Intermediates of ecteinascidin derivatives and methods for their synthesis

Abstract

This invention provides an intermediate for a jugating glycoside derivative and a method for its synthesis. The method involves directly protecting the amino group of safflowerin B with phenyl isothiocyanate, followed by protection of the hydroxyl group (the thiourea group undergoes alkylation simultaneously), yielding an intermediate compound with a novel structure. This is then followed by a photocatalytic cyclization reaction, further protection of the 5-hydroxyl group, and finally, a simple Edman degradation reaction to obtain the target compound. Compared to existing technologies, this method has a shorter reaction route and significantly improved yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to intermediates of sucrose derivatives and their synthesis methods, particularly to intermediates of sucrose 743 (Et-743) and sucrose 736 (Et-736) and their synthesis methods. Background Technology

[0002] Ecteinascidiaturbinata is a highly effective antitumor drug isolated from the marine organism mangrove tunicate (Ecteinascidiaturbinata). Ecteinascidiaturbinata 729, 743, 745, 770, and 736, along with their structures and preparation methods, have been disclosed in US patents US5256663, US5089273, and US5149804, and international applications WO2000069862 and WO2001077115.

[0003] Trabectedin (Et-743, brand name Yondelis), developed by Johnson & Johnson, was designated as an orphan drug for soft tissue sarcoma in the European Union in 2001, becoming the first modern marine drug. In 2004, it was designated as an orphan drug for soft tissue sarcoma by the US Food and Drug Administration (FDA), and in the same year, it was designated as an orphan drug in Europe and the United States for the treatment of acute lymphoblastic leukemia, soft tissue sarcoma, and ovarian cancer. Lurbinectedin (brand name Zepzelca), an analogue of the marine compound ET-736 isolated from the sea squirt Ecteinacidiaturbinata, has also been developed for the treatment of adult patients with metastatic small cell lung cancer (SCLC) whose disease has progressed during or after platinum-based chemotherapy.

[0004]

[0005] Patent WO2003014127 discloses a method for first converting cyanosafracin B into an ET-743 intermediate, and then synthesizing lurbinectedin. WO2011147828 reports a synthetic route for preparing lurbinectedin using cyanosafracin B as the initial raw material.

[0006] ET-743 was isolated from marine organisms at extremely low concentrations, only 10%. -6 ~10 -7%w / w. Several total synthetic methods have been published. For example, Corey et al. disclosed a total synthetic method for trabectedine, with a yield of 0.5% after 36 steps (J.Am.Chem.Soc.1996,118,9202-9203); Fukuyama et al. reported a total synthesis with a yield of 0.56% after 50 steps (J.Am.Chem.Soc.2002,124,6552-6554); Zhu et al. reported a total synthetic route with a yield of 1.7% after 31 steps (J.Am.Chem.Soc.2006,128,87-89); and Fukuyama et al. again reported a new total synthetic route with a total yield of 1.3% after 30 steps (J.Am.Chem.Soc.2013,135,13684-13687).

[0007] WO2000069862, WO2001077115, and the paper "Synthesis of Ecteinascidin ET-743 and Phthalascidin Pt-650 from Cyanosafracin B" (Org. Lett. 2000, 2, 16, 2545–2548) disclose a method for preparing trabectedin (ET-743) from cyanosafracin B as a starting material. This semi-synthetic route is shorter than the total synthetic route and is currently the industrially available synthetic route.

[0008] CN1646539A and Pharma Mar (reference J.Org.Chem., Vol.68, No.23, 2003) disclose a method for preparing trabectedin using compound NTb08A01.

[0009] Compound NTb08A01 is a key intermediate in the preparation of trabectedine and rubotedelineate, and its structure is as follows:

[0010]

[0011] The synthetic method of compound NTb08A01 is disclosed in documents such as WO2000069862 and US20080146580A. It mainly uses cyanobenzin B as the starting material, and prepares compound NTb01 by Boc protection of the amino group, with a yield of 81%. Then, it reacts with MOMBr in acetonitrile to prepare compound NTb02, with a yield of 83%. Compound NTb02 is hydrolyzed to obtain compound NTb03, with a yield of 68%. Compound NTb03 is further processed by Pb / C-catalyzed hydrogenation reduction of 1,4-benzoquinone to 1,4-diol, followed by a ring-closure reaction, yields compound NTb04. This hydroxyl group is then protected by AllyBr / Cs₂CO₃ to give compound NTb05 (56% yield). Compound NTb05 is then deprotected by the hydroxyl protecting agent MOM (95% yield), and subsequently reacted with phenyl thioisocyanate to form thiourea (87% yield). Finally, after Edman degradation (82% yield), compound NTb08 is obtained. The specific reaction formula is as follows:

[0012]

[0013]

[0014] This method requires palladium-carbon catalytic hydrogenation reduction of 1,4-benzoquinone to 1,4-diol during the five-membered ring closure process. However, the thiourea group required for the Edman degradation reaction is incompatible with palladium-carbon (leading to palladium poisoning). Therefore, the amino group cannot be directly protected with the thiourea group. Instead, the amino group needs to be protected with a Boc group first, followed by palladium-carbon catalytic reduction, and then the Boc group is removed. The amino group is then protected with phenyl thioisocyanate, and finally, the compound NTb08A01 is obtained through the Edman degradation reaction. The reaction route is long, and the overall yield is low, only 17%.

