Preparation method and application of suzertraline intermediate

Abstract

The invention relates to a preparation method and application of a suzertraline intermediate, 3, 4-difluoro-2-methoxyaniline is taken as a raw material, diazotization is carried out to obtain a stable intermediate compound 3, 4-difluoro-2-methoxybenzene diazonium tetrafluoroborate, then coupling is carried out through a copper catalyst to obtain (R)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 4-difluoro-2-methoxyphenyl)-4, 4-difluoro-2-methoxybenzene diazonium tetrafluoroborate, and then the (R)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 4-difluoro-2-methoxybenzene diazonium tetrafluoroborate is taken as a raw material to obtain the suzertraline intermediate. The catalyst is 2, 5-dimethyl-5-(trifluoromethyl) furan-2 (5H) ketone. A diazotization reaction site is an amino group of 3, 4-difluoro-2-methoxyaniline, a copper catalyst coupling reaction site is a diazonium tetrafluoroboric acid group of 3, 4-difluoro-2-methoxybenzene diazonium tetrafluoroborate and one end of a hydrogen atom on a carbon-carbon double bond in (R)-4, 5-dimethyl-5-(trifluoromethyl) furan-2 (5H) ketone, and by-products are not easy to generate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing a suztriline intermediate and its application. Background Technology

[0002] Suzetrigine, a newly approved non-opioid drug by the FDA under the brand name Journavx, is a novel analgesic targeting NaV1.8. (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one is a key intermediate in the synthesis of suzetrigine. Currently, there is limited publicly available literature on this key intermediate; the relevant synthetic methods are as follows: International patent WO2022256660A1 discloses two synthetic methods, using 3,4-difluoro-2-methoxyphenylacetic acid as the starting material, which undergoes a condensation reaction with (R)-4,4,4-trifluoro-3-hydroxy-3-methylbut-2-one to obtain the key intermediate (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one. The condensation reaction in this method requires the use of CDI (N,N'-carbonyldiimidazole). This reagent has strict requirements for the control of moisture, low temperature and substrate ratio. The condensation reaction process will generate carbon dioxide gas, so the reaction feeding rate and the progress of the reaction need to be controlled to avoid the sudden escape of carbon dioxide. Moreover, the reaction selectivity is poor. The activated intermediate obtained by CDI and 3,4-difluoro-2-methoxyphenylacetic acid can not only react with the target nucleophile ((R)-4,4,4-trifluoro-3-hydroxy-3-methylbut-2-one), but is also easily reacted by the starting material (3,4-difluoro-2-methoxyphenylacetic acid) in the system and the activated intermediate itself, and finally generate byproducts such as acid anhydride, imidazole carbonate, and self-condensate. In addition, the starting material used is difficult to produce and not easy to obtain, which is not conducive to industrial production.

[0003] International patent WO2025122953A1 discloses the use of [2-(3,4-difluoro-2-methoxyphenyl)ethynyl]trimethylsilane as a raw material, and the addition reaction of the alkynyl group under the action of organozinc reagent and titanium catalyst to obtain (2R)-4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-2-methyl-3-butyn-2-ol. Further, in the presence of copper chloride and lithium chloride, the mixture is refluxed in tetrahydrofuran, then cooled to 2°C, methyl magnesium chloride is added, and then cooled to -73°C and carbon dioxide is introduced to carry out a carboxylation reaction to obtain the key intermediate (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one. This process route uses organozinc reagents and Grignard reagents, which are unstable and difficult to store. Strict control of moisture and oxygen is required during the reaction. The reaction process involves high-temperature reflux, the addition of Grignard reagent (methylmagnesium chloride) at 2°C, and the introduction of carbon dioxide at -73°C. The reaction steps are complex, and the reaction conditions are harsh, requiring strict temperature control. Excessive reaction temperature has several drawbacks: first, the complexes formed by copper chloride and lithium chloride with tetrahydrofuran may decompose, affecting the catalytic activity; second, Grignard reagents are prone to decomposition or self-coupling at high temperatures, affecting subsequent reactions; and third, intermediate compounds may not undergo carboxylation with carbon dioxide at high temperatures but may self-coupling, affecting the purity and yield of the final key intermediate. Furthermore, this reaction process poses significant safety hazards, as the quenching process generates large amounts of wastewater, which does not meet the requirements of green, environmentally friendly, and sustainable development. Summary of the Invention

[0004] The first technical problem to be solved by this invention is to provide a new method for preparing a suzertrine intermediate, namely (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one, which addresses the current state of the prior art. This method has a single reaction site, is less prone to generating byproducts, has simple post-reaction processing, is easy to control the temperature during the reaction process, and has mild reaction conditions, which is more in line with green and environmentally friendly requirements. Moreover, the synthesized intermediate compound has high quality stability.

