Preparation method of fluorinated compound

Abstract

The invention discloses a preparation method of a fluorinated compound. Specifically, the invention discloses a preparation method of a compound as shown in a formula VI, which comprises the following step: in a solvent, under the action of alkali, carrying out an alkylenation reaction on a compound as shown in a formula IV (R) and a Julia-Kocienski reagent to prepare the compound as shown in the formula VI. The fluorinated compound prepared by the preparation method disclosed by the invention is high in yield, and can be used for further better preparing the [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidyl] methanol.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing a fluorinated compound. BACKGROUND

[0002] Ras, the rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. However, the drug development against Ras in the past decades shows that due to the smooth surface of the Ras protein, the lack of obvious groove or pocket structure for binding small molecule inhibitors, and its very high affinity for guanine substrate (picomolar level), the development of small molecule inhibitors for it has been in an unsolvable dilemma, thus Ras has long been considered as an "undruggable" target in the industry. At the same time, there is still a great need for more structural types or modes of compounds as KRas inhibitors, to provide more treatment options, or to provide further improved inhibitory activity relative to existing KRas inhibitors, thereby providing more potent therapeutic drugs for clinical use.

[0003] The KRAS G12D inhibitors disclosed in CN117624170A and CN117800975A patent applications solve these problems and other needs, providing new structural inhibitor compounds with KRas mutant protein inhibitory activity. These compounds have improved structural patterns, have enhanced inhibitory activity of KRas mutant proteins and related tumor inhibitory activity compared to existing KRas mutant protein inhibitors in the prior art, have good pharmacokinetic properties, and thus have good drugability, such as easier absorption in the body after being administered in a convenient manner, reduced toxicity and side effects, improved drug resistance and safety, and reduced risk of drug interactions.

[0004] An important intermediate compound 1 ([(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidyl] methanol) is involved in the preparation process of these KRAS G12D inhibitors. In the drug discovery stage, the preparation method and process of the intermediate are as follows:

[0005] As shown above, the synthesis of the API material in the gram scale in the drug discovery stage can be used for in vivo and PK assays. However, it has several drawbacks, including expensive starting material compound 9, low yield of several steps, sensitive reaction conditions, the need for SFC separation of enantiomers and chromatographic purification of several steps. The specific analysis is as follows: The synthetic route of the drug discovery stage of compound 1 starts from the alkylation reaction of compound 9 to generate compound 10, and then goes through Wittig reaction, Boc group deprotection, reductive amination, and finally ester reduction to obtain the oil-like intermediate compound 1 product. The advantage of this route is to directly synthesize compound 1, and the steps are relatively short (5 steps). However, there are several inherent disadvantages.

[0006] a) In step 1, the methylation requires a long heating time, which may be due to the weak basicity of K2CO3. In addition, SFC (SFC, i.e. supercritical CO2 chromatographic separation) separation is required to provide the required enantiomer, which is costly.

[0007] b) For step 2, in addition to the expensive Wittig reagent and low-temperature conditions, another disadvantage is the mediocre stereoselectivity (E / Z ratio is about 3:1), which leads to very time-consuming and costly chromatographic purification.

[0008] c) In step 4, the reaction process is complicated and requires pH adjustment. In addition, highly flammable sodium cyanoborohydride may pose a safety risk in future large-scale production.

[0009] d) Step 5 should be noted that the use of LiAlH4 leads to the release of H2 during the quenching process.

[0010] Based on the above many deficiencies in the intermediate synthesis route of the drug discovery stage, it is urgent to develop an intermediate synthesis route suitable for industrial production. SUMMARY

[0011] In view of the problems existing in the prior art, the purpose of the present application is to provide a preparation method of a fluorinated compound. The fluorinated compound prepared by the preparation method of the present application has high yield and can be used to further prepare [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidyl] methanol.

[0012] The present application solves the above technical problems by the following technical solutions.

[0013] The present application provides a preparation method of a compound as shown in formula VI, which comprises the following steps: in a solvent, under the action of a base, a compound as shown in formula IV (R) is subjected to olefination reaction with a reagent to prepare a compound as shown in formula VI, Julia-Kocienski ; wherein, the wavy line indicates that the configuration of the double bond is E configuration, Z configuration or a mixture thereof; R and R 1 are independently C1-C6 alkyl; the base is​ , R a , R b , R c , R d , R e , and R f are each independently C1-C6 alkyl, and M is an alkali metal; said solvent is , R m , and R n are independently C1-C4 alkyl; said Julia-Kocienski agent is a compound as shown in Formula V ; said ene reaction has a reaction temperature of -50°C to 25°C.