[0015] There is still a need in this field to develop new methods for preparing NTb08A01 in order to improve the overall yield of compound NTb08, thereby reducing the production cost of active pharmaceutical ingredients trabectedine and rupettedine and meeting the clinical needs for these drugs. Summary of the Invention

[0016] To address the aforementioned problems in existing technologies, the present invention aims to provide a novel method for preparing compound NTb08A, particularly compound NTb08A01, as well as a novel method for preparing sucrose derivatives, particularly trabectedin and rubotede. Compared with existing technologies, the method provided by the present invention has a shorter reaction route, higher yield, and is suitable for industrial application.

[0017] Specifically, in a first aspect, the present invention provides a method for preparing compound NTb08A, the method comprising the following steps: obtaining compound NTc04A through an Edman degradation reaction:

[0018]

[0019] Wherein, R1 is a hydroxyl protecting group, preferably R1 is MOM, MEM, benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBOM) or 2-(trimethylsilyl)ethoxymethyl;

[0020] R2 is a hydroxyl protecting group II, preferably allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl.

[0021] In one specific embodiment, the method for preparing compound NTbO8A includes the following step: compound NTcO4A is obtained by reacting compound NTcO3A with a reagent capable of introducing an R2 group.

[0022]

[0023] Wherein, R2 is a hydroxyl protecting group II, preferably allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl.

[0024] Preferably, when R2 is allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or p-nitrobenzyl, the reagent capable of introducing R2 is X-R2, wherein X is F, Cl, Br, I, methanesulfonyloxy or p-toluenesulfonyloxy.

[0025] When R2 is acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl, the corresponding reagent capable of introducing R2 is selected from the corresponding haloacyl or acid anhydride. For example, when R2 is acetyl, the reagent capable of introducing R2 is selected from acetyl chloride or acetic anhydride; when R2 is benzoyl, the reagent capable of introducing R2 is selected from benzoyl chloride; when R2 is allyloxycarbonyl or benzyloxycarbonyl, the reagent capable of introducing R2 is allyloxycarbonyl chloride or benzyloxycarbonyl chloride, respectively; when R2 is tert-butoxycarbonyl, the reagent capable of introducing R2 is (Boc)2O.

[0026] Furthermore, in one specific embodiment, the method for preparing compound NTbO8A includes the following step: compound NTcO3A is obtained from compound NTcO2A via a photocatalytic reaction.

[0027]

[0028] Furthermore, the compound NTc02A is obtained by reacting compound NTc01 with a reagent capable of introducing an R1 group:

[0029]

[0030] R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl.

[0031] A second aspect of the present invention provides a method for preparing compound NTco4A, the method comprising the following steps: reacting compound NTco3A with a reagent capable of introducing an R2 group to obtain compound NTco4A:

[0032]

[0033] Wherein, R2 is a hydroxyl protecting group II, preferably allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl.

[0034] Preferably, when R2 is allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or p-nitrobenzyl, the reagent capable of introducing R2 is X-R2, wherein X is F, Cl, Br, I, methanesulfonyloxy or p-toluenesulfonyloxy.

[0035] When R2 is acetyl, benzoyl, allyloxycarbonyl, or benzyloxycarbonyl, the corresponding reagent capable of introducing R2 is selected from the corresponding haloacyl or acid anhydride. For example, when R2 is acetyl, the reagent capable of introducing R2 is selected from acetyl chloride or acetic anhydride; when R2 is benzoyl, the reagent capable of introducing R2 is selected from benzoyl chloride; when R2 is allyloxycarbonyl or benzyloxycarbonyl, the reagent capable of introducing R2 is allyloxycarbonyl chloride or benzyloxycarbonyl chloride, respectively; when R2 is tert-butoxycarbonyl, the reagent capable of introducing R2 is (Boc)2O.

[0036] Further preferably, the compound NTcO3A is obtained by converting compound NTcO2A through a photocatalytic reaction:

[0037]

[0038] Further preferably, the compound NTc02A is obtained by reacting compound NTc01 with a reagent capable of introducing an R1 group:

[0039]

[0040] Wherein, R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl.

[0041] A third aspect of the present invention provides a method for preparing compound NTO3A, the method comprising the following steps: subjecting compound NTCO2A to a photocatalytic reaction to obtain compound NTCO3A:

[0042]

[0043] Further preferably, the compound NTc02A is obtained by reacting compound NTc01 with a reagent capable of introducing an R1 group:

[0044]

[0045] R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl.

[0046] A fourth aspect of the present invention provides a method for preparing compound NTco2A, the method comprising the following steps: reacting compound NTco1 with a reagent capable of introducing an R1 group to obtain compound NTco2A:

[0047]

[0048] R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl.

[0049] In a fourth aspect, this invention provides a method for preparing trabectedine and / or rubettedine, the method comprising preparing compound NTb08A (preferably compound NTb08A01) using the method described herein, and then converting compound NTb08A (preferably compound NTb08A01) into trabectedine and / or rubettedine. The method for converting compound NTb08A into trabectedine and / or rubettedine can be implemented using methods known in the art, including but not limited to those disclosed in WO2000069862, US20080146580A, WO2003014127, and WO2011147828, the contents of which are incorporated herein by reference.

[0050] In a fifth aspect of the invention, an intermediate for preparing trabectedine or rubettedine is also provided, the intermediate compound having the following structure:

[0051]

[0052] Wherein, R1 is a hydroxyl protecting group, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl;

[0053] R2 is a hydroxyl protecting group, preferably allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, or benzyloxycarbonyl.

[0054] Further preferred, R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl, and R2 is allyl.

[0055] In a preferred embodiment, the intermediate for preparing trabectedine or rubotedine is compound NTc02A, wherein R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl, or 2-(trimethylsilyl)ethoxymethyl.

[0056] In a preferred embodiment, the intermediate for preparing trabectedine or rubotedine is compound NTc03A, wherein R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl, or 2-(trimethylsilyl)ethoxymethyl.

