Preparation method of tigorazan intermediate

Abstract

The invention discloses a preparation method of a tigorazan intermediate. The method comprises the following steps: by taking 1-benzyl-2-methyl-1H-imidazole-5-formaldehyde as a starting material, carrying out Horner-Wadsworth-Emmons reaction on the starting material and O, O '-diethyl-(2-succinic acid diethyl ester) phosphonate to prepare (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl) methylene] succinic acid diethyl ester, and reacting the (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl) methylene] succinic acid diethyl ester with the O, O'-diethyl-(2-succinic acid diethyl ester) phosphonate to prepare (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl) methylene] succinic acid diethyl ester; and then hydrolyzing under an alkaline condition, and acidifying to obtain the tegorazan intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazole-5-yl)-3-(ethoxycarbonyl) butyl-3-olefine acid. The invention provides a brand new preparation method, the yield is improved by more than 30% compared with a mainstream process, the materials used in the method are cheap and easily available, the step operation is simple and convenient, the reaction condition is mild and safe, the production cost can be greatly reduced, and the industrial production is favorably realized.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis, and in particular to a method for preparing a ticlopidine intermediate. Background Art

[0002] Tegoprazan, also known as tegrazan, is a novel potassium-competitive acid blocker (P-CAB) primarily used to treat gastric acid-related diseases such as gastroesophageal reflux disease (GERD) and peptic ulcers. It was approved for marketing by the Ministry of Food and Drug Safety (MFDS) of South Korea in July 2018 and launched in China on April 13, 2022. It is the most extensively studied P-CAB after vonoprazan.

[0003] Gastric acid is secreted by parietal cells in the gastric fundus and body. H+ / K+-ATPase is a key enzyme in gastric acid secretion, pumping intracellular H+ into the gastric tubules via a reversible concentration gradient, thereby achieving gastric acid secretion. Previously, commonly used proton pump inhibitors (PPIs) are prodrugs that require conversion to active substances in an acidic environment to exert their effects. They inhibit H+ / K+-ATPase through irreversible covalent bonds, and require an average of 2–3 days of administration to achieve maximal acid suppression. In comparison, ticagrelor, a novel P-CAB, has the greatest advantage of competitively and reversibly binding to the K+ binding site of H+ / K+-ATPase without acid activation or conversion. This results in faster gastric acid suppression than PPIs and nearly complete inhibition of gastric acid secretion. Ticagrelor exhibits rapid onset of action after the first dose, and its sustained acid suppression has been demonstrated in preclinical and clinical studies.

[0004] Currently, there is only one reported synthetic route for tiglasan suitable for industrial production (Org.ProcessRes.Dev.2024,28,1159-1169.):

[0005]

[0006]

[0007] In the report on this synthetic route, the finished product ticagrelor is prepared from two key intermediates, 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (24) and (R)-5,7-difluorochroman-4-ol (14), through a Mitsunobu reaction to obtain benzyl-protected ticagrelor (27) in a 79% molar yield. The benzyl group is then removed by catalytic hydrogenation to obtain ticagrelor (16) in a 94% molar yield. Since both steps can obtain the target product in high yields, the development of a low-cost industrial production process for intermediates 24 and 14 is of great significance for enhancing the commercial value of this product.

[0008] In the industrialized route reported above, the yield of each step in the preparation of intermediate 14 reached over 90%, demonstrating high overall efficiency. However, in the synthesis of intermediate 24, the molar yield of intermediate 21, prepared from intermediate 20 and diethyl succinate via a Stobbe condensation reaction, was only 55%. Although the yields of the other steps remained above 90%, the inefficiency of this step significantly restricted the production cost of intermediate 24.

[0009] Based on the above problems, in order to improve the molar yield of the intermediate 21, the present invention provides a new method for preparing the tigrasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid. The method still uses 1-benzyl-2-methyl-1H-imidazol-5-carboxaldehyde (20) as a substrate, replaces diethyl succinate with O,O'-diethyl-(2-diethyl succinate)phosphonate, and prepares (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate through the Horner-Wadsworth-Emmons reaction. (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid (21) in high yield by direct hydrolysis without separation.

