Process for the preparation of piperidone compounds

Abstract

This invention discloses a method for preparing piperidinone compounds. Specifically, this invention discloses a method for preparing a compound as shown in Formula III, comprising the following steps: in a solvent, under the action of an organic base, a compound as shown in Formula II, paraformaldehyde, and a methylamine salt undergo the Mannich reaction as shown below to prepare the compound as shown in Formula III. The preparation method of this invention uses inexpensive 2-methylacetoacetate as a raw material and can prepare piperidinone compounds in high yields on a 100-gram scale, which is beneficial for subsequent preparations [( S )-( E )-4-fluoroenyl-1-methyl-3-methyl-3-piperidinyl)methanol, suitable for industrial production.

Description

Technical Field

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

[0002] Ras, a homologue of the rat sarcoma oncogene, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. Specifically, under normal physiological conditions, Ras is activated by growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, and differentiation. These regulatory functions of Ras are carried out through the switching between GDP-bound and GTP-bound states, or "molecular switches" (Alamgeer et al., Current Opin Pharmacol. 2013, 13:394-401). Ras bound to GDP is an inactive form, in a dormant or closed state, where the signaling system is shut down. When exposed to certain proliferative stimuli, it is activated, for example, by being induced by guanine nucleotide exchange factor (GEF) to release GDP and bind to GTP. As a result, Ras is "turned on" and converted into its active form, which recruits and activates various downstream effectors to conduct signal transduction. It can transmit signals from the cell surface to the cytoplasm, thereby controlling many key cellular processes such as differentiation, survival, and proliferation (ZhiTan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).

[0003] Ras possesses GTPase activity, capable of cleaving the terminal phosphate of GTP to convert it into GDP, effectively rendering it inactive. However, Ras' endogenous GTPase activity is very low; the conversion of GTP-Ras to GDP-Ras requires the exogenous protein GAP (GTPase activator). GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any Ras gene mutation affecting the interaction between Ras and GAP or the conversion of GTP to GDP will result in Ras remaining in an activated state for an extended period. This continuously transmits growth and division signals to the cell, stimulating cell proliferation and ultimately leading to tumor formation and development.

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

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

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

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

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

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

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

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

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

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

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

[0015] To address the problems existing in the prior art, the present invention aims to provide a method for preparing piperidinone compounds. The method of the present invention uses inexpensive 2-methylacetoacetate as a raw material, and can prepare piperidinone compounds in high yield on a 100-gram scale, which is beneficial for subsequent preparations [( S )-( E )-4-fluoroenyl-1-methyl-3-methyl-3-piperidinyl)methanol, suitable for industrial production.

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

[0017] This invention provides a method for preparing a compound as shown in Formula III, comprising the following steps: in a solvent, under the action of an organic base, a compound as shown in Formula II, paraformaldehyde, and a methylamine salt undergo a Mannich reaction as shown below to prepare a compound as shown in Formula III: ; Wherein, R is a C1-C6 alkyl group; The organic base is N(R) a )3, R a Independently H or C1-C6 alkyl, and R a Not both H; The organic base is added in batches, wherein the molar ratio of the first batch of organic base to the methylamine salt is (0.05~0.2):1.

[0018] In one embodiment of the present invention, in the Mannich reaction, the methylamine salt is methylamine hydrochloride.

[0019] In one embodiment of the present invention, the reaction temperature of the Mannich reaction is 60~70°C, for example 60°C.

[0020] 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.

[0021] In one embodiment of the present invention, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, preferably ethyl.

[0022] In one aspect of the present invention, R a It is a C1-C6 alkyl group.

[0023] In one aspect of the present invention, 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.

[0024] In one embodiment of the present invention, the organic base is triethylamine.

[0025] The solvent can be an inert solvent commonly used in this type of reaction in the art. 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.

[0026] 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 salt is (1~1.5):1, for example 1.05:1.

