Gastrogenin and acetaminophen twin drug, and preparation method and application thereof

Abstract

The invention relates to a gastrodigenin and acetaminophen twin drug and a preparation method and application thereof, and belongs to the technical field of medicines.The preparation method comprises the synthesis steps that 1, functional groups in gastrodigenin and acetaminophen are protected; (2) carrying out condensation on the protected amino acid and acetaminophen under the action of a condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, so as to form amino acid-acetaminophen ester; 3) performing deprotection on benzyl of the amino acid side chain of the compound; (4) ester is formed from the deprotected compound and the protected gastrodin under the action of EDCI; 5, the protective agent on the amino acid is removed, and the product is obtained.By means of the preparation method, the defects that gastrodigenin is not remarkable in curative effect, large in dosage and long in period when being independently used as a medicine are overcome, damage of acetaminophen to the liver is reduced, and the treatment effect of acetaminophen on headache is improved.

Description

Technical Field

[0001] The invention relates to a twin medicine of gastrodia elata aglycone and acetaminophen, a preparation method and application thereof, and belongs to the technical field of medicine. Background Art

[0002] The principle of splicing refers to the new drug or twin drug obtained by combining the structures of two drugs into one molecule, or by making the pharmacological groups of the two drugs compatible in one molecule. After metabolism in the body, the above two drugs with synergistic effects are produced, resulting in enhanced activity or new pharmacological activity, or higher selectivity. According to the splicing structure modification, it is divided into three methods: ester splicing, salt splicing, and non-ester non-salt splicing.

[0003] Ester formation is the most widely used in drug formation. It is the combination of the carboxyl group in one drug molecule and the hydroxyl group in another drug molecule to form an ester. The most famous benoyl ester (also known as paracetamol) is formed by the combination of acetylsalicylic acid and acetaminophen. It solves the gastric irritation of acetylsalicylic acid, enhances the efficacy, and reduces the side effects of both.

[0004] Acetaminophen, also known as paracetamol, is a metabolite of phenacetin in the body. Acetaminophen is similar to phenacetin. It has few side effects and is a widely used antipyretic and analgesic in clinical practice, but it still has shortcomings such as obvious first-pass effect in the liver. According to the principle of prodrug design, acetaminophen and carboxyl-containing compounds are synthesized into ester prodrugs, which can release two molecules of the original drug through enzymatic hydrolysis in the body, achieving the dual pharmacological effects of antipyretic and analgesia. In this way, it can not only expand the scope of clinical use, improve oral absorption, increase blood drug concentration and utilization, and reduce the dosage of medication, but also overcome the toxic and side effects of the original drug and reduce adverse reactions.

[0005] Gastrodia elata is the dried tuber of Gastrodia elata, a plant of the genus Gastrodia of the orchid family. It is a traditional precious Chinese medicine, mainly used to treat dizziness, vertigo, limb numbness, convulsions and stroke. Studies have reported that gastrodin is the main chemical component of Gastrodia elata that exerts its pharmacological effects. Although gastrodin can directly pass through the blood-brain barrier, it needs to be metabolized to form gastrodin aglycone before it can exert its effects, and gastrodin aglycone is easier to pass through the blood-brain barrier than gastrodin. A large number of studies have reported that Gastrodia elata has good sedative and analgesic pharmacological effects. Summary of the invention

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

[0007] The invention utilizes amino acids to splice acetaminophen and gastrodin aglycone into one drug molecule, thereby overcoming the irritation of acetylsalicylic acid to the stomach and enhancing the pharmacological activity of gastrodin aglycone.

[0008] The specific technical solution adopted by the invention is: A twin medicine of gastrodia elata aglycone and acetaminophen, characterized in that the chemical formula of the twin medicine is: , wherein R is -CH2CH2CH(NH2)- or -CH2CH(NH2)-.

[0009] A method for preparing a twin medicine of gastrodia elata aglycone and acetaminophen, characterized in that it comprises the following steps: 1) Protect the functional groups in Gastrodia elata aglycone and acetaminophen. The method and steps are as follows: First, the phenolic hydroxyl group of gastrodia aglycone is protected by benzyloxycarbonyl (Cbz); second, glutamic acid and aspartic acid protected by N-tert-butyloxycarbonyl (Boc) and benzyl (Bn) (β-carboxyl) are used as starting materials; 2) Condensing the protected amino acid with acetaminophen in the presence of a condensing agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), to form an amino acid-acetaminophen ester; 3) deprotecting the benzyl group (Bn) of the amino acid side chain of the above compound; 4) forming an ester with the deprotected compound and the protected gastrodia elata aglycone under the action of EDCI; 5) Removing the protecting agent from the amino acid, the product is obtained.