[0014] Preferably, said ene reaction is carried out in two stages, the first stage has a reaction temperature of -50°C to -40°C (e.g., -45°C to -42°C), and the second stage has a reaction temperature of 15°C to 25°C (e.g., 20°C).

[0015] Preferably, said C1-C6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl, preferably methyl or ethyl.

[0016] Preferably, said C1-C4 alkyl is methyl, ethyl, or n-propyl, preferably methyl.

[0017] Preferably, said M is Li, Na, or K, preferably Li.

[0018] Preferably, said R is ethyl.

[0019] Preferably, said R 1 is methyl.

[0020] Preferably, in said ene reaction, said base is selected from one or more of , , and , preferably .

[0021] Preferably, in said ene reaction, said solvent is ethylene glycol dimethyl ether.

[0022] Preferably, in said ene reaction, the volume-to-mass ratio of said solvent to said compound as shown in Formula IV(R) is 1 to 15 L / kg, e.g., 5 to 10 L / kg.

[0023] Preferably, in the enolization reaction, the molar ratio of the base to the compound of formula IV(R) is (0.5-2):1, for example (1-1.5):1, preferably 1.1:1.

[0024] Preferably, in the enolization reaction, the molar ratio of the base to the compound of formula IV(R) is (0.5-2):1, for example (1-1.5):1, preferably 1.1:1. Julia-Kocienski Preferably, in the enolization reaction, the molar ratio of the base to the compound of formula IV(R) is (0.5-2):1, for example (1-1.5):1, preferably 1.1:1.

[0025] Preferably, in the enolization reaction, the reaction raw materials of the enolization reaction are the solvent, the base, the compound of formula IV(R) and the reagent. Julia-Kocienski Preferably, in the enolization reaction, the reaction raw materials of the enolization reaction are the solvent, the base, the compound of formula IV(R) and the reagent.

[0026] Preferably, in the preparation method, the base is added to the mixture of the solvent, the compound of formula IV(R) and the reagent; and the temperature of the reaction system is preferably controlled to be -50°C to -40°C during the addition of the base. Julia-Kocienski Preferably, in the preparation method, the base is added to the mixture of the solvent, the compound of formula IV(R) and the reagent; and the temperature of the reaction system is preferably controlled to be -50°C to -40°C during the addition of the base.

[0027] Preferably, the base is in the form of a solution of the base, and the solvent in the solution of the base is a cyclic ether solvent, for example tetrahydrofuran.

[0028] Preferably, the base is in the form of a 0.5-1.5 mol / L solution of the base in tetrahydrofuran, for example a 1 mol / L solution of the base in tetrahydrofuran. Preferably, the base is in the form of a 0.5-1.5 mol / L solution of the base in tetrahydrofuran, for example a 1 mol / L solution of the base in tetrahydrofuran.

[0029] The reaction time of the enolization reaction is the conventional reaction time of such reactions in the art, and is generally until a certain raw material no longer reacts or the reaction is complete. Preferably, the enolization reaction is carried out in two stages, the reaction time of the first stage is 1-5 h (for example 2-3 h), and the reaction time of the second stage is 10-20 h (for example 14-18 h, preferably 16 h); the reaction temperature of the first stage is -50°C to -40°C (for example -45°C to -42°C), and the reaction temperature of the second stage is 15-25°C (for example 20°C).

[0030] The enolization reaction can be post-treated by one or more of the following steps: quenching, extraction, concentration, acidification to salt, neutralization.

[0031] Preferably, the post-treatment comprises the following steps in sequence: quenching, first extraction, concentration, dilution, acidification to salt, retention of the aqueous phase, neutralization, second extraction.

[0032] Preferably, the quenching is carried out using a saturated aqueous ammonium chloride solution.

[0033] Preferably, the solvent used in the first extraction is a water-insoluble organic solvent, such as ethyl acetate.

[0034] Preferably, the solvent used in the dilution is a cyclic ether solvent, such as 2-methyltetrahydrofuran.

