Preparation method of chiral piperidone compound

Abstract

The invention discloses a preparation method of a chiral piperidone compound. Specifically, the invention discloses a preparation method of a compound as shown in a formula IV (R), which comprises the following steps: (i) in a solvent, carrying out salt forming reaction on the compound IV and a resolving agent to obtain salt formed by the compound as shown in the formula IV (R) and the resolving agent; and (ii) carrying out free reaction on the salt prepared in the step (i) under the action of alkali to obtain a compound shown as a formula IV (R), the resolving agent is D-(+)-di-p-methyl benzoyl tartaric acid and / or D-tartaric acid.

Description

Technical Field

[0001] This invention relates to a method for preparing chiral piperidone compounds. Background Technology

[0002] Ras, or homologues of the rat sarcoma oncogene, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. However, decades of drug development targeting Ras have revealed significant challenges. The smooth surface of Ras proteins lacks distinct grooved or pocket-like structures for binding small-molecule inhibitors, and their extremely high affinity for guanine substrates (picomolar levels) has made the development of small-molecule inhibitors a long and difficult process. 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.

[0003] 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.

[0004] 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:

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] d) In step 5, it should be noted that the application of LiAlH4 leads to the release of H2 during the quenching process.

[0010] 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

[0011] To address the problems existing in the prior art, the present invention aims to provide a method for preparing chiral piperidone compounds. The preparation method of the present invention has one or more of the following advantages: (1) high yield; (2) good purity; (3) high optical purity; (4) simple operation; and (5) low cost. The chiral piperidone compounds prepared by the method of the present invention can be used to further improve the preparation of [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidinyl]methanol.

[0012] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0013] This invention provides a method for preparing a compound as shown in formula IV(R), comprising the following steps: (i) In a solvent, compound IV is reacted with a resolving agent to form a salt to obtain the salt formed by the compound of formula IV(R) and the resolving agent; ; (ii) The salt obtained in step (i) is subjected to a free reaction under the action of an alkali to obtain the compound shown in formula IV(R); Among them, R and R 1 Independently, it is a C1-C6 alkyl group; The resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid (CAS: 32634-68-7) and / or D-tartaric acid (CAS: 147-71-7).

[0014] In one embodiment of the present invention, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example methyl or ethyl, preferably ethyl.

[0015] In one aspect of the present invention, the R 1 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0016] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, and in the salt, the molar ratio of IV(R) to D-(+)-di-p-methylbenzoyl tartaric acid is 1:1.

[0017] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-tartaric acid, and in the salt, the molar ratio of IV(R) to D-tartaric acid is 1:1.

[0018] In one aspect of the present invention, in the salt-forming reaction, the molar ratio of the resolving agent to the compound IV is (0.3~1.5):1, for example (0.4~1.0):1, and further for example 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1 or 1.0:1.

[0019] In one aspect of the present invention, in the salt-forming reaction, the resolving agent reacts with compound IV in a single reaction or in multiple reactions, for example, in a single reaction or in two reactions.

[0020] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent reacts with compound IV in a single reaction, and the molar ratio of the resolving agent to compound IV is (0.3~1.0):1, for example (0.4~0.5):1.

[0021] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent reacts with compound IV in two separate salt-forming reactions. In the first reaction, the molar ratio of the resolving agent to compound IV is (0.3~0.6):1, for example (0.4~0.5):1. In the second reaction, the molar ratio of the resolving agent to compound IV is (0.3~0.6):1, for example (0.4~0.5):1.

[0022] In one aspect of the present invention, the resolving agent in the salt-forming reaction is added either all at once or in multiple stages, for example, all at once or in two stages.

[0023] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is added all at once, and the molar ratio of the resolving agent to compound IV is (0.3~1.0):1, for example (0.4~0.5):1.

[0024] In one embodiment of the present invention, in the salt formation reaction, the resolving agent is added in two parts. In the first part, the molar ratio of the resolving agent to compound IV is (0.3~0.6):1, for example (0.4~0.5):1. In the second part, the molar ratio of the resolving agent to compound IV is (0.3~0.6):1, for example (0.4~0.5):1.

[0025] In one aspect of the present invention, in the salt-forming reaction, the solvent is an inert solvent, for example, selected from one or more of nitrile solvents, ester solvents and alcohol solvents; Preferably, the nitrile solvent is acetonitrile; Preferably, the ester solvent is ethyl acetate; Preferably, the alcohol solvent is ethanol.

[0026] In one embodiment of the present invention, in the salt formation reaction, the solvent is a nitrile solvent, an ester solvent, or a mixture of an ester solvent and an alcohol solvent. Preferably, in the mixture of an ester solvent and an alcohol solvent, the volume ratio of the ester solvent to the alcohol solvent is (3~5):1, for example, 4:1.

[0027] In one embodiment of the present invention, in the salt formation reaction, the solvent is acetonitrile, ethyl acetate, or a mixture of ethyl acetate and ethanol. Preferably, in the mixture of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol is (3~5):1, for example, 4:1.

[0028] In one aspect of the present invention, the solvent in the salt-forming reaction is a nitrile solvent, such as acetonitrile.

[0029] In one aspect of the present invention, the solvent in the salt-forming reaction is an ester solvent, such as ethyl acetate.

[0030] In one aspect of the present invention, in the salt-forming reaction, the solvent is a mixed solvent of ester solvent and alcohol solvent, such as a mixed solvent of ethyl acetate and ethanol. Preferably, in the mixed solvent, the volume ratio of the ester solvent to the alcohol solvent is (3~5):1, for example 4:1.

[0031] In one aspect of the present invention, in the salt-forming reaction, the volume-to-mass ratio of the solvent to compound IV is 3-15 mL / g, for example 5-12.5 mL / g, and more specifically 5 mL / g, 10 mL / g, or 12.5 mL / g.

[0032] In one aspect of the present invention, the temperature of the salt-forming reaction is 50~70℃, for example 60~65℃.

[0033] In one aspect of the present invention, the temperature of the salt formation reaction is the temperature at which the solvent is refluxed.

[0034] In one aspect of the present invention, the salt formation reaction is divided into two stages. The reaction temperature of the first stage is 50~70°C, and the reaction temperature of the second stage is the temperature at which the solvent is refluxed. Preferably, the resolving agent is added in two stages. In the first stage, the molar ratio of the resolving agent to compound IV is (0.4~0.5):1, and in the second stage, the molar ratio of the resolving agent to compound IV is (0.4~0.5):1. Preferably, the reaction time for the first stage is 2-4 hours, and the reaction time for the second stage is 23-25 ​​hours.

[0035] The reaction time for the salt-forming reaction is the conventional reaction time for such reactions in the art. In one aspect of the present invention, the reaction time for the salt-forming reaction is 2 to 30 hours, for example 2 to 4 hours, 15 to 17 hours or 26 to 28 hours, and more specifically 3 hours, 16 hours or 27 hours.

[0036] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, and the solvent is ethyl acetate, acetonitrile, or a mixed solvent of ethyl acetate and ethanol. In the mixed solvent of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol can be (3~5):1, for example, 4:1.

[0037] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-tartaric acid, and the solvent is a mixed solvent of ethyl acetate and ethanol. In the mixed solvent of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol can be (3~5):1, for example 4:1.

[0038] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is ethyl acetate or a mixed solvent of ethyl acetate and ethanol, and the salt-forming reaction is carried out in two stages. Accordingly, the resolving agent is added twice. In the first stage, the molar ratio of the amount of the resolving agent added to the compound IV is (0.4~0.5):1. In the second stage, the molar ratio of the amount of the resolving agent added to the compound IV is (0.4~0.5):1. Preferably, in the mixed solvent of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol is (3~5):1, for example 4:1; Preferably, the reaction temperature of the first stage is 60~65℃ (e.g., 60℃), and the reaction time is 2~4h (e.g., 3h). Preferably, the reaction temperature of the second stage is 75~80℃ (e.g., 78℃), and the reaction time is 23~25h (e.g., 24h).

[0039] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is acetonitrile, the reaction temperature of the salt-forming reaction is 60~65℃ (e.g., 60℃), and the reaction time can be 15~17h (e.g., 16h).

[0040] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, the reaction temperature of the salt-forming reaction is 60~65℃ (e.g., 60℃), and the reaction time can be 2~4h (e.g., 3h).

