Preparation method of tergorazan and amorphous form thereof

Abstract

The invention discloses a preparation method of tergorazan and an amorphous form thereof, and belongs to the field of pharmaceutical preparation. The method is realized through eight-step reaction: a compound 2 and a compound 3 generate a compound 4 in the presence of a solvent and alkali; performing catalytic reduction on the compound 5 to obtain a compound 6; carrying out substitution reaction on the compounds 6 and 7 to obtain a compound 8; reacting the compound 8 with ammonia to obtain a compound 9; reducing the compound 9 to obtain a compound 10; reacting the compound 10 with auxiliary materials to obtain a compound 1; reacting the compound 1 with paratoluensulfonyl chloride to obtain a compound 11; and reacting the compound 11 under an alkaline condition to obtain the tergorazan and the amorphous form thereof. The method has the advantages of easily available raw materials, simple operation, mild conditions, high yield and low cost, avoids highly toxic reagents and expensive catalysts, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, specifically to a method for preparing tegorazan and its amorphous form. Background Technology

[0002] Tegoprazan, also known as tegorazan or CJ-12420, was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) in July 2018 for the treatment of duodenal ulcers, esophagitis, and gastroesophageal reflux disease.

[0003] Tegolazane is a competitive potassium-ion phenolic antagonist (P-CAB) and hydrogen / potassium ion exchange ATPase (H+ / K+ ATPase) inhibitor. It has a rapid onset of action and can control gastric pH for a long time. It is a novel drug for the treatment of gastroesophageal reflux disease (GERD) and erosive esophagitis, and is considered to be the most advanced drug currently available for treating GERD.

[0004] Currently, the publicly available methods for preparing tegrazan mainly include the following: 1. Technical approach of Method 1 (CN112851646A): The raw materials used in this patent, compounds 2 and 5, are very expensive, and their industrial production is difficult. Step B, in preparing compound 6, produces a certain proportion of enantiomers, and the condensing agent ADDP used in this step is expensive; the purification yield of compound 6 is only between 60% and 70%. Step C, using palladium reduction on carbon, is too expensive, and step D has too low a yield and uses too much imine hydrochloride (there are few patent examples, but the yields are too low; other literature mentions higher yields, but the amount of imine hydrochloride used is too large). The method for preparing the cyclization of chlorosuccinimide (NCS) used in step E is not suitable for scale-up production; after scaling up, the reaction system becomes disordered, impurities are difficult to control, and purification is also difficult. In summary, this preparation method is costly and unsuitable for industrial production.

[0005] 2. Technical approach of Method 2 (CN101341149B): The preparation yield of compound A-3 in this patent is low, and the isomers are difficult to remove; the preparation of compounds A-5 and A-10 uses expensive palladium catalysts; the racemic 5,7-difluorobenzodihydropyran-4-ol used in compound A-11 requires chiral HPLC resolution of the final compound, which results in extremely low overall yields of the route and extremely high yields of tegorazan, making industrial production impossible.

[0006] 3. Technical approach of Method 3 (CN111303131A): The two raw materials used in the preparation of tegorazan in this patent are expensive, and the price of ADDP used in the condensation is relatively high, with a yield of 70-80%. The final purification yield of tegorazan is about 60%, and the total preparation cost of tegorazan is very high.

[0007] 4. Technical approach of Method 4 (WO2007072146): This patented method yields only 6.8% of tegorazane. The preparation of compounds A-9 and A-10 involves carbon monoxide gas via coupling, posing safety risks. Furthermore, both reactions utilize palladium catalysts, resulting in excessively high production costs for compound A-10. Therefore, this method for preparing tegorazane is unsuitable for industrial production, both from a safety and cost perspective. Compound A-11 is prepared from chiral 5,7-difluorobenzodihydropyran-4-(R)-ol and compound A-10 via Misunobu reaction. This method yields A-11 with 5-10% corresponding isomers. After crystallization purification, the optical purity can reach >99%, but the yield is only 60-65%, which is low. In summary, this patented method suffers from low yield, high cost, and is difficult to scale up for industrial production.

[0008] 5. Technical approach of Method 5 (CN2024101142874): Step 10 of this patent, the preparation of compound A-12, requires controlling the temperature below -50°C, which is more demanding, places stringent requirements on equipment, and is more difficult to control. The preparation of the final product, Tegrazan, involves a long reduction and cyclization process, and the post-processing is complex and causes significant pollution. In summary, some steps in this patent involve demanding reaction conditions, placing considerable pressure on industrial production. Summary of the Invention

[0009] The purpose of this invention is to provide a method for preparing tegorazan and its amorphous form, so as to solve the problems mentioned in the background art.

[0010] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing tegorazan and its amorphous form, the synthetic route of which is as follows: .