[0010] Wherein, the step 1) comprises the following steps: 248 mg (2 mmol) of gastrodia elata aglycone and 0.5 ml of triethylamine are dissolved in 50 ml of acetonitrile, and 1.1 ml of 50% benzyloxycarbonyl (Cbz) toluene solution is added at 0°C under stirring and reacted at room temperature for 1 hour. The reaction solution is poured into 100 ml of pure 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, which is purified by a silica gel column [eluent (V (ethyl acetate): V (n-hexane) 2:1] to obtain 500 mg of a white solid with a yield of 90%, namely Cbz-gastrodia elata aglycone (compound C1). The chemical reaction formula of the above steps is as follows: , Wherein, step 2) is specifically as follows: using a condensation reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) to condense to form an ester under the condition of a catalyst 4-dimethylaminopyridine (4-DMAP).

[0011] Reaction conditions: Add 1.81g (12.0 mmol) of acetaminophen and 12.0mmol of protected amino acid to a 200 mL round-bottom flask, add to 30ml of acetone, stir in an ice-water bath to dissolve; add EDCI (12.0 mmol) and catalyst 4-DMAP (0.5 mmol), stir evenly and let stand, react at room temperature for 2 h. Then slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in batches within 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.

[0012] Add 30 mL of 1 mol / L hydrochloric acid solution to wash, repeat this operation twice, then add 30 mL of 1 mol / L NaOH solution to wash, repeat this operation twice, then add 30 mL of saturated brine to wash once, and then transfer the upper organic phase to a 250 mL conical flask. Weigh 2 g of anhydrous sodium sulfate and add it to the conical flask, let it stand for 10 min, filter, and distill the filtrate under reduced pressure to obtain 4.12 g of white solid, called compound C2. The chemical reaction formula is as follows: , Among them, step 3) is as follows: take 2mmol of compound C2, add it to a 1L hydrogenation reactor, add 1g of 10% industrial palladium / carbon (Pd / C) and 50ml of methanol, and react for 4h at below 8°C and 0.3MPa hydrogen pressure. Filter to remove palladium carbon, concentrate under reduced pressure, add 50mL of deionized water, filter, wash the water layer with 30mL of n-butanol and ethyl acetate twice, concentrate under reduced pressure to remove ethyl acetate in the water, adjust the pH to 6.8 with saturated sodium bicarbonate solution, and freeze-dry to obtain compound C3, the chemical reaction formula is as follows: , In step 4), a commonly used condensation reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) is used in the art to condense the ester in the presence of 4-dimethylaminopyridine (4-DMAP).

[0013] Reaction conditions: In a 200 mL round-bottom flask, add 5 mmol of Cbz-Gastrodia aglycone and compound C3 (5 mmol), add to 30 ml of acetone, stir in an ice-water bath to dissolve; add EDCI (12.0 mmol) and catalyst 4-DMAP (0.5 mmol), stir evenly and let stand, react at room temperature for 2 h. Then slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in batches within 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. Add 30 mL of 1 mol / L hydrochloric acid solution for washing, repeat this operation twice, then add 30 mL of 1 mol / L NaOH solution for washing, repeat this operation twice, then add 30 mL of saturated brine for washing once, and then transfer the upper organic phase to a 250 mL conical flask. Weigh 5 g of anhydrous sodium sulfate and add it to a conical flask, let it stand for 10 min, filter it, and distill the filtrate under reduced pressure to obtain 2.91 g or 3.02 g of a white solid (when N-Boc-Glu-acetaminophen is used as the reactant), which is called compound C4. The chemical reaction formula is as follows: , In step 5), trifluoroacetic acid, a reagent commonly used in the art, is used to remove the Boc protecting group; and a solution of hydrogen bromide in acetic acid is used to remove the Cbz protecting group.

[0014] Reaction conditions for removing Boc: Take 5mmol of compound C4, dissolve it in 50ml of 50% (V / V) trifluoroacetic acid (F3CCOOH) dichloromethane (CH2Cl2) solution, stir at 0℃ for 10 minutes, and then continue to react for 60 minutes at room temperature. After the reaction is completed, remove dichloromethane by rotary evaporation, then add 30ml of ethyl acetate to dissolve, and then wash with 5% NaHCO3 until neutral, and then obtain Cbz-Gastrodia aglycone-Asp-acetaminophen or Cbz-Gastrodia aglycone-Glu-acetaminophen, which is called compound C5.

