Preparation method of 1, 1-bis (4-fluorophenyl)-2-acetone

Abstract

The invention discloses a preparation method of 1, 1-bis (4-fluorophenyl)-2-acetone and a preparation method of the 1, 1-bis (4-fluorophenyl)-2-acetone. The invention provides a preparation method of a compound 4, which comprises the following steps: carrying out condensation reaction on a compound 3 and Meldrum's acid in a first solvent in the presence of a condensing agent to obtain the compound 4; wherein the condensing agent is pivaloyl chloride or N, N-carbonyldiimidazole, and when the condensing agent is pivaloyl chloride, the condensation reaction is carried out in the presence of alkali and a catalyst. Compared with the prior art, the method has one or more characteristics as follows: the used production raw materials are low in cost, the production process is more environment-friendly, the yield is high, and the method is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical technology, and in particular, relates to a method for preparing 1,1-di(4-fluorophenyl)-2-propanone. Background Art

[0002] Florylpicoxamid is a second-generation pyridine amide fungicide developed by Dow AgroSciences. This product can be used in multiple growth stages of crops and can improve crop yield and quality. The structural formula of Florylpicoxamid is shown in Formula A below.

[0003]

[0004] WO2018009618A1 reports a method for preparing Florylpicoxamid, and the specific process is as follows:

[0005]

[0006] Specifically, (R)-ethyl lactate reacts with p-fluorophenylmagnesium bromide to obtain compound H, which is reduced to compound K, which is then esterified with compound G to obtain compound L, which is then hydrolyzed and amidated with pyridinecarboxylic acid compound B to obtain Florylpicoxamid. Compound K (S)-1,1-di(4-fluorophenyl)-2-propanol is an important intermediate.

[0007] CN 111057725 A provides a method for preparing a Florylpicoxamid intermediate (S)-1,1-di(4-fluorophenyl)-2-propanol using 1,1-di(4-fluorophenyl)-2-propanone as a raw material. The structural formula of 1,1-di(4-fluorophenyl)-2-propanone is as follows:

[0008]

[0009] Among them, a preparation method of 1,1-bis(4-fluorophenyl)-2-propanone was also reported, and the specific preparation route is as follows:

[0010]

[0011] This method uses expensive ethyl lactate and 4-fluorophenylmagnesium bromide as production raw materials, which is costly and not suitable for industrial production. Therefore, it is very important to find a method for preparing 1,1-bis(4-fluorophenyl)-2-propanone with low cost and high efficiency that is suitable for industrial production. Summary of the invention

[0012] The technical problem to be solved by the present invention is that the cost of raw materials in the prior art is high and is not suitable for industrial production. The present invention provides a method for preparing 1,1-bis(4-fluorophenyl)-2-propanone, which has one or more of the following characteristics: the cost of raw materials used is low, the production process is more environmentally friendly, the yield is high, and it is suitable for industrial production.

[0013] The first aspect of the present invention provides a method for preparing compound 4, comprising the following steps: in a first solvent, in the presence of a condensing agent, compound 3 and Michaelis acid undergo a condensation reaction to obtain compound 4;

[0014]

[0015] Wherein, the condensation agent is pivaloyl chloride (PivCl) or N,N-carbonyldiimidazole (CDI);

[0016] When the condensing agent is pivaloyl chloride, the condensation reaction is also carried out in the presence of a base and a first catalyst.

[0017] In a certain scheme of the preparation method, the definitions of certain technical features are as described below, and the definitions of other technical features are as described in any of the following schemes (hereinafter referred to as "in a certain scheme").

[0018] In a certain embodiment, when the condensing agent is N,N-carbonyldiimidazole, the reaction starting materials are the first solvent, the N,N-carbonyldiimidazole, the compound 3 and the Michaelis acid;

[0019] When the condensing agent is pivaloyl chloride, the reaction starting materials are the first solvent, the pivaloyl chloride, the base, the first catalyst, the compound 3 and the Michaelis acid.

[0020] In a certain embodiment, the preparation method of compound 4 may include the following specific steps:

[0021] When the condensing agent is pivaloyl chloride, the steps may be:

[0022] (1-1) mixing the first solvent, the compound 3, the Michaelis acid, the first catalyst and the base to obtain a mixed solution 1;

[0023] (1-2) mixing the mixed solution 1 with the pivaloyl chloride to carry out a condensation reaction to obtain the compound 4;

[0024] When the condensing agent is N,N-carbonyldiimidazole, the steps may be:

[0025] (2-1) mixing a first solvent, the compound 3 and the N,N-carbonyldiimidazole to react to obtain a mixed reaction solution 2;

[0026] (2-2) The mixed reaction solution 2 is mixed with the Michaelis acid to carry out a condensation reaction to obtain the compound 4.

[0027] In step (1-1), the mixing temperature may be less than 40°C, such as room temperature (25°C).

[0028] In step (1-2), the mixing may be performed by dropping the pivaloyl chloride into the mixed solution 1.

[0029] In step (1-2), the temperature of the condensation reaction may be 40 to 42°C, for example 40°C.

[0030] In step (1-2), the condensation reaction time may be 12 to 16 hours, for example 12 hours.

[0031] In step (2-1), the temperature of the mixing reaction may be 18 to 22°C, for example 20°C.

[0032] In step (2-1), the mixing reaction time may be 1-3 hours, for example 2 hours.

[0033] In step (2-2), the temperature of the condensation reaction may be 18 to 22°C, for example 20°C.

[0034] In one embodiment, the molar ratio of the compound 3 to the Michaelis acid can be 1:1-1:1.5, for example 1:1.

[0035] In a certain embodiment, the molar ratio of the compound 3 to the condensing agent can be 1:1-1:1.5, for example 1:1 or 1:1.1.

[0036] In a certain embodiment, the first solvent may be a halogenated hydrocarbon solvent, such as dichloromethane (DCM).

[0037] In a certain embodiment, the volume ratio of the molar amount of the compound 3 to the first solvent can be (0.5-1) mol:1L, for example, 0.75 mol:1L.

[0038] In a certain embodiment, the base can be an organic base, preferably N,N-diisopropylethylamine, triethylamine or N-methylmorpholine; for example, N,N-diisopropylethylamine.

[0039] In a certain embodiment, the molar ratio of the compound 3 to the base can be 1:2-1:3, for example 1:2.

[0040] In a certain embodiment, the first catalyst may be 4-dimethylaminopyridine.

[0041] In one embodiment, the molar ratio of the compound 3 to the first catalyst may be 1:(0.08-1.2), for example, 1:0.08.

[0042] In a certain embodiment, the preparation method of the compound 4 may also include: after the condensation reaction is terminated, performing a first post-treatment on the condensation reaction liquid to obtain the compound 4, and the first post-treatment includes: extracting, washing, concentrating, beating, filtering or drying the condensation reaction liquid. One or more.

[0043] In a certain embodiment, the solvent used for the slurrying may be an ether solvent, such as methyl tert-butyl ether.

[0044] The preparation method of the compound 4 may further include a preparation method of the compound 3, which comprises the following steps: in the presence of an acidic solvent and a second catalyst, the compound 1 and the compound 2 react to obtain the compound 3, and the reaction formula is shown below:

[0045]

[0046] In one embodiment, the acidic solvent may be an organic acid, such as acetic acid.