[0027] In one embodiment of the present invention, in the Mannich reaction, the molar ratio of the paraformaldehyde to the methylamine salt is (2~5):1, for example 3:1, wherein the amount of paraformaldehyde is calculated based on the relative molecular mass of the monomer formaldehyde therein.

[0028] In one embodiment of the present invention, in the Mannich reaction, the molar ratio of the organic base to the methylamine salt is (1~2):1, for example, 1.1:1.

[0029] In one embodiment of the present invention, in the Mannich reaction, the molar ratio of the first batch of organic base to the methylamine salt is (0.08~0.12):1, for example 0.1:1.

[0030] In one embodiment of the present invention, the organic base is added in two batches during the Mannich reaction.

[0031] 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 salt reaction is complete or no longer occurs, for example, by continuing the stirring reaction for 2 to 5 hours, preferably 2 to 3 hours.

[0032] 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 salt reaction is complete or no longer occurs, for example, by continuing the stirring reaction for 2 to 5 hours, preferably 2 to 3 hours.

[0033] In one embodiment of the present invention, the reactants for the Mannich reaction are the solvent, the organic base, the compound as shown in Formula II, the paraformaldehyde, and the methylamine salt.

[0034] 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 salt, the paraformaldehyde, 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.

[0035] 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.

[0036] 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.

[0037] The reagents and raw materials used in this invention are all commercially available.

[0038] The positive and progressive effects of this invention are as follows: the raw materials used in the preparation method of this invention are inexpensive, especially compared with the conventional Mannich reaction conditions in the art. The Mannich reaction conditions involved in the preparation method of this invention can obtain the target product in a high yield when scaled up to the hundred-gram scale, which is beneficial to subsequent preparations. S )-( E )-4-Fluorenyl-1-methyl-3-methyl-3-piperidinyl)methanol. Attached Figure Description

[0039] Figure 1 Molecular ellipsoid diagram of a single crystal of the D-DTTA salt of compound 3 with a single configuration.

[0040] Figure 2 Molecular ellipsoid diagram of a single crystal of L-tartrate of compound 3 with a single configuration. Detailed Implementation

[0041] 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.

[0042] Preparation route of compound 1:

[0043] The preparation route of compound 5 is shown below:

[0044] Step 1: Using inexpensive and readily available compound 2, paraformaldehyde, and methylamine salt 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.

[0045] 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.

[0046] 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.

[0047] Step 4: The mixture was reconfigured into a single configuration compound 8 in the presence of AIBME and compound 7.

[0048] 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.

[0049] Example 1.1 Preparation of Compound 3

[0050] 1) Add ethanol (20 L, 10 vol.), methylamine hydrochloride (2.00 kg, 1.0 eq.), and paraformaldehyde (2.67 kg, 3.0 eq.) to the reaction flask. 2) Add ethyl 2-methylacetoacetate (4.48 kg, 1.05 eq.) and triethylamine (0.30 kg, 0.1 eq.). 3) Nitrogen gas was purged three times; 4) Heat to 60℃ (60℃-70℃ is acceptable) and stir for at least 16 hours until n （2-甲基乙酰乙酸乙酯） / n （2-甲基乙酰乙酸乙酯+化合物3） The amount of substance is <15% (HPLC 214 nm), where n represents the amount of substance; 5) Add triethylamine (3.00 kg, 1.0 eq.) and continue the reaction at 60℃ (60℃-70℃ is acceptable) for 2-3 h; after the reaction is completed, the in-situ yield of compound 3 in the reaction solution is determined by HPLC external standard method to be 60%.

[0051] 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%.

[0052] 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).

[0053] LCMS (m / z): 200.1 [M+H].

[0054] Example 1.2 uses the same reaction conditions as Example 1.1, and triethylamine is added in batches, only adjusting the equivalent amount of the first batch of triethylamine (the equivalent amount is based on the amount of methylamine hydrochloride).

