A method for the synthesis of a key intermediate for the synthesis of tianeptine

Abstract

This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for synthesizing key intermediates of telexamine, aiming to solve the problems of expensive raw materials, high pollution, high safety risks, and unsuitability for industrial production in existing telexamine intermediate synthesis processes. The key intermediates of this invention are 2-(2-thienyl)cyclohexanone and 2-bromo-2-(2-thienyl)cyclohexanone. The synthesis method uses thiophene and cyclohexanecarboxylic acid as starting materials, and obtains 2-(2-thienyl)cyclohexanone through a solvent-free condensation reaction mediated by polyphosphoric acid, followed by bromination with a brominating reagent and purification in an alcohol phase to obtain 2-bromo-2-(2-thienyl)cyclohexanone. This invention uses inexpensive and readily available raw materials, operates under mild conditions, is simple to operate, is environmentally friendly and safe, and achieves a target product yield of up to 73% and an HPLC purity of up to 98.22%, significantly reducing the synthesis cost of telexamine and making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to a method for synthesizing a key intermediate of tledamine. Background Technology

[0002] Tiletamine, chemically named 2-thienyl-2-ethylaminocyclohexanone, is a heteroaromatic cyclohexylpiperidine dissociative anesthetic. Pharmacologically, it shares many similarities with ketamine, and at the same dose, tiletamine's anesthetic effect is two to three times that of ketamine. Tiletamine has a simple skeletal structure and significant pharmaceutical value, leading to its widespread clinical application.

[0003] In the field of veterinary anesthesia abroad, telazol is formulated with telazine and zoprazepam in a 1:1 ratio to create a compound anesthetic called Telazol. This is widely used for general anesthesia of domestic pets, wild animals, and laboratory animals, typically providing about 30 minutes of surgical anesthesia. Telazol is the dominant anesthetic component in Telazol, which primarily works by inhibiting the thalamus and neocortex system, selectively blocking pain impulse transmission to achieve analgesia. It possesses core advantages such as rapid and stable induction, minimal adverse reactions, and strong analgesic effect.

[0004] Currently available synthetic routes for telexamine and its intermediates all have varying degrees of defects and cannot meet the needs of large-scale industrial production, as detailed below: US Patent 5969159 discloses a method for synthesizing teretamine: cyclohexanecarboxylic acid is reacted with thionyl chloride to generate an acyl chloride, which is then reacted with tin chloride or aluminum trichloride via a Friedel-Crafts reaction to yield the intermediate 2-(2-thienyl)cyclohexanone; this intermediate is then brominated by adding bromine to carbon tetrachloride to give 2-bromo-2-(2-thienyl)cyclohexanone; finally, it is reacted with ethylamine, rearranged at 250°C, and salted to obtain teretamine hydrochloride. This route uses large amounts of thionyl chloride, tin chloride, aluminum trichloride, and bromine, causing severe environmental pollution and making it unsuitable for industrial production.

[0005] In 2016, Synthesis 2016, 48, 882-892 reported a synthetic route for teretamine: first, (N-(benzoyloxy)-N-(trifluoroacetyl)enamine was prepared, followed by [3,3]-σ rearrangement and reaction with an organoaluminum reagent to deprotect the group, yielding β-(2-thiophene)-β-amino alcohol. Then, teretamine was obtained through reductive amination and Jones reagent oxidation. This route uses expensive reagents, involves cumbersome reaction steps and complex operations, making it unsuitable for industrial production.

[0006] In 2018, patent number CN201810877447.5 disclosed a synthetic route for telalactamine: thiophene, iodine, and p-toluenesulfonic acid are reacted with m-chloroperoxybenzoic acid to generate di(2-thienyl)iodide; under alkaline conditions, di(2-thienyl)iodide reacts with 2-nitrocyclohexanone to obtain an intermediate, which is then subjected to zinc powder nitroreduction and aminoethylation to generate telalactamine. The 2-nitrocyclohexanone used in this route is expensive and difficult to obtain, and zinc powder poses significant safety risks during use and storage. Furthermore, the post-processing generates a large amount of waste metal solution, which is environmentally unfriendly.

