Preparation method of (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative

Abstract

The present invention discloses a preparation method of a (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazole-4'-yl)-6-methylhept-5-enoate derivative of a compound of formula I. The preparation method comprises the following steps: using an R1-substituted dimethoxy phosphate derivative 1 and 5-bromo-2-methylpent-2-ene 8 as starting materials, performing a Horner-Wadsworth-Emmons reaction, an Appel reaction, a substitution reaction, an intramolecular Michael addition reaction, and deprotecting the group to obtain a (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazole-4'-yl)-6-methylhept-5-enoate derivative (Formula I).

Description

Technical Field

[0001] The present invention relates to a preparation method of (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (compound of formula I), belonging to the technical field of medicine. Background Art

[0002] Diabetes is one of the most common chronic diseases in humans. It is a complex disease characterized by hyperglycemia caused by insufficient insulin secretion, low insulin action, or both, and can occur at any stage of life. In recent years, with the continuous increase in calorie intake and the decrease in physical activity, the incidence of diabetes has been rising rapidly. According to a report from the International Diabetes Federation (IDF), the global population with diabetes reached 537 million in 2023, with a total prevalence of 6.1%; by 2050, it is estimated that more than 1.31 billion people worldwide will have diabetes. In addition, diabetes is the leading cause of renal failure, non-traumatic lower limb amputation and new-onset blindness in adults, and is also an important cause of heart disease and stroke.

[0003] Type 2 diabetes (T2D) accounts for 95% of all diabetes cases and carries the greatest risk. It is characterized by hyperglycemia, resulting from impaired glucose, fat, and protein metabolism caused by insufficient insulin secretion or function, leading to a variety of acute and chronic complications. The liver is the primary site of glucose production and is crucial for maintaining normal glucose homeostasis, producing glucose during fasting and storing it after meals. However, these processes are dysregulated in T2D, leading to hyperglycemia in both the fasting and postprandial states. Insulin lowers postprandial blood glucose, while fasting blood glucose homeostasis is primarily maintained by hepatic gluconeogenesis, mediated by glucagon. Abnormal hepatic gluconeogenesis, caused by dysregulation of hepatic glucagon production, is the direct cause of elevated fasting blood glucose in diabetes. Therefore, understanding the molecular mechanisms regulating hepatic gluconeogenesis is crucial for improving T2D treatment strategies. Currently, most diabetes treatments rely on Western medications, which have significant side effects, making long-term use unsuitable and ineffective in controlling diabetic complications. Natural Chinese medicine can significantly improve the clinical symptoms of diabetes. Its advantages are that it has few side effects, can prevent and treat diabetes complications in multiple aspects, and is not prone to drug resistance.

[0004] Plantain is the dried whole herb of Plantago asiatica L. or Plantago depressa Willd., a member of the Plantaginaceae family. It is a commonly used Chinese medicine listed in the 2010 edition of the Chinese Pharmacopoeia. Plantain is cold in nature and sweet in taste. It has multiple pharmacological effects, including lowering blood lipids, protecting against liver damage, providing antioxidants, anti-inflammatory effects, lowering blood uric acid, and lowering blood sugar. It is often added to traditional Chinese medicine prescriptions for the treatment of diabetes. It has been reported that research on the active ingredients of Plantain has found that the guanidine acid (i.e., compound of formula II) contained in its acetone extract can significantly inhibit the production of carbohydrates (J Nat Prod. 2015;78(11): 2822-2826.).

[0005] Although plantagogue acid (Formula II) has a significant inhibitory effect on the formation of carbohydrates, the current method for extracting the active ingredients from plantain is mainly through traditional organic solvent extraction, and multiple separations are performed using various types of chromatographic columns. Studies have shown that only 200 mg of plantagogue acid can be extracted and separated from 8 kg of plantain (J Nat Prod. 2013;76(7): 1351-1357). In addition, the extraction and separation process uses a large amount of organic solvents and produces a large amount of waste liquid, which poses a certain harm to the environment. At the same time, the product quality and separation efficiency are difficult to control and are greatly affected by the quality of the Chinese medicinal materials. The extraction and separation technology is demanding. Large-scale preparation and purification are relatively difficult, the production cost is high, and it is difficult to industrialize production.