[0057] In a preferred embodiment, the intermediate for preparing trabectedine or rubotedine is compound NTc04A, wherein R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl, and R2 is allyl.

[0058] In a preferred embodiment, the intermediate for preparing trabectedine or rubotedin is compound NTc04A, wherein R1 is MOM or MEM, and R2 is allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, or benzyloxycarbonyl.

[0059] Detailed Description of the Invention

[0060] Method for preparing compound NTc01 from NTb00 (safrubin B):

[0061]

[0062] In the method described in this invention, compound NTc01 can be prepared using safflower B as a starting material. For example, patent CN100475822C discloses a method for preparing compound NTc01 from safflower B, the contents of which are incorporated herein by reference. Alternatively, compound NTb00 can be dissolved in a suitable organic solvent, such as acetonitrile, methanol, ethanol, 2,6-epoxide, or isopropanol, and then phenyl isothiocyanate is added. The reaction is carried out at room temperature. Preferably, the molar ratio of compound NTb00 to phenyl isothiocyanate is 1:1 to 3, for example, 1:2. Optionally, after the reaction, the compound is washed with saturated sodium bicarbonate solution, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and pulped to obtain the purified standard compound NTc01.

[0063] Method for preparing compound NTc02A from NTc01:

[0064] The method of the present invention, wherein the preparation of compound NTO2A from NTCO1 includes the following steps: reacting compound NTCO1 with a reagent capable of introducing an R1 group to obtain compound NTCO2A:

[0065]

[0066] R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl.

[0067] In a preferred embodiment, the molar ratio of compound NTc01 to the reagent capable of introducing the R1 group is 1:1 to 5, for example 1:1 to 3, 1:1 to 4, 1:2 to 3, 1:2 to 4, or 1:2.5, and any value therein. In a preferred embodiment, the reaction is carried out under basic conditions, and the molar ratio of compound NTc01 to the base is 1:1 to 6, for example 1:2 to 4 or 1:3; the base is selected from C. 3-10 The base is a tertiary amine compound, such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N,N-dimethylethylamine, tetramethylethylenediamine, and tetramethylpropylenediamine. Preferably, the base is selected from triethylamine, tetramethylethylenediamine, and diisopropylethylamine (DIPEA), and more preferably, the base is DIPEA. The base may also be selected from sodium methoxide, lithium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, NaH, or DBU, preferably NaH.

[0068] In a preferred embodiment, the "reagent capable of introducing the R1 group" is a reagent that, after reacting with compound NTc01, can introduce a "hydroxyl protecting group I" defined by R1. Preferably, the "reagent capable of introducing the R1 group" is bromomethyl methyl ether, chloromethyl methyl ether, 2-methoxyethoxymethyl chloride, 2-methoxyethoxymethyl bromide, benzyloxymethyl chloride, benzyloxymethyl bromide, or 2-(trimethylsilyl)ethoxymethyl chloride; more preferably, the "reagent capable of introducing the R1 group" is bromomethyl methyl ether or 2-(trimethylsilyl)ethoxymethyl chloride.

[0069] In a preferred embodiment, the reaction solvent is DCM, THF, 2-methyltetrahydrofuran, DMF, acetonitrile, methanol, ethanol, methyl tert-butyl ether, isopropanol, or ethyl acetate, etc., and more preferably, the reaction solvent is DCM or THF.

[0070] In a preferred embodiment, the reaction temperature is not higher than 10°C, for example, not higher than 0°C, or not higher than -10°C; more preferably, the reaction temperature is -20°C to 0°C, such as -10°C to -15°C. In a preferred embodiment, the above method further includes a post-treatment process, which includes, after the reaction is completed, adding an aqueous citric acid solution while controlling the internal temperature ≤0°C during the dropwise addition, stirring, then allowing the mixture to stand and separate, washing the organic phase with water, and performing one or more of the following processes: drying, concentration, crystallization / recrystallization, pulping, and / or drying. In a preferred embodiment of the present invention, the drying and / or concentration of the organic phase can be performed using anhydrous magnesium sulfate or anhydrous sodium sulfate.

[0071] In one specific embodiment, a method for preparing compound NTO2A is provided, the method comprising the following steps: reacting compound NTCO1 with a reagent capable of introducing an R1 group (preferably bromomethyl methyl ether, chloromethyl methyl ether, or 2-methoxyethoxymethyl chloride) under alkaline conditions (preferably DIPEA or NaH) in an organic solvent (preferably DCM or THF), the reaction temperature being 20°C to 0°C (preferably -10°C to -15°C), to obtain compound NTCO2A; wherein the molar ratio of compound NTCO1 to the reagent capable of introducing an R1 group is 1:2 to 4; and the molar ratio of compound NTCO1 to the base (preferably DIPEA or NaH) is 1:2 to 4.

[0072] Method for preparing compound NTc03A from NTc02A:

[0073] In the method described in this invention, the preparation of compound NTO3A from NTO2A includes the following steps: subjecting compound NTCO2A to a photocatalytic reaction to obtain compound NTCO3A:

[0074]

[0075] Wherein R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl.

[0076] In a preferred embodiment, the photocatalytic reaction is carried out under LED illumination, more preferably, the LED is a blue LED. The power of the LED used in the reaction is not limited here, and can be, for example, 5–1000W, preferably 10–90W, or 20–80W, or 30–70W, or 40–60W, or 50W, etc. Using a high-power LED will shorten the reaction time; conversely, using a low-power LED may prolong the reaction time. The reaction progress can be monitored by methods known in the art, such as, but not limited to, TLC or HPLC monitoring.

