A method for synthesizing heterocyclic compounds

Abstract

The present invention relates to a method for synthesizing a heterocyclic compound, and belongs to the field of pharmaceutical chemistry. The method for synthesizing the heterocyclic compound may include: a raw material is subjected to a Grignard reaction, and then subjected to condensation, and the resulting product reacts with a halogenating agent in the presence of an initiator, and then reacts and post-processes in the presence of a base to obtain the heterocyclic compound. The scheme of the present invention has the advantages of safety, environmental protection, low cost, high purity, high yield, etc., and is conducive to industrial production.

Description

Technical Field

[0001] The invention relates to the field of medicinal chemistry, and in particular to a method for synthesizing a heterocyclic compound. Background Art

[0002] Baloxavir marboxil is an innovative Cap-dependent endonuclease inhibitor used to treat influenza A and influenza B. The advantage of baloxavir is that it requires fewer doses and has a long-lasting efficacy; its chemical structure is as follows:

[0003]

[0004] Currently, there are few public disclosures on the synthesis methods of baloxavir and its intermediates. In the prior art, the intermediate for synthesizing baloxavir involves a heterocyclic compound, among which patent CN109311911A discloses a method for preparing the fragment intermediate 8-difluorodibenzo[b,e]thiaheptacyclopentane-11(6H)-ol (i.e., compound 6 in the following route).

[0005]

[0006] This patent involves two low-temperature sensitive reactions (the first step of the reaction needs to be cooled to -40°C), using LDA (lithium diisopropylamide) or directly preparing LDA (lithium diisopropylamide), and requires high operating and material storage conditions. In addition, the reagents and solvents required for the reaction must strictly remove moisture, and the conditions are harsh. The reagent thiophenol is used in the second step of the reaction. This product has a foul odor and is extremely toxic when inhaled. It has been included in the list of controlled chemicals-highly toxic chemicals. Its purchase and use are restricted, which is extremely harmful to production personnel and the environment. It places higher requirements on the construction of production plants and is not suitable for commercial production.

[0007] Patents CN 110105327 A and CN 109134428 A disclose a method for synthesizing 6 using compound 7 as a raw material, as shown in the following route:

[0008]

[0009] In this route, 2-bromomethyl-3,4-difluorobenzeneacetonitrile is used as raw material. On the one hand, the cyano group preparation involves highly toxic controlled products such as potassium cyanide and sodium cyanide. On the other hand, the cyano group route prepared by amide is longer, and the raw material price is very high. During industrial production, there is a problem that raw materials are not easy to obtain due to control, and the price is high. Although sodium thiophenolate is used instead of thiophenol, this route still inevitably produces thiophenol. Sodium thiophenolate also belongs to controlled chemicals at the same time.

[0010] The literature Organic Process Research & Development, 23 (12), 2716-2723; 2019, reported another synthesis route:

[0011]

[0012] This route uses 2-bromomethyl-3,4-difluorophenylacetonitrile (i.e., compound 8) as a raw material. Although diphenyl sulfide is used in the second step of the reaction, the odor is somewhat reduced compared to the thiophenol or sodium thiophenol used in the aforementioned route, there is still a stench of thiophenol during the operation, and it is still necessary to operate with caution to reduce toxic damage. In the fourth step, PPA (polyphthalamide) is used, which has a large equivalent, and a large amount of waste acid is generated in the post-processing, which is highly polluting and not conducive to industrial production.

[0013] In summary, the prior art for synthesizing heterocyclic compounds of baloxavir intermediates and analogs thereof has at least one of the following defects:

[0014] (1) Involving low-temperature sensitive reactions, the operation and material storage conditions require high standards;

[0015] (2) Water needs to be removed strictly and the conditions are harsh;

[0016] (3) The reaction contains highly toxic and smelly reagents, the purchase and use of which are regulated and pose a great threat to production personnel and the environment;

[0017] (4) The API is expensive;

[0018] (5) Post-treatment easily produces a large amount of waste acid, which causes serious pollution and is not conducive to industrial production.