[0055] Comparative Example 1.1 used the same reaction conditions as Example 1, but triethylamine was added all at once.

[0056] When triethylamine is added to the reaction system all at once, the in-situ yield of compound 3 in the reaction solution after the reaction is completed is only 12.7%.

[0057] Comparative Example 1.2 uses other Mannich reaction systems

[0058] A scale-up experiment was conducted based on the Mannich reaction system that yielded the highest yield in the small-scale experiment. However, the yield was significantly lower than that in Examples 1.1 and 1.2, specifically as follows: Comparative Example 1.2.1 Add 500 mL of ethanol and (115 g, 1.0 eq.) of methylamine in flask 1, cool to 0-10℃, add (182 g, 2.25 eq.) of formaldehyde in aqueous solution dropwise, and keep warm and stir for half an hour.

[0059] Add 1 L of ethanol, ethyl 2-methylacetoacetate (151 g, 1.05 eq.), and (101 g, 1.05 eq.) methanesulfonic acid to reaction flask 2. Heat to reflux and stir. Add the system from reaction flask 1 dropwise to reaction flask 2, completing the addition over 1 hour. Reflux and stir overnight. Then, add (154 mL, 1.1 eq.) triethylamine and (24 g, 0.3 eq.) an aqueous solution of formaldehyde dropwise. Continue reflux for 20 hours. After central control, cool and concentrate until no more distillate is produced. Add 0.8 L of DCM and use 0.4 L of [unclear - possibly a specific solvent or solution]. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and concentrated to give 154.3 g of oil. The in-situ yield was 14.7%.

[0060] Comparative Example 1.2.2

[0061] Add 500 mL of ethanol and (126.5 g, 1.1 eq.) of methylamine ethanol solution to reaction flask 1, cool to 0-10℃, add (182 g, 2.25 eq.) of formaldehyde aqueous solution dropwise, and keep warm and stir for half an hour.

[0062] Add 1 L of ethanol, ethyl 2-methylacetoacetate (151 g, 1.05 eq.), and (101 g, 1.05 eq.) methanesulfonic acid to reaction flask 2. Heat to reflux and stir. Add the system from reaction flask 1 dropwise to reaction flask 2, completing the addition over approximately 3.5 hours. Reflux and stir overnight. Add (154 mL, 1.1 eq.) triethylamine and (24 g, 0.3 eq.) an aqueous solution of formaldehyde dropwise sequentially. Continue reflux for 20 hours. Add the imine solution system (18.9 g methylamine in ethanol + 27.3 g formaldehyde in aqueous solution), and continue reflux for 2 hours. After central cooling, concentrate until no more distillate is produced. Add 0.8 L of ethyl acetate and use 0.4 L of [unclear - possibly a specific solvent or solution]. The sample was washed twice with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 138.5 g of oil. The in-situ yield was 24.7%.

[0063] Example 2.1 Preparation of Compound 4

[0064] 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%.

[0065] The D-DTTA salt of compound 3 with a single configuration was added in portions to a tetrahydrofuran / methyl tert-butyl ether (1 / 1) mixed solvent until the solid did not completely dissolve after 0.5 hours at 60°C. The suspension was then rapidly filtered while hot into a glass sample vial preheated to 60°C. The vial was sealed, allowed to stand, 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.

[0066] 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).

[0067] Example 2.2 Synthesis of Compound 4

[0068] 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 in addition, and the temperature was raised to 78°C to begin reflux. After reflux for 24 hours, the heating was 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%.

[0069] Then, 10 g of the solid was dissolved in DMF (4 vol.), and water (4 vol.) was added dropwise while 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.

[0070] Example 2.3 Preparation of Compound 4

[0071] 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.

[0072] 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).

[0073] Example 2.4 Preparation of Compound 4

[0074] 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%.

[0075] Example 2.5 Preparation of Compound 4

[0076] 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%.

[0077] Example 2.6 Preparation of Compound 4

[0078] 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%.

