Process for the asymmetric synthesis of 7-oxorepandiolide and uses thereof

Abstract

The present application relates to a kind of preparation methods of 7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-oxo-7-ox

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation, specifically to a method for preparing 7-oxo-repôtene, a key intermediate for preparing triptolide and triptonide, and a series of new compounds generated during the preparation of 7-oxo-repôtene using this method. Background Technology

[0002] Tripterygium wilfordii Hook.f. is a traditional Chinese medicine with a long history of use in my country, used for dispelling wind and dampness, promoting blood circulation, reducing swelling and relieving pain, killing parasites, reducing inflammation, and detoxifying. In 1972, American scientist Kupchan isolated triptolide (compound 2) and triptonide (compound 3) from the Tripterygium wilfordii plant. Subsequent studies have shown that these two compounds have good anti-tumor, immunosuppressive, and anti-inflammatory activities. Recent studies have shown that triptonide can be used as a potential non-hormonal male contraceptive. The complex molecular structure and good biological activity make triptolide a hot topic in synthetic chemistry and medicinal chemistry. However, the content of triptolide in the plant Tripterygium wilfordii is extremely low, with an isolation yield of only about 0.001%, which limits the development of related research. Therefore, developing efficient chemical synthesis routes to prepare these precious compounds is of great significance.

[0003]

[0004] In 1980, Berchtold's group reported the first total synthesis of triptolide (J. Am. Chem. Soc. 1980, 102, 1200.). They used 6-methoxy-1-naphthoquinone as the starting material, constructing a full-carbon quaternary carbon center at the C10 position via alkylation. Then, through intramolecular Aldol and lactone reactions, they formed the molecular skeleton. Subsequent adjustments to the oxidation state completed the total synthesis of triptolide. This method has significant academic value, but due to its lengthy route, expensive starting materials, and limitation to the synthesis of racemic products, it lacks practical application.

[0005]

[0006] In 1999, Yang Dan's research group completed the first asymmetric total synthesis of triptolide (J. Am. Chem. Soc. 1999, 121, 5579.). They used 2-isopropylphenol as the starting material, and after a multi-step carbon chain propagation reaction, it condensed with 8-phenylmenthol to obtain a chiral ester compound. This compound reacted with manganese acetate to undergo a tandem radical cyclization reaction to obtain a tricyclic compound. Subsequently, an unsaturated lactone ring was constructed through ester reduction and palladium-catalyzed cyclization carbonylation reaction, completing the construction of the tetracyclic skeleton. This synthetic route is lengthy, involves harsh reaction conditions for radical cyclization, and uses expensive reagents such as 8-phenylmenthol, making it difficult to prepare large quantities of the compound.

[0007]

[0008] In 2010, Li Yuanchao's research group reported a synthetic route using rosin acid as a starting material (Tetrahedron 2007, 63, 11204). They aromatized the isopropyl-containing six-membered ring of rosin acid through multiple transformations, and then constructed an unsaturated lactone ring. Although rosin acid is inexpensive, the route is lengthy, and the reagents used, such as osmium tetroxide, are highly toxic heavy metal reagents, expensive, and difficult to obtain, limiting the application of this method in industrial-scale preparation.

[0009]

[0010] In 2014, Li Ying's group reported a novel method for synthesizing the triptolide skeleton (Org. Biomol. Chem. 2014, 12, 732.). Using 5-methoxy-1-methylnaphthoquinone as a starting material, they constructed two key chiral centers through a chiral phenethylamine-induced asymmetric Robinson cyclization reaction and substrate-controlled selective reduction of the double bond. Subsequently, an unsaturated lactone ring was constructed via palladium-catalyzed carbonyl insertion cyclization, and an isopropyl group was introduced via a Friedel-Crafts reaction to complete the molecular skeleton construction. However, the raw materials used in this route, such as 5-methoxy-1-methylnaphthoquinone, are not commercially available, require multiple reaction steps, and have a long overall route, making them difficult to apply to industrial production.