[0011] Preferably, the specific steps are as follows: Step 1: Add compound 2 and compound 3 to a solvent, add an alkaline reagent, and heat to 0℃~90℃ to react for 1~6 hours; after the reaction is completed, concentrate, add water to the residue, stir, filter, and dry the filter cake to obtain compound 4; Step 2: Add formic acid to the reaction vessel, cool to 0℃~5℃, add triethylamine dropwise, heat to 10℃~20℃ and add compound 5, stir for 30 minutes, add a chiral catalyst, keep warm at 20℃~35℃ for 3~72 hours; after the reaction is complete, add citric acid aqueous solution, stir, filter, and dry the filter cake to obtain compound 6. Step 3: Add organic solvent and compound 7 to the reaction flask, add alkaline reagent while stirring, cool to -20℃~40℃, add compound 6, and stir the reaction at this temperature for 12~72 hours; after the reaction is completed, add water, separate the liquid and liquid phases, wash, dry and concentrate the organic phase to obtain compound 8; Step 4: Add compound 8 and organic solvent to a reaction flask, introduce ammonia gas, and stir the reaction at an external temperature of 0℃~100℃ for 1~5 days; after the reaction is completed, cool down, add ethyl acetate, wash with saturated sodium chloride solution, dry the organic phase and concentrate to obtain compound 9; Step 5: Add compound 9 to a three-necked flask, add methanol and water, add alkaline reagent, add reducing agent while stirring, and stir at room temperature for 1 to 24 hours; after the reaction is complete, concentrate, extract the residue with ethyl acetate, dry the organic phase, filter, and concentrate to obtain compound 10; Step 6: Dissolve compound 10 in an organic solvent and add it to a three-necked flask. Add excipients and stir at 0℃~100℃ for 12~48 hours. After the reaction is complete, concentrate to obtain compound 1. Step 7: Dissolve compound 1 in an organic solvent and add it to a three-necked flask. Add p-toluenesulfonyl chloride and add an alkaline reagent. Stir the mixture at room temperature for 12–72 hours. After the reaction is complete, add water, separate the liquid and liquid phases, dry the organic phase, filter, and concentrate to obtain compound 11. Step 8: Dissolve compound 11 in an organic solvent and add it to a reaction flask. Add an aqueous solution of an alkaline reagent and stir for 48–144 hours. After the reaction is complete, concentrate the solution, add methanol to dissolve it, let it stand, filter, wash it, and dry the filter cake under reduced pressure to obtain tegorazan and its amorphous form.

[0012] Preferably, the alkaline reagent in the first step is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, pyridine, trimethylamine, triethylamine, or diisopropylethylamine; the solvent is selected from water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,2-dichloroethane, acetonitrile, propionitrile, butyronitrile, or any mixture thereof; the molar ratio of compound 2 to the alkaline reagent is 1:1.0 to 6.0.

[0013] Preferably, the chiral catalyst in the second step is (s,s)-(-)-2-amino-1,2-diphenylethylamino}(m-trimethylbenzene)ruthenium(II) chloride; the molar ratio of compound 5 to the chiral catalyst is 1:0.0001-0.1; the molar ratio of compound 5 to formic acid is 1:1-5; and the molar ratio of compound 5 to triethylamine is 1:1-5.

[0014] Preferably, the alkaline reagent in the third step is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium bicarbonate, sodium ethoxide, or potassium acetate; the organic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, or butyronitrile; the molar ratio of compound 7 to the alkaline reagent is 1:0.8 to 3.0.

[0015] Preferably, the organic solvent in the fourth step is selected from water, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, or butyronitrile.

[0016] Preferably, the reducing agent in step five is selected from hydrogen-palladium on carbon, hydrogen-Raney nickel, iron powder-ammonium chloride, zinc powder-ammonium chloride, iron powder-acetic acid, zinc powder-acetic acid, zinc powder-formic acid, or sodium hydrosulfite; the alkaline reagent is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, pyridine, trimethylamine, triethylamine, or diisopropylethylamine; the organic solvent is selected from water, water-ethanol, water-methanol, water-isopropanol, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, dichloromethane, chloroform, or 1,2-dichloroethane; Compound 9 The molar ratio of the reducing agent to the reducing agent is 1:1 to 5.0.

[0017] Preferably, the excipients in step six are selected from acetaldehyde, acetic acid, trimethyl orthoacetate, triethyl orthoacetate, or esters of orthoacetic acid; the organic solvents are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, or butyronitrile; the molar ratio of compound 10 to the excipients is 1:1 to 4.0.

[0018] Preferably, the alkaline reagent in step seven is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium bicarbonate, calcium hydride, sodium methoxide, sodium ethoxide, potassium acetate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine, diethylamine, diisopropylethylamine, or pyridine; the organic solvent is selected from water, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2- Dichloroethane, acetonitrile, propionitrile, or butyronitrile; the molar ratio of compound 1 to the base is 1:1 to 3.0.

[0019] Preferably, the alkaline reagent in step eight is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium bicarbonate, calcium hydride, sodium methoxide, sodium ethoxide, potassium acetate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diethylamine, diisopropylethylamine, methylamine, ethylamine, propylamine, dimethylamine, or diethylamine; the organic solvent is selected from methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N- Methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, or butyronitrile; the molar ratio of compound 11 to the base is 1:1 to 3.0.

[0020] Compared with the prior art, the beneficial effects of the present invention are: 1. The second step of this invention uses a solvent-free reduction method, which reduces the amount of solvent used, lowers energy consumption, simplifies the post-processing process, and shortens the production cycle.