[0079] Example 2.7 Preparation of Compound 4

[0080] 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%.

[0081] 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.

[0082] 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.

[0083] Example 2.8 Preparation of Compound 4

[0084] 2 g of compound 3 (10 mmol, 1 eq.) was dissolved in 20 mL (10 vol.) of ethyl acetate and 5 mL (2.5 vol.) of ethanol. 750 mg of D-tartaric acid (CAS: 147-71-7, 5 mmol, 0.5 eq) was added, the mixture was heated to 60 °C, stirred for 3 h, then another 750 mg of D-tartaric acid was added, and the mixture was refluxed and stirred for 24 h. The mixture was then allowed to cool naturally to room temperature (20 °C), filtered, and dried under vacuum to obtain 1.98 g of a white solid. This white solid was added to 100 mL of saturated sodium bicarbonate aqueous solution, and then dissolved in 100 mL of ethyl acetate. 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, and rotary drying were performed to finally obtain 1.13 g of free compound 4 with an ee value of 87%.

[0085] Example 3 Preparation of Compound 8

[0086] 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 extract the impurities again with 2-methyltetrahydrofuran (4.5 L, 3 vol.); 12) Separate the liquid and discard the organic phase. Add n-heptane (7.5 L, 5 vol.) to the aqueous phase, and add an aqueous solution of NaOH (391 g NaOH + 0.8 L water) dropwise. Control the temperature at 10-20℃ and adjust the pH of the system to 12-13 (the system contains a small amount of flocculent matter). 13) Separate the liquid and extract the product again from the aqueous phase using n-heptane (3.0 L, 2 vol.); 14) Combine the n-heptane phases, wash with 15% sodium chloride aqueous solution (4.5 L, 3 vol.), and separate the layers; 15) The organic phase was dried with 2.0 kg of anhydrous sodium sulfate, filtered, and washed with n-heptane (1.5 L, 1 vol.); 16) Transfer the filtrate to a reaction flask, bubble with nitrogen for 0.5-1 h, and add diphenyl disulfide (263 g, 0.16 eq.). 17) Replace with nitrogen and heat to 65-70℃; 18) Add a mixed solution of dimethyl azobisisobutyrate (277 g, 0.16 eq.) and ethyl acetate (1.5 L, 1 vol.) dropwise, completing the addition in about 1 hour; 19) The mixture was kept at 65-70℃ and stirred for 12-16 h. The configuration ratio detected by the central control was Z / E=9 / 91, and the olefin recovery rate was 94.7%. 20) Concentrate the system to dryness under reduced pressure at an external temperature of 50°C, and add ethyl acetate (4.5 L, 3 vol.). 21) Heat to 40-50℃, add dropwise a solution of 4 mol / L hydrogen chloride in ethyl acetate (1.88 L, 1.0 eq.), and add a small amount of seed crystals when about 1 / 3 of the solution has been added; 22) After the dripping is complete, stop heating and slowly cool to room temperature, stirring for 1-2 hours; 23) Filter and wash with ethyl acetate (3.0 L, 2 vol.); 24) After drying, 1.36 kg of crude product was obtained, with an HPLC purity of 96.6% and a configuration ratio of Z / E = 1.5 / 96.6; 25) Add methanol (0.91 L, 0.67 vol, based on crude product) to the reaction flask, along with the crude product (1.36 kg, 1.0 Y), and heat to 40-50℃ to dissolve completely; 26) Control the temperature at 40-50℃ and add methyl tert-butyl ether (13.6 L, 10 vol.) dropwise, completing the addition in about 2 hours; 27) Turn off the heating and let it cool naturally to room temperature (25℃), then cool to 5℃ (0-10℃ is also acceptable), and stir for 0.5-1 h; 28) Filter and rinse with methyl tert-butyl ether (2.7 L, 2 vol.); 29) 1.28 kg of product was obtained after drying, with an HPLC purity of 99.8% and a configuration ratio of Z / E = 0.06 / 99.94; 30) Dissolve 1.28 kg of the product in water (2.6 L, 2 vol.) and add dichloromethane (3.8 L, 3 vol.); 31) Add 20wt% potassium phosphate aqueous solution dropwise to adjust the pH to ~9; 32) Separate the liquid phase, and extract the aqueous phase again with dichloromethane (3.8 L, 3 vol.); 33) Separate the liquid and combine the organic phases, then wash with 15% sodium chloride aqueous solution (2.6 L, 2 vol.); 34) The product compound 8 (1.09 kg) was dried with anhydrous sodium sulfate (2.6 kg, 2.0 X) and concentrated under reduced pressure to obtain product compound 8. The product had an HPLC purity of 99.85%, a configuration ratio of Z / E = 0.04 / 99.85, ee% > 99.0%, and a yield of 65.4% (the yield here is the total yield of compound 8 prepared from compound 4).