[0041] In one embodiment of the present invention, in the salt-forming reaction, the resolving agent is D-tartaric acid, the solvent is a mixed solvent of ethyl acetate and ethanol, and the salt-forming reaction is carried out in two stages. Accordingly, the resolving agent is added twice. In the first stage, the molar ratio of the amount of the resolving agent added to the compound IV is (0.4~0.5):1. In the second stage, the molar ratio of the amount of the resolving agent added to the compound IV is (0.4~0.5):1. Preferably, in the mixed solvent of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol is (3~5):1, for example 4:1; Preferably, the reaction temperature of the first stage is 60~65℃ (e.g., 60℃), and the reaction time is 2~4h (e.g., 3h). Preferably, the reaction temperature of the second stage is 75~80℃ (e.g., 78℃), and the reaction time is 23~25h (e.g., 24h).

[0042] The type and amount of alkali used in the described free reaction are standard practice for this type of reaction in the field.

[0043] In one aspect of the present invention, in the free reaction, the base is an alkali metal carbonate or an alkali metal bicarbonate, preferably an alkali metal bicarbonate. Preferably, the alkali metal carbonate is selected from one or more of sodium carbonate, potassium carbonate, and cesium carbonate; Preferably, the alkali metal bicarbonate is sodium bicarbonate and / or potassium bicarbonate, for example, sodium bicarbonate.

[0044] In one aspect of the present invention, in the free reaction, the alkali is in the form of an aqueous solution, such as a sodium bicarbonate aqueous solution, more preferably a sodium bicarbonate aqueous solution with a mass fraction of 1-10%, preferably a sodium bicarbonate aqueous solution with a mass fraction of 3-6%, and more preferably a sodium bicarbonate aqueous solution with a mass fraction of 5%.

[0045] In one embodiment of the present invention, the reaction temperature of the free reaction is 5~15℃.

[0046] In one embodiment of the present invention, in the free reaction, the alkali is in the form of an aqueous solution, and the salt obtained in step (i) is added to the alkali.

[0047] After the free reaction is completed, post-processing can be performed through the following steps, which include one or more of the following steps: extraction, washing, drying, filtration and concentration; Preferably, the post-processing includes extraction, washing, drying, filtration, and concentration; Preferably, the solvent used for extraction is an ester solvent, such as ethyl acetate; Preferably, the washing is performed using a NaCl solution with a mass fraction of 10-20% (e.g., 15%). Preferably, the drying is performed using anhydrous sodium sulfate.

[0048] In one aspect of the present invention, after the salt-forming reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. Preferably, the recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a poor solvent, respectively; The volume ratio of the good solvent to the poor solvent can be 1:(1~3), for example 1:1 or 1:2; The good solvent may be N,N-dimethylformamide and / or dimethyl sulfoxide, such as dimethyl sulfoxide; The unsuitable solvent may be water; Preferably, the volume of the good solvent is sufficient to dissolve the crude product undergoing recrystallization, for example, to dissolve the crude product undergoing recrystallization at 15~50°C (e.g., 15~45°C, further for example, 15°C, 30°C, 40°C or 45°C). Further, for example, the volume-to-mass ratio of the good solvent to the crude product undergoing recrystallization is 1~5 mL / g, preferably 1.5~4 mL / g, for example 1.6 mL / g, 1.7 mL / g or 4 mL / g.

[0049] In one aspect of the present invention, the recrystallization includes the following steps: mixing a good solvent solution of the crude product to be recrystallized with a bad solvent; For example, the undesirable solvent is added dropwise to the good solvent solution, and the temperature of this process can be controlled at 15~45℃, for example 25~35℃; Preferably, after the good solvent solution is mixed with the bad solvent, it is kept at 15~35℃ (e.g. 15~25℃) for, for example, for 2~20h, 2~3h, 4~6h or 15~17h.

[0050] The recrystallization may or may not use seed crystals.

[0051] In one aspect of the present invention, the recrystallization uses seed crystals. The seed crystals are added when they are added to a good solvent solution of the crude product to be recrystallized, or when the good solvent solution of the crude product to be recrystallized is mixed with a poor solvent before adding the seed crystals. The mass ratio of the seed crystals to the crude product to be recrystallized is (0.0001~0.1):1, for example (0.0009~0.026):1.

[0052] The recrystallization can be performed once or multiple times, for example, once or twice.

[0053] Those skilled in the art will understand that, in the above scheme, the crude product to be recrystallized should be the crude product that needs further purification after simple post-treatment after the salt formation reaction is completed. The simple post-treatment can be filtration, or further washing after filtration, for example, washing with the reaction solvent of the salt formation reaction.

[0054] In one aspect of the present invention, R 1 The method for preparing the compound of formula IV(R) further comprises a method for preparing the compound of formula IV, wherein the method for preparing the compound of formula IV comprises the following steps: in a solvent, in the presence of an organic base, the compound of formula II, a formaldehyde source, and methylamine undergo the Mannich reaction as shown below to prepare the compound of formula IV: .

[0055] In one aspect of the present invention, in the Mannich reaction, the solvent is an alcohol solvent, such as methanol, ethanol or isopropanol, preferably ethanol.

[0056] In one embodiment of the present invention, in the Mannich reaction, the organic base is N(R) a )3, R a Independently H or C1-C6 alkyl; Ideally, R a Not both H; Ideally, R a In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, preferably ethyl.

[0057] In one embodiment of the present invention, the organic base in the Mannich reaction is triethylamine.

[0058] In one aspect of the present invention, in the Mannich reaction, the formaldehyde source is formaldehyde and / or paraformaldehyde, for example, paraformaldehyde. Preferably, when the formaldehyde source is formaldehyde, the formaldehyde is in the form of an aqueous formaldehyde solution.

[0059] In one aspect of the present invention, in the Mannich reaction, the methylamine is in the form of a methylamine salt or a methylamine solution; Preferably, the methylamine salt is methylamine hydrochloride; Preferably, in the methylamine solution, the solvent is selected from alcohol solvents and / or water, such as methanol, ethanol or isopropanol, with ethanol being preferred.

[0060] In one embodiment of the present invention, in the Mannich reaction, the molar ratio of the compound as shown in Formula II to the methylamine is (1~1.5):1, for example 1.05:1.

[0061] In one embodiment of the present invention, in the Mannich reaction, the molar ratio of the formaldehyde source to the methylamine is (2~5):1, for example 3:1, wherein the amount of the formaldehyde source is calculated based on the relative molecular mass of formaldehyde.

[0062] In one aspect of the present invention, the reaction temperature of the Mannich reaction is a temperature at which the solvent can be refluxed.

[0063] In one embodiment of the present invention, the reaction temperature of the Mannich reaction is 60~70°C, for example 60°C.

[0064] In one aspect of the invention, the Mannich reaction is carried out in an atmosphere of an inert gas, such as nitrogen or an inert gas, preferably nitrogen.

[0065] In one embodiment of the present invention, in the Mannich reaction, the molar ratio of the organic base to the methylamine is (0.2~2):1, for example (1~2):1, and more specifically, 1.1:1.

[0066] In one embodiment of the present invention, the organic base is added in batches, wherein the molar ratio of the first batch of organic base to the methylamine is (0.05~0.2):1, preferably (0.08~0.12):1, for example 0.1:1.

[0067] In one embodiment of the present invention, the organic base is added in two batches during the Mannich reaction.

[0068] In one aspect of the present invention, in the Mannich reaction, after the first batch of organic bases is added, the reaction is stirred first, and then the remaining organic bases are added. The stirring time is preferably 14 to 18 hours, for example, 16 hours. Preferably, after the remaining organic base is added, the reaction is continued with stirring until the methylamine reaction is complete or no longer occurs, for example, by continuing the stirring reaction for 2 to 5 hours, preferably 2 to 3 hours.

[0069] In one embodiment of the present invention, in the Mannich reaction, after the first batch of organic bases is added, until the percentage of "the amount of substance of the compound shown in Formula II" and "the sum of the amounts of the compound shown in Formula II and the compound shown in Formula III" in the reaction solution is less than 20%, preferably less than 15%, more preferably not 0%, the remaining organic bases are added and the reaction continues until the methylamine reaction is complete or no longer occurs, for example, by continuing the stirring reaction for 2 to 5 hours, preferably 2 to 3 hours.

