Preparation method for and use of camptothecin derivative

Abstract

Provided are a preparation method for and a use of a camptothecin derivative. Specifically provided is a preparation method for belotecan or a salt thereof that is suitable for large‑scale production, comprising the step of preparing belotecan or a salt thereof from a compound as represented by formula III or a salt thereof and isopropylamine in the presence of an acid catalyst. By improving the synthesis process route and optimizing the reaction conditions, a preparation method for belotecan with a high overall reaction yield and suitable for large‑scale production is achieved.

Description

Preparation method and application of a camptothecin derivative

[0001] This application is based on and claims priority to Chinese Patent Application No. 202510084719.6, filed on January 20, 2025, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure relates to the field of drug synthesis, specifically to a method for preparing and applying a camptothecin derivative. Background Technology

[0003] Camptothecin, derived from the plant *Camptotheca acuminata* (family Davidia involucrata), is a natural antitumor drug that exerts its antitumor effect by acting on topoisomerase I in cells. Over the past 40 years, researchers have performed various structural modifications on camptothecin, synthesizing a series of camptothecin derivatives with antitumor activity. Currently approved camptothecin drugs for clinical treatment include irinotecan, topotecan, belotecone, and 10-hydroxycamptothecin.

[0004] Belotecone is a drug used to treat small cell lung cancer and ovarian cancer, and it was first approved in South Korea in 2005. Structurally, belotecone is modified at the 7-position of the pyridine ring, and the modified side chain is 2-(isopropylamino)ethyl. Currently, there are semi-synthetic and total synthetic methods for the synthesis of this modified side chain.

[0005] The total synthesis of beloteccan begins with the construction of a 2-(isopropylamino)ethyl side chain at the 7-position of the camptothecin core from readily available raw materials, followed by condensation with a 7-ethyl-10-hydroxycamptothecin intermediate to synthesize beloteccan. Existing total synthetic routes suffer from cumbersome procedures, low yields, and complex purification steps. Furthermore, the intermediate (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyranO[3,4-F]indoleazine-3,6,10(4H)-one used in the preparation process is costly and difficult to use for large-scale production.

[0006] The semi-synthetic method for beloteccan uses camptothecin as a starting material and extends the carbon chain at the C7 carbon atom of the pyridine ring in various ways to construct the side chain of the target compound. Current semi-synthetic methods involve first constructing a methyl group at C7 of the pyridine ring using a Minisci-type radical reaction, followed by a Mannich reaction to synthesize beloteccan. This route suffers from several drawbacks: the first step of the radical reaction generates difficult-to-remove dimethylated impurities, the second step involves an unstable Mannich reaction intermediate, resulting in low yields and requiring column chromatography purification after the reaction. Consequently, this route suffers from low overall yields, high synthesis costs, and is difficult to scale up for mass production. Therefore, there is still a need to develop a beloteccan synthesis method with high overall yields and ease of large-scale production. Summary of the Invention

[0007] This disclosure provides a method for preparing camptothecin derivatives and their applications. By improving the synthetic process route and optimizing the reaction conditions, this disclosure yields a method for preparing beloteccan with high overall yield and ease of large-scale production.

[0008] On one hand, this disclosure provides a method for preparing belotecone or a salt thereof, the method comprising the following steps:

[0009] In the presence of an acidic catalyst, a compound of formula III or its salt undergoes an addition reaction with isopropylamine to give belotecamine or its salt.

[0010] In some embodiments, the molar ratio of the compound of formula III or its salt to isopropylamine is 1:(1-10), for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0011] In some embodiments, the acidic catalyst is selected from one or more of bis(trifluoromethanesulfonyl)imide, pentafluorobenzoic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, and ytterbium trifluoromethanesulfonate. In some specific embodiments, the acidic catalyst is bis(trifluoromethanesulfonyl)imide, acetic acid, or ytterbium trifluoromethanesulfonate. In one specific embodiment, the acidic catalyst is bis(trifluoromethanesulfonyl)imide.

[0012] In some embodiments, the solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, and dimethyl sulfoxide. In some embodiments, the solvent is N,N-dimethylacetamide.

[0013] In some embodiments, the compound of formula III or its salt is reacted with isopropylamine for 1-10 hours, for example 2-8 hours, 3-7 hours, 4-6 hours, 4-5 hours or 5-6 hours.