[0087] 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.

[0088] The double bond in compound 8 has an E configuration, which was confirmed by 1H NMR and NOE spectra.

[0089] The 1H NMR spectrum data of compound 8 are as follows:

[0090] 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).

[0091] 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.

[0092]

[0093] 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).

[0094] 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.

[0095]

[0096] Example 4 Preparation of Compound 1

[0097] 1) Add ethylene glycol dimethyl ether (4.2 L, 5.0 vol.) and compound 8 (834 g, 1.0 eq.) to the reactor, turn on nitrogen protection and start stirring; 2) Cool the system to 0~10℃; 3) Control the temperature at 0~10℃, and slowly add LiAlH4 / THF (2.5 M) solution (1.13 L, 0.73 eq.) dropwise over a period of about 1 hour; 4) After the addition is complete, keep the mixture at 0~10℃ and stir for 30 min, then take a sample for monitoring: the raw materials have reacted completely; 5) Control the temperature T < 10℃, slowly add sodium sulfate decahydrate (583 g) in batches. The system releases heat and gas. Pay attention to ensuring the pipeline is unobstructed and to ensure the safe release of gas. 6) After the addition is complete, the system becomes viscous (colloidal) and the stirring is poor. The stirring condition improves over time. 7) Add 1.67 kg of anhydrous sodium sulfate and stir for 0.5 h; filter the system, wash the filter cake three times with 2.5 L of ethylene glycol dimethyl ether, combine the filtrates and concentrate under reduced pressure at T≤45℃, then pump until almost no fraction remains, to obtain 642 g of a light yellow oily compound 1 with a purity >99.0%. ee %>99.0%, content 99.5%, yield of content 97.5%.

[0098] 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).

[0099] Example 5 Preparation of Compound 20

[0100] 1) Add compound 19 (420 g, 1.0 eq.) and DMF (2.1 L, 5 vol.) to the reaction flask and start stirring; 2) Add potassium hydroxide (211 g, 1.5 eq.) in batches and stir for 0.5 hours; 3) Cool down to -30 ~ -20℃; 4) Introduce chlorofluoromethane (266 g, 1.5 eq.) over approximately half an hour, maintaining the temperature at -30 ~ -20℃; 5) Keep warm at -30 ~ -20℃ for half an hour, remove the cold bath, slowly warm to 20-30℃ and stir for 48 hours until the raw material content is less than 3%; 6) After the reaction is complete, add water dropwise to the system (3.78 L, 9 vol.). After the addition is complete, stir at 15-25℃ for 1-2 h. 7) Filtration: The filter cake was washed twice with water (1.68 L, 4 vol.), resulting in a 4% product loss in the mother liquor. 8) Add 0.5% acetic acid aqueous solution (1.68 L, 4 vol.) to the reaction flask, add filter cake, and stir for 0.5-1 h; 9) Filter and rinse with water (1.26 L, 3 vol.); 10) Dry the product compound 20 (434 g) at 40-50℃ with forced air drying to obtain a content of 92% and a yield of 80% based on the content.

