An exatecan intermediate and its preparation method

Abstract

The present invention discloses an exatecan intermediate and a preparation method thereof. The present invention provides a preparation method of a compound represented by formula 7, wherein R 1 As defined in the specification, the preparation method comprises the following steps: in a solvent, in the presence of a catalyst and a halosilane reagent, subjecting the compound represented by Formula 6 to a cyclization reaction to obtain a compound represented by Formula 7. The intermediate obtained in the present invention can be used to further prepare the exatecan product, with fewer reaction steps and higher product yield.

Description

Technical Field

[0001] The present invention relates to an exatecan intermediate and a preparation method thereof. Background Art

[0002] Exatecan, whose chemical name is (1S,9S)-9-ethyl-5-fluoro-1-amino-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline, was developed by Daiichi Sankyo Co., Ltd. The ADC drug Enhertu (fam-trastuzumab deruxtecan-nxki), which is combined with trastuzumab, was approved for marketing by the U.S. FDA under the accelerated approval process on December 20, 2019, for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer in adults.

[0003] The synthesis of ixatecan is prepared by splicing a key intermediate 1 with a chiral tricyclic lactone (2) and then deprotecting it. The synthesis of the key intermediate 1 is described in compound patent EP0495432. It uses 2-fluoro-toluene as the starting material and is prepared through more than ten steps of acylation, reduction, esterification, nitration, hydrolysis, decarbonylation and repeated oxidation of the carbonyl group, with a total yield of only 2.3%.

[0004] In patent WO1996026181, the synthesis of intermediate 1 uses 2-fluoro-toluene as the starting material and is prepared through more than ten steps of reactions including acylation, reduction, cyclization, amination, Beckmann rearrangement, and repeated ring-opening and ring-closure, with an overall yield of 2.6%.

[0005] In the recent patent WO2019044946, the synthesis of intermediate 1 uses 2-fluoro-4-nitrotoluene as the starting material and is obtained through eight steps including bromination, reduction, acetylation, Heck reaction, double bond reduction, cyclization, nitrosation, and reduction, with a total yield of 14%.

[0006]

[0007] The synthesis of intermediate 1 in patent WO2019044946 has greatly improved both process steps and yield compared to the previous literature route. However, this process still has significant limitations. For example, the first step of bromination has poor selectivity, and the by-products produced are difficult to remove. It needs to be crystallized and removed after three steps of reaction to intermediate 3, resulting in a low yield of the first three steps (37%). In addition, three hydrogenation reduction reactions, nitro reduction, double bond reduction, and nitroso reduction, occur in the entire route, which is repeated and has reduced efficiency. In response to the above two points, the present invention has made improvements, improving the yield and efficiency. Summary of the Invention

[0008] The technical problem to be solved by the present invention is that the existing preparation process of exatecan is long and the yield is low. To this end, the present invention provides an exatecan intermediate and a preparation method thereof. The preparation method of the present invention can efficiently prepare the exatecan pharmaceutical intermediate, which can be used to improve the yield of the production of exatecan products.

[0009] The present invention provides a method for preparing a compound as shown in Formula 7, comprising the following steps: subjecting the compound as shown in Formula 6 to a cyclization reaction as shown below in a solvent in the presence of a catalyst and a halosilane reagent to obtain a compound as shown in Formula 7;

[0010]

[0011] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0012] In the cyclization reaction, the solvent is a conventional reaction solvent for this type of reaction in the art, such as a halogenated hydrocarbon solvent, preferably 1,2-dichloroethane.

[0013] In the cyclization reaction, the catalyst is a conventional catalyst for this type of reaction in the art, such as indium halide, preferably indium trichloride or indium tribromide. Indium tribromide is more expensive, and indium trichloride is more preferred.

[0014] In the cyclization reaction, the halosilane reagent can be a conventional halosilane reagent used in this type of reaction in the art, for example Wherein, X can be a halogen, such as Cl or Br, preferably Cl; R a It can be H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, R b and R c It can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halosilane reagent is preferably HSi(CH3)2Cl.

[0015] In the cyclization reaction, the molar ratio of the compound represented by Formula 6 to the catalyst may be 1:0.5 to 1:4, for example, 1:1, 1:2 or 1:3, preferably 1:1.5 to 1:3.5, and more preferably 1:2.

[0016] In the cyclization reaction, the molar ratio of the compound represented by Formula 6 to the halosilane reagent can be 1:1.0 to 1:3.5, for example, 1:1.2, 1:2.3 or 1:2.9, preferably 1:2.3 to 1:2.9, and more preferably 1:2.3.

[0017] In the cyclization reaction, the mass-to-volume ratio of the compound represented by Formula 6 to the solvent can be a conventional mass-to-volume ratio in this type of reaction in the art, preferably 10 g / L to 150 g / L, for example 20 g / L, 50 g / L and 100 g / L, more preferably 50 g / L.

[0018] In the cyclization reaction, the reaction temperature is a conventional reaction temperature for this type of reaction in the art, such as room temperature (10-30°C) to 110°C. Preferably, the reaction is kept at room temperature within 4 hours after the start of the reaction, and then heated to reflux conditions for the reaction; the heating to reflux conditions can be heated to 70-110°C, preferably 90°C.

[0019] The progress of the cyclization reaction can be monitored using conventional monitoring methods for such reactions in the art (e.g., LCMS), and the reaction endpoint is generally determined when the compound shown in Formula 6 disappears or no longer reacts. The reaction time can be 8-48 hours, for example, 24 hours.

[0020] The cyclization reaction can be carried out in an inert atmosphere, which can be nitrogen or argon.

[0021] The preparation method may further include the following post-processing step: after the cyclization reaction is completed, water is added to separate the liquids, the aqueous phase is extracted with an organic solvent (e.g., three times with dichloromethane), the organic phases are combined, washed (e.g., sequentially with water and saturated brine), dried (e.g., dried over anhydrous sodium sulfate), and concentrated (e.g., under reduced pressure) to obtain the compound represented by Formula 7; or further recrystallization may be performed to obtain the compound represented by Formula 7. The solvent for the recrystallization may be a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:1.

[0022] In one embodiment, the materials for the cyclization reaction are the compound represented by Formula 6, dimethylchlorosilane, indium trichloride and the solvent.

[0023] In one embodiment, the compound represented by Formula 6 can be prepared by the following method, which comprises the following steps: subjecting the compound represented by Formula 5-B to an amidation reaction with an acetylating agent in a solvent to obtain the compound represented by Formula 6;

[0024]

[0025] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0026] In the amidation reaction, the solvent is a conventional reaction solvent in this type of reaction in the art, such as an ether solvent, preferably tetrahydrofuran.