[0077] In a preferred embodiment, the reaction solvent is dichloromethane, ethyl acetate, tetrahydrofuran, isopropanol, or 1,2-dichloroethane; preferably, the reaction solvent is dichloromethane.

[0078] In a preferred embodiment, the reaction optionally further includes a post-processing procedure, which includes, but is not limited to, concentration, drying, crystallization / recrystallization, etc., used in one or more steps in an alternating or sequential manner. In a preferred embodiment, after the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a crude product, which is then directly used in the next reaction step.

[0079] In a preferred embodiment, a method for preparing compound NTO3A is provided, comprising adding compound NTCO2A to an organic solvent (preferably dichloromethane), stirring under 30-70W (preferably 40-60W) blue LED light irradiation, and after the reaction is completed, compound NTO3A is obtained. Optionally, after the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure to obtain crude compound NTO3A.

[0080] Method for preparing compound NTc04A from NTc03A:

[0081] In the method described in this invention, the method for preparing compound NTO4A from NTO3A includes the following steps: reacting compound NTO3A with a reagent capable of introducing an R2 group to obtain compound NTO4A:

[0082]

[0083] Wherein, R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl;

[0084] R2 is a hydroxyl protecting group II, preferably allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl.

[0085] In a preferred embodiment, the molar ratio of compound NTc03A to the reagent capable of introducing the R2 group is 1:1 to 8, for example 1:3 to 6, or 1:4 to 6 or 1:5, etc.

[0086] In a preferred embodiment, the "reagent capable of introducing the R2 group" is a reagent that, upon reaction with compound NTc03A, introduces a "hydroxyl protecting group II" defined by R2, preferably X-R2, where X is F, Cl, Br, I, methanesulfonyloxy, or p-toluenesulfonyloxy, and R2 is allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, or p-nitrobenzyl, or the reagent capable of introducing R2 is selected from acetyl chloride, acetic anhydride, benzoyl chloride, allyloxycarbonyl chloride, benzyloxycarbonyl chloride, or (Boc)2O. In a particularly preferred embodiment, the reagent capable of introducing the R2 group is... Wherein X is F, Cl, Br, or I, preferably Br. Particularly preferred is that the reagent capable of introducing the R2 group is allyl bromide.

[0087] In a preferred embodiment, the reaction of compound NTc03A with the reagent capable of introducing an R2 group is carried out under alkaline conditions, wherein the base is selected from metal weak acid salts and tertiary amines; preferably, the metal weak acid salt is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal monohydrogen phosphates, alkali metal dihydrogen phosphates, and alkali metal acetates, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium monohydrogen phosphate, sodium phosphate, potassium monohydrogen phosphate, potassium phosphate, sodium acetate, or potassium acetate, more preferably sodium carbonate, potassium carbonate, or cesium carbonate; preferably, the tertiary amine is selected from C 3-10 Tertiary amine compounds, wherein C 3-10 The tertiary amine compound is selected from trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N,N-dimethylethylamine, tetramethylethylenediamine, or tetramethylpropylenediamine, preferably triethylamine, tetramethylethylenediamine, or diisopropylethylamine. In a more preferred embodiment, the base is selected from sodium carbonate, potassium carbonate, or cesium carbonate. Further, the molar ratio of the base to compound NTco3A is 1 to 5:1, for example, 2 to 4:1 or 3:1.

[0088] In a preferred embodiment, the reaction solvent is acetonitrile, DMF, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, or methyl tert-butyl ether, and more preferably, the reaction solvent is acetonitrile.

[0089] In a preferred embodiment, the reaction temperature is 0–20°C, preferably 5–15°C.

[0090] In a preferred embodiment, the process also includes a post-processing step, such as purification by one or more steps after the reaction, including filtration, extraction, washing, drying, crystallization, recrystallization, and silica gel column chromatography. The steps of filtration, extraction, washing, drying, crystallization, recrystallization, and silica gel column chromatography can be performed sequentially or alternately, and the extraction and drying steps can be repeated once or multiple times.

[0091] In a more preferred embodiment, a method for preparing compound NTc04A is provided, comprising adding compound NTc03A to an organic solvent (preferably acetonitrile), cooling to 5–15°C, then adding a base (preferably cesium carbonate, sodium carbonate, or potassium carbonate), and then adding a reagent capable of introducing an R2 group (preferably allyl bromide), reacting at 5–15°C to obtain compound NTc04A; optionally, the method further includes a post-treatment process, preferably, the post-treatment process comprising filtering after the reaction, washing the filtrate with EA, combining the filtrates and concentrating under reduced pressure, then adding water and EA for extraction, drying the organic phase, concentrating, and then performing silica gel column chromatography to obtain compound NTc04A.

[0092] Method for preparing compound NTbO8 from NTcO4A:

[0093] In the method described in this invention, the method for preparing compound NTb08A from NTO4A includes the following steps: subjecting compound NTc04A to an Edman degradation reaction to obtain compound NTb08A:

[0094]

[0095] Wherein, R1 is a hydroxyl protecting group I, preferably R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl;

[0096] R2 is a hydroxyl protecting group II, preferably allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, more preferably allyl.

[0097] In a preferred embodiment, the Edman degradation reaction of NTc04A is carried out under acidic conditions, wherein the acid is selected from one or more of HCl, sulfuric acid, phosphoric acid, sodium dihydrogen phosphate, acetic acid, and formic acid; preferably, the acid is HCl. More preferably, the molar ratio of the acid to compound NTc04A is 5–20:1, for example, 5–15:1, or 8–12:1. More preferably, the acid is HCl, such as an ethyl acetate solution of HCl.