[0011]

[0012] Over the past forty years, more than twenty synthetic routes for the total synthesis of triptolide (compound 2) have been reported. However, due to the long routes, low yields, and expensive materials, none of these routes have been suitable for industrial production. Therefore, developing novel and industrially feasible synthetic routes for triptolide is of great significance. Summary of the Invention

[0013] The purpose of this invention is to provide a method for preparing 7-oxorepinel lactone (compound 1) with high yield, low cost, and simple convenience.

[0014] Another object of the present invention is to provide an intermediate for the preparation of 7-oxorepinel lactone (compound 1).

[0015] In a first aspect of the present invention, a method for preparing 7-oxorepinel lactone is provided, the method comprising the following steps:

[0016] (a) Compound 4 was mixed with a first oxidizing agent in a first solvent and benzylic oxidizing to give compound 5.

[0017]

[0018] In another preferred embodiment, compound 4 is prepared from dehydrorosinic acid as a starting material through a seven-step conversion process according to the method reported in the literature (Tetrahedron 2021,85,132031; Heterocycles 1997,44,95).

[0019] In another preferred embodiment, the first oxidant is selected from the group consisting of: selenium dioxide, chromium trioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, potassium dichromate, cerium ammonium nitrate, cerium trifluoromethanesulfonate, 2-iodobenzoic acid, Desmond-Martin reagent, copper bromide, ketone sulfate, pyridine chlorochromate, 3,5-dimethylpyrazole, pyridine dichlorochromate, diphenyldiselenes, iodobenzoylbenzene, sodium dichromate, chromium hexacarbonyl, peroxytert-butanol, palladium on carbon, palladium hydroxide on carbon, manganese acetate, palladium acetate, cuprous bromide, cuprous iodide, cobalt acetylacetonate, oxygen, ruthenium trichloride, iodobenzoyl acetate, and trifluoroacetyliodobenzoylbenzene; preferably selenium dioxide, chromium trioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, potassium dichromate, cerium ammonium nitrate, or combinations thereof.

[0020] In another preferred embodiment, the first oxidant is chromium trioxide.

[0021] In another preferred embodiment, the equivalence ratio of the first oxidant to compound 4 is 0.1-5.0, preferably 1.0-5.0, and more preferably 2.0-2.5.

[0022] In another preferred embodiment, the first solvent is selected from the group consisting of acetic acid, water, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, benzene, ethyl acetate, or combinations thereof, preferably dichloromethane, 1,4-dioxane, acetonitrile, or combinations thereof.

[0023] In another preferred embodiment, the first solvent is a mixed solvent, preferably a mixed solvent of water and an organic solvent, and more preferably a mixed solvent of water and acetic acid.

[0024] In another preferred embodiment, the volume ratio of water to organic solvent in the first solvent is 0.8-1.2:0.8-1.2, preferably 1:1.

[0025] In another preferred embodiment, step (a) is performed at 15-40°C.

[0026] In another preferred embodiment, the reaction time of step (a) is 8-16 hours.

[0027] (b) In a second solvent, compound 5 undergoes a condensation reaction with a hydroxylamine compound to give compound 6.

[0028]

[0029] Among them, R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl;

[0030] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl, more preferably C1-C3 alkyl.

[0031] In another preferred embodiment, the hydroxylamine compound is selected from the group consisting of: methoxyamine or a salt thereof, ethoxyamine or a salt thereof, propoxyamine or a salt thereof, hydroxylamine or a salt thereof, hydroxylamine formate or a salt thereof, hydroxylamine acetate or a salt thereof, or combinations thereof.

[0032] In another preferred embodiment, the equivalence ratio of the hydroxylamine compound to compound 5 is 1.0-5.0, more preferably 1.5-3.0.

