Preparation method of fluorine-substituted trans-olefin compound

Abstract

The invention discloses a preparation method of a fluorine-substituted trans-olefin compound. Specifically, the invention discloses a preparation method of a compound as shown in a formula VII, which comprises the following steps: in a solvent, in the presence of a free radical initiator and a free radical source, a compound as shown in a formula VI-1 is subjected to an isomerization reaction to prepare the compound as shown in the formula VII, the free radical initiator is dimethyl azobis (2-methylpropionate), and the free radical source is dimethyl azobis (2-methylpropionate). The free radical source is diphenyl disulfide.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for the preparation of fluorine substituted trans-olefins. BACKGROUND

[0002] Ras, the rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. Specifically, under normal physiological conditions, Ras is activated by growth factors and various other extracellular signals and is responsible for regulating functions such as cell growth, survival, migration and differentiation. These regulatory functions of Ras are performed through a switch between the GDP-bound state and the GTP-bound state, i.e. the "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13:394-401). Ras bound to GDP is in the inactive form, in a dormant or off state, when the signaling system is off, and is activated when it is exposed to some pro-growth stimuli, for example it can be induced by guanine nucleotide exchange factors (GEFs) to release GDP and bind to GTP, with the result that Ras is thereby "switched on" and is converted to the active form of Ras, which recruits and activates various downstream effectors to perform signal transduction, enabling the transmission of signals from the cell surface into the cytoplasm, thereby controlling numerous key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).

[0003] Ras has GTPase activity, which can cleave the terminal phosphate of GTP to convert it to GDP, i.e. to convert itself to the inactive state. However, the endogenous GTPase activity of Ras is very low and the conversion of GTP-Ras to GDP-Ras requires the exogenous protein GAP (GTPase-activating protein). GAP interacts with Ras and facilitates the conversion of GTP to GDP. Therefore, any mutation in the Ras gene that affects the interaction of Ras with GAP or affects the conversion of GTP to GDP, results in Ras being in the activated state for a long time, thereby continuously signaling the cell to grow and divide, stimulating the cell to proliferate continuously, ultimately leading to tumor formation and progression.

[0004] Among human tumor-associated genes, three ubiquitously expressed Ras genes—H-RAS, K-RAS, and N-RAS—encode highly homologous, approximately 21 kDa HRas, NRas, and KRas proteins, respectively. In 1982, researchers first discovered that Ras is activated by mutations in cancer cell lines (Chang, E.H. et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large-scale genome sequencing studies in different cancer types revealed that Ras proteins are mutated in more than 30% of cancer types, with the highest mutation rates in pancreatic cancer (>90%), colon cancer (45%), and lung cancer (35%). Transgenic and genetically engineered mouse models have also revealed that mutated Ras proteins are sufficient to drive and induce multiple types of cancer, and that Ras oncogenes are crucial for the maintenance and progression of tumors in various cancer types. For example, in Ras-mutated cancer cell lines and animal models, RNA intervention has been shown to slow tumor growth. These studies make Ras tumor proteins a widely accepted and highly attractive target for anticancer drugs in the pharmaceutical field.

[0005] Studies have shown that Ras mutations are most common in KRas, and KRas mutations can be observed in approximately 85% of Ras mutation-driven cancers. The vast majority of Ras mutations occur at codons G12, G13, and Q61, with approximately 80% of KRas mutations occurring at the glycine residue of codon 12, such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations. KRas mutations are commonly found in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer, and are also observed in 25% of non-small cell lung cancer patients (McCormick, F. et al., Clinical Cancer Research 21(8), 1797-1801, 2015). Therefore, KRas mutant proteins have become the most important branch of Ras drug target research, and the development of its inhibitors is considered a very promising research direction in anticancer / tumor drug development.

[0006] However, decades of drug development targeting Ras have revealed a significant challenge: the smooth surface of the Ras protein lacks distinct grooves or pockets for binding small molecule inhibitors, and its extremely high affinity for guanine substrates (picomolar levels) has made the development of small molecule inhibitors a long and difficult task. Consequently, Ras has long been considered an "untreatable" target. Furthermore, there remains a strong need for compounds with more structural types or modalities to serve as KRas inhibitors, providing more therapeutic options or offering improved inhibitory activity compared to existing KRas inhibitors, thereby providing more potent therapeutic drugs for clinical use.

[0007] The KRAS G12D inhibitors disclosed in patent applications CN117624170A and CN117800975A address these issues and other needs, providing novel structural inhibitory compounds with KRas mutant protein inhibitory activity. Due to their improved structural patterns, these compounds exhibit enhanced inhibitory activity against KRas mutant proteins and related tumor-suppressing activity compared to existing KRas mutant protein inhibitors. They also possess favorable pharmacokinetic properties, resulting in good drug-likeness; for example, they can be conveniently administered and more easily absorbed in vivo, with reduced toxic side effects, improved drug resistance and safety, and a reduced risk of drug interactions.

[0008] The preparation of these KRAS G12D inhibitors involves an important intermediate compound 1 ([(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidinyl]methanol). During the drug discovery phase, the preparation method and process of this intermediate are as follows:

[0009] The above illustrates the synthesis of gram-scale API materials in the drug discovery phase, suitable for in vivo and pharmacokinetic assays. However, it has several drawbacks, including the expensive starting material compound 9, low yields across several steps, sensitivity to reaction conditions, and the need for SFC separation of enantiomers and several chromatographic purification steps. A detailed analysis follows: The synthetic route for the drug discovery phase of compound 1 begins with the alkylation of compound 9 to generate compound 10, followed by a Wittig reaction, deprotection of the Boc group, reductive amination, and finally ester reduction to obtain the oily intermediate product, compound 1. The advantage of this route is that it directly synthesizes compound 1, and the number of steps is relatively short (5 steps). However, it has several inherent disadvantages.

[0010] a) In step 1, methylation requires a relatively long heating time, likely due to the weak basicity of K2CO3. Furthermore, SFC (supercritical CO2 chromatography) separation is required to provide the desired enantiomers, which is costly.

[0011] b) For step 2, in addition to the expensive Wittig reagent and low temperature conditions, another drawback is the mediocre stereoselectivity (E / Z ratio of about 3:1), which leads to very time-consuming and costly chromatographic purification.

[0012] c) Step 4 involves a complex reaction process that requires pH adjustment. Furthermore, the highly flammable sodium cyanoborohydride may pose safety risks in future large-scale production.

[0013] d) In step 5, it should be noted that the application of LiAlH4 leads to the release of H2 during the quenching process.

[0014] Given the numerous shortcomings of the intermediate synthesis routes in the drug discovery stage, there is an urgent need to develop an intermediate synthesis route suitable for industrial production. Summary of the Invention

[0015] To address the problems existing in the prior art, the present invention aims to provide a method for preparing fluorinated trans-olefin compounds. The fluorinated trans-olefin compounds prepared by the method of the present invention have good purity and high yield, and can be used to further improve the preparation of [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidinyl]methanol.

[0016] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0017] This invention provides a method for preparing a compound as shown in Formula VII, comprising the following steps: in a solvent, in the presence of a free radical initiator and a free radical source, the compound as shown in Formula VI-1 undergoes an isomerization reaction to prepare the compound as shown in Formula VII. ; in, R is a C1-C6 alkyl group; The free radical initiator is dimethyl azobisisobutyrate, and the free radical source is diphenyl disulfide.

[0018] In one embodiment of the present invention, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, ethyl.