[0019] Therefore, we still need a safe, environmentally friendly, low-cost, and easy-to-operate method for synthesizing baloxavir intermediates or their analogs. Summary of the invention

[0020] In order to solve the above problems, the present invention provides a method for preparing a baloxavir intermediate.

[0021] In a first aspect, the present invention provides a method for preparing a compound of formula (B), comprising:

[0022]

[0023] The compound of formula (A) undergoes a Grignard reaction with a Grignard reagent in a first reaction solvent under the protection of an inert gas, and then reacts with a compound of formula (F), and undergoes a first post-treatment to obtain a compound of formula (B), wherein R1 is selected from chlorine, bromine and iodine; and R5 is selected from methyl, ethyl, isopropyl, tert-butyl and carbonyl chloride.

[0024] The Grignard reagent comprises at least one selected from isopropylmagnesium chloride, isopropylmagnesium bromide, methylmagnesium bromide, methylmagnesium chloride and isopropylmagnesium chloride-lithium chloride. In some embodiments, the Grignard reagent is isopropylmagnesium chloride or isopropylmagnesium bromide.

[0025] The first reaction solvent includes at least one selected from tetrahydrofuran and methyltetrahydrofuran.

[0026] The temperature of the Grignard reaction is -10°C to 10°C. In some embodiments, the temperature of the Grignard reaction is -5°C to 5°C. In some embodiments, the temperature of the Grignard reaction is 0°C.

[0027] The temperature of the reaction with the compound of formula (F) is -10°C to 10°C. In some embodiments, the temperature of the reaction with the compound of formula (F) is -5°C to 5°C. In some embodiments, the temperature of the reaction with the compound of formula (F) is 0°C.

[0028] The molar ratio of the compound of formula (A) to the Grignard reagent can be 1:0.9-1:1.3. In some embodiments, the molar ratio of the compound of formula (A) to the Grignard reagent is 1:1-1.2. In some embodiments, the molar ratio of the compound of formula (A) to the compound of formula (F) is 1:0.9-1:1.3. In some embodiments, the molar ratio of the compound of formula (A) to the compound of formula (F) is 1:1-1.2.

[0029] The inert gas can be any suitable gas that does not participate in the reaction, such as nitrogen.

[0030] The first post-treatment comprises: quenching with water, separating the liquids, extracting with a first organic solvent, combining the organic layers, and distilling the combined organic layers under reduced pressure. The organic solvent is selected from ethyl acetate.

[0031] In a second aspect, the present invention provides a method for preparing a compound of formula (C), comprising:

[0032]

[0033] The compound of formula (B) undergoes a halogenation reaction with a halogenating agent in the presence of an initiator in a second reaction solvent, and undergoes a second post-treatment to obtain a compound of formula (C), wherein R2 is selected from chlorine, bromine or iodine.

[0034] The second reaction solvent includes at least one selected from dichloromethane, chloroform, carbon tetrachloride, petroleum ether, n-hexane, n-heptane, n-hexane, cyclohexane, heptane, 1,2-dichloroethane and ethyl acetate. In some embodiments, the second reaction solvent is dichloromethane, which is conducive to the reaction and the acquisition of the target product.

[0035] The initiator comprises at least one selected from benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, tert-butyl perbenzoate, tert-butyl pervalerate, methyl ethyl ketone peroxide, cyclohexanone peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, azobisisobutyronitrile and azobisisoheptanitrile. In some embodiments, the initiator is azobisisobutyronitrile or azobisisoheptanitrile, or a combination thereof, which is conducive to reaction control and conduction.

[0036] The halogenating agent includes at least one selected from N-bromosuccinimide, dibromohydantoin, bromine, N-chlorosuccinimide, and N-iodosuccinimide. In some embodiments, the halogenating agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, or a combination thereof.

[0037] The temperature of the halogenation reaction is 30°C-80°C. In some embodiments, the temperature of the halogenation reaction is 35°C-70°C. In some embodiments, the temperature of the halogenation reaction is 40°C-60°C. In some embodiments, the temperature of the halogenation reaction is 45°C-55°C.