[0015] Reaction conditions for removing Cbz: Take 10mmol of compound C5, place it in a 100ml round-bottom flask, add 25ml of 35.5% (V / V) hydrogen bromide acetic acid solution, stir at room temperature for 5 hours, remove hydrogen bromide and glacial acetic acid, add 50ml of ether for recrystallization, filter, and vacuum dry the residual solid to obtain the target compound Gastrodia elata aglycone-Asp-acetaminophen or Gastrodia elata aglycone-Glu-acetaminophen (Compound C6). The above chemical reaction formula is as follows: , A twin medicine of gastrodia elata aglycone and acetaminophen is used in the preparation of a medicine for treating or assisting in the treatment of analgesia and anti-inflammation.

[0016] Compared with the prior art, the present invention has the following beneficial effects: In the present invention, the linking molecule Glu or Asp contains -NH, which increases the solubility of the twin drugs and is more conducive to absorption; after the drug is absorbed, it can effectively avoid the damage of acetaminophen to the liver; gastrodia aglycone can pass through the blood-brain barrier, is used to treat headaches, and has a sedative and tranquilizing effect. Further research has found that the twin drugs of the present invention have lower dosages and treatment cycles in terms of anti-inflammatory and analgesia than two separate drugs.

[0017] The present invention overcomes the disadvantages of gastrodia aglycone used alone as a drug, which has insignificant therapeutic effect, large dosage and long cycle. The present invention reduces the damage of acetaminophen to the liver; The present invention improves the therapeutic effect of acetaminophen on headache; The invention reduces the dosage of analgesics and shortens the medication cycle. DETAILED DESCRIPTION

[0018] Example 1: Synthesis

[0019] 1. Take 248mg (2mmol) of gastrodia elata aglycone and 0.5ml of triethylamine and dissolve them in 50ml of acetonitrile. Under stirring, add 1.1ml of 50% benzyloxycarbonyl (Cbz) toluene solution at 0℃ and react at room temperature for 1 hour. Pour the reaction solution into 100ml of pure water, extract with ethyl acetate (2×150ml), combine the organic phases, dry with calcium sulfate, and concentrate the organic liquid to obtain a yellow oily crude product. Purify it on a silica gel column [eluent (V (ethyl acetate): V (n-hexane) 2:1] to obtain 500mg of a white solid with a yield of 90%, namely Cbz-gastrodia elata aglycone (compound C1).

[0020] 2. Take 1.81 g (12.0 mmol) of acetaminophen and 12.0 mmol of modified amino acid, add them to a 200 mL round-bottom flask, add 30 ml of acetone, stir in an ice-water bath to dissolve; add EDCI (12.0 mmol) and catalyst 4-DMAP (0.5 mmol), stir evenly and let stand, react at room temperature for 2 h. Then slowly add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in batches within 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] Add 30 mL of 1 mol / L hydrochloric acid solution for washing, repeat this operation twice, then add 30 mL of 1 mol / L NaOH solution for washing, repeat this operation twice, then add 30 mL of saturated brine for washing once, and then transfer the upper organic phase to a 250 mL conical flask. Weigh 2 g of anhydrous sodium sulfate and add it to the conical flask, let it stand for 10 min, filter, and distill the filtrate under reduced pressure to obtain 4.12 g of white solid, called compound C2.

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

[0023] 4. Take 5 mmol of Cbz-Gastrodia aglycone and compound C3 (5 mmol), place them in a 200 mL round-bottom flask, add 30 ml of acetone, stir and dissolve in an ice-water bath; add EDCI (12.0 mmol) and catalyst 4-DMAP (0.5 mmol), stir evenly and let stand, react at room temperature for 2 h. Add 12.0 mmol of EDCI and 5 mmol of 4-DMAP in batches slowly within 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. Add 30 mL of 1 mol / L hydrochloric acid solution for washing, repeat this operation twice, then add 30 mL of 1 mol / L NaOH solution for washing, repeat this operation twice, then add 30 mL of saturated brine for washing once, and then transfer the upper organic phase to a 250 mL conical flask. Weigh 5 g of anhydrous sodium sulfate and add it to a conical flask. Let it stand for 10 min and filter it. Distill the filtrate under reduced pressure to obtain 2.91 g or 3.02 g (when N-Boc-Glu-acetaminophen is used as the reactant) of a white solid, referred to as compound C4.

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

[0025] Implementation case 2: Comparison of the acute toxicity test on animal liver between the new compound and acetaminophen.