[0019] In one aspect of the present invention, in the isomerization reaction, the solvent is selected from one or more of cyclic ether solvents, ester solvents, and hydrocarbon solvents; Preferably, the cyclic ether solvent is tetrahydrofuran; Preferably, the ester solvent is ethyl acetate; Preferably, the hydrocarbon solvent is n-heptane.

[0020] In one embodiment of the present invention, in the isomerization reaction, the solvent is an ester solvent, a cyclic ether solvent, or a "mixed solvent of hydrocarbon solvent and ester solvent". Preferably, in the "mixed solvent of hydrocarbon solvent and ester solvent", the volume ratio of ester solvent to hydrocarbon solvent is 1:(5~10), for example 1:8.

[0021] In one embodiment of the present invention, in the isomerization reaction, the solvent is ethyl acetate, tetrahydrofuran, or a mixture of ethyl acetate and n-heptane. Preferably, in the mixture of ethyl acetate and n-heptane, the volume ratio of ethyl acetate to n-heptane is 1:(5~10), for example, 1:8.

[0022] In one aspect of the present invention, in the isomerization reaction, the volume molar ratio of the solvent to the compound shown in Formula VI-1 is (1~8) L / mol, for example (2~4) L / mol.

[0023] In one aspect of the present invention, in the isomerization reaction, the molar ratio of the free radical source to the compound shown in Formula VI-1 is (0.1~1):1, for example (0.15~0.3):1.

[0024] In one aspect of the present invention, in the isomerization reaction, the molar ratio of the free radical initiator to the compound shown in Formula VI-1 is (0.1~1):1, for example (0.15~0.3):1.

[0025] In one aspect of the present invention, the reaction temperature of the isomerization reaction is 60~80℃, for example 65~70℃.

[0026] The reaction time for the isomerization reaction is the conventional reaction time for such reactions in the art, generally until one of the reactants reacts completely or ceases to react. In one embodiment of the present invention, the reaction time for the isomerization reaction is 10-25 hours, for example, 12-19 hours.

[0027] In one aspect of the invention, the isomerization reaction is carried out in an atmosphere of an inert gas, such as nitrogen or argon, preferably nitrogen.

[0028] In one embodiment of the present invention, the raw materials for the isomerization reaction are the solvent, the free radical initiator, the free radical source, and the compound shown in Formula VI-1.

[0029] In one aspect of the present invention, the compound represented by Formula VI-1 participates in the reaction in the form of a mixture, wherein the mixture comprises the compound represented by Formula VI-1 and... A mixture, wherein the compound as shown in Formula VI-1 and The molar ratio can be (0.1-10):1, for example (0.5-1.5):1.

[0030] In one embodiment of the present invention, the raw materials for the isomerization reaction are the solvent, the free radical initiator, the free radical source, and the compound as shown in Formula VI-1. .

[0031] In one aspect of the present invention, in the preparation method, the free radical initiator is added in solution form to the mixture of the solvent, the free radical source and the compound shown in Formula VI-1. The solvent in the solution of the free radical initiator is selected from one or more of cyclic ether solvents, ester solvents and hydrocarbon solvents, for example, ester solvents. Preferably, the cyclic ether solvent is tetrahydrofuran; Preferably, the ester solvent is ethyl acetate; Preferably, the hydrocarbon solvent is n-heptane.

[0032] Preferably, when the free radical initiator is added in solution form, it is added dropwise, for example, over 0.5 to 2 hours, preferably over 1 hour.

[0033] After the isomerization reaction is completed, post-processing can be carried out through the following steps, including: acidification, recrystallization, neutralization, extraction, and concentration.

[0034] In one embodiment of the present invention, the post-processing steps include acidification, recrystallization, neutralization, extraction, and concentration performed sequentially.

[0035] In one aspect of the present invention, in the post-processing step, the acidification is performed using an inorganic acid, such as hydrochloric acid or sulfuric acid, preferably hydrochloric acid, and the hydrochloric acid is preferably in the form of a hydrochloric acid solution, wherein the solvent in the hydrochloric acid solution is selected from one or more of cyclic ether solvents, ester solvents and hydrocarbon solvents. Preferably, the cyclic ether solvent is tetrahydrofuran; Preferably, the ester solvent is ethyl acetate; Preferably, the hydrocarbon solvent is n-heptane.

[0036] In one aspect of the present invention, the acidification in the post-processing step is performed using an ethyl acetate solution of hydrochloric acid, for example, a 1-5 mol / L ethyl acetate solution of hydrochloric acid, or for example, a 4 mol / L ethyl acetate solution of hydrochloric acid.

[0037] In one aspect of the present invention, in the post-processing step, the molar ratio of the acid used for acidification to the compound shown in Formula VI-1 is (1~2):1, for example, 1:1.

[0038] In one aspect of the present invention, the solid obtained after acidification in the post-processing step is a salt.

[0039] In one aspect of the present invention, the recrystallization in the post-processing step refers to recrystallizing the solid obtained by acidification.

[0040] In one aspect of the present invention, the recrystallization in the post-processing step is solvent-antisolvent recrystallization; Preferably, in the solvent-antisolvent recrystallization, the solvent is an alcohol solvent, such as methanol; Preferably, in the solvent-antisolvent recrystallization, the solvent is an ether solvent, such as methyl tert-butyl ether; Preferably, in the solvent-antisolvent recrystallization, the volume-to-mass ratio of the solvent to the solid to be recrystallized is (0.5~0.8) L / kg, for example 0.67 L / kg; Preferably, in the solvent-antisolvent recrystallization, the volume-to-mass ratio of the antisolvent to the solid to be recrystallized is (8~12) L / kg, for example, 10 L / kg.

[0041] In one aspect of the present invention, the recrystallization in the post-processing step is a solvent-antisolvent recrystallization, which specifically includes the following steps: mixing the solid to be recrystallized with the solvent to dissolve it, and then mixing it with the antisolvent. Preferably, the solid to be recrystallized is mixed with the solvent and dissolved at 40-50°C; Preferably, the "mixing with the antisolvent" means adding the antisolvent dropwise to the "solution of the solid to be recrystallized and the solvent"; Preferably, after mixing with the antisolvent, the temperature is lowered to 0~10°C to separate the solid.

[0042] In one aspect of the present invention, the neutralization in the post-processing step is to neutralize to a pH of 8.5-9.5, for example, to a pH of 9.

[0043] In one aspect of the present invention, in the post-processing step, the neutralization is performed by using a weak acid salt of an alkali metal to liberate the salt obtained from the recrystallization, and the weak acid salt of the alkali metal is preferably in the form of an aqueous solution. Preferably, the weak acid salt of the alkali metal is potassium phosphate, which is preferably in the form of an aqueous solution with a mass percentage of 15-25%, for example, in the form of an aqueous solution with a mass percentage of 20%.

[0044] In one aspect of the present invention, in the post-processing step, the solvent used for extraction is a water-insoluble organic solvent, such as a haloalkane water-insoluble organic solvent, preferably dichloromethane.

[0045] In one aspect of the present invention, the post-processing step further includes the use of seed crystals. Specifically, seed crystals are added during or after acidification, for example, during acidification. The seed crystals are salts of compounds as shown in Formula VII, wherein the acid that forms a salt with the compound as shown in Formula VII is the acid used in the acidification, and the number of acids is the same as the number of acids in the salt obtained after acidification.

[0046] In one embodiment of the present invention, in the post-processing step, the acidification involves adding the acid dropwise to the crude isomerization reaction solution to be acidified, and then adding the seed crystals when the amount of acid added is 1 / 3 to 1 / 2 of the original amount.