[0014] In some embodiments, in step (c), the compound of formula III or its salt reacts with isopropylamine at 40-80°C, for example 45-75°C, 50-70°C, 55-65°C, 55-60°C or 60-65°C.

[0015] In some implementations, the method further includes the following steps:

[0016] In the presence of a catalyst, a compound of formula II or its salt undergoes an elimination reaction to yield a compound of formula III or its salt.

[0017] In some embodiments, the catalyst is selected from one or more of T3P, T4P, Ms2O, and TsCl. In some specific embodiments, the catalyst is T3P or T4P.

[0018] In some embodiments, the molar ratio of the compound of formula II or its salt to the catalyst is 1:(1-20), for example 1:(1-15) or 1:(1-10), and even more for example 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0019] In some embodiments, the compound of formula II or its salt is first dispersed in a solvent, and then a catalyst, an acidic reagent, and a basic reagent are added to carry out an elimination reaction to obtain the compound of formula III or its salt. In some specific embodiments, the catalyst, acidic reagent, and basic reagent are added sequentially, optionally with stirring, for example, for 1-10 minutes, before adding the next reagent. In some specific embodiments, the catalyst is added during the reaction, for example, 0.1-1 molar (based on the amount of catalyst added), such as 0.5 molar.

[0020] In some embodiments, the compound of formula II or its salt is first dispersed in a solvent, a catalyst is added, an acidic reagent is added after stirring, and a basic reagent is added after further stirring to carry out an elimination reaction to obtain the compound of formula III or its salt.

[0021] In some embodiments, the acidic agent is selected from one or more of methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid, benzenesulfonic acid, and nitric acid. In one specific embodiment, the acidic agent is methanesulfonic acid.

[0022] In some embodiments, the basic reagent is selected from one or more of isopropylamine, triethylamine, diethylamine, DIPEA, DMAP, and pyridine. In one specific embodiment, the basic reagent is diethylamine.

[0023] In some embodiments, the reaction solvent is selected from one or more of tetrahydrofuran, dichloromethane, and dimethyl sulfoxide. In one specific embodiment, the reaction solvent is tetrahydrofuran.

[0024] In some implementations, the reaction time for elimination is 1-8 hours, such as 2-8 hours, 2-6 hours, 3-8 hours, 3-6 hours, 3-5 hours, or 3-4 hours.

[0025] In some implementations, the reaction temperature for the elimination reaction is controlled at 40-95°C, for example 45-90°C, 50-85°C, 55-80°C, 55-75°C, or 60-70°C.

[0026] In some implementations, the method further includes the following steps:

[0027] In the presence of a catalyst, compound I (camptothecin, CPT) or its salt undergoes a coupling reaction with a radical source capable of generating hydroxyethyl radicals to yield compound II or its salt.

[0028] In some embodiments, the radical source is acrolein. In some embodiments, the radical source (e.g., acrolein) is prepared as a solution in advance. In some embodiments, acrolein is prepared in advance as an acrolein-acetonitrile solution, for example, an acrolein-acetonitrile solution of 0.3-2 g / ml, such as 0.5 g / ml, 0.8 g / ml, 1.0 g / ml, 1.2 g / ml, 1.5 g / ml, 1.8 g / ml, or 2.0 g / ml.

[0029] In some embodiments, the molar ratio of the compound of formula I or its salt to the radical source is 1:(5-20), 1:(8-15), or 1:(10-15).

[0030] In some embodiments, an acidic reagent is added to a compound of formula I or a salt thereof, followed by stirring and then adding a catalyst, then adding a radical source, followed by stirring and then adding a radical initiator, to obtain a compound of formula II or a salt thereof through a coupling reaction.

[0031] In some implementations, the acidic reagent is prepared as an aqueous solution in advance, or the acidic reagent is added directly to the aqueous suspension of camptothecin under ice bath conditions.

[0032] In some embodiments, the acidic agent is selected from one or more of sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. In one specific embodiment, the acidic agent is sulfuric acid.

[0033] In some embodiments, concentrated sulfuric acid (e.g., sulfuric acid with a concentration of 70% or higher, 80% or higher, 90% or higher, 95% or higher, or 98% higher) is added to an aqueous suspension of camptothecin (compound of formula I) at 0-10°C, or sulfuric acid with a concentration of 30-50% is added to camptothecin.

