Process for the synthesis of n-boc-vinylglycine methyl ester and its isomer

Abstract

The application relates to the technical field of medicine synthesis, and discloses a synthesis method of N-Boc-vinylglycine methyl ester and isomerate, which comprises the following steps: L-N-tert-butoxycarbonylmethionine methyl ester is prepared by taking L-methionine methyl ester hydrochloride as raw material; L-N-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester is synthesized by taking L-N-tert-butoxycarbonylmethionine methyl ester and sodium periodate as raw material; and compound 13 is obtained by reacting L-N-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester and 1,2,4-trimethylbenzene at 180-190 DEG C for 6-8 h; the Boc protection methionine is directly eliminated in the application, and unnecessary complicated steps are reduced; N-Boc-vinylglycine methyl ester is synthesized in high yield and high selectivity by taking N-Boc-methionine methyl ester sulfoxide as raw material, removing low-boiling-point by-products methylsulfinic acid by evaporation and accurately controlling the reaction temperature; and the structural formula of the compound 13 is as follows:

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing N-Boc-vinylglycine methyl ester and its isomers. Background Technology

[0002] α-Vinyl amino acids are a class of naturally occurring non-protein β,γ-unsaturated amino acids, among which vinylglycine (VG) has the simplest structure but the most widely used. Vinylglycine exists in three forms: DL-vinylglycine 1 (DL-VG), D-vinylglycine 2 (D-VG), and L-vinylglycine 3 (L-VG). Figure 1 Of these, 2 can be isolated from natural red-leaf mushrooms, while 3 is mostly generated by the enzymatic reaction of pyridoxal phosphate, and is a common metabolite or mechanism intermediate produced in the process of various phosphatases.

[0003] The enantiomers of VG can be used as chiral building blocks or as key intermediates in the synthesis of many alkaloids, novel amino acids, and azathoses. Figure 2 VG, in single isomers or racemic mixtures, is widely used for aspartate aminotransferase, D-amino acid transaminase, kynurenine aminotransferase, rat liver alanine aminotransferase, cystathionine C-synthase, etc. Furthermore, VG and its derivatives also exhibit broad-spectrum antibacterial activity.

[0004] The wide range of applications of volatile organic compounds (VG) and their derivatives has led to their synthesis attracting considerable attention from synthetic chemists. Since 1977, synthetic strategies for the mass production of VG have flourished, with numerous synthetic methods developed from methionine, serine, homoserine, homocysteine, mannitol, xylose, aspartic acid, glutamic acid, or other suitable starting materials, employing stereoselective or racemic strategies, including enzymatic degradation.

[0005] Among the numerous existing strategies for synthesizing VG and its derivatives, the most practical synthetic method is the pyrolysis of methionine sulfoxide derivatives. Figure 3 This strategy typically involves first converting methionine into a methyl ester, then protecting N-Cbz, oxidizing it with sodium periodate to a sulfoxide derivative, and finally eliminating it at high temperature to obtain N-Cbz-VG methyl ester.

[0006] Originally reported by Rapoport, a scalable pyrolysis process for N-Cbz-L-methionine sulfoxide-derived sulfoxides was subsequently reproduced by Quintard JP et al. in a Kugelrhor distillation apparatus. Experiments showed the formation of a certain amount of olefin isomers among the reaction byproducts. After optimization, using trimethylbenzene as the solvent for reflux pyrolysis, the reaction became time-consuming; even the elimination reaction of 16.5 g of N-Cbz-L-methionine sulfoxide methyl ester required 48 hours to complete, yielding the target compound in approximately 60% yield. The experiments also revealed that the elimination reaction was simultaneously affected by product isomerization and degradation byproducts. Precise control of reaction temperature and time is crucial for achieving high conversion and selectivity, but other parameters such as additives and solvent properties also significantly influence the reaction results.

[0007] When N-Cbz-L-vinylglycine methyl ester is used as a synthetic intermediate, the removal of N-Cbz after derivatization into the target molecule presents rather harsh conditions. Many compounds cannot withstand the catalytic hydrogenation and strong acid conditions required for N-Cbz removal; therefore, the N-Cbz protecting group is often replaced with other protecting groups that are relatively easy to remove. N-Boc removal conditions are relatively mild; therefore, N-Boc-α-vinylglycine methyl ester is often chosen as a chiral building block in synthetic chemistry.