[0007] In 2022, ChemBiol Drug Des. 2022;100:13-24 reported a synthetic route for a key intermediate of telexamine: reacting 2-cyanothiophene with the Grignard reagent cyclopentylmagnesium chloride to obtain 2-(2-thienyl)cyclohexanone, followed by bromination with bromine to obtain 2-bromo-2-(2-thienyl)cyclohexanone. The Grignard reagent cyclopentylmagnesium chloride used in this route is difficult to procure, and its preparation and use pose high safety risks, hindering industrial production.

[0008] In summary, existing methods for synthesizing key intermediates of telexamine generally suffer from core problems such as expensive and unavailable raw materials, significant reagent pollution, high safety risks, cumbersome operations, and unsuitability for industrial scale-up. Therefore, developing a low-cost, simple, green, safe, and industrially viable method for synthesizing key intermediates of telexamine has significant economic value and application implications. Summary of the Invention

[0009] Technical problems to be solved To address the aforementioned deficiencies in existing technologies, the present invention aims to provide a key intermediate compound for the synthesis of telexamine, as well as a method for synthesizing the intermediate. This method utilizes inexpensive and readily available raw materials, employs mild reaction conditions, is simple and safe to operate, generates minimal environmental pollution, and yields high product purity and yield. It is suitable for large-scale industrial production while significantly reducing the synthesis cost of telexamine.

[0010] (II) Technical Solution To achieve the above objectives, the present invention provides the following technical solution: a method for synthesizing a key intermediate of telexamine, wherein the compounds are 2-(2-thienyl)cyclohexanone (I1) and 2-bromo-2-(2-thienyl)cyclohexanone (I2), and their chemical structural formulas are as follows: I1, I2.

[0011] Furthermore, the synthesis method of the intermediate compound includes the following steps: using thiophene and cyclohexanecarboxylic acid as starting materials, a polyphosphoric acid-mediated condensation reaction is used to obtain 2-(2-thienyl)cyclohexanone (I1), followed by bromination with a brominating reagent and purification with an alcohol phase to obtain 2-bromo-2-(2-thienyl)cyclohexanone (I2): .

[0012] Furthermore, the condensation reagent used in the condensation reaction is polyphosphoric acid.

[0013] Furthermore, the reaction is a solvent-free reaction.

[0014] Furthermore, the brominating reagent used in the bromination reaction is selected from one of bromine, NBS, and dibromohydantoin.

[0015] Furthermore, the reaction temperature for the bromination reaction is -10 to 25°C.

[0016] Furthermore, the solvent used for the alcohol phase purification is methanol.

[0017] (III) Beneficial Effects Compared with the prior art, the present invention provides a method for synthesizing key intermediates of telexamine, which has the following beneficial effects: The present invention provides a method for synthesizing key intermediates of teretamine. The method uses thiophene and cyclohexanecarboxylic acid as starting materials. The condensation reagents and bromination reagents used are all readily available industrial chemical raw materials, which are convenient to purchase and inexpensive. This method completely solves the problem of expensive and difficult-to-obtain raw materials in the prior art and significantly reduces the synthesis cost of key intermediates of teretamine.

[0018] This invention avoids the use of high-risk, high-polluting, and highly corrosive reagents such as thionyl chloride, tin chloride, aluminum trichloride, Grignard reagent, and zinc powder. It eliminates high-temperature and high-pressure reaction steps, operates under mild reaction conditions, and generates minimal waste, significantly reducing safety risks and environmental pressures during production and meeting the requirements of green chemical production.

[0019] The present invention has a short synthesis process, requiring only two reaction steps to obtain the target intermediate. The condensation reaction uses a solvent-free system, which is simple to operate. Furthermore, the filtrate from the first reaction can be directly used for the second reaction without additional separation and purification steps, enabling continuous production. At the same time, the process of the present invention maintains stable yield and purity in kilogram-scale experiments, demonstrating excellent feasibility for industrial scale-up.

[0020] This invention significantly improves the yield and purity of the target intermediate by optimizing reaction parameters and purification process. Under optimal process conditions, the yield of the target intermediate I2 can reach 73%, the HPLC purity can reach 98.22%, and the product quality is stable, which can meet the raw material quality requirements for subsequent synthesis of telexamine. Attached Figure Description

[0021] Figure 1 The chemical structural formula of the key intermediate I1 of telexamine described in this invention; Figure 2 The chemical structural formula of the key intermediate I2 of telexamine described in this invention; Figure 3 This is a synthetic reaction route diagram for the key intermediate of telexamine described in this invention; Figure 4 The above describes the synthetic route of telactamine as disclosed in the prior art US patent "US5969159". Detailed Implementation

[0022] 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.