[0021] 2. The third step of this invention uses cheaper inorganic bases such as sodium hydroxide, which allows the reaction to be carried out at room temperature, with fewer byproducts, higher yield, lower energy consumption, simpler post-processing, and is more suitable for industrial production.

[0022] 3. Designing the key intermediate as compound 10 makes the ring-closing reaction easier, increases the yield, and reduces impurities, thus creating conditions for improving the overall yield, reducing costs, and purifying the API (active pharmaceutical ingredient).

[0023] 4. Throughout the entire preparation process, the use of highly toxic carbon monoxide, hydrogenation reduction, and expensive palladium catalysts is avoided. The Mitsunobu reaction is replaced by a substitution reaction, which solves the problems of low yield, expensive condensing agents, and difficult purification caused by chiral isomerism.

[0024] Overall, this invention significantly improves the total yield, simplifies post-processing steps, reduces solvent usage, shortens the production cycle, and lowers production energy consumption, making the preparation of tegorazan fully industrial-scale. Attached Figure Description

[0025] Figure 1: The ¹H NMR spectrum of compound 6 from the embodiments of this application; Figure 2: High-performance liquid chromatography (HPLC) purity detection diagram of compound 6 in the embodiments of this application; Figure 3: High performance liquid chromatography (HPLC) purity detection graph of compound 10 in the embodiments of this application; Figure 4: High-performance liquid chromatography (HPLC) purity detection diagram of compound 11 in the embodiments of this application; Figure 5: High performance liquid chromatography (HPLC) purity detection diagram of compound of formula (1) in the embodiments of this application. Detailed Implementation

[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] This invention provides a technical solution: a method for preparing tegorazan and its amorphous form, used to prepare compounds as shown in formula (1): The preparation of this compound includes the following steps: Step 1: Compound 2 reacts with Compound 3 in the presence of a solvent and a base reagent to produce Compound 4; Step 2: Compound 5 undergoes a reduction reaction under the action of a catalytic reduction system to generate compound 6; Step 3: Compound 6 and Compound 7 undergo a substitution reaction in the presence of a solvent and a base reagent to generate Compound 8; Step 4: Compound 8 reacts with ammonia in the presence of a solvent and a base reagent via a substitution reaction to generate compound 9; Step 5: Compound 9 undergoes a reduction reaction under the action of a reducing agent and a basic reagent to generate compound 10; Step 6: Compound 10 reacts with the excipients in an organic solvent to generate Compound 1; Step 7: Compound 1 reacts with p-toluenesulfonyl chloride in the presence of a solvent and a base reagent via a substitution reaction to generate compound 11; Step 8: Compound 11 reacts in an organic solvent and under alkaline conditions to produce the compound (Tegolazan) shown in formula (1) and its amorphous form.

[0028] In an embodiment of the present invention, the reaction in step 1 is the complexation of compound 2 and compound 3 to prepare compound 4. The specific route is as follows: In an embodiment of the present invention, specifically, compound 2 (6.64 g, 10.84 mmol, 1.0 eq) and isopropanol (130 mL) were added to a 250 mL three-necked flask. Triethylamine (4.38 g, 43.36 mmol, 4 eq) and compound 3 (7.95 g, 21.7 mmol, 2.0 eq) were then added sequentially with stirring. After the addition was complete, the reaction mixture was stirred at 70–90 °C for 2–6 h. The reaction solution was concentrated, and water (70 mL, 10V) was added directly to the residue. The mixture was stirred for 1 hour, filtered, and the filter cake was dried to obtain 13.95 g of a brownish-yellow solid, yield: 95%.

[0029] The proton NMR spectrum data of compound 4 are as follows: 1 HNMR (400MHz, CDC13) δ: 7.19-7.00 (m, 5H), 6.87-6.80 (m, 4H), 6.77-6.62 (m, 5H), 5.30 (s ,3H), 4.30-4.11(m,1H), 4.05-3.91(m,1H), 3.86-3.60(m,2H), 2.38(s,9H), 3.24(s,3H).

[0030] In embodiments of the present invention, the solvent for the complexation reaction is water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,2-dichloroethane, acetonitrile, propionitrile, butyronitrile, or any mixture thereof.

[0031] In a preferred embodiment of the present invention, the solvent for the complexation reaction is ethanol, propanol, or isopropanol. The base for the complexation reaction is preferably an organic tertiary amine such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, pyridine, trimethylamine, triethylamine, or diisopropylethylamine, and more preferably trimethylamine, triethylamine, or diisopropylethylamine.

[0032] In an embodiment of the present invention, the molar ratio of compound 2 to the base reagent in step 1 is 1:1.0 to 6.0.

[0033] In a preferred embodiment of the present invention, the molar ratio of compound 2 to the base reagent in step 1 is 1:2.0 to 4.0.

[0034] In an embodiment of the present invention, the reaction temperature in step 1 is 0°C to 90°C.

[0035] In a preferred embodiment of the present invention, the reaction temperature in step 1 is 60°C to 80°C.

[0036] In an embodiment of the present invention, the reaction time in step 1 is 1 to 6 hours.