[0047] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0048] The reagents and raw materials used in this invention are all commercially available.

[0049] The positive and progressive effects of this invention are as follows: the fluorinated trans-olefin compounds prepared by the method of this invention have good purity and high yield, and can be used to further prepare [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidinyl]methanol. Attached Figure Description

[0050] Figure 1 Molecular ellipsoid diagram of a single crystal of the D-DTTA salt of compound 3 with a single configuration.

[0051] Figure 2 Molecular ellipsoid diagram of a single crystal of L-tartrate of compound 3 with a single configuration. Detailed Implementation

[0052] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0053] Preparation route of compound 1:

[0054] The preparation route of compound 5 is shown below:

[0055] Step 1: Using inexpensive and readily available compound 2, formaldehyde source, and methylamine as raw materials, carry out two Mannich reactions in an inert solvent (including but not limited to ethanol, methanol, or isopropanol) to generate compound 3.

[0056] Step 2: Then, in an inert solvent and in the presence of a chiral organic acid, compound 3 was chemically chirally resolved to obtain chiral pure compound 4 in a high yield.

[0057] Step 3: Next, in an inert solvent and in the presence of a base, compound 4 and compound 5 undergo a Julia-Kocienski olefination reaction to give a mixture of E-type compound 6 and Z-type compound 6A.

[0058] Step 4: The mixture is reconfigured into a single-configuration compound 8 in the presence of an initiator and a free radical source.

[0059] Step 5: Compound 8 is then reduced with a reducing agent in an inert solvent (including but not limited to methyl tert-butyl ether, toluene, acetonitrile, tetrahydrofuran, methyl tetrahydrofuran or ethylene glycol dimethyl ether) to obtain compound 1.

[0060] Example 1: Preparation of Compound 3

[0061] 1) Add ethanol (20 L, 10 vol.), methylamine hydrochloride (2.00 kg, 1.0 eq.), and paraformaldehyde (2.67 kg, 3.0 eq.) to the reaction flask. 2) Add ethyl 2-methylacetoacetate (4.48 kg, 1.05 eq.) and triethylamine (0.30 kg, 0.1 eq.). 3) Nitrogen gas was purged three times; 4) Heat to 60℃ (60℃-70℃ is acceptable) and stir for at least 16 hours until n （2-甲基乙酰乙酸乙酯） / n （2-甲基乙酰乙酸乙酯+化合物3） The amount of substance is <15% (HPLC 214 nm), where n represents the amount of substance; 5) Add triethylamine (3.00 kg, 1.0 eq.) and continue the reaction at 60℃ (60℃-70℃ is acceptable) for 2-3 h; after the reaction is completed, the in-situ yield of compound 3 in the reaction solution is determined by HPLC external standard method to be 60%.

[0062] Post-processing: Cool down and concentrate under reduced pressure until no distillation occurs (rotary evaporation, concentration temperature 50℃); mix the concentrated residue with ethyl acetate and water, extract and separate; combine the organic phases, wash with 10% NaCl aqueous solution, and separate; dry the organic phase with anhydrous sodium sulfate, filter, and rinse with ethyl acetate; combine the eluent and filtrate, concentrate to 22 L, add 4.5 L of 4 mol / L hydrogen chloride ethyl acetate solution dropwise, stir for 1 h after addition; filter, rinse the filter cake with ethyl acetate; add the filter cake to saturated sodium bicarbonate solution and adjust the pH to 7-8; add ethyl acetate for extraction and separate; combine the organic phases, wash with 10% sodium chloride aqueous solution; separate, dry the organic phase with anhydrous sodium sulfate; filter, rinse the filter cake with ethyl acetate, combine the filtrate and eluent, concentrate to obtain 3.30 kg of crude compound 3, with a purity of 86.7% and a yield of 48%.

[0063] 1 H NMR (400 MHz, Chloroform- d ) δ 4.21 (q, J = 7.1 Hz, 2H), 3.42 (dd, J = 11.6, 2.8 Hz, 1H), 3.06 – 2.95 (m, 1H), 2.92 – 2.81 (m, 1H), 2.43 – 2.26(m, 2H), 2.33 (s, 3H), 2.07 (d, J = 11.6 Hz, 1H), 1.24 (t, 3H), 1.22 (s, 3H).

[0064] LCMS (m / z): 200.1 [M+H].

[0065] Example 2.1 Preparation of Compound 4

[0066] 2000 mg of compound 3 (10 mmol, 1 eq.) was dissolved in 20 mL (10 vol.) of acetonitrile, and 1.54 g of D-DTTA (CAS: 32634-68-7, 4 mmol, 0.4 eq) was added. The mixture was heated to 60 °C, stirred for 3 h, and allowed to cool naturally to room temperature (20 °C). The solution was filtered and dried under vacuum to obtain 1.94 g of a white solid (a D-DTTA salt of compound 3 in a single configuration, ee value 95.06%). 0.97 g of this white solid was added to 100 mL of saturated sodium bicarbonate aqueous solution, and then diluted with 100 mL of ethyl acetate. 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, and rotary drying were performed to prepare 312.9 mg of free compound 4. The ee value of compound 4 was measured to be 95.06%.

[0067] The D-DTTA salt of compound 3 with a single configuration was added in portions to a tetrahydrofuran / methyl tert-butyl ether (1 / 1) mixed solvent until the solid did not completely dissolve after 0.5 hours at 60°C. The suspension was then rapidly filtered while hot into a glass sample vial preheated to 60°C. The vial was sealed, kept still, and then allowed to cool naturally to room temperature, allowing single crystal growth. The absolute configuration of the compound in the single crystal was determined by X-ray single-crystal diffraction.

[0068] The specific test parameters are as follows: Testing instrument: D8 Venture Instrument Model: D8 Venture Instrument parameters: Light source: Cu target; X-rays: Cu-Kα (=1.54178 Å) Detector: CMOS surface detector; Resolution: 0.80 Å Current and voltage: 50 kV, 1.2mA; Exposure time: 3 s Distance from surface detector to sample: 40 mm; Test temperature: 170(2)K The molecular stereoscopic structure ellipsoid of the single crystal obtained in the above example is detailed in [link to example]. Figure 1 It was confirmed that the chiral carbon atom in the isolated compound 4 should be in the R configuration (corresponding to...). Figure 1 (C25 in the middle).

[0069] Example 2.2 Preparation of Compound 4

[0070] Ethyl acetate (100 mL, 10 vol.) and D-DTTA (9.7 g, 0.5 eq.) were added to a 500 mL reaction flask. The mixture was heated to 60°C, and compound 3 (10 g, 1.0 eq.) was added dropwise over a period of 0.5 hours. The mixture was then stirred at 60°C for 3 hours. D-DTTA (9.7 g, 0.5 eq.) was added, and the mixture was heated to 78°C and refluxed for 24 hours. The heating was then stopped, and the mixture was stirred overnight and allowed to cool naturally to room temperature. The mixture was filtered and dried to give 18.5 g of solid, yield 62.9%, ee% = 86.7%.

[0071] Then, 10 g of the solid was dissolved in DMF (4 vol.), and water (4 vol.) was added dropwise with stirring at room temperature. After the addition was complete, the mixture was stirred for 2-3 hours, filtered, and dried to obtain 5.7 g of solid (D-DTTA salt of compound 4), with a yield of 65.9% and ee% = 97.1%. The X-ray single crystal diffraction test results were the same as in Example 2.1.