[0070] In one aspect of the present invention, the preparation method of the compound as shown in Formula III includes the following steps: under a nitrogen atmosphere, the solvent, the methylamine, the formaldehyde source, the compound as shown in Formula II, and the first batch of organic base are stirred at 60-70°C for 14-18 hours (e.g., 16 hours), or stirred until the percentage of "the amount of substance of the compound as shown in Formula II" to "the sum of the amounts of the compound as shown in Formula II and the compound as shown in Formula III" is less than 15%, preferably not 0%, and then stirred with the remaining organic base at 60-70°C for 2-3 hours.

[0071] In one embodiment of the present invention, the Mannich reaction is carried out under acidic or acid-free conditions. When the Mannich reaction is carried out under acid-free conditions, the reaction raw materials are the solvent, the organic base, the compound as shown in Formula II, the formaldehyde source, and the methylamine. When the Mannich reaction is carried out under acidic conditions, the acid is selected from one or more of hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, L-tartaric acid, S-mandelic acid, D(+)-10-camphorsulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; the molar ratio of the acid to the methylamine can be (0.1-1.5):1, for example, 1:1; When the Mannich reaction is carried out under acidic conditions, the reactants may be the solvent, the organic base, the compound as shown in Formula II, the formaldehyde source, the methylamine, and the acid.

[0072] After the Mannich reaction is completed, post-processing can be performed through the following steps, which include one or more of the following operations: concentration, extraction, acidification, filtration, and neutralization; the operations are routine operations for this type of reaction in the art; Preferably, the post-processing steps sequentially include the following operations: concentration, extraction, acidification, filtration, neutralization of the filter cake, extraction, and concentration; Preferably, the acidification comprises: acidifying the organic phase obtained after extraction with hydrochloric acid (e.g., an aqueous solution of hydrochloric acid), wherein the concentration of the hydrochloric acid is, for example, 3-5 mol / L (preferably 4 mol / L); more preferably, the acidification comprises: adding the hydrochloric acid dropwise to the organic phase obtained after extraction at 20-35°C, and stirring at 15-25°C for 1-2 h; Preferably, the neutralization is to neutralize to a pH of 7-8, for example, by mixing the filter cake with a saturated sodium bicarbonate solution and adjusting the pH to 7-8.

[0073] The present invention also provides a method for preparing a compound as shown in Formula VI, comprising the following steps: The compound shown in Formula IV(R) was prepared according to the preparation method of the compound shown in Formula IV(R) according to any of the above schemes; In a solvent, under the action of a base, the compound shown in formula IV(R) reacts with... Julia-Kocienski The reagent was used to perform an olefination reaction to prepare the compound shown in Formula VI. ; The wavy line indicates that the double bond configuration is E configuration, Z configuration, or a mixture thereof.

[0074] In one aspect of the present invention, in the olefination reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, cyclic ether solvents, and amide solvents; Preferably, the ether solvent is R m and R n Independently, it is a C1-C4 alkyl group; Preferably, the alkylbenzene solvent is toluene; Preferably, the cyclic ether solvent is tetrahydrofuran and / or 2-methyltetrahydrofuran; Preferably, the amide solvent is N,N-dimethylformamide.

[0075] In one embodiment of the present invention, the solvent in the olefination reaction is ethylene glycol dimethyl ether.

[0076] In one embodiment of the present invention, in the olefination reaction, the base is... and / or alkali metal alkoxides; wherein, R a R b R c R d R e and R f Each of them is independently a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl), and M is an alkali metal (e.g., Li, Na or K, preferably Li). Preferably, the alkali metal alkoxide is a tert-butoxide of an alkali metal, such as one or more selected from sodium tert-butoxide, lithium tert-butoxide, and potassium tert-butoxide.

[0077] In one aspect of the present invention, in the olefination reaction, the base is selected from... , and One or more of them, preferably .

[0078] The aforementioned Julia-Kocienski The reagents can be those conventional for this type of reaction in the art. Julia-Kocienski Reagent. In one embodiment of the present invention, in the olefination reaction, the... Julia-Kocienski The reagent is Ar is C6-C 10 aryl, 5-10 heteroaryl, with one or more Ar 1 Replacement C6-C 10 aryl or aryl with one or more Ar 1 Substituted 5-10 heteroaryl groups, Ar 1 Independently C1-C6 alkyl, C6-C 10Aryl or 5-10 heteroaryl, wherein in each 5-10 heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0079] In one aspect of the present invention, in the olefination reaction, the... Julia-Kocienski The reagent is , or Preferred .

[0080] In one embodiment of the present invention, the reaction temperature of the olefination reaction is -50℃ to 25℃.

[0081] In one aspect of the present invention, the olefination reaction is carried out in two stages. The reaction temperature of the first stage is -50℃ to -40℃ (e.g., -45℃ to -42℃), and the reaction temperature of the second stage is 15℃ to 25℃ (e.g., 20℃).

[0082] In one aspect of the present invention, in the olefination reaction, the volume-to-mass ratio of the solvent to the compound represented by formula IV(R) is 1 to 15 L / kg, for example, 5 to 10 L / kg.

[0083] In one aspect of the present invention, in the olefination reaction, the molar ratio of the base to the compound as shown in formula IV(R) is (0.5~2):1, for example (1~1.5):1, preferably 1.1:1.

[0084] In one aspect of the present invention, 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, for example (1~1.5):1, preferably 1.1:1.

[0085] In one embodiment of the present invention, the reactants for the olefination reaction are the solvent, the base, the compound as shown in formula IV(R), and the... Julia-Kocienski Reagents.

[0086] In one aspect of the present invention, the preparation method involves adding the base to the solvent, the compound as shown in formula IV(R), and the... Julia-Kocienski In the mixture of reagents; during the addition of the alkali, it is preferable to control the temperature of the reaction system to be -50℃ to -40℃.

[0087] In one aspect of the present invention, in the olefination reaction, the base is in the form of a base solution, and the solvent in the base solution is a cyclic ether solvent, such as tetrahydrofuran.

[0088] In one aspect of the invention, in the olefination reaction, the base is in the form of a 0.5-1.5 mol / L tetrahydrofuran solution, for example, a 1 mol / L solution. It is in the form of a tetrahydrofuran solution.

[0089] The olefination reaction time is the conventional reaction time for such reactions in the art, generally until a certain raw material no longer reacts or the reaction is complete. Preferably, the olefination reaction is carried out in two stages: the first stage reaction time is 1-5 hours (e.g., 2-3 hours), and the second stage reaction time is 10-20 hours (e.g., 14-18 hours, preferably 16 hours). The reaction temperature of the first stage is -50°C to -40°C (e.g., -45°C to -42°C), and the reaction temperature of the second stage is 15-25°C (e.g., 20°C).

[0090] The olefination reaction can be post-processed by the following steps, which include one or more of the following steps: quenching, extraction, concentration, acidification to salt, and neutralization.

[0091] Preferably, 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.

[0092] Preferably, the quenching is performed using a saturated ammonium chloride aqueous solution.

[0093] Preferably, the solvent used in the first extraction is a water-insoluble organic solvent, such as ethyl acetate.

[0094] Preferably, the solvent used for dilution is a cyclic ether solvent, such as 2-methyltetrahydrofuran.

[0095] Preferably, the acid used for acidification into salt is hydrochloric acid, which may be in the form of an aqueous solution, such as a 1-2 mol / L aqueous solution of hydrochloric acid.

[0096] Preferably, during the neutralization process, the system temperature is controlled at 10~20℃.

[0097] Preferably, the base used for neutralization is an alkali metal hydroxide, such as sodium hydroxide, which may be in the form of an aqueous solution of sodium hydroxide (e.g., a 10-15 mol / L aqueous solution of sodium hydroxide, or more specifically, a 12 mol / L aqueous solution of sodium hydroxide).

[0098] Preferably, the neutralization is to neutralize to a pH of 12-13.

[0099] Preferably, the solvent used in the second extraction is an alkane solvent, such as n-heptane.

[0100] The present invention also provides a method for preparing a compound as shown in Formula VII, comprising the following steps: The compound shown in Formula VI was prepared according to the preparation method of the compound shown in Formula VI as described in any of the above schemes; In a solvent, in the presence of a free radical initiator and a free radical source, the compound shown in Formula VI undergoes an isomerization reaction to prepare the compound shown in Formula VII. .

[0101] In one embodiment of the present invention, in the isomerization reaction, the solvent is selected from one or more of cyclic ether solvents, ester solvents, alcohol solvents, and hydrocarbon solvents.