[0037] In a preferred embodiment of the present invention, the reaction time in step 1 is 2-4 hours.

[0038] In an embodiment of the present invention, the reaction in step 2 is the chiral catalytic reduction of compound 5 to prepare compound 6. The technical route is as follows: Specifically, formic acid (15.01 g, 0.326 mol, 3 eq) was added to a 100 mL three-necked flask and cooled to 0℃~5℃. Then, triethylamine (21.96 g, 0.217 mol, 2 eq) was slowly added dropwise to the reaction system at 5℃~20℃ during the addition. After the addition was completed, the temperature was slowly raised to 10℃~20℃. Compound 5 (20 g, 0.109 mol, 1 eq) was added to the reaction system. After stirring for 30 minutes, the chiral catalyst {[(s,s)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(m-trimethylbenzene)ruthenium(II) chloride (68 mg, 0.109 mmol, 0.1% eq) was added. The reaction was then maintained at 20℃~35℃ for 30 h. The reaction was completed by TLC. After the reaction was completed, 200 mL of 5% citric acid aqueous solution was added to the reaction solution, stirred at room temperature for 30 minutes, filtered, and the filter cake was dried to obtain 19 g of off-white solid with a purity of 98% and a yield of 94%.

[0039] The optical rotation and enantiomeric excess of compound 6: [a]D25℃ = -143. (c = 1 g / 100 mL, MeOH), ee%: >99%; Please see Figure 1 , Figure 2 The ¹H NMR data of compound 6 are as follows: 1 HNMR (400MHz, CDCl3) δ: 6.43-6.38 (m, 2H), 5.01-4.99 (t, J=4.0Hz, 1H), 4.30-4.23 (m, 2H), 2.08-1.95 (m, 2H). In the figure, the vertical axis represents the signal strength in AU (absorbance units), and the horizontal axis represents the retention time.

[0040] In the embodiments of the present invention, the solvent for the reduction reaction in step 2 is methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, toluene, ethyl acetate, isopropyl acetate, or butyl acetate.

[0041] In a preferred embodiment of the present invention, the solvent for the reduction reaction in step 2 is dichloromethane or no solvent.

[0042] In an embodiment of the present invention, the temperature of the reduction reaction in step 2 is -20°C to 80°C.

[0043] In a preferred embodiment of the present invention, the temperature of the reduction reaction in step 2 is 10°C to 40°C.

[0044] In an embodiment of the present invention, the molar ratio of compound 5 in the reduction reaction to the chiral ruthenium catalyst in step 2 is 1:0.0001 to 0.1.

[0045] In a preferred embodiment of the present invention, the molar ratio of compound 5 in the reduction reaction to the chiral ruthenium catalyst in step 2 is 1:0.001 to 0.05.

[0046] In an embodiment of the present invention, the molar ratio of compound 5 in the reduction reaction to formic acid in step 2 is 1:1 to 5.

[0047] In a preferred embodiment of the present invention, the molar ratio of compound 5 in the reduction reaction to formic acid in step 2 is 1:1.5 to 3.

[0048] In an embodiment of the present invention, the molar ratio of compound 5 in the reduction reaction to triethylamine in step 2 is 1:1 to 5.

[0049] In a preferred embodiment of the present invention, the molar ratio of compound 5 in the reduction reaction to triethylamine in step 2 is 1:1 to 2.

[0050] In an embodiment of the present invention, the reaction time of the reduction reaction in step 2 is 3 to 72 hours.

[0051] In a preferred embodiment of the present invention, the reaction time of the reduction reaction in step 2 is 12 to 24 hours.

[0052] In an embodiment of the present invention, the technical route of step 3 is as follows: Specifically, tetrahydrofuran (50 mL, 5 times the mass of compound 7, i.e., 5V) and compound 7 (10 g, 43.44 mmol, 1.0 equivalent) were added to the reaction vessel and stirred until homogeneous. Then, sodium hydroxide (2.6 g, 65 mmol, 1.5 equivalent) was added. The reaction system was cooled to 0°C–10°C, and then compound 6 (7.76 g, 41.68 mmol, 0.96 equivalent) was added. The mixture was stirred at the above temperature for 14–18 hours (substitution reaction). Liquid chromatography-mass spectrometry (LC-MS) was used to confirm that the reactants had reacted completely.

[0053] After the reaction was complete, 3 volumes of water (based on the mass of compound 7) were added to the system at 0℃~10℃. After stirring, the mixture was allowed to stand and separated to obtain the organic phase. The organic phase was then washed once with 3 volumes of water (based on the mass of compound 7), allowed to stand and separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 45℃ to obtain 18g of a yellow oily liquid (the yield was not calculated at this time because the product was oily and may contain trace amounts of residual solvent). LCMS analysis showed that the purity of the product was 93.6%.

[0054] In embodiments of the present invention, the substitution reaction of compound 6 and compound 7 in step 3 is carried out in an organic solvent, preferably tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, chlorobenzene, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetyl, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, more preferably tetrahydrofuran, methyl tert-butyl ether and ethylene glycol dimethyl ether or any mixture thereof.