[0047] In one embodiment, the second catalyst may be sulfonic acid, preferably sulfuric acid, such as sulfuric acid with a concentration greater than or equal to 98%. The "sulfonic acid" refers to a group with the general formula R-SO3H, where R is a hydrocarbon group; the "hydrocarbon group" refers to a group containing only carbon and hydrogen atoms, such as hydrogen, methyl, ethyl, etc. The % is a mass percentage.

[0048] In a certain embodiment, the preparation method of compound 3 may include the following specific steps:

[0049] (3-1) mixing the compound 1, the compound 2 and the acidic solvent to obtain a mixed solution 3;

[0050] (3-2) mixing the mixed solution 3 with the second catalyst and reacting them to obtain the compound 3;

[0051] Preferably, in step (3-2), the mixing may be performed by dropping the second catalyst into the mixed solution 3.

[0052] In step (3-2), the mixing temperature may be 0 to 4°C, for example 0°C.

[0053] In a certain embodiment, the molar ratio of the compound 1 to the compound 2 may be (2-5):1, for example 2:1.

[0054] In a certain embodiment, the ratio of the molar amount of the compound 2 to the volume of the acidic solvent may be (2.5-5) mol:1L, for example, 3.3 mol:1L.

[0055] In a certain embodiment, the molar ratio of the second catalyst to the compound 2 may be (3-10):1, for example, 5:1.

[0056] In one embodiment, the reaction temperature may be 60-90°C, such as 85°C.

[0057] In a certain embodiment, the preparation method of the compound 3 may further include: after the reaction of step (3-2) is terminated, the reaction solution is subjected to a second post-treatment step to obtain the compound 3, wherein the second post-treatment step includes one or more of cooling, diluting, filtering, washing or drying;

[0058] Preferably, the cooling may be performed in batches (eg, twice), and the temperature after the cooling is preferably 0-4°C.

[0059] The first cooling is to cool the reaction solution obtained after the reaction is completed to room temperature, for example, it can be cooled to room temperature naturally or cooled to room temperature in a normal temperature water bath. Dilution is to dilute the reaction solution cooled to room temperature with water. The second cooling is slow cooling, and the cooling rate can be 1-5°C / min. The temperature after cooling is preferably 0-4°C. After the second cooling, it is necessary to keep warm for a period of time (for example, 2h) so that the solute is evenly precipitated.

[0060] In a certain embodiment, the second solvent used for the dilution is preferably water; the ratio of the volume of the second solvent to the sum of the volumes of the acidic solvent and the catalyst is preferably 1:(1.8-3).

[0061] The second aspect of the present invention provides a method for preparing compound 5, which comprises the following steps:

[0062] (4-1) Compound 4 is obtained according to the preparation method of compound 4 in any of the above schemes;

[0063] (4-2) In a third solvent, in the presence of an acid or at a high temperature, the compound 4 undergoes a decomposition reaction to obtain the compound 5; the high temperature is 100° C.-150° C.;

[0064]

[0065] In one embodiment, in step (4-2), when the decomposition reaction is carried out in the presence of an acid, the third solvent may be a ketone solvent, such as acetone; when the decomposition reaction is carried out at a high temperature, the third solvent may be an aromatic solvent, such as toluene.

[0066] In one embodiment, in step (4-2), the acid may be an inorganic acid, preferably hydrochloric acid, such as 10% hydrochloric acid. The % is a mass percentage.

[0067] In a certain embodiment, in step (4-2), when the decomposition reaction is carried out in the presence of an acid, the molar ratio of the compound 4 to the volume of the third solvent may be (1.10-3.60) mol:1L, for example, 1.19 mol:1L; when the decomposition reaction is carried out at a high temperature, the molar ratio of the compound 4 to the volume of the third solvent may be (0.45-1) mol:1L, for example, 0.55 mol:1L.

[0068] In a certain embodiment, the molar ratio of the compound 4 to the acid can be 1:(3.6-12), for example 1:6.8.

[0069] In a certain embodiment, in step (4-2), when the decomposition reaction is carried out in the presence of an acid, the temperature of the decomposition reaction may be 60-80°C, for example 60°C; the time of the decomposition reaction may be 3-6 hours, for example 5 hours; when the decomposition reaction is carried out at a high temperature, the high temperature is preferably 110°C; the time of the decomposition reaction may be 10-14 hours, for example 12 hours. At the same time, according to common sense in the art, the temperature should not exceed the reflux temperature of the solvent.

[0070] In a certain embodiment, the preparation method of the compound 5 may further include: after the decomposition reaction of step (4-2) is terminated, the decomposition reaction liquid is subjected to a third post-treatment to obtain the compound 5, and the third post-treatment step includes one or more of concentration, extraction, washing, drying and column chromatography. Concentration is to remove the third solvent. Extraction is to separate compound 5 from the reaction liquid after the third solvent is removed using an extractant (such as DCM). After extraction, compound 5 is enriched in the organic phase formed by the extractant. Washing is to remove residual impurities in the organic phase.

[0071] The third aspect of the present invention provides a method for preparing compound 5, which comprises the following steps: in a third solvent, in the presence of an acid or at a high temperature, compound 4 undergoes a decomposition reaction to obtain compound 5; the high temperature is 100° C.-150° C.;

[0072]

[0073] In one embodiment, the reaction conditions of the preparation method of compound 5 are as described above.

[0074] The fourth aspect of the present invention provides a method for preparing compound 5, comprising the following steps: in a fourth solvent, in the presence of an acid, subjecting compound 7 to acid hydrolysis to obtain compound 5;

[0075]

[0076] Wherein, R is methyl or ethyl.

[0077] In a certain embodiment, the fourth solvent may be a ketone solvent, such as acetone.

[0078] In a certain embodiment, the acid may be an inorganic acid, preferably hydrochloric acid or sulfuric acid, more preferably 10%-30% sulfuric acid or 5%-30% hydrochloric acid, for example 10% hydrochloric acid. The % is a mass percentage.

[0079] In one embodiment, the volume ratio of the molar amount of the compound 7 to the fourth solvent is (0.2-3.34) mol:1L, for example, 3.34 mol:1L.

[0080] In one embodiment, the volume ratio of the molar amount of the compound 7 to the acid can be (0.6-2) mol:1L; for example, 1.2 mol:1L.

[0081] In one embodiment, the acid hydrolysis temperature may be 100°C-120°C, for example 100°C.

[0082] In a certain embodiment, the preparation method of the compound 5 may further include: after the acid hydrolysis reaction is terminated, the acid hydrolysis reaction liquid is subjected to a fourth post-treatment step to obtain the compound 5, and the fourth post-treatment step includes one or more of concentration, extraction, washing, drying and column chromatography.

[0083] The preparation method of the compound 5 may further include a preparation method of the compound 7, which comprises the following steps: in a fifth solvent, compound 6 and compound 8 undergo a substitution reaction to obtain the compound 7;

[0084]

[0085] Wherein, R is methyl or ethyl.