[0023] Please see Figures 1 to 4 This invention discloses a method for synthesizing a key intermediate of telexamine, wherein the compounds are 2-(2-thienyl)cyclohexanone (I1) and 2-bromo-2-(2-thienyl)cyclohexanone (I2), and their chemical structural formulas are as follows: I1, I2.

[0024] In this scheme, the synthesis method of the intermediate compound includes the following steps: using thiophene and cyclohexanecarboxylic acid as starting materials, a polyphosphoric acid-mediated condensation reaction is used to obtain 2-(2-thienyl)cyclohexanone (I1), followed by bromination with a brominating reagent and purification with an alcohol phase to obtain 2-bromo-2-(2-thienyl)cyclohexanone (I2): .

[0025] In this scheme, the condensation reagent used in the condensation reaction is polyphosphoric acid. The essence of the condensation reaction in this invention is the Friedel-Crafts acylation electrophilic substitution reaction of cyclohexanecarboxylic acid and thiophene. Existing techniques require first converting the carboxylic acid to acyl chloride using thionyl chloride, followed by Lewis acid catalysis such as tin chloride / aluminum trichloride, which is cumbersome and produces highly polluting reagents. Polyphosphoric acid (PPA) is a high-viscosity protonic acid mixture that possesses both carboxylic acid activation and Friedel-Crafts reaction catalysis functions: it can directly protonate the carboxyl group of cyclohexanecarboxylic acid, generating a highly active acyl cation intermediate in situ, without the need for prior preparation of acyl chloride; simultaneously, it provides a strong protonic acid environment to catalyze the reaction of the acyl cation with thiophene. Directed electrophilic substitution occurs at the site, generating the target intermediate I1 in one step.

[0026] The acidic environment of polyphosphoric acid can directionally activate thiophene. Position, avoid Substitution side reactions are eliminated, ensuring regioselectivity of the reaction. The acyl chloride step, necessary in existing technologies, is eliminated, completing the condensation reaction in one step, shortening the production cycle and reducing the difficulty of industrial operation. The use of highly corrosive, highly toxic, and highly polluting reagents such as thionyl chloride, tin chloride, and aluminum trichloride is completely avoided, significantly reducing the generation of acidic wastewater and waste salts, and lowering environmental treatment costs. Polyphosphoric acid is a readily available and inexpensive industrial raw material, with procurement costs far lower than dedicated Lewis acid catalysts, and no additional corrosion prevention and tail gas treatment equipment is required for acyl chloride, reducing equipment investment. Directional realization of thiophene... Acylation at position 1 results in fewer byproducts, and the condensation reaction solution can be directly used for the next bromination reaction without additional purification, improving process continuity. Polyphosphoric acid exhibits stable chemical properties, a mild and controllable reaction process, and no risk of violent exothermic reactions or toxic gas release; kilogram-scale scale-up experiments still demonstrate stable reaction performance.

[0027] In this scheme, the reaction is a solvent-free reaction. Polyphosphoric acid, when heated to above 60°C, transforms into a highly fluid liquid, which can simultaneously serve as both the reaction medium (solvent) and the condensation catalyst, eliminating the need for additional organic solvents. The rate of the Friedel-Crafts acylation reaction is positively correlated with the concentrations of the reactants and the catalytically active sites. The solvent-free system avoids the dilution of the protic acid concentration by organic solvents, ensuring the catalytic activity of polyphosphoric acid, while significantly increasing the reactant concentration, accelerating the reaction rate, and shortening the reaction time.

[0028] Solvent-free systems eliminate the influence of organic solvents on reaction equilibrium, ensuring complete acylation and improving feedstock conversion rates. Completely eliminating the use of organic solvents in condensation reactions reduces raw material procurement costs and eliminates VOC emissions from the condensation process, meeting green chemical production requirements. The high reactant concentration in solvent-free systems significantly increases the reaction rate; the optimal process completes the reaction in just 4 hours, far shorter than similar reactions in existing technologies, thus improving production efficiency. After the reaction, product separation is achieved directly by adding water and extracting with dichloromethane, eliminating the need for organic solvent recovery and distillation, reducing energy consumption and operational complexity. Avoiding impurities from organic solvents further reduces the probability of side reactions, improves the purity of the condensation products, and provides high-quality feedstock for subsequent bromination reactions.