[0027] In the amidation reaction, the acetylating agent is a conventional acetylating agent in this type of reaction in the art, such as acetic acid and / or acetic anhydride, preferably acetic acid and acetic anhydride.

[0028] In the amidation reaction, when the acetylating agents are acetic acid and acetic anhydride, the volume ratio of acetic acid and acetic anhydride can be a conventional volume ratio in this type of reaction in the art, for example, 1:0.1 to 1:10, preferably 1:1 to 1:3, and more preferably 3:4.

[0029] In the amidation reaction, when the acetylating agents are acetic acid and acetic anhydride, the mass-to-volume ratio of the compound represented by Formula 5-B to the acetic anhydride can be a conventional mass-to-volume ratio in this type of reaction in the art, for example, 40 g / L to 150 g / L, preferably 120 g / L.

[0030] In the amidation reaction, the reaction temperature can be a conventional reaction temperature for such reactions in the art, such as 20-40°C, preferably 30°C.

[0031] During the amidation reaction, the progress of the reaction can be monitored using conventional monitoring methods for such reactions in the art (e.g., LCMS, TLC, HPLC, or NMR). The reaction endpoint is generally determined when the starting material 5-B disappears or no longer reacts. The amidation reaction time can be 8-48 hours, e.g., 20 hours or 24 hours.

[0032] After the amidation reaction is completed, the following post-treatment steps may be included: filtering the reaction solution, neutralizing with a base (e.g., 5N sodium hydroxide solution), extracting (e.g., extracting three times with 2-methyltetrahydrofuran), combining the organic phases and washing (e.g., with saturated brine), drying (e.g., with anhydrous sodium sulfate), and concentrating (e.g., under reduced pressure) to obtain the compound represented by Formula 6; or further purification may be performed to obtain the compound represented by Formula 6. The purification may be performed by ethyl acetate / petroleum ether column chromatography.

[0033] In one embodiment, the materials for the amidation reaction are the compound represented by formula 5-B, an acetylating agent (acetic acid and acetic anhydride) and the solvent.

[0034] In one embodiment, the compound represented by the above formula 5-B can be prepared by the following method, which comprises the following steps:

[0035] (1) In a solvent, in the presence of a base, the compound represented by Formula 5 is subjected to a nitrosation reaction with isoamyl nitrite as shown below to obtain substance 5-A;

[0036] (2) in the presence of a catalyst, subjecting the substance 5-A to a reduction reaction with a reducing agent to obtain the compound represented by the formula 5-B;

[0037]

[0038] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0039] In the nitrosation reaction, the solvent is a conventional reaction solvent in this type of reaction in the art, such as an ether solvent, preferably tetrahydrofuran.

[0040] The temperature of the nitrosation reaction is a conventional reaction temperature for this type of reaction in the art, for example, 0°C to -40°C, preferably -12°C to -40°C, more preferably -20°C.

[0041] The nitrosation reaction can be carried out in an inert atmosphere, and the inert atmosphere can be nitrogen or argon.

[0042] In the nitrosation reaction, the base is a conventional base used in this type of reaction in the art, such as an alkali metal alcoholate, preferably potassium tert-butoxide.

[0043] In the nitrosation reaction, the molar ratio of the isoamyl nitrite to the compound represented by Formula 5 can be a conventional molar ratio in this type of reaction in the art, preferably 2.0:1 to 1.0:1, such as 1.4:1, 1.8:1 or 1.1:1, and more preferably 1.4:1.

[0044] In the nitrosation reaction, the molar ratio of the base to the compound represented by Formula 5 can be a conventional molar ratio in this type of reaction in the art, such as 1.5:1, 1.3:1 or 1.1:1, preferably 1.5:1 to 1.1:1, and more preferably 1.3:1.

[0045] In the nitrosation reaction, the mass-to-volume ratio of the compound represented by Formula 5 to the solvent can be a conventional mass-to-volume ratio in this type of reaction in the art, for example, 5 g / L to 500 g / L, preferably 50 g / L.

[0046] In the nitrosation reaction, the progress of the reaction can be monitored using conventional monitoring methods for such reactions in the art (e.g., LCMS, TLC, HPLC, or NMR). The reaction endpoint is generally determined when the compound represented by Formula 5 disappears or no longer reacts. The reaction time can be 0.5-3 hours, for example, 1 hour.

[0047] In one embodiment, the materials for the nitrosation reaction are the compound represented by Formula 5, isoamyl nitrite, a base (such as potassium tert-butoxide) and the solvent.

[0048] In one embodiment, the reaction solution obtained after the nitrosation reaction is completed can be directly used in the reduction reaction of step (2) without post-treatment.

[0049] The reaction temperature of the reduction reaction is a conventional reaction temperature for this type of reaction in the art, for example, 20°C to 50°C, preferably 30°C to 40°C.

[0050] The catalyst for the reduction reaction is a conventional catalyst for this type of reaction in the art, such as platinum-carbon or palladium-carbon, preferably platinum-carbon, more preferably 5% platinum-carbon.

[0051] In the reduction reaction, the mass ratio of the catalyst to the compound represented by Formula 5 may be 1:1 to 1:10, such as 1:5, 1:10 or 3:10, preferably 1:5 to 3:10, and more preferably 1:5.

[0052] The reducing agent of the reduction reaction is a conventional reducing agent in this type of reaction in the art, such as a reducing gas, preferably hydrogen.

[0053] The pressure of the reduction reaction is a conventional reaction pressure in this type of reaction in the art, such as 0.5 atm, 1 atm, 2 atm or 3 atm, preferably 1 atm to 3 atm, most preferably 1 atm.

[0054] During the reduction reaction, the progress of the reaction can be monitored using conventional monitoring methods for such reactions in the art (e.g., LCMS, TLC, HPLC, or NMR). The reaction endpoint is generally determined when the substance 5-A disappears or ceases to react. The reduction reaction can be performed for 8-48 hours, for example, 24 hours.

[0055] In one embodiment, the reaction solution obtained after the reduction reaction can be directly used in the amidation reaction without post-treatment.

[0056] In one embodiment, the compound represented by Formula 6 can be obtained by sequentially reacting the compound represented by Formula 5 through the above step (1), the above step (2) and the above amidation reaction.