[0086] In a certain embodiment, the fifth solvent may be a halogenated hydrocarbon solvent, an aromatic solvent, an ester solvent, an ether solvent or a nitrile solvent; the halogenated hydrocarbon solvent is preferably dichloromethane, chloroform or 1,2-dichloroethane, the aromatic solvent is preferably toluene or xylene, the ester solvent is preferably ethyl acetate, the ether solvent is preferably tetrahydrofuran, the nitrile solvent is preferably acetonitrile, and the solvent is preferably dichloromethane.

[0087] In a certain embodiment, the compound 8 can be dimethyl malonate or diethyl malonate, for example, dimethyl malonate.

[0088] In a certain embodiment, the volume ratio of the molar amount of the compound 6 to the fifth solvent may be (0.34-2) mol:1L, for example, 0.5 mol:1L.

[0089] In a certain embodiment, the molar ratio of the compound 6 to the compound 8 can be 1:(1-1.2), for example 1:1.

[0090] In a certain embodiment, the substitution reaction is also carried out in the presence of a base, and the base can be one or both of an organic base or an inorganic base. The organic base is preferably triethylamine, diisopropylethylamine, diisobutylamine or pyridine, and the inorganic base is preferably sodium hydroxide, potassium carbonate or sodium carbonate. The base is preferably an organic base, and more preferably triethylamine.

[0091] In a certain embodiment, the substitution reaction is also carried out in the presence of a metal chloride, preferably magnesium chloride.

[0092] In one embodiment, the preparation method of compound 7 may include the following specific steps:

[0093] (1) mixing the compound 8, the base, the metal chloride and a portion of the fifth solvent to obtain a mixed solution 4;

[0094] (2) mixing the compound 6 with the rest of the fifth solvent to obtain a mixed solution 5;

[0095] (3) mixing the mixed solution 4 and the mixed solution 5, and performing a substitution reaction to obtain the compound 7;

[0096] Preferably, in step (3), the mixing is performed by dropping the mixed solution 5 into the mixed solution 4, and the mixing temperature is preferably 0°C.

[0097] In one embodiment, the temperature of the substitution reaction can be 10°C-30°C, for example 20°C.

[0098] The preparation method of the compound 5 may further include a preparation method of the compound 6, which comprises the following steps: in a sixth solvent, the compound 3 is subjected to an acyl chlorination reaction with an acyl chlorination agent to obtain the compound 6;

[0099]

[0100] In a certain embodiment, the sixth solvent may be an aromatic solvent, a halogenated hydrocarbon solvent or a nitrile solvent. The aromatic solvent is preferably toluene or xylene, the halogenated hydrocarbon solvent is preferably chloroform, dichloromethane or 1,2-dichloroethane, the nitrile solvent is preferably acetonitrile, and the solvent is preferably toluene.

[0101] In a certain embodiment, the acyl chlorination agent can be thionyl chloride, triphosgene (bis(trichloromethyl) carbonate), oxalyl chloride, phosphorus trichloride or phosphorus pentachloride, such as thionyl chloride.

[0102] In a certain embodiment, the volume ratio of the molar amount of the compound 3 to the sixth solvent may be (1.1-3.34) mol:1L, for example, 1.25 mol:1L.

[0103] In one embodiment, the molar ratio of the compound 3 to the acyl chloride reagent may be 1:(1.2-1.5), for example 1:1.5.

[0104] In a certain embodiment, the temperature of the chlorination reaction may be 20°C-100°C; when the chlorination reagent is oxalyl chloride, the temperature of the chlorination reaction is preferably 20°C-30°C; when the chlorination reagent is thionyl chloride, triphosgene, phosphorus trichloride or phosphorus pentachloride, the temperature of the chlorination reaction is preferably 80°C-100°C, for example 100°C.

[0105] In one embodiment, in the method for preparing compound 6, after the acyl chlorination reaction is completed, the reaction solution is concentrated and directly used for the substitution reaction as described above to prepare compound 7.

[0106] The preparation method of the compound 5 may further include a preparation method of the compound 3, which comprises the following steps: in the presence of an acidic solvent and a second catalyst, the compound 1 and the compound 2 react to obtain the compound 3;

[0107]

[0108] In one embodiment, the reaction conditions of the preparation method of compound 3 are as described above.

[0109] The present invention provides a compound 7-1 as shown below;

[0110]

[0111] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0112] In the present invention, "room temperature" means "20 to 40°C", for example, 25°C.

[0113] The reagents and raw materials used in the present invention are commercially available.

[0114] The positive progressive effect of the present invention is that the present invention has one or more of the following characteristics: the cost of using raw materials is low, the production process is more environmentally friendly, the yield is high, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 This is the 1H NMR spectrum of compound 3.

[0116] Figure 2 The HPLC graph of compound 3. Parameters: PDAMulti 1 210nm, 4nm. The same applies to the following HPLC graphs.

[0117] Figure 3 This is the HPLC chart of compound 1.

[0118] Figure 4 This is the HPLC chart of compound 2.

[0119] Figure 5 This is the 1H NMR chart of compound 4.

[0120] Figure 6 This is the HPLC chart of compound 4.

[0121] Figure 7 This is the HPLC chart of compound 4 reference substance.

[0122] Figure 8 This is the 1H NMR spectrum of compound 5.

[0123] Fig. 9 This is the HPLC chart of compound 5.

[0124] Fig.10 This is the HPLC chart of compound 5 reference substance.

[0125] Fig.11 This is the 1H NMR chart of compound 7-1.

[0126] Fig.12 It is the HPLC chart of compound 7-1.

[0127] Fig.13 This is the MS / MS spectrum of compound 7-1. DETAILED DESCRIPTION

[0128] To further illustrate the technical means and effects of the present invention, the following is a detailed description in conjunction with the accompanying drawings and preferred embodiments of the present invention. The experimental methods in the following examples that do not specify specific conditions are selected according to conventional methods and conditions, or according to the product specifications. Reagents that do not specify specific sources are conventional reagents purchased from the market. The following examples are used to further describe the present disclosure, but these examples are not intended to limit the scope of the present disclosure.

[0129] HPLC detection method:

[0130] The concentration of the product (1,1-bis(4-fluorophenyl)-2-propanone) in the reaction solution was detected by high performance liquid chromatography (HPLC). The specific analysis method is as follows:

[0131] Chromatographic column: Agilent Eclipse plus C18 (3.5 μm, 150 × 4.6 mm);

[0132] Mobile phase: 0.1% TFA aqueous solution as mobile phase A, 0.1% TFA acetonitrile solution as mobile phase B, gradient elution according to the following program: 0 min (90% A + 10% B), 10 min (100% B), 11 min (100% B), 11.5 min (90% A + 10% B), 16 min (90% A + 10% B);

[0133] Detection wavelength: 210 nm; flow rate: 1.0 mL / min; column temperature: 30°C.

[0134] Column purification method: Flash Column Silica column chromatography, flow rate 40 mL / min, petroleum ether: ethyl acetate (PE / EA) = 50 / 1 (v:v) elution for 5 min to remove impurities with less polarity. Petroleum ether: ethyl acetate (PE / EA) = 10 / 1 (v:v) elution for 10 min to obtain compound 5.