[0035] Preferably, the acid used in the acidification is hydrochloric acid, which can be in the form of an aqueous solution of hydrochloric acid, such as an aqueous solution of hydrochloric acid at 1-2 mol / L.

[0036] Preferably, the temperature of the system is controlled at 10-20 °C during the neutralization.

[0037] Preferably, the base used in the neutralization is an alkali hydroxide, such as sodium hydroxide, which can be in the form of an aqueous solution of sodium hydroxide (such as an aqueous solution of sodium hydroxide at 10-15 mol / L, further such as an aqueous solution of sodium hydroxide at 12 mol / L).

[0038] Preferably, the neutralization is to a pH of 12-13.

[0039] Preferably, the solvent used in the second extraction is an alkane solvent, such as n-heptane.

[0040] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any manner, thereby obtaining preferred embodiments of the present application.

[0041] The reagents and raw materials used in the present application are commercially available.

[0042] The positive progress effect of the present application is that the fluorinated compound prepared by the preparation method of the present application has a high yield, and can be used for further preparation of [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidyl]methanol. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 Molecular ellipsoid plot of a single crystal of the D-DTTA salt of compound 3 in a single configuration.

[0044] Figure 2 Molecular ellipsoid plot of a single crystal of the L-tartaric acid salt of compound 3 in a single configuration. DETAILED DESCRIPTION

[0045] The present application will be further described by way of examples, but the present application is not limited to the examples. The experimental methods in the following examples, for which no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the commercial products.

[0046] Preparation route of compound 1:

[0047] The preparation route of compound 5 is shown as follows:

[0048] Step 1: two Mannich reactions are carried out in an inert solvent (including but not limited to ethanol, methanol or isopropanol) using cheap and readily available compound 2, a formaldehyde source and methylamine as raw materials to generate compound 3.

[0049] Step 2: then, a chiral organic acid is added to the compound 3 in an inert solvent to carry out a chemical chiral resolution to obtain a chiral pure compound 4 in a high yield.

[0050] Step 3: then, a base is added to the compound 4 in an inert solvent to carry out a Julia-Kocienski olefination reaction with compound 5 to obtain a mixture of E compound 6 and Z compound 6A.

[0051] Step 4: the mixture is subjected to a configuration transformation to obtain a single configuration compound 8 in the presence of an initiator and a free radical source.

[0052] Step 5: the compound 8 is 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.

[0053] Example 1 Preparation of compound 3

[0054] 1) ethanol (20 L, 10 vol.), methylamine hydrochloride (2.00 kg, 1.0 eq.) and paraformaldehyde (2.67 kg, 3.0 eq.) are added to a reaction bottle; 2) 2-methylacetoacetate ethyl ester (4.48 kg, 1.05 eq.) and triethylamine (0.30 kg, 0.1 eq.) are added; 3) nitrogen replacement for 3 times; 4) temperature is raised to 60°C (60°C-70°C can be used) and stirred for 16 h or more until the amount of substance of 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), wherein n represents the amount of substance; 5) triethylamine (3.00 kg, 1.0 eq.) is added and the reaction is continued at 60°C (60°C-70°C can be used) for 2-3 h; after the reaction is completed, the in-situ yield of compound 3 in the reaction solution is 60% measured by HPLC external standard method.

[0055] Post-treatment: cooling, concentration under reduced pressure until the system does not distill (rotary evaporation, the external concentration temperature is 50°C); the concentrated residue is mixed with ethyl acetate and water, and extracted and separated; the organic phase is combined, washed with 10% NaCl aqueous solution, and separated; the organic phase is dried with anhydrous sodium sulfate, filtered, and washed with ethyl acetate; the washing liquid and the filtrate are combined, concentrated to 22 L, 4.5 L of 4 mol / L hydrogen chloride ethyl acetate solution is added dropwise, and after dripping, stirring is carried out for 1 h; filtration is carried out, and the filter cake is washed with ethyl acetate; the filter cake is added to saturated sodium bicarbonate solution, and the pH is adjusted to 7-8; ethyl acetate is added for extraction and separation; the organic phase is combined, and the organic phase is washed with 10% sodium chloride aqueous solution; separation is carried out, and anhydrous sodium sulfate is added to the organic phase for drying; filtration is carried out, and the filter cake is washed with ethyl acetate; the combined filtrate and washing liquid is concentrated to obtain 3.30 kg of compound 3 crude product with a content of 86.7%, and the yield is 48% based on the content.