[0072] Example 2.3 Preparation of Compound 4

[0073] 1) Add ethyl acetate (31 L, 10 vol.) to the reaction vessel. D -DTTA (3.00 kg, 0.5 eq.); 2) Raise the temperature to 60-65℃; 3) Add crude compound 3 (3.10 kg, 1.0 eq.) dropwise, and complete the dripping in 0.5-1 h; 4) Keep warm at 60-65℃ and stir for 3 hours (a large amount of yellow solid will precipitate); 5) Add D -DTTA (3.00 kg, 0.5 eq.), heated to 75-80℃ and refluxed with stirring for 24 h; 6) Cool to 15-25℃ and keep warm while stirring for 1-2 hours; 7) Filter and wash the filter cake with ethyl acetate (6.2 L, 2 vol.); 8) 6.31 kg of wet product was obtained (the total content of D-DTTA salt of compound 4 and its stereoisomers was 88.9%). ee Value 78%, resolution yield 71% (reduced content yield, i.e., total yield of D-DTTA salt of compound 4 and its stereoisomers); 9) Add DMF (22 L, 4 vol.) and the above wet product (5.53 kg) to the reactor. 10) Stir until dissolved, 25℃ (15~30℃ is acceptable); 11) Add water dropwise at 30℃ (25-35℃ is acceptable) (11 L, 2 vol.), which releases heat relatively quickly. Add 5 g of seed crystals (the seed crystals added are the D-DTTA salt of compound 4, which was obtained from the small-scale test in 2.1), and stir for 15 min (10-20 min is acceptable). 12) Continue adding water (12.3 L, 2 vol.), the dripping will be completed in about 1 hour; 13) Keep warm and stir at 20℃ (or within the range of 15-25℃) for 5 hours (or within the range of 4-6 hours); 14) Filter and rinse with water (6.2 L, 2 vol.); 15) Drying at 50℃ yielded 3.54 kg of crude compound 4 (i.e., crude D-DTTA salt of compound 4). ee Value 98.6%, recrystallization yield 67% (pure yield, yield of recrystallization step only); 16) Add DMF (5.78 L, 1.7 vol.) and dried crude product (3.4 kg) to the reactor. 17) Heat to 40-45℃ and stir until dissolved; 18) Cool down to 30℃ and add 90 g of seed crystals (the added seed crystals are the D-DTTA salt of compound 4, which were obtained from the small-scale test in 2.1). 19) Add water (11.9 L, 3.5 vol.) dropwise at 30℃ (any temperature range of 25-35℃ is acceptable), completing the dripping process in 1-1.5 h; 20) Stir at 20℃ (or within the range of 15-25℃) for 5 hours (or within the range of 4-6 hours); 21) Filter and rinse with water (6.8 L, 2 vol.); 22) 3.36 kg of wet product was obtained. ee Value 99.7%, recrystallization yield 90.9% (content yield, yield of the second recrystallization only); 23) Add water (16.8 L) and sodium bicarbonate (0.88 kg) to the reactor to prepare a 5% sodium bicarbonate aqueous solution; 24) Control the temperature at 10℃ (5~15℃ is acceptable), slowly add the obtained wet product to the reactor, and the pH of the system is 7-8; 25) Add ethyl acetate (7 L) 3 extractions, 3 times; 26) Combine the organic phases, wash with 15% sodium chloride aqueous solution (5 L), and separate the layers; 27) Add 1 kg of anhydrous sodium sulfate to dry the organic phase, filter; concentrate to obtain a yellow oily compound 4. Product 977.4 g, HPLC purity 97.0%. ee Value: 99.5%, yield of content is 96%, which is the yield of the final step of adding alkali to release the free content.

[0074] 1 H NMR (400 MHz, Chloroform- d ): δ 4.20 (q, J = 7.1 Hz, 2H), 3.41 (d, J= 11.6 Hz, 1H), 3.05 – 2.96 (m, 1H), 2.93 – 2.81 (m, 1H), 2.42 – 2.33 (m,2H), 2.33 (S, 3H), 2.07 (d, J = 11.6 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.21(s, 3H).

[0075] Example 2.4 Preparation of Compound 4

[0076] 200 mg of compound 3 (1 mmol, 1 eq.) was dissolved in 2 mL (10 vol.) of acetonitrile, and 386 mg of D-DTTA (CAS: 32634-68-7, 1 mmol, 1 eq.) was added. The mixture was heated to 60 °C and stirred for 16 h. After naturally cooling to room temperature (20 °C), the mixture was filtered and dried under vacuum to obtain 236.8 mg of a white solid. This white solid was added to a saturated sodium bicarbonate aqueous solution (15 mL), and then dissolved in ethyl acetate (15 mL). 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, and rotary evaporation were performed to finally obtain 86.3 mg of free compound 4 with an ee value of 95.16%.

[0077] Example 2.5 Preparation of Compound 4

[0078] 2 g of compound 3 (10 mmol, 1 eq.) was dissolved in 20 mL (10 vol.) of ethyl acetate and 5 mL (2.5 vol.) of ethanol. 1.93 g of D-DTTA (CAS: 32634-68-7, 5 mmol, 0.5 eq) was added, the mixture was heated to 60 °C and stirred for 3 h. Then, another 1.93 g of D-DTTA was added, and the mixture was refluxed and stirred for 24 h. The mixture was allowed to cool naturally to room temperature (20 °C), filtered, and dried under vacuum to obtain 1.39 g of a white solid. The X-ray single-crystal diffraction results were the same as in Example 2.1. This white solid was added to a saturated sodium bicarbonate aqueous solution (100 mL), and then dissolved in ethyl acetate (100 mL). 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, followed by rotary evaporation, finally yielded 750.3 mg of free compound 4 with an ee value of 95%.

[0079] Example 2.6 Preparation of Compound 4

[0080] 2 g of compound 3 (10 mmol, 1 eq.) was dissolved in 20 mL (10 vol.) of ethyl acetate. 1.93 g of D-DTTA (CAS: 32634-68-7, 5 mmol, 0.5 eq) was added, the mixture was heated to 60 °C, stirred for 3 h, and then another 1.93 g of D-DTTA was added. The mixture was refluxed and stirred for 24 h, allowed to cool naturally to room temperature (20 °C), filtered, and dried under vacuum to obtain 4.16 g of a white solid. This white solid was added to a saturated sodium bicarbonate aqueous solution (100 mL), and then further dissolved in ethyl acetate (100 mL). 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, and rotary drying were performed to finally obtain 1.44 g of free compound 4 with an ee value of 86.8%.

[0081] Example 2.7 Preparation of Compound 4

[0082] 2 g of compound 3 (10 mmol, 1 eq.) was dissolved in 20 mL (10 vol.) of ethyl acetate and 5 mL (2.5 vol.) of ethanol. 750 mg of D-tartaric acid (CAS: 147-71-7, 5 mmol, 0.5 eq) was added, the mixture was heated to 60 °C, stirred for 3 h, and allowed to cool naturally to room temperature. After further cooling to 20 °C, the mixture was filtered and dried under vacuum to obtain 1.95 g of a white solid. Half of this white solid was added to a saturated sodium bicarbonate aqueous solution (100 mL), and then dissolved in ethyl acetate (100 mL). 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, and rotary evaporation were performed to finally obtain 311.4 mg of free compound 4 with an ee value of 87.32%.

