A gastrodin-acetaminophen twin, its preparation method and application

Abstract

A gastrodin and acetaminophen twin drug, its preparation method, and its application belong to the field of pharmaceutical technology. The synthetic steps are as follows: 1) Protecting the functional groups in gastrodin and acetaminophen; 2) Condensing the protected amino acid with acetaminophen in the presence of the condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to form an amino acid-acetaminophen ester; 3) Deprotecting the benzyl group of the amino acid side chain of the above compound; 4) Forming an ester by reacting the deprotected compound with the protected gastrodin in the presence of EDCI; 5) Removing the protecting agent from the amino acid to obtain the product. This invention overcomes the shortcomings of gastrodin alone as a drug, which has insignificant efficacy, requires large dosage, and has a long treatment cycle; reduces the liver damage caused by acetaminophen; and improves the therapeutic effect of acetaminophen on headaches.

Description

Technical Field

[0001] This invention relates to a gastrodin and acetaminophen twin drug, its preparation method and application, belonging to the field of pharmaceutical technology. Background Technology

[0002] The principle of drug combination refers to the merging of the structures of two drugs into a single molecule, or the compatibility of the pharmacophores of two drugs within a single molecule, resulting in new drugs or twin drugs. After metabolism in vivo, these two drugs with synergistic effects are produced, resulting in enhanced activity, the generation of new pharmacological activities, or higher selectivity. Based on structural modification, drug combination is classified into three types: esterification, salt formation, and non-ester / non-salt combination.

[0003] Esterification is currently the most widely used method in drug combination. It involves the dehydration of a carboxyl group in one drug molecule to an ester with a hydroxyl group in another drug molecule. The most famous example is benorilate (also known as acetaminophen), which is formed by combining acetylsalicylic acid and acetaminophen. This combination solves the stomach irritation problem of acetylsalicylic acid, enhances efficacy, and reduces the side effects of both drugs.

[0004] Acetaminophen, also known as paracetamol, is a metabolite of phenacetin in the body, and is similar to phenacetin. It has relatively few side effects and is a widely used clinical antipyretic and analgesic, but it still has drawbacks such as a significant first-pass effect in the liver. Based on the prodrug design principle, acetaminophen is synthesized into an ester prodrug by combining it with a carboxyl-containing compound. This ester prodrug is then enzymatically hydrolyzed in vivo, releasing two molecules of the original drug; achieving a dual pharmacological effect of antipyresis and analgesia. This not only expands the scope of clinical use, improves oral absorption, increases blood drug concentration and bioavailability, and reduces dosage, but also overcomes the toxic side effects of the original drug and reduces adverse reactions.

[0005] Gastrodia elata, the dried tuber of the plant *Gastrodia elata* (family Orchidaceae), is a traditional and valuable Chinese medicine, primarily used to treat dizziness, vertigo, numbness of limbs, convulsions, and stroke. Studies have reported that gastrodin is the main chemical component responsible for the pharmacological effects of Gastrodia elata. Although gastrodin can directly cross the blood-brain barrier, it needs to be metabolized to form gastrodin aglycone before it can exert its effects, and gastrodin aglycone crosses the blood-brain barrier more easily than gastrodin. Numerous studies have reported that Gastrodia elata possesses good sedative and analgesic pharmacological effects. Summary of the Invention

[0006] This invention is based on the principle of drug twin design and the application of traditional Chinese medicine. It utilizes modern pharmaceutical technology to combine drugs with clear pharmacological effects to design new drugs with higher pharmacological activity.

[0007] This invention utilizes amino acids to splice acetaminophen and gastrodin into a single drug molecule, which overcomes the gastric irritation of acetylsalicylic acid and enhances the pharmacological activity of gastrodin.

[0008] The specific technical solution adopted in the invention is as follows: A gastrodin-acetaminophen twin, characterized in that the chemical formula of the twin is: , Where R is -CH2CH2CH(NH2)- or -CH2CH(NH2)-.

[0009] A method for preparing a gastrodin-acetaminophen twin, characterized by comprising the following steps: 1) The method and steps for protecting the functional groups in gastrodin and acetaminophen are as follows: First, benzyloxycarbonyl (Cbz) is used to protect the phenolic hydroxyl group of gastrodin; second, glutamic acid and aspartic acid protected by N-tert-butyloxycarbonyl (Boc) and benzyl (Bn) (β-carboxyl) are used as starting materials. 2) The protected amino acid is condensed with acetaminophen in the presence of the condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) to form amino acid-acetaminophen ester; 3) Deprotect the benzyl (Bn) groups on the amino acid side chains of the above compounds; 4) The deprotected compound and the protected gastrodin were esterified by EDCI. 5) Remove the protecting agent from the amino acids to obtain the product.