[0010] Compared with currently reported industrial routes, the method of the present invention uses the reagent O,O'-diethyl-(2-diethyl succinate)phosphonate, which is inexpensive and widely commercially available. The method uses the highly efficient Horner-Wadsworth-Emmons reaction instead of the Stobbe condensation reaction to prepare the intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid with a yield of over 85%. This significantly reduces production costs, is simple to operate, and operates under mild and safe reaction conditions, facilitating industrial production. Summary of the Invention

[0011] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for preparing a ticagrelor intermediate in view of the deficiencies in the prior art, so as to solve the problem of low yield in the Stobbe condensation reaction during the preparation of the ticagrelor intermediate 4-hydroxy-N,N,2-trimethyl-1-(phenylmethyl)-1H-benzimidazole-6-carboxamide (24) in the prior art, and to provide a new preparation route, which replaces the Stobbe condensation reaction with the Horner-Wadsworth-Emmons reaction, significantly improves the yield, and has the advantages of low production cost, simple operation and good reaction safety.

[0012] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0013] A method for preparing a ticagrelor intermediate, such as Figure 1 As shown, the following steps are included:

[0014] (1) 1-Benzyl-2-methyl-1H-imidazole-5-carboxaldehyde and O,O'-diethyl-(2-diethyl succinate)phosphonate undergo a Horner-Wadsworth-Emmons reaction in an organic solvent under the catalysis of a base to prepare (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinic acid diethyl ester (Compound I), which is directly used in the next step;

[0015] (2) The diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate (Compound I) prepared in the previous step was hydrolyzed with a base in an alcohol and then acidified with an acid to obtain the tigrasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid.

[0016] Preferably, in step (1), the organic solvent for the Horner-Wadsworth-Emmons reaction is any one or a combination of tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide, preferably tetrahydrofuran; the volume mass ratio of the organic solvent to the mass of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde is 1-8 mL:1 g, such as 3-6 mL:1 g.

[0017] Preferably, in step (1), the base of the Horner-Wadsworth-Emmons reaction is any one or a combination of sodium hydride, sodium amide, potassium tert-butoxide, sodium tert-butoxide, triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably potassium carbonate.

[0018] Preferably, in step (1), the molar ratio of the raw materials of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde, O,O'-diethyl-(2-diethyl succinate)phosphonate, and base is 1:(1-2):(1-3), such as 1:(1-1.2):(1-1.5).

[0019] Preferably, in step (1), in the Horner-Wadsworth-Emmons reaction, the temperature of the reaction system O,O'-diethyl-(2-diethyl succinate)phosphonate and the organic solvent is first controlled to -10 to 5°C, a base is added, and the mixture is stirred at this temperature for a period of time, and then benzyl-2-methyl-1H-imidazole-5-carboxaldehyde is added and the temperature is raised to react; the stirring time is 15 to 45 minutes.

[0020] Preferably, in step (1), the temperature of the Horner-Wadsworth-Emmons reaction is 30-70° C., and the reaction time is 1-12 h.

[0021] Preferably, in step (1), after the reaction is completed, the resulting reaction solution is cooled to room temperature, water and an organic solvent are added, stirred, and then allowed to stand for stratification, and the organic layer is evaporated to dryness under reduced pressure to obtain compound I; the organic solvent includes ethyl acetate, and the volume ratio of water to organic solvent is (3 to 7):5; the stirring time is 10 to 20 min.

[0022] Preferably, in step (2), the alcohol comprises ethanol.

[0023] Preferably, in step (2), the alcohol is added in portions, the compound I obtained in step (1) is dissolved in a portion of the alcohol, and the base is dissolved in the remaining alcohol; the two solutions are mixed and then subjected to a hydrolysis reaction, and then acidified with an acid. The portion of alcohol is 50% to 80% of the total volume of the alcohol.

[0024] Preferably, in step (2), the volume mass ratio of the alcohol in the hydrolysis reaction to 1-benzyl-2-methyl-1H-imidazole-5-carbaldehyde is 1-8 mL:1 g, such as 2-5 mL:1 g.

[0025] Preferably, in step (2), the base for the hydrolysis reaction is any one or a combination of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably lithium hydroxide.

[0026] Preferably, in step (2), the molar ratio of the raw materials of (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinic acid diethyl ester (calculated based on the yield of 100% in step (1)) and the base is 1:(1-5); the molar ratio of the base to 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde is (0.5-2):1, such as (1-1.5):1.

[0027] Preferably, in step (2), the temperature of the hydrolysis reaction is -10 to 50° C., and the reaction time is 1 to 12 h, such as 1 to 2 h.

[0028] Preferably, in step (2), the acid used for acidification after the hydrolysis reaction is any one or a combination of sulfuric acid, hydrochloric acid, methanesulfonic acid, acetic acid, and formic acid, preferably hydrochloric acid; preferably, the acid is acidified to a pH of 5 to 7.