[0083] The resolving agent was replaced with L-tartaric acid, and the resulting free compound was further resolved using L-tartaric acid. The prepared L-tartarate (i.e., the white solid obtained before neutralization with sodium bicarbonate) was added in batches to an acetonitrile / methyl tert-butyl ether (V:V=1:1) mixed solvent until the solid did not completely dissolve after 0.5 h at 60°C. The suspension was then rapidly filtered while hot into a glass sample vial preheated to 60°C. The vial was sealed, kept still, and then allowed to cool naturally to room temperature, resulting in single crystal growth. The absolute configuration of the compound in the single crystal was determined by X-ray single crystal diffraction.

[0084] The specific test parameters are as follows: Testing instrument: D8 Venture Instrument Model: D8 Venture Instrument parameters: Light source: Cu target; X-rays: Cu-Kα (=1.54178 Å) Detector: CMOS surface detector; Resolution: 0.80 Å Current and voltage: 50 kV, 1.2mA; Exposure time: 3 s Distance from surface detector to sample: 40 mm; Test temperature: 170(2)K The molecular stereoscopic structure ellipsoid of the single crystal obtained in the above example is detailed in [link to example]. Figure 2 It shows that the chiral carbon atom in the stereoisomer of compound 3 obtained by resolution is in the S configuration (corresponding to...). Figure 2 Based on this, it is confirmed that when the resolving agent is D-tartaric acid, the chiral carbon atom in the other stereoisomer of compound 3 (i.e., compound 4) obtained by resolving should be in the R configuration.

[0085] Example 2.8 Preparation of Compound 4

[0086] 2 g of compound 3 (10 mmol, 1 eq.) was dissolved in 20 mL (10 vol.) of ethyl acetate and 5 mL (2.5 vol.) of ethanol. 750 mg of D-tartaric acid (CAS: 147-71-7, 5 mmol, 0.5 eq) was added, the mixture was heated to 60 °C and stirred for 3 h, then another 750 mg of D-tartaric acid was added, and the mixture was refluxed and stirred for 24 h. The mixture was then allowed to cool naturally to room temperature (20 °C), filtered, and dried under vacuum to obtain 1.98 g of a white solid. This white solid was added to 100 mL of saturated sodium bicarbonate aqueous solution, and then dissolved in 100 mL of ethyl acetate. 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, and rotary drying were performed to finally obtain 1.13 g of free compound 4 with an ee value of 87%.

[0087] Example 3 Preparation of Compound 8

[0088] 1) Add ethylene glycol dimethyl ether (7.5 L, 5 vol.) and compound 4 (1.50 kg, 1.0 eq.) to the reaction flask; 2) Add compound 5 (1.92 kg, 1.1 eq.), and replace with nitrogen; 3) Cool down to -50℃; 4) Control the temperature to -50~-40℃, and slowly add 8.28L (1.1 eq.) of tetrahydrofuran solution of bis(trimethylsilylaminolithium) (1.0M), which will be completed in about 2 hours; 5) After dripping, keep warm at -45℃ (-50~-40℃ is also acceptable) and stir for 1 hour, then slowly return to 20℃ (about 2-3 hours to return to 20℃); 6) Sampling control, compound 4 < 1%, (reaction) in-situThe assay yield was 92.6%; the double bond configuration ratio of the product was approximately Z / E = 55.4 / 44.6. 7) Control the temperature T < 30℃, and quench the reaction by adding saturated ammonium chloride aqueous solution (3.75 L, 2.5 vol.); 8) Separate the liquid and aqueous phases. The aqueous phase contains a large amount of solid. Add ethyl acetate (4.0 L, 2.67 vol.) and water (2.0 L, 1.33 vol.) to the aqueous phase and stir. 9) Separate the liquid and combine the organic phases, then concentrate and evaporate the solvent under reduced pressure at T<45℃; 10) Add 2-methyltetrahydrofuran (7.5 L, 5 vol.) to the concentrated system, then add 1 mol / L hydrochloric acid aqueous solution (8.28 L, 1.1 eq.), stir and separate the liquid, and temporarily store the aqueous phase (mainly the product). 11) Wash the above organic phase once with water (3.0 L, 2 vol.), separate the liquid and combine the aqueous phases, and add 2-methyltetrahydrofuran (4.5 L, 3 vol.) to extract impurities again; 12) Separate the liquid and discard the organic phase. Add n-heptane (7.5 L, 5 vol.) to the aqueous phase, and add an aqueous solution of NaOH (391 g NaOH + 0.8 L water) dropwise. Control the temperature at 10-20℃ and adjust the pH of the system to 12-13 (the system contains a small amount of flocculent matter). 13) Separate the liquid and extract the product again from the aqueous phase using n-heptane (3.0 L, 2 vol.); 14) Combine the n-heptane phases, wash with 15% sodium chloride aqueous solution (4.5 L, 3 vol.), and separate the layers; 15) The organic phase was dried with 2.0 kg of anhydrous sodium sulfate, filtered, and washed with n-heptane (1.5 L, 1 vol.); 16) Transfer the filtrate to a reaction flask, bubble with nitrogen for 0.5-1 h, and add diphenyl disulfide (263 g, 0.16 eq.). 17) Replace with nitrogen and heat to 65-70℃; 18) Add a mixed solution of dimethyl azobisisobutyrate (277 g, 0.16 eq.) and ethyl acetate (1.5 L, 1 vol.) dropwise, completing the addition in about 1 hour; 19) The mixture was kept at 65-70℃ and stirred for 12-16 h. The configuration ratio detected by the central control was Z / E=9 / 91, and the olefin recovery rate was 94.7%. 20) Concentrate the system to dryness under reduced pressure at an external temperature of 50°C, and add ethyl acetate (4.5 L, 3 vol.). 21) Heat to 40-50℃, add dropwise a solution of 4 mol / L hydrogen chloride in ethyl acetate (1.88 L, 1.0 eq.), and add a small amount of seed crystals when about 1 / 3 of the solution has been added; 22) After the dripping is complete, stop heating and slowly cool to room temperature, stirring for 1-2 hours; 23) Filter and wash with ethyl acetate (3.0 L, 2 vol.); 24) After drying, 1.36 kg of crude product was obtained, with an HPLC purity of 96.6% and a configuration ratio of Z / E = 1.5 / 96.6; 25) Add methanol (0.91 L, 0.67 vol, based on crude product) to the reaction flask, along with the crude product (1.36 kg, 1.0 Y), and heat to 40-50℃ to dissolve completely. 26) Control the temperature at 40-50℃ and add methyl tert-butyl ether (13.6 L, 10 vol.) dropwise, completing the addition in about 2 hours; 27) Turn off the heating and let it cool naturally to room temperature (25℃), then cool to 5℃ (0-10℃ is also acceptable), and stir for 0.5-1 h; 28) Filter and rinse with methyl tert-butyl ether (2.7 L, 2 vol.); 29) 1.28 kg of product was obtained after drying, with an HPLC purity of 99.8% and a configuration ratio of Z / E = 0.06 / 99.94; 30) Dissolve 1.28 kg of the product in water (2.6 L, 2 vol.) and add dichloromethane (3.8 L, 3 vol.); 31) Add 20wt% potassium phosphate aqueous solution dropwise to adjust the pH to ~9; 32) Separate the liquid phase, and extract the aqueous phase again with dichloromethane (3.8 L, 3 vol.); 33) Separate the liquid and combine the organic phases, then wash with 15% sodium chloride aqueous solution (2.6 L, 2 vol.); 34) The product compound 8 (1.09 kg) was dried with anhydrous sodium sulfate (2.6 kg, 2.0 X) and concentrated under reduced pressure to obtain product compound 8. The product had an HPLC purity of 99.85%, a configuration ratio of Z / E = 0.04 / 99.85, ee% > 99.0%, and a yield of 65.4% (the yield here is the total yield of compound 8 prepared from compound 4).