[0135] Compound 1 and compound 2 were purchased from Shanghai Adamas Reagent Co., Ltd.

[0136] The various compounds involved in the invention are shown in Table 1 below:

[0137] Table 1 Summary of various compounds involved in the present invention

[0138]

[0139] Example 1 Synthesis of crude product of the synthetic intermediate compound 3 of 1,1-bis(4-fluorophenyl)-2-propanone

[0140] This embodiment provides a method for synthesizing a crude product of the synthetic intermediate compound 3 of 1,1-di(4-fluorophenyl)-2-propanone, and the reaction equation is as follows:

[0141]

[0142] In this embodiment, the reaction conditions are screened, as shown below:

[0143] Example 1-1

[0144] The synthesis method of the crude compound 3 of Example 1-1 comprises the following steps:

[0145] In a 250mL single-necked flask, add 14.8g of compound 2 (glyoxylic acid; 0.1mol, in the form of a 50wt% aqueous solution) and 19.2g of compound 1 (fluorobenzene; 0.2mol), add 60mL of acetic acid (AcOH; 100%), stir and dissolve, and cool to 0°C. Slowly drop 50mL of 98% (mass percentage concentration) concentrated sulfuric acid into the single-necked flask; after the addition is complete, heat to 85°C and react for 12h. Then take the reaction solution and analyze it by thin-layer chromatography (TLC), petroleum ether: ethyl acetate (PE / EA) = 3 / 1 (v:v). TLC results show that compound 1 has been converted. At this time, cool the reaction solution to room temperature (25°C). Dilute with 50mL of water, then slowly drop to 0°C and keep warm for 2h, during which brown solids precipitate. After filtering out the solvent, a filter cake was obtained, which was washed twice with 20 mL of water, and then dried at 60°C to obtain 22 g of crude compound 3 (in solid form). The crude compound 3 did not need to be purified and was directly used as a raw material for the next step of the reaction. The structure of compound 3 was confirmed by hydrogen nuclear magnetic resonance spectroscopy. The 1H NMR spectrum of compound 3 is shown in FIG. Figure 1 As shown, the characterization results are as follows: 1H NMR (400 MHz, CDCl) δ 9.0 (b, 1H), 7.31-7.28 (m, 4H), 7.06-7.02 (m, 4H), 5.03 (s, 1H).

[0146] In Example 1-1, the HPLC chart of the crude compound 3 is as follows: Figure 2 As shown, the HPLC diagram of compound 1 reference substance is as follows Figure 3 As shown, the HPLC diagram of compound 2 reference substance is as follows Figure 4 shown.

[0147] It was determined that the purity of the crude compound 3 of Example 1-1 was 84.8%, the content of isomeric impurities was 13.0%, and the yield of compound 3 was 75.23%. The two fluorine atoms of compound 3 are respectively connected to the para position of the benzene ring. If any of the two fluorine atoms are not connected to the para position of the benzene ring, but to the ortho position or meta position of the benzene ring, it is an isomeric impurity.

[0148] In this example, the purity and isomeric impurity content of compound 3, one of the target products, were calculated by comparing the relative peak areas of the respective standard spectra. Figure 2The retention time in the HPLC spectrum is 21.906min for compound 3 (the fluorine atoms in the two fluorobenzene substituents are both in the para position), and the retention time is 17.335min and the retention time is 18.485min for the two main isomeric impurities of compound 3. The calculation method of the yield of the target product is: yield = actual production amount of the target product (compound 3 in this embodiment) ÷ theoretical production amount of the target product × 100% = actual production amount of the crude target product (compound 3 in this embodiment) × purity of the crude target product ÷ theoretical production amount of the target product × 100%. The following examples are calculated in the same way.

[0149] Example 1-2

[0150] Compared with Example 1-1, the difference of Example 1-2 is that after the temperature is lowered to 0° C., 10 mL of concentrated sulfuric acid is slowly added dropwise to the single-necked flask. The remaining steps and parameters of Example 1-2 are the same as those of Example 1-1.

[0151] The reaction solution obtained after 12 hours of reaction was subjected to TLC analysis. The TLC results showed that compound 1 had been completely converted, but the target product (compound 3) was basically not produced, and the purity of the crude compound 3 could not be calculated. In addition, the content of the isomeric impurities produced was also relatively high.

[0152] Examples 1-3

[0153] Compared with Example 1-1, the difference of Example 1-3 is that after the temperature is lowered to 0° C., 30 mL of concentrated sulfuric acid is slowly added dropwise to the single-necked flask. The remaining steps and parameters of Example 1-3 are the same as those of Example 1-1.

[0154] The reaction solution obtained after 12 h of reaction was subjected to TLC analysis. The TLC results showed that compound 1 had been completely converted and some target product (compound 3) was generated, but the content of isomeric impurities was still high.

[0155] Examples 1-4

[0156] Compared with Example 1-1, the difference of Example 1-4 is that after the temperature is lowered to 0° C., 90 mL of concentrated sulfuric acid is slowly added dropwise to the single-necked flask. The remaining steps and parameters of Example 1-4 are the same as those of Example 1-1.

[0157] The reaction solution obtained after 12 hours of reaction was subjected to TLC analysis. The TLC results showed that the conversion of compound 1 was complete, the purity of the crude compound 3 was 79.6%, the content of isomeric impurities was 13.3%, and the yield of compound 3 was 69.18%.

[0158] Table 2 Comparison of reaction conditions of Examples 1-1 to 1-4

[0159]

[0160] In Table 2, the amount of acetic acid added is 60 mL. Yield of compound 3 = actual amount of crude compound 3 × purity of crude compound 3 ÷ theoretical amount of compound 3 × 100%. The theoretical amount of compound 3 is calculated based on the added molar amount of compound 2. In this reaction, the added molar amount of compound 1 needs to be greater than the added molar amount of compound 2, otherwise isomer impurities are likely to be generated.

[0161] According to the results of Example 1-1 to Example 1-4, when the addition amount of concentrated sulfuric acid is low, the target product generation amount is little or no, and the amount of impurities is more. But when the addition amount of concentrated sulfuric acid is 50mL, the purity of the crude product of Compound 3 can reach more than 84.8%, meeting the requirements of industrial production. When the addition amount of concentrated sulfuric acid is further increased, the purity and yield of the crude product of Compound 3 are reduced instead. It can be seen that concentrated sulfuric acid, as a strong protonic acid, can help fluorobenzene to combine with glyoxylic acid in the para position. But other experimental data of the inventor prove that if the addition amount of concentrated sulfuric acid is too large (for example, when 150mL), then concentrated sulfuric acid will cause dehydration carbonization (Carbonation) of raw materials and products, thereby causing the generation of other types of impurities except isomeric impurities. Therefore, when the addition amount of acetic acid is 60 mL, the addition amount of concentrated sulfuric acid is appropriately within the range of 50 mL to 120 mL, and at this time, the ratio of the addition amount of concentrated sulfuric acid (mL) to the addition amount of acetic acid (mL) is within the range of (0.83-2):1.