[0098] In a preferred embodiment, the reaction solvent is one or more of methanol, ethanol, ethyl acetate, isopropanol, or tetrahydrofuran. Methanol, ethyl acetate, or a mixture thereof are preferred.

[0099] In a preferred embodiment, the reaction temperature is -5 to 40°C, preferably 0 to 30°C, and more preferably, acid is added to the organic solvent of compound NTc04A at -5 to 5°C, and then the temperature is raised to 10 to 40°C.

[0100] In a preferred embodiment, the reaction further includes a post-treatment process, which includes purification by one or more steps after the reaction, such as adjusting pH, extraction, filtration, washing, crystallization, recrystallization, concentration, drying, and silica gel column chromatography. These steps can be performed sequentially or alternately, or a purification method such as crystallization or recrystallization can be performed multiple times.

[0101] In a preferred embodiment of the present invention, a method for preparing compound NTb08A is provided, comprising adding compound NTc04A to an organic solvent (preferably methanol or ethyl acetate), cooling to -5 to 5°C, then adding an acid (preferably HCl / EA solution), then heating to 10 to 40°C and stirring until the reaction is complete, thereby obtaining compound NTb08A. Optionally, after the reaction is complete, the solvent is evaporated, EA and water are added to the residue, the pH of the aqueous phase is adjusted to 7 to 8 with saturated sodium bicarbonate solution, the mixture is allowed to stand and separate into layers, the organic phase is separated, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the target compound NTb08A.

[0102] The "hydroxyl protecting group I" and "hydroxyl protecting group II" described in this invention are suitable groups known in the art for hydroxyl protection, see the hydroxyl protecting groups section in "Protective Groups in Organic Synthesis", 5th Ed. TW Greene & P. ​​GMWuts, and "Protective Group Chemistry", edited by Wu Qinpei and Li Shanmao, Chemical Industry Press, 2007. As an example, preferably, the hydroxyl protecting groups I and II are independently selected from C... 1-10 Alkyl, C1-10 alkoxy-substituted C 1-10 Alkyl, C 6-10 aryl-substituted C 1-10 Alkyl groups, halogenated, nitro groups, C 1-10 Alkyl, C 1-10 Benzyl groups substituted with one or more substituents in the alkoxy group: for example, methyl, tert-butyl, allyl, benzyl, triphenylmethyl, methoxymethyl (MOM), methoxyethoxymethyl (MEM), ethoxyethyl, 2-tetrahydropyranyl (THP), benzyloxymethyl (BOM), p-nitrobenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxybenzyloxymethyl (PMBOM), or 2-(trimethylsilyl)ethoxymethyl, etc.; can be (C 1-10 Alkyl or aryl) 3-silyl, for example, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10The aryloxycarbonyl group can be, for example, benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (Boc); or it can be allyloxycarbonyl (Alloc). In a preferred embodiment, the "reagent capable of introducing the R1 group" described in this invention is a reagent that can introduce the "hydroxyl protecting group I" defined by R1 after reacting with the compound NTco1, such as a reagent capable of introducing groups such as MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl; preferably, the "reagent capable of introducing the R1 group" is selected from bromomethyl methyl ether, chloromethyl methyl ether, 2-methoxyethoxymethyl chloride, 2-methoxyethoxymethyl bromide, benzyloxymethyl chloride, benzyloxymethyl bromide, p-methoxybenzyloxymethyl chloride, p-methoxybenzyloxymethyl bromide or 2-(trimethylsilyl)ethoxymethyl chloride; preferably, the "reagent capable of introducing the R1 group" is bromomethyl methyl ether or 2-(trimethylsilyl)ethoxymethyl chloride. In a preferred embodiment, the "reagent capable of introducing the R2 group" described in this invention refers to reagents that, after reacting with compound NTc03A, can introduce a "hydroxyl protecting group II" defined by R2. For example, when R2 is allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, or p-nitrobenzyl, the reagent capable of introducing the R2 group is X-R2, wherein X is F, Cl, Br, I, methanesulfonyloxy, or p-toluenesulfonyloxy; when R2 is acetyl, benzoyl, or allyloxycarbonyl... When R2 is an acetyl group, the reagent capable of introducing R2 is selected from the corresponding halogenated acyl group or acid anhydride. For example, when R2 is an acetyl group, the reagent capable of introducing R2 is selected from acetyl chloride or acetic anhydride; when R2 is a benzoyl group, the reagent capable of introducing R2 is selected from benzoyl chloride; when R2 is an allyloxycarbonyl group or a benzyloxycarbonyl group, the reagent capable of introducing R2 is allyloxycarbonyl chloride or benzyloxycarbonyl chloride, respectively; when R2 is a tert-butoxycarbonyl group, the reagent capable of introducing R2 is (Boc)2O. In a particularly preferred embodiment, when R2 is an allyl group, the reagent capable of introducing the R2 group is... Where X is F, Cl, Br or I, preferably Br.

[0103] The blue LED lamp described in this invention refers to an LED lamp with a wavelength of 460-470nm.

[0104] Abbreviations: "MOM" stands for methyl methoxy; "MEM" stands for methyl methoxyethoxy; Boc stands for tert-butyloxycarbonyl; Alloc stands for allyloxycarbonyl; Cbz stands for benzyloxycarbonyl; Troc stands for 2,2,2-trichloroethoxycarbonyl.