[0005] The second technical problem to be solved by the present invention is to provide an application of the above-mentioned (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one in the preparation of suzetreline, in view of the current status of the prior art.

[0006] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows: This invention provides an intermediate compound for the preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one, wherein the intermediate compound is 3,4-difluoro-2-methoxyphenyldiazotetrafluoroborate, and the structural formula is: .

[0007] This invention provides a method for preparing (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one, namely, a method for preparing the compound of formula (IV) below. , The method involves converting a compound of formula (I) or a salt thereof into a compound of formula (II): , The compounds of formula (II) and (III) are then converted into the compound of formula (IV) under a copper catalyst: .

[0008] In some embodiments of the present invention, the reagents used to convert the compound of formula (I) or its salt into the compound of formula (II) are tetrafluoroboric acid and reagents containing nitrite groups.

[0009] In some embodiments of the present invention, the reaction steps for converting compound (I) or its salt into compound (II) are as follows: first, tetrafluoroboric acid solution is added to the reaction flask, then compound (I) is added to the reaction flask, and after the addition is complete, the mixture is stirred for a period of time. Then, a reagent solution containing nitrite groups is added to the reaction flask to obtain compound (II).

[0010] In some embodiments of the present invention, the molar ratio of compound of formula (I) or its salt: tetrafluoroboric acid: nitrous acid group is 1:2~3:1~2, preferably 1:2:1, 1:2.5:1, 1:3:1, 1:2:1.2, 1:2.5:1.2, 1:3:1.2, 1:2.5:1.5 or 1:2.5:2.

[0011] In some embodiments of the present invention, the reaction temperature for converting the compound of formula (I) or its salt into the compound of formula (II) is -5 to 10°C, preferably -5 to 5°C, -5 to 0°C or 0 to 5°C, more preferably 0°C, 1°C, 2°C, 3°C, 4°C or 5°C.

[0012] In some embodiments of the present invention, the reagent containing the nitrite group is selected from one or more of tert-butyl nitrite, isoamyl nitrite, and sodium nitrite.

[0013] In some embodiments of the present invention, the reaction steps for converting compound (II) and compound (III) into compound (IV) are as follows: first, compound (III) and copper catalyst are added to a reaction flask containing a mixture of water-soluble solvent and water; then, compound (II) is added; the reaction is carried out at a first temperature and then heated to a second temperature to obtain compound (IV).

[0014] In some embodiments of the present invention, the molar ratio of compound (II): compound (III): copper catalyst is 1:1~3:0.1~1, preferably 1:2:0.2.

[0015] In some embodiments of the present invention, the copper catalyst is selected from one or more of CuCl, CuBr, CuI, CuCl2, CuBr2, CuI2, and Cu(OAc)2.

[0016] In some embodiments of the present invention, the ratio of the mixed solvent is water-soluble solvent: water = 3~5:1, preferably water-soluble solvent: water = 4:1.

[0017] In some embodiments of the present invention, the water-soluble solvent is acetonitrile or acetone.

[0018] In some embodiments of the present invention, the first temperature is -5~5℃, preferably 0~5℃, and more preferably 0℃, 1℃, 2℃, 3℃, 4℃ or 5℃.

[0019] In some embodiments of the present invention, the second temperature is 20~40°C, preferably 25~35°C, and more preferably 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C or 35°C.

[0020] In some embodiments of the present invention, the post-processing steps after the conversion of the compound of formula (II) and the compound of formula (III) into the compound of formula (IV) are as follows: extraction is performed by adding an extraction solvent to the reaction solution, the extraction solvents are combined, dried and filtered, and the extraction solvent is distilled off under reduced pressure to obtain the compound of formula (IV); preferably, the extraction solvent is ethyl acetate.