[0102] 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.

[0103] Preferably, the cyclic ether solvent is tetrahydrofuran.

[0104] Preferably, the ester solvent is ethyl acetate.

[0105] Preferably, the alcohol solvent is methanol.

[0106] Preferably, the hydrocarbon solvent is n-heptane.

[0107] 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.

[0108] In one embodiment of the present invention, in the isomerization reaction, the free radical initiator is selected from one or more of azobisisobutyronitrile, azobisisoheptanenitrile, and dimethyl azobisisobutyrate, preferably dimethyl azobisisobutyrate.

[0109] In one embodiment of the present invention, the isomerization reaction, wherein the free radical source is... , I2 , , , , thiourea or Preferred .

[0110] In one aspect of the present invention, the isomerization reaction, wherein the compound shown in Formula VI is a compound shown in Formula VI-1: .

[0111] In one aspect of the present invention, in the isomerization reaction, the volume molar ratio of the solvent to the compound as shown in Formula VI is (1~8) L / mol, for example (2~4) L / mol.

[0112] 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 is (0.1~1):1, for example (0.15~0.3):1.

[0113] 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 is (0.1~1):1, for example (0.15~0.3):1.

[0114] In one aspect of the present invention, the reaction temperature of the isomerization reaction is 60~80℃, for example 65~70℃.

[0115] 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.

[0116] In one aspect of the invention, the isomerization reaction is carried out in an atmosphere of an inert gas, such as nitrogen or an inert gas, preferably nitrogen.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] After the isomerization reaction is completed, post-processing can be carried out through the following steps, including: acidification, recrystallization, neutralization, extraction, and concentration.

[0121] In one embodiment of the present invention, the post-processing steps include acidification, recrystallization, neutralization, extraction, and concentration performed sequentially.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] In one aspect of the present invention, in the post-processing step, the solid obtained after acidification is a salt.

[0126] In one aspect of the present invention, the recrystallization in the post-processing step refers to recrystallizing the salt obtained by acidification.

[0127] 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 antisolvent 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.

[0128] 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.

[0129] 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.

[0130] 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, wherein 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%.

[0131] 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.

[0132] 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.

[0133] In one embodiment of the present invention, in the post-processing step, the acidification is performed by 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.

[0134] The present invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: The compound shown in Formula VII was prepared according to the preparation method of the compound shown in Formula VII as described in any of the above schemes; In a solvent, under the action of a reducing agent, the compound shown in Formula VII undergoes a reduction reaction to prepare the compound shown in Formula I; .

[0135] In one aspect of the present invention, in the reduction reaction, the solvent is an inert solvent, for example, selected from one or more of ether solvents, alkylbenzene solvents, nitrile solvents and cyclic ether solvents; Preferably, the ether solvent is methyl tert-butyl ether and / or ethylene glycol dimethyl ether; Preferably, the alkylbenzene solvent is toluene; Preferably, the nitrile solvent is acetonitrile; Preferably, the cyclic ether solvent is tetrahydrofuran and / or 2-methyltetrahydrofuran.

[0136] In one aspect of the present invention, the solvent in the reduction reaction is an ether solvent, such as ethylene glycol dimethyl ether.

[0137] The reducing agent can be a conventional reducing agent in the art for reducing esters to hydroxyl groups. In one aspect of the present invention, in the reduction reaction, the reducing agent is selected from one or more of lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, and NaAlH2(OCH2CH2OCH3)2, for example, lithium aluminum hydride.

[0138] In one aspect of the invention, the reduction reaction is carried out in an atmosphere of an inert gas, such as nitrogen and / or an inert gas, for example, nitrogen.

[0139] In one aspect of the present invention, the reaction temperature of the reduction reaction is -5 to 10°C, for example, 0 to 10°C.

[0140] In one aspect of the present invention, in the reduction reaction, the molar ratio of the reducing agent to the compound shown in Formula VII is (0.5~1.5):1, for example 0.7:1.

[0141] The present invention also provides a salt formed by the compound of formula IV(R) according to any of the above embodiments and a resolving agent, for example... or .

[0142] The present invention also provides the use of a salt formed by the compound of formula IV(R) and a resolving agent according to any of the above embodiments in the preparation of the compound of formula IV(R).

[0143] In one aspect of the present invention, the method for preparing the compound represented by formula IV(R) comprises the free reaction described in any of the above-described aspects.

[0144] The present invention also provides a method for preparing a salt formed by the compound of formula IV(R) and a resolving agent according to any of the above embodiments, which includes the salt-forming reaction described in any of the above embodiments.

[0145] The present invention also provides the use of D-(+)-di-p-methylbenzoyl tartaric acid (CAS: 32634-68-7) and / or D-tartaric acid (CAS: 147-71-7) as resolving agents in resolving compound IV to prepare a compound as shown in formula IV(R), wherein compound IV and the compound as shown in formula IV(R) are as described in any embodiment of the present invention.

[0146] In one aspect of the present invention, the method of resolving compound IV to prepare the compound represented by formula IV(R) is the preparation method of the compound represented by formula IV(R) described in any of the above aspects.

[0147] 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.

[0148] The reagents and raw materials used in this invention are all commercially available.

[0149] The positive and progressive effects of this invention are as follows: the preparation method of the compound shown in IV(R) of this invention has one or more of the following advantages: (1) high yield; (2) good purity; (3) high optical purity; (4) simple operation; (5) low cost. The preparation method of this invention can be used to prepare chiral piperidinone compounds for further better preparation of [(S)-(E)-4-fluorovinyl-1-methyl-3-methyl-3-piperidinyl]methanol.

[0150] Furthermore, compared to the prior art, the method for preparing the compound as shown in Formula I according to the present invention has the following beneficial effects: 1. This invention efficiently synthesizes numerous intermediates of KRAS G12D inhibitors, as shown in Formula I; 2. Compared with existing synthetic routes, the starting materials used in the process of this invention are inexpensive and readily available; 3. The process of this invention avoids SFC chiral splitting, greatly reducing costs; 4. The process of this invention realizes the conversion of olefin cis-trans isomers, avoids chromatographic separation, greatly reduces costs, and improves yield; 5. The process of this invention can avoid the use of multiple column chromatography purification operations, making it suitable for industrial production; 6. The process of this invention is simple to operate and easy to purify and obtain high-quality, high-purity intermediates such as compounds represented by Formula I; 7. The new approach of this invention has significant advantages and stronger industrialization prospects compared with existing methods. Attached Figure Description

[0151] Figure 1 Molecular ellipsoid diagram of a single crystal of the D-DTTA salt of compound 3 with a single configuration.

[0152] Figure 2 Molecular ellipsoid diagram of a single crystal of L-tartrate of compound 3 with a single configuration. Detailed Implementation

[0153] 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.

[0154] Preparation route of compound 1:

[0155] The preparation route of compound 5 is shown below:

[0156] 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.

[0157] 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.

[0158] Step 3: Next, in the presence of a base in an inert solvent (including but not limited to ethylene glycol dimethyl ether, toluene, tetrahydrofuran or methyltetrahydrofuran), 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.

[0159] Step 4: The mixture is reconfigured into a single-configuration compound 8 in the presence of an initiator and a free radical source.

[0160] 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.

[0161] Example 1: Preparation of Compound 3

[0162] 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 more than 16 h until the amount of n(ethyl 2-methylacetoacetate) / n(ethyl 2-methylacetoacetate + compound 3) 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%.

[0163] 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%.

[0164] 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).

[0165] LCMS (m / z): 200.1 [M+H].

[0166] Example 2.1 Preparation of Compound 4

[0167] 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%.

[0168] The D-DTTA salt of compound 3, obtained in 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 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.

[0169] 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).

[0170] Example 2.2 Synthesis of Compound 4

[0171] 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 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 turned off, 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%.

[0172] 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.

[0173] Example 2.3 Preparation of Compound 4

[0174] 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.

[0175] 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).

[0176] Example 2.4 Preparation of Compound 4

[0177] 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%.

[0178] Example 2.5 Preparation of Compound 4

[0179] 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, and rotary evaporation were performed to finally obtain 750.3 mg of free compound 4 with an ee value of 95%.

[0180] Example 2.6 Preparation of Compound 4

[0181] 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%.

[0182] Example 2.7 Preparation of Compound 4

[0183] 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%.

[0184] 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.

[0185] 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.

[0186] Example 2.8 Preparation of Compound 4

[0187] 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%.