[0056] 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).

[0057] LCMS (m / z): 200.1 [M+H]。

[0058] Example 2.1 Preparation of compound 4

[0059] 2000 mg of compound 3 (10 mmol, 1 eq.) is dissolved in 20 mL (10 vol.) of acetonitrile, 1.54 g of D-DTTA (CAS:32634-68-7, 4 mmol, 0.4 eq.) is added, heated to 60°C, stirred for 3 h, naturally cooled to room temperature 20°C, filtered, and vacuum dried to obtain 1.94 g of white solid (D-DTTA salt of compound 3 in single configuration, with an ee value of 95.06%). 0.97 g of the white solid is added to saturated sodium bicarbonate aqueous solution (100 mL), and then extracted with ethyl acetate (100 mL 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%.

[0060] 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.

[0061] The specific test parameters are as follows: Testing instrument: D8 Venture Instrument Model: D8 Venture Instrument parameters: Light source: Cu target; X-rays: Cu-Ka (=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).

[0062] Example 2.2 Preparation of Compound 4

[0063] 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%.

[0064] 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.

[0065] Example 2.3 Preparation of Compound 4

[0066] 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.

[0067] 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).

[0068] Example 2.4 Preparation of Compound 4

[0069] 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%.

[0070] Example 2.5 Preparation of Compound 4

[0071] 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%.

[0072] Example 2.6 Preparation of Compound 4

[0073] 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%.

[0074] Example 2.7 Preparation of Compound 4

[0075] 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 drying were performed to finally obtain 311.4 mg of free compound 4 with an ee value of 87.32%.

[0076] 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.

[0077] 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.

[0078] Example 2.8 Preparation of Compound 4

[0079] 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, 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%.

[0080] Example 3 Preparation of Compound 8

[0081] 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 at -45℃ (-50~-40℃ is acceptable), and slowly add 8.28 L, 1.1 eq. of tetrahydrofuran solution of bis(trimethylsilylamine) lithium (1.0M) dropwise, completing the addition 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-situ The 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).

[0082] 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.

[0083] The double bond in compound 8 has an E configuration, which was confirmed by 1H NMR and NOE spectra.

[0084] The 1H NMR spectrum data of compound 8 are as follows:

[0085] 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).

[0086] 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.

[0087]

[0088] 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).

[0089] 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.

[0090]

[0091] Example 3.1 Preparation of Compound 6 and Compound 6A from Compound 4

[0092] Compound 4 (90 mg, 0.451 mmol) and compound 5 (156.7 mg, 0.677 mmol) were dissolved in ethylene glycol dimethyl ether (0.9 mL) and cooled to -42°C using a dry ice / acetonitrile bath. Under nitrogen protection, LiHMDS (1 M tetrahydrofuran solution, 0.677 mL, 0.677 mmol) was added to the solution (temperature controlled between -50°C and -40°C). The reaction mixture was stirred at -42°C for 3 hours, then the cooling bath was removed, and the mixture was allowed to rise naturally to 20°C and stirred for another 16 hours. The reaction mixture was quenched with saturated ammonium chloride (0.2 mL), then diluted with ethanol and brought to a final volume of 50 mL. HPLC external standard analysis showed an E / Z ratio of 1 / 2.7, with an in-situ yield of 98.5% (E-type plus Z-type). In-situ yield = reaction mixture content Reaction liquid weight / theoretical yield.

[0093] Comparative Example 3.1 Preparation of Compound 6 and Compound 6A from Compound 4

[0094] Under nitrogen protection, 1.5 equivalents of compound 4 (162.78 mg, 0.817 mmol) and 1.0 equivalent of 2-fluoromethanesulfonylbenzothiazole (126.04 mg, 0.545 mmol) were added to a 25 mL round-bottom flask, dissolved in 2.2 mL of freshly distilled tetrahydrofuran (THF), and cooled to -78 °C. Subsequently, 2.0 equivalents of 1 M LiHMDS in THF solution (1.09 mL, 1.09 mmol) were slowly added dropwise over 10 minutes, while stirring for 45 minutes.