[0038] The molar ratio of the compound of formula (B) to the initiator is 1:0.1-1:0.5. In some embodiments, the molar ratio of the compound of formula (B) to the initiator is 1:0.2-1:0.4.

[0039] The second post-treatment comprises: quenching with an aqueous sodium sulfite solution, separating the liquids, washing the organic phase with water, and concentrating the organic phase under reduced pressure.

[0040] The mass percentage concentration of the sodium sulfite aqueous solution is 5%-25%.

[0041] In a third aspect, the present invention provides a method for preparing a compound of formula (D), comprising:

[0042]

[0043] The compound of formula (C) reacts with the compound of formula (K) in a third reaction solvent in the presence of a first base, and undergoes a third post-treatment to obtain a compound of formula (D), wherein R2 is selected from chlorine, bromine and iodine, M is selected from sulfur and oxygen; R3 is selected from H, aryl and C1-C6 alkyl; and R4 is selected from hydrogen, potassium and sodium.

[0044] The third reaction solvent includes at least one selected from acetone, tetrahydrofuran, toluene and water. In some embodiments, the third reaction solvent is acetone, tetrahydrofuran, water, or a combination thereof, which is more conducive to the reaction.

[0045] The first base includes at least one selected from triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, 1,8-diazabicycloundec-7-ene and N,N-diisopropylethylamine. In some embodiments, the first base is triethylamine, 1,8-diazabicycloundec-7-ene, N,N-diisopropylethylamine or a combination thereof.

[0046] The temperature of the reaction with the compound of formula (K) is 5° C.-40° C. In some embodiments, the temperature of the reaction with the compound of formula (K) is 10° C.-30° C. In some embodiments, the temperature of the reaction with the compound of formula (K) is 20° C.

[0047] The molar ratio of the first base to the compound of formula (C) is not less than 1:1.

[0048] The molar ratio of the compound of formula (K) to the compound of formula (C) is 0.9:1-1.5:1.

[0049] The third post-treatment includes: concentrating under reduced pressure, adding a third organic solvent for stirring, extracting, combining organic phases, and concentrating the combined organic phases under reduced pressure. The third organic solvent includes or is dichloromethane.

[0050] In a fourth aspect, the present invention provides a method for preparing a compound of formula (E), comprising:

[0051]

[0052] The compound of formula (D) reacts with a second base in a fourth reaction solvent and undergoes a fourth post-treatment to obtain a compound of formula (E), wherein M is selected from sulfur and oxygen; and R3 is selected from H, C1-C6 alkyl, and aryl.

[0053] The fourth reaction solvent comprises at least one selected from methanol, ethanol, isopropanol, dichloromethane, ethyl acetate, isopropyl acetate, toluene, acetone, n-heptane and cyclohexane. In some embodiments, the fourth reaction solvent is methanol or ethanol or a combination thereof.

[0054] The second base includes at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicycloundec-7-ene and N,N-diisopropylethylamine. In some embodiments, the second base is potassium carbonate, which is conducive to obtaining the target product.

[0055] The temperature of the reaction with the second base is 10° C.-60° C. In some embodiments, the temperature of the reaction with the second base is 20° C.-50° C. In some embodiments, the temperature of the reaction with the second base is 30° C.-40° C.

[0056] The molar ratio of the second base to the compound of formula (D) is not less than 0.9:1.

[0057] The fourth post-treatment comprises: concentrating under reduced pressure, adding a fourth organic solvent and water, extracting, combining organic phases, concentrating the combined organic phases, and recrystallizing.

[0058] The fourth organic solvent includes or is dichloromethane.

[0059] The recrystallization comprises recrystallization using acetone.

[0060] In some embodiments, a method of preparing a compound comprises at least one of the aforementioned methods.

[0061] In some embodiments, a method for preparing a compound of formula (E) comprises: preparing a compound of formula (D) by the aforementioned method, and then reacting the compound of formula (D) with a second base in a fourth reaction solvent, and performing a fourth post-treatment to obtain a compound of formula (E).