[0006] The structure of psyllium guanidine is as follows

[0007]

[0008] The (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative represented by Formula I of the present invention is an important intermediate of plantagogue acid (Formula II) with potential hypoglycemic activity. The guanidine acid compound is mainly used to treat diabetes, infectious diseases and cancer.

[0009] Currently, there is little research on the preparation methods of (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivatives, and there is an urgent need to develop efficient and suitable synthetic methods for industrial production. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a preparation method of (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I) as a potential hypoglycemic drug intermediate by means of chemical synthesis.

[0011] To achieve the purpose of the present invention, the following technical scheme is used to prepare (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivatives:

[0012] The following steps are involved:

[0013]

[0014] Among them, R1 is methyl, ethyl, or tert-butyl.

[0015] The preferred route includes the following steps:

[0016] a) Using R1-substituted dimethoxyphosphate derivative 1 and 5-bromo-2-methylpent-2-ene 8 as raw materials, 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 was prepared;

[0017]

[0018] b) using 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 and tert-butyldimethylsilyloxyacetaldehyde 9 as starting materials to prepare (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3;

[0019]

[0020] c) using (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 as a starting material to prepare (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4;

[0021]

[0022] d) using (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 as a starting material to prepare (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5;

[0023]

[0024] e) Using (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 and tert-butyloxycarbonylguanidine 10 as starting materials, 2-(2'-((tert-butyloxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 was prepared;

[0025]

[0026] f) preparing (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 7 (Formula I) using 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 as a starting material;

[0027]

[0028] R1 is methyl, ethyl or tert-butyl.

[0029] Specifically, the preparation method of the present invention is as follows:

[0030] Step a) Preparation of 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2

[0031] The starting materials for step a) are a Horner-Wadsworth-Emmons reaction (HWE reaction) of an R1-substituted dimethoxyphosphonate derivative 1 and 5-bromo-2-methylpent-2-ene 8 under alkaline conditions. The molar ratio of the R1-substituted dimethoxyphosphonate derivative 1 to 5-bromo-2-methylpent-2-ene 8 is 1:0.8-1.5, preferably 1:1.

[0032] The reaction is carried out in a conventional chemical reaction vessel, such as a flask or a reactor. The reaction vessel is preferably dried.

[0033] The solvent used in the reaction can be a protic solvent, an aprotic solvent, or a mixed solvent, to dissolve the reactants. Preferred aprotic solvents are selected from tetrahydrofuran, dichloromethane, diethyl ether, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, toluene, and N,N-dimethylformamide; preferred protic solvents are selected from ethanol, isopropanol, methanol, and tert-butanol; and most preferred solvents are selected from dichloromethane and N,N-dimethylformamide.

[0034] The preferred base for the reaction can be selected from alkali metal carbonates, alkali metal acetates, alkali metal and alkaline earth metal hydroxides, alkali metal fluorides, alkali metal phosphates, alkali metal hydrides, alkali metal alcoholates, alkali metal amides, and alkali metal alkyls; more preferably selected from sodium hydroxide, sodium hydride, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, tert-butyl lithium, potassium tert-butoxide, and lithium diisopropylamide; most preferably potassium tert-butoxide, sodium hydride, and potassium bis(trimethylsilyl)amide.

[0035] The reaction conditions are preferably inert gas protection, most preferably argon protection; the reaction conditions are preferably controlled reaction temperature, which can be controlled between -10°C and 5°C, and more preferably the reaction temperature is 0°C.

[0036] Step b) Preparation of (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3

[0037] Step b) using a 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 and tert-butyldimethylsilyloxyacetaldehyde 9 as raw materials to undergo a HWE reaction under alkaline conditions. The molar ratio of the 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 to tert-butyldimethylsilyloxyacetaldehyde 9 is 1:0.8-1.2, preferably 1:1.

[0038] The reaction is carried out in a conventional chemical reaction vessel, such as a flask or a reactor. The reaction vessel is preferably dried.

[0039] The solvent used in the reaction can be a protic solvent, an aprotic solvent, or a mixed solvent, to dissolve the reactants. Preferred aprotic solvents are selected from tetrahydrofuran, dichloromethane, diethyl ether, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and N,N-dimethylformamide; preferred protic solvents are selected from ethanol, isopropanol, methanol, and tert-butanol; and most preferred solvents are selected from ethylene glycol dimethyl ether and tetrahydrofuran.