[0162] In addition, the inventors have further proved through experiments that when the amount of acetic acid added in the reaction system increases, the amount of concentrated sulfuric acid added can be increased according to the above ratio. However, the ratio of the amount of acetic acid added (mL) to the molar amount of glyoxylic acid added (mol) is preferably in the range of 600-1000mL:1mol.

[0163] Examples 1-5

[0164] Compared with Example 1-1 (adding concentrated sulfuric acid and heating to 85° C. for 12 h), Example 1-5 is different in that after slowly adding 50 mL of concentrated sulfuric acid, the temperature is raised to 50° C. and then reacted for 12 h. The remaining steps and parameters of Example 1-5 are the same as those of Example 1-1.

[0165] The reaction solution obtained after 12 hours of reaction was subjected to TLC analysis. The TLC results showed that compound 1 had been completely converted, but more impurities were generated. After drying at 60°C, 15g of crude compound 3 (solid form) was obtained. It was determined that the purity of the crude compound 3 obtained in Example 1-5 was 67.1%, the content of isomeric impurities was 31.6%, and the yield of compound 3 was 40.59%.

[0166] It can be seen that when the temperature after adding concentrated sulfuric acid is low, the amount of isomer impurities produced by the reaction at a lower temperature is greater. Further experiments show that after adding acetic acid and concentrated sulfuric acid, the reaction temperature is suitable in the range of 60-90°C.

[0167] Example 2 Preparation of 1,1-bis(4-fluorophenyl)-2-propanone using crude compound 3 as raw material

[0168] This embodiment provides a method for preparing 1,1-bis(4-fluorophenyl)-2-propanone, and the reaction equation is as follows:

[0169]

[0170] The preparation method of this embodiment comprises the following steps:

[0171] 2.1 Add 40 mL of dichloromethane (DCM; used as solvent) to a 250 mL single-necked flask, and then add 8.78 g of crude compound 3 (containing 0.03 mol of compound 3; obtained by the method of Example 1-1), 4.32 g of Michaelis acid (0.03 mol; molecular weight 144.125), 0.29 g of 4-dimethylaminopyridine (DMAP; molecular weight 122.168; 2.4 mmol; used as a catalyst) and 7.76 g of N,N-diisopropylethylamine (DIPEA; molecular weight 129.25; 0.06 mol; used to neutralize the acid generated during the reaction), stir and dissolve to obtain a mixed solution. Keep the temperature of the mixed solution below 40°C, and then slowly add 3.98 g of pivaloyl chloride (PivCl; 0.033 mol, equivalent to 1.1 eq of the molar amount of substrate compound 3; used as a condensing agent for activating acidic substances) to the mixed solution. After the addition is completed, the temperature is raised to 40°C and the reaction is carried out for 12 hours. The reaction solution obtained after the reaction for 12 hours is subjected to TLC analysis, and TLC (PE / EA=3 / 1) shows that the conversion of compound 3 is complete. The temperature is lowered to 20°C; after adding 40mL of deionized water, the phases are separated into an aqueous phase and a first organic phase. The aqueous phase is extracted with 30mL of DCM to obtain a second organic phase. The first organic phase and the second organic phase are combined, washed with 30mL of brine, and then dried and concentrated with anhydrous sodium sulfate to obtain a solid. The solid is slurried with 10mL of methyl tert-butyl ether (MTBE); 11.45g of white solid compound 4 crude product is filtered to obtain a purity of 78.1%, and the single-step yield of compound 4 from compound 3 is 79.6%.

[0172] The structure of the crude compound 4 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, wherein the 1H NMR of compound 4 is as follows Figure 5 The characterization results are shown below.1 H NMR (400MHz,CDCl3)7.31-7.26(m,4H),7.04-7.00(m,4H),6.77(s,1H),1.70(s,6H). The HPLC chart of crude compound 4 is shown in Figure 6 As shown, the HPLC diagram of compound 4 reference substance is as follows Figure 7 shown.

[0173] 2.2 Add 11.45g of crude compound 4 obtained in step 2.1 to a 100mL single-necked flask, add 20mL of acetone to dissolve; add 50mL of 10% (mass percentage concentration) dilute hydrochloric acid; heat to 60°C and react for 5h. The reaction solution obtained after 5h of reaction was subjected to TLC analysis, and TLC (PE / EA=3 / 1) showed that the conversion of compound 4 was complete; cool to 20°C and concentrate under reduced pressure to remove acetone. The remaining aqueous phase obtained after removing acetone was extracted twice with 30mL of DCM. The organic phases obtained after the two extractions were combined and washed with 30mL of brine, and then dried over anhydrous sodium sulfate. The organic phases were concentrated and dried to obtain crude compound 5, which was purified by column to obtain 6.20g of compound 5 product, with a purity of 80.08%. The single-step yield of compound 5 generated from compound 4 was 84.5%. The two-step total yield of compound 5 generated from compound 3 was 67.26%. The HPLC graph of compound 5 is shown in the figure below. Fig. 9 As shown, the reference compound 5 is shown in Fig.10 The retention time of compound 5 is 9.370 min.

[0174] The product structure of compound 5 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, where the 1H NMR of compound 5 is as follows Figure 8 The characterization results are shown below: 1H NMR (400 MHz, CDCl3) 7.20-7.16 (m, 4H), 7.05-7.01 (m, 4H), 5.09 (s, 1H), 2.25 (s, 3H).

[0175] Example 3 Preparation of 1,1-bis(4-fluorophenyl)-2-propanone using crude compound 3 as raw material

[0176] This embodiment provides a method for preparing 1,1-bis(4-fluorophenyl)-2-propanone, and the reaction equation is as follows:

[0177]

[0178] The preparation method of this embodiment comprises the following steps:

[0179] 3.1 Add 40mL DCM to a 250mL single-necked flask; add 8.78g crude compound 3 (containing 0.03mol of compound 3; obtained by the method of Example 1-1) and 4.86g CDI (molecular weight 162.15; 0.03mol; used as a condensing agent) in turn and stir to dissolve. Keep the temperature of the mixed solution at 20℃ and stir to react for 2h. Add 4.32g of Michaelis acid (0.03mol), and then react at 20℃ for 12h. The reaction solution obtained after 12h of reaction was analyzed by TLC, and TLC (PE / EA=3 / 1) showed that the conversion of compound 3 was complete; after adding 40mL of water, the phases were separated into an aqueous phase and a first organic phase. The aqueous phase was extracted with 30mL DCM to obtain a second organic phase. The first organic phase and the second organic phase were combined, washed with 30mL of brine, and then dried with anhydrous sodium sulfate. After concentration, 12.51g of crude compound 4 was obtained as a solid, and the purity of the crude compound 4 was 79.43%. The single-step yield of compound 4 from compound 3 was 88.5%.

[0180] 3.2 12.51 g of crude compound 4 obtained in step 3.1 was prepared according to the method described in step 2.2 of Example 2 to obtain 6.93 g of compound 5. The purity of compound 5 was 80.63%. The single-step yield of compound 5 from compound 4 was 85.6%. The two-step total yield of compound 5 from compound 3 was 75.76%.

[0181] The structure of compound 5 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, and the characterization results are shown below: 1H NMR (400 MHz, CDCl3) 7.20-7.16 (m, 4H), 7.05-7.00 (m, 4H), 5.09 (s, 1H), 2.25 (s, 3H).