[0062] In some embodiments, a method for preparing a compound of formula (E) comprises: a compound of formula (A) undergoes a Grignard reaction with a Grignard reagent in a first reaction solvent under the protection of an inert gas, and then reacts with a compound of formula (F), and undergoes a first post-treatment to obtain a compound of formula (B); the compound of formula (B) undergoes a halogenation reaction with a halogenating agent in the presence of an initiator in a second reaction solvent, and undergoes a second post-treatment to obtain a compound of formula (C); the compound of formula (C) reacts with a compound of formula (K) in the presence of a first base in a third reaction solvent, and undergoes a third post-treatment to obtain a compound of formula (D); then, the compound of formula (D) reacts with a second base in a fourth reaction solvent, and undergoes a fourth post-treatment to obtain a compound of formula (E); each compound is as described above.

[0063] In a fifth aspect, the present invention provides a compound, the structure of which is shown in the compound of formula (B):

[0064]

[0065] In a sixth aspect, the present invention provides a compound, the structure of which is shown in the compound of formula (C):

[0066]

[0067] wherein R2 is selected from chlorine, bromine and iodine.

[0068] In a seventh aspect, the present invention provides a compound, the structure of which is shown in the compound of formula (D):

[0069]

[0070] Wherein M is selected from sulfur and oxygen; R3 is selected from H, aryl and C1-C6 alkyl.

[0071] Beneficial effects:

[0072] Compared with the prior art, the technical solution of the present invention has at least one of the following technical effects:

[0073] (1) The reaction conditions are mild, which is conducive to industrial production;

[0074] (2) APIs are cheap and readily available;

[0075] (3) It is safe and environmentally friendly, and is not likely to cause harm to production personnel and the environment. It avoids the use of highly toxic substances such as thiophenol or diphenyl sulfide used in common literature processes (thiophenol and diphenyl sulfide are controlled substances and have a strong smell, which is not good for the environment and health);

[0076] (4) Post-processing is simple and environmentally friendly;

[0077] (5) Low production cost, which is conducive to industrial production;

[0078] (6) The obtained product has high yield and high purity.

[0079] Terminology Note:

[0080] g means gram, mg means milligram, °C means degree Celsius, h means hour, mL means milliliter, min means minute, mol means mole, and mmol means millimole.

[0081] In the description of the present invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0082] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0083] In the present invention, expressions such as "compound A" and "compound represented by formula A" refer to the same compound. DETAILED DESCRIPTION

[0084] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0085] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0086] 1. Preparation of compound of formula (B)

[0087]

[0088] 10.00 g of the compound of formula (L) and 10.00 g of tetrahydrofuran were mixed, cooled to 0°C, and protected by nitrogen. 72.46 ml of 1 mol / ml isopropyl magnesium chloride tetrahydrofuran solution was slowly added dropwise. After the addition, the mixture was reacted at 0°C for 24 hours. No residual compound of formula (L) was detected by high performance liquid chromatography to obtain solution 1. 8.19 g of methyl o-fluorobenzoate was dissolved in 50.00 g of tetrahydrofuran to obtain a tetrahydrofuran solution of methyl o-fluorobenzoate, and the temperature was lowered to 0° C. Solution 1 was added to the tetrahydrofuran solution of methyl o-fluorobenzoate, and the reaction was continued at 0° C. for 4 h. The main product, compound of formula (B), was obtained by high performance liquid chromatography; 30 mL of water was added to quench the mixture, and after the addition was completed, the mixture was stirred at 10° C.-30° C., separated, and the aqueous layer was extracted once with 10 ml of ethyl acetate, the organic layers were combined, and the organic layers were washed once with 10 ml of water, and then distilled under reduced pressure at 40° C. to obtain 10.87 g of compound of formula (B) (yield 90%, purity 95.0%); the obtained compound of formula (B) was tested for mass spectrum and hydrogen spectrum, and the results were as follows:

[0089] GC-MS: [M] = 249.0;

[0090] 1H-NMR (400MHz, d-DMSO) δ7.69-7.71(m,1H),7.61-7.65(m,1H),7.32-7.40(m,3H),7.24-7.26(m,1H),2.31-2.32(d,3H).