[0010] Step 1) includes the following steps: 248 mg (2 mmol) of gastrodin and 0.5 ml of triethylamine are dissolved in 50 ml of acetonitrile. While stirring, 1.1 ml of a 50% benzyloxycarbonyl (Cbz) toluene solution is added at 0°C, and the reaction is carried out at room temperature for 1 hour. The reaction solution is poured into 100 ml of purified water, extracted with ethyl acetate (2 × 150 ml), the organic phases are combined, dried with calcium sulfate, and the organic liquid is concentrated to obtain a yellow oily crude product. This product is purified by silica gel column chromatography [eluent (V(ethyl acetate):V(n-hexane) 2:1]] to obtain 500 mg of a white solid, with a yield of 90%, namely Cbz-gastrodin (compound C1). The chemical reaction formula for the above step is as follows: , Step 2) is as follows: an ester is formed by condensation of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) with the catalyst 4-dimethylaminopyridine (4-DMAP).

[0011] Reaction conditions: In a 200 mL round-bottom flask, add 1.81 g (12.0 mmol) of acetaminophen and 12.0 mmol of protected amino acids, then add 30 mL of acetone and stir in an ice-water bath to dissolve. Add 12.0 mmol of EDCI and 0.5 mmol of 4-DMAP catalyst, stir well, and let stand at room temperature for 2 h. Then, slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in portions over 5 min, remove the ice-water bath, and continue stirring at room temperature for 2 h. Transfer the reaction mixture to a 250 mL separatory funnel and add 50 mL of ethyl acetate.

[0012] Wash with 30 mL of 1 mol / L hydrochloric acid solution, repeating this operation twice. Then wash with 30 mL of 1 mol / L NaOH solution, repeating this operation twice. Finally, wash once with 30 mL of saturated saline solution. Transfer the upper organic phase to a 250 mL Erlenmeyer flask. Weigh 2 g of anhydrous sodium sulfate and add it to the Erlenmeyer flask. Let it stand for 10 min, filter, and distill the filtrate under reduced pressure to obtain 4.12 g of a white solid, designated as compound C2. The chemical reaction formula is as follows: , Step 3) is as follows: Take 2 mmol of compound C2 and add it to a 1 L hydrogenation reactor. Add 1 g of 10% industrial palladium / carbon (Pd / C) and 50 mL of methanol. React at below 8 °C and 0.3 MPa hydrogen pressure for 4 h. Filter to remove the palladium on carbon, concentrate under reduced pressure, add 50 mL of deionized water, filter, and wash the aqueous layer twice with 30 mL each of n-butanol and ethyl acetate. Concentrate under reduced pressure to remove ethyl acetate from the water, adjust the pH to 6.8 with saturated sodium bicarbonate solution, and lyophilize to obtain compound C3. The chemical reaction formula is as follows: , In step 4), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), a commonly used condensation reagent in the art, is used to condense and form an ester under the condition that 4-dimethylaminopyridine (4-DMAP) is used as a catalyst.

[0013] Reaction conditions: In a 200 mL round-bottom flask, add 5 mmol of Cbz-gastrodin and 5 mmol of compound C3, then add 30 mL of acetone and stir in an ice-water bath to dissolve. Add 12.0 mmol of EDCI and 0.5 mmol of 4-DMAP catalyst, stir well, and let stand at room temperature for 2 h. Then, slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in portions over 5 min, remove the ice-water bath, and continue stirring at room temperature for 2 h. Transfer the reaction solution to a 250 mL separatory funnel and add 100 mL of ethyl acetate. Wash with 30 mL of 1 mol / L hydrochloric acid solution, repeating this operation twice. Then wash with 30 mL of 1 mol / L NaOH solution, repeating this operation twice. Finally, wash once with 30 mL of saturated saline solution, and then transfer the upper organic phase to a 250 mL Erlenmeyer flask. Weigh 5g of anhydrous sodium sulfate and add it to an Erlenmeyer flask. Let it stand for 10 min, filter, and distill the filtrate under reduced pressure to obtain 2.91g or 3.02g of a white solid (when N-Boc-Glu-acetaminophen is used as a reactant). This solid is called compound C4, and the chemical reaction formula is as follows: , In step 5), trifluoroacetic acid, a commonly used reagent in the art, is used to remove the Boc protecting group; and acetic acid solution of hydrogen bromide is used to remove the Cbz protecting group.