[0034] In some implementations, concentrated sulfuric acid is added to the aqueous suspension of camptothecin at 5°C, or 40% sulfuric acid is added to camptothecin.

[0035] In some implementations, the catalyst is ferrous sulfate heptahydrate.

[0036] In some embodiments, the molar ratio of the compound of formula I or its salt to ferrous sulfate heptahydrate is 1:(0.8-20), 1:(1-15), 1:(1-10), 1:(1-8), 1:(1-5), 1:(1-2), or 1:1.

[0037] In some implementations, the free radical initiator is hydrogen peroxide.

[0038] In some embodiments, the concentration of hydrogen peroxide is 10-50%, for example 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0039] In some implementations, the coupling reaction is carried out for 0.1–5 hours, such as 0.2–4 hours, 0.3–3 hours, 0.4–2 hours, 0.5–1 hour, or 0.5–0.8 hours.

[0040] In some implementations, the temperature of the reaction solution does not exceed 40°C, for example, not exceeding 35°C, not exceeding 30°C, not exceeding 25°C, not exceeding 20°C, not exceeding 15°C, or not exceeding 10°C.

[0041] On the other hand, this disclosure provides a method for preparing a compound of formula II or a salt thereof, comprising, in the presence of a catalyst, coupling a compound of formula I (camptothecin, CPT) or a salt thereof with a radical source capable of generating a hydroxyethyl radical to obtain a compound of formula II or a salt thereof.

[0042] In some embodiments, the compound of formula II or its salt is characterized as defined above.

[0043] On the other hand, this disclosure provides a method for preparing a compound of formula III or a salt thereof, comprising causing a compound of formula II or a salt thereof to undergo an elimination reaction in the presence of a catalyst to obtain a compound of formula III or a salt thereof.

[0044] In some embodiments, the preparation of a compound of formula III or a salt thereof is characterized as defined in any of the preceding descriptions.

[0045] On the other hand, this disclosure provides a compound for preparing belotecone, the compound being selected from:

[0046] On the other hand, this disclosure provides the use of compounds in the preparation of belotecone, the compounds being selected from:

[0047] Unless otherwise specified, the term "concentration" as used herein refers to mass concentration.

[0048] In this article, the term "concentrated sulfuric acid" refers to an aqueous solution of sulfuric acid with a mass fraction of 70% or higher.

[0049] Beneficial effects of the invention

[0050] 1. This disclosure provides a novel semi-synthetic route for belotecone, which achieves a higher yield than existing semi-synthetic routes by optimizing reaction conditions, and the purification process is simple with a clear reaction mechanism.

[0051] 2. Compared with existing semi-synthetic routes, the synthetic route disclosed in this paper has simpler steps and lower material costs. Detailed Implementation

[0052] The embodiments of this disclosure will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustration only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0053] The abbreviations used in this disclosure have the following meanings:

[0054] Example 1: Preparation of belotecone

[0055] Step 1: Synthesis of Compound II

[0056] Add 6g of camptothecin (CPT, compound I) and 600ml of purified water to a 2000ml round-bottom flask and stir for 5min. Transfer the reaction solution to an ice-water bath and add 323.9g of 98% sulfuric acid dropwise, ensuring the temperature of the reaction solution does not exceed 25℃ during the addition. After the 98% sulfuric acid has been added, wait until the camptothecin is completely dissolved, then add 8.41g of FeSO4·7H2O with stirring, and stir for 10min until completely dissolved. Add 17.3ml of acrolein, stir for 5min, and then add 7ml of 30% H2O2 dropwise, ensuring the temperature of the reaction solution does not exceed 25℃ during the addition. After reacting at room temperature for 30min, add 8.4g of FeSO4·7H2O and 7ml of 30% H2O2 dropwise, ensuring the temperature of the reaction solution does not exceed 25℃ during the addition. After the addition is complete, continue reacting at room temperature for 30min, and determine the reaction endpoint based on the LC-MS results.