[0021] In some embodiments of the present invention, the compound of formula (I) or a salt thereof is obtained by the following methods:

[0022] (1) Hydrolysis: Compound (I-1) reacts under alkaline conditions, and then an acidic reagent is added to adjust the pH to 3-6 to obtain compound (I-2); (2) Alkylation: Compound (I-2) undergoes alkylation reaction with alkylating agent under the action of phase transfer catalyst and acid-binding agent to obtain compound (I-3); (3) Reductive hydrogenation: Compound of formula (I-3) is passed through a reducing agent, and then an acidic reagent is added to adjust the pH to less than or equal to 1 to obtain compound of formula (I) or its salt.

[0023] In some embodiments of the present invention, the alkali used for hydrolysis is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide, and the acidic reagent used is selected from sulfuric acid, hydrochloric acid, and hydrobromic acid.

[0024] In some embodiments of the present invention, the phase transfer catalyst used for alkylation is selected from benzyltriethoxyammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, and benzyltriethoxyammonium chloride.

[0025] In some embodiments of the present invention, the acid-binding agent used for alkylation is selected from potassium hydroxide, sodium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.

[0026] In some embodiments of the present invention, the alkylating agent used for alkylation is selected from dimethyl sulfate and iodomethane.

[0027] In some embodiments of the present invention, the ratio of alkylated compound of formula (I-2): phase transfer catalyst: acid binder: alkylating agent is 1:0.05~0.1:1~2:1~2, preferably 1:0.05~0.1:1~1.5:1~1.5, more preferably 1:0.07:1.2:1.2, 1:0.075:1.2:1.2 or 1:0.08:1.2:1.2.

[0028] In some embodiments of the present invention, the solvent used in alkylation is a mixture of a non-water-soluble solvent and water; further, the ratio of the mixed solvent is non-water-soluble:water = 2~4:1, preferably 3:1; even further, the non-water-soluble solvent is selected from toluene.

[0029] In some embodiments of the present invention, the reducing agents used for reducing hydrogenation include hydrogen gas and a hydrogenation catalyst, a reducing metal chloride, iron powder and Lewis acid or NH4Cl, zinc powder and acetic acid, LiAlH4, NaBH4 and Lewis acid, Na2S2O4 and an alcohol solvent. The acidic reagent used is selected from sulfuric acid, hydrochloric acid, and hydrobromic acid. Preferably, the hydrogenation catalyst is selected from Pt, Pd / C, and Raney Ni, the reducing metal chloride is selected from SnCl2 and TiCl3, the Lewis acid is selected from AlCl3, FeCl3, ZnCl3, and BF3, and the alcohol solvent is selected from methanol and ethanol.

[0030] The present invention also provides an application of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one, wherein the (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one obtained according to the above preparation method is used to prepare suztriline.

[0031] Compared with the prior art, the advantages of this invention are as follows: using 3,4-difluoro-2-methoxyaniline as a raw material, a relatively stable solid intermediate compound 3,4-difluoro-2-methoxyphenyldiazotetrafluoroborate is obtained by diazotization, and then the key intermediate (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one is obtained by coupling reaction under the catalysis of copper catalyst. The raw materials of this route are cheaper and more readily available than 3,4-difluoro-2-methoxyphenylacetic acid, resulting in lower cost; at the same time, it does not use reagents that are highly sensitive to water or air, such as CDI, organozinc reagents, and Grignard reagents, thus ensuring higher reaction safety. In this invention, the diazotization reaction site is the amino group of 3,4-difluoro-2-methoxyaniline, and the copper catalyst catalyzes the coupling reaction site at the diazonium tetrafluoroborate group of 3,4-difluoro-2-methoxybenzenediazotetrafluoroborate and one end of the hydrogen atom (with low steric hindrance) on the carbon-carbon double bond in (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one. The single reaction site makes it less likely to generate byproducts, simplifying post-reaction processing, making temperature control during the reaction process easier, and providing mild reaction conditions that better meet green and environmentally friendly requirements. The synthesized intermediate compounds are of stable quality, which is beneficial for quality control of intermediate compounds. The overall yield of the reaction route is high, making it suitable for large-scale and industrial production. Detailed Implementation

[0032] Unless otherwise stated, the content of a compound solution in this application generally refers to the mass fraction of the compound relative to the total mass of the solution. For example, the 40% tetrafluoroboric acid aqueous solution in Example 4 refers to the mass fraction of tetrafluoroboric acid relative to the total mass of the solution being 40%.