[0008] The most direct method for synthesizing N-Boc-α-vinylglycine methyl ester is to continue using... Figure 3 The route strategy involves replacing N-Cbz with N-Boc. Unfortunately, when using N-Boc-L-vinylglycine methyl ester sulfoxide as a starting material under the same conditions, the reaction did not proceed as expected. Only trace amounts of N-Boc-L-vinylglycine methyl ester product were detected, while a large number of complex byproducts with difficult-to-identify structures were generated. The Monbaliu JCM research group reported that by pyrolyzing sulfoxide derivatives in a superheated toluene solution at 270°C under 1000 psi pressure, vinylglycine derivative 13 was obtained with a daily output efficiency of 11-46 g. The reaction still resulted in the formation of olefin isomers. Therefore, it was necessary to extend the synthetic steps, protecting methionine with N-Cbz, eliminating the olefin, removing the Cbz-protecting group under strong acid conditions, and then protecting it with Boc- (…). Figure 4 From the perspective of the synthesis route, the protection and removal reactions of N-Cbz appear to have no synthetic value. Therefore, it is necessary to develop a synthetic method for N-Boc-vinylglycine methyl ester and its isomers that does not require the protection and removal reactions of N-Cbz. Summary of the Invention

[0009] This invention discloses a method for synthesizing N-Boc-vinylglycine methyl ester and its isomers, which solves the problem that the prior art requires additional N-Cbz protection and removal reactions when synthesizing N-Boc-vinylglycine methyl ester.

[0010] The synthesis method of N-Boc-vinylglycine methyl ester specifically includes the following steps:

[0011] Synthesis of S1.LN-tert-butoxycarbonylmethionine methyl ester: The prepared L-methionine methyl ester hydrochloride was suspended in an organic solvent, and triethylamine was added at 0-10℃. After the addition was completed, the temperature was lowered to 0-10℃, and a dichloromethane solution of ditert-butyl dicarbonate was added. The reaction was carried out at room temperature for 10-24 h, and LN-tert-butoxycarbonylmethionine methyl ester was obtained after purification.

[0012] Synthesis of S2.LN-tert-butoxycarbonyl-4-methylsulfinylbutyrine methyl ester: Methanol, water and LN-tert-butoxycarbonylmethionine methyl ester were mixed and cooled to 0-10℃. A saturated aqueous solution containing sodium periodate was added. After the addition was complete, the mixture was reacted at room temperature for 8-10 h. The mixture was filtered and the filtrate was purified to obtain LN-tert-butoxycarbonyl-4-methylsulfinylbutyrine methyl ester.

[0013] S3. Synthesis of compound 13: Under nitrogen atmosphere, LN-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester and 1,2,4-trimethylbenzene were refluxed at 180-190 °C for 6-8 h, and then purified to obtain compound 13.

[0014]

[0015] Preferably, the preparation method of L-methionine methyl ester hydrochloride in S1 is as follows: L-methionine and anhydrous methanol are mixed and homogenized under ice bath conditions, and thionyl chloride is added dropwise at 0-5°C. After reacting for 30-40 minutes, the system is transferred to an oil bath for heating and reflux after the system returns to room temperature. After the reaction is completed, L-methionine methyl ester hydrochloride is obtained by purification.

[0016] Preferably, the molar ratio of L-methionine methyl ester hydrochloride, triethylamine, and di-tert-butyl dicarbonate in S1 is 1.75:4.9:2.63.

[0017] Preferably, the purification method described in S1 is as follows: after the reaction is complete, water is added to separate the organic phase, and the organic phase is washed with saturated sodium bicarbonate solution and water, respectively.

[0018] Preferably, in S2, the ratio of methanol:water:LN-tert-butoxycarbonylmethionine methyl ester:sodium periodate is 3.5L:1.5L:1.65mol:1.82mol.

[0019] Preferably, the filtrate purification method in S2 is as follows: after removing methanol from the filtrate under reduced pressure, it is washed with dichloromethane, separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined and washed with water, separated, and dried to obtain LN-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester.

[0020] Preferably, in S3, the ratio of LN-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester: 1,2,4-trimethylbenzene is 1.1 mol: 3 L.

[0021] Preferably, the purification method described in S3 is as follows: after the reaction is completed, the mixture is cooled to room temperature, concentrated under reduced pressure, and subjected to column chromatography to obtain compound 13.