[0188] Comparative Example 2.1 Preparation of Compound 4

[0189] 200 mg of compound 3 (1 mmol, 1 eq.) was dissolved in 1 mL (5 vol.) of acetonitrile, and 358 mg of D-DBTA (CAS: 17026-42-5, 1 mmol, 1 eq) was added. The mixture was heated to 60 °C and stirred for 16 h. No precipitate was formed.

[0190] Preparation of Compound 4 (Comparative Example 2.2)

[0191] 200 mg of compound 3 (1 mmol, 1 eq.) was dissolved in 1 mL (5 vol.) of acetonitrile, and 108 mg of (S)-(-)-2-chloropropionic acid (CAS: 29617-66-1, 1 mmol, 1 eq) was added. The mixture was heated to 60 °C and stirred for 16 h. No precipitate was formed.

[0192] Preparation of Compound 4 (Comparative Example 2.3)

[0193] 200 mg of compound 3 (1 mmol, 1 eq.) was dissolved in 1 mL (5 vol.) of acetonitrile, and 232 mg of dextrorotatory camphor sulfonic acid (CAS: 3144-16-9, 1 mmol, 1 eq) was added. The mixture was heated to 60 °C and stirred for 16 h. No precipitate was formed.

[0194] Preparation of Compound 4 (Comparative Example 2.4)

[0195] 200 mg of compound 3 (1 mmol, 1 eq.) was dissolved in 1 mL (5 vol.) of acetonitrile, and 152 mg of mandelic acid (CAS: 17199-29-0, 1 mmol, 1 eq.) was added. The mixture was heated to 60 °C and stirred for 16 h. No precipitate was formed.

[0196] Example 3 Preparation of Compound 8

[0197] 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-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 20% potassium phosphate 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).

[0198] 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.

[0199] The double bond in compound 8 has an E configuration, which was confirmed by 1H NMR and NOE spectra.

[0200] The 1H NMR spectrum data of compound 8 are as follows: 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). 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.

[0201]

[0202] The 1H NMR spectra of the Z-configuration compound corresponding to compound 8 are as follows: 1 H 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).

[0203] 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.

[0204]

[0205] Example 4 Preparation of Compound 1

[0206] 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 as time goes on. 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%.

[0207] 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).

[0208] Example 5 Preparation of Compound 20

[0209] 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 to obtain a content of 92% and a yield of 80%.

[0210] 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).

[0211] Example 6 Preparation of Compound 5

[0212] 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, release the lower aqueous phase (13.3 L, experimental value, subject to actual conditions), and retain the organic phase; 6) Control the temperature at 25℃ (20~30℃ is also acceptable), 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% and an assay of 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%.

[0213] 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 IV(R), comprising the following steps: (i) In a solvent, compound IV is reacted with a resolving agent to form a salt to obtain the salt formed by the compound of formula IV(R) and the resolving agent; ； (ii) The salt obtained in step (i) is subjected to a free reaction under the action of an alkali to obtain the compound shown in formula IV(R); in, R and R 1 Independently, it is a C1-C6 alkyl group; The resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid and / or D-tartaric acid.

2. The method for preparing the compound as shown in formula IV(R) 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) The R mentioned above 1 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (3) In the salt formation reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, and in the salt, the molar ratio of IV(R) to D-(+)-di-p-methylbenzoyl tartaric acid is 1:1; Alternatively, the resolving agent is D-tartaric acid, and in the salt, the molar ratio of IV(R) to D-tartaric acid is 1:1; (4) In the salt-forming reaction, the molar ratio of the resolving agent to compound IV is (0.3~1.5):1; (5) In the salt-forming reaction, the resolving agent reacts with compound IV in a single reaction or in multiple reactions. (6) In the salt-forming reaction, the resolving agent is added at once or in multiple batches; (7) In the salt-forming reaction, the solvent is an inert solvent; (8) In the salt formation reaction, the volume-to-mass ratio of the solvent to compound IV is 3-15 mL / g; (9) The temperature of the salt formation reaction is 50~70℃; Alternatively, the temperature of the salt-forming reaction is the temperature at which the solvent is refluxed; (10) In the free reaction, the base is an alkali metal carbonate or an alkali metal bicarbonate; (11) In the free reaction described above, the base is in the form of an aqueous solution; (12) The reaction temperature of the free reaction is 5~15℃; (13) After the free reaction is completed, the following steps are performed for post-processing, which includes one or more of the following steps: extraction, washing, drying, filtration and concentration.

3. The method for preparing the compound as shown in formula IV(R) according to claim 2, characterized in that, It meets one or more of the following conditions: (1) The R mentioned is an ethyl group; (2) The R mentioned above 1 It is methyl; (3) In the salt-forming reaction, the molar ratio of the resolving agent to compound IV is (0.4~1.0):1; (4) In the salt formation reaction, the solvent is selected from one or more of nitrile solvents, ester solvents and alcohol solvents; (5) In the salt-forming reaction, the volume-to-mass ratio of the solvent to compound IV is 5~12.5 mL / g; (6) The temperature of the salt formation reaction is 60~65℃; (7) In the salt-forming reaction, the resolving agent reacts with compound IV in one or two separate salt-forming reactions; (8) In the salt-forming reaction, the resolving agent is added either once or in two separate additions; (9) In the free reaction, the base is an alkali metal carbonate or an alkali metal bicarbonate, and the alkali metal carbonate is selected from one or more of sodium carbonate, potassium carbonate and cesium carbonate. (10) In the free reaction, the base is an alkali metal carbonate or an alkali metal bicarbonate, and the alkali metal bicarbonate is sodium bicarbonate and / or potassium bicarbonate. (11) In the free reaction, the base is in the form of an aqueous solution, and the salt obtained in step (i) is added to the base; (12) After the free reaction is completed, the following steps are performed for post-processing, which includes extraction, washing, drying, filtration and concentration; (13) In the post-treatment after the free reaction is completed, the solvent for extraction is an ester solvent; (14) In the post-treatment after the free reaction is completed, the washing is performed using a NaCl solution with a mass fraction of 10-20%; (15) In the post-treatment after the free reaction is completed, the drying is performed using anhydrous sodium sulfate; (16) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed.

4. The method for preparing the compound as shown in formula IV(R) according to claim 2, characterized in that, It meets one or more of the following conditions: (1) In the salt-forming reaction, the resolving agent reacts with compound IV in a single reaction, and the molar ratio of the resolving agent to compound IV is (0.3~1.0):1; Alternatively, in the salt-forming reaction, the resolving agent reacts with compound IV in two separate salt-forming reactions, wherein in the first reaction, the molar ratio of the resolving agent to compound IV is (0.3~0.6):1; and in the second reaction, the molar ratio of the resolving agent to compound IV is (0.3~0.6):

1. (2) In the salt formation reaction, the resolving agent is added at once, and the molar ratio of the resolving agent to compound IV is (0.3~1.0):1; Alternatively, in the salt-forming reaction, the resolving agent is added in two parts, wherein in the first part, the molar ratio of the resolving agent to compound IV is (0.3~0.6):1, and in the second part, the molar ratio of the resolving agent to compound IV is (0.3~0.6):

1. (3) In the salt formation reaction, the solvent is a nitrile solvent, an ester solvent, or a mixture of an ester solvent and an alcohol solvent; (4) The salt formation reaction is divided into two stages. The reaction temperature of the first stage is 50~70℃, and the reaction temperature of the second stage is the temperature at which the solvent is refluxed. (5) In the free reaction, the base is an alkali metal bicarbonate; (6) In the post-treatment after the free reaction is completed, the solvent for extraction is ethyl acetate; (7) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent. (8) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed, wherein the recrystallization may or may not use seed crystals.