[0033] In another preferred embodiment, the second solvent is selected from the group consisting of pyridine, 2,6-dimethylpyridine, methanol, ethanol, isopropanol, tert-butanol, acetic acid, trifluoroacetic acid, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, benzene, ethyl acetate, or combinations thereof; preferably pyridine, methanol, acetonitrile, or combinations thereof.

[0034] In another preferred embodiment, step (b) is performed at 15-80°C.

[0035] In another preferred embodiment, the reaction time of step (b) is 6-18 hours.

[0036] In another preferred embodiment, when the hydroxylamine compound is hydroxylamine, step (b) further includes:

[0037] (b.1) The obtained oxime compound 6-1 was mixed with an esterifying agent and subjected to an esterification reaction to obtain compound 6.

[0038]

[0039] Among them, R 1 Selected from the following group: C1-C6 alkyl acyl or C6-C10 aryl acyl.

[0040] In another preferred embodiment, the esterifying agent is an acid anhydride, such as acetic anhydride.

[0041] In another preferred embodiment, the esterifying agent to oxime compound 6-1 has an equivalent ratio of 5-20, more preferably 8-12, and even more preferably 8-10.

[0042] In another preferred embodiment, step (b.1) also requires the addition of a first catalyst, such as DMAP.

[0043] In another preferred embodiment, in step (b.1), the equivalence ratio of the first catalyst to the compound 6-1 is 0.05-0.5, preferably 0.05-0.1.

[0044] In another preferred embodiment, step (b.1) is performed at 15-40°C.

[0045] In another preferred embodiment, the reaction time of step (b.1) is 1-3 hours.

[0046] (c) In a third solvent, under the action of a second catalyst, compound 6 is mixed with a second oxidant and optionally a ligand to undergo an oxidation reaction to give compound 7.

[0047]

[0048] Where R 2 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl;

[0049] In another preferred embodiment, R 2 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl, more preferably C1-C3 alkyl or C1-C3 alkyl acyl.

[0050] In another preferred embodiment, R 1 and R 2 Whether they are the same or different, the different ones are preferred.

[0051] In another preferred embodiment, the second oxidant is selected from the group consisting of hydrogen peroxide, potassium persulfate, potassium peroxymonosulfate, potassium peroxymonosulfate, potassium peroxymonosulfonate, (diacetoxyiodine)benzene, trifluoroacetyliodobenzene, benzoquinone, copper acetate, oxygen, or combinations thereof, preferably potassium peroxymonosulfonate or (diacetoxyiodine)benzene.

[0052] In another preferred embodiment, the equivalence ratio of the second oxidant to compound 6 is 1-5, preferably 1-2.

[0053] In another preferred embodiment, the second catalyst is selected from the group consisting of palladium acetate, palladium trifluoroacetate, palladium chloride, or palladium neopentanoate, preferably palladium acetate.

[0054] In another preferred embodiment, the equivalence ratio of compound 6 to the second catalyst is 5-100, more preferably 10-30.

[0055] In another preferred embodiment, the ligand is selected from the group consisting of triphenylphosphine, dimethyl azodicarbonate, diethyl azodicarbonate, or diisopropyl azodicarbonate, or combinations thereof, preferably triphenylphosphine.

[0056] In another preferred embodiment, the equivalence ratio of compound 6 to the ligand is 5-100, more preferably 10-30.

[0057] In another preferred embodiment, the third solvent is selected from the group consisting of acetic acid, acetic anhydride, trifluoroacetic acid, methanol, ethanol, isopropanol, tert-butanol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, benzene, ethyl acetate, or combinations thereof; preferably acetic acid, acetic anhydride, 1,1,2,2-tetrachloroethane, trifluoroacetic acid, methanol, or combinations thereof.

[0058] In another preferred embodiment, step (c) is performed at 60-100°C.

[0059] In another preferred embodiment, the reaction time of step (c) is 4-24 hours.

[0060] (d) In a fourth solvent, compound 7 was mixed with a hydrolysis reagent to give compound 1.