[0040] The preferred base for the reaction can be selected from alkali metal carbonates, alkali metals, alkaline earth metal hydroxides, alkali metal phosphates, alkali metal hydrides, alkali metal alcoholates, alkali metal amides, and alkali metal alkyls; more preferably, it is selected from sodium hydride, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, tert-butyl lithium, potassium tert-butoxide, and lithium diisopropylamide; and most preferably, potassium tert-butoxide, sodium hydride, and potassium bis(trimethylsilyl)amide.

[0041] The reaction conditions are preferably inert gas protection, most preferably argon protection; the reaction conditions are preferably controlled reaction temperature, which can be controlled between -100 ° C and -60 ° C, and the more preferred reaction temperature is -78 ° C.

[0042] Step c) Preparation of (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4

[0043] Step c) Using (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 as a starting material, the TBS protecting group is removed under fluoride or acidic conditions.

[0044] The reaction is carried out in a conventional chemical reaction vessel, such as a flask or a reactor. The reaction vessel is preferably dried.

[0045] The preferred acidic conditions in the reaction are hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid, and dilute sulfuric acid; more preferred acidic conditions are hydrochloric acid and trifluoroacetic acid.

[0046] The preferred fluorides in the reaction are alkali metal fluorides and quaternary ammonium fluorides; more preferred is TBAF.

[0047] The molar ratio of (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 and TBAF is 1:1.2-2.4; preferably 1:1.5;

[0048] The solvent used in the reaction can be an aprotic solvent to dissolve the reactants. Preferred aprotic solvents are selected from tetrahydrofuran, dichloromethane, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and N,N-dimethylformamide; the most preferred solvents are selected from dioxane and tetrahydrofuran.

[0049] The reaction temperature is preferably controlled between room temperature and 50°C, and the more preferred reaction temperature is 30°C.

[0050] Step d) Preparation of (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5

[0051] Step d) Using (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 as raw material, (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 is prepared under the action of a halogenating agent and a ligand.

[0052] The molar ratio of (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 to the halogenating agent is 1:1-1.2; preferably 1:1.05;

[0053] Preferred halogenating agents in the reaction are phosphorus tribromide, carbon tetrabromide, and N-bromosuccinimide; a more preferred halogenating agent is N-bromosuccinimide. Preferred ligands in the reaction are triphenylphosphine, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, tributylphosphine, and tricyclohexylphosphine; a more preferred ligand is triphenylphosphine.

[0054] The preferred molar ratio of the halogenating agent to the ligand in the reaction is 1:1-1.2; more preferably 1:1.

[0055] The reaction is carried out in a conventional chemical reaction vessel, such as a flask or a reactor. The reaction vessel is preferably dried.

[0056] The solvent used in the reaction can be an aprotic solvent to dissolve the reactants. Preferred aprotic solvents are selected from tetrahydrofuran, dichloromethane, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and N,N-dimethylformamide; the most preferred solvent is dichloromethane.

[0057] The reaction temperature is preferably controlled between room temperature and 50°C, and the more preferred reaction temperature is 30°C.

[0058] Step e) Preparation of 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6

[0059] Step e) Using a (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 and tert-butoxycarbonylguanidine 10 as raw materials, a 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 is prepared under alkaline conditions. The molar ratio of the (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 to tert-butoxycarbonylguanidine 10 is 1:1.5 to 3; preferably 1:2.

[0060] The preferred alkaline conditions in the reaction are the addition of alkali metal phosphates, alkali metal carbonates, and alkali metal acetates; more preferred alkaline conditions are potassium carbonate and cesium carbonate.

[0061] The reaction is carried out in a conventional chemical reaction vessel, such as a flask or a reactor. The reaction vessel is preferably dried.

[0062] The solvent used in the reaction can be an aprotic solvent to dissolve the reactants. Preferred aprotic solvents are selected from tetrahydrofuran, acetonitrile, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and N,N-dimethylformamide; the most preferred solvents are selected from tetrahydrofuran and dioxane.

[0063] The reaction temperature is preferably controlled between 50° C. and 80° C., and more preferably 65° C. The reaction temperature varies with different solvents.

[0064] Step f) Preparation of (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I)

[0065] Step f) Using 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 as a starting material, the BOC protecting group is selectively removed under metal halide conditions to prepare a (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I).

[0066] The preferred molar ratio of the 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 to the metal halide in the reaction is 1:1.5-3; more preferably 1:2;

[0067] The preferred metal halide in the reaction is alkaline metal chloride, alkaline metal bromide, or alkaline metal iodide; the more preferred condition is the addition of alkaline metal bromide; and the most preferred condition is the addition of zinc bromide.