[0182] Comparing the experimental data of Example 2 and Example 3, it can be seen that for the reaction process of generating a crude compound 4 from a crude compound 3, the single-step yield (88.5%) of the reaction condition combination of CDI / Michael's acid is much higher than the single-step yield (79.6%) of the reaction condition combination of PivCl / Michael's acid / DMAP / DIPEA. In addition, comparing the experimental data of Example 2 and Example 3, it can be seen that for the reaction process of generating a crude compound 5 from a crude compound 3, the multi-step yield (75.76%) of the reaction condition combination of CDI / Michael's acid / HCl is also much higher than the single-step yield (67.26%) of the reaction condition combination of PivCl / Michael's acid / DMAP / DIPEA.

[0183] Example 4 Preparation of 1,1-bis(4-fluorophenyl)-2-propanone using crude compound 3 as raw material

[0184] This embodiment provides a method for preparing 1,1-bis(4-fluorophenyl)-2-propanone, and the reaction equation is as follows:

[0185]

[0186] The preparation method of this embodiment comprises the following steps:

[0187] 4.1 According to step 2.1 of Example 2, 11.40 g of crude compound 4 was obtained. The purity of crude compound 4 was 78.69%. The single-step yield of compound 4 from compound 3 was 79.9%.

[0188] 4.2 Add 11.40g of crude compound 4 obtained in step 4.1 into a 100mL single-mouth bottle, add 50mL of toluene to dissolve; heat to 110°C and react for 12h. The reaction solution obtained after 12h of reaction was subjected to TLC analysis, and TLC (PE / EA=3 / 1) showed that the conversion of compound 4 was complete; and the mixture was concentrated under reduced pressure to remove toluene. The residue after removing toluene was purified by column to obtain 5.79g of compound 5 product, and the purity of compound 5 product was 81.81%. The single-step yield of compound 5 product from compound 4 was 80.40%. The two-step total yield of compound 5 from compound 3 was 64.24%.

[0189] The structure of compound 5 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, and the characterization results are shown below: 1H NMR (400 MHz, CDCl3) 7.20-7.16 (m, 4H), 7.05-7.00 (m, 4H), 5.09 (s, 1H), 2.25 (s, 3H).

[0190] Comparing the experimental data of Example 2 and Example 4, it can be seen that after eliminating the error factor, for the reaction process of generating crude compound 5 from crude compound 4, the single-step yield of the reaction conditions using HCl is not much different from the single-step yield of the reaction conditions using toluene and heating. However, compared with the reaction conditions using toluene and heating at 110°C in Example 4, the reaction time of Example 2 using HCl and heating at 60°C is shortened by more than half, the reaction conditions are also milder, the requirements for reaction equipment are lower, and the equipment investment is less.

[0191] Example 5 Preparation of 1,1-bis(4-fluorophenyl)-2-propanone using crude compound 3 as raw material

[0192] This embodiment provides a method for preparing 1,1-bis(4-fluorophenyl)-2-propanone, and the reaction equation is as follows:

[0193]

[0194] The preparation method of this embodiment comprises the following steps:

[0195] 5.1 According to step 3.1 of Example 3, 12.72 g of crude compound 4 was obtained, and the purity of crude compound 4 was 79.37%. The single-step yield of compound 4 generated from compound 3 was 89.9%.

[0196] 5.2 According to step 4.2 of Example 4, 6.61 g of compound 5 was obtained, and the purity of compound 5 was 81.63%. The single-step yield of compound 5 generated from compound 4 was 81.3%. The two-step total yield of compound 5 generated from compound 3 was 73.09%.

[0197] The structure of compound 5 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, and the characterization results are shown below: 1H NMR (400 MHz, CDCl3) 7.20-7.16 (m, 4H), 7.05-7.00 (m, 4H), 5.09 (s, 1H), 2.25 (s, 3H).

[0198] The yield and purity of compound 5 of Examples 2 to 5 are shown in Table 3 below:

[0199] Table 3 Yield and purity of compound 5 in Examples 2 to 5

[0200]

[0201] In Table 3, the single step yield of compound 4 generated from compound 3 = the actual amount of crude compound 4 generated from crude compound 3 × the purity of crude compound 4 ÷ the theoretical amount of compound 4 × 100%. The theoretical amount of compound 4 is calculated based on the added molar amount of compound 3. The added molar amount of compound 3 = the actual amount of crude compound 3 × the purity of crude compound 3 ÷ the molecular weight of compound 3.

[0202] The single step yield of compound 5 generated from compound 4 = the actual amount of crude compound 5 generated from crude compound 4 × the purity of crude compound 5 / the theoretical amount of compound 5 × 100%. The theoretical amount of compound 5 is calculated based on the added molar amount of compound 4.

[0203] The total yield of the two steps of generating compound 5 from compound 3 = the single step yield of generating compound 4 from compound 3 × the single step yield of generating compound 5 from compound 4.

[0204] It can be seen from the experimental data in Table 3 that among Examples 2 to 5, the total yield of compound 5 in Example 3 is the highest.

[0205] Example 6 Preparation of 1,1-bis(4-fluorophenyl)-2-propanone using crude compound 3 as raw material

[0206]

[0207] The preparation method of this embodiment comprises the following steps:

[0208] 6.1 Add 50 mL of toluene to a 250 mL single-necked flask; add the crude compound 3 (17.56 g, 0.06 mol) obtained in Example 1-1 and SOCl2 (10.71 g, 0.09 mol) in sequence and stir to dissolve. Heat to 100 °C and react for 3 h; concentrate under reduced pressure and dry; dilute with 20 mL of DCM to obtain a solution of compound 6 for later use; take another 250 mL three-necked flask and add 100 mL of DCM, and add dimethyl malonate (7.93 g, 0.06 mol), MgCl2 (7.43 g, 0.078 mol, 1.3 eq) and TEA (15.2 g, 0.15 mol, 2.5 eq) in sequence, and cool to 0 °C. The solution of compound 6 was slowly added dropwise to a three-necked flask, and the temperature was raised to 20°C and kept for 2h; TLC (PE / EA=3 / 1) showed that the conversion of compound 3 was complete; 50mL of water was added to quench the reaction; pH was adjusted to 5 with 1M dilute hydrochloric acid; the phases were separated to form an organic phase and an aqueous phase. The aqueous phase was extracted with 30mL of DCM, the organic phases were combined, and washed with saturated brine; dried and preliminarily purified to obtain 26.07g of crude compound 7-1, and the purity of the crude compound 7-1 was 81.74%. The yield of compound 7-1 was 98%. The product structure and molecular weight of compound 7-1 were confirmed by nuclear magnetic resonance hydrogen spectrum and electrospray ionization mass spectrum, respectively. The characterization results of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, cdCl3) δ13.71 (d, J = 1.5Hz, 1H) 7.26-7.14 (m, 8H), 7.07-6.97 (m, 8H), 5.44 (s, 2H), 4.61 (s, 1H), 3.75 (s, 29H), 3.40 (s, 10H). The H NMR spectrum showed that compound 7-1 was a mixture of keto and enol forms. LCMS = m / z 361.00 [MH] - The 1HNMR of compound 7-1 is as follows Fig.11 As shown. The HPLC of compound 7-1 is as follows Fig.12 As shown, the retention time of compound 7-1 is 10.335min, and the MS / MS spectrum of compound 7-1 is as shown Fig.13 The eq of this example is relative to the molar amount of compound 3 (0.06 mol).