[0055] In an embodiment of the present invention, the alkaline reagent used in the substitution reaction in step 3 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or any mixture thereof.

[0056] In a preferred embodiment of the present invention, the alkaline reagent used in the substitution reaction in step 3 is sodium hydroxide, sodium hydrogen hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, or any mixture thereof.

[0057] In an embodiment of the present invention, the molar ratio of compound 7 to the base reagent in step 3 of the substitution reaction is 1:0.8 to 3.0.

[0058] In a preferred embodiment of the present invention, the molar ratio of compound 7 to the base reagent in the substitution reaction in step 3 is 1:1 to 1.5.

[0059] In an embodiment of the present invention, the reaction temperature of the substitution reaction in step 3 is -20°C to 40°C.

[0060] In a preferred embodiment of the present invention, the reaction temperature of the substitution reaction in step 3 is -5°C to 15°C.

[0061] In an embodiment of the present invention, the substitution reaction in step 3 takes 12 to 72 hours.

[0062] In a preferred embodiment of the present invention, the substitution reaction in step 3 takes 14 to 18 hours.

[0063] In an embodiment of the present invention, the technical route of step 4 is as follows: Specifically, compound 8 (27.5 g, 69.4 mmol, 1.0 equivalent) and N-methylpyrrolidone (55 mL, twice the volume of compound 8, i.e., 2V) were added to the reaction vessel and stirred until homogeneous. Ammonia gas was then introduced in batches until the system was saturated. Subsequently, the external temperature of the reaction system was controlled at 70℃~80℃, and the reaction was stirred for 2 to 3 days.

[0064] After the reaction was complete, the system was cooled to room temperature, and a sample was taken for analysis using liquid chromatography-mass spectrometry (LCMS) to confirm that the starting materials had reacted completely. Five volumes of ethyl acetate (based on the mass of compound 8) were added to the reaction solution. The resulting mixture was washed three times with five volumes of saturated sodium chloride solution (based on the mass of compound 8). After standing and separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 25 g of a dark red solid. The purity of the solid was determined to be 92%, and the yield was 91%.

[0065] In embodiments of the present invention, the substitution reaction of compound 8 with ammonia is carried out in an organic solvent, such as tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, or any mixture thereof.

[0066] In a preferred embodiment of the present invention, the organic solvent in step 4 is tetrahydrofuran, tertiary methyl ether, and ethylene glycol dimethyl ether or any mixture thereof.

[0067] In embodiments of the present invention, the alkaline reagent used in the substitution reaction in step 4 is ammonia gas, liquid ammonia, ammonia water, and various organic solutions of ammonia, acetamide, acetamidine, various salts of acetamidine, or any mixture thereof.

[0068] In a preferred embodiment of the present invention, the alkaline reagent used in the substitution reaction in step 4 is ammonia gas, liquid ammonia, ammonia water, or any mixture thereof.

[0069] In an embodiment of the present invention, the reaction temperature of the substitution reaction in step 4 is 0°C to 100°C.

[0070] In a preferred embodiment of the present invention, the reaction temperature of the substitution reaction in step 4 is 60°C to 90°C.

[0071] In an embodiment of the present invention, the substitution reaction in step 4 takes 1 to 5 days.

[0072] In a preferred embodiment of the present invention, the substitution reaction in step 4 takes 2 to 3 days.

[0073] In an embodiment of the present invention, the technical approach in step 5 is as follows: The reduction reaction is carried out in an organic solvent, which is water, water-ethanol, water-methanol, water-isopropanol, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, or any mixture thereof.

[0074] In a preferred embodiment of the present invention, the organic solvent in step 5 is water-ethanol, water-methanol, water-isopropanol, or any mixture thereof.

[0075] The technical approach for step 5 is as follows: Specifically, compound 9 (8.8 g, 22.4 mmol, 1.0 equivalent) was added to a three-necked reaction flask, followed by methanol (88 mL, 10 times the mass of compound 9, i.e., 10V). After stirring to dissolve compound 9, water (44 mL, 5 times the mass of compound 9, i.e., 5V) was added. Then, sodium hydroxide (5.82 g, 145.6 mmol, 6.5 equivalent) was added, and the mixture was stirred until homogeneous. Finally, sodium hydrosulfite (11.7 g, 67.2 mmol, 3.0 equivalent) was added, and the reaction was stirred at room temperature for 14 to 18 hours.

[0076] The sample was analyzed by liquid chromatography-mass spectrometry (LCMS) to confirm that the starting material had reacted completely. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The combined ethyl acetate phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7.5 g of a yellow oily liquid. The purity of the product was determined to be 97%, and the yield was 92%.

[0077] Please see Figure 3 The proton NMR spectrum of composition 10 is as follows: 1 HNMR(400 MHz, DMSO) δ 6.81 (td,J= 9.7, 2.0 Hz, 1H), 6.66 (d,J = 10.4 Hz, 1H), 6.54 (s, 1H), 6.40 (s, 1H),5.50 (s, 1H), 4.70 (s, 2H), 4.40 – 4.29 (m, 4H), 2.95 (s, 6H), 2.08 (d,J =13.9 Hz, 1H), 1.94, (ddd,J = 18.0, 9.8, 4.6 Hz, 1H).