[0057] In one embodiment, the compound represented by the above formula 5 can be prepared by the following method, which comprises the following steps: in a solvent, in the presence of a catalyst or a catalyst and a ligand, in the presence of a base, subjecting the compound represented by formula 4 to a coupling reaction with an alkenoate represented by formula (I) as shown below to obtain the compound represented by formula 5;

[0058]

[0059] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0060] In the coupling reaction, the solvent is a conventional reaction solvent in this type of reaction in the art, such as an ether solvent or a mixed solvent of an ether solvent and water; preferably, the ether solvent is tetrahydrofuran; more preferably, the solvent is a mixed solvent of an ether solvent and water, such as a mixed solvent of tetrahydrofuran and water.

[0061] In the coupling reaction, when the solvent is a mixed solvent of an ether solvent and water, the volume ratio of the ether solvent to the water can be a conventional volume ratio for this type of reaction in the art, preferably 1:1 to 10:1, such as 5:1 or 4.7:1, further preferably 4:1 to 5:1, and most preferably 4:1.

[0062] In the coupling reaction, the mass volume ratio of the compound represented by Formula 4 to the solvent can be a conventional mass volume ratio in this type of reaction in the art, preferably 100 g / L to 200 g / L, for example, 111.1 g / L, 100 g / L or 164.7 g / L, further preferably 111.1 g / L to 133.3 g / L, and most preferably 133.3 g / L.

[0063] In the coupling reaction, the catalyst is a conventional catalyst for this type of reaction in the art, such as a transition metal catalyst, preferably palladium acetate.

[0064] In the coupling reaction, the ligand is a conventional phosphine ligand in this type of reaction in the art, such as tri-o-tolylphosphine; more preferably, the mass ratio of tri-o-tolylphosphine to palladium acetate can be 1:1 to 4:1, preferably 8:3 to 55:23, and most preferably 8:3.

[0065] In the coupling reaction, the mass ratio of the catalyst to the compound represented by Formula 4 can be a conventional mass ratio in this type of reaction in the art, preferably 1:100 to 5:100, for example, 2.5:100, 1.6:100, 3.8:100, more preferably 2.5:100 to 3.8:100, and most preferably 2.5:100.

[0066] In the coupling reaction, the base can be a conventional organic base used in this type of reaction in the art. Preferably, the base is diisopropylethylamine.

[0067] In the coupling reaction, the molar ratio of the compound represented by Formula 4 to the base can be a conventional molar ratio in this type of reaction in the art, such as 1:4.4, 1:3.1 or 1:2.9, preferably 1:1 to 1:5.5, more preferably 1:2.9 to 1:4.4, and most preferably 1:4.4.

[0068] In the coupling reaction, the enoate represented by formula (I) is selected from tert-butyl 3-butenoate, isopropyl 3-butenoate, allyl 3-butenoate and benzyl 3-butenoate, preferably tert-butyl 3-butenoate.

[0069] In the coupling reaction, the molar ratio of the compound represented by Formula 4 to the enoate represented by Formula (I) can be a conventional molar ratio in this type of reaction in the art, preferably 1:1.2 to 1:2.0, such as 1:1.8 or 1:1.9, more preferably 1:1.8.

[0070] In the coupling reaction, the reaction temperature is a conventional reaction temperature for this type of reaction in the art, preferably 50°C to 65°C, such as 50°C or 60°C, more preferably 60°C.

[0071] In the coupling reaction, the progress of the reaction can be monitored using conventional monitoring methods for such reactions in the art (e.g., LCMS, TLC, HPLC, or NMR), and the reaction endpoint is generally determined when the compound represented by Formula 4 disappears or no longer reacts. The reaction time can be 8-48 hours, for example, 24 hours.

[0072] In the coupling reaction, the reaction can be carried out in an inert atmosphere, and the inert atmosphere can be nitrogen or argon.

[0073] After the coupling reaction is completed, the following post-treatment steps may be included: cooling the reaction solution to room temperature (e.g., 10° C. to 30° C.), filtering, washing the filter cake (e.g., eluting with ethyl acetate), collecting the filtrate and washing it (e.g., sequentially with semi-saturated brine and saturated brine), drying the filtrate (e.g., drying with anhydrous sodium sulfate), and concentrating (e.g., under reduced pressure) to obtain the compound represented by Formula 5; or further recrystallization may be performed to obtain the compound represented by Formula 5. The solvent for the recrystallization may be a mixed solvent of ethyl acetate / petroleum ether with a volume ratio of 1:15.

[0074] In one embodiment, the materials for the coupling reaction are the compound represented by formula 4, the enoate (tert-butyl 3-butenoate) represented by formula (I), the base (diisopropylethylamine), the ligand (tri-o-tolylphosphine), the catalyst (palladium acetate) and the solvent.

[0075] In one embodiment, the compound represented by the above formula 4 can be prepared by the following method, which comprises the following steps: in a solvent, 2-fluoro-4-nitrotoluene is subjected to a halogenation reaction with an iodine reagent as shown below to obtain a compound represented by formula 4;

[0076]

[0077] In the halogenation reaction, the solvent is a conventional reaction solvent for this type of reaction in the art, such as concentrated sulfuric acid.

[0078] In the halogenation reaction, the mass volume ratio of the 2-fluoro-4-nitrotoluene to the solvent can be a conventional mass volume ratio in this type of reaction in the art, preferably 50 g / L to 200 g / L, such as 80 g / L, 100 g / L and 200 g / L, preferably 50 g / L to 80 g / L, and most preferably 80 g / L.

[0079] In the halogenation reaction, the iodination reagent is a conventional iodination reagent in this type of reaction in the art, such as periodic acid and iodine molecular combination.

[0080] In the halogenation reaction, when the iodination reagent is a combination of periodic acid and iodine molecules, the molar ratio of periodic acid to iodine molecules is preferably 3.1:10 to 3.5:10, for example, 3.3:10.

[0081] The iodine reagent can be prepared by conventional methods in the art for this type of reaction. In the present invention, the following steps are preferred: sodium periodate is added (e.g., added in batches) to a mixed solution of concentrated sulfuric acid and iodine molecules, and the mixture is mixed (e.g., stirred) to obtain the iodine reagent;

[0082] In the step, the temperature of the addition may be 0°C to 20°C, for example, 5°C to 10°C;

[0083] In the step, the mixing temperature may be 20°C to 40°C, for example, 25°C to 30°C.

[0084] In the halogenation reaction, the molar ratio of the 2-fluoro-4-nitrotoluene to the iodine molecule in the iodination reagent can be a conventional molar ratio in this type of reaction in the art, preferably 2.5:1 to 1.3:1, more preferably 2.1:1 to 1.3:1, and most preferably 2:1.

[0085] In the halogenation reaction, the reaction temperature is a conventional reaction temperature for this type of reaction in the art, for example, 20°C to 40°C, preferably 25°C to 30°C.