[0029] Preferably, in step (2), after the reaction is completed, the concentrate is concentrated, water and a first organic solvent are added to the concentrate, the mixture is stirred and allowed to stand for stratification, the organic layer is evaporated to dryness under reduced pressure, a second organic solvent is added, the mixture is stirred at 40-50° C. for 0.5-1.5 h, then cooled to 0-5° C. and stirred for 0.5-1.5 h, filtered, and the resulting cake is the ticagrelor intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid; the first organic solvent comprises dichloromethane, the volume ratio of water to the first organic solvent is (3-7):5; the stirring time is 10-20 min; the second organic solvent comprises methyl ethyl ketone; the volume ratio of water to the first organic solvent is 1:(0.5-1.5).

[0030] Beneficial effects:

[0031] The present invention develops a brand-new preparation method. The method replaces the Stobbe condensation reaction of the mainstream process with the highly efficient Horner-Wadsworth-Emmons reaction. The key intermediate of ticlopidine, (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid, can be prepared with a yield of over 85%, which is over 30% higher than the yield of the mainstream process. The materials used are all inexpensive and readily available, the steps are simple to operate, and the reaction conditions are mild and safe. The method can significantly reduce production costs and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0033] Figure 1 The following is a reaction scheme of step (1) and step (2) of each embodiment of the present invention.

[0034] Figure 2 The (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene] diethyl succinate obtained in Example 1 of the present invention 1 H-NMR spectrum.

[0035] Figure 3 (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid obtained in Example 1 of the present invention 1 H-NMR spectrum.

[0036] Figure 4 This is the HRMS spectrum of (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0037] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0038] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0039] In the following examples, the yield is the total yield of step (1) and step (2).

[0040] Example 1: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0041] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0042] At room temperature, 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde, 186.0 g (599.28 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate, 103.5 g (749.10 mmol) of potassium carbonate and 600 mL of tetrahydrofuran were added to a reaction vessel. The mixture was stirred at 55-65°C for 6 h, and the solvent was evaporated under reduced pressure. 300 mL of purified water and 500 mL of ethyl acetate were added to the concentrate. The mixture was stirred at room temperature for 15 min, and then allowed to stand for separation. The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure to obtain a light yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate, which was used directly in the next reaction.

[0043] like Figure 2 As shown, 1H NMR (400MHz, DMSO-d6): δ=8.085(s,1H),7.420–7.354(m,4H),7.245–7.228(m,2H),5.572(s,2H),4.147(q,J=7 .2Hz, 2H), 4.076 (q, J = 7.2Hz, 2H), 3.524 (s, 2H), 2.770 (s, 3H), 1.207 (t, J = 7.2Hz, 3H), 1.164 (t, J = 7.2Hz, 3H).

[0044] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0045] Add 400 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 12.0 g (499.40 mmol) of lithium hydroxide in 100 mL of ethanol. Add the dissolved lithium hydroxide to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at 0-10°C for 2 hours, then adjust the pH to 5-6 with hydrochloric acid. Evaporate the ethanol under reduced pressure, add 300 mL of purified water and 500 mL of dichloromethane to the concentrate, stir at room temperature for 15 minutes, and allow the mixture to stand for separation. Discard the aqueous layer, evaporate the organic layer to dryness, and add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 147.6 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 90%.

[0046] like Figure 3 As shown, 1 H NMR (400MHz, DMSO-d6): δ=12.502(s,1H),7.456(s,1H),7.376–7.248(m,3H),7.202(s,1H),7.052–7. 033(m,2H),5.293(s,2H),4.107(q,J=7.2Hz,2H),3.444(s,2H),2.376(s,3H),1.195(t,J=7.2Hz,3H).

[0047] like Figure 4 As shown, HRMS (ESI) found 329.1499 [M + H] + .

[0048] Example 2: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0049] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0050] At room temperature, 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde, 155.0 g (499.40 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate, 75.9 g (549.34 mmol) of potassium carbonate and 600 mL of tetrahydrofuran were added to a reaction vessel. The mixture was stirred at 55-65°C for 10 h, and the solvent was evaporated under reduced pressure. 300 mL of purified water and 500 mL of ethyl acetate were added to the concentrate. The mixture was stirred at room temperature for 15 min, and then allowed to stand for separation. The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure to obtain a light yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate, which was used directly in the next reaction.