[0105] MsCl: p-Methylsulfonyl chloride;

[0106] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0107] BOM: Benzyloxymethyl;

[0108] BOMBr: Benzyl (bromomethyl) ether;

[0109] PMBOM: p-Methoxybenzyloxymethyl;

[0110] DIPEA: N,N-diisopropylethylamine;

[0111] EA: Ethyl acetate;

[0112] DMF: N,N-dimethylformamide;

[0113] DMAP: 4-Dimethylaminopyridine;

[0114] PMB: p-Methoxybenzyl.

[0115] The method provided by this invention involves directly protecting the amino group of safflower B with phenyl isothiocyanate, followed by protection of the hydroxyl group (the thiourea group undergoes alkylation simultaneously) to obtain an intermediate compound NTc02A with a novel structure. Subsequently, a photocatalytic ring-closing reaction is achieved through blue LED irradiation, followed by protection of the 5-hydroxyl group to obtain NTc04A. Finally, the target compound NTb08A is obtained through a simple Edman degradation reaction. This method effectively shortens the reaction steps for preparing compound NTb08A from safflower B (from 8 steps in the prior art to 5 steps) and significantly improves the overall yield (from 17% in the prior art to approximately 52%), thereby effectively reducing the production cost of trabectedin and rubettedin. Specific Implementation

[0116] The present invention will be explained in detail below with reference to specific examples, so that those skilled in the art can have a more comprehensive understanding of the present invention. The specific examples are only used to illustrate the technical solutions of the present invention and do not limit the present invention in any way.

[0117] Example 1: Preparation of compound NTc01

[0118]

[0119] Method 1: 25.0 g (45.5 mmol) of compound NTb00 was dissolved in 150 mL of acetonitrile. After stirring and dissolving, 12.3 g (91 mmol) of phenyl isothiocyanate was added at room temperature. The reaction was stirred at room temperature. After the reaction was completed by TLC monitoring, the solvent was removed under reduced pressure. 200 mL of ethyl acetate was added to the residue, and the mixture was washed with 50 mL of saturated sodium bicarbonate solution, followed by 50 mL of saturated brine. The residue was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product. 50 mL of a 1 / 5 EA / PE mixture was added to the crude product, and the mixture was slurried. The solid was collected by filtration and dried under vacuum to obtain 23.6 g of the target compound NTc01, with a yield of 75.8%.

[0120] Method 2: A method for preparing compound NTc01 from safflowerin B is disclosed in CN100475822C: A solution of Cyanosafracin B (3.0 g, 5.46 mmol) and phenyl isothiocyanate (3.92 ml, 32.76 mmol) in CH2Cl2 (27 ml) was stirred at 23 °C for 1.5 hours. The reaction mixture was then partitioned between CH2Cl2 (10 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (SiO2, hexane to 2 / 3 hexane / ethyl acetate gradient) to give compound NTc01 (3.29 g, 88%) as a yellow solid.

[0121] Example 2: Preparation of compound NTc02A01

[0122]

[0123] 23.0 g (33.6 mmol) of compound NTc01 was dissolved in 100 mL of DCM and cooled to -15 °C. 13.0 g (101 mmol) of DIPEA was added to the system, followed by the slow dropwise addition of 11.9 g (84 mmol) of MOMBr, maintaining the internal temperature ≤ -10 °C during the addition. After the addition was complete, the reaction was continued at -10 to -15 °C. After the reaction was completed by TLC monitoring, 100 mL of 10% citric acid aqueous solution was added dropwise to the reaction system, maintaining the internal temperature ≤ 0 °C during the addition. The mixture was stirred for 15 min, then allowed to stand and separate. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was added to 50 mL of a 1 / 8 EA / PE mixture, slurried, filtered to collect the solid, and dried under vacuum to obtain 24.4 g of compound NTc02A01, with a yield of 94%.

[0124] 1H NMR(400MHz, CDCl3):7.41-6.93(m,5H),6.74(s,1H),5.34(bs,1H),5.12(s,2H),4.90(s,2H),4.5 3(bs,1H),4.26(d,J=2.7Hz,1H),4.03(d,J=2.7Hz,1H),3.97(s,3H),3.84(br,1H),3.82-3.65(m,1 H),3.69(s,3H),3.61(s,3H),3.56(s,3H),3.31-3.27(m,1H),3.20-3.00(m,5H),2.44(d,J=18Hz, 1H),2.35(s,3H),2.23(s,3H),1.85(s,3H),1.73-1.63(m,1H),0.92(d,J=5.1Hz,3H); ESI-MS(M+H) + :772.4.

[0125] Example 3: Preparation of compound NTc03A01

[0126]

[0127] 24.0 g (31.1 mmol) of compound NTc02A01 was dissolved in 250 mL of dichloromethane, purged with nitrogen. The mixture was stirred for 12 hours under 50 W 460-465 nm blue LED illumination, with the reaction solution temperature controlled at 25-30 °C. The reaction was monitored by HPLC until completion. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product NTc03A01, which was used directly in the next reaction without purification.

[0128] Example 4: Preparation of compound NTc04A01

[0129]

[0130] 24.0 g (31.1 mmol) of compound NTc03A01 was dissolved in 250 mL of acetonitrile and cooled to 8 °C. 30.4 g (93.2 mmol) of cesium carbonate was added with stirring, followed by 18.9 g (156.5 mmol) of allyl bromide. The mixture was stirred at 8 °C for 1 hour, then stirred at room temperature for 4 hours. The reaction was monitored by TLC until completion. The solid was removed by filtration and washed with EA. The filtrates were combined and evaporated to dryness under reduced pressure. 300 mL of water and 500 mL of EA were added to the residue, and the mixture was stirred and allowed to stand before separation. The organic phase was washed with saturated brine, dried over sodium sulfate solution, filtered, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give 18.8 g of the target compound NTc04A01, with a yield of 74.5%.