[0086] In the halogenation reaction, the progress of the reaction can be monitored using conventional monitoring methods for such reactions in the art (e.g., TLC). The monitoring preferably comprises the following steps: (1) taking a sample and adding it to saturated sodium bicarbonate to obtain a mixed system; (2) adding ethyl acetate to the mixed system, collecting the organic phase, and analyzing it by TLC. The reaction endpoint is generally determined when the 2-fluoro-4-nitrotoluene disappears or is no longer produced. The reaction time can be 0.5 to 3 hours, for example, 1 hour.

[0087] After the halogenation reaction is completed, the following post-treatment step may be further included: after the reaction is completed, the reaction solution is poured into water containing sodium thiosulfate (for example, ice water containing sodium thiosulfate with a volume 4 times that of concentrated sulfuric acid) to quench the reaction, stirred, filtered, and the filter cake is washed (for example, with water and petroleum ether in sequence), and dried; to obtain the compound represented by formula 4.

[0088] In a certain embodiment, the materials for the halogenation reaction are the 2-fluoro-4-nitrotoluene, the sodium periodate and iodine molecule composition, and the solvent.

[0089] The present invention provides a compound as shown in Formula 5, Formula 5-B or Formula 6;

[0090]

[0091] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0092] The present invention provides a method for preparing a compound represented by Formula 6, comprising the following steps: subjecting a compound represented by Formula 5-B to an amidation reaction with an acetylating agent in a solvent to obtain the compound represented by Formula 6;

[0093]

[0094] Among them, R 1is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0095] In the preparation method, the reaction conditions and operations may be the same as the reaction conditions and operations in any of the methods for preparing the compound of Formula 6 in the preparation method of the compound of Formula 7.

[0096] The present invention provides a method for preparing a compound represented by formula 5-B, comprising the following steps:

[0097] (1) In a solvent, in the presence of a base, the compound represented by Formula 5 is subjected to a nitrosation reaction with isoamyl nitrite as shown below to obtain substance 5-A;

[0098] (2) in the presence of a catalyst, subjecting the substance 5-A to a reduction reaction with a reducing agent to obtain the compound represented by the formula 5-B;

[0099]

[0100] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0101] In the preparation method, the reaction conditions and operations may be the same as the reaction conditions and operations in any method for preparing the compound of Formula 5-B in the preparation method of the compound of Formula 7.

[0102] The present invention provides a method for preparing a compound represented by Formula 5, comprising the following steps: in a solvent, in the presence of a catalyst or a catalyst and a ligand, subjecting the compound represented by Formula 4 to a coupling reaction with an alkenoate represented by Formula (I) as shown below in the presence of a base, to obtain a compound represented by Formula 5;

[0103]

[0104] Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl, preferably tert-butyl.

[0105] In the preparation method, the reaction conditions and operations may be the same as the reaction conditions and operations in any method for preparing the compound of Formula 5 in the preparation method of the compound of Formula 7.

[0106] The present invention provides a method for preparing a compound represented by Formula 4, comprising the following steps: subjecting 2-fluoro-4-nitrotoluene to a halogenation reaction with an iodine reagent in a solvent as shown below to obtain a compound represented by Formula 4;

[0107]

[0108] In the preparation method, the reaction conditions and operations may be the same as the reaction conditions and operations in any method for preparing the compound of Formula 4 in the preparation method of the compound of Formula 7.

[0109] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0110] The reagents and raw materials used in the present invention are commercially available.

[0111] The positive progress of the present invention is that the exatecan intermediate disclosed in the present invention can be used to further prepare the exatecan product with fewer reaction steps and higher product yield. DETAILED DESCRIPTION

[0112] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0113] Example 1 Preparation of the compound represented by formula 4

[0114] At 5-10°C, sodium periodate (8.8g, 0.041mol) was added portionwise to a mixture of concentrated sulfuric acid (400ml) and iodine (31g, 0.122mol). The temperature was raised to 25-30°C and stirred for 1 hour to prepare an oxidant solution. This solution was then slowly added to a mixture of 2-fluoro-4-nitrotoluene (40g, 0.25mol) and concentrated sulfuric acid (100ml). The temperature was controlled at 25-30°C and the reaction continued for 1 hour. The reaction solution was slowly poured into ice water containing 25g of sodium thiosulfate, stirred, and filtered. The filter cake was washed with petroleum ether and dried to obtain 50.5g of the compound represented by Formula 4, with a yield of 69.7% and a purity of 93.20%.

[0115] Example 2 Preparation of the compound represented by formula 5

[0116] The compound shown in formula 4 (60.0 g, 0.213 mol) was dissolved in a solution of tetrahydrofuran (360 ml) and water (90 ml), and tert-butyl 3-butenoate (55.0 g, 0.386 mol), diisopropylethylamine (120 g, 0.928 mol), tri-o-tolylphosphine (4 g) and palladium acetate (1.5 g) were added in sequence. The mixture was protected by nitrogen and heated to 60 ° C for 24 h.

[0117] The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate. The filtrate was washed sequentially with semi-saturated brine and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether in a volume ratio of 1:15 to obtain 52 g of the compound of Formula 5, with a yield of 82.4%.

[0118] 1 H-NMR(400MHz,DMSO-d6)δ8.10(1H,s),7.95(1H,dd,J=9.4,2.1Hz),6.81(1H,d,J=15.8Hz), 6.42(1H,dt,J=15.6,7.0Hz),3.31(2H,dd,J=7.0,1.1Hz),2.31(3H,d,J=2.1Hz),1.45(9H,s)

[0119] Example 3 Preparation of the compound represented by formula 6

[0120] Add the compound of formula 5 (5 g, 16.9 mmol) and tetrahydrofuran (100 ml) to the reaction flask, protect with nitrogen, cool to -20°C, add isoamyl nitrite (2.8 g, 23.9 mmol) and potassium tert-butoxide (2.4 g, 21.3 mmol), and react for 1 h.

[0121] 5% platinum on carbon (1 g) was added to the reaction solution, and hydrogen was added. The reaction was carried out at 1 atm and 30-40°C for 24 h to obtain the compound shown in formula 5-B. MS (m / z): 283.1 [M+H]+

[0122] Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction solution, and the reaction was continued at approximately 30°C for 20 hours. The reaction solution was filtered to remove the platinum on carbon, and the filtrate was neutralized with 5N sodium hydroxide solution and extracted three times with 2-methyltetrahydrofuran. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate / petroleum ether column chromatography to obtain 4.2 g of the compound represented by Formula 6, in a yield of 67.7%.