[0014] The reaction conditions for deBoc removal were as follows: 5 mmol of compound C4 was dissolved in 50 mL of a solution of 50% (v / v) trifluoroacetic acid (F3CCOOH) in dichloromethane (CH2Cl2). The solution was stirred at 0°C for 10 minutes, then the reaction was continued at room temperature for 60 minutes. After the reaction was completed, the dichloromethane was removed by rotary evaporation, and then 30 mL of ethyl acetate was added to dissolve the compound. The solution was then washed with 5% NaHCO3 until neutral to obtain Cbz-gastrodin-Asp-acetaminophen or Cbz-gastrodin-Glu-acetaminophen, referred to as compound C5.

[0015] Reaction conditions for Cbz removal: 10 mmol of compound C5 was placed in a 100 mL round-bottom flask, and 25 mL of a 35.5% (v / v) solution of hydrogen bromide in acetic acid was added. After stirring at room temperature for 5 hours, the hydrogen bromide and glacial acetic acid were removed. 50 mL of diethyl ether was added for recrystallization. The mixture was filtered, and the residual solid was dried under vacuum to obtain the target compound gastrodin-Asp-acetaminophen or gastrodin-Glu-acetaminophen (compound C6). The above chemical reaction formula is as follows: , The application of a gastrodin and acetaminophen twin in the preparation of drugs for the treatment or adjuvant treatment of analgesia and anti-inflammation.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: In this invention, the linker molecule Glu or Asp contains -NH, which increases the solubility of the twin drugs and facilitates absorption. After absorption, the liver damage caused by acetaminophen can be effectively avoided. Gastrodin can cross the blood-brain barrier to treat headaches and has a sedative effect. Further research has found that the twin drugs of this invention have lower dosages and treatment cycles than the two individual drugs in terms of anti-inflammatory and analgesic effects.

[0017] This invention overcomes the shortcomings of gastrodin as a single drug, such as insignificant efficacy, large dosage, and long treatment period. This invention reduces the liver damage caused by acetaminophen; This invention improves the therapeutic effect of acetaminophen on headaches; This invention reduces the dosage of analgesics and shortens the treatment cycle. Detailed Implementation

[0018] Example 1: Synthesis

[0019] 1. Dissolve 248 mg (2 mmol) of gastrodin and 0.5 ml of triethylamine in 50 ml of acetonitrile. With stirring, add 1.1 ml of 50% benzyloxycarbonyl (Cbz) toluene solution at 0 °C and react at room temperature for 1 hour. Pour the reaction solution into 100 ml of purified water, extract with ethyl acetate (2 × 150 ml), combine the organic phases, dry with calcium sulfate, concentrate the organic liquid to obtain a yellow oily crude product, and purify by silica gel column chromatography [eluent (V(ethyl acetate):V(n-hexane) 2:1)] to obtain 500 mg of white solid, yield 90%, namely Cbz-gastrodin (compound C1).

[0020] 2. Take 1.81 g (12.0 mmol) of acetaminophen and 12.0 mmol of the modified amino acid, add them to a 200 mL round-bottom flask, add 30 mL of acetone, and stir to dissolve in an ice-water bath. Add 12.0 mmol of EDCI and 0.5 mmol of 4-DMAP catalyst, stir well, and let stand at room temperature for 2 h. Then, slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in portions over 5 min, remove the ice-water bath, and continue stirring at room temperature for 2 h. Transfer the reaction solution to a 250 mL separatory funnel and add 50 mL of ethyl acetate.

[0021] Wash with 30 mL of 1 mol / L hydrochloric acid solution, repeating this operation twice. Then wash with 30 mL of 1 mol / L NaOH solution, repeating this operation twice. Finally, wash once with 30 mL of saturated saline solution. Transfer the upper organic phase to a 250 mL Erlenmeyer flask. Weigh 2 g of anhydrous sodium sulfate and add it to the Erlenmeyer flask. Let it stand for 10 min, filter, and distill the filtrate under reduced pressure to obtain 4.12 g of a white solid, designated as compound C2.