5. The method for preparing the compound as shown in formula IV(R) according to claim 4, characterized in that, It meets one or more of the following conditions: (1) In the salt-forming reaction, the resolving agent reacts with compound IV in a single reaction, and the molar ratio of the resolving agent to compound IV is (0.4~0.5):1; Alternatively, in the salt-forming reaction, the resolving agent reacts with compound IV in two separate salt-forming reactions, wherein in the first reaction, the molar ratio of the resolving agent to compound IV is (0.4~0.5):1; and in the second reaction, the molar ratio of the resolving agent to compound IV is (0.4~0.5):

1. (2) In the salt formation reaction, the resolving agent is added at once, and the molar ratio of the resolving agent to compound IV is (0.4~0.5):1; Alternatively, in the salt-forming reaction, the resolving agent is added in two parts, wherein in the first part, the molar ratio of the resolving agent to compound IV is (0.4~0.5):1; and in the second part, the molar ratio of the resolving agent to compound IV is (0.4~0.5):

1. (3) In the salt formation reaction, the solvent is a nitrile solvent, an ester solvent, or a mixture of an ester solvent and an alcohol solvent, wherein the volume ratio of the ester solvent to the alcohol solvent in the mixture of the ester solvent and the alcohol solvent is (3~5):1; (4) The salt formation reaction is divided into two stages. The reaction temperature of the first stage is 50~70℃, and the reaction temperature of the second stage is the temperature at which the solvent is refluxed. Accordingly, the resolving agent is added in two stages. In the first stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. In the second stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. (5) The salt formation reaction is divided into two stages. The reaction temperature of the first stage is 50~70℃, and the reaction temperature of the second stage is the temperature at which the solvent is refluxed. The reaction time of the first stage is 2~4h, and the reaction time of the second stage is 23~25h. (6) In the free reaction, the base is sodium bicarbonate; (7) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent, and the volume ratio of the good solvent to the bad solvent is 1: (1~3). (8) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a poor solvent, and the good solvent is N,N-dimethylformamide and / or dimethyl sulfoxide. (9) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent, and the bad solvent is water. (10) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent, and the volume of the good solvent is such that the crude product to be recrystallized is dissolved. (11) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent, and the recrystallization includes the following steps: mixing the good solvent solution of the crude product to be recrystallized with the bad solvent. (12) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a poor solvent. Seed crystals are used in the recrystallization. The seed crystals are added when they are added to the good solvent solution of the crude product to be recrystallized, or when the good solvent solution of the crude product to be recrystallized is mixed with the poor solvent, and then the seed crystals are added. The mass ratio of the seed crystals to the crude product to be recrystallized is (0.0001~0.1):

1. (13) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed, wherein the recrystallization is performed once or multiple times. (14) In the salt-forming reaction, the nitrile solvent in the solvent is acetonitrile; (15) In the salt-forming reaction, the ester solvent in the solvent is ethyl acetate; (16) In the salt formation reaction, the alcohol solvent in the solvent is ethanol.

6. The method for preparing the compound as shown in formula IV(R) according to claim 5, characterized in that, It meets one or more of the following conditions: (1) In the salt formation reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, and the solvent is ethyl acetate, acetonitrile, or a mixture of ethyl acetate and ethanol. Alternatively, in the salt-forming reaction, the resolving agent is D-tartaric acid, and the solvent is a mixture of ethyl acetate and ethanol. (2) The free reaction mentioned above, wherein the base is a 1-10% sodium bicarbonate aqueous solution; (3) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent, and the volume ratio of the good solvent to the bad solvent is 1:1 or 1:

2. (4) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent, and the good solvent is dimethyl sulfoxide. (5) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a poor solvent, and the volume of the good solvent is such that the crude product to be recrystallized is dissolved at 15~50°C. (6) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent. The recrystallization includes the following steps: mixing the good solvent solution of the crude product to be recrystallized with the bad solvent. Specifically, the mixing involves adding the bad solvent dropwise to the good solvent solution of the crude product to be recrystallized. The temperature of this process is controlled at 15~45℃. (7) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent. The recrystallization includes the following steps: mixing the good solvent solution of the crude product to be recrystallized with the bad solvent, and after mixing the good solvent solution with the bad solvent, keeping it at 15~35℃. (8) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a poor solvent. Seed crystals are used in the recrystallization. The seed crystals are added when the seed crystals are added to the good solvent solution of the crude product to be recrystallized, or when the good solvent solution of the crude product to be recrystallized is mixed with the poor solvent, and then the seed crystals are added. The mass ratio of the seed crystals to the crude product to be recrystallized is (0.0009~0.026):

1.

7. The method for preparing the compound as shown in formula IV(R) according to claim 6, characterized in that, It meets one or more of the following conditions: (1) In the salt formation reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, and the solvent is ethyl acetate, acetonitrile or a mixed solvent of ethyl acetate and ethanol. In the mixed solvent of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol is (3~5):

1. Alternatively, in the salt-forming reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, and the volume ratio of ethyl acetate to ethanol in the mixture of ethyl acetate and ethanol is (3~5):

1. (2) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a poor solvent, and the volume-to-mass ratio of the good solvent to the crude product being recrystallized is 1~5 mL / g. (3) After the salt formation reaction in step (i) is completed, a post-treatment including a recrystallization step is performed, and then step (ii) is performed. The recrystallization is a dual-solvent recrystallization, wherein the dual solvents are a good solvent and a bad solvent. The recrystallization includes the following steps: mixing the good solvent solution of the crude product to be recrystallized with the bad solvent, and after mixing the good solvent solution with the bad solvent, keeping it at 15~25℃.

8. The method for preparing the compound as shown in formula IV(R) according to claim 6, characterized in that, It satisfies any one of the following conditions: (1) In the salt formation reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is ethyl acetate or a mixed solvent of ethyl acetate and ethanol, the salt formation reaction is carried out in two stages, and correspondingly, the resolving agent is fed in two batches. In the first stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):1, and in the second stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. (2) In the salt formation reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is acetonitrile, and the reaction temperature of the salt formation reaction is 60~65℃. (3) In the salt formation reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, and the reaction temperature of the salt formation reaction is 60~65℃. (4) In the salt formation reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, and the salt formation reaction is carried out in two stages. Accordingly, the resolving agent is fed in two batches. In the first stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. In the second stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1.

9. The method for preparing the compound as shown in formula IV(R) according to claim 8, characterized in that, It satisfies any one of the following conditions: (1) In the salt-forming reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is ethyl acetate or a mixture of ethyl acetate and ethanol, the salt-forming reaction is carried out in two stages, and correspondingly, the resolving agent is added twice. In the first stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):1, and in the second stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. The reaction temperature of the first stage is 60~65℃; the reaction temperature of the second stage is 75~80℃. (2) In the salt-forming reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is ethyl acetate or a mixture of ethyl acetate and ethanol, and the salt-forming reaction is carried out in two stages. Accordingly, the resolving agent is added twice. In the first stage, the molar ratio of the amount of the resolving agent added to the compound IV is (0.4~0.5):

1. In the second stage, the molar ratio of the amount of the resolving agent added to the compound IV is (0.4~0.5):

1. The reaction time of the first stage is 2~4h. The reaction time of the second stage is 23~25h. (3) In the salt formation reaction, the resolving agent is D-(+)-di-p-methylbenzoyl tartaric acid, the solvent is acetonitrile, the reaction temperature of the salt formation reaction is 60~65℃, and the reaction time is 15~17h. (4) In the salt formation reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, the reaction temperature of the salt formation reaction is 60~65℃, and the reaction time is 2~4h. (5) In the salt formation reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, the salt formation reaction is carried out in two stages, and correspondingly, the resolving agent is added twice. In the first stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):1, and in the second stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. The reaction temperature of the first stage is 60~65℃, and the reaction temperature of the second stage is 75~80℃. (6) In the salt-forming reaction, the resolving agent is D-tartaric acid, the solvent is a mixture of ethyl acetate and ethanol, and the salt-forming reaction is carried out in two stages. Accordingly, the resolving agent is added twice. In the first stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. In the second stage, the molar ratio of the amount of the resolving agent to the compound IV is (0.4~0.5):

1. The reaction time of the first stage is 2~4h. The reaction time of the first stage is 23~25h.

10. A method for preparing a compound as shown in formula IV(R) according to any one of claims 1-9, characterized in that, R 1 The method for preparing the compound of formula IV(R), which is methyl, further comprises a method for preparing the compound of formula IV, wherein the method for preparing the compound of formula IV comprises the following steps: in a solvent, in the presence of an organic base, the compound of formula II, a formaldehyde source, and methylamine undergo the Mannich reaction as shown below to prepare the compound of formula IV: 。 11. The method for preparing the compound as shown in formula IV(R) according to claim 10, characterized in that, It meets one or more of the following conditions: (1) In the Mannich reaction, the solvent is an alcohol solvent; (2) In the Mannich reaction, the organic base is N(R) a )3, R a Independently H or C1-C6 alkyl; (3) In the Mannich reaction, the formaldehyde source is formaldehyde and / or paraformaldehyde; (4) In the Mannich reaction, the methylamine is in the form of a methylamine salt or a methylamine solution; (5) In the Mannich reaction, the molar ratio of the compound as shown in Formula II to the methylamine is (1~1.5):1; (6) In the Mannich reaction, the molar ratio of the formaldehyde source to the methylamine is (2~5):1; wherein the amount of the formaldehyde source is calculated based on the relative molecular mass of formaldehyde. (7) The reaction temperature of the Mannich reaction is the temperature at which the solvent can be refluxed; Alternatively, the reaction temperature of the Mannich reaction is 60~70℃; (8) The Mannich reaction is carried out in an atmosphere of inert gas; (9) In the Mannich reaction, the molar ratio of the organic base to the methylamine is (0.2~2):1; (10) The Mannich reaction described herein is carried out under acidic or acid-free conditions; (11) After the Mannich reaction is completed, the following post-processing steps are performed, which include one or more of the following operations: concentration, extraction, acidification, filtration, and neutralization.