[0057] The solid precipitated from the reaction solution was filtered. 880 ml of 30% NaOH aqueous solution was added to the filtrate to adjust the pH to 6.10. The precipitated solid was filtered again, and the aqueous phase obtained was extracted with EA until no product spot was observed during TLC. The organic phases were combined. The solids obtained from the two filtrations were combined, and the solids were slurried with purified water to remove inorganic salts. The remaining solid was dissolved in a DCM / EtOH mixed solvent (2:1), and the organic phase was collected. The combined organic phases were concentrated, and the crude solid was dissolved in a DCM / EtOH mixed solvent and passed through a Flash column. Pure DCM, a DCM and MeOH mixed solvent (20:1 v / v), and a DCM and MeOH mixed solvent (10:1 v / v) were used as eluents successively. The fractions were collected, concentrated, and dried to obtain compound II (3.37 g, yield 49.92%).

[0058] The structural characterization data of compound II are as follows: ¹H NMR (400MHz, DMSO-d6) δ 8.29 (dd, J = 8.6, 1.4Hz, 1H), 8.17 (dd, J = 8.6, 1.3Hz, 1H), 7.93-7.81 (m, 1H), 7.72 (ddd, J = 8.3, 6.8, 1.3Hz, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 4.89 (t, J = 5.6Hz, 1H), 3.82 (q, J = 6.1Hz, 2H), 3.39 (t, J = 6.4Hz, 2H), 1.97-1.79 (m, J = 7.2Hz, 2H), 0.89 (t, J = 7.3Hz, 3H).

[0059] Step 2: Synthesis of Compound III

[0060] Compound II (133 mg, 0.3 mmol) was dispersed in 4.39 mL of THF. T3P (667 mg, 1.05 mmol, 50% EA solution) was added to the suspension, and the mixture was stirred at room temperature for 5 min. Then, MsOH (136 μL, 2.10 mmol) was added, and the mixture was stirred for 2 min. Diethylamine (194 μL, 2.39 mmol) was added, and the mixture was reacted at 70 °C for 3 h. After the reaction was completed, water was added to quench the reaction. The precipitated yellow solid was filtered and then treated with 5 mL of water and 5 mL of MTBE, respectively. The mixture was filtered to obtain an orange solid (75 mg, yield 68.77%).

[0061] The structural characterization data of compound III are as follows: ¹H NMR (400MHz, DMSO-d6) δ 8.33 (dd, J = 8.5, 1.4Hz, 1H), 8.20 (dd, J = 8.5, 1.3Hz, 1H), 7.89 (ddd, J = 8.4, 6.8, 1.4Hz, 1H), 7.75 (ddd, J = 8.3, 6.8, 1.3Hz, 1H), 7.58 (dd, J = 17.7, 11.7Hz, 1H), 7.36 (s, 1H), 6.18–6.03 (m, 2H), 5.44 (s, 2H), 5.40 (s, 2H), 1.88 (hept, J = 7.1Hz, 2H), 0.97–0.81 (m, 3H).

[0062] Step 3: Synthesis of belotecone

[0063] 20 mg of the compound of formula III prepared in step 2, 28 μL of isopropylamine, 6 mg of Tf₂NH₃, and 0.9 mL of DMA were added to a 3 mL sealed reaction flask, and the mixture was reacted at 60 °C for 5 h. After the reaction was completed, the reaction solution was filtered, and the mother liquor was subjected to reversed-phase preparative chromatography (Agilent Prep C18 ODS). The fractions were combined to obtain beloteccan (9 mg, yield 38.86%).

[0064] The structural characterization data of belotecone are as follows:

[0065] 1H NMR (400MHz, DMSO-d6) δ9.61 (dd, J=12.1, 6.1Hz, 1H), 8.48 (d, J=8.4Hz, 1H), 8.18 (d ,J=8.4Hz,1H),7.86(t,J=7.6Hz,1H),7.73(t,J=7.6Hz,1H),7.36(s,1H),5.45(s,2H ),5.34(s,2H),3.72-3.63(m,2H),3.37(hept,J=6.2Hz,1H),3.20(dq,J=12.6,6.6,6 .0Hz,2H),1.99-1.81(m,J=7.2Hz,2H),1.31(d,J=6.5Hz,6H),0.90(t,J=7.3Hz,3H).