[0101] 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).

[0102] Example 6 Preparation of Compound 5

[0103] 1) Add ethyl acetate (3.6 L, 5.0 V) and compound 20 (717 g, 1.0 eq.) to the reaction vessel and stir until dissolved; 2) Add glacial acetic acid (1.44 L, 2.0 V); 3) Control the temperature at 20~30℃, and add the first batch of 8~10% NaClO aqueous solution (13.5 L, 5.0 eq.) dropwise over 3 h; 4) After the addition is complete, keep the mixture warm and stir for 30 minutes. A yellow solid precipitates in the system. A sample is taken for monitoring: the raw materials have reacted completely, and about 8% of the intermediate remains. 5) Allow the reaction system to stand and separate into layers, then release the lower aqueous phase (13.3 L, experimental value, subject to actual conditions); 6) Control the temperature at 20~30℃, and add the second batch of 8~10% NaClO aqueous solution (8.1 L, 3.0 eq.) dropwise over 1 h; 7) After dripping, keep warm at 20-30℃ and stir overnight; 8) Sampling control: Approximately 3.4% of intermediates remain; 9) Filter by suction, and record the filter cake as LB1; record the mother liquor as MY1; 10) After washing the filter cake LB1 with 10% Na2SO3 aqueous solution (2.0 L, 2.8 V) and saturated NaHCO3 aqueous solution (2.0 L, 2.8 V), filter the filter cake by vacuum filtration. The filter cake is counted as LB2. 11) After drying the filter cake LB2 at 45℃, 498 g of white crude product was obtained, with a purity of 96.2% (Assay: 98.0%). 12) Separate the mother liquor MY1 into layers. Wash the organic phase sequentially with water (2.8 L, 4 V), 10% Na2SO3 aqueous solution (2.8 L, 4 V), and saturated NaHCO3 aqueous solution (2.0 L, 2.8 V). After separation, dry the organic phase with Na2SO4, filter and concentrate to obtain 218 g of yellow crude product with a purity of 92.9%. 13) Combine the two batches of crude product (686 g), add to isopropyl acetate (4 L, 5.8 V), heat to 80~85℃, stir until dissolved, and keep warm and stirring for 0.5 h; 14) Turn off the heating and allow the temperature 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%.

[0104] 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 III, comprising the following steps: in a solvent, under the action of an organic base, a compound as shown in Formula II, paraformaldehyde, and a methylamine salt undergo a Mannich reaction as shown below to prepare a compound as shown in Formula III: ； in, R is a C1-C6 alkyl group; The organic base is N(R) a )3, R a Independently H or C1-C6 alkyl, and R a Not both H; The organic base is added in batches, wherein the molar ratio of the first batch of organic base to the methylamine salt is (0.05~0.2):

1.

2. The method for preparing the compound as shown in Formula III according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In the Mannich reaction, the methylamine salt is methylamine hydrochloride; (2) The reaction temperature of the Mannich reaction is 60~70℃; (3) The Mannich reaction is carried out in an atmosphere of inert gas; (4) R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (5) R a It is a C1-C6 alkyl group; (6) In the Mannich reaction described above, the solvent is an alcohol solvent; (7) The molar ratio of the compound as shown in Formula II to the methylamine salt is (1~1.5):1; (8) The molar ratio of the paraformaldehyde to the methylamine salt is (2~5):1, wherein the molar amount of the paraformaldehyde is calculated based on the relative molecular mass of the monomer formaldehyde therein. (9) In the Mannich reaction, the molar ratio of the organic base to the methylamine salt is (1~2):1; (10) In the Mannich reaction, the molar ratio of the first batch of organic base to the methylamine salt is (0.08~0.12):1; (11) In the Mannich reaction described above, the organic base is added in two batches; (12) 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. (13) The reaction raw materials for the Mannich reaction are the solvent, the organic base, the compound as shown in Formula II, the paraformaldehyde and the methylamine salt.