[0033] In this application, since the compounds or structures shown in formula (I) contain amino analogs that react with acids to form salts, the term "salt" as used herein refers to these salts.

[0034] The present invention will be further described in detail below with reference to the embodiments. Example

[0035] In this example, 3,4-difluoro-2-hydroxynitrobenzene (compound 2) was synthesized from 1,2,3-trifluoro-4-nitrobenzene (compound 1). The reaction steps are as follows:

[0036] Preparation of Compound 2: Water (1400 mL) was added to a reaction flask, and the temperature was lowered to 0°C. Potassium hydroxide solid (256.6 g, 4.57 mol) was added in portions, maintaining the temperature at 10–20°C. Compound 1 (300 g, 1.69 mol) was added dropwise. The reaction was carried out at 20–30°C for 4 hours. After confirming the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to 2–4. The mixture was stirred for 2 hours, filtered, and the filter cake was rinsed three times with 300 g of water. The mixture was then dried to obtain Compound 2. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.86 (ddd, J = 9.6, 5.6, 2.4Hz, 1H), 7.09 (td, J = 9.6, 7.3Hz, 1H), 3.47 (s, 1H), HPLC purity 99.0%, MS m / z (ESI): [MH] - =174.0. Example

[0037] In this example, 3,4-difluoro-2-hydroxynitrobenzene (compound 2) was synthesized into 3,4-difluoro-2-methoxynitrobenzene (compound 3). The reaction steps are as follows:

[0038] Preparation of Compound 3: Compound 2 (200 g, 1.14 mol) was added to a reaction flask, followed by toluene (600 mL), water (200 mL), benzyltriethoxyammonium chloride (20 g, 87.42 mol), and dimethyl sulfate (172.9 g, 1.37 mol). Potassium hydroxide aqueous solution (512.7 g, 1.37 mol) was slowly added dropwise, controlling the addition temperature at -5 to 5 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 24 h. Once the reaction was complete, 400 g of water was added to the reaction system, and the mixture was extracted to separate the layers. The aqueous phase was then extracted twice in batches with 300 mL of toluene. The organic phases were combined, washed with saturated brine, and distilled under reduced pressure to obtain 201.7 g of Compound 3, with a yield of 93.4%. Compound 3: 1 ¹H NMR (400MHz, DMSO-d₆) δ 7.88 (ddd, J=9.5, 5.4, 2.4Hz, 1H), 7.42 (td, J=9.5, 7.4Hz, 1H), 4.06 (d, J=2.1Hz, 3H), HPLC purity 97.0%. Example

[0039] In this example, 3,4-difluoro-2-methoxynitrobenzene (compound 3) was synthesized into 3,4-difluoro-2-methoxyaniline (the hydrochloride salt of compound 4). The reaction steps are as follows:

[0040] Preparation of the hydrochloride salt of compound 4: Compound 3 (200 g, 1.06 mol) was added to a reaction flask, followed by methanol (600 mL) and Raney Ni (20 g). After nitrogen purging, hydrogen gas was introduced at 0.8–1 MPa, and the reaction was carried out at 20–30 °C for 8 h. The reaction was checked for complete reaction of the starting materials, filtered, and the filter cake was washed with 120 g of methanol. The filtrate was concentrated to 200 mL (1 V) volume, and hydrogen chloride gas was introduced to adjust the pH of the reaction system to ≤1. After the pH was deemed acceptable, the system was concentrated under reduced pressure until no obvious liquid distillation occurred. 200 g of ethyl acetate was added, and the mixture was stirred at room temperature for 1 h. After filtration, the filter cake was washed with 100 g of cooled ethyl acetate, and the filter cake was dried to obtain 187.6 g of the hydrochloride salt of compound 4, with a yield of 90.7%. Compound 4: 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 9.15 (s, 2H), 7.21–7.13 (m, 2H), 3.98 (d, J = 1.9 Hz, 3H), HPLC purity 98.0%, MS m / z (ESI): [M+H] + =160.1. Example

[0041] In this example, 3,4-difluoro-2-methoxyaniline (the hydrochloride salt of compound 4) was synthesized from 3,4-difluoro-2-methoxyphenyldiazotetrafluoroborate (compound 5). The reaction steps are as follows:

[0042] Add 689.75 g (3.14 mol) of 40% tetrafluoroboric acid aqueous solution to a clean 1000 mL four-necked flask. Add 200 g (1.26 mol) of compound 4 hydrochloride to a constant pressure dropping funnel and slowly add it dropwise to the four-necked flask at a low temperature of -5 to 10 °C. After the addition is complete, continue stirring for 0.5 to 3 h. Then, slowly add 231.2 g (1.51 mol) of 45% sodium nitrite aqueous solution to the four-necked flask. After the addition is complete, continue stirring for 1 to 3 h to obtain a suspension. Filter under reduced pressure to obtain 278.7 g of compound 5, with a yield of 76.7% and an HPLC purity of 97%. Compound 5: 1HNMR (400MHz, DMSO-d6) δ8.53(ddd,J=9.6,4.9,2.3Hz,1H),7.67(td,J=9.6,6.8Hz,1H),4.45(d,J=4.7Hz,3H); 19 FNMR(376MHz, DMSO-d6)δ-109.49,-109.54,-148.36,-148.42(d,J=2.5Hz),-149.95,-150.01. Example

[0043] In this embodiment, (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one (compound 7) was synthesized from 3,4-difluoro-2-methoxyphenyl)diazotetrafluoroborate (compound 5) and (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one (compound 6). The reaction steps are as follows:

[0044] Example 5-1: Compound 6 (13.97 g, 77.54 mmol), 40 mL of acetonitrile, and 10 mL of water were added to a 250 mL reaction flask. Cuprous chloride (1.04 g, 7.75 mmol) was added at 0-10 °C, followed by compound 5 (10 g, 38.77 mmol) in portions. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 8 h. After the reaction was confirmed to be complete by TLC, 50 mL of ethyl acetate was added to the reaction flask for extraction three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Column chromatography (n-heptane:ethyl acetate = 100:1 to 1:1) was then performed to obtain 9.3 g of compound 7, with a yield of 74.44%.

[0045] Example 5-2: Compound 6 (13.97 g, 77.54 mmol), 40 mL of acetone, and 10 mL of water were added to a 250 mL reaction flask. Cuprous chloride (1.04 g, 7.75 mmol) was added at 0–10 °C, followed by compound 5 (10 g, 38.77 mmol) in portions. The reaction was carried out at 0–5 °C for 0.5–1 h, then slowly heated to room temperature for 8 h. After the reaction was confirmed to be complete by TLC, the acetone was removed under reduced pressure. Ethyl acetate was added in portions (50 mL) to the reaction flask for extraction three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Column chromatography (n-heptane:ethyl acetate = 100:1–1:1) was then performed to obtain 8.9 g of compound 7, with a yield of 71.24% and an HPLC purity of 97.5%.

[0046] Compound 7: 1HNMR(400MHz, CDCl3)δ7.01–6.94(m,2H),3.92(d, J =2.2Hz,3H),2.06(s,3H),1.77(s,3H). Stability test I. Purpose of the Test Verify the stability of compounds under normal storage conditions, determine whether they are prone to degradation or deterioration, and provide a basis for storage and subsequent use.

[0047] II. Test Preparation 1. Information on the tested compound: Compound 5, a pale yellow solid with an initial HPLC purity of 97.06%.

[0048] 2. Solution preparation and instruments: The sample was dissolved in a 10% acetonitrile aqueous solution, and the purity was determined by high performance liquid chromatography (HPLC).

[0049] III. Test Conditions Standard storage conditions: temperature -3±2℃, relative humidity 60±5%, protected from light.

[0050] IV. Test Procedures 1. Initial sample testing: Take 0.1g of sample, and determine the purity to be 97.06% by HPLC. Visually, it appears as a pale yellow solid.

[0051] 2. Sample placement: Seal the sample in a container and place it under the test conditions described above.

[0052] 3. Periodic testing: After being stored under the above-mentioned conventional storage conditions for 2 weeks, the sample was taken out, dissolved in a 10% acetonitrile aqueous solution, clarified, and the purity was determined by HPLC to be 96.38%. It appeared as a pale yellow solid.

[0053] V. Test Results After compound 5 was refrigerated for 2 weeks, its purity was retested. There were no significant changes in purity or appearance, indicating that the sample was relatively stable under the above storage conditions.