[0022] Preferably, the column chromatography method involves eluting with petroleum ether first, followed by elution with a volume ratio of dichloromethane / petroleum ether = 1:2.

[0023] The second objective of this invention is to provide a method for synthesizing the isomer of N-Boc-vinylglycine methyl ester, specifically comprising the following steps: under nitrogen conditions, mixing LN-tert-butoxycarbonyl-4-methylsulfinylbutyrate methyl ester, sodium bicarbonate and 1,2,4-trimethylbenzene, heating to 180-200°C, refluxing for 8-10 h, and purifying after the reaction to obtain isomer compound 16 of N-Boc-vinylglycine methyl ester;

[0024]

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] 1. This invention employs Boc-protected methionine, directly eliminating it and reducing unnecessary and cumbersome steps. Using N-Boc-methionine methyl ester sulfoxide as raw material, high-yield and high-selectivity synthesis of N-Boc-vinylglycine methyl ester is achieved by evaporating the low-boiling-point byproduct methylene sulfenic acid and precisely controlling the reaction temperature.

[0027] 2. Simultaneously, carbon-carbon double bond shift isomers were selectively obtained by adding a base to LN-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester. Attached Figure Description

[0028] Figure 1 The structural formula for the vinylglycine isomer;

[0029] Figure 2 The structural formula of the compound constructed from vinylglycine;

[0030] Figure 3 This is a synthetic route diagram for N-Cbz-VG methyl ester;

[0031] Figure 4A route diagram for the synthesis of N-Boc-VG methyl ester using existing technologies;

[0032] Figure 5 A route diagram for the synthesis of N-Boc-VG methyl ester provided by the present invention;

[0033] Figure 6 The route diagram for synthesizing N-Boc-2-aminobutyric acid methyl ester by adding base provided by the present invention;

[0034] Figure 7 The 1H NMR spectrum of L-methionine methyl ester;

[0035] Figure 8 The 1H NMR spectrum of compound 15 is shown.

[0036] Figure 9 The photon NMR spectrum of compound 14 is shown below.

[0037] Figure 10 The image shows the carbon NMR spectrum of compound 14.

[0038] Figure 11 The photon NMR spectrum of compound 13 is shown below.

[0039] Figure 12 The image shows the carbon NMR spectrum of compound 13.

[0040] Figure 13 The photon NMR spectrum of compound 16 is shown below.

[0041] Figure 14 The image shows the carbon NMR spectrum of compound 16. Detailed Implementation

[0042] The technical solutions of the present invention will be clearly and completely described below with reference to the data in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0043] It should be noted that the technical terms used in this invention are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of this invention. Unless otherwise specified, all raw materials, reagents, instruments and equipment used in the following embodiments of this invention can be purchased from the market or prepared by existing methods.

[0044] 1. Experimental Section

[0045] 1.1 Main Instruments and Reagents

[0046] Bruker Avance 400MHz NMR spectrometer (TMS as internal standard, CDCl3 as solvent); SB-1100 rotary evaporator (Zhengzhou Changcheng Science & Industry Trade Co., Ltd.); DLSB-10 / 40 cryogenic coolant circulation pump (Gongyi Yuhua Instrument Co., Ltd.); Thin-layer chromatography (TLC, using GF254 silica gel, observed under 254nm UV light, Qingdao Ocean Chemical Plant).

[0047] L-methionine, thionyl chloride, di-tert-butyl dicarbonate, sodium periodate, 1,2,4-trimethylbenzene (analytical grade, Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd.).

[0048] Synthesis of 1,2LN-tert-butoxycarbonylvinylglycine methyl ester (synthetic route see [link]) Figure 5 )

[0049] 1.2.1 Synthesis of Compound 8 (L-methionine methyl ester hydrochloride)

[0050] 7298.4 g (2 mol) of L-methionine and 2 L of anhydrous methanol were added separately to a 5 L three-necked flask. The flask was cooled in an ice-salt bath, and the mixture was mechanically stirred to form a homogeneous suspension. Once the system temperature had cooled to 0 °C, 321.2 g (2.7 mol) of thionyl chloride was slowly added dropwise, controlling the dropping rate and maintaining the reaction system temperature below 5 °C. During the addition, the suspension gradually dissolved into a homogeneous phase. After the addition was complete, the mixture was stirred for 30 min, then the ice-salt bath was removed. The system was allowed to return to room temperature before being transferred to an oil bath and heated under reflux overnight. The next day, TLC monitoring showed the reaction was complete. After distilling off methanol and acidic substances under reduced pressure, the residue was washed with 10 L of dichloromethane (DCM) with stirring, filtered, and dried to obtain 8354.7 g of the compound, with a yield of 88.8%.