[0061]

[0062] In another preferred embodiment, the hydrolysis reagent is an acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, trifluoroacetic acid, zinc chloride, boron trifluoride ether, lithium chloride, ferric chloride, cerium trichloride or cobalt dichloride, or combinations thereof; preferably concentrated hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, or combinations thereof.

[0063] In another preferred embodiment, the mass-to-volume ratio of the hydrolysis reagent to compound 7 is 0.05-0.2 g / mL, preferably 0.05-0.1 g / mL.

[0064] In another preferred embodiment, the fourth solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, toluene, acetonitrile, water, DMSO, tetrahydrofuran, 1,4-dioxane, ethyl acetate, or combinations thereof; preferably methanol, tetrahydrofuran, 1,4-dioxane, or combinations thereof.

[0065] In another preferred embodiment, step (d) is performed at 60-120°C, preferably 100°C.

[0066] In another preferred embodiment, the reaction time for step (d) is 8-16 hours.

[0067] In a second aspect of the invention, a compound is provided having the following structure:

[0068]

[0069] Among them, R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl;

[0070] R 2 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl.

[0071] In another preferred embodiment, R 1 and R 2 Whether they are the same or different, the different ones are preferred.

[0072] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl, more preferably C1-C3 alkyl.

[0073] In another preferred embodiment, R 2 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl, more preferably C1-C3 alkyl or C1-C3 alkyl acyl.

[0074] In another preferred embodiment, the compound is selected from the group consisting of:

[0075]

[0076] In a third aspect of the invention, use of the compounds as described in the second aspect of the invention is provided, said compounds being used to prepare 7-oxorepôt, triptolide, and triptolide ketone.

[0077] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0078] Through extensive and in-depth research, the inventors have unexpectedly discovered a novel asymmetric synthetic route for the synthesis of 7-oxorepinel lactone. This method boasts high yield, simplicity, convenience, efficiency, and low raw material costs, making it highly suitable for industrial production and possessing excellent economic value. Based on this discovery, the inventors have completed this invention.

[0079] the term

[0080] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0081] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0082] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0083] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0084] As used herein, the terms “multiple” or “more than” refer to two or more species, such as 2, 3, 4, 5 or 6 species.

[0085] As used herein, the term "equivalent ratio" refers to the molar equivalent ratio, preferably the molar ratio.

[0086] As used herein, the term “C1-C6 alkyl” refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., or similar groups.

[0087] As used herein, the term "aryl" refers to a C6-C10 aromatic group, such as phenyl or naphthyl, that is unsubstituted or substituted by one or more (e.g., 2, 3, 4, or 5) atoms or groups selected from the following: halogen, nitro, hydroxyl, amino, cyano, haloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C2-C6 alkanoyl, and substituted or unsubstituted C2-C6 alkanoamide.

[0088] As used herein, the term “C1-C6 alkyl acyl” refers to -(C=O)-C1-C6 alkyl, wherein the “C1-C6 alkyl” is as described above, for example, methyl acyl, ethyl acyl, propyl acyl, isopropyl acyl, butyl acyl, isobutyl acyl, sec-butyl acyl, tert-butyl acyl, etc., or similar groups.

[0089] As used herein, the term "hydroxylamine compounds" refers to compounds having a hydroxylamine (H2N-OH)-like structure, such as alkoxyamines (H2N-OR).

[0090] Preparation method

[0091] This invention provides a method for preparing 7-oxorepinel lactone, the process of which is shown below:

[0092]

[0093] The preparation method of compound 1 involved in this invention includes the following steps: compound 4 is first subjected to benzylic oxidation to obtain compound 5, which is then condensed with a hydroxylamine compound to generate compound 6, and then subjected to directed sp... 2 Oxidation of the CH bond yields compound 7, which is then followed by oxime hydrolysis and desubstituenting of the phenolic hydroxyl group to give compound 1.