[0068] The reaction is carried out in a conventional chemical reaction vessel, such as a flask or a reactor. The reaction vessel is preferably dried.

[0069] The solvent used in the reaction can be an aprotic solvent to dissolve the reactants. Preferred aprotic solvents are selected from dichloromethane, tetrahydrofuran, acetonitrile, dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, and N,N-dimethylformamide; the most preferred solvents are selected from dichloromethane and tetrahydrofuran.

[0070] The reaction temperature is preferably controlled between 0°C and 30°C, and the more preferred reaction temperature is 25°C.

[0071] Beneficial technical effects:

[0072] The present invention provides a preparation method of a compound of formula I, namely a (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative, which belongs to the field of medical technology.

[0073] (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivatives (Formula I) are important intermediates of the hypoglycemic active substance psyllium guanidine (Formula II); their preparation methods have the advantages of high yield and ease of industrialization; some intermediates (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivatives (Formula I) are new compounds, potential pharmaceutical intermediates, and substances with potential hypoglycemic activity.

[0074] In the synthetic route provided by the present invention:

[0075] In step a), the method for preparing 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 using R1-substituted dimethoxyphosphonate derivative 1 and 5-bromo-2-methylpent-2-ene 8 as raw materials has readily available raw materials, does not require special reagents, is simple and easy to operate, operates under mild conditions, has high yield, and is easily industrialized.

[0076] In step b), a method for preparing a (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 by HWE reaction using a 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 and tert-butyldimethylsilyl acetaldehyde 9 as raw materials has mild reaction conditions, high yield, easy post-processing, and the target intermediate can be obtained by simple separation, which is easy to industrialize.

[0077] Step c) Using a (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 as a raw material, removing the protecting group TBS under TBAF conditions or acidic conditions to prepare a (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 has the advantages of simple operation, simple post-treatment, economical and practical, and easy industrialization.

[0078] Step d) uses a (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 as a raw material and conducts a halogenation reaction in the presence of a halogenating agent and a ligand to prepare a (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5. The method is economical and practical, has readily available reagents, is simple to operate, and is easily industrialized.

[0079] Step e) A method for preparing a 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4-yl)-6-methylhept-5-enoate derivative 6 using a (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 and tert-butoxycarbonylguanidine 10 as raw materials by reacting under alkaline conditions. The reagents are readily available, no special reagents are required, the method is economical and practical, the operation is simple, and industrialization is easy.

[0080] Step f) Using a 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 as a raw material, the BOC protecting group is selectively removed under metal halide conditions to prepare a (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I). ​​This method has a mild reaction, simple post-treatment, is economical and practical, and can be easily industrialized.

[0081] In summary, the synthetic route of the present invention has readily available raw materials, a short reaction route, and is easy to operate. Only simple column chromatography separation is required to purify the target molecule. This method is economical and practical, and is suitable for industrial production. It can overcome the shortcomings of the extraction and separation of the active substance psyllium guanidine acid (Formula II) from the plantain plant, such as the cumbersome steps and low yield.

[0082] The (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I) prepared by the preparation method of the present invention is an important intermediate of the glucose-lowering compound psyllium guanidine. Example 2 illustrates this glucose-lowering active substance, psyllium guanidine (Formula II). As can be seen, compared to the classic glucose-lowering drug metformin, the compound in Example 2 significantly inhibits hepatocyte gluconeogenesis, representing a novel class of glucose-lowering active molecules. Furthermore, Examples 1, 3, and 4 also exhibit a certain inhibitory effect on hepatocyte gluconeogenesis.

[0083] Terms and abbreviations

[0084] THF: Tetrahydrofuran

[0085] DMF: N,N-dimethylformamide

[0086] NBS: N-bromosuccinimide

[0087] BOC: tert-Butyloxycarbonyl

[0088] TBS: tert-butyldimethylsilyl

[0089] TBAF: Tetrabutylammonium fluoride BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 Schematic diagram of the structural formula of the (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I) of the present invention. DETAILED DESCRIPTION

[0091] Example 1 (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoic acid tert-butyl ester

[0092] (1) tert-Butyl 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate:

[0093]

