Fisher's exact test. ***P ≤ 0.001 compared with the model group.

[0217] As shown in Table 2, both Compound 1 and Compound 8 can inhibit tonic convulsions, indicating that they have significant anti-epileptic activity.

[0218] As can be seen from the above examples, the present invention provides a 4,5-dimethoxyphenyl ester compound and its preparation method and application. The structural formula of the 4,5-dimethoxyphenyl ester compound of the present invention is shown in Formula 1: The compound prepared by the invention can significantly reduce the incidence of tonic seizures and has significant anti-epileptic activity.

[0219] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A 4,5-dimethoxyphenyl ester compound, characterized in that The structural formula of the 4,5-dimethoxyphenyl ester compound is shown in Formula 1: Among them, R 1 Selected from hydrogen, C 1-6 Alkyl or C 1-6 Alkyl derivatives; When R in Formula 1 2 and R 3 When the dashed line between is not present, R 2 、R 3 independently selected from hydrogen or C 1-6 Alkyl, and R 2 、R 3 Not simultaneously hydrogen; When R in Formula 1 2 and R 3 When the dotted line between the two is a bond, R 2 、R 3 Independently selected from C 1-3 Alkylene.

2. The 4,5-dimethoxyphenyl ester compound according to claim 1, characterized in that The 4,5-dimethoxyphenyl ester compound is selected from the following compounds:

3. A method for preparing the 4,5-dimethoxyphenyl ester compound according to claim 2, characterized in that: The steps include: 1) dissolving compound a in dichloromethane, cooling, adding a dichloromethane solution of boron tribromide to react, and obtaining compound b; 2) Ethyltriphenylphosphine bromide was mixed in tetrahydrofuran, and after cooling, n-butyl lithium was added dropwise to carry out a primary reaction. After cooling again, a tetrahydrofuran solution of compound b was added dropwise to carry out a secondary reaction to obtain compound c; 3) (4-bromobutyl)triphenylphosphonium bromide was mixed in tetrahydrofuran, and after cooling, potassium tert-butoxide solution was added dropwise to carry out a primary reaction, and after cooling again, a tetrahydrofuran solution of compound b was added dropwise to carry out a secondary reaction to obtain compound d; 4) Compound b is mixed with tetrahydrofuran, cooled, and isopropylmagnesium bromide is added dropwise to carry out a primary reaction to obtain an alcohol intermediate, which is then dehydrated with toluene and anhydrous copper sulfate to obtain compound e; 5) Compound c, a basic compound and an organic solvent are mixed, cooled, and then an acyl chloride is added to react to obtain compound 1-5. or Compound d, a basic compound, and an organic solvent are mixed, cooled, and then acyl chloride is added to react to obtain compound 7. or, Compound e, a basic compound, and an organic solvent are mixed, cooled, and then an acyl chloride is added to react to obtain compound 8; 6) Mixing acetic anhydride and formic acid for a first reaction, and then adding compound c and sodium bicarbonate for a second reaction to obtain compound 6; The structural formula of the compound a is: The structural formula of the compound b is: The structural formula of the compound c is: The structural formula of the compound d is: The structural formula of the compound e is:

4. The method for preparing 4,5-dimethoxyphenyl ester compounds according to claim 3, wherein In the step 1), the molar volume ratio of compound a and dichloromethane is 140-160 mmol: 340-350 mL; The molar volume ratio of boron tribromide to dichloromethane in the dichloromethane solution of boron tribromide is 140-160 mmol:150-160 mL; The molar ratio of compound a to boron tribromide is 140-160:140-160; In the step 1), the reaction temperature is 20-40°C.

5. The method for preparing 4,5-dimethoxyphenyl ester compounds according to claim 3, wherein In the step 2), the ratio of ethyltriphenylphosphine bromide, tetrahydrofuran and n-butyl lithium is 280-295 mmol: 275 mL: 280-295 mmol; The molar volume ratio of compound b to tetrahydrofuran in the tetrahydrofuran solution of compound b is 130-140 mmol:140-160 mL; The molar ratio of ethyltriphenylphosphonium bromide to compound b is 280-295:130-140; In the step 2), the temperature of the primary reaction is 20-40° C., and the time of the primary reaction is 30-60 min; the temperature of the secondary reaction is 20-40° C.

6. The method for preparing 4,5-dimethoxyphenyl ester compounds according to claim 3, wherein In the step 3), the ratio of (4-bromobutyl)triphenylphosphine bromide, tetrahydrofuran and potassium tert-butoxide solution is 8-10 mmol:10-15 mL:15-20 mmol; The molar volume ratio of compound b to tetrahydrofuran in the tetrahydrofuran solution of compound b is 5-6 mmol:10-15 mL; The molar ratio of (4-bromobutyl)triphenylphosphonium bromide to compound b is 8-10:5-6; In the step 3), the temperature of the primary reaction is 60-80°C, and the time of the primary reaction is 50-70 minutes; the temperature of the secondary reaction is 60-80°C.

7. The method for preparing 4,5-dimethoxyphenyl ester compounds according to claim 3, wherein In the step 4), the ratio of compound b, tetrahydrofuran and isopropylmagnesium bromide is 15-18 mmol: 60-70 mL: 40-50 mmol; The alcohol intermediate, toluene and anhydrous copper sulfate are used in a ratio of 11-15 mmol: 40-60 mL: 15-25 mmol; In the step 4), the temperature of the primary reaction is 20-40° C., the time of the primary reaction is 50-70 min; the temperature of the dehydration reaction is 100-120° C.

8. The method for preparing 4,5-dimethoxyphenyl ester compounds according to claim 3, wherein In step 5), the basic compound independently includes 4-dimethylaminopyridine and / or triethylamine; The acyl chlorides independently include one or more of acetyl chloride, propionyl chloride, isobutyryl chloride, 2-methylbutyryl chloride and 2-ethylbutyryl chloride; The organic solvent independently comprises anhydrous dichloromethane and / or anhydrous tetrahydrofuran; The ratio of compound c, alkaline compound, organic solvent and acyl chloride is 1-11 mmol: 2-21 mmol: 5-25 mL: 1.6-13 mmol; The ratio of compound d, basic compound, organic solvent and acyl chloride is 1-2 mmol: 2-3 mmol: 5-10 mL: 1-3 mmol; The ratio of compound e, alkaline compound, organic solvent and acyl chloride is 3-5 mmol: 8-11 mmol: 5-10 mL: 6-8 mmol; In the step 5), the reaction temperature is 20-40°C.

9. The method for preparing 4,5-dimethoxyphenyl ester compounds according to claim 3, wherein In step 6), the molar ratio of acetic anhydride, formic acid, compound c and sodium bicarbonate is 32-33:41-42:4-5:8-9; In step 6), the temperature of the first reaction is 50-70° C., the time of the first reaction is 0.5-2 h, the temperature of the second reaction is 20-40° C., and the time of the second reaction is 16-24 h; In the steps 1) to 5), the cooling temperature is independently ≤-5°C.

10. Use of the 4,5-dimethoxyphenyl ester compound according to claim 1 or 2 in the preparation of anti-epileptic drugs, characterized in that: The anti-epileptic drugs include 4,5-dimethoxyphenyl ester compounds and stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable cocrystals thereof.

Images