[0066] Example 2: Preparation of belotecone

[0067] Add 2g of CPT and 40ml of 40% sulfuric acid aqueous solution to a 100ml round-bottom flask, stir for 5min, and after the camptothecin dissolves completely, add 1.6g of FeSO4·7H2O while stirring. After the addition is complete, stir for 10min to ensure complete dissolution. Add 2.58g of acrolein solution dissolved in 2.5ml of acetonitrile, stir for 5min, and then continue to add 2.34ml of 30% H2O2 dropwise, ensuring the temperature of the reaction solution does not exceed 25℃ during the dropwise addition. After reacting at room temperature for 30min, while maintaining the temperature of the reaction solution below 25℃, add 1.6g of FeSO4·7H2O and 2.34ml of 30% H2O2 dropwise. After the addition is complete, continue reacting at room temperature for 30min, and determine the reaction endpoint based on the LC-MS results.

[0068] Add 79 ml of 30% NaOH to the reaction solution, adjust the pH to 5.20, filter to precipitate solid, wash the red solid with water and DCM / EtOH mixed solvent (2:1), and dry the washed organic phase to obtain 2.687 g of crude solid. The crude product was directly purified by reverse phase preparation to obtain 403 mg of compound II, solid.

[0069] Belottican was prepared according to steps 2 and 3 of Example 1.

[0070] Example 3: Screening of acidic reagents in the preparation of compound II

[0071] Experiment 1: 50 mg of camptothecin (CPT) and 0.6 ml of purified water were added to a 3 ml reaction flask and stirred for 5 min. The reaction system was cooled to 5 °C, and 0.4 mL of 98% sulfuric acid was added dropwise. After the acid was completely added, 40 mg of FeSO4·7H2O was added with stirring. After the FeSO4·7H2O was completely dissolved, 77 μL of acrolein solution dissolved in 120 μL of acetonitrile was added. After 5 min, 59 μL of 30% H2O2 was added dropwise. After reacting at room temperature for 30 min, 40 mg of FeSO4·7H2O and 59 μL of 30% H2O2 were added again. After the addition was complete, the reaction was continued at room temperature for another 30 min. After the reaction was completed, the conversion rate of compound I was analyzed by LC-MS.

[0072] Experiment 2: Replace 0.4 mL of 98% sulfuric acid in Experiment 1 with 0.487 mL of methanesulfonic acid. All other steps and reaction conditions are the same as in Experiment 1. Determine the conversion rate of compound I when using methanesulfonic acid as the acidic reagent.

[0073] Experiment 3: Replace 0.4 mL of 98% sulfuric acid in Experiment 1 with 0.575 mL of trifluoroacetic acid. All other steps and reaction conditions are the same as in Experiment 1. Determine the conversion rate of compound I when trifluoroacetic acid is used as the acidic reagent.

[0074] Experiment 4: Replace the 0.4 mL of 98% sulfuric acid in Experiment 1 with 0.605 mL of 36% concentrated hydrochloric acid. All other steps and reaction conditions are the same as in Experiment 1. Determine the conversion rate of compound I when concentrated hydrochloric acid is used as the acidic reagent.

[0075] Experiment 5: Replace 0.4 mL of 98% sulfuric acid in Experiment 1 with 0.530 mL of acetic acid. All other steps and reaction conditions are the same as in Experiment 1. Determine the conversion rate of compound I when acetic acid is used as the acidic reagent.

[0076] The conversion rates of compound I using different acidic reagents in experiments 1-5 are shown in Table 1 below.

[0077] Table 1. Effect of different acidic reagents on the conversion rate of compound I.

[0078] ND. indicates that no reaction product (compound of formula II) was detected.

[0079] As can be seen from Table 1 above, when hydrochloric acid and acetic acid are used as acidic reagents, compounds of formula I basically do not undergo chemical reactions. Sulfuric acid, methanesulfonic acid and trifluoroacetic acid can effectively promote compounds of formula I to generate compounds of formula II through coupling reactions. Among them, the conversion rate of compounds of formula I is the highest when sulfuric acid is used.

[0080] Example 4: Screening of the amount of acrolein used in the reaction for preparing compound II

[0081] Add 2g of camptothecin (CPT) and 40ml of pre-prepared 40% sulfuric acid aqueous solution to a 100ml reaction flask, and stir for 5min. Add 2.8g of FeSO4·7H2O while stirring. After the FeSO4·7H2O is completely dissolved, add acrolein solution of different equivalents (3.75eq, 7.5eq, 8eq, 11.25eq, and 15eq relative to 1eq of camptothecin) dissolved in 5mL of acetonitrile. Stir for 5min, then add 2.35mL of 30% H2O2 dropwise, controlling the reaction temperature below 20℃. After reacting at room temperature for 30min, add 2.8g of FeSO4·7H2O and 2.35mL of 30% H2O2. After the addition is complete, continue the reaction at room temperature for another 30min. The conversion rate of compound I is then analyzed by LC-MS.