[0209] 6.2 Add 26.07 g of the crude compound 7-1 obtained in step 6.1 into a 100 mL single-mouth bottle, add 20 mL of acetone to dissolve; add dilute hydrochloric acid (50 mL, 10%); heat to 100 ° C and react for 5 h; TLC (PE / EA=3 / 1) shows that the conversion of compound 7-1 is complete; cool to 20 ° C; concentrate under reduced pressure to remove acetone; extract the remaining aqueous phase twice with 30 mL of DCM; combine the organic phases and wash with 30 mL of brine; then dry with anhydrous sodium sulfate and concentrate to obtain a solid crude compound 5; purify by column to obtain 14.65 g of compound 5 product. The purity of compound 5 product is 81.93%. Calculated by taking the crude compound 3 as the reaction starting material, the multi-step total yield of compound 5 generated from compound 3 is 83%.

[0210] The structure of compound 5 was confirmed by hydrogen nuclear magnetic resonance spectroscopy, and the characterization results are shown below: 1H NMR (400 MHz, CDCl3) 7.20-7.16 (m, 4H), 7.05-7.00 (m, 4H), 5.09 (s, 1H), 2.25 (s, 3H).

[0211] Example 6 has the characteristics of high yield, low cost of raw materials, and more environmentally friendly production process, and is suitable for industrial production. Example 3 has a higher yield, low reaction cost, milder reaction conditions, and is suitable for operation. In Example 2, pivaloyl chloride (PivCl) with a lower price is used to replace the expensive condensing agent in the prior art, and the reaction conditions are mild and the effect is better.

Claims

1. A method for preparing compound 4, characterized in that: The method comprises the following steps: in a first solvent, in the presence of a condensing agent, compound 3 and Michaelis acid undergo a condensation reaction to obtain compound 4; Wherein, the condensation agent is pivaloyl chloride or N,N-carbonyldiimidazole; When the condensation agent is pivaloyl chloride, the condensation reaction is also carried out in the presence of a base and a first catalyst; Preferably, the first solvent is a halogenated hydrocarbon solvent, such as dichloromethane; and / or, The molar ratio of the compound 3 to the Michaelis acid is 1:1-1:1.5, for example 1:1; and / or, The molar ratio of the compound 3 to the condensing agent is 1:1-1:1.5, for example 1:1 or 1:1.1; and / or, The volume ratio of the molar amount of the compound 3 to the first solvent is (0.5-1) mol:1L, for example 0.75 mol:1L; and / or, The preparation method of the compound 4 further comprises: after the condensation reaction is terminated, performing a first post-treatment on the condensation reaction liquid to obtain the compound 4; the first post-treatment comprises: performing one or more of extraction, washing, concentration, pulping, filtering or drying on the condensation reaction liquid; More preferably, the solvent used for the pulping is an ether solvent, such as methyl tert-butyl ether.

2. The method for preparing compound 4 according to claim 1, characterized in that: The condensing agent is pivaloyl chloride, and the preparation method of compound 4 comprises the following specific steps: (1-1) mixing the first solvent, the compound 3, the Michaelis acid, the first catalyst and the base to obtain a mixed solution 1; (1-2) mixing the mixed solution 1 with the pivaloyl chloride to carry out a condensation reaction to obtain the compound 4; Preferably, in step (1-1), the mixing temperature is less than 40°C, for example, 25°C; and / or, In step (1-1), the base is an organic base, preferably N,N-diisopropylethylamine, triethylamine or N-methylmorpholine; for example, N,N-diisopropylethylamine; and / or, In step (1-1), the molar ratio of the compound 3 to the base is 1:2-1:3, for example 1:2; and / or, In step (1-1), the first catalyst is 4-dimethylaminopyridine; and / or, The molar ratio of the compound 3 to the first catalyst is 1:(0.08-1.2), for example 1:0.08; and / or, In step (1-2), the mixing is to dropwise add the pivaloyl chloride into the mixed solution 1; and / or, In step (1-2), the temperature of the condensation reaction is 40 to 42°C, for example 40°C.

3. The method for preparing compound 4 according to claim 1, characterized in that: The condensing agent is N,N-carbonyldiimidazole, and the preparation method of compound 4 comprises the following specific steps: (2-1) mixing a first solvent, the compound 3 and the N,N-carbonyldiimidazole to react to obtain a mixed reaction solution 2; (2-2) mixing the mixed reaction solution 2 with the Michaelis acid to carry out a condensation reaction to obtain the compound 4; Preferably, in step (2-1), the temperature of the mixed reaction is 18 to 22°C, for example 20°C; In step (2-2), the temperature of the condensation reaction is 18 to 22°C, for example 20°C.

4. The method for preparing compound 4 according to any one of claims 1 to 3, characterized in that: The preparation method of the compound 4 further comprises the following steps: in the presence of an acidic solvent and a second catalyst, the compound 1 and the compound 2 react to obtain the compound 3, and the reaction formula is as follows: Preferably, the acidic solvent is an organic acid, such as acetic acid; and / or, The second catalyst is sulfonic acid, preferably sulfuric acid, such as sulfuric acid at a concentration greater than or equal to 98%; and / or, The molar ratio of the compound 1 to the compound 2 is (2-5):1, for example 2:1; and / or The ratio of the molar amount of the compound 2 to the volume of the acidic solvent is (2.5-5) mol:1L, for example 3.3 mol:1L; and / or The molar ratio of the second catalyst to the compound 2 is (3-10):1, for example, 5:1; and / or, The reaction temperature is 60-90°C, for example 85°C; and / or, The preparation method of compound 3 comprises the following specific steps: (3-1) mixing the compound 1, the compound 2 and the acidic solvent to obtain a mixed solution 3; (3-2) mixing the mixed solution 3 with the second catalyst and reacting them to obtain the compound 3; More preferably, in step (3-2), the mixing is to dropwise add the second catalyst into the mixed solution 3; and / or, In step (3-2), the mixing temperature is 0 to 4°C, for example 0°C; and / or, The preparation method of the compound 3 further comprises: after the reaction of step (3-2) is terminated, performing a second post-treatment on the reaction solution to obtain the compound 3, wherein the second post-treatment step comprises one or more of cooling, diluting, filtering, washing or drying; More preferably, the cooling is performed in batches, for example, twice, and the temperature after the cooling is preferably 0-4°C; And / or, the second solvent used for the dilution is preferably water; the ratio of the volume of the second solvent to the sum of the volumes of the acidic solvent and the catalyst is preferably 1:(1.8-3).