12. The method for preparing the compound as shown in formula IV(R) according to claim 11, characterized in that, It meets one or more of the following conditions: (1) In the Mannich reaction, the organic base is N(R) a )3, R a Independently H or C1-C6 alkyl, R a Not both H; (2) In the Mannich reaction, the organic base is N(R) a )3, R a Independently, it is H or C1-C6 alkyl, wherein the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (3) In the Mannich reaction, when the formaldehyde source is formaldehyde, the formaldehyde is in the form of an aqueous solution of formaldehyde; (4) In the Mannich reaction, the methylamine is in the form of a methylamine salt or a methylamine solution, wherein the methylamine salt is methylamine hydrochloride; and in the methylamine solution, the solvent is selected from alcohol solvents and / or water. (5) In the Mannich reaction, the molar ratio of the compound as shown in Formula II to the methylamine is 1.05:1; (6) In the Mannich reaction, the molar ratio of the formaldehyde source to the methylamine is 3:1, wherein the amount of the formaldehyde source is calculated based on the relative molecular mass of formaldehyde. (7) The reaction temperature of the Mannich reaction is 60°C; (8) The Mannich reaction is carried out in an atmosphere of inert gas, which is nitrogen or an inert gas; (9) In the Mannich reaction, the molar ratio of the organic base to the methylamine is (1~2):1; (10) In the Mannich reaction, the organic base is added in batches, wherein the molar ratio of the first batch of organic base to the methylamine is (0.05~0.2):1; (11) When the Mannich reaction is carried out under acid-free conditions, the reaction raw materials are the solvent, the organic base, the compound as shown in Formula II, the formaldehyde source, and the methylamine; (12) When the Mannich reaction is carried out under acidic conditions, the acid is selected from one or more of hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, L-tartaric acid, S-mandelic acid, D(+)-10-camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid. (13) When the Mannich reaction is carried out under acidic conditions, the reaction raw materials are the solvent, the organic base, the compound as shown in Formula II, the formaldehyde source, the methylamine and the acid; (14) The post-processing steps after the completion of the Mannich reaction include the following operations in sequence: concentration, extraction, acidification, filtration, neutralization of the filter cake, extraction, and concentration.

13. The method for preparing the compound as shown in formula IV(R) according to claim 12, characterized in that, It meets one or more of the following conditions: (1) In the Mannich reaction, the organic base is triethylamine; (2) In the Mannich reaction, the formaldehyde source is paraformaldehyde; (3) In the Mannich reaction, the organic base is added in two batches; (4) In the Mannich reaction, after the first batch of organic bases is added, until the percentage of the amount of the compound shown in Formula II and the sum of the amounts of the compound shown in Formula II and the compound shown in Formula III in the reaction solution is less than 20%, the remaining organic bases are added and the reaction continues until the methylamine reaction is complete or no longer occurs. (5) When the Mannich reaction is carried out under acidic conditions, the molar ratio of the acid to the methylamine is (0.1-1.5):1; (6) In the post-processing steps after the Mannich reaction, the acidification includes: acidifying the organic phase obtained after extraction with hydrochloric acid; (7) In the post-treatment step after the completion of the Mannich reaction, the neutralization is to neutralize to a pH of 7-8.

14. The method for preparing the compound as shown in formula IV(R) according to claim 13, characterized in that, The preparation method of the compound shown in Formula IV comprises the following steps: under a nitrogen atmosphere, the solvent, the methylamine, the formaldehyde source, the compound shown in Formula II, and the first batch of organic base are stirred at 60-70°C for 14-18 hours, or stirred until the percentage of the amount of the compound shown in Formula II to the sum of the amounts of the compounds shown in Formula II and Formula III is less than 15%, and then stirred with the remaining organic base at 60-70°C for 2-3 hours.

15. A method for preparing a compound as shown in Formula VI, comprising the following steps: The compound shown in formula IV(R) is prepared according to the method for preparing the compound as described in any one of claims 1-14; In a solvent, under the action of a base, the compound shown in formula IV(R) reacts 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.

16. The method for preparing the compound as shown in Formula VI according to claim 15, characterized in that, It meets one or more of the following conditions: (1) In the olefination reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, cyclic ether solvents and amide solvents; (2) In the olefination reaction, the base is and / or alkali metal alkoxides, wherein 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; (3) In the olefination reaction, the... Julia-Kocienski The reagent is Ar is C6-C 10 aryl, 5-10 heteroaryl, with one or more Ar 1 Replacement C6-C 10 aryl or aryl with one or more Ar 1 Substituted 5-10 heteroaryl groups, Ar 1 Independently C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein in each 5-10 heteroaryl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; (4) The reaction temperature of the olefination reaction is -50℃ to 25℃; (5) 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; (6) In the olefination reaction, the molar ratio of the base to the compound shown in formula IV(R) is (0.5~2):1; (7) 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; (8) The reactants for the olefination reaction are the solvent, the base, the compound as shown in formula IV(R), and the... Julia-Kocienski Reagents; (9) 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; (10) In the olefination reaction, the base is in the form of a base solution, and the solvent in the base solution is a cyclic ether solvent; (11) After the olefination reaction is completed, the post-processing is carried out through the following steps, which include one or more of the following steps: quenching, extraction, concentration, acidification to salt, and neutralization.

17. The method for preparing the compound as shown in Formula VI according to claim 16, characterized in that, It meets one or more of the following conditions: (1) In the olefination reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, cyclic ether solvents, and amide solvents, wherein the ether solvent is... R m and R n Independently C1-C4 alkyl; (2) In the olefination reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, cyclic ether solvents and amide solvents, and the alkylbenzene solvent is toluene; (3) In the olefination reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, cyclic ether solvents and amide solvents, wherein the cyclic ether solvent is tetrahydrofuran and / or 2-methyltetrahydrofuran; (4) In the olefination reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, cyclic ether solvents and amide solvents, and the amide solvent is N,N-dimethylformamide; (5) In the olefination reaction, the base is selected from... , and One or more of the following; (6) In the olefination reaction, the... Julia-Kocienski The reagent is , or ; (7) 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℃. (8) 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; (9) In the olefination reaction, the molar ratio of the base to the compound shown in formula IV(R) is (1~1.5):1; (10) In the olefination reaction described above, the olefination reaction described above Julia-Kocienski The molar ratio of the reagent to the compound shown in formula IV(R) is (1~1.5):

1.

18. The method for preparing the compound as shown in Formula VI according to claim 17, characterized in that, It meets one or more of the following conditions: (1) In the olefination reaction, the solvent is ethylene glycol dimethyl ether; (2) The alkali mentioned is ; (3) The above Julia-Kocienski The reagent is ; (4) 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℃.