[0131] 1 H NMR (400MHz, CDCl3): 7.45-6.92(m,5H),6.74(s,1H),6.27-6.02(m,1H),5.94(s,1H),5.83(s,1H),5.39(dd,J1=1.0Hz,J2=16.8Hz,1H),5. 41(bs,1H),5.25(dd,J1=1.0Hz,J2=10.2Hz,1H),5.10(s,2H),4.91(bs,1H),4.92(s,2H),4.25-4.22(m,1H),4.19(d,J=2.4Hz,1H),4.14-4. 10(m,1H),4.08(d,J=2.4Hz,1H),4.02(bs,1H),3.70(s,3H),3.58(s,3H),3.55(s,3H),3.56-3.35(m,2H),3.26-3.20(m,2H),3.05-2.96(dd ,J1=8.1Hz, J2=18Hz,1H),2.64(d,J=18Hz,1H),2.30(s,3H),2.21(s,3H),2.09(s,3H),1.91-1.80(m,1H),0.91(d,J=6.6,3H); ESI-MS(M+H) + :813.4.

[0132] Example 5: Preparation of compound NTb08A01

[0133]

[0134] 18.0 g (22.1 mmol) of compound NTc04A01 was dissolved in 120 mL of methanol and cooled to 0 °C. 60 mL of 4 M HCl / EA solution was added with stirring. The mixture was then heated to room temperature and stirred continuously. The reaction was monitored by TLC until completion. The solvent was then evaporated to dryness. 150 mL of EA and 50 mL of water were added to the residue, and the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was allowed to stand and separate into layers, separating the organic phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 9.7 g of the target compound NTb08A01, in 84.8% yield.

[0135] Example 6: Preparation of compound NTc02A02

[0136]

[0137] 16.0 g (23.4 mmol) of compound NTc01 was dissolved in 130 mL of THF and cooled to -20 °C. 2.8 g (70 mmol) of 60% NaH (dispersed in mineral oil) was added to the system, and the mixture was stirred at -20 °C for 1 hour. 0.1 g of sodium iodide was added, followed by the slow dropwise addition of 10.5 g (63.2 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride, with the internal temperature controlled to ≤-15 °C during the addition. After the addition was complete, the reaction was continued at -20 to -15 °C for 2 hours, then the temperature was raised to room temperature and stirred for 1 hour. After the reaction was completed under TLC monitoring, 100 mL of 10% citric acid aqueous solution was added dropwise to the reaction system, with the internal temperature controlled to ≤0 °C during the addition. The mixture was stirred for 15 min, and solid NaCl was added to saturate the aqueous phase. The mixture was then allowed to stand and separate into layers. The aqueous phase was separated and extracted with 50 mL of ethyl acetate. The ethyl acetate phase was combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 19.9 g of compound NTc02A02, with a yield of 90%.

[0138] 1 H NMR(400MHz, CDCl3):7.41-6.93(m,5H),6.71(s,1H),5.32(bs,1H),5.17(s,2H),4.98(s,2H),4.53(bs,1H),4.26(d,J=2 .7Hz,1H),4.00(d,J=2.7Hz,1H),3.97(s,3H),3.84(br,1H),3.82-3.65(m,1H),3.69(s,3H),3.66(t,J=7.2Hz,2H),3.60( t,J=7.1Hz,2H),3.39-3.37(m,1H),3.20-3.00(m,5H),2.46(d,J=18Hz,1H),2.33(s,3H),2.23(s,3H),1.85(s,3H),1.73 -1.63(m,1H),0.97(d,J=5.1Hz,3H),0.92(t,J=7.2Hz,2H),0.86(t,J=7.1Hz,2H),0.21(s,9H),0.19(s,9H); ESI-MS(M+H) + :945.4.

[0139] Example 7: Preparation of compound NTc03A02

[0140]

[0141] 19.0 g (20.1 mmol) of compound NTc02A02 was dissolved in 150 mL of 1,2-dichloroethane, purged with nitrogen. The mixture was stirred for 10 hours under 50 W 460-470 nm blue LED illumination, with the reaction solution temperature controlled at 20-25 °C. The reaction was monitored by HPLC until completion. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product NTc03A02, which was used directly in the next reaction without purification.

[0142] ESI-MS(M+H) + :945.4.

[0143] Example 8: Preparation of compound NTc04A02

[0144]

[0145] 19.0 g (20.1 mmol) of compound NTc03A02 was dissolved in 120 mL of pyridine, and 0.25 g of DMAP (2.0 mmol) was added. The mixture was then cooled to 10 °C. 10.2 g (100.5 mmol) of acetic anhydride was added with stirring, and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC until completion. 20 mL of water was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then evaporated to dryness under reduced pressure. 200 mL of water and 400 mL of EA were added to the residue, and the mixture was stirred and allowed to stand before separation. The organic phase was washed with 100 mL of saturated citric acid solution and 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give 13.9 g of the target compound NTc04A02, with a yield of 70.4%.

[0146] 1H NMR(400MHz, CDCl3):7.45-6.92(m,5H),6.70(s,1H),5.95(s,1H),5.84(s,1H),5.40(bs,1H),5.15(s,2H),4.91(bs,1H),4.96(s,2H),4.25-4 .22(m,1H),4.21(d,J=2.4Hz,1H),4.14-4.10(m,1H),4.08(d,J=2.4Hz ,1H),4.00(bs,1H),3.70(s,3H),3.64(t,J=7.2Hz,2H),3.59(t,J=7.1H z,2H),3.56-3.35(m,2H),3.26-3.20(m,2H),3.05-2.96(dd,J1=8.1Hz,J2=18Hz,1H),2.63(d,J=18Hz,1H),2.35(s,3H),2.30(s,3H),2.21(s, 3H),2.09(s,3H),1.91-1.80(m,1H),0.94(d,J=6.6,3H),0.89(t,J=7.2Hz,2H),0.83(t,J=7.1Hz,2H),0.17(s,9H),0.15(s,9H); ESI-MS(M+H) + :1016.6.