[0123] MS (m / z): 367.0 [M+H]+

[0124] 1 H-NMR(600MHz,CD3OD)δ7.20(1H,d,J=11.7Hz),6.96(1H,s),4.26-4.10(1H,m),2.58( 2H,t,J=7.9Hz),2.05(3H,s),2.00(3H,s),1.98-1.92(2H,m),1.91(3H,s),1.38(9H,s)

[0125] Example 4 Preparation of the compound represented by formula 7

[0126] The compound represented by Formula 6 (2.0 g, 5.4 mmol) was added to 1,2-dichloroethane (40 mL) under nitrogen. Indium trichloride (2.4 g, 10.8 mmol) and dimethylsilyl chloride (1.2 g, 12.6 mmol) were added. The mixture was allowed to react at room temperature for 4 hours, then heated to reflux (approximately 90°C) for 24 hours. The reaction solution was poured into water, separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether (1:1 by volume) to obtain 1.2 g of the compound represented by Formula 7, with a yield of 75.2%.

[0127] MS(m / z): 293.1[M+H]+,315.0[M+Na]+.

[0128] Example 5 Preparation of the compound represented by formula 1

[0129] The compound represented by Formula 7 (2.2 g, 7.5 mmol) was added to 2N hydrochloric acid / ethanol (30 ml) under nitrogen and heated to 50°C for 5 hours. The reaction solution was cooled to 0-5°C, water (50 ml) was added, and triethylamine (10 ml) was added dropwise. The mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was washed with cold 50% ethanol aqueous solution and dried under reduced pressure to obtain 1.7 g of crude compound 1. The crude compound represented by Formula 1 was slurried in 20 ml of acetone at 50°C for 5 hours, cooled to room temperature, filtered, and the filter cake was dried under reduced pressure to obtain 1.5 g of compound represented by Formula 1, with a yield of 79.6%.

[0130] MS (m / z): 251.1 [M+H]+

[0131] 1 H-NMR(400MHz,DMSO-d6)δ8.07(1H,d,J=7.9Hz),7.41(2H,brs),6.39(1H,d,J=12.5Hz),4.51-4.44(1H,m) ,3.01-2.74(2H,m),2.20-2.10(1H,m),1.98(3H,d,J=1.1Hz,),1.91(3H,s),1.86(1H,dd,J=13.0,5.0Hz).

[0132] Example 6 Preparation of the compound represented by formula 4

[0133] Sodium periodate (21 g, 98.2 mmol) was added portionwise to a mixture of concentrated sulfuric acid (1000 ml) and iodine (75 g, 0.295 mol) at 0-10°C. The mixture was heated to 20-30°C and stirred for 1 hour to prepare an oxidant solution. This solution was then slowly added to a mixture of 2-fluoro-4-nitrotoluene (60 g, 0.387 mol) and concentrated sulfuric acid (200 ml). The temperature was controlled at 20-30°C and the reaction continued for 3 hours. The reaction solution was slowly poured into ice water containing 25 g of sodium thiosulfate, stirred, and filtered. The filter cake was washed with petroleum ether and dried to obtain 68 g of the compound of Formula 4, with a yield of 62.5%.

[0134] Example 7 Preparation of the compound represented by formula 4

[0135] At 10-20°C, sodium periodate (7.1 g, 33.2 mmol) was added portionwise to a mixture of concentrated sulfuric acid (300 ml) and iodine (25.4 g, 0.100 mol). The temperature was raised to 30-40°C and stirred for 1 hour to prepare an oxidant solution. This solution was then slowly added to a mixture of 2-fluoro-4-nitrotoluene (40 g, 0.25 mol) and concentrated sulfuric acid (100 ml). The temperature was controlled at 30-40°C and the reaction continued for 0.5 hour. The reaction solution was slowly poured into ice water containing 25 g of sodium thiosulfate, stirred, and filtered. The filter cake was washed with petroleum ether and dried to obtain 41.5 g of the compound represented by Formula 4, with a yield of 57.3%.

[0136] Example 8 Preparation of the compound represented by formula 5

[0137] The compound shown in formula 4 (6.0 g, 21.3 mmol) was dissolved in tetrahydrofuran (60 ml), and tert-butyl 3-butenoate (5.5 g, 38.6 mmol), diisopropylethylamine (12 g, 92.8 mmol), tri-o-tolylphosphine (0.4 g) and palladium acetate (0.15 g) were added in sequence. The mixture was protected by nitrogen and heated to 50 ° C for 24 h.

[0138] The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate. The filtrate was washed sequentially with semi-saturated brine and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether (1:15, by volume) to obtain 4.8 g of the compound of Formula 5, with a yield of 76.1%.

[0139] Example 9 Preparation of the compound represented by formula 5

[0140] The compound shown in formula 4 (14 g, 49.8 mmol) was dissolved in a solution of tetrahydrofuran (70 ml) and water (15 ml), and tert-butyl 3-butenoate (8.4 g, 59.2 mmol), diisopropylethylamine (35 g, 0.271 mol), tri-o-tolylphosphine (0.9 g) and palladium acetate (0.33 g) were added in sequence. The mixture was protected by nitrogen and heated to 65 ° C for 24 h.

[0141] The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate. The filtrate was washed sequentially with semi-saturated brine and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether (1:15, by volume) to obtain 8.9 g of the compound of Formula 5, in a yield of 73.6%.

[0142] Example 10 Preparation of the compound represented by formula 5

[0143] The compound shown in formula 4 (6.0 g, 21.3 mmol) was dissolved in a solution of tetrahydrofuran (45 ml) and water (9 ml), and tert-butyl 3-butenoate (5.5 g, 38.6 mmol), diisopropylethylamine (8 g, 61.9 mmol), tri-o-tolylphosphine (0.55 g) and palladium acetate (0.23 g) were added in sequence. The mixture was protected by nitrogen and heated to 60°C for 24 h.

[0144] The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate. The filtrate was washed sequentially with semi-saturated brine and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether (1:15, by volume) to obtain 5.0 g of the compound of Formula 5, in a yield of 79.3%.

[0145] Example 11 Preparation of the compound represented by formula 6

[0146] Add the compound of formula 5 (5 g, 16.9 mmol) and tetrahydrofuran (100 ml) to the reaction flask, protect with nitrogen, cool to 0°C, add isoamyl nitrite (2.8 g, 23.9 mmol) and potassium tert-butoxide (2.4 g, 21.3 mmol), and react for 1 h.