[0051] Dissolve an appropriate amount of compound 8 in water, adjust the pH to 8-9 with sodium carbonate solution, extract with dichloromethane, separate the contents, and dry to obtain L-methionine methyl ester.

[0052] 1 ¹H NMR (400MHz, CDCl₃) δ 3.74 (s, 3H), 3.61 (dd, J = 8.3, 5.0Hz, 1H), 2.63 (t, J = 7.4Hz, 2H), 2.11 (s, 3H), 2.09–2.00 (m, 1H), 1.86–1.76 (m, 1H). The ¹H NMR spectrum is shown below. Figure 7 .

[0053] 1.2.2 Synthesis of Compound 15 (LN-tert-Butoxycarbonylmethionine methyl ester)

[0054] 3.2 L of DCM was added to a 10 L three-necked flask, and 8349.5 g (1.75 mol) of compound was suspended in it. The mixture was cooled to <5 °C using an external ice-salt bath, and 685 mL (4.9 mol) of triethylamine was added dropwise. The dropping rate was controlled to keep the temperature of the reaction system below 10 °C. As triethylamine was added, the solution gradually changed from turbid to clear, and then back to turbid. After the triethylamine addition was complete and the temperature of the reaction system dropped to 0–5 °C, 1 L of DCM solution containing 574 g (2.63 mol) of di-tert-butyl dicarbonate was slowly added dropwise, keeping the temperature below 10 °C during the addition. After the addition was complete, the ice-salt bath was removed, and the reaction system was stirred overnight at room temperature.

[0055] The reaction was monitored by TLC the following day to confirm completion. 2.5 L of cold water was added to the reaction system, and the mixture was stirred thoroughly before separation. The organic phase was separated and washed thoroughly with saturated sodium bicarbonate solution and water, respectively. The organic layer was dried and then dried over anhydrous magnesium sulfate to obtain 15435.6 g of the compound, with a yield of 94.5%.

[0056] 1 ¹H NMR (400MHz, CDCl₃) δ 5.24 (s, 1H), 4.41 (s, 1H), 3.75 (s, 3H), 2.54 (t, J = 7.5Hz, 2H), 2.10 (s, 3H), 2.10–1.96 (m, 2H), 1.45 (s, 9H). The ¹H NMR spectrum is shown below. Figure 8 .

[0057] 1.2.3 Synthesis of Compound 14 (LN-tert-butoxycarbonyl-4-methylsulfinylbutyric acid methyl ester)

[0058] 15434.5 g (1.65 mol) of compound was added to a 10 L three-necked flask containing 3.5 L methanol and 1.5 L water. After stirring to dissolve, the system was cooled to 0–5 °C using an ice-salt bath. A saturated solution of 389.3 g (1.82 mol) of sodium periodate was added dropwise to the reaction solution, controlling the dropping rate to keep the temperature of the reaction system below 10 °C. After the addition was complete, the ice-salt bath was removed, and the reaction system was allowed to react at room temperature for 8 h. The reaction was monitored by TLC to indicate completion.

[0059] The reaction system was filtered, and the filter cake was thoroughly washed with methanol (150 mL x 3). The filtrates were combined, and methanol was removed under reduced pressure. The residue was thoroughly washed with 1.5 L DCM and separated. The aqueous phase was extracted with 1 L DCM. The organic phases were combined and washed with water, separated, and dried to give 14309.8 g of the compound, with a yield of 67.3%.

[0060] 11H NMR (400MHz, CDCl3) δ 5.53 (dd, J = 16.7, 8.0 Hz, 1H), 4.52–4.33 (m, 1H), 3.77 (s, 3H), 2.79 (d, J = 7.9 Hz, 2H), 2.60 (d, J = 2.1 Hz, 3H), 2.40–2.31 (m, 1H), 2.16–2.07 (m, 1H), 1.45 (s, 9H). The 1H NMR spectrum is shown below. Figure 9 .

[0061] 13 C NMR (101MHz, CDCl3) δ 175.11, 153.96, 79.63, 52.68, 52.37, 50.29, 38.65, 28.27, 26.36. See [reference needed for C NMR spectra]. Figure 10 .