[0029] In this scheme, the brominating reagent used in the bromination reaction is selected from bromine, NBS, and dibromohydantoin. The essence of the bromination reaction in this invention is the intermediate I1 carbonyl group. Electrophilic substitution reaction at the carbonyl group The hydrogen at the 1 / 2 position is acidic and can be replaced by an electrophilic brominator to produce... - Monobromoketone intermediate I2. All three brominating reagents are commonly used electrophilic brominating reagents in industry, enabling directed bromination under mild conditions, and each has its suitable application scenarios: bromine is a classic brominating reagent with strong brominating activity and a fast reaction rate, suitable for rapid production scenarios; NBS (N-bromosuccinimide) is a mild brominating reagent that slowly releases bromide ions at room temperature, precisely controlling the bromination process and avoiding polybromination side reactions; dibromohydantoin is a highly efficient brominating reagent with high active bromine content, low feed amount, and hydantoin as a byproduct, easily removed by water washing, simplifying post-processing. All three reagents can directionally achieve monobromination at the carbonyl α-position, avoiding bromination side reactions on the thiophene aromatic ring and ensuring regioselectivity of the reaction.

[0030] In this scheme, the reaction temperature for the bromination reaction is -10 to 25°C. Carbonyl group Bromination is an exothermic reaction, and the reaction temperature directly determines the activity of the brominating reagent, the reaction rate, the selectivity, and the amount of byproducts formed: at temperatures above 25°C, the brominating reagent is too reactive and easily forms carbonyl groups. Side reactions such as dibromination and thiophene ring bromination can lead to bromine volatilization and NBS thermal decomposition, reducing reagent utilization. At temperatures below -10℃, the brominating reagent has insufficient activity, resulting in extremely slow reaction rates, incomplete conversion of raw materials, significantly extended production cycles, and the need for ultra-low temperature equipment, increasing production costs. A temperature range of -10~25℃ allows for precise control of the brominating reagent's activity, ensuring complete conversion of raw materials within a reasonable timeframe while kinetically suppressing side reactions, achieving directional monobromination. It effectively suppresses polybromination and ring bromination side reactions, significantly reducing impurity formation, simplifying subsequent refining processes, and significantly improving the purity of the final product. It avoids the volatilization and decomposition of brominating reagents at high temperatures, increasing the effective utilization rate of brominating reagents by over 20%, reducing raw material consumption and production costs. The temperature range covers room temperature, eliminating the need for ultra-low temperature refrigeration or high-temperature heating equipment, significantly reducing equipment investment and energy consumption, and is suitable for conventional production conditions in ordinary chemical plants. The reaction process is mild and controllable, with no risk of violent exothermic reaction or boiling. Even in kilogram-scale production, the reaction temperature can be stably controlled without scale-up effect, making it highly feasible for industrialization.

[0031] In this scheme, methanol is used as the solvent for the alcohol phase purification. Methanol is the recrystallization purification solvent for intermediate I2. After the bromination reaction, the crude product contains unreacted raw materials, residual bromide salts, polybrominated byproducts, and other impurities, which need to be purified by recrystallization. Intermediate I2 has unique solubility characteristics in methanol: hot methanol above 55°C has extremely high solubility for I2, which can completely dissolve the target product, while its solubility for insoluble impurities and byproducts is extremely low. Insoluble impurities can be removed by hot dissolution and settling; after cooling, the solubility of I2 in methanol decreases sharply, allowing high-purity crystals to precipitate directionally, while soluble impurities remain in the mother liquor, achieving efficient separation of product and impurities. Methanol is a protic polar solvent with a high polarity match with intermediate I2, and regular crystals can be formed during recrystallization. It has excellent filtration and drying performance, without problems of sticking to the wall or clumping. After recrystallization and purification with methanol, the HPLC purity of the product can be increased from about 80% of the crude product to over 93%, and the optimal process can reach 98.22%, which fully meets the raw material quality requirements for subsequent synthesis of telexamine.

[0032] An intermediate compound for the synthesis of telexamine according to the present invention is obtained by comprising the following steps: Example 1

[0033] Reaction: Add 220g of polyphosphoric acid to a reaction flask, slowly heat to 60-65℃, then slowly add 100g of S1 and 81g of S2 dropwise while maintaining the reaction temperature at 70-80℃. After the addition is complete, keep the reaction at this temperature for 4 hours. After the reaction is complete, add 400g of water and 700g of dichloromethane, stir to separate the layers, and retain the organic phase. Add 200g of water, stir for 15 minutes, allow to stand to separate the layers, and retain the organic phase. Dry the organic phase with anhydrous sodium sulfate for 4 hours, filter, and use the filtrate directly for the next reaction.