[0147] 5% platinum on carbon (0.5 g) was added to the reaction solution, and hydrogen was introduced. The reaction was carried out at 2 atm and 20-30° C. for 24 h to obtain the compound represented by formula 5-B.

[0148] Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction solution, and the reaction was continued at approximately 20°C for 24 hours. The reaction solution was filtered to remove the platinum on carbon, and the filtrate was neutralized with 5N sodium hydroxide solution and extracted three times with 2-methyltetrahydrofuran. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate / petroleum ether column chromatography to obtain 4.2 g of the compound of Formula 6, in a yield of 45.1%.

[0149] Example 12 Preparation of the compound represented by formula 6

[0150] Add the compound of formula 5 (5 g, 16.9 mmol) and tetrahydrofuran (100 ml) to the reaction flask, protect with nitrogen, cool to -20°C, add isoamyl nitrite (3.6 g, 30.7 mmol) and potassium tert-butoxide (2.8 g, 24.9 mmol), and react for 1 h.

[0151] 5% platinum on carbon (1.5 g) was added to the reaction solution, and hydrogen was introduced. The reaction was carried out at 3 atm and 30-40°C for 24 h to obtain the compound of Formula 5-B. Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction solution, and the reaction was continued at approximately 40°C for 24 h. The reaction solution was filtered to remove the platinum on carbon, and the filtrate was neutralized with 5N sodium hydroxide solution and extracted three times with 2-methyltetrahydrofuran. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate / petroleum ether column chromatography to obtain 3.5 g of the compound of Formula 6, with a yield of 56.4%.

[0152] Example 13 Preparation of the compound represented by formula 6

[0153] Add the compound of formula 5 (5 g, 16.9 mmol) and tetrahydrofuran (100 ml) to the reaction flask, protect with nitrogen, cool to -40°C, add isoamyl nitrite (2.2 g, 18.7 mmol) and potassium tert-butoxide (2.1 g, 18.7 mmol), and react for 1 h.

[0154] 5% platinum on carbon (1 g) was added to the reaction solution, and hydrogen was introduced. The reaction was carried out at 1 atm and 40-50°C for 24 hours to obtain the compound of Formula 5-B. Acetic acid (30 ml) and acetic anhydride (40 ml) were added to the reaction solution, and the reaction was continued at approximately 30°C for 24 hours. The reaction solution was filtered to remove the platinum on carbon, and the filtrate was neutralized with 5N sodium hydroxide solution and extracted three times with 2-methyltetrahydrofuran. The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was purified by ethyl acetate / petroleum ether column chromatography to obtain 3.0 g of the compound of Formula 6 in a yield of 48.3%.

[0155] Example 14 Preparation of the compound represented by formula 7

[0156] The compound represented by Formula 6 (2.0 g, 5.4 mmol) was added to 1,2-dichloroethane (100 mL) under nitrogen. Indium trichloride (3.6 g, 16.3 mmol) and dimethylsilyl chloride (1.5 g, 15.8 mmol) were added. The reaction was allowed to react at room temperature for 4 hours, then heated to approximately 90°C for 48 hours. The reaction solution was poured into water, separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether in a 1:1 volume ratio to obtain 1.1 g of the compound represented by Formula 7, in a yield of 68.9%.

[0157] Example 15 Preparation of the compound represented by formula 7

[0158] The compound represented by Formula 6 (2.0 g, 5.4 mmol) was added to 1,2-dichloroethane (20 mL) under nitrogen atmosphere. Indium trichloride (1.2 g, 5.4 mmol) and dimethylsilyl chloride (0.62 g, 6.55 mmol) were added and reacted at room temperature for 4 hours. The reaction was then heated to approximately 110°C for 24 hours. The reaction solution was poured into water and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether (1:1 by volume) to obtain 0.55 g of the compound represented by Formula 7, with a yield of 34.5%.

[0159] Example 16 Preparation of the compound represented by formula 7

[0160] The compound represented by Formula 6 (1.0 g, 2.7 mmol) was added to 1,2-dichloroethane (20 mL) under nitrogen atmosphere. Indium tribromide (1.9 g, 5.4 mmol) and dimethylsilyl chloride (0.6 g, 6.3 mmol) were added and allowed to react at room temperature for 4 hours. The reaction was then heated to approximately 70°C for 8 hours. The reaction solution was poured into water and separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting concentrate was recrystallized from ethyl acetate / petroleum ether (1:1 by volume) to obtain 0.56 g of the compound represented by Formula 7, in a yield of 70.2%.

Claims

1. A method for preparing a compound represented by formula 7, characterized in that: The method comprises the following steps: in a solvent, in the presence of a catalyst and a silane halide reagent, subjecting the compound represented by Formula 6 to a cyclization reaction to obtain a compound represented by Formula 7; Among them, R 1 is isopropyl, allyl, benzyl or tert-butyl; The catalyst is indium halide; The molar ratio of the compound represented by Formula 6 to the catalyst is 1:1.15 to 1:4; The halosilane reagent is X is halogen, R a H, R b and R c are independently methyl or ethyl; The molar ratio of the compound represented by Formula 6 to the halosilane reagent is 1:10 to 1:2.

3.

2. The preparation method according to claim 1, wherein The preparation method meets one or more of the following conditions: (1) In the cyclization reaction, the R 1 is tert-butyl; (2) In the cyclization reaction, the solvent is a halogenated hydrocarbon solvent; (3) In the cyclization reaction, the catalyst is indium trichloride or indium tribromide; (4) In the cyclization reaction, in the halosilane reagent, X is Cl or Br; (5) In the cyclization reaction, the molar ratio of the compound represented by Formula 6 to the catalyst is 1:1.15, 1:2 or 1:3; (6) In the cyclization reaction, the molar ratio of the compound represented by Formula 6 to the halosilane reagent is 1:2.3 or 1:2.9; (7) In the cyclization reaction, the mass volume ratio of the compound represented by Formula 6 to the solvent is 10 g / L to 150 g / L; (8) In the cyclization reaction, the reaction temperature is room temperature to 110°C; (9) The cyclization reaction is carried out in an inert atmosphere; (10) The preparation method further comprises the following post-processing step: after the cyclization reaction is completed, water is added to separate the phases, extraction is performed, the organic phases are combined, washed, dried, and concentrated to obtain the compound of formula 7; Alternatively, the method further comprises recrystallizing in a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:1 to obtain the compound represented by formula 7; (11) The materials for the cyclization reaction are the compound represented by Formula 6, a catalyst, a silane halide reagent, and the solvent.