[0026] Male KM mice (10 weeks old, 26-27 g, clean grade) were selected. Before the experiment, the mice were allowed free access to food and water and were adaptively fed under circadian rhythm conditions 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. They were fasted for 6 hours before the experiment. Each group of mice was orally administered (gavage), with the control group given the same volume of saline, the C6-A group given compound C6-A (300 mg / kg body weight), the C6-G group given compound C6-B (300 mg / kg body weight), and the acetaminophen group given acetaminophen 300 mg / kg body weight. After feeding for 12 hours after administration, the mice were fasted for 6 hours and the same dose of drugs was orally administered to each group of mice again. After feeding for 12 hours, blood was taken from the eyeballs of the mice, and the supernatant was taken to determine the serum alanine aminotransferase (ALT) activity; after the mice were killed by cervical dislocation, the fresh liver was taken and homogenized with 0.9% saline to make a 20% homogenate, and the glutathione (GSH) content was determined by the Griess method. The experimental results are shown in Table 1: Table 1 Biochemical indexes of mouse liver function Group ALT activity (IU / L) GSH content (nmol / mg) 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 damage to animals compared with acetaminophen.

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

[0029] Adult SD rats were randomly divided into 11 groups: control group, model group, C6-A low, medium and high dose groups, C6-G low, medium and high dose groups and acetaminophen low, medium and high dose groups, with 10 rats in each group. Oral administration, according to the dosage: the control group and the model group received the same dose of normal saline, the C6-A and C6-G low, medium and high dose groups were given 10 mg / kg body weight, 20 mg / kg body weight and 30 mg / kg body weight of C6-A and C6-G respectively; the acetaminophen low, medium and high dose groups were given 10 mg / kg body weight, 20 mg / kg body weight and 30 mg / kg body weight of acetaminophen. Except for the control group rats, the rats in other groups were treated as follows: 10 mg / kg nitroglycerin was injected subcutaneously at the head and neck; the control group was given the same amount of normal saline. 30 minutes after the injection of nitroglycerin, the rats in each group were orally administered, and 1 hour later, the behavioral observation was carried out, and the observation was continuously observed for 30 minutes and recorded (data were rounded). Behavioral observations included: the number of times the forelimbs or hindlimbs scratched and shook the head, and other symptoms were not recorded. The total behavioral score of each rat was recorded. The experimental results are shown in Table 2: Table 2 Rat migraine model and behavioral manifestations after drug administration , The results showed that the same dose of C6-A and C6-G had a better therapeutic effect on migraine in rats than acetaminophen. To achieve similar therapeutic effects, the dosage of C6-A and C6-G was less than that of acetaminophen.

[0030] Case study 4: Effects of new compounds and acetaminophen on writhing responses in acetic acid-induced pain model in mice Adult KM mice were randomly divided into 4 groups: model group, C6-A group, C6-G group and acetaminophen group, with 12 mice in each group. Oral administration, the dosage was as follows: the model group received the same dose of normal saline, C6-A and C6-G groups were given 10 mg / kg body weight of C6-A and C6-G respectively; the acetaminophen group was given 10 mg / kg body weight of acetaminophen. Each group of mice was orally administered once, and 1 hour later, each group of mice was intraperitoneally injected with 0.6% glacial acetic acid 10 mL / kg. The number of writhing reactions of mice within 15 minutes was observed (abdomen concave, hind limbs extended, buttocks raised as a complete writhing), and the latency time of the first writhing was recorded, and the writhing inhibition rate was calculated. [Writhing inhibition rate = (number of writhing in the model group - number of writhing in the drug group) / number of writhing in the model group]. The experimental results are shown in Table 3: Table 3: Effects of drugs on writhing response in acetic acid-induced pain model in mice Group Latent period / min Number of twists in 15 minutes Inhibition rate 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 period of mouse writhing 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 period of mice, had the highest writhing inhibition rate, and had better analgesic effect.

Claims

1. A twin medicine of gastrodia elata aglycone and acetaminophen, characterized in that: The chemical formula of the twin drug is: ， wherein R is -CH2CH2CH(NH2)- or -CH2CH(NH2).

2. A method for preparing a twin medicine of gastrodia elata aglycone and acetaminophen, characterized in that: The steps include: 1) Protect the functional groups in Gastrodia elata aglycone and acetaminophen. The steps are as follows: First, the phenolic hydroxyl group of gastrodia aglycone is protected by benzyloxycarbonyl; second, glutamic acid and aspartic acid are protected by N-tert-butyloxycarbonyl and benzyl groups; 2) Condensing the protected amino acid with acetaminophen in the presence of a 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 with the deprotected compound and the protected gastrodia elata aglycone under the action of EDCI; 5) Removing the protecting agent from the amino acid, the product is obtained.

