Preparation method of a tegoprazan intermediate

Abstract

The present invention provides a novel preparation method of a ticagrelor intermediate compound. Compound 5 is used as a raw material to obtain an intermediate compound 1 through a simple chemical reaction, and ticagrelor is further obtained through a one-step reaction. The method has fewer reaction steps and a high yield.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to the preparation of a ticagrelor intermediate. Background Art

[0002] Tigorapen, developed by CJ Health Care in South Korea and successfully launched in South Korea in July 2018, is primarily used to treat gastroesophageal reflux disease and erosive esophagitis. Its chemical name is 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]oxy]-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide, with a CAS number of 942195-55-3. Its chemical structure is as follows:

[0003]

[0004] Patent CN111303131A discloses a method for preparing ticagrelor. 4-bromo-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, (S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol, cuprous iodide, sodium tert-butoxide and N1,N2-bis(phenylethyl)oxalyl diamide are added to the reaction flask, and the atmosphere is replaced with nitrogen three times. Then, anhydrous N,N-dimethylformamide is added, and the reaction system is replaced with nitrogen three times again. Subsequently, the mixture is stirred and heated to 85°C for 24 hours. After the reaction is completed, the mixture is cooled to room temperature naturally. Ethyl acetate is added for dilution, and the mixture is vigorously stirred for 0.5 hours and filtered through diatomaceous earth. The filtrate is desolventized to remove the organic solvent under reduced pressure. The residue is purified by column chromatography (ethyl acetate / heptane) to obtain ticagrelor. The specific synthetic route is as follows:

[0005]

[0006] The synthesis of tiogolaxan in the aforementioned patent does not disclose a method for synthesizing the intermediate 4-bromo-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, nor is the synthesis of this compound described in the prior art. Therefore, a method for synthesizing this intermediate is needed. Summary of the Invention

[0007] Based on the above technical problems, the present invention provides a method for preparing a ticlopidine intermediate, which can be used to synthesize ticlopidine, reduce the reaction steps and lower the cost.

[0008] The present invention provides a method for preparing a tiogolaxan intermediate compound, wherein the intermediate compound is 4-bromo-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, and the structural formula is shown in Formula 1:

[0009]

[0010] The preparation method of the intermediate compound formula 1 is as follows, comprising bromination, cyclization, and neutralization of compound 5 to obtain compound 1.

[0011]

[0012] Preferably, the bromination reaction is carried out by a bromination reagent, which includes N-bromosuccinimide.

[0013] Preferably, the cyclization reaction is carried out by reacting compound 4 with acetic acid under the action of stannous chloride.

[0014] Preferably, compound 3 is neutralized with dimethylamine or a salt thereof to obtain compound 1.

[0015] Preferably, compound 3 is hydrolyzed to obtain compound 2, which is then reacted with dimethylamine to obtain compound 1.

[0016]

[0017] Preferably, compound 3 is hydrolyzed under alkaline conditions.

[0018] The intermediate compound 1 provided by the present invention can be used to synthesize ticagrelor, comprising reacting compound 1 with compound 7, (S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol, to obtain ticagrelor.

[0019]

[0020] The present invention provides a preparation method of a ticaglassen intermediate of formula 1, which can be used to synthesize ticaglassen. Compared with the preparation method of synthesizing ticaglassen in the compound patent, the method reduces the reaction steps, reduces the cost, improves the yield, and is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the HPLC spectrum of compound 1;

[0022] Figure 2 This is the HPLC spectrum of tigolaxant. DETAILED DESCRIPTION

[0023] The present invention will be described in further detail below with reference to the accompanying drawings and embodiments.

[0024] Example 1:

[0025] Synthesis of compound 4:

[0026] To a solution of compound 6 (10 g) in acetonitrile (200 mL) was added N-bromosuccinimide (10.02 g). The mixture was stirred at 80°C for 3 hours. After the reaction was complete, it was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow solid compound 5 (12.98 g). Yield: 92.6%.

[0027] Example 2:

[0028] Synthesis of compound 3:

[0029] To a solution of compound 4 (14.3 g) in acetic acid (50 mL) was added stannous chloride (29.57 g). The mixture was stirred at 80°C for 5 hours. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to 7-8. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain solid compound 3 (12.51 g). Yield: 89.4%.

[0030] Example 3:

[0031] Synthesis of compound 2

[0032] To a solution of compound 3 (25 g) in tetrahydrofuran / water / methanol (350 mL, 4:2:1) was added NaOH (11.15 g). The mixture was stirred at 60°C overnight. 6 M HCl (55 mL) was added to adjust the pH to 3. A large amount of solid precipitated. The mixture was stirred for 20 minutes, filtered, and dried to obtain compound 2 (22.46 g) as an off-white solid. Yield: 94.8%.

[0033] Example 4:

[0034] Synthesis of compound 1:

[0035] To a solution of compound 2 (23.7 g) in dichloromethane (600 mL) were added triethylamine (28.21 g), 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (52.99 g), and dimethylamine hydrochloride (9.09 g). The mixture was stirred at room temperature overnight and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to afford compound 1 (23.60 g) as a light yellow solid. Yield: 90.3%.

[0036] Example 5:

[0037] Synthesis of compound 1:

[0038] To a solution of compound 3 (25 g) in tetrahydrofuran / water / methanol (350 mL, 4:2:1) were added dimethylamine (8.98 g), sodium methoxide (27.5 g), and sodium amide (28.7 g). The mixture was stirred at room temperature overnight and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried to obtain a light yellow solid compound 1 (22.5 g). Yield: 88.7%

[0039] Example 6:

[0040] Synthesis of Tigorazan:

[0041] Compound 1 (2.4 g), compound 7 (2.3 g), cuprous iodide (100 mg), sodium tert-butoxide (1.5 g), and N,N-bis(phenylethyl)oxalyldiamide (150 mg) were added to a reaction flask. Anhydrous N,N-dimethylformamide (15 mL) was added under a nitrogen atmosphere and heated to 85°C with stirring for 24 hours. After the reaction, the mixture was cooled to room temperature, ethyl acetate was added with stirring, and the mixture was filtered through celite. The solvent was removed by distillation under reduced pressure, and tegrasane was purified by column chromatography to obtain a white solid. Yield: 87%.

Claims

1. A method for preparing a ticagrelor intermediate compound, characterized in that Compound 5 is subjected to bromination, cyclization, and neutralization to obtain compound 1. 。 2. The preparation method according to claim 1, characterized in that Compound 5 undergoes bromination reaction with a bromination reagent to obtain compound 4.

3. The preparation method according to claim 2, characterized in that The brominating agent is selected from N-bromosuccinimide.

4. The preparation method according to claim 1, characterized in that Compound 4 and acetic acid undergo a cyclization reaction under the action of stannous chloride to obtain compound 3.

5. The preparation method according to claim 1, characterized in that Compound 3 is hydrolyzed to obtain compound 2, which is then reacted with dimethylamine to obtain compound 1.

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