[0091] Example 2 Preparation of compound of formula (H)

[0092]

[0093] 3.00 g of the compound of formula (B), 30 mL of dichloromethane, 2.34 g of N-bromosuccinimide and 0.06 g of azobisisobutyronitrile were mixed, stirred and heated to 50° C., and refluxed until no compound of formula (B) remained after detection by high performance liquid chromatography, 30 mL of a 5% by mass aqueous sodium sulfite solution was added thereto for quenching, and after separation, the organic phase was washed with water (10 ml×2 times), and distilled under reduced pressure at 40° C. to obtain 3.90 g of the compound of formula (H) (semi-solid, yield 99.0%, purity 95.2%); the mass spectrum of the compound of formula (H) was detected, and the results were as follows: MS: [M+1]=330.1.

[0094] Example 3 Preparation of the compound of formula (I)

[0095]

[0096] 3.50 g of the compound of formula (H) was dissolved in 17.5 mL of acetone and 17.5 mL of water, and 1.46 g of potassium thioacetate and 1.61 g of triethylamine were added thereto under stirring. The mixture was reacted at 20° C. until no compound of formula (H) remained after detection by high performance liquid chromatography. The mixture was concentrated under reduced pressure at 40° C., 20 mL of dichloromethane was added, and stirred for 10 min. The mixture was extracted and separated. The organic phase was washed twice with 10 mL of water respectively, and then concentrated under reduced pressure at 40° C. to obtain 3.65 g of the compound of formula (I) (yellow solid, yield 95.0%, purity 94.8%). The mass spectrum and hydrogen spectrum of the obtained compound of formula (I) were detected, and the results were as follows:

[0097] MS: [M+1] = 325.20;

[0098] 1H NMR (400MHz, CDCl3): δ7.94(m,1H),7.76(m,1H),7.41(m,1H),7.34(m,1H),7.32(m,1H),7.13(m,1H),4.59(s,2H),2.30(s,3H).

[0099] Example 4 Preparation of Compound of Formula (J)

[0100]

[0101] 3.24 g of the compound of formula (I) was weighed, 15 ml of methanol and 4.0 g of potassium carbonate were added, and the mixture was stirred at 10°C-60°C. After 3 hours, the mixture was detected by high performance liquid chromatography. When no compound of formula (I) remained, the solvent was removed by concentration under reduced pressure, 15 ml of dichloromethane and 5 ml of water were added, the mixture was extracted, the liquids were separated, the organic phase was concentrated, and the mixture was purified by recrystallization with 6 ml of acetone to obtain 2.3 g of the compound of formula (J) (yield 88%, purity 95%). The obtained compound of formula (J) was tested for hydrogen spectrum and mass spectrum, and the results were as follows:

[0102] 1H NMR (400MHz, CDCl3): δ8.19(dd,1H),7.38(m,3H),7.28(m,1H),7.12(m,1H),4.13(s,2H);

[0103] MS: [M+1] = 263.02.

[0104] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing a compound of formula (E), comprising: ， The compound of formula (D) reacts with a second base in a fourth reaction solvent and undergoes a fourth post-treatment to obtain a compound of formula (E), wherein M is selected from sulfur and oxygen; R3 is selected from methyl; the fourth reaction solvent includes at least one selected from methanol, ethanol, isopropanol and acetone; the second base includes at least one selected from sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine and 1,8-diazabicycloundec-7-ene; and the temperature of the reaction with the second base is 10°C-60°C.

2. The method according to claim 1, characterized in that The molar ratio of the second base to the compound of formula (D) is not less than 0.9:

1.

3. The method for preparing a compound of formula (E) according to claim 1, wherein the method for preparing a compound of formula (E) further comprises a method for preparing a compound of formula (D), wherein the method for preparing a compound of formula (D) comprises: ， The compound of formula (C) reacts with the compound of formula (K) in the presence of a first base in a third reaction solvent, and undergoes a third post-treatment to obtain a compound of formula (D), wherein R2 is selected from chlorine, bromine and iodine, M is selected from sulfur and oxygen; R3 is selected from methyl; and R4 is selected from hydrogen, potassium and sodium.