[0095] The reaction solution was quenched with water (2.2 mL) at -78°C, diluted with dichloromethane, stirred at room temperature for 15 minutes, and then extracted twice with dichloromethane (5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation.

[0096] The residue was dissolved in 5.5 mL of dry THF, and 2.0 equivalents of DBU (165.94 mg, 1.09 mmol) were added. The mixture was stirred for 1 hour, and the reaction solution was diluted with ethanol to 50 mL. The reaction yield was determined to be 82.0% by HPLC external standard method.

[0097] Comparative Example 3.2 Preparation of Compound 6 and Compound 6A from Compound 4

[0098] Replace the reaction temperature of -78℃ in Comparative Example 3.1 above with -50~-40℃ (only change the reaction temperature), and the specific operation is as follows: Under nitrogen protection, 1.5 equivalents of compound 4 (162.78 mg, 0.817 mmol) and 1.0 equivalent of 2-fluoromethanesulfonylbenzothiazole (126.04 mg, 0.545 mmol) were added to a 25 mL round-bottom flask, dissolved in 2.2 mL of freshly distilled tetrahydrofuran (THF), and the mixture was cooled to -50 to -40 °C. Subsequently, 2.0 equivalents of a 1 M LiHMDS THF solution (1.09 mL, 1.09 mmol) were slowly added dropwise over 10 minutes, while stirring for 45 minutes.

[0099] The reaction solution was quenched with water (2.2 mL) at -50 to -40 °C, diluted with dichloromethane, stirred at room temperature for 15 minutes, and then extracted twice with dichloromethane (5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation.

[0100] The residue was dissolved in 5.5 mL of dry THF, and 2.0 equivalents of DBU (165.94 mg, 1.09 mmol) were added. The mixture was stirred for 1 hour, and the reaction solution was diluted with ethanol to 50 mL. The reaction yield was determined to be 77.4% by HPLC external standard method.

[0101] Example 4 Preparation of Compound 1

[0102] 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%.

[0103] 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).

[0104] Example 5 Preparation of Compound 20

[0105] 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.

[0106] 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).

[0107] Example 6 Preparation of Compound 5

[0108] 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%.

[0109] 1H 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 VI, comprising the following steps: in a solvent, under the action of a base, reacting the compound as shown in Formula IV(R) with... Julia-Kocienski The reagent was used to perform an olefination reaction to prepare the compound shown in Formula VI. ； in, The wavy line indicates that the double bond configuration is E configuration, Z configuration, or a mixture thereof; R and R 1 Independently, it is a C1-C6 alkyl group; The alkali mentioned is R a R b R c R d R e and R f Each is independently a C1-C6 alkyl group, and M is an alkali metal; The solvent is R m and R n Independently, it is a C1-C4 alkyl group; The aforementioned Julia-Kocienski The reagent is a compound as shown in formula V. ; The reaction temperature for the olefination reaction is -50℃ to 25℃.

2. The method for preparing the compound as shown in Formula VI according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The olefination reaction is carried out in two stages. The reaction temperature of the first stage is -50℃ to -40℃, and the reaction temperature of the second stage is 15℃ to 25℃. (2) The C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl; (3) The C1-C4 alkyl group is methyl, ethyl or n-propyl, preferably methyl; (4) M is Li, Na or K; (5) In the olefination reaction, the solvent is ethylene glycol dimethyl ether; (6) In the olefination reaction, the volume-to-mass ratio of the solvent to the compound shown in formula IV(R) is 1~15 L / kg; (7) In the olefination reaction, the molar ratio of the base to the compound shown in formula IV(R) is (0.5~2):1; (8) In the olefination reaction, the... Julia-Kocienski The molar ratio of the reagent to the compound shown in formula IV(R) is (0.5~2):1; (9) The reactants for the olefination reaction are the solvent, the base, the compound as shown in formula IV(R), and the... Julia-Kocienski Reagents; (10) In the preparation method described above, the base is added to the solvent, the compound as shown in formula IV(R), and the... Julia-Kocienski In the mixture of reagents; (11) The base is in the form of a solution of the base, and the solvent in the solution of the base is a cyclic ether solvent.