3. The method for preparing the twin medicine of gastrodia elata aglycone and acetaminophen according to claim 2, characterized in that: The step 1) comprises the following steps: dissolving 2 mmol of gastrodia elata aglycone and 0.5 ml of triethylamine in 50 ml of acetonitrile, adding 1.1 ml of 50% benzyloxycarbonyl toluene solution at 0°C under stirring, and reacting at room temperature for 1 hour; pouring the reaction solution into 100 ml of pure water, extracting with ethyl acetate 1-2 times, combining the organic phases, drying and concentrating the organic liquid to obtain a yellow oily crude product, and purifying it with a silica gel column to obtain 500 mg of a white solid with a yield of 90%.

4. The method for preparing the twin medicine of gastrodia elata aglycone and acetaminophen according to claim 2, characterized in that: Step 2) is specifically as follows: add 12.0 mmol of acetaminophen and 12.0 mmol of protected amino acid to a round-bottom flask, add to 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 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 within 5 minutes, remove the ice-water bath, continue stirring at room temperature for 2 hours, transfer the reaction solution to a 250 mL separatory funnel, and add 50 mL of ethyl acetate and 30 mL of 1 mol / L hydrochloric acid solution for washing, then add 30 mL of 1 mol / L NaOH solution for washing, and then add 30 mL of saturated brine for washing once, and then transfer the upper organic phase to a conical flask; weigh 2 g of anhydrous sodium sulfate and add it to the conical flask, let stand for 10 min, filtered, and the filtrate was distilled under reduced pressure to obtain 4.12 g of a white solid, referred to as compound C2.

5. The method for preparing the twin medicine of gastrodia elata aglycone and acetaminophen according to claim 2, characterized in that: Step 3) is as follows: take 2 mmol of compound C2, add it to a 1 L hydrogenation reactor, add 1 g of 10% industrial palladium / carbon and 50 ml of methanol, and react for 4 hours at below 8°C and 0.3 MPa hydrogen pressure; filter to remove palladium carbon, concentrate under reduced pressure, add 50 mL of deionized water, filter, wash the water layer with 30 mL of n-butanol and 30 mL of ethyl acetate in turn, concentrate under reduced pressure to remove ethyl acetate in 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 twin medicine of gastrodia elata aglycone and acetaminophen according to claim 2, characterized in that: Step 4) is specifically as follows: in a round-bottom flask, add 5 mmol of Cbz-Gastrodia elata aglycone and 5 mmol of compound C3, add to 30 ml of acetone, and stir in an ice-water bath to dissolve; add 12.0 mmol EDCI and 0.5 mmol catalyst 4-DMAP, stir evenly and let stand, react at room temperature for 2 h, then slowly add 12.0 mmol EDCI and 5 mmol 4-DMAP in batches within 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 add 30 mL of 1 mol / L hydrochloric acid solution for washing, then add 30 mL of 1 mol / L NaOH solution for washing, and then add 30 mL of saturated brine for washing once, and then transfer the upper organic phase to a conical flask; weigh 5 g of anhydrous sodium sulfate and add it to the conical flask, let stand for 10 min, filtered, and the filtrate was distilled under reduced pressure to obtain 2.91 g or 3.02 g of a white solid, referred to as compound C4.

7. The method for preparing the twin medicine of gastrodia elata aglycone and acetaminophen according to claim 2, characterized in that: in, Step 5) is: Take 5 mmol of compound C4, dissolve it in 50 ml of 50% (V / V) trifluoroacetic acid (F3CCOOH) dichloromethane solution, stir at 0°C for 10 minutes, and then continue to react for 60 minutes at room temperature; after the reaction is completed, remove dichloromethane by rotary evaporation, then add 30 ml of ethyl acetate to dissolve, and then wash with 5% NaHCO3 until neutral, so as to obtain Cbz-Gastrodia aglycone-Asp-acetaminophen or Cbz-Gastrodia aglycone-Glu-acetaminophen, which is called compound C5; Take 10 mmol of compound C5, place it in a round-bottom flask, add 25 ml of 35.5% (V / V) hydrogen bromide acetic acid solution, stir at room temperature for 5 hours, remove the hydrogen bromide and glacial acetic acid, add 50 ml of ether for recrystallization, filter, and vacuum dry the residual solid to obtain the target compound Gastrodia elata aglycone-Asp-acetaminophen or Gastrodia elata aglycone-Glu-acetaminophen.

8. Use of a twin drug of Gastrodia elata aglycone and acetaminophen in the preparation of a drug for the treatment or auxiliary treatment of analgesia and anti-inflammation.

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