[0051] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0052] Add 400 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 20.0 g (499.40 mmol) of sodium hydroxide in 100 mL of ethanol. Add the dissolved sodium hydroxide to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at -5-0°C for 1 hour, then adjust the pH to 5-6 with hydrochloric acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 142.7 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 87%.

[0053] Example 3: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0054] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0055] At room temperature, add 162.7 g (524.37 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate and 600 mL of tetrahydrofuran to the reaction vessel. Add 20.9 g (524.37 mmol) of 60% sodium hydride while controlling the temperature at -10 to 0°C. After the addition is complete, stir the mixture while maintaining the temperature for 30 minutes. After adding 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde to the system, the temperature was raised to 55-65°C and stirred for 2 hours, and the solvent was evaporated under reduced pressure. 300 mL of purified water and 500 mL of ethyl acetate were added to the concentrate, and the mixture was stirred at room temperature for 15 minutes. The liquid was allowed to stand and the aqueous layer was discarded. The organic layer was evaporated under reduced pressure to obtain a light yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl)methylene]succinate, which was used directly in the next reaction.

[0056] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0057] Add 400 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 28.0 g (499.40 mmol) of potassium hydroxide in 100 mL of ethanol. Add the dissolved solution to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at -10-5°C for 1 hour, then adjust the pH to 5-6 with hydrochloric acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 139.4 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 85%.

[0058] Example 4: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0059] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0060] At room temperature, 162.7 g (524.37 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate and 300 mL of N,N-dimethylformamide were added to the reaction vessel. 20.9 g (524.37 mmol) of 60% sodium hydride was added while controlling the temperature at -10 to 0°C. After the addition was complete, the mixture was stirred for 30 min while maintaining the temperature. After adding 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde to the system, the temperature was raised to 55-65°C and stirred for 1 hour, then cooled to room temperature. 700 mL of purified water and 500 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 15 minutes, then allowed to stand for separation. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure to obtain a yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl)methylene]succinate, which was directly used in the next reaction.

[0061] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0062] Add 300 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 12.6 g (524.38 mmol) of lithium hydroxide in 100 mL of ethanol. Add the dissolved lithium hydroxide to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at 40-50°C for 1 hour, then adjust the pH to 5-6 with hydrochloric acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 141.0 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 86%.

[0063] Example 5: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0064] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0065] At room temperature, add 170.5 g (549.34 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate and 300 mL of N,N-dimethylacetamide to the reaction vessel. Add 21.4 g (549.34 mmol) of sodium amide while controlling the temperature at -10 to 0°C. After the addition is complete, stir the mixture while maintaining the temperature for 30 min. After adding 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde to the system, the temperature was raised to 35-45°C and stirred for 1 hour, then cooled to room temperature. 700 mL of purified water and 500 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 15 minutes, then allowed to stand for separation. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure to obtain a yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl)methylene]succinate, which was used directly in the next reaction.

[0066] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0067] Add 500 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 24.0 g (599.29 mmol) of sodium hydroxide in 200 mL of ethanol. Add the dissolved sodium hydroxide to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at 20-30°C for 1 hour, then adjust the pH to 6-7 with acetic acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 141.0 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 86%.

[0068] Example 6: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0069] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0070] At room temperature, 170.5 g (549.34 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate and 400 mL of acetonitrile were added to the reaction vessel. 61.6 g (549.34 mmol) of potassium tert-butoxide was added at -5 to 5°C. After the addition was complete, the mixture was stirred for 30 min. After adding 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde to the system, the temperature was raised to 40-50°C and stirred for 1.5 hours, and the solvent was evaporated under reduced pressure. 300 mL of purified water and 500 mL of ethyl acetate were added to the concentrate, and the mixture was stirred at room temperature for 15 minutes. The liquid was allowed to stand and the aqueous layer was discarded. The organic layer was evaporated under reduced pressure to obtain a yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazole-5-yl)methylene]succinate, which was used directly in the next reaction.

[0071] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0072] Add 200 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 42.0 g (749.11 mmol) of potassium hydroxide in 200 mL of ethanol. Add the dissolved solution to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at 10-20°C for 1 hour, then adjust the pH to 5-6 with formic acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 146.0 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 89%.