3. The method for preparing the compound as shown in Formula III according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The reaction temperature of the Mannich reaction is 60℃; (2) The Mannich reaction is carried out in an atmosphere of inert gas, which is nitrogen or an inert gas; (3) R is ethyl; (4) R a In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; (5) In the Mannich reaction, the solvent is methanol, ethanol or isopropanol; (6) In the Mannich reaction, the molar ratio of the compound as shown in Formula II to the methylamine salt is 1.05:1; (7) In the Mannich reaction, the molar ratio of the paraformaldehyde to the methylamine salt is 3:1, wherein the amount of the paraformaldehyde is calculated based on the relative molecular mass of the monomer formaldehyde. (8) In the Mannich reaction, the molar ratio of the organic base to the methylamine salt is 1.1:1; (9) In the Mannich reaction, the molar ratio of the first organic base to the methylamine salt is 0.1:1; (10) 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 14-18 hours. (11) 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. After the remaining organic bases are added, the reaction is stirred until the methylamine salt reaction is complete or no longer occurs.

4. The method for preparing the compound as shown in Formula III according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The Mannich reaction is carried out in a nitrogen atmosphere; (2) R a In this context, the C1-C6 alkyl group is an ethyl group; (3) In the Mannich reaction, the solvent is ethanol; (4) 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 16 hours. (5) 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. After the remaining organic bases are added, the reaction is stirred for 2 to 5 hours.

5. The method for preparing the compound as shown in Formula III according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The organic base mentioned is triethylamine; (2) In the Mannich reaction, after the first batch of organic bases is added, the remaining organic bases are added and the reaction continues 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%, and the reaction continues until the methylamine salt reaction is complete or no longer occurs.

6. The method for preparing the compound as shown in Formula III according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In the Mannich reaction, after the first batch of organic bases is added, the remaining organic bases are added and the reaction continues 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 15%, and the reaction continues until the methylamine salt reaction is complete or no longer occurs. (2) 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.

7. The method for preparing the compound as shown in Formula III according to claim 6, characterized in that, It meets one or more of the following conditions: (1) 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 15% but not 0%, the remaining organic bases are added and the reaction continues until the methylamine salt reaction is complete or no longer occurs. (2) The post-processing includes the following operations in sequence: concentration, extraction, acidification, filtration, retention of filter cake for neutralization, extraction, and concentration; (3) In the post-processing, the acidification includes: acidifying the organic phase obtained after extraction with hydrochloric acid; (4) In the post-processing, the neutralization is to neutralize to a pH of 7-8.

8. The method for preparing the compound as shown in Formula III according to claim 7, characterized in that, It meets one or more of the following conditions: (1) 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 15% but not 0%, the remaining organic bases are added and the reaction continues for 2 to 5 hours. (2) In the post-processing, the acidification includes: acidifying the organic phase obtained after extraction with hydrochloric acid, wherein the concentration of the hydrochloric acid is 3~5 M; (3) In the post-processing, the neutralization is to mix the filter cake with a saturated sodium bicarbonate solution and adjust the pH to 7-8.

9. The method for preparing the compound as shown in Formula III according to claim 7, characterized in that, It meets one or more of the following conditions: (1) The preparation method of the compound shown in Formula III includes the following steps: under a nitrogen atmosphere, the solvent, the methylamine salt, the paraformaldehyde, the compound shown in Formula II and the first batch of organic base are stirred at 60~70°C for 14~18h, or stirred 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" is less than 15%, and then stirred with the remaining organic base at 60~70°C for 2~3h. (2) In the post-treatment, the acidification includes: adding 3~5 mol / L hydrochloric acid dropwise to the organic phase obtained after extraction at 20~35℃, and stirring at 15-25℃ for 1~2h.

Images