[0147] Example 9: Preparation of compound NTb08A02

[0148]

[0149] 13.9 g (13.7 mmol) of compound NTc04A02 was dissolved in 100 mL of dioxane and cooled to 0 °C. 50 mL of 4 M HCl / EA solution was added with stirring. The mixture was then heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC until complete. The solvent was then evaporated under reduced pressure. 150 mL of EA and 50 mL of water were added to the residue, and the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was allowed to stand and separate into layers, separating the organic phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 6.2 g of the target compound NTb08A02, in 87% yield.

[0150] Example 10: Preparation of compound NTc02A03

[0151]

[0152] 16.0 g (23.4 mmol) of compound NTc01 was dissolved in 100 mL of DCM and cooled to -15 °C. 11.8 g (117 mmol) of triethylamine was added to the system, followed by the slow dropwise addition of 28.1 g (140 mmol) of BOMpr, maintaining the internal temperature ≤ -10 °C during the addition. After the addition was complete, the reaction was continued at -10 to -15 °C. After the reaction was completed by TLC monitoring, 100 mL of 10% citric acid aqueous solution was added dropwise to the reaction system, maintaining the internal temperature ≤ 0 °C during the addition. The mixture was stirred for 15 min, then allowed to stand and separate. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 19.6 g of the target product, with a yield of 91%. ESI-MS (M+H) + :925.5.

[0153] Example 11: Preparation of compound NTc03A03

[0154]

[0155] 19.6 g of NTc02A03 was dissolved in 200 mL of dichloromethane to obtain a dichloromethane solution of crude product NTc03A03. Compound NTc03A03 was prepared by a similar method to that in Example 3. The reaction solution was used directly in the next reaction without any treatment.

[0156] Example 12: Preparation of compound NTc04A03

[0157]

[0158] 6.43 g of triethylamine was added to the dichloromethane solution of NTc03A03 from the previous step, followed by dropwise addition of 8.9 g of allyl chloroformate at room temperature. After the addition was complete, the mixture was stirred at room temperature for 8 hours. After the reaction was completed under TLC monitoring, the reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give 13.4 g of the target product, with a two-step yield of 63%. ESI-MS (M+H) + :1009.6.

[0159] Example 13: Preparation of compound NTb08A03

[0160]

[0161] 13.4 g of NTc04A03 was dissolved in 100 mL of THF and cooled to 0 °C. 60 mL of 4 M HCl / ethyl acetate solution was added with stirring, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in 150 mL of ethyl acetate, extracted with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5.4 g of the target product, with a yield of 72%.

[0162] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. For example, when R1 in the structure of compound NTc02A of the present invention is a substituted alkyl group such as MEM, it can be prepared by reacting compound NTc01 with 2-methoxyethoxymethyl chloride or 2-methoxyethoxymethyl bromide in a similar manner to Example 2. Correspondingly, the preparation of compound NTc03A and compound NTc08A can be prepared by similar methods to Examples 3 and 5, respectively. When R2 in the structure of compound NTc04A and NTc08A is an acyl group such as benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl, it can be prepared by similar methods to Examples 8 and 9.

Claims

1. Process for the preparation of the compound NTb08A, characterized in that, The method includes the following steps: obtaining compound NTc04A through an Edman degradation reaction: Wherein, R1 is MOM, MEM, benzyloxymethyl, p-methoxybenzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl; R2 is allyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, allyloxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl. The compound NTco4A is obtained by reacting compound NTco3A with a reagent capable of introducing an R2 group: ； The compound NTcO3A is obtained from compound NTcO2A via a photocatalytic reaction: 。 2. The method according to claim 1, characterized in that, The compound NTc02A is obtained by reacting compound NTc01 with a reagent capable of introducing an R1 group: 。 3. The method according to claim 2, characterized in that, The molar ratio of compound NTc01 to a reagent capable of introducing an R1 group is 1:1 to 5.

4. The method according to claim 2, characterized in that, The reaction of the compound NTc01 with a reagent capable of introducing an R1 group is carried out under alkaline conditions, and the molar ratio of the compound NTc01 to the base is 1:1 to 6; the base is DIPEA or NaH.

5. The method according to claim 1, characterized in that, The photocatalytic reaction is carried out under LED light irradiation.

6. The method according to claim 5, characterized in that, The LED light is a blue LED light.

7. The method according to claim 1, characterized in that, The molar ratio of compound NTc03A to a reagent capable of introducing an R2 group is 1:1~8; 8. The method according to claim 1, wherein the reaction of compound NTco3A with a reagent capable of introducing an R2 group is carried out under alkaline conditions; the molar ratio of the base to compound NTco3A is 1 to 5:1; and the base is one or more of pyridine, 4-dimethylaminopyridine, triethylamine, DIPEA, potassium carbonate, or cesium carbonate.

9. The method according to claim 1, characterized in that, The NTc04A degradation reaction was carried out under acidic conditions by Edman.

10. The method according to claim 1, characterized in that, The NTc04A degradation reaction is carried out under acidic conditions, and the acid is HCl.

11. A method for preparing trabectedine or rupettedine, the method comprising: Compound NTb08A was prepared using the method described in claim 1, and then compound NTb08A was converted into trabectedine or rupettedine.

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