[0062] 1.2.4 Synthesis of Compound 13 (LN-tert-Butoxycarbonylvinylglycine methyl ester)

[0063] 307 g (1.1 mol) of compound 14 and 3 L of 1,2,4-trimethylbenzene were added to a 5 L three-necked flask, which was then connected to a water separator equipped with a spherical condenser. Under nitrogen purging and protection, the system was rapidly heated to 180 °C to ensure good reflux. The mixture was stirred and refluxed for 8 h, and the reaction was confirmed by TLC. The reaction system was cooled to room temperature and concentrated to approximately 800 mL under reduced pressure (0.08 MPa). The residue was then directly subjected to column chromatography. First, residual trimethylbenzene solvent was removed by elution with petroleum ether, then the eluent was changed to dichloromethane / petroleum ether (1:2) to give 13150.7 g of the oily compound, with a yield of 63.7%.

[0064] 1 H NMR (400MHz, CDCl3) δ5.90 (ddd, J=16.6, 10.4, 5.6Hz, 1H), 5.39-

[0065] 5.25(m,2H),4.88(s,1H),3.77(s,3H),1.45(s,9H). 13 C10 NMR (101 MHz, CDCl3) δ 170.40, 154.10, 132.67, 116.63, 80.14, 55.77, 51.42, 28.19. (See the 1H NMR spectrum for reference.) Figure 11 The carbon NMR spectrum is shown below. Figure 12 .

[0066] 1.3 Synthesis of Compound 16 (the carbon-carbon double bond shift isomer of LN-tert-butoxycarbonylvinylglycine methyl ester) (synthetic route see [link to synthetic route]). Figure 6 )

[0067] 175.8 g (0.63 mol) of compound 14, 106 g (0.63 mol) of sodium bicarbonate powder, and 1.7 L of 1,2,4-trimethylbenzene were added to a 3 L three-necked flask, which was then connected to a water separator equipped with a spherical condenser. The system was rapidly heated to 180 °C under nitrogen purging and protection to ensure good reflux conditions. The mixture was stirred and refluxed for 8 h, and the reaction was confirmed by TLC. The reaction system was cooled to room temperature and concentrated to approximately 500 mL under reduced pressure (0.08 MPa). The residue was then directly subjected to column chromatography. First, residual trimethylbenzene solvent was removed by elution with petroleum ether, then the eluent was changed to dichloromethane / petroleum ether (1:2) to give 1675.4 g of the oily compound, with a yield of 55.6%.

[0068] 1 H NMR (400MHz, CDCl3) δ6.68(q,J=7.2Hz,1H),6.08–5.94(m,1H),3.77(s,3H),1.81(d,J=7.2Hz,3H),1.47(s,9H). 13 C10 NMR (101 MHz, CDCl3) δ 165.35, 153.12, 132.09, 126.68, 80.44, 52.26, 28.19, 14.26. (See the 1H NMR spectrum for reference.) Figure 13 The carbon NMR spectrum is shown below. Figure 14 .

[0069] We hypothesized that the complex thermal decomposition products of N-Boc-L-vinylglycine methyl ester might be due to the initial smooth reaction, followed by the presence of methanesulfonic acid byproducts in the reaction mixture. Prolonged heating under strongly acidic conditions caused the N-Boc to detach, leading to further complex polymerization of vinylglycine methyl ester. Therefore, we proposed neutralizing the methanesulfonic acid byproduct in the reaction system with alkali to allow the reaction to proceed as expected. The reaction yielded N-Boc-2-aminobutyric acid methyl ester. Since the methanesulfonic acid byproduct has a low boiling point, a water separator was used to remove it during optimization. As expected, the reaction yielded the target compound N-Boc-L-vinylglycine methyl ester in a moderate yield (30–50%). Through rigorous temperature optimization and the use of nitrogen protection in the reaction system, the reaction ultimately yielded the target compound 13 (…). Figure 5 ).