[0094] Compound 4 can be obtained from commercially available dehydrorosin acid through a seven-step transformation using methods reported in the literature (Tetrahedron 2021, 85, 132031; Heterocycles 1997, 44, 95). Dehydrorosin acid is inexpensive and readily available, therefore the synthetic route of this invention has a significant economic advantage and better commercialization prospects compared to other reported routes.

[0095] a. Compound 4 is subjected to benzylic oxidation to obtain compound 5.

[0096]

[0097] The oxidants used in the benign oxidation include selenium dioxide, chromium trioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, potassium dichromate, cerium ammonium nitrate, cerium trifluoromethanesulfonate, 2-iodobenzoic acid, Desmond-Martin reagent, copper bromide, ketone sulfate, pyridine chlorochromate, 3,5-dimethylpyrazole, pyridine dichlorochromate, diphenyldiselenes, iodobenzoylbenzene, sodium dichromate, chromium hexacarbonyl, tert-butanol peroxide, palladium on carbon, palladium hydroxide on carbon, manganese acetate, palladium acetate, cuprous bromide, cuprous iodide, cobalt acetylacetonate, oxygen, ruthenium trichloride, iodobenzoyl acetate, and trifluoroacetyliodobenzoylbenzene; the optimal choices are selenium dioxide, chromium trioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, potassium dichromate, and cerium ammonium nitrate. The amount of oxidant used is 0.1-5.0 equivalents.

[0098] The solvent used may be dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, benzene, ethyl acetate, or a mixture of any two of the above solvents; the optimal choice is dichloromethane, 1,4-dioxane, acetonitrile, or a mixture of any two of the above solvents.

[0099] b. Condensate compound 5 with hydroxylamine compounds to form oxime ethers or oxime esters.

[0100]

[0101] Where R 1 It can be hydrogen, alkyl, aryl, alkyl acyl or aryl acyl.

[0102] The condensation-promoting agent used can be an organic base, inorganic base, organic acid, or inorganic acid. The amount of condensation agent used is 1.0-3.0 equivalents.

[0103] The solvents used may be pyridine, 2,6-dimethylpyridine, methanol, ethanol, isopropanol, tert-butanol, acetic acid, trifluoroacetic acid, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, benzene, ethyl acetate; the optimal choices are pyridine, methanol, acetonitrile, or a mixture of any two of the above solvents.

[0104] c. Oxidation of compound 6 yields compound 7

[0105]

[0106] Where R 2 It can be hydrogen, alkyl, aryl, alkyl acyl or aryl acyl.

[0107] The catalyst used to promote the oxidation reaction can be palladium acetate, palladium trifluoroacetate, palladium chloride, or palladium neopentanoate. The amount of catalyst used is 0.01-1.0 equivalents.

[0108] The ligands used are triphenylphosphine, dimethyl azodicarbonate, diethyl azodicarbonate, or diisopropyl azodicarbonate. The amount of ligand used is 0.01-1.0 equivalents.

[0109] The oxidizing agent used can be hydrogen peroxide, potassium persulfate, potassium monopersulfate, potassium persulfate, acetoiodobenzene, trifluoroacetoiodobenzene, benzoquinone, copper acetate, or oxygen. The amount of oxidizing agent used is 1.0-5.0 equivalents.

[0110] The solvent used can be acetic acid, acetic anhydride, trifluoroacetic acid, methanol, ethanol, isopropanol, tert-butanol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, benzene, or ethyl acetate; the optimal choices are acetic acid, trifluoroacetic acid, methanol, or a mixture of any two of the above. d. Compound 7 is hydrolyzed by oxime and the substituents on the phenolic hydroxyl group are removed to obtain compound 1.

[0111]

[0112] The acid that promotes this reaction can be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, trifluoroacetic acid, zinc chloride, boron trifluoride ether, lithium chloride, ferric chloride, cerium trichloride, or cobalt dichloride, preferably hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid. The amount of acid used is 1.0-5.0 equivalents.