[0089] The seed crystals in the above-mentioned operation steps can be prepared by the following method: Take 1.2 L of the n-heptane solution obtained in step 15) above (containing 115 g of compounds E / Z), add 21.9 g of diphenyl disulfide, heat to 69℃, add dropwise a mixed solution of 23.1 g of dimethyl azobisisobutyrate and 125 mL of ethyl acetate, stir at 70℃ for 16 h, concentrate to remove the solvent, add 390 mL of ethyl acetate, heat to 45℃, add dropwise 163 mL of ethyl acetate solution of hydrogen chloride (4 M), after the addition is complete, slowly lower to 20℃ and stir for 16 h, filter, dry to obtain 115 g of solid, take 105 g of solid, add 70 mL of methanol, heat to 46℃ to dissolve, add dropwise 1.05 L of methyl tert-butyl ether, after the addition is complete, slowly lower to 3℃, filter, dry to obtain 98.8 g of solid (i.e., the hydrochloride salt of compound 8), which is the seed crystal.

[0090] The double bond in compound 8 has an E configuration, which was confirmed by 1H NMR and NOE spectra.

[0091] The 1H NMR spectrum data of compound 8 are as follows:

[0092] 1 H NMR (400 MHz, CDCl3) δ 6.62 (d, J = 1.9 Hz, 0.5 H), 6.41 (d, J =1.9 Hz, 0.5 H), 4.17 (m, 2H), 3.23 (d, J = 15.5 Hz, 1H), 2.85 – 2.70 (m, 2H), 2.25 (s, 3H), 2.22 – 2.11 (m, 1H), 1.97 – 1.84 (m, 1H), 1.77 (d, J = 11.0 Hz,1H), 1.27-1.23 (m, 3H), 1.24 (s, 3H).

[0093] The NOE spectrum of compound 8 shows a strong NOE cross peak between the hydrogen atom (H1) on the double bond and the hydrogen atom (H2) on the methyl group attached to the chiral carbon atom. Among them, δ 6.62 and δ 6.41 are attributed to H1, and δ 1.24 is attributed to H2. Therefore, H1 and H2 are related, proving that δ 6.62 and 6.41 are E-type olefinic hydrogens.

[0094]

[0095] The 1H NMR spectra of the Z-configuration compound corresponding to compound 8 are as follows: 1H NMR (400 MHz, CDCl3)δ 6.53 (d, J = 0.72 Hz, 0.5 H), 6.32 (d, J = 0.72 Hz, 0.5 H), δ 4.22-4.16 (m,2H), 3.01 (d, J = 11.3 Hz, 1H), 2.66 – 2.55 (m, 1H), 2.25 (s, 3H), 2.24 –2.16 (m, 1H), 2.15 – 2.02 (m, 2H), 2.00 (d, J = 11.1 Hz, 1H), 1.48 (d, J =4.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0096] The NOE spectrum of the Z-configuration compound shows that there is no observable NOE cross peak between the hydrogen atom (H3) on the double bond and the hydrogen atom (H2) on the methyl group attached to the chiral carbon atom. δ 6.53 and δ 6.32 are attributed to H3, and δ 1.48 is attributed to H2. Therefore, H3 and H2 are not correlated, proving that δ 6.53 and 6.32 are Z-type olefinic hydrogens.

[0097]

[0098] Example 3.1 Preparation of compound 8 from compound 6 and compound 6A

[0099] 100 mg of a mixture of compounds 6 and 6A (77.8% assay, molar ratio of compounds 6 and 6A 59:41) was dissolved in 1 mL (10 vol.) of tetrahydrofuran. 11.9 mg of diphenyl disulfide (CAS: 882-33-7, 0.054 mmol, 0.15 eq) and 13.4 mg of dimethyl azobisisobutyrate (CAS: 2589-57-3, 0.054 mmol, 0.15 eq) were added. The mixture was purged with nitrogen six times and stirred at 70 °C for 19 h. After cooling, the reaction solution was diluted to a 20 mL volumetric flask. HPLC analysis revealed an E / Z ratio of 7.47 / 1 and a product recovery rate (also known as olefin recovery rate) of 98.4%.

[0100] Comparative Example 3.1 Preparation of Compound 8 from Compound 6 and Compound 6A

[0101] Using the same preparation method as in Example 3.1, except that the initiator dimethyl azobisisobutyrate was replaced, the specific results are as follows:

[0102] Comparative Example 3.2 Preparation of Compound 8 from Compound 6 and Compound 6A

[0103] Using the same preparation method as in Example 3.1, except that the diphenyl disulfide was replaced with other free radical sources, the specific results are as follows:

[0104] Example 4 Preparation of Compound 1

[0105] 1) Add ethylene glycol dimethyl ether (4.2 L, 5.0 vol.) and compound 8 (834 g, 1.0 eq.) to the reactor, turn on nitrogen protection and start stirring; 2) Cool the system to 0~10℃; 3) Control the temperature at 0~10℃, and slowly add LiAlH4 / THF (2.5 M) solution (1.13 L, 0.73 eq.) dropwise over a period of about 1 hour; 4) After the addition is complete, keep the mixture at 0~10℃ and stir for 30 min, then take a sample for monitoring: the raw materials have reacted completely; 5) Control the temperature T < 10℃, slowly add sodium sulfate decahydrate (583 g) in batches. The system releases heat and gas. Pay attention to ensuring the pipeline is unobstructed and to ensure the safe release of gas. 6) After the addition is complete, the system becomes viscous (colloidal) and the stirring is poor. The stirring condition improves over time. 7) Add 1.67 kg of anhydrous sodium sulfate and stir for 0.5 h; filter the system, wash the filter cake three times with 2.5 L of ethylene glycol dimethyl ether, combine the filtrates and concentrate under reduced pressure at T≤45℃, then pump until almost no fraction remains, to obtain 642 g of a light yellow oily compound 1 with a purity >99.0%. ee %>99.0%, content 99.5%, yield of content 97.5%.

[0106] 1 H NMR (400 MHz, Chloroform- d ): δ 6.48 (d, J = 88.7 Hz, 1H), 4.47 (s,1H), 3.74 (d, J = 11.7 Hz, 1H), 3.53 (d, J= 10.4 Hz, 1H), 2.89 – 2.81 (m,1H), 2.79 – 2.70 (m, 2H), 2.51 – 2.39 (m, 1H), 2.00 – 1.87 (m, 2H), 2.22 (s,3H), 0.92 (s, 3H).