5. A method for preparing compound 5, characterized in that: It includes the following steps: (4-1) Compound 4 is obtained according to the preparation method of compound 4 according to any one of claims 1 to 4; (4-2) In a third solvent, in the presence of an acid or at a high temperature, the compound 4 undergoes a decomposition reaction to obtain the compound 5; the high temperature is 100° C.-150° C.; Preferably, the method for preparing the compound 5 further comprises: after the decomposition reaction in step (4-2) is terminated, performing a third post-treatment on the decomposition reaction liquid to obtain the compound 5; the third post-treatment comprises one or more of concentration, extraction, washing, drying and column chromatography.

6. The method for preparing compound 5 according to claim 5, characterized in that: When the decomposition reaction is carried out in the presence of the acid, the preparation method of the compound 5 satisfies one or more of the following conditions: In step (4-2), the third solvent is a ketone solvent, such as acetone; In step (4-2), the acid is an inorganic acid, preferably hydrochloric acid, such as 10% hydrochloric acid; In step (4-2), the molar ratio of the compound 4 to the volume of the third solvent is (1.10-3.60) mol:1L, for example, 1.19 mol:1L; In step (4-2), the molar ratio of the compound 4 to the acid is 1:(3.6-12), for example 1:6.8; In step (4-2), the temperature of the decomposition reaction is 60-80°C, for example 60°C.

7. The method for preparing compound 5 according to claim 5, characterized in that: When the decomposition reaction is carried out at the high temperature, the preparation method of the compound 5 satisfies one or more of the following conditions: In step (4-2), the third solvent is an aromatic solvent, such as toluene; In step (4-2), the molar ratio of the compound 4 to the volume of the third solvent is (0.45-1) mol:1L, for example 0.55 mol:1L; In step (4-2), the high temperature is 110°C.

8. A method for preparing compound 5, characterized in that: The method comprises the following steps: in a third solvent, in the presence of an acid or at a high temperature, compound 4 undergoes a decomposition reaction to obtain compound 5; the high temperature is 100° C.-150° C.; Preferably, the reaction conditions of the preparation method of compound 5 are as described in any one of claims 5-7.

9. A method for preparing compound 5, characterized in that: The method comprises the following steps: in a fourth solvent, in the presence of an acid, subjecting compound 7 to acid hydrolysis to obtain compound 5; Wherein, R is methyl or ethyl.

10. The method for preparing compound 5 according to claim 9, characterized in that: The preparation method of compound 5 satisfies one or more of the following conditions: The fourth solvent is a ketone solvent, such as acetone; The acid is an inorganic acid, preferably hydrochloric acid or sulfuric acid, more preferably 10%-30% sulfuric acid or 5%-30% hydrochloric acid, such as 10% hydrochloric acid; The volume ratio of the molar amount of the compound 7 to the fourth solvent is (0.2-3.34) mol:1L, for example, 3.34 mol:1L; The volume ratio of the molar amount of the compound 7 to the acid is (0.6-2) mol:1L, for example 1.2 mol:1L; The acid hydrolysis temperature is 100°C-120°C, for example 100°C; The preparation method of the compound 5 further comprises: after the acid hydrolysis reaction is terminated, performing a fourth post-treatment on the acid hydrolysis reaction liquid to obtain the compound 5, and the fourth post-treatment step comprises one or more of concentration, extraction, washing, drying and column chromatography.

11. The method for preparing compound 5 according to claim 9 or 10, characterized in that: The preparation method of compound 5 further comprises one or more of the following steps: (I) in a fifth solvent, compound 6 and compound 8 undergo a substitution reaction to obtain compound 7; Wherein, R is methyl or ethyl; (II) in a sixth solvent, compound 3 is subjected to an acyl chlorination reaction with an acyl chlorination agent to obtain compound 6; (III) in the presence of an acidic solvent and a second catalyst, compound 1 and compound 2 react to obtain compound 3; 12. The method for preparing compound 5 according to claim 11, characterized in that: The preparation method of compound 7 satisfies one or more of the following conditions: In step (I), the fifth solvent is a halogenated hydrocarbon solvent, an aromatic solvent, an ester solvent, an ether solvent or a nitrile solvent; the halogenated hydrocarbon solvent is preferably dichloromethane, chloroform or 1,2-dichloroethane, the aromatic solvent is preferably toluene or xylene, the ester solvent is preferably ethyl acetate, the ether solvent is preferably tetrahydrofuran, the nitrile solvent is preferably acetonitrile, and the solvent is preferably dichloromethane; In step (I), the compound 8 is dimethyl malonate or diethyl malonate, for example, dimethyl malonate; In step (I), the volume ratio of the molar amount of the compound 6 to the fifth solvent is (0.34-2) mol:1L, for example 0.5 mol:1L; In step (I), the molar ratio of the compound 6 to the compound 8 is 1:(1-1.2), for example 1:1; In step (I), the substitution reaction is also carried out in the presence of a base, the base is one or both of an organic base or an inorganic base, the organic base is preferably triethylamine, diisopropylethylamine, diisobutylamine or pyridine, the inorganic base is preferably sodium hydroxide, potassium carbonate or sodium carbonate, the base is preferably an organic base, more preferably triethylamine; In step (I), the substitution reaction is also carried out in the presence of a metal chloride, and the metal chloride is magnesium chloride; In step (I), the temperature of the substitution reaction is 10°C-30°C, for example 20°C; Preferably, in step (I), the preparation method of compound 7 comprises the following specific steps: (a) mixing the compound 8, the base, the metal chloride and a portion of the fifth solvent to obtain a mixed solution 4; (b) mixing the compound 6 with the rest of the fifth solvent to obtain a mixed solution 5; (c) mixing the mixed solution 4 and the mixed solution 5, and performing a substitution reaction to obtain the compound 7; More preferably, in step (c), the mixing is performed by dropping the mixed solution 5 into the mixed solution 4, and the mixing temperature is preferably 0°C.

13. The method for preparing compound 5 according to claim 11, characterized in that: The preparation method of compound 7 satisfies one or more of the following conditions: In step (II), the sixth solvent is an aromatic solvent, a halogenated hydrocarbon solvent or a nitrile solvent, the aromatic solvent is preferably toluene or xylene, the halogenated hydrocarbon solvent is preferably chloroform, dichloromethane or 1,2-dichloroethane, the nitrile solvent is preferably acetonitrile, and the solvent is preferably toluene; In step (II), the acyl chloride reagent is thionyl chloride, triphosgene, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride, such as thionyl chloride; In step (II), the volume ratio of the molar amount of the compound 3 to the sixth solvent is (1.1-3.34) mol:1L, for example, 1.25 mol:1L; In step (II), the molar ratio of the compound 3 to the acyl chloride reagent is 1:(1.2-1.5), for example 1:1.5; In step (II), the temperature of the chlorination reaction is 20°C-100°C; when the chlorination reagent is oxalyl chloride, the temperature of the chlorination reaction is preferably 20°C-30°C; when the chlorination reagent is thionyl chloride, triphosgene, phosphorus trichloride or phosphorus pentachloride, the temperature of the chlorination reaction is preferably 80°C-100°C, for example 100°C; In step (II), in the method for preparing compound 6, after the acyl chlorination reaction is completed, the reaction solution is concentrated and directly used for the substitution reaction as described above to prepare compound 7; The reaction conditions of step (III) are as described in claim 4.

14. A compound 7-1 as shown below;

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