[0082] The conversion rates of compound I using different equivalents of acrolein are shown in Table 2 below.

[0083] Table 2. Effect of different acrolein equivalents on the conversion rate of compound I.

[0084] As can be seen from Table 2 above, the conversion rate of compound I is only 12.63% when using 3.75 eq of acrolein. When the amount of acrolein is increased to 7.5 eq, the conversion rate of compound I is significantly increased to 45.81%. When the amount of acrolein reaches 8 eq or more, the conversion rate of compound I can be increased to more than 60%.

[0085] Example 5: Screening of basic reagents in the preparation of compound III

[0086] Experiment 1: 90 mg of compound II was added to a 10 ml reaction flask, dispersed by stirring with 3 ml of THF, 473 mg of T3P (50% EA solution) was added, and after stirring for 5 min, 96 μL of MsOH was added. After stirring for 2 min, 145 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C. After reacting for 3 h, 237 mg of T3P, 48 μL of MsOH, and 73 μL of isopropylamine were added, and the mixture was stirred overnight. The reaction solution was sampled after overnight, and the conversion rate of compound II was analyzed by LC-MS.

[0087] Experiment 2: 30 mg of compound II was added to a 3 ml reaction flask, dispersed with 1 ml of THF by stirring, and 158 mg of T3P (50% EA solution) was added. After stirring for 5 min, 32 μL of MsOH was added. After stirring for 2 min, 78 μL of triethylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C. After reacting for 3 h, 79 mg of T3P, 16 μL of MsOH, and 39 μL of triethylamine were added, and the mixture was stirred overnight. The reaction solution was sampled after overnight, and the conversion rate of compound II was analyzed by LC-MS.

[0088] Experiment 3: Replace 78 μL of triethylamine and 39 μL of triethylamine in Experiment 2 with 58 μL and 29 μL of diethylamine, respectively. All other steps and experimental conditions are the same as in Experiment 2. The conversion rate of compound II when diethylamine is used as a basic reagent is detected.

[0089] Experiment 4: Replace 78 μL of triethylamine and 39 μL of triethylamine in Experiment 2 with 98 μL of DIPEA and 49 μL of diethylamine, respectively. All other steps and experimental conditions are the same as in Experiment 2. The conversion rate of compound II was measured when DIPEA was used as the basic reagent.

[0090] Experiment 5: Replace 78 μL of triethylamine and 39 μL of triethylamine in Experiment 2 with 69 mg DMAP and 35 mg DMAP respectively. All other steps and experimental conditions are the same as in Experiment 2. The conversion rate of compound II was detected when DMAP was used as an alkaline reagent.

[0091] Experiment 6: 46 μL and 23 μL of pyridine were used to replace 78 μL and 39 μL of triethylamine in Experiment 2, respectively. All other steps and experimental conditions were the same as in Experiment 2. The conversion rate of compound II was measured when pyridine was used as the basic reagent. The conversion rates of compound II in Experiments 1-6 using different basic reagents are shown in Table 3 below.

[0092] Table 3. Effects of different alkaline reagents on the conversion rate of compounds of formula II.

[0093] As can be seen from Table 3 above, the conversion rate of compound II is only 21.44% when pyridine is used as a basic reagent, while other basic reagents such as isopropylamine can achieve a conversion rate of over 50% for compound II. Among them, the conversion rate of compound II can reach over 87% when isopropylamine, triethylamine, diethylamine and DIPEA are used as basic reagents.

[0094] Example 6: Screening of catalysts for the preparation of compound III

[0095] Experiment 1: 90 mg of compound II was added to a reaction flask and dispersed with 3 ml of THF solution by stirring. 473 mg of T3P was added, and after stirring for 5 min, 96 μL of MsOH was added. After stirring for 2 min, 145 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C. After 3 h of reaction, 237 mg of T3P, 48 μL of MsOH, and 73 μL of isopropylamine were added, and the mixture was stirred overnight. A sample of the reaction solution was taken after overnight, and the conversion rate of compound II was analyzed by LC-MS.