[0094] Potassium tert-butoxide (8.3 g, 74.1 mmol) was weighed and placed in a 500 ml three-necked flask. 200 ml of dichloromethane was added under argon. After stirring for 10 minutes, tert-butyl dimethoxyphosphonoacetate (16.6 g, 74.1 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was then placed in an ice bath and 5-bromo-2-methylpent-2-ene (11.0 g, 67.4 mmol) was added dropwise. The mixture was allowed to react at room temperature for 12 hours. The reaction was stopped and quenched with water. 2N hydrochloric acid was added to adjust the pH to 4-5 under ice bath conditions. Extraction was then performed with dichloromethane and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain 14.9 g of tert-butyl 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate as a pale yellow oil. The yield was 72.3%. 1 H NMR (400 MHz, Chloroform-d) δ 5.06 (t, J = 6.8 Hz, 1H, =CH-), 3.83 – 3.75 (m, 6H, -CH3), 2.96 – 2.85 (m, 1H, -CH-), 2.14 – 1.74 (m, 4H, -CH2-), 1.69 (s, 3H, -CH3), 1.59 (s, 3H, -CH3), 1.48 (s, 9H, -t-Bu). MS (FAB): 307(M+1).

[0095] (2) Tert-butyl (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate:

[0096]

[0097] Potassium tert-butoxide (6.7 g, 59.67 mmol) was weighed and placed in a 500 ml three-necked flask and dissolved in 120 ml of ethylene glycol dimethyl ether. 2-(dimethoxyphosphoryl)-6-methylhept-5-enoic acid tert-butyl ester (14.1 g, 45.9 mmol) was added under ice-bath conditions. The mixture was heated to room temperature and stirred for 30 min. Under argon protection, tert-butyldimethylsilyl acetaldehyde (8.0 g, 45.9 mmol) was slowly added dropwise at -78°C. After stirring at -78°C for 3 h, the mixture was slowly heated to room temperature and stirred for 1 h. The reaction was quenched by the addition of 12 ml of saturated ammonium chloride solution. Ethyl acetate and water were then added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. 13.9 g of tert-butyl (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate was obtained as a colorless oil by silica gel column chromatography. Yield 85.8%. 1 H NMR (400 MHz, Chloroform-d) δ6.69 (t, J = 5.8 Hz, 1H, =CH-), 5.19 – 5.04 (m, 1H, =CH-), 4.34 (d, J = 5.8Hz, 2H, -CH2-), 2.33 – 2.20 (m, 2H, -CH2-), 2.11 (dq, J = 14.2, 7.8 Hz, 2H, -CH2-), 1.70 (s, 3H, -CH3), 1.61 (s, 3H, -CH3), 1.51 (s, 9H, -t-Bu), 0.98 –0.80 (m, 9H, -Si-t-Bu), 0.09 (s, 6H, -CH3). MS (FAB): 355(M+1).

[0098] (3) (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoic acid tert-butyl ester

[0099]

[0100] 13.8 g, 44.2 mmol of tert-butyl (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate was weighed and placed in a 500 ml single-necked flask. The mixture was dissolved in 200 ml of anhydrous tetrahydrofuran. 66.3 ml of a 1 M / L tetrabutylammonium fluoride solution in tetrahydrofuran was added. After stirring at room temperature for 3 h, the reaction was stopped and extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. 6.23 g of tert-butyl (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate was obtained as a light yellow oil by silica gel column chromatography. The yield was 58.5%.1 H NMR (400MHz, Chloroform-d) δ 6.76 (t, J = 6.4 Hz, 1H, =CH-), 5.12 (t, J = 7.7 Hz, 1H,=CH-), 4.31 (d, J = 6.5 Hz, 2H, -CH2-), 2.40 – 2.23 (m, 2H, -CH2-), 2.18 –2.07 (m, 2H, -CH2-), 1.70 (s, 3H, -CH3), 1.59 (s, 3H, -CH3), 1.51 (s, 9H, -t-Bu). MS (FAB): 241 (M+1).