[0078] In an embodiment of the present invention, the alkaline reagent used in the reduction reaction in step 5 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or any mixture thereof.

[0079] In a preferred embodiment of the present invention, the alkaline reagent used in the reduction reaction in step 5 is sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, or any mixture thereof.

[0080] In an embodiment of the present invention, the molar ratio of compound 10 to reducing agent in the original reaction in step 5 is 1:1 to 5.0.

[0081] In a preferred embodiment of the present invention, the molar ratio of compound 10 to reducing agent in the original reaction in step 5 is 1:1 to 3.0.

[0082] In an embodiment of the present invention, the reaction temperature of the substitution reaction in step 5 is -10°C to 70°C.

[0083] In a preferred embodiment of the present invention, the reaction temperature of the substitution reaction in step 5 is 15°C to 35°C.

[0084] In an embodiment of the present invention, the reduction reaction time in step 5 is 1 hour to 24 hours.

[0085] In a preferred embodiment of the present invention, the reduction reaction time in step 5 is 14 to 18 hours.

[0086] In an embodiment of the present invention, the technical approach in step 6 is as follows: Specifically, compound 10 (21 g, 57.8 mmol, 1.0 equivalent) was added to a three-necked flask and dissolved in ethyl acetate (105 mL, 5 times its volume), followed by the addition of trimethyl orthoformate (6.94 g, 57.8 mmol, 1.0 equivalent). The reaction system was stirred at an external temperature of 70°C for 18–24 hours, and the complete conversion of the starting material was confirmed by liquid chromatography-mass spectrometry (LC-MS). After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 19.5 g of a pale yellow solid product with a purity of 96% and a yield of 87%.

[0087] In an embodiment of the present invention, the ring-closing reaction in step 6 is carried out in an organic solvent, which is acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, butyronitrile, or any mixture thereof.

[0088] In a preferred embodiment of the present invention, the cyclization reaction in step 6 is carried out in an organic solvent of ethyl acetate, dichloromethane, chloroform, or any mixture thereof.

[0089] In an embodiment of the present invention, the excipients used in the ring-closing reaction in step 6 are acetaldehyde, acetic acid, trimethyl orthoacetate, triethyl orthoacetate, various esters of orthoacetic acid, or any mixture thereof.

[0090] In a preferred embodiment of the present invention, the excipients used in the cyclization reaction in step 6 are acetic acid, trimethyl orthoacetate, triethyl orthoacetate, or any mixture thereof.

[0091] In an embodiment of the present invention, the molar ratio of compound 10 to raw materials and excipients in the ring-closing reaction in step 6 is 1:1 to 4.0.

[0092] In a preferred embodiment of the present invention, the molar ratio of compound 10 to raw materials and excipients in the ring-closing reaction in step 6 is 1:1 to 1.5.

[0093] In an embodiment of the present invention, the reaction temperature of the cyclization reaction in step 6 is 0°C to 100°C.

[0094] In a preferred embodiment of the present invention, the reaction temperature of the cyclization reaction in step 6 is 30°C to 80°C.

[0095] In an embodiment of the present invention, the time for the ring-closing reaction in step 6 is 12 to 48 hours.

[0096] In a preferred embodiment of the present invention, the time for the ring-closing reaction in step 6 is 18-24 hours.

[0097] In an embodiment of the present invention, the technical approach in step 7 is as follows: Specifically, compound 1 (30 g, 77.4 mmol, 1.0 equivalent) was added to a three-necked flask, followed by the addition of ethyl acetate (150 mL, 5 times its volume) to dissolve it. Then, p-toluenesulfonyl chloride (17.7 g, 92.9 mmol, 1.2 equivalent) was added, and finally, triethylamine (10.9 g, 108.4 mmol, 1.4 equivalent) was added dropwise. The reaction system was stirred at room temperature for 18–24 hours, and the complete reaction of the starting materials was confirmed by liquid chromatography-mass spectrometry (LC-MS).

[0098] After the reaction was completed, the following post-processing was performed: water (150 mL, 5 times the volume) was added to the reaction solution, stirred and allowed to stand for separation. The ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 38.1 g of pale yellow solid product. Its purity was tested to be 97% and the yield was 91%.

[0099] Please see Figure 4 The 1H NMR spectrum of composition 11 is as follows: δ (400 MHz, DMSO) 8.01 (d, J = 7.9 Hz, 2H), 7.55 (s, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.18 (s, 1H), 6.81 (t, J = 9.0 Hz, 1H), 6.69 (d, J = 10.1 Hz, 1H), 6.02 (s, 1H), 4.35 (d, J = 10.2 Hz, 1H), 4.16 (t, J = 11.8 Hz, 1H), 2.99 (d, J = 45.4 Hz, 6H), 2.80 (s, 3H), 2.37 (s, 3H), 2.24 (d, J = 7.9 Hz, 2H), 2.24 (t, J = 7.9 Hz, 2H), 2.37 (s, 3H), 2.24 (d ...37 (s, 3H), 2.37 (s, 3H), 2.37 (s, 3H), 2.37 (s, 3H), 2.37 (s, 3H), 2.37 (s, 3H), 2.37 (s, 3H), = 14.7 Hz, 1H), 2.05 (s, 1H).