[0022] 3. Take 2 mmol of compound C2 and add it to a 1 L hydrogenation reactor. Add 1 g of 10% industrial palladium / carbon (Pd / C) and 50 mL of methanol. React at 8 °C or below and 0.3 MPa hydrogen pressure for 4 h. Filter to remove palladium on carbon, concentrate under reduced pressure, add 50 mL of deionized water, filter, and wash the aqueous layer twice with 30 mL each of n-butanol and ethyl acetate. Concentrate under reduced pressure to remove ethyl acetate from the water, adjust the pH to 6.8 with saturated sodium bicarbonate solution, and lyophilize to obtain compound C3.

[0023] 4. Take 5 mmol of Cbz-gastrodin and 5 mmol of compound C3, place them in a 200 mL round-bottom flask, add 30 mL of acetone, and stir to dissolve in an ice-water bath. Add 12.0 mmol of EDCI and 0.5 mmol of 4-DMAP catalyst, stir well, and let stand at room temperature for 2 h. Over 5 min, slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in portions, remove the ice-water bath, and continue stirring at room temperature for 2 h. Transfer the reaction solution to a 250 mL separatory funnel and add 100 mL of ethyl acetate. Wash with 30 mL of 1 mol / L hydrochloric acid solution, repeating this operation twice. Then wash with 30 mL of 1 mol / L NaOH solution, repeating this operation twice. Finally, wash once with 30 mL of saturated saline solution, and then transfer the upper organic phase to a 250 mL Erlenmeyer flask. Weigh 5g of anhydrous sodium sulfate and add it to an Erlenmeyer flask. Let it stand for 10 minutes, filter it, and distill the filtrate under reduced pressure to obtain 2.91g or 3.02g of white solid (when N-Boc-Glu-acetaminophen is used as a reactant), which is called compound C4.

[0024] 7. Take 5 mmol of compound C4 and dissolve it in 50 ml of a solution of 50% (v / v) trifluoroacetic acid (F3CCOOH) in dichloromethane (CH2Cl2). Stir at 0°C for 10 minutes, then raise the temperature to room temperature and continue the reaction for 60 minutes. After the reaction is complete, remove the dichloromethane by rotary evaporation, then add 30 ml of ethyl acetate to dissolve it, and wash with 5% NaHCO3 until neutral to obtain Cbz-gastrodin-Asp-acetaminophen or Cbz-gastrodin-Glu-acetaminophen, named compound C5. Take 10 mmol of the above compound C5 and place it in a 100 ml round-bottom flask. Add 25 ml of 35.5% (V / V) hydrogen bromide in acetic acid solution. Stir at room temperature for 5 hours, remove hydrogen bromide and glacial acetic acid, add 50 ml of diethyl ether for recrystallization, filter, and dry the residual solid under vacuum to obtain the target compound gastrogenin-Asp-acetaminophen or gastrogenin-Glu-acetaminophen (compound C6).

[0025] Implementation Case 2: Comparison of acute liver toxicity tests of the new compound and acetaminophen in animals.

[0026] Male KM mice (10 weeks old, 26-27g, clean grade) were used. Before the experiment, the mice were allowed free access to food and water and were acclimatized to a circadian rhythm for 4 days.

[0027] Animal Grouping and Treatment: Forty male KM mice were randomly divided into a control group, a C6-A group, a C6-G group, and an acetaminophen group, with 10 mice in each group. Mice were fasted for 6 hours before the experiment, but allowed free access to water. Each group of mice was administered the drug orally (by gavage). The control group received the same volume of physiological saline, the C6-A group received compound C6-A (300 mg / kg body weight), the C6-G group received compound C6-B (300 mg / kg body weight), and the acetaminophen group received acetaminophen 300 mg / kg body weight. After administration, mice were fed for 12 hours, then fasted for 6 hours, and all groups were again administered the same dose of drug orally. 12 hours after feeding, blood was collected from the eyes, and the supernatant was used to measure serum alanine aminotransferase (ALT) activity. Mice were euthanized by cervical dislocation, and fresh livers were collected, homogenized with 0.9% physiological saline to prepare a 20% homogenate, and the glutathione (GSH) content was determined using the Griess method. The experimental results are shown in Table 1. Table 1. Biochemical indicators of liver function in mice control group 9.8±1.89 18.3±2.34 Group C6-A 12.5±2.45 16.1±3.45 Group C6-G 12.3±2.18 16.9±3.21 Acetaminophen group 56.1±20.2 3.22±1.32 , The results showed that the new compounds C6-A and C6-G significantly reduced liver toxicity in animals compared to acetaminophen.

[0028] Implementation Case 3: Comparison of the therapeutic effects of the new compound and acetaminophen on migraines.