[0107] Example 5 Preparation of Compound 20

[0108] 1) Add compound 19 (420 g, 1.0 eq.) and DMF (2.1 L, 5 vol.) to the reaction flask and start stirring; 2) Add potassium hydroxide (211 g, 1.5 eq.) in batches and stir for 0.5 hours; 3) Cool down to -30 ~ -20℃; 4) Introduce chlorofluoromethane (266 g, 1.5 eq.) over approximately half an hour, maintaining the temperature at -30 ~ -20℃; 5) Keep warm at -30 ~ -20℃ for half an hour, remove the cold bath, slowly warm to 20-30℃ and stir for 48 hours until the raw material content is less than 3%; 6) After the reaction is complete, add water dropwise to the system (3.78 L, 9 vol.). After the addition is complete, stir at 15-25℃ for 1-2 h. 7) Filtration: The filter cake was washed twice with water (1.68 L, 4 vol.), resulting in a 4% product loss in the mother liquor. 8) Add 0.5% acetic acid aqueous solution (1.68 L, 4 vol.) to the reaction flask, add filter cake, and stir for 0.5-1 h; 9) Filter and rinse with water (1.26 L, 3 vol.); 10) Dry the product compound 20 (434 g) at 40-50℃ with forced air drying to obtain a content of 92% and a yield of 80% based on the content.

[0109] 1 H NMR (400 MHz, Chloroform-d): δ 7.96 (d, J = 8.1 Hz, 1H), 7.80 (d,J = 8.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 6.16 (d,J = 51.0 Hz, 2H).

[0110] Example 6 Preparation of Compound 5

[0111] 1) Add ethyl acetate (3.6 L, 5.0 V) and compound 20 (717 g, 1.0 eq.) to the reaction vessel and stir until dissolved; 2) Add glacial acetic acid (1.44 L, 2.0 V); 3) Control the temperature at 20~30℃, and add the first batch of 8~10% NaClO aqueous solution (13.5 L, 5.0 eq.) dropwise over 3 h; 4) After the addition is complete, keep the mixture warm and stir for 30 minutes. A yellow solid precipitates in the system. A sample is taken for monitoring: the raw materials have reacted completely, and about 8% of the intermediate remains. 5) Allow the reaction system to stand and separate into layers, then release the lower aqueous phase (13.3 L, experimental value, subject to actual conditions); 6) Control the temperature at 20~30℃, and add the second batch of 8~10% NaClO aqueous solution (8.1 L, 3.0 eq.) dropwise over 1 h; 7) After dripping, keep warm at 20-30℃ and stir overnight; 8) Sampling control: Approximately 3.4% of intermediates remain; 9) Filter by suction, and record the filter cake as LB1; record the mother liquor as MY1; 10) After washing the filter cake LB1 with 10% Na2SO3 aqueous solution (2.0 L, 2.8 V) and saturated NaHCO3 aqueous solution (2.0 L, 2.8 V), filter the filter cake by vacuum filtration. The filter cake is counted as LB2. 11) After drying the filter cake LB2 at 45℃, 498 g of white crude product was obtained, with a purity of 96.2% (Assay: 98.0%). 12) Separate the mother liquor MY1 into layers. Wash the organic phase sequentially with water (2.8 L, 4 V), 10% Na2SO3 aqueous solution (2.8 L, 4 V), and saturated NaHCO3 aqueous solution (2.0 L, 2.8 V). After separation, dry the organic phase with Na2SO4, filter and concentrate to obtain 218 g of yellow crude product with a purity of 92.9%. 13) Combine the two batches of crude product (686 g), add to isopropyl acetate (4 L, 5.8 V), heat to 80~85℃, stir until dissolved, and keep warm and stirring for 0.5 h; 14) Turn off the heating and allow it to cool naturally to 30-35℃; add petroleum ether (4.0 L, 5.8 V) dropwise over 1 hour; 15) After the dripping is complete, cool the system to 0~5℃, keep it at this temperature and stir for 1 h, then filter it. Wash the filter cake with petroleum ether (1.0 L, 1.5V). 16) The filter cake was dried by forced air at 45°C for 5 hours to obtain a white solid product, compound 5 (558 g), with a purity of 98.3% and a yield of 75%.

[0112] 1 H NMR (400 MHz, Chloroform-d): δ 8.26 (d, J = 8.9 Hz, 1H), 8.04 (d,J = 8.8 Hz, 1H), 7.71 – 7.56 (m, 2H), 5.59 (d, J = 46.8 Hz, 2H).

Claims

1. A method for preparing a compound as shown in Formula VII, comprising the following steps: in a solvent, in the presence of a free radical initiator and a free radical source, the compound as shown in Formula VI-1 undergoes an isomerization reaction to prepare the compound as shown in Formula VII. ； in, R is a C1-C6 alkyl group; The free radical initiator is dimethyl azobisisobutyrate, and the free radical source is diphenyl disulfide.

2. The method for preparing the compound as shown in Formula VII according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) In the isomerization reaction, the solvent is selected from one or more of cyclic ether solvents, ester solvents and hydrocarbon solvents; (3) In the isomerization reaction, the volume molar ratio of the solvent to the compound shown in Formula VI-1 is (1~8) L / mol; (4) In the isomerization reaction, the molar ratio of the free radical source to the compound shown in Formula VI-1 is (0.1~1):1; (5) In the isomerization reaction, the molar ratio of the free radical initiator to the compound shown in Formula VI-1 is (0.1~1):1; (6) The reaction temperature of the isomerization reaction is 60~80℃; (7) The reaction time for the isomerization reaction is 10-25 h; (8) The isomerization reaction is carried out in an atmosphere of inert gas; (9) The raw materials for the isomerization reaction are the solvent, the free radical initiator, the free radical source and the compound shown in Formula VI-1; (10) The free radical initiator is added in solution form to the mixture of the solvent, the free radical source and the compound shown in Formula VI-1, wherein the solvent in the solution of the free radical initiator is selected from one or more of cyclic ether solvents, ester solvents and hydrocarbon solvents; (11) After the isomerization reaction is completed, the following steps are performed for post-processing, including: acidification, recrystallization, neutralization, extraction and concentration.

3. The method for preparing the compound as shown in Formula VII according to claim 2, characterized in that, It meets one or more of the following conditions: (1) The R mentioned above is an ethyl group; (2) The cyclic ether solvent is tetrahydrofuran; (3) The ester solvent is ethyl acetate; (4) The hydrocarbon solvent is n-heptane; (5) In the isomerization reaction, the solvent is an ester solvent, a cyclic ether solvent, or a "mixed solvent of hydrocarbon solvent and ester solvent"; (6) In the isomerization reaction, the volume molar ratio of the solvent to the compound shown in Formula VI-1 is (2~4) L / mol; (7) In the isomerization reaction, the molar ratio of the free radical source to the compound shown in Formula VI-1 is (0.15~0.3):1; (8) In the isomerization reaction, the molar ratio of the free radical initiator to the compound shown in Formula VI-1 is (0.15~0.3):1; (9) The reaction temperature of the isomerization reaction is 65~70℃; (10) The reaction time for the isomerization reaction is 12-19 h; (11) The isomerization reaction is carried out in an atmosphere of inert gas, wherein the inert gas is nitrogen or argon; (12) The free radical initiator is added in solution form to the mixture of the solvent, the free radical source and the compound shown in Formula VI-1, wherein the solvent in the solution of the free radical initiator is an ester solvent; (13) When the free radical initiator is added in solution form, it is added dropwise; (14) In the post-processing steps, acidification, recrystallization, neutralization, extraction and concentration are carried out in sequence.