[0100] In embodiments of the present invention, the substitution reaction between compound 1 and p-toluenesulfonyl chloride (p-TsCl) is carried out in an organic solvent, which is acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile or butyronitrile, or any mixture thereof.

[0101] In a preferred embodiment of the present invention, the organic solvent in step 7 is ethyl acetate, butyl acetate, isopropyl acetate, or any mixture thereof.

[0102] In an embodiment of the present invention, the alkaline reagent used in the substitution reaction in step 7 is an organic tertiary amine such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine, diisopropylethylamine, or any mixture thereof.

[0103] In a preferred embodiment of the present invention, the alkaline reagent used in the substitution reaction in step 7 is sodium hydroxide, dimethylamine, triethylamine, diisopropylethylamine, or any mixture thereof.

[0104] In an embodiment of the present invention, the molar ratio of compound 1 to base in the substitution reaction in step 7 is 1:1 to 3.0.

[0105] In a preferred embodiment of the present invention, the molar ratio of compound 1 to base in the substitution reaction in step 7 is 1:1 to 1.5.

[0106] In an embodiment of the present invention, the reaction temperature of the substitution reaction in step 7 is -10°C to 80°C.

[0107] In a preferred embodiment of the present invention, the reaction temperature of the substitution reaction in step 7 is 20°C to 50°C.

[0108] In an embodiment of the present invention, the substitution reaction time in step 7 is 12 hours to 72 hours.

[0109] In a preferred embodiment of the present invention, the substitution reaction in step 7 takes 18 to 24 hours.

[0110] In an embodiment of the present invention, the technical approach in step 8 is as follows: Specifically, compound 12 (35 g, 64.6 mmol, 1.0 equivalent) was added to a reaction flask, followed by the addition of tetrahydrofuran (70 mL, 2 times the volume) to dissolve it. Then, 70 mL of 10% sodium hydroxide aqueous solution was added, and the mixture was stirred for 18 hours. The complete reaction of the starting materials was confirmed by liquid chromatography-mass spectrometry (LCMS).

[0111] After the reaction was complete, the reaction solution was concentrated under reduced pressure. 100 mL of methanol was added to the residue to dissolve it. The resulting methanol solution was allowed to stand at room temperature for 30 minutes, then filtered. The filter cake was washed and dried under reduced pressure to obtain a powdery white solid. Crystal form analysis showed that the product was amorphous with a purity of 99% and a yield of 80%.

[0112] Please see Figure 5 The optical rotation and enantiomeric excess of the amorphous compound are: [a]D25℃=103. (c=1.0g / 100mL, MeOH), ee%:>99%. The 1H NMR spectrum of the compound. 1 HNMR(400MHz, CDC13)δ:7.12(brs,1H),6.88(s,1H),6.39-6.28(m,2H), 5.76(brs,1H),4.30-4.19(m,2H),3.1-3.02(br,6H),2.39(s,3H),2.28-2.24(m,1H),2.01-1.92(m,1H).

[0113] In embodiments of the present invention, the organic solvent used in the reaction process is acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, butyronitrile, or any mixture thereof.

[0114] In a preferred embodiment of the present invention, the organic solvent in step 8 is tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, or any mixture thereof.

[0115] In an embodiment of the present invention, the alkaline reagent used in step 8 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, dimethylamine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, or any mixture thereof.

[0116] In a preferred embodiment of the present invention, the alkaline reagent used in step 8 is dimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or any mixture thereof.

[0117] In an embodiment of the present invention, the molar ratio of compound 12 to base in step 8 is 1:1 to 3.0.

[0118] In a preferred embodiment of the present invention, the molar ratio of compound 12 to base in step 8 is 1:1 to 2.0.

[0119] In an embodiment of the present invention, the reaction temperature in step 8 is -20°C to 80°C.

[0120] In a preferred embodiment of the present invention, the reaction temperature in step 8 is 0°C to 35°C.

[0121] In an embodiment of the present invention, the substitution reaction in step 8 takes 48-144 hours.

[0122] In a preferred embodiment of the present invention, the substitution reaction in step 8 takes 72 to 120 hours.