3. The preparation method according to claim 2, wherein The preparation method meets one or more of the following conditions: (1) In the cyclization reaction, the solvent is 1,2-dichloroethane; (2) In the cyclization reaction, the catalyst is indium trichloride; (3) In the cyclization reaction, X in the halosilane reagent is Cl; (4) In the cyclization reaction, the mass volume ratio of the compound represented by Formula 6 to the solvent is 20 g / L, 50 g / L or 100 g / L; (5) In the cyclization reaction, the reaction was maintained at room temperature for 4 hours after the reaction was started, and then heated to reflux for reaction; (6) The inert atmosphere is nitrogen or argon.

4. The preparation method according to claim 3, wherein The preparation method meets one or more of the following conditions: (1) The halosilane reagent is HSi(CH3)2Cl; (2) The heating to reflux condition is heating to 70-110°C.

5. The preparation method according to claim 4, wherein The heating to reflux condition is heating to 90°C.

6. The preparation method according to claim 1 or 2, characterized in that The preparation method further comprises the following steps: subjecting the compound represented by Formula 5-B to an amidation reaction with an acetylating agent in a solvent to obtain the compound represented by Formula 6; Among them, R 1 As shown in claim 1 or 2.

7. The preparation method according to claim 6, wherein The amidation reaction satisfies one or more of the following conditions: (1) In the amidation reaction, the solvent is an ether solvent; (2) In the amidation reaction, the acetylating agent is acetic acid and / or acetic anhydride; (3) In the amidation reaction, when the acetylating agent is acetic acid and acetic anhydride, the mass volume ratio of the compound represented by Formula 5-B to the acetic anhydride is 40 g / L to 150 g / L; (4) The temperature of the amidation reaction is 20°C to 30°C; (5) After the amidation reaction is completed, the following post-processing step is further included: after the reaction is completed, the reaction solution is filtered, neutralized, extracted, the organic phases are combined and washed, dried, and concentrated to obtain the compound represented by Formula 6; Alternatively, the method further comprises purifying the compound by ethyl acetate / petroleum ether column chromatography to obtain the compound represented by formula 6; (6) The materials for the amidation reaction are the compound represented by formula 5-B, the acetylating agent and the solvent.

8. The preparation method according to claim 7, wherein The amidation reaction satisfies one or more of the following conditions: (1) In the amidation reaction, the solvent is tetrahydrofuran; (2) In the amidation reaction, the acetylating agent is acetic acid and acetic anhydride; (3) In the amidation reaction, when the acetylating agent is acetic acid and acetic anhydride, the mass volume ratio of the compound represented by Formula 5-B to the acetic anhydride is 120 g / L; (4) The temperature of the amidation reaction is 30°C.

9. The preparation method according to claim 8, wherein The volume ratio of the acetic acid to the acetic anhydride is 1:0.1 to 1:

10.

10. The preparation method according to claim 9, wherein The volume ratio of the acetic acid to the acetic anhydride is 1:1 to 1:

3.

11. The preparation method according to claim 10, characterized in that The volume ratio of the acetic acid to the acetic anhydride is 3:

4.

12. The preparation method according to claim 6, wherein The preparation method further comprises the following steps: (1) In a solvent, in the presence of a base, the compound represented by formula 5 is subjected to a nitrosation reaction with isoamyl nitrite to obtain substance 5-A; In the nitrosation reaction, the base is an alkali metal alcoholate; (2) in the presence of a catalyst, subjecting the substance 5-A to a reduction reaction with a reducing agent to obtain the compound represented by the formula 5-B; In the reduction reaction, the catalyst of the reduction reaction is platinum carbon or palladium carbon; The reducing agent of the reduction reaction is a reducing gas; Among them, R 1 As shown in claim 6.

13. The preparation method according to claim 12, wherein The preparation method meets one or more of the following conditions: (1) In the nitrosation reaction, the solvent is an ether solvent; (2) In the nitrosation reaction, the reaction temperature is 0°C to -40°C; (3) The nitrosation reaction can be carried out in an inert atmosphere; (4) In the nitrosation reaction, the molar ratio of the isoamyl nitrite to the compound represented by Formula 5 is 2:1 to 1:1; (5) In the nitrosation reaction, the molar ratio of the base to the compound represented by Formula 5 is 2:1 to 1:1; (6) In the nitrosation reaction, the mass volume ratio of the compound represented by Formula 5 to the solvent is 5 g / L to 500 g / L; (7) The materials for the nitrosation reaction are the compound represented by Formula 5, isoamyl nitrite, a base, and the solvent; (8) In the reduction reaction, the reaction temperature is 20°C to 50°C; (9) In the reduction reaction, the mass ratio of the catalyst to the compound represented by Formula 5 is 1:3 to 1:10; (10) The pressure of the reduction reaction is 1 atm to 3 atm; (11) The reaction solution obtained after the nitrosation reaction in step (1) is directly involved in the reduction reaction in step (2) without post-treatment; (12) After the reduction reaction is completed, the reaction solution obtained is directly used in the amidation reaction according to claim 6 without post-treatment.

14. The preparation method according to claim 13, wherein The preparation method meets one or more of the following conditions: (1) In the nitrosation reaction, the solvent is tetrahydrofuran; (2) In the nitrosation reaction, the reaction temperature is -12°C to -40°C; (3) The inert atmosphere is nitrogen or argon; (4) In the nitrosation reaction, the base is potassium tert-butoxide; (5) In the nitrosation reaction, the molar ratio of the isoamyl nitrite to the compound represented by Formula 5 is 1.4:1, 1.8:1 or 1.1:1; (6) In the nitrosation reaction, the molar ratio of the base to the compound represented by Formula 5 is 1.5:1, 1.3:1 or 1.1:1; (7) In the nitrosation reaction, the mass volume ratio of the compound represented by Formula 5 to the solvent is 50 g / L; (8) In the reduction reaction, the reaction temperature is 30°C to 40°C; (9) In the reduction reaction, the catalyst for the reduction reaction is 5% platinum on carbon; (10) In the reduction reaction, the mass ratio of the catalyst to the compound represented by Formula 5 is 1:10, 2:10 or 3:10; (11) The reducing agent of the reduction reaction is hydrogen; (12) The pressure of the reduction reaction is 1 atm or 2 atm.

15. The preparation method according to claim 14, wherein In the nitrosation reaction, the reaction temperature is -20°C.

16. The preparation method according to claim 12, wherein The preparation method further comprises the following steps: in a solvent, in the presence of a catalyst or a catalyst and a ligand, and in the presence of a base, coupling the compound represented by Formula 4 with the enoate represented by Formula (I) to obtain the compound represented by Formula 5; Among them, R 1 As described in claim 12.