[0073] Example 7: The preparation method of the intermediate of tigolaxant in this example is:

[0074] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0075] At room temperature, 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde, 186.0 g (599.28 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate, 77.5 g (599.28 mmol) of N,N-diisopropylethylamine and 300 mL of dimethyl sulfoxide were added to a reaction vessel. The mixture was stirred at 55-65°C for 5 h, then cooled to room temperature. 700 mL of purified water and 500 mL of ethyl acetate were added. The mixture was stirred at room temperature for 15 min, then allowed to stand for separation. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure to obtain a yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate, which was used directly in the next reaction.

[0076] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0077] Add 500 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 13.2 g (549.35 mmol) of lithium hydroxide in 100 mL of ethanol. Add the dissolved solution to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at 0-10°C for 2 hours, then adjust the pH to 5-6 with methanesulfonic acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate, stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 142.7 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 87%.

[0078] Example 8: The preparation method of the intermediate of tigolaxant in this example is as follows:

[0079] (1) Preparation of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate

[0080] At room temperature, 100.0 g (499.40 mmol) of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde, 170.5 g (549.34 mmol) of O,O'-diethyl-(2-diethyl succinate)phosphonate, 179.0 g (544.37 mmol) of cesium carbonate, and 300 mL of N-methylpyrrolidone were added to a reaction vessel. The mixture was stirred at 45-55°C for 3 h, then cooled to room temperature. 700 mL of purified water and 500 mL of ethyl acetate were added. The mixture was stirred at room temperature for 15 min, then allowed to stand for separation. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure to obtain a light yellow oil, i.e., diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate, which was used directly in the next reaction.

[0081] (2) (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid

[0082] Add 200 mL of ethanol to diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate and stir at room temperature to dissolve. Separately, dissolve 12.6 g (524.38 mmol) of lithium hydroxide in 100 mL of ethanol. Add the dissolved solution to the ethanol solution of diethyl (E)-2-[(1-benzyl-2-methyl-1H-imidazol-5-yl)methylene]succinate. Stir at 0-10°C for 2 hours, then adjust the pH to 5-6 with sulfuric acid. Evaporate the ethanol under reduced pressure. Add 300 mL of purified water and 500 mL of dichloromethane to the concentrate. Stir at room temperature for 15 minutes, then allow the mixture to stand and separate. Discard the aqueous layer and evaporate the organic layer to dryness. Add 300 mL of methyl ethyl ketone to the concentrate. Stir at 40-50°C for 1 hour, then cool to 0-5°C and stir for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 144.2 g of tigolasen intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid in a yield of 88%.

[0083] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for preparing a ticagrelor intermediate, characterized in that: The following steps are involved: (1) In an organic solvent, 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde and O,O'-diethyl-(2-diethyl succinate)phosphonate undergo a Horner-Wadsworth-Emmons reaction under the catalysis of a base to prepare compound I; (2) Compound I is hydrolyzed with a base in an alcohol and then acidified with an acid to obtain the intermediate (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxycarbonyl)but-3-enoic acid; 2. The method for preparing a ticagrelor intermediate according to claim 1, wherein: In step (1), the organic solvent is any one or a combination of tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the volume mass ratio of the organic solvent to 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde is 1-8 mL: 1 g.

3. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (1), the base is any one or a combination of sodium hydride, sodium amide, potassium tert-butoxide, sodium tert-butoxide, triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate and cesium carbonate.

4. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (1), the molar ratio of the raw materials of 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde, O,O'-diethyl-(2-diethyl succinate)phosphonate and base is 1:(1-2):(1-3).

5. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (1), the reaction temperature is 30-70° C., and the reaction time is 1-12 h.

6. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (1), after the reaction is completed, the reaction solution is cooled to room temperature, water and an organic solvent are added, and the mixture is allowed to stand to separate layers. The organic layer is evaporated to dryness under reduced pressure to obtain Compound I.

7. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (2), the alcohol is ethanol; the volume mass ratio of the alcohol to 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde is 1-8 mL:1 g.

8. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (2), the base is any one or a combination of lithium hydroxide, sodium hydroxide and potassium hydroxide; the molar ratio of the base to 1-benzyl-2-methyl-1H-imidazole-5-carboxaldehyde is (0.5-2):

1.

9. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (2), the temperature of the hydrolysis reaction is -10 to 50° C., and the reaction time is 1 to 12 hours.

10. The method for preparing a ticlopidine intermediate according to claim 1, wherein: In step (2), the acid used in the acidification is any one or a combination of sulfuric acid, hydrochloric acid, methanesulfonic acid, acetic acid and formic acid; preferably, the acidification is carried out to a pH of 5 to 7.

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