[0034] Add 140g of bromine slowly to the above solution at 0-10℃ and stir for 8 hours. Use TLC (dichloromethane:petroleum ether = 1:2) to determine if I1 is complete. If not, add more bromine until I1 reacts completely. After the reaction is complete, add 400g of water, stir to separate the layers, and retain the organic phase. Dichloromethane is then distilled off under vacuum.

[0035] Add 600g of methanol to the residue, heat to 55℃, stir for 1 hour, let stand for 5-10 minutes, and collect the supernatant. Evaporate 2 / 3 of the supernatant by rotary evaporation, cool to 0-10℃, stir to precipitate crystals for 6-8 hours, filter, wash the filter cake with a small amount of methanol, and dry the solid at 35-37℃ to obtain 137g of intermediate I2, yield 61%, HPLC purity 93.57%. Example 2

[0036] Reaction: Add 220g of polyphosphoric acid to a reaction flask, slowly heat to 60-65℃, then slowly add 100g of S1 and 81g of S2 dropwise while maintaining the reaction temperature at 70-80℃. After the addition is complete, keep the reaction at this temperature for 4 hours. After the reaction is complete, add 400g of water and 700g of dichloromethane, stir to separate the layers, and retain the organic phase. Add 200g of water, stir for 15 minutes, allow to stand to separate the layers, and retain the organic phase. Dry the organic phase with anhydrous sodium sulfate for 4 hours, filter, and use the filtrate directly for the next reaction.

[0037] Slowly add 171g of NBS to the above solution at 15-25℃ and stir for 6 hours. Use TLC (dichloromethane: petroleum ether = 1:2) to determine if I1 reaction is complete. If not, add more NBS until the I1 reactant reacts completely. After the reaction is complete, add 400g of water, stir to separate the layers, and retain the organic phase. Dichloromethane is then distilled off under vacuum.

[0038] Add 600g of methanol to the residue, heat to 55℃, stir for 1 hour, let stand for 5-10 minutes, and collect the supernatant. Evaporate 2 / 3 of the supernatant by rotary evaporation, cool to 0-10℃, stir to precipitate crystals for 6-8 hours, filter, wash the filter cake with a small amount of methanol, and dry the solid at 35-37℃ to obtain 162g of intermediate I2, yield 72%, HPLC purity 96.57%. Example 3

[0039] Reaction: 114g S1, 84g S2, and 228g polyphosphoric acid were added to a reaction flask. The temperature was slowly raised to 60-65℃. 100g S1 and 81g S2 were mixed thoroughly and then slowly added dropwise, maintaining the reaction temperature at 70-80℃. After the addition was complete, the reaction was kept at this temperature for 4 hours. After the temperature was maintained, 456g water and 798g dichloromethane were added, and the mixture was stirred to separate the layers, retaining the organic phase. 228g water was added, and the mixture was stirred for 15 minutes. The mixture was allowed to stand and separate into layers, retaining the organic phase. The organic phase was dried with 20g anhydrous sodium sulfate, filtered, and the filtrate was used directly for the next reaction.

[0040] Add 286g of dibromohydantoin slowly to the above solution at 15-25℃, stir for 1 hour, and use TLC (dichloromethane: petroleum ether = 1:2) to determine if I1 is complete. If the reaction is incomplete, add more dibromohydantoin until the I1 reactant reacts completely. After the reaction is complete, add 456g of water, stir to separate the layers, and retain the organic phase; dichloromethane is then distilled off under vacuum.

[0041] Add 684 g of methanol to the residue, heat to 55 °C, stir for 1 hour, let stand for 5-10 min, and collect the supernatant. Evaporate 2 / 3 of the supernatant by rotary evaporation, cool to 0-10 °C, stir to induce crystallization for 6-8 h, filter, wash the filter cake with a small amount of methanol, and dry the solid at 35-37 °C with forced air to obtain 166 g of intermediate I2, yield 65%, HPLC purity 95.00%. Example 4

[0042] Reaction: 220g of polyphosphoric acid was added to a reaction flask, and the temperature was slowly raised to 60-65℃. 100g of S1 and 81g of S2 were mixed thoroughly and then slowly added dropwise, maintaining the reaction temperature at 80-90℃. After the addition was complete, the reaction was kept at this temperature for 8 hours. After the temperature was maintained, 400g of water and 700g of dichloromethane were added, and the mixture was stirred to separate the layers, retaining the organic phase. 200g of water was added, and the mixture was stirred for 15 minutes. The mixture was allowed to stand and separate into layers, retaining the organic phase. The organic phase was dried with anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was used directly for the next reaction.