[0123] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A process for the preparation of tegoprazan and its amorphous form, characterized in that, The synthetic route is as follows: 。 2. Tigilazone according to claim 1, characterized in that, The specific steps are as follows: Step 1: Compound 2 and compound 3 are added to a solvent, a base reagent is added, and the temperature is raised to 0-90°C for 1-6 hours; after the reaction is completed, the remaining substance is concentrated, water is added, stirred, filtered, and the filter cake is dried to obtain compound 4; Step 2: Formic acid is added to the reaction container, the temperature is lowered to 0-5°C, triethylamine is added dropwise, the temperature is raised to 10-20°C, compound 5 is added, stirred for 30 minutes, a chiral catalyst is added, and the temperature is kept at 20-35°C for 3-72 hours; after the reaction is completed, citric acid aqueous solution is added, stirred, filtered, and the filter cake is dried to obtain compound 6; Step 3: Organic solvent and compound 7 are added to the reaction bottle, a base reagent is added with stirring, the temperature is lowered to -20-40°C, compound 6 is added, and the reaction is stirred at this temperature for 12-72 hours; after the reaction is completed, water is added, the liquid is separated, the organic phase is washed, dried, and concentrated to obtain compound 8; Step 4: Compound 8 and organic solvent are added to the reaction bottle, ammonia gas is introduced, and the reaction is stirred at 0-100°C for 1-5 days; after the reaction is completed, the temperature is lowered, ethyl acetate is added, and the organic phase is washed with saturated sodium chloride solution, dried, and concentrated to obtain compound 9; Step 5: Compound 9 is added to a three-necked flask, methanol and water are added, a base reagent is added, a reducing agent is added with stirring, and the reaction is stirred at room temperature for 1-24 hours; after the reaction is completed, the remaining substance is concentrated, extracted with ethyl acetate, and dried to obtain compound 10; Step 6: Compound 10 is dissolved in an organic solvent and added to a three-necked flask, an auxiliary material is added, and the reaction is stirred at 0-100°C for 12-48 hours; after the reaction is completed, the remaining substance is concentrated to obtain compound 1; Step 7: Compound 1 is dissolved in an organic solvent and added to a three-necked flask, p-toluenesulfonyl chloride is added, a base reagent is added dropwise, and the reaction is stirred at room temperature for 12-72 hours; after the reaction is completed, water is added, the liquid is separated, the organic phase is dried, filtered, and concentrated to obtain compound 11; Step 8: Compound 11 is dissolved in an organic solvent and added to a reaction bottle, a base reagent aqueous solution is added, and the reaction is stirred for 48-144 hours; after the reaction is completed, the remaining substance is concentrated, dissolved in methanol, and filtered to obtain tegoprazan and its amorphous form.

3. Tigilazone according to claim 2, characterized in that: The base reagent in the first step is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, pyridine, trimethylamine, triethylamine or diisopropylethylamine; the solvent is selected from water, methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,2-dichloroethane, acetonitrile, propionitrile, butyronitrile or any mixture thereof; the molar ratio of compound 2 to the base reagent is 1:1.0-6.

0.

4. Tigilazone according to claim 3, characterized in that: The chiral catalyst in the second step is (s,s)-(-)-2-amino-1,2-diphenylethylamino(m-mesitylene)ruthenium(II) chloride; the molar ratio of compound 5 to the chiral catalyst is 1:0.0001-0.1; the molar ratio of compound 5 to formic acid is 1:1-5; the molar ratio of compound 5 to triethylamine is 1:1-5.

5. Tigilazone according to claim 4, characterized in that it is prepared in amorphous form. The base reagent in the third step is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium bicarbonate, sodium ethoxide or potassium acetate; the organic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile or butyronitrile; the molar ratio of compound 7 to the base reagent is 1:0.8-3.

0.

6. Tigilazone according to claim 5, characterized in that it is prepared in amorphous form. The organic solvent in the fourth step is selected from water, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile or butyronitrile.

7. Tigilazone according to claim 6, characterized in that it is prepared in amorphous form. The reducing agent in the fifth step is selected from hydrogen-palladium on carbon, hydrogen- Raney nickel, iron powder-ammonium chloride, zinc powder-ammonium chloride, iron powder-acetic acid, zinc powder-acetic acid, zinc powder-formic acid or sodium hydrosulfite; the base reagent is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, pyridine, trimethylamine, triethylamine or diisopropylethylamine; the organic solvent is selected from water, water-ethanol, water-methanol, water-isopropanol, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, dichloromethane, chloroform or 1,2-dichloroethane; the molar ratio of compound 9 to the reducing agent is 1:1-5.

0.

8. Tigilazone according to claim 7, characterized in that it is prepared in amorphous form. The auxiliary reagent in the sixth step is selected from acetaldehyde, acetic acid, trimethyl orthoacetate, triethyl orthoacetate or ester of orthoacetic acid; the organic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile or butyronitrile; the molar ratio of compound 10 to the auxiliary reagent is 1:1-4.

0.

9. Tigilazone according to claim 8, characterized in that it is prepared in amorphous form. The base reagent in the seventh step is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium bicarbonate, calcium hydride, sodium methoxide, sodium ethoxide, potassium acetate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, trimethylamine, triethylamine, diethylamine, diisopropylethylamine or pyridine; the organic solvent is selected from water, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile or butyronitrile; the molar ratio of compound 1 to the base is 1:1-3.

0.

10. Tigilazone according to claim 1, characterized in that it is prepared in amorphous form. The base reagent in the eighth step is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium bicarbonate, calcium hydride, sodium methoxide, sodium ethoxide, potassium acetate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diethylamine, diisopropylethylamine, methylamine, ethylamine, propylamine, dimethylamine, or diethylamine; the organic solvent is selected from methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, chlorobenzene, cyclohexane, n-hexane, n-heptane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propionitrile, or butyronitrile; and the molar ratio of compound 11 to the base is 1:1 to 3.0.

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