[0096] Experiment 2: 15 mg of compound II was added to a 3 ml reaction flask and dispersed with 0.5 ml of THF solution. 89 mg of T4P (50% EA solution) was added, and the mixture was stirred for 5 min. 16 μL of MsOH was then added. After stirring for 2 min, 24 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C. After 3 h of reaction, 45 mg of T4P, 8 μL of MsOH, and 12 μL of isopropylamine were added, and the mixture was stirred overnight. The reaction solution was sampled overnight, and the conversion rate of compound II was analyzed by LC-MS.

[0097] Experiment 3: Replace 89mg T4P and 45mg T4P in Experiment 2 with 79mg Ms2O and 40mg Ms2O respectively. All other steps and experimental conditions are the same as in Experiment 2. The conversion rate of compound II when using Ms2O as catalyst is detected.

[0098] Experiment 4: Replace 89mg T4P and 45mg T4P in Experiment 2 with 79mg TsCl and 40mg TsCl respectively. All other steps and experimental conditions are the same as in Experiment 2. The conversion rate of compound II when using TsCl as catalyst is detected.

[0099] The conversion rates of compound II using different catalysts in experiments 1-4 are shown in Table 4 below.

[0100] Table 4. Effect of different catalysts on the conversion rate of compound II

[0101] As can be seen from Table 4 above, the conversion rate of compound II is only 8.81% when TsCl is used as a catalyst, while the conversion rate of compound II can reach more than 87% when T3P and T4P are used as catalysts.

[0102] Example 7: Screening of reaction temperature for preparing compound III

[0103] Experiment 1: 90 mg of compound II was added to a 10 ml reaction flask, dispersed by stirring with 3 ml of THF, then 473 mg of T3P was added. After stirring for 5 min, 96 μL of MsOH was added. After stirring for 2 min, 145 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C. After reacting for 3 h, 237 mg of T3P, 48 μL of MsOH, and 73 μL of isopropylamine were added, and the mixture was stirred overnight. The reaction solution was sampled after overnight, and the conversion rate of compound II was analyzed by LC-MS.

[0104] Experiment 2: 15 mg of compound II was added to a 3 ml reaction flask, dispersed by stirring with 0.5 ml of THF, 79 mg of T3P was added, and after stirring for 5 min, 16 μL of MsOH was added. After stirring for 2 min, 24 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at different temperatures (room temperature, 50℃, 70℃, 80℃, and 95℃). After 5 h of reaction, samples were taken and the conversion rate of compound II was analyzed by LC-MS.

[0105] The conversion rates of Formula II compounds under different temperature conditions in Experiments 1-2 are shown in Table 5 below.

[0106] Table 5. Effect of different reaction temperatures on the conversion rate of compound II.

[0107] As can be seen from Table 5 above, the conversion rate of compound II at room temperature is only 6.56%, while the conversion rate of compound II at a reaction temperature above 60℃ can reach more than 85%.

[0108] Example 8: Screening of catalysts in the chemical reaction for the preparation of beloteracon

[0109] Experiment 1: 20 mg of compound III and 0.9 ml of DMA were added to a 3 ml reaction flask. After stirring to partially dissolve the starting material, 6 mg of Tf₂NH₃ was added. After stirring for 5 min, 28 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C for 5 h. After the reaction was completed, the conversion rate of compound III was analyzed by LC-MS.

[0110] Experiment 2: 20 mg of compound III and 0.8 ml of DMA were added to a 3 ml reaction flask. After stirring to partially dissolve the starting material, 9 μL of AcOH was added. After stirring for 5 min, 14 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C for 5 h. After the reaction was completed, the conversion rate of compound III was analyzed by LC-MS.

[0111] Experiment 3: 20 mg of compound III and 0.9 ml of DMA were added to a 3 ml reaction flask. After stirring to partially dissolve the starting material, 3 mg of Yb(OTf)3 solution dissolved in 0.1 ml THF was added. After stirring for 5 min, 18 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C for 5 h. After the reaction was completed, the conversion rate of compound III was analyzed by LC-MS.