[0029] Adult SD rats were randomly divided into 11 groups: control group, model group, low-, medium-, and high-dose C6-A groups, low-, medium-, and high-dose C6-G groups, and low-, medium-, and high-dose acetaminophen groups, with 10 rats in each group. Oral administration was performed at the following dosages: the control and model groups received the same volume of saline; the low-, medium-, and high-dose C6-A and C6-G groups received 10 mg / kg body weight, 20 mg / kg body weight, and 30 mg / kg body weight, respectively; the low-, medium-, and high-dose acetaminophen groups received 10 mg / kg body weight, 20 mg / kg body weight, and 30 mg / kg body weight, respectively. Except for the control group, all other groups received the following treatment: subcutaneous injection of 10 mg / kg nitroglycerin in the head and neck; the control group received an equal volume of saline. Thirty minutes after nitroglycerin injection, all rats in each group received the oral administration of the drug. Behavioral observations were conducted one hour later, and data were recorded continuously for 30 minutes (rounded to the nearest whole number). Behavioral observations included the number of times the rat scratched or shook its head with its forelimbs or hindlimbs; other symptoms were not recorded. The total behavioral score for each rat was recorded. The experimental results are shown in Table 2. Table 2. Behavioral Performance of the Rat Migraine Model After Drug Administration , The results showed that C6-A and C6-G were more effective than acetaminophen in treating migraines in rats at the same dose. However, to achieve similar therapeutic effects, the dosages of C6-A and C6-G were lower than those of acetaminophen.

[0030] Implementation Case 4: Effects of a novel compound and acetaminophen on the writhing response in an acetic acid-induced mouse pain model Adult KM mice were randomly divided into four groups: a model group, a C6-A group, a C6-G group, and an acetaminophen group, with 12 mice in each group. Oral administration was performed at the following dosages: the model group received the same volume of saline; the C6-A and C6-G groups received 10 mg / kg body weight of C6-A and C6-G, respectively; and the acetaminophen group received 10 mg / kg body weight of acetaminophen. After each oral administration, mice in each group received an intraperitoneal injection of 10 mL / kg of 0.6% glacial acetic acid. The number of writhing responses (abdominal concavity, hind limb extension, and hip elevation constitute one complete writhing response) within 15 minutes was observed, and the latency of the first writhing response was recorded. The writhing inhibition rate was calculated. [Writhing inhibition rate = (number of writhing responses in the model group - number of writhing responses in the drug-treated group) / number of writhing responses in the model group]. The experimental results are shown in Table 3. Table 3: Effects of drugs on writhing response in an acetic acid-induced mouse pain model Model group 3.9±1.0 30.8±5.2 - Group C6-A 5.6±0.9 15.1±2.1 51.0% Group C6-G 5.7±1.1 15.7±1.9 49.0% Acetaminophen group 4.9±1.2 21.2±3.2 31.2% , By comparing the latency of writhing in mice and calculating the writhing inhibition rate, it was found that compared with the acetaminophen group, compounds C6-A and C6-G could significantly prolong the latency of mice, and had the highest writhing inhibition rate, resulting in better analgesic effects.

Claims

1. A gastrodin-acetaminophen twin, characterized in that, The chemical formula of the twin drugs is: Where R is -CH2CH2CH(NH2)- or -CH2CH(NH2)-.

2. A method for preparing the gastrodin and acetaminophen twin drug of claim 1, characterized in that, Includes the following steps: 1) The functional groups in gastrodin and acetaminophen are protected by the following steps: First, benzyloxycarbonyl is used to protect the phenolic hydroxyl group of gastrodin; second, glutamic acid and aspartic acid protected by N-tert-butyloxycarbonyl and benzyl groups are used. 2) The protected amino acid is condensed with acetaminophen in the presence of the condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to form amino acid-acetaminophen ester; 3) Deprotect the benzyl groups on the amino acid side chains of the above compounds; 4) The deprotected compound and the protected gastrodin were esterified by EDCI. 5) Remove the protecting agent on the amino acid by removing the Cbz protecting group with a hydrogen bromide acetic acid solution to obtain the product.

3. The method for preparing the gastrodin and acetaminophen twin drug according to claim 2, characterized in that, Step 1) includes the following steps: 2 mmol of gastrodin and 0.5 ml of triethylamine are dissolved in 50 ml of acetonitrile. Under stirring, 1.1 ml of 50% benzyloxycarbonyl toluene solution is added at 0°C and the mixture is reacted at room temperature for 1 hour. The reaction solution is poured into 100 ml of purified water and extracted 1-2 times with ethyl acetate. The organic phases are combined, dried, and concentrated to obtain a yellow oily crude product. The crude product is purified by silica gel column chromatography to obtain 500 mg of white solid, with a yield of 90%.