[0070] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0071] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing N-Boc-vinylglycine methyl ester, characterized in that, Specifically, the following steps are included: Synthesis of compound 8: 298.4 g of L-methionine 7 and 2 L of anhydrous methanol were added to a 5 L three-necked flask, cooled in an external ice-salt bath, and mechanically stirred to form a homogeneous suspension. After the system temperature cooled to 0 °C, 321.2 g of thionyl chloride was slowly added dropwise, controlling the dropping rate and keeping the system temperature below 5 °C. During the addition, the suspension gradually dissolved into a homogeneous phase. After the addition was complete, the mixture was stirred for 30 min and then the ice-salt bath was removed. After the system returned to room temperature, it was transferred to an oil bath and heated under reflux overnight. The next day, TLC monitoring showed that the reaction was complete. The methanol and acidic substances were distilled off under reduced pressure. The residue was washed with 10 L of dichloromethane, stirred, filtered, and dried to obtain 354.7 g of compound 8. Dissolve an appropriate amount of compound 8 in water, adjust the pH to 8-9 with sodium carbonate solution, extract with dichloromethane, separate the liquid and dry to obtain L-methionine methyl ester; Synthesis of compound 15: 3.2 L of dichloromethane was added to a 10 L three-necked flask, and 349.5 g of compound 8 was suspended in it. The mixture was cooled in an external ice-salt bath to lower the temperature to <5 °C. 685 mL of triethylamine was added dropwise, and the dropping rate was controlled to keep the temperature of the reaction system below 10 °C. As the triethylamine was added, the solution gradually changed from turbid to clear, and then back to turbid. After the triethylamine was added, the temperature of the reaction system was lowered to 0-5 °C. Then, 1 L of dichloromethane solution containing 574 g of di-tert-butyl dicarbonate was slowly added dropwise, keeping the temperature of the system below 10 °C during the addition. After the addition was completed, the ice-salt bath was removed, and the reaction system was stirred at room temperature overnight. The next day, the reaction was monitored by TLC to indicate completion. 2.5 L of cold water was added to the reaction system, and the mixture was stirred thoroughly before separation. The organic phase was separated and washed thoroughly with saturated sodium bicarbonate solution and water, respectively. The organic layer was dried and dried with anhydrous magnesium sulfate to obtain 435.6 g of compound 15. Synthesis of compound 14: 434.5 g of compound 15 was added to a 10 L three-necked flask containing 3.5 L methanol and 1.5 L water. After stirring and dissolving, the system was cooled to 0-5 °C using an ice-salt bath. A saturated solution containing 389.3 g of sodium periodate was added dropwise to the reaction solution, and the dropping rate was controlled so that the temperature of the reaction system did not exceed 10 °C. After the addition was complete, the ice-salt bath was removed, and the reaction system was allowed to react at room temperature for 8 h. The reaction was monitored by TLC to indicate that the reaction was complete. The reaction system was filtered, and the filter cake was washed three times with 150 mL of methanol. The filtrates were combined, and methanol was removed under reduced pressure. The residue was washed with 1.5 L of dichloromethane and separated. The aqueous phase was extracted with 1 L of dichloromethane. The organic phases were combined and washed with water. The mixture was separated and dried to obtain 309.8 g of compound 14. Synthesis of compound 13: 307g of compound 14 and 3L of 1,2,4-trimethylbenzene were added to a 5L three-necked flask. A water separator equipped with a spherical condenser was connected to the top. Under nitrogen purging and protection, the system was rapidly heated to 180℃ to ensure that the system was in a good reflux state. The system was stirred and refluxed for 8 hours. The reaction was detected by TLC and the system was cooled to room temperature. The system was then reduced to a vacuum of 0.08MPa and concentrated to about 800mL. The residue was then directly subjected to column chromatography. The residual trimethylbenzene solvent was first removed by elution with petroleum ether. Then the eluent was changed to dichloromethane / petroleum ether with a volume ratio of 1:2 to obtain 150.7g of oily compound 13. Synthesis of compound 16: 175.8 g of compound 14, 106 g of sodium bicarbonate powder, and 1.7 L of 1,2,4-trimethylbenzene were added to a 3 L three-necked flask. A water separator equipped with a spherical condenser was connected to the top. The system was rapidly heated to 180 °C under nitrogen purging and protection to ensure that the system was in a good reflux state. The system was stirred and refluxed for 8 h. The reaction was detected by TLC to indicate that the system was complete. The reaction system was cooled to room temperature and then reduced to a vacuum of 0.08 MPa. The reaction system was concentrated to about 500 mL and the residue was directly subjected to column chromatography. The residual trimethylbenzene solvent was first removed by elution with petroleum ether, and then the eluent was changed to dichloromethane / petroleum ether with a volume ratio of 1:2 to obtain 75.4 g of oily compound 16. The synthesis route is as follows: ， 。

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