3. The method for preparing the compound as shown in Formula VI according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The C1-C6 alkyl group is methyl or ethyl; (2) The C1-C4 alkyl group is methyl; (3) M is Li; (4) In the olefination reaction, the volume-to-mass ratio of the solvent to the compound shown in formula IV(R) is 5-10 L / kg; (5) In the olefination reaction, the molar ratio of the base to the compound shown in formula IV(R) is (1~1.5):1; (6) In the olefination reaction, the... Julia-Kocienski The molar ratio of the reagent to the compound shown in Formula IV(R) is (1~1.5):1; (7) In the preparation method described above, the base is added to the solvent, the compound as shown in formula IV(R), and the... Julia-Kocienski In the reagent mixture, during the addition of the alkali, the temperature of the reaction system is controlled to be -50℃ to -40℃; (8) The alkali is in the form of a solution of alkali, wherein the solvent in the solution of alkali is tetrahydrofuran.

4. The method for preparing the compound as shown in Formula VI according to claim 1, characterized in that, It meets one or more of the following conditions: (1) R is an ethyl group; (2) R 1 It is methyl; (3) In the olefination reaction, the base is selected from... , and One or more of the following; (4) The molar ratio of the base to the compound shown in formula IV(R) is 1.1:1; (5) Julia-Kocienski The molar ratio of the reagent to the compound shown in Formula IV(R) is 1.1:1; (6) The base is in the form of a tetrahydrofuran solution of 0.5~1.5 mol / L base; (7) The olefination reaction is carried out in two stages. The reaction time of the first stage is 1 to 5 hours and the reaction time of the second stage is 10 to 20 hours. The reaction temperature of the first stage is -50℃ to -40℃ and the reaction temperature of the second stage is 15 to 25℃.

5. The method for preparing the compound as shown in Formula VI according to claim 4, characterized in that, It meets one or more of the following conditions: (1) In the olefination reaction, the base is ; (2) The olefination reaction is carried out in two stages, with the reaction time of the first stage being 2-3 hours; (3) The olefination reaction is carried out in two stages, and the reaction time of the second stage is 14-18 hours; (4) The olefination reaction is carried out in two stages, and the reaction temperature of the first stage is -45℃ to -42℃; (5) The olefination reaction is carried out in two stages, and the reaction temperature of the second stage is 20°C.

6. The method for preparing the compound as shown in Formula VI according to claim 5, characterized in that, It meets one or more of the following conditions: (1) The alkali is 1 mol / L In the form of tetrahydrofuran solution; (2) The olefin reaction is post-processed by the following steps, which include one or more of the following steps: quenching, extraction, concentration, acidification to salt, and neutralization.

7. The method for preparing the compound as shown in Formula VI according to claim 6, characterized in that, The post-processing includes the following steps in sequence: quenching, first extraction, concentration, dilution, acidification to salt, retention of aqueous phase, neutralization, and second extraction.

8. The method for preparing the compound as shown in Formula VI according to claim 7, characterized in that, It meets one or more of the following conditions: (1) The quenching mentioned above is quenching using a saturated ammonium chloride aqueous solution; (2) The solvent used in the first extraction is a water-insoluble organic solvent; (3) The solvent used for dilution is a cyclic ether solvent; (4) The acid used in the acidification to form salt is hydrochloric acid; (5) During the neutralization process, the system temperature is controlled at 10~20℃; (6) The alkali used for neutralization is an alkali metal hydroxide; (7) The neutralization mentioned refers to neutralizing to a pH of 12-13; (8) The solvent used in the second extraction is an alkane solvent.

9. The method for preparing the compound as shown in Formula VI according to claim 8, characterized in that, It meets one or more of the following conditions: (1) The solvent used in the first extraction was ethyl acetate; (2) The solvent used for dilution is 2-methyltetrahydrofuran; (3) The acid used in the acidification to form salt is in the form of hydrochloric acid aqueous solution; (4) The alkali used for neutralization is sodium hydroxide; (5) The solvent used in the second extraction is n-heptane.

10. The method for preparing the compound as shown in Formula VI according to claim 9, characterized in that, It meets one or more of the following conditions: (1) The acid used for acidification into salt is a 1-2 mol / L hydrochloric acid aqueous solution; (2) The base used for neutralization is in the form of a 10-15 mol / L sodium hydroxide aqueous solution.

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