17. The preparation method according to claim 16, wherein The coupling reaction satisfies one or more of the following conditions: (1) In the coupling reaction, the solvent is an ether solvent or a mixed solvent of an ether solvent and water; (2) In the coupling reaction, when the solvent is a mixed solvent of an ether solvent and water, the volume ratio of the ether solvent to the water is 1:1 to 10:1; (3) In the coupling reaction, the mass volume ratio of the compound represented by Formula 4 to the solvent is 100 g / L to 200 g / L; (4) In the coupling reaction, the catalyst is a transition metal catalyst; (5) In the coupling reaction, the ligand is a phosphine ligand; (6) The mass ratio of the ligand to the transition metal catalyst is 1:1 to 4:1; (7) In the coupling reaction, the mass ratio of the catalyst to the compound represented by Formula 4 is 1:100 to 5:100; (8) In the coupling reaction, the base is an organic base; (9) In the coupling reaction, the molar ratio of the compound represented by Formula 4 to the base is 1:1 to 1:5.5; (10) In the coupling reaction, the enoate represented by formula (I) is selected from tert-butyl 3-butenoate, isopropyl 3-butenoate, allyl 3-butenoate and benzyl 3-butenoate; (11) In the coupling reaction, the molar ratio of the compound represented by Formula 4 to the enoate represented by Formula (I) is 1:1.2 to 1:2.0; (12) In the coupling reaction, the reaction temperature is 50°C to 65°C; (13) In the coupling reaction, the reaction is carried out in an inert atmosphere; (14) After the coupling reaction is completed, the following post-treatment step is further included: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, washed, the filtrate is collected and washed, dried, and concentrated to obtain the compound represented by formula 5; Alternatively, the method further comprises recrystallizing in a mixed solvent of ethyl acetate / petroleum ether in a volume ratio of 1:15 to obtain the compound represented by formula 5; (15) The materials for the coupling reaction are the compound represented by formula 4, the enoate represented by formula (I), a base, a catalyst, a ligand, and the solvent.

18. The preparation method according to claim 17, wherein The coupling reaction satisfies one or more of the following conditions: (1) In the coupling reaction, the ether solvent is tetrahydrofuran; (2) In the coupling reaction, when the solvent is a mixed solvent of an ether solvent and water, the volume ratio of the ether solvent to the water is 4:1, 5:1 or 4.7:1; (3) In the coupling reaction, the mass volume ratio of the compound represented by Formula 4 to the solvent is 111.1 g / L to 164.7 g / L; (4) In the coupling reaction, the catalyst is palladium acetate; (5) In the coupling reaction, the ligand is tri-o-tolylphosphine; (6) The mass ratio of the ligand to the transition metal catalyst is 8:3 to 55:23; (7) In the coupling reaction, the mass ratio of the catalyst to the compound represented by Formula 4 is 2.5:100, 1.6:100 or 3.8:100; (8) In the coupling reaction, the base is diisopropylethylamine; (9) In the coupling reaction, the molar ratio of the compound represented by Formula 4 to the base is 1:4.4, 1:3.1 or 1:2.9; (10) In the coupling reaction, the enoate represented by formula (I) is tert-butyl 3-butenoate; (11) In the coupling reaction, the molar ratio of the compound represented by Formula 4 to the enoate represented by Formula (I) is 1:1.8 or 1:1.9; (12) In the coupling reaction, the reaction temperature is 50°C or 60°C; (13) In the coupling reaction, the inert atmosphere is nitrogen or argon.

19. The preparation method according to claim 18, characterized in that The coupling reaction satisfies one or more of the following conditions: (1) The mixed solvent of the ether solvent and water is a mixed solvent of tetrahydrofuran and water; (2) In the coupling reaction, the mass volume ratio of the compound represented by Formula 4 to the solvent is 133.3 g / L.

20. The preparation method according to claim 16, wherein The preparation method further comprises the following steps: performing a halogenation reaction on 2-fluoro-4-nitrotoluene and an iodine reagent in a solvent to obtain a compound represented by formula 4; 21. The preparation method according to claim 20, characterized in that The halogenation reaction satisfies one or more of the following conditions: (1) In the halogenation reaction, the solvent is concentrated sulfuric acid; (2) In the halogenation reaction, the mass volume ratio of the 2-fluoro-4-nitrotoluene to the solvent is 50 g / L to 200 g / L; (3) In the halogenation reaction, the iodine reagent is a combination of periodic acid and iodine molecules; (4) In the halogenation reaction, when the iodine reagent is a combination of periodic acid and iodine molecules, the molar ratio of the periodic acid to the iodine molecules is 3.1:10 to 3.5:10; (5) The iodine reagent is prepared by the following method, which comprises the following steps: adding sodium periodate to a mixed solution of concentrated sulfuric acid and iodine molecules, and mixing to obtain the iodine reagent; Wherein, the temperature during the addition is 0°C to 20°C; the temperature during the mixing is 20°C to 40°C; (6) In the halogenation reaction, the molar ratio of the 2-fluoro-4-nitrotoluene to the iodine molecules in the iodination reagent is 2.5:1 to 1.3:1; (7) In the halogenation reaction, the reaction temperature is 20°C to 40°C; (8) After the halogenation reaction is completed, the following post-treatment step is further included: after the reaction is completed, the reaction solution is poured into water containing sodium thiosulfate to quench, filtered, the filter cake is washed, and dried to obtain the compound represented by formula 4; (9) In the halogenation reaction, the reaction materials are the 2-fluoro-4-nitrotoluene, the sodium periodate and iodine molecule composition and the solvent.

22. The preparation method according to claim 21, wherein The halogenation reaction satisfies one or more of the following conditions: (1) In the halogenation reaction, the mass volume ratio of the 2-fluoro-4-nitrotoluene to the solvent is 200 g / L, 100 g / L or 80 g / L; (2) In the halogenation reaction, when the iodine reagent is a composition of periodic acid and iodine molecules, the molar ratio of the periodic acid to the iodine molecules is 3.3:10; (3) The iodine reagent is prepared by the following method, which comprises the following steps: adding sodium periodate to a mixed solution of concentrated sulfuric acid and iodine molecules, and mixing to obtain the iodine reagent; Wherein, the temperature during the addition is 5 to 10°C; the temperature during the mixing is 25 to 30°C; (4) In the halogenation reaction, the molar ratio of the 2-fluoro-4-nitrotoluene to the iodine molecules in the iodination reagent is 2.1:1 to 1.3:1; (5) In the halogenation reaction, the reaction temperature is 25°C to 30°C.

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