4. The method for preparing the compound as shown in Formula VII according to claim 3, characterized in that, It meets one or more of the following conditions: (1) In the isomerization reaction, the solvent is an ester solvent, a cyclic ether solvent or a "mixed solvent of hydrocarbon solvent and ester solvent", wherein the volume ratio of ester solvent to hydrocarbon solvent in the "mixed solvent of hydrocarbon solvent and ester solvent" is 1:(5~10). (2) The isomerization reaction is carried out in an atmosphere of inert gas, wherein the inert gas is nitrogen; (3) When the free radical initiator is added in the form of a solution, it is added dropwise and the addition is completed in 0.5 to 2 hours; (4) In the post-processing step, the acidification is performed using an inorganic acid; (5) In the post-processing step, the molar ratio of the acid used for acidification to the compound shown in Formula VI-1 is (1~2):1; (6) In the post-processing step, the solid obtained after acidification is a salt; (7) In the post-processing step, the recrystallization is the recrystallization of the solid obtained by acidification; (8) In the post-processing step, the recrystallization is solvent-antisolvent recrystallization; (9) In the post-processing step, the neutralization is to neutralize to a pH of 8.5 to 9.5; (10) In the post-processing step, the neutralization is to use a weak acid salt of an alkali metal to free the salt obtained by recrystallization; (11) In the post-processing step, the solvent used for extraction is a water-insoluble organic solvent; (12) The post-processing step further includes the use of seed crystals. Specifically, seed crystals are added during or after acidification. The seed crystals are salts of compounds as shown in Formula VII. In the salt, the acid that forms a salt with the compound as shown in Formula VII is the acid used in the acidification. The number of acids is the same as the number of acids in the salt obtained after acidification.

5. The method for preparing the compound as shown in Formula VII according to claim 4, characterized in that, It meets one or more of the following conditions: (1) In the isomerization reaction, the solvent is an ester solvent, a cyclic ether solvent or a "mixed solvent of hydrocarbon solvent and ester solvent", wherein the volume ratio of ester solvent to hydrocarbon solvent in the "mixed solvent of hydrocarbon solvent and ester solvent" is 1:8; (2) When the free radical initiator is added in the form of a solution, it shall be added dropwise and the addition shall be completed in 1 hour; (3) In the post-processing step, the acidification is performed using an inorganic acid, which is hydrochloric acid or sulfuric acid; (4) In the post-processing step, the molar ratio of the acid used for acidification to the compound shown in Formula VI-1 is 1:1; (5) In the solvent-antisolvent recrystallization process, the solvent is an alcohol solvent; (6) In the solvent-antisolvent recrystallization process, the solvent is an ether solvent; (7) In the solvent-antisolvent recrystallization, the volume-to-mass ratio of the solvent to the solid to be recrystallized is (0.5~0.8) L / kg; (8) In the solvent-antisolvent recrystallization, the volume-to-mass ratio of the antisolvent to the solid to be recrystallized is (8~12) L / kg; (9) The solvent-antisolvent recrystallization specifically includes the following steps: the solid to be recrystallized is mixed with the solvent to dissolve it, and then mixed with the antisolvent; (10) In the post-processing step, the neutralization is to neutralize to a pH of 9; (11) In the post-processing step, the neutralization is to use a weak acid salt of an alkali metal to free the salt obtained by recrystallization, wherein the weak acid salt of the alkali metal is in the form of an aqueous solution. (12) In the post-processing step, the neutralization is to use a weak acid salt of an alkali metal to free the salt obtained by recrystallization, wherein the weak acid salt of the alkali metal is potassium phosphate. (13) In the post-processing step, the solvent used for extraction is a water-insoluble organic solvent of haloalkanes; (14) The post-processing step further includes the use of seed crystals, specifically, the addition of seed crystals during the acidification process.

6. The method for preparing the compound as shown in Formula VII according to claim 5, characterized in that, It meets one or more of the following conditions: (1) In the isomerization reaction, the solvent is ethyl acetate, tetrahydrofuran or "a mixed solvent of ethyl acetate and n-heptane"; (2) In the post-processing step, the acidification is performed using hydrochloric acid; (3) In the solvent-antisolvent recrystallization, the solvent is methanol; (4) In the solvent-antisolvent recrystallization, the solvent is methyl tert-butyl ether; (5) In the solvent-antisolvent recrystallization, the volume-to-mass ratio of the solvent to the solid to be recrystallized is 0.67 L / kg; (6) In the solvent-antisolvent recrystallization, the volume-to-mass ratio of the antisolvent to the solid to be recrystallized is 10 L / kg; (7) The solvent-antisolvent recrystallization specifically includes the following steps: mixing the solid to be recrystallized with the solvent, dissolving it at 40~50℃, and then mixing it with the antisolvent; (8) The solvent-antisolvent recrystallization specifically includes the following steps: mixing the solid to be recrystallized with the solvent, dissolving it, and adding the antisolvent dropwise into the "solution of the solid to be recrystallized and the solvent"; (9) The solvent-antisolvent recrystallization specifically includes the following steps: mixing the solid to be recrystallized with the solvent, dissolving it, then mixing it with the antisolvent, cooling it to 0~10℃, and separating the solid; (10) In the post-processing step, the neutralization is to use a weak acid salt of an alkali metal to free the salt obtained by recrystallization, wherein the weak acid salt of the alkali metal is potassium phosphate, and the potassium phosphate is in the form of an aqueous solution with a mass percentage of 15-25%. (11) In the post-processing step, the solvent used for extraction is dichloromethane; (12) In the post-processing step, the acidification is to add acid dropwise to the crude isomerization reaction solution to be acidified, and when the amount of acid added is 1 / 3 to 1 / 2 of the original amount, the seed crystal is added.

7. The method for preparing the compound as shown in Formula VII according to claim 6, characterized in that, It meets one or more of the following conditions: (1) In the isomerization reaction, the solvent is ethyl acetate, tetrahydrofuran or "a mixed solvent of ethyl acetate and n-heptane", and in the "mixed solvent of ethyl acetate and n-heptane", the volume ratio of ethyl acetate to n-heptane is 1:(5~10). (2) In the post-processing step, the acidification is acidification with hydrochloric acid, the hydrochloric acid is a hydrochloric acid solution, and the solvent in the hydrochloric acid solution is selected from one or more of cyclic ether solvents, ester solvents and hydrocarbon solvents; (3) In the post-processing step, the neutralization is to use a weak acid salt of an alkali metal to free the salt obtained by recrystallization, wherein the weak acid salt of the alkali metal is potassium phosphate, and the potassium phosphate is in the form of an aqueous solution with a mass percentage of 20%.

8. The method for preparing the compound as shown in Formula VII according to claim 7, characterized in that, It meets one or more of the following conditions: (1) In the isomerization reaction, the solvent is ethyl acetate, tetrahydrofuran or "a mixed solvent of ethyl acetate and n-heptane", and in the "mixed solvent of ethyl acetate and n-heptane", the volume ratio of ethyl acetate to n-heptane is 1:8; (2) In the post-processing step, the acidification is performed using an ethyl acetate solution of hydrochloric acid.

9. The method for preparing the compound as shown in Formula VII according to claim 8, characterized in that, It meets one or more of the following conditions: (1) In the post-processing step, the acidification is carried out using an ethyl acetate solution of 1~5 mol / L hydrochloric acid; (2) The compound shown in Formula VI-1 participates in the reaction in the form of a mixture, wherein the mixture is the compound shown in Formula VI-1 and A mixture.

10. The method for preparing the compound as shown in Formula VII according to claim 9, characterized in that, It meets one or more of the following conditions: (1) In the post-processing step, the acidification is performed using an ethyl acetate solution of 4 mol / L hydrochloric acid; (2) The compound shown in Formula VI-1 participates in the reaction in the form of a mixture, wherein the mixture is the compound shown in Formula VI-1 and A mixture, wherein the compound as shown in Formula VI-1 and The molar ratio is (0.1-10):1.

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