[0043] Add 187g of NBS slowly to the above solution at 0-10℃, stir for 8 hours, and determine whether I1 is complete by TLC (dichloromethane: petroleum ether = 1:2). After the reaction is complete, add 400g of water, stir to separate the layers, and retain the organic phase; dichloromethane is then distilled off under vacuum.

[0044] Add 600g of methanol to the residue, heat to 55℃, stir for 1 hour, let stand for 5-10 minutes, and collect the supernatant. Evaporate 2 / 3 of the supernatant by rotary evaporation, cool to 0-10℃, stir to precipitate crystals for 6-8 hours, filter, wash the filter cake with a small amount of methanol, and dry the solid at 35-37℃ to obtain 155g of intermediate I2, yield 69%, HPLC purity 97.17%. Example 5

[0045] Reaction: 22 kg of polyphosphoric acid was added to a reaction flask, and the temperature was slowly raised to 60-65℃. 10 kg of S1 and 8.1 kg of S2 were mixed thoroughly and then slowly added dropwise, maintaining the reaction temperature at 70-80℃. After the addition was complete, the reaction was kept at this temperature for 8 hours. After the reaction was complete, 40 kg of water and 70 kg of dichloromethane were added, and the mixture was stirred to separate the layers, retaining the organic phase. 20 kg of water was added, and the mixture was stirred for 15 minutes. The mixture was allowed to stand and separate into layers, retaining the organic phase. The organic phase was dried with anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was used directly for the next reaction step.

[0046] The above solution was slowly added to 17.1 kg of NBS at 15-25°C, and stirred for 6 hours. TLC was used to determine whether I1 was complete by spotting (dichloromethane: petroleum ether = 1:2). After the reaction was complete, 40 kg of water was added, and the mixture was stirred to separate the layers, retaining the organic phase. Dichloromethane was then distilled off under vacuum.

[0047] Add 60 kg of methanol to the residue, heat to 55 °C, stir for 1 hour, let stand for 5-10 minutes, and collect the supernatant. Evaporate 2 / 3 of the supernatant by rotary evaporation, cool to 0-10 °C, stir to induce crystallization for 6-8 hours, filter, wash the filter cake with a small amount of methanol, and dry the solid at 35-37 °C with forced air to obtain 16.3 kg of intermediate I2, yield 73%, HPLC purity 98.22%. 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 method of synthesis of a key intermediate for synthesis of tianeptine, characterized in that, The compounds are 2-(2-thienyl)cyclohexanone (I1) and 2-bromo-2-(2-thienyl)cyclohexanone (I2), and their chemical structural formulas are as follows: I1 、 I2 。 2. The method for synthesizing a key intermediate of telexamine according to claim 1, characterized in that, The synthesis method of the intermediate compound includes the following steps: using thiophene and cyclohexanecarboxylic acid as starting materials, a polyphosphoric acid-mediated condensation reaction is used to obtain 2-(2-thienyl)cyclohexanone (I1), followed by bromination with a brominating reagent and purification with an alcohol phase to obtain 2-bromo-2-(2-thienyl)cyclohexanone (I2): 。 3. The method for synthesizing a key intermediate of telexamine according to claim 2, characterized in that, The condensation reagent used in the condensation reaction is polyphosphoric acid.

4. The method for synthesizing a key intermediate of telexamine according to claim 3, characterized in that, The reaction is a solvent-free reaction.

5. The method for synthesizing a key intermediate of telexamine according to claim 2, characterized in that, The brominating reagent used in the bromination reaction is selected from one of bromine, NBS, and dibromohydantoin.

6. The method for synthesizing a key intermediate of telexamine according to claim 5, characterized in that, The reaction temperature for the bromination reaction is -10 to 25°C.

7. The method for synthesizing a key intermediate of teletamin according to claim 2, characterized in that, The solvent used in the alcohol phase purification is methanol.

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