[0101] (4) (E)-2-(2-bromoethylidene)-6-methylhept-5-enoic acid tert-butyl ester

[0102]

[0103] N-Bromosuccinimide (1.63 g, 9.17 mmol) was weighed and placed in a 100 ml single-necked flask and dissolved in 30 ml of dichloromethane. Triphenylphosphine (2.4 g, 9.17 mmol) was added portionwise in an ice bath. After 30 min of reaction, (E)-tert-butyl 2-(2-hydroxyethylidene)-6-methylhept-5-enoate (2.0 g, 8.33 mmol) was added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 4 h. The reaction was then terminated and extracted with dichloromethane and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain 1.80 g of (E)-tert-butyl 2-(2-bromoethylidene)-6-methylhept-5-enoate as a pale yellow oil in a yield of 71.7%. The product was carried on to the next step without purification. MS (FAB): 303 (M+1).

[0104] (5) tert-Butyl 2-(2'-((tert-Butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate

[0105]

[0106] Tert-butyl (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate (930 mg, 3.07 mmol) was weighed into a 100 ml single-necked flask and dissolved in 30 ml of anhydrous tetrahydrofuran. Tert-butyloxycarbonylguanidine (976 mg, 6.14 mmol) and cesium carbonate (2.0 g, 6.14 mmol) were added. The mixture was heated to reflux and stirred for 5 h. The reaction was stopped and extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain 875 mg of tert-butyl 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate as a pale yellow oil. Yield: 58.5%. The product was used directly in the next step without purification. MS (FAB): 382 (M+1).

[0107] (6) (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoic acid tert-butyl ester

[0108]

[0109] tert-Butyl 2-(2'-((tert-Butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate (720 mg, 1.88 mmol) was weighed into a 100 ml single-necked flask and dissolved in 10 ml of anhydrous dichloromethane. Zinc bromide (848 mg, 3.76 mmol) was added and allowed to react at room temperature for 5 h. The reaction was stopped and filtered through celite. The filtrate was evaporated to dryness and then chromatographed on a silica gel column using a 10:1 ratio of dichloromethane to methanol (0.5% aqueous ammonia added) as the eluent to obtain tert-butyl 2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate as a white solid (392 mg, yield 74.2%). 1 H NMR (400MHz, Methanol-d4) δ 5.11 (t, J = 7.1 Hz, 1H, =CH-), 4.58 (s, 3H, -CH2-), 4.06– 4.15 (m, 1H, -CH-), 3.76 (m, 1H, -CH2-), 3.55 (m, 1H, -CH2-), 2.33 (m, 1H, -CH-), 2.05 (m, 1H, -CH2-), 1.65 (s, 3H, -CH3), 1.59 (s, 3H, -CH3), 1.51 (s,9H, -t-Bu). MS (FAB): 282 (M+1).

[0110] Example 2 (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoic acid

[0111]

[0112] 4 ml of trifluoroacetic acid was placed in a 100 ml single-necked bottle and dissolved in 8 ml of anhydrous dichloromethane. 2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoic acid tert-butyl ester (350 mg, 0.92 mmol) was added dropwise. After reacting at room temperature for 3 h, the reaction was stopped, the solvent was evaporated, and chiral preparative separation (semi-preparative column: CHIRALPAK ® AD-H, inner diameter * length 20 mm * 250 mm, filler particle size 5 μm, chromatographic conditions: n-hexane / isopropanol = 50:50), to obtain 186 mg of (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoic acid as a white solid. 1 H NMR (400 MHz, Methanol-d4) δ 5.14 (t, J = 7.1 Hz, 1H, =CH-), 4.55 (s, 3H, -CH2-), 4.06 –4.11 (m, 1H, -CH-), 3.75 (t, J = 9.7 Hz, 1H, -CH2-), 3.55 (m, 1H, -CH2-), 2.33(m, 1H, -CH-), 2.05 (m, 1H, -CH2-), 1.67 (s, 3H, -CH3), 1.61 (s, 3H, -CH3). MS(FAB): 226 (M+1).

[0113] Example 3 Methyl 2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate

[0114]

[0115] Substituting tert-butyl dimethoxyphosphonoacetate with methyl 2-(dimethoxyphosphoryl)acetate, the operation was carried out according to Example 1 to obtain 120 mg of methyl 2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate as a white solid.

[0116] The NMR and mass spectrometry data of the relevant intermediates in the above experimental process are as follows:

[0117]

[0118] NMR data: 1 H NMR (400 MHz, Chloroform-d) δ 5.04 (t, J = 7.1 Hz, 1H, =CH-), 3.81 (d, J = 5.3 Hz, 3H, -CH3), 3.78 (d, J = 5.3 Hz, 3H, -CH3), 3.77 (s,3H, -CH3), 3.02 (ddd, J = 23.1, 10.9, 3.5 Hz, 1H, -CH-), 2.13 – 1.95 (m, 3H,-CH2-), 1.91 – 1.81 (m, 1H, -CH2-), 1.69 (s, 3H, -CH3), 1.57 (s, 3H, -CH3). MS (FAB): 265 (M+1).