[0054] This invention provides a method for preparing (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one, a compound of formula (IV), and its application. The method uses the inexpensive and readily available compound 2,3,4-trifluoronitrobenzene as a starting material, and obtains the raw material 3,4-difluoro-2-methoxyaniline through hydrolysis, alkylation, and reductive hydrogenation. Then, 3,4-difluoro-2-methoxyaniline is reacted with nitrosamine... The basic reagent was diazotized in tetrafluoroboric acid solution to obtain a relatively stable solid intermediate compound 3,4-difluoro-2-methoxyphenyldiazotetrafluoroborate, which was then coupled with compound (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one in the presence of a copper catalyst to obtain the key intermediate (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one. This route uses cheaper and more readily available raw materials compared to 3,4-difluoro-2-methoxyphenylacetic acid, resulting in lower costs. It also avoids the use of highly water- or air-sensitive reagents such as CDI, organozinc reagents, and Grignard reagents, ensuring higher reaction safety. The diazotization reaction site is the amino group of 3,4-difluoro-2-methoxyaniline, while the copper catalyst catalyzes the coupling reaction site at the diazonium tetrafluoroborate group of 3,4-difluoro-2-methoxyphenyldiazotetrafluoroborate and one end of the hydrogen atom (with low steric hindrance) on the carbon-carbon double bond in (R)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one. This single reaction site minimizes the generation of byproducts, simplifying post-reaction processing. Temperature control during the reaction is also relatively easy, and the mild reaction conditions better meet green and environmentally friendly requirements. The synthesized intermediate compounds are of stable quality, facilitating quality control. The overall yield of the reaction route is high, making it suitable for large-scale and industrial production.

[0055] The above description of the embodiments disclosed in this application enables those skilled in the art to make or use this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing a suzertrine intermediate, used to prepare an intermediate compound of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)one, characterized in that, The intermediate compound is 3,4-difluoro-2-methoxyphenyldiazotetrafluoroborate, with the structural formula [structure omitted]. 。 2. A method for preparing a suzertrine intermediate, namely, a method for preparing the compound of formula (IV) below, ， Its features are, To convert a compound of formula (I) or a salt thereof into a compound of formula (II), ， The compounds of formula (II) and (III) are then converted into the compound of formula (IV) under a copper catalyst. 。 3. The method for preparing the suzothrix intermediate according to claim 2, characterized in that, The reagents used to convert the compound of formula (I) or its salt into the compound of formula (II) are tetrafluoroboric acid and reagents containing nitrous groups; the reagents containing nitrous groups are selected from one or more of tert-butyl nitrite, isoamyl nitrite, and sodium nitrite.

4. The method for preparing the suzothrix intermediate according to claim 3, characterized in that, The reaction steps for converting compound (I) or its salt into compound (II) are as follows: first, add tetrafluoroboric acid solution to the reaction flask, then add compound (I) to the reaction flask, stir for a period of time after addition, and then add a reagent solution containing nitrite group to the reaction flask to obtain compound (II).

5. The method for preparing the suzothrix intermediate according to claim 4, characterized in that, The molar ratio of compound of formula (I) or its salt: tetrafluoroboric acid: nitrite group is 1:2~3:1~2.

6. The method for preparing the suzetriline intermediate according to claim 3, characterized in that, The reaction temperature for converting compound (I) or its salt into compound (II) is -5 to 10 °C.

7. The method for preparing the suzothrix intermediate according to claim 2, characterized in that, The reaction steps for converting compound (II) and compound (III) into compound (IV) are as follows: first, compound (III) and copper catalyst are added to a reaction flask containing a mixture of water-soluble solvent and water; then, compound (II) is added; the reaction is carried out at a first temperature and then heated to a second temperature to obtain compound (IV).

8. The method for preparing the suzothrix intermediate according to claim 7, characterized in that, The molar ratio of compound (II) to compound (III) and copper catalyst is 1:1~3:0.1~1; The ratio of the mixed solvent is water-soluble solvent: water = 3~5:

1.

9. The method for preparing the suzothrix intermediate according to claim 7, characterized in that, The copper catalyst is selected from one or more of CuCl, CuBr, CuI, CuCl2, CuBr2, CuI2, and Cu(OAc)2; The water-soluble solvent is acetonitrile or acetone; The first temperature is -5~5℃; The second temperature range is 20~40℃.

10. An application of the thazetrol intermediate according to any one of claims 2 to 9, characterized in that, Used to prepare suzothrix.

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