19. A method for preparing a compound as shown in Formula VII, comprising the following steps: The compound shown in Formula VI is prepared by the method of preparation of the compound shown in Formula VI according to claim 15; In a solvent, in the presence of a free radical initiator and a free radical source, the compound shown in Formula VI undergoes an isomerization reaction to prepare the compound shown in Formula VII. 。 20. The method for preparing the compound as shown in Formula VII according to claim 19, characterized in that, It meets one or more of the following conditions: (1) In the isomerization reaction, the solvent is selected from one or more of cyclic ether solvents, ester solvents, alcohol solvents and hydrocarbon solvents; (2) In the isomerization reaction, the free radical initiator is selected from one or more of azobisisobutyronitrile, azobisisoheptanenitrile and dimethyl azobisisobutyrate; (3) The isomerization reaction, wherein the free radical source is , I2 , , , , thiourea or ; (4) The isomerization reaction, wherein the compound shown in Formula VI is the compound shown in Formula VI-1: ; (5) In the isomerization reaction, the volume molar ratio of the solvent to the compound shown in Formula VI is (1~8) L / mol; (6) In the isomerization reaction, the molar ratio of the free radical source to the compound shown in Formula VI is (0.1~1):1; (7) In the isomerization reaction, the molar ratio of the free radical initiator to the compound shown in Formula VI is (0.1~1):1; (8) The reaction temperature of the isomerization reaction is 60~80℃; (9) The reaction time for the isomerization reaction is 10-25 h; (10) The isomerization reaction is carried out in an atmosphere of inert gas; (11) 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; (12) In the preparation method described above, 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; (13) After the isomerization reaction is completed, the following steps are performed for post-processing, including: acidification, recrystallization, neutralization, extraction and concentration.

21. The method for preparing the compound as shown in Formula VII according to claim 20, 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 mixture of a hydrocarbon solvent and an ester solvent; (2) In the isomerization reaction, the free radical initiator is dimethyl azobisisobutyrate; (3) In the isomerization reaction, the volume molar ratio of the solvent to the compound shown in Formula VI is (2~4) L / mol; (4) In the isomerization reaction, the molar ratio of the free radical source to the compound shown in Formula VI is (0.15~0.3):1; (5) In the isomerization reaction, the molar ratio of the free radical initiator to the compound shown in Formula VI is (0.15~0.3):1; (6) The reaction temperature of the isomerization reaction is 65~70℃; (7) The reaction time for the isomerization reaction is 12-19 h; (8) The isomerization reaction is carried out in an atmosphere of inert gas, wherein the inert gas is nitrogen or an inert gas; (9) In the preparation method described above, 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; (10) In the preparation method described above, when the free radical initiator is added in the form of a solution, it is added dropwise; (11) In the post-processing steps after the isomerization reaction, the acidification, recrystallization, neutralization, extraction and concentration are carried out in sequence; (12) In the post-processing steps after the isomerization reaction, the acidification is performed using an inorganic acid. (13) In the post-processing step after the isomerization reaction, the molar ratio of the acid used for acidification to the compound shown in Formula VI-1 is (1~2):

1. (14) In the post-processing step after the isomerization reaction, the solid obtained after acidification is a salt; (15) In the post-processing steps after the isomerization reaction, the recrystallization is the recrystallization of the salt obtained by acidification. (16) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization; (17) In the post-processing step after the isomerization reaction, the neutralization is to neutralize to a pH of 8.5 to 9.5; (18) In the post-processing step after the isomerization reaction, the solvent used for extraction in the post-processing step is a water-insoluble organic solvent. (19) The post-processing steps after the isomerization reaction further include 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.

22. The method for preparing the compound as shown in Formula VII according to claim 21, 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 mixture of ethyl acetate and n-heptane; (2) In the post-processing steps after the isomerization reaction, the acidification is performed using hydrochloric acid. (3) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the solvent is an alcohol solvent; (4) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the antisolvent is an ether solvent; (5) In the post-processing step after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the volume-to-mass ratio of the solvent to the solid to be recrystallized is (0.5~0.8) L / kg; (6) In the post-processing step after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the volume-to-mass ratio of the antisolvent to the solid to be recrystallized is (8~12) L / kg. (7) In the post-processing steps after the isomerization reaction, the recrystallization is 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. (8) In the post-processing step after the isomerization reaction, the neutralization is performed by using a weak acid salt of an alkali metal to free the salt obtained by recrystallization. (9) The post-processing step after the isomerization reaction is further performed by adding seed crystals during the acidification process. 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.

23. The method for preparing the compound as shown in Formula VII according to claim 22, 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 mixture of ethyl acetate and n-heptane, and the volume ratio of ethyl acetate to n-heptane in the mixture of ethyl acetate and n-heptane is 1:(5~10). (2) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the solvent is methanol; (3) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the antisolvent is methyl tert-butyl ether; (4) In the post-processing step after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the volume-to-mass ratio of the solvent to the solid to be recrystallized is 0.67 L / kg. (5) In the post-processing step after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, and the volume-to-mass ratio of the antisolvent to the solid to be recrystallized is 10 L / kg. (6) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, which specifically includes the following steps: mixing the solid to be recrystallized with the solvent and then mixing it with the antisolvent. The mixing and dissolving involves mixing the solid to be recrystallized with the solvent and dissolving it at 40~50℃. (7) In the post-processing steps after the isomerization reaction, the recrystallization is solvent-antisolvent recrystallization, which specifically includes the following steps: mixing the solid to be recrystallized with the solvent to dissolve it, then mixing it with the antisolvent, cooling it to 0~10℃, and separating the solid. (8) In the post-processing step after the isomerization reaction, the neutralization is to use a weak acid salt of an alkali metal to free the salt obtained by recrystallization, and the weak acid salt of the alkali metal is potassium phosphate. (9) In the post-processing steps after the isomerization reaction, the acidification is to add the acid dropwise to the crude isomerization reaction solution to be acidified, and when the amount of the acid added is 1 / 3 to 1 / 2 of the original amount, the seed crystal is added.

24. A method for preparing a compound as shown in Formula I, comprising the following steps: The compound shown in Formula VII was prepared according to the method for preparing the compound as described in claim 19; In a solvent, under the action of a reducing agent, the compound shown in Formula VII undergoes a reduction reaction to prepare the compound shown in Formula I; 。 25. The method for preparing the compound as shown in Formula I according to claim 24, wherein one or more of the following conditions are satisfied: (1) In the reduction reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, nitrile solvents and cyclic ether solvents; (2) In the reduction reaction, the reducing agent is selected from one or more of lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride and NaAlH2(OCH2CH2OCH3)2; (3) The reduction reaction is carried out in an atmosphere of inert gas; (4) The reaction temperature of the reduction reaction is -5~10℃; (5) In the reduction reaction, the molar ratio of the reducing agent to the compound shown in Formula VII is (0.5~1.5):

1.

26. The method for preparing the compound as shown in Formula I according to claim 25, wherein one or more of the following conditions are satisfied: (1) In the reduction reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, nitrile solvents and cyclic ether solvents, and the ether solvent is methyl tert-butyl ether and / or ethylene glycol dimethyl ether; (2) In the reduction reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, nitrile solvents and cyclic ether solvents, and the alkylbenzene solvent is toluene; (3) In the reduction reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, nitrile solvents and cyclic ether solvents, and the nitrile solvent is acetonitrile; (4) In the reduction reaction, the solvent is selected from one or more of ether solvents, alkylbenzene solvents, nitrile solvents and cyclic ether solvents, and the cyclic ether solvent is tetrahydrofuran and / or 2-methyltetrahydrofuran; (5) The reduction reaction is carried out in an atmosphere of inert gas, wherein the inert gas is nitrogen and / or an inert gas; (6) In the reduction reaction, the reducing agent is lithium aluminum hydride; (7) The reaction temperature of the reduction reaction is 0~10℃; (8) In the reduction reaction, the molar ratio of the reducing agent to the compound shown in Formula VII is 0.7:

1.

27. A salt formed by a compound of formula IV(R) and a resolving agent, wherein the salt is formed by a compound of formula IV(R) as claimed in claim 1 and a resolving agent.

28. The salt formed by the compound of formula IV(R) as described in claim 27 and the resolving agent, wherein the salt is: or .

29. Use of a salt formed by the compound of formula IV(R) as claimed in claim 27 and a resolving agent in the preparation of the compound of formula IV(R), wherein the method for preparing the compound of formula IV(R) comprises the free reaction as described in any one of claims 1-9.

30. A method for preparing a salt formed by the compound of formula IV(R) as described in claim 27 and a resolving agent, comprising the salt-forming reaction as described in any one of claims 1-9.

31. Use of D-(+)-di-p-methylbenzoyl tartaric acid and / or D-tartaric acid as resolving agents in resolving compound IV to prepare a compound as shown in formula IV(R), wherein compound IV and the compound as shown in formula IV(R) are as described in any one of claims 1-9; the method for resolving compound IV to prepare a compound as shown in formula IV(R) is the method for preparing a compound as shown in formula IV(R) as described in any one of claims 1-9.

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