[0112] Experiment 4: 20 mg of compound III and 0.8 ml of DMA were added to a 3 ml reaction flask. After stirring to partially dissolve the starting material, 6 μL of TFA was added. After stirring for 5 min, 14 μL of isopropylamine was added, the reaction flask was sealed, and the reaction was carried out at 60 °C for 5 h. After the reaction was completed, the conversion rate of compound III was analyzed by LC-MS.

[0113] The conversion rates of compound III using different catalysts in experiments 1-4 are shown in Table 6 below.

[0114] Table 6. Effect of different catalysts on the conversion rate of compound III

[0115] As can be seen from Table 6 above, the conversion rate of compound III is only 22.78% when TFA is used as a catalyst, while the conversion rate of compound III can reach more than 40% when Yb(OTf)3, AcOH and Tf2NH are used as catalysts.

[0116] Although specific embodiments of the invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and all such changes are within the scope of protection of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

1. A method for preparing belotecone or a salt thereof, wherein, The method includes the following steps: In the presence of an acidic catalyst, a compound of formula III or its salt undergoes an addition reaction with isopropylamine to give belotecamine or its salt.

2. The method according to claim 1, wherein, The molar ratio of the compound of formula III or its salt to isopropylamine is 1:(1-10).

3. The method according to claim 1, wherein, The acid catalyst is selected from one or more of bis(trifluoromethanesulfonyl)imide, pentafluorobenzoic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, and ytterbium trifluoromethanesulfonate.

4. The method according to any one of claims 1-3, wherein, The method further includes the following steps: In the presence of a catalyst, a compound of formula II or its salt undergoes an elimination reaction to yield a compound of formula III or its salt.

5. The method according to claim 4, wherein, The catalyst is selected from one or more of T3P, T4P, Ms2O and TsCl.

6. The method according to claim 4, wherein, The molar ratio of the compound of formula II or its salt to the catalyst is 1:(1-20), for example 1:(1-15) or 1:(1-10).

7. The method according to claim 4, wherein, First, disperse the compound of formula II or its salt in a solvent, add a catalyst, an acidic reagent, and a basic reagent, and carry out an elimination reaction to obtain the compound of formula III or its salt.

8. The method according to claim 7, wherein, The acidic reagent is selected from one or more of methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid, benzenesulfonic acid, and nitric acid.

9. The method according to claim 7, wherein, The alkaline reagent is selected from one or more of isopropylamine, triethylamine, diethylamine, DIPEA, DMAP, and pyridine.

10. The method according to claim 4, wherein, The reaction temperature for the elimination reaction is controlled between 40-95℃.

11. The method according to any one of claims 1-10, wherein, The method further includes the following steps: In the presence of a catalyst, a compound of formula I or a salt thereof undergoes a coupling reaction with a radical source capable of generating hydroxyethyl radicals to yield a compound of formula II or a salt thereof.

12. The method according to claim 11, wherein, The free radical source is acrolein.

13. The method according to claim 11, wherein, The molar ratio of the compound of formula I or its salt to the free radical source is 1:(5-20).

14. The method according to claim 11, wherein, An acidic reagent is added to a compound of formula I or its salt, and after stirring, a catalyst is added, followed by a free radical source. After stirring, a free radical initiator is added, and a coupling reaction is carried out to obtain a compound of formula II or its salt.

15. The method according to claim 14, wherein, The acidic reagent is selected from one or more of sulfuric acid, methanesulfonic acid, and trifluoroacetic acid.

16. The method of claim 14, wherein, The catalyst is ferrous sulfate heptahydrate, and the free radical initiator is hydrogen peroxide.

17. A compound for preparing belotecone, wherein, The compound is selected from:

18. The use of the compound in the preparation of belotecone, among which, The compound is selected from:

19. A method for preparing a compound of formula II or a salt thereof, comprising, in the presence of a catalyst, coupling a compound of formula I (camptothecin, CPT) or a salt thereof with a radical source capable of generating a hydroxyethyl radical to obtain a compound of formula II or a salt thereof. Preferably, the characteristics of the compound of formula II or its salt are as defined in any one of claims 11-16.

20. A method for preparing a compound of formula III or a salt thereof, comprising subjecting a compound of formula II or a salt thereof to an elimination reaction in the presence of a catalyst to obtain a compound of formula III or a salt thereof. Preferably, the characteristics of the preparation of the compound of formula III or its salt are as defined in any one of claims 4-10.

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