4. The method for preparing the gastrodin and acetaminophen twin drug according to claim 2, characterized in that, Step 2) Specifically: In a round-bottom flask, add 12.0 mmol of acetaminophen and 12.0 mmol of protected amino acids, then add 30 mL of acetone and stir in an ice-water bath to dissolve. Add 12.0 mmol of EDCI and 0.5 mmol of 4-DMAP catalyst, stir, and let stand. React at room temperature for 2 hours. Then, slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in batches over 5 minutes. Remove the ice-water bath and continue stirring at room temperature for 2 hours. Transfer the reaction solution to a 250 mL separatory funnel and wash with 50 mL of ethyl acetate and 30 mL of 1 mol / L hydrochloric acid solution. Then wash with 30 mL of 1 mol / L NaOH solution, followed by another wash with 30 mL of saturated saline solution. Transfer the upper organic phase to an Erlenmeyer flask. Weigh 2 g of anhydrous sodium sulfate and add it to the Erlenmeyer flask. Let stand for 10 minutes. After filtration, the filtrate was distilled under reduced pressure to obtain 4.12 g of a white solid, which was named compound C2.

5. The method for preparing the gastrodin and acetaminophen twin drug according to claim 2, characterized in that, Step 3) is as follows: Take 2 mmol of compound C2 and add it to a 1 L hydrogenation reactor. Add 1 g of 10% industrial palladium / carbon and 50 mL of methanol. React at 8 °C or below and 0.3 MPa hydrogen pressure for 4 h. Filter to remove palladium / carbon, concentrate under reduced pressure, add 50 mL of deionized water, filter, wash the aqueous layer with 30 mL each of n-butanol and ethyl acetate, concentrate under reduced pressure to remove ethyl acetate from the water, adjust the pH to 6.8 with saturated sodium bicarbonate solution, and freeze-dry to obtain compound C3.

6. The method for preparing the gastrodin and acetaminophen twin drug according to claim 2, characterized in that, Step 4) Specifically: In a round-bottom flask, add 5 mmol of Cbz-gastrodin and 5 mmol of compound C3, then add 30 mL of acetone and stir in an ice-water bath to dissolve. Add 12.0 mmol of EDCI and 0.5 mmol of catalyst 4-DMAP, stir well, and let stand at room temperature for 2 h. Then, slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in batches over 5 min, remove the ice-water bath, and continue stirring at room temperature for 2 h. Transfer the reaction solution to a separatory funnel and add 100 mL of ethyl acetate. Then, wash with 30 mL of 1 mol / L hydrochloric acid solution, then wash with 30 mL of 1 mol / L NaOH solution, and then wash once with 30 mL of saturated saline solution. Transfer the upper organic phase to an Erlenmeyer flask. Weigh 5 g of anhydrous sodium sulfate and add it to the Erlenmeyer flask, let stand for 10 minutes. After filtration, the filtrate was distilled under reduced pressure to obtain 2.91 g or 3.02 g of a white solid, which was named compound C4.

7. The method for preparing the gastrodin and acetaminophen twin drug according to claim 2, characterized in that, in, Step 5) is: Take 5 mmol of compound C4 and dissolve it in 50 ml of 50% (V / V) trifluoroacetic acid (F3CCOOH) in dichloromethane. Stir at 0°C for 10 minutes, then raise the temperature to room temperature and continue the reaction for 60 minutes. After the reaction is complete, remove the dichloromethane by rotary evaporation, then add 30 ml of ethyl acetate to dissolve it, and wash with 5% NaHCO3 until neutral to obtain Cbz-gastrodin-Asp-acetaminophen or Cbz-gastrodin-Glu-acetaminophen, which is called compound C5. Take 10 mmol of compound C5 and place it in a round-bottom flask. Add 25 ml of 35.5% (V / V) acetic acid solution of hydrogen bromide. Stir at room temperature for 5 hours, then remove the hydrogen bromide and glacial acetic acid. Add 50 ml of diethyl ether for recrystallization. Filter and dry the residual solid under vacuum to obtain the target compound gastrogenin-Asp-acetaminophen or gastrogenin-Glu-acetaminophen.

8. The use of the gastrodin of claim 1 and acetaminophen twin in the preparation of analgesic and anti-inflammatory drugs.

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