[0119]

[0120] NMR data: 1 H NMR (400 MHz, Chloroform-d) δ 5.12 (t, J = 7.4 Hz, 1H, =CH-), 4.36 (d, J = 5.8 Hz, 2H, -CH2-), 3.77 (s, 3H, -CH3), 2.29 (dd, J = 8.6,6.7 Hz, 2H, -CH2-), 2.18 – 2.06 (m, 2H, -CH2-), 1.70 (s, 3H, -CH3), 1.60 (s,3H, -CH3), 0.93 (s, 9H, -t-Bu), 0.10 (s, 6H, -CH3). MS (FAB): 313 (M+1).

[0121]

[0122] NMR data: 1H NMR (400 MHz, Chloroform-d) δ 6.86 (t, J = 6.3 Hz, 1H, -OH), 5.12 (m, 1H, =CH-), 4.34 (dd, J = 6.3, 2.3 Hz, 2H, -CH2-), 3.78 (s, 3H, -CH3), 2.35 (t, J = 7.4 Hz, 2H, -CH2-), 2.12 (q, J = 7.3 Hz, 2H, -CH2-), 1.70 (s, 3H, -CH3), 1.60 (s, 3H, -CH3). Mass spectral data: MS (FAB): 199 (M+1).

[0123]

[0124] NMR data: 1 H NMR (400 MHz, Methanol-d4) δ 5.12 (t, J = 7.0 Hz, 1H, =CH-), 4.54 (s, 3H, -CH2-), 4.05 – 4.13 (m, 1H, -CH-), 3.85 (s, 3H, -CH3), 3.75(t, J = 9.7 Hz, 1H, -CH2-), 3.55 (m, 1H, -CH2-), 2.33 (m, 1H, -CH-), 2.05 (m,1H, -CH2-), 1.67 (s, 3H, -CH3), 1.61 (s, 3H, -CH3). MS (FAB): 240 (M+1).

[0125] Example 4 (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoic acid ethyl ester

[0126]

[0127] Ethyl 2-(dimethoxyphosphoryl)acetate was substituted for methyl 2-(dimethoxyphosphoryl)acetate. The procedure was similar to that in Example 2 to obtain 43 mg of ethyl (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate as a white solid. The final yield was 48%. 1H NMR (400 MHz, Methanol-d4) δ 5.12 (t, J= 7.0 Hz, 1H, =CH-), 4.54 (s, 3H, -CH2-), 4.05 – 4.13 (m, 1H, -CH-), 4.09 (t,J = 7.2 Hz, 2H, -OCH2-), 3.75 (t, J = 9.7 Hz, 1H, -CH2-), 3.55 (m, 1H, -CH2-), 2.33 (m, 1H, -CH-), 2.05 (m, 1H, -CH2-), 1.67 (s, 3H, -CH3), 1.61 (s, 3H, -CH3), 1.26 (q, J = 7.2 Hz, 3H, -CH3). MS (FAB): 254 (M+1).

[0128] Note: The compound in Example 2 is a known compound

[0129] Example 2 is prepared by hydrolyzing the carboxylic acid ester based on the compounds of Examples 1, 3, and 4, and the compounds of Examples 1, 3, and 4 are also new compounds with certain hypoglycemic potential.

[0130] Pharmacological activity

[0131] In vitro activity evaluation: The in vitro glucose content was detected using the tissue cell glucose oxidase assay kit (Cat. No. abs47047405) from Aibixin.

[0132] Principles and methods of glucose content detection

[0133] 1. Principle: According to the Trinder reaction principle, glucose generates gluconic acid and hydrogen peroxide (H2O2) under the action of glucose oxidase (GOD). Peroxidase (POD) then catalyzes hydrogen peroxide to convert the chromogen (4-aminoantipyrine) into quinoneimine. The color depth is proportional to the glucose concentration.