4. The method for preparing a compound of formula (E) according to claim 3, characterized in that: The third reaction solvent includes at least one selected from acetone, tetrahydrofuran, toluene and water; the first base includes at least one selected from triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, 1,8-diazabicycloundec-7-ene and N,N-diisopropylethylamine; the temperature of the reaction with the compound of formula (K) is 5°C-40°C; the molar ratio of the first base to the compound of formula (C) is not less than 1:1; the molar ratio of the compound of formula (K) to the compound of formula (C) is 0.9:1-1.5:

1.

5. The method for preparing a compound of formula (E) according to claim 3, wherein the method for preparing a compound of formula (E) further comprises a method for preparing a compound of formula (C), wherein the method for preparing a compound of formula (C) comprises: ， The compound of formula (B) undergoes a halogenation reaction with a halogenating agent in the presence of an initiator in a second reaction solvent, and undergoes a second post-treatment to obtain a compound of formula (C), wherein R2 is selected from chlorine, bromine or iodine.

6. The method for preparing a compound of formula (E) according to claim 5, characterized in that: The second reaction solvent includes at least one selected from dichloromethane, chloroform, carbon tetrachloride, petroleum ether, n-hexane, n-heptane, n-hexane, cyclohexane, heptane, 1,2-dichloroethane and ethyl acetate; and / or the initiator includes at least one selected from benzoyl peroxide, lauroyl peroxide, isopropylbenzene hydroperoxide, tert-butyl hydroperoxide, tert-butyl perbenzoate, tert-butyl pervalerate, methyl ethyl ketone peroxide, cyclohexanone peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, azobisisobutyronitrile and azobisisoheptylonitrile; and / or the halogenating agent is selected from at least one selected from N-bromosuccinimide, dibromohydantoin, bromine, N-chlorosuccinimide and N-iodosuccinimide.

7. The method for preparing a compound of formula (E) according to claim 5 or 6, characterized in that: The temperature of the halogenation reaction is 30°C-80°C; and / or the molar ratio of the compound of formula (B) to the initiator is 1:0.1-1:0.5; and / or the molar ratio of the compound of formula (B) to the halogenating agent is 1:0.9-1:1.

5.

8. The method for preparing a compound of formula (E) according to claim 5, wherein the method for preparing a compound of formula (E) further comprises a method for preparing a compound of formula (B), wherein the method for preparing a compound of formula (B) comprises: ， The compound of formula (A) undergoes a Grignard reaction with a Grignard reagent in a first reaction solvent under the protection of an inert gas, and then reacts with a compound of formula (F), and undergoes a first post-treatment to obtain a compound of formula (B), wherein R1 is selected from chlorine, bromine and iodine; and R5 is selected from methyl, ethyl, isopropyl, tert-butyl and carbonyl chloride.

9. The method for preparing a compound of formula (E) according to claim 8, wherein the Grignard reagent comprises at least one selected from isopropylmagnesium chloride, isopropylmagnesium bromide, methylmagnesium bromide, methylmagnesium chloride and isopropylmagnesium chloride-lithium chloride; and / or the temperature of the Grignard reaction is -10°C to 10°C; and / or the molar ratio of the compound of formula (A) to the Grignard reagent is 1:0.9-1:1.

3.

10. The method for preparing a compound of formula (E) according to claim 8 or 9, wherein the temperature of the reaction with the compound of formula (F) is -10°C to 10°C; and the molar ratio of the compound of formula (A) to the compound of formula (F) is 1:0.9 to 1:1.

3.

11. The method according to claim 8 or 9, wherein the first post-processing comprises: Add water to quench, stir at 10°C-30°C, extract, combine the organic layers, and evaporate under reduced pressure.

12. A compound whose structure is selected from the compound of formula (D): ； wherein M is selected from sulfur and oxygen; and R3 is selected from methyl.

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