[0134] 2. Experimental Methods: Hepatocytes were isolated from SD rats fasted for 20 to 24 hours by collagenase digestion. The cells were cultured in DMEM medium (low glucose) at a density of 3 × 10 5The cells were placed on a 24-well plate at a density of 10 cells / well overnight. The compound was dissolved in DMSO and diluted with a glucose-free DMEM diluent containing lactate / pyruvate. The cells were treated with a single concentration of compound, a positive control (metformin) and a blank dilution in triplicate. After 6 hours of drug treatment, the cells were lysed and the supernatant to be tested or the glucose standard was taken to a 96-well plate and the working solution was added according to the kit instructions. React at 37°C for 20 minutes. After the reaction is balanced, the color is stable within 60 minutes. First, adjust the blank tube to zero with distilled water + working solution, and then measure the OD value of each tube. Draw a standard curve and calculate the glucose concentration. Glucose concentration (mmol / L) = standard concentration × (sample tube OD - blank tube OD) / (standard tube OD - blank tube OD), and the data is normalized using the corresponding protein content. Hepatocyte gluconeogenesis inhibition rate (%) = .

[0135] 3. Test Results

[0136] Example concentration Inhibition rate 1 40 μM <5% 2 40 μM 15.2% 3 40 μM 11.2% 4 40 μM 9.4% Metformin 40 μM 8.3% Metformin 2mM 28.4%

Claims

1. A method for preparing a (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative (Formula I), characterized in that: The following steps are involved: a) using R1-substituted dimethoxyphosphate derivative 1 and 5-bromo-2-methylpent-2-ene 8 as raw materials to prepare 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2; b) using 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 and tert-butyldimethylsilyloxyacetaldehyde 9 as raw materials to prepare (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3; c) using (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 as a starting material to prepare (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4; d) using (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 as a starting material to prepare (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5; e) using (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 and tert-butyloxycarbonylguanidine 10 as starting materials to prepare 2-(2'-((tert-butyloxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6; The (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 and tert-butyloxycarbonylguanidine 10 undergo a substitution reaction and an intramolecular Michael addition reaction to generate a 2-(2'-((tert-butyloxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6, which is carried out under alkaline conditions; the alkaline conditions are selected from potassium carbonate and cesium carbonate. f) using 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 as a starting material to prepare (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 7 (Formula I); The substituent R1 is methyl, ethyl or tert-butyl.

2. The preparation method according to claim 1, characterized in that In step a), the R1-substituted dimethoxyphosphate derivative 1 and 5-bromo-2-methylpent-2-ene 8 undergo a Horner-Wadsworth-Emmons reaction (HWE reaction) to produce a 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2, which is carried out under alkaline conditions.

3. The preparation method according to claim 2, characterized in that The base is selected from sodium tert-butoxide, sodium hydride, and potassium bis(trimethylsilyl)amide.

4. The preparation method according to claim 1, characterized in that In step b), the HWE reaction of 2-(dimethoxyphosphoryl)-6-methylhept-5-enoate derivative 2 and tert-butyldimethylsilyloxyacetaldehyde 9 to produce (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 is carried out under alkaline conditions.

5. The preparation method according to claim 4, characterized in that The base is selected from sodium tert-butoxide, sodium hydride, and potassium bis(trimethylsilyl)amide.

6. The preparation method according to claim 1, characterized in that Step c) (E)-2-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-6-methylhept-5-enoate derivative 3 is subjected to TBS removal under fluoride or acidic conditions to prepare (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4.

7. The preparation method according to claim 6, characterized in that The fluoride is selected from tetrabutylammonium fluoride; and the acidic condition is selected from hydrochloric acid.

8. The preparation method according to claim 1, characterized in that Step d: (E)-2-(2-bromoethylidene)-6-methylhept-5-enoate derivative 5 is prepared by (E)-2-(2-hydroxyethylidene)-6-methylhept-5-enoate derivative 4 under the action of a halogenating agent and a ligand.

9. The preparation method according to claim 8, characterized in that The halogenating agent is selected from N-bromosuccinimide; and the ligand is selected from triphenylphosphine.

10. The preparation method according to claim 1, characterized in that Step e) Selective removal of the BOC protecting group of 2-(2'-((tert-butoxycarbonyl)amino)-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 6 to generate (R)-2-((R)-2'-amino-4',5'-dihydro-1'H-imidazol-4'-yl)-6-methylhept-5-enoate derivative 7 (Formula I) is carried out under metal halide conditions.

11. The preparation method according to claim 10, characterized in that The metal halide is selected from zinc bromide.

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