[0113] The solvent used can be methanol, ethanol, isopropanol, tert-butanol, toluene, acetonitrile, water, DMSO, tetrahydrofuran, ethyl 1,4-dioxane, preferably methanol, tetrahydrofuran, 1,4-dioxane, or a mixture of any two of the above.

[0114] The main advantages of this invention include:

[0115] (a) This invention uses a novel approach to synthesize the key intermediate (compound 1);

[0116] (b) The method of the present invention has high yield and simple and efficient steps.

[0117] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0118] Example 1: Preparation of Compound 5

[0119]

[0120] Dissolve 4 (2 g, 6.8 mmol) in a mixed solvent of acetic acid (30 mL) and water (30 mL), add chromium trioxide (1.7 g, 17 mmol) under ice bath conditions, and stir overnight at room temperature. Dilute with ethyl acetate, wash with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dry to anhydrous sodium sulfate. Filter and concentrate to obtain the crude product, which is then purified by column chromatography with Hex:EA = 10:1-5:1 eluent to give product 5 (1.2 g, 3.9 mmol), yield 57%. 1 H NMR (400MHz, CDCl3) δ7.95 (d, J=2.1Hz, 1H), 7.47 (dd, J=8.1, 2.1Hz, 1H), 7.41 (d ,J=8.1Hz,1H),4.86–4.72(m,2H),3.29–3.18(m,1H),2.96(p,J=6.9Hz,1H),2.78 (s,1H),2.75(d,J=3.8Hz,1H),2.60(dd,J=13.4,6.1Hz,2H),2.44(ddt,J=14.9,7 .7,3.7Hz,1H),1.83(td,J=12.4,6.4Hz,1H),1.27(d,J=6.9Hz,6H),1.16(s,3H); 13 C NMR (100MHz, CDCl3) δ195.7,173.4,160.2,148.8,147.9,132.8,131.0,126.3,1 25.9,123.7,70.0,40.8,36.4,33.7,31.6,23.8,23.7,21.8,17.8; MS(ESI):m / z calcd for C 20 H 23 O3+,[M+H]+:311.2,found:311.3.

[0121] Example 2: Preparation of compound 6a

[0122]

[0123] Compound 5 (7.2 g, 23.2 mmol) and methoxyamine hydrochloride (3.8 g, 45.8 mmol) were dissolved in methanol (209 mL), and then pyridine (4.0 g, 50.6 mmol) was added dropwise. The reaction was carried out at room temperature for six hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by purification by column chromatography with Hex:EA = 20:1-10:1 to give product 6a (6.7 g, 19.7 mmol), in 85% yield. 1 H NMR (400MHz, CDCl3) δ7.84(d,J=1.9Hz,1H),7.29(d,J=8.1Hz,1H),7.24(dd,J=8.1,1.9 Hz,1H),4.90–4.72(m,2H),4.04(s,3H),3.00(dd,J=18.1,5.3Hz,1H),2.94(p,J=6.9Hz ,1H),2.80–2.69(m,1H),2.62–2.48(m,3H),2.38(dddd,J=15.3,12.0,7.7,3.3Hz,1H), 1.76(td,J=12.4,6.5Hz,1H),1.27(d,J=7.0Hz,3H),1.27(d,J=7.0Hz,3H),1.00(s,3H). 13 C NMR (100MHz, CDCl3) δ173.7,161.1,152.1,147.4,144.2,129.1,127.8,125.6,123 .3,123.1,70.3,62.3,38.9,35.9,33.8,31.5,24.1,23.7,20.6,17.7.MS(ESI):m / z calcd for C 21 H 26 NO3 + [M+H] + :340.2,found:340.2.

[0124] Example 3: Preparation of compound 6b

[0125]

[0126] Compound 5 (2.3 g, 7.4 mmol) and hydroxylamine hydrochloride (1.5 g, 22.2 mmol) were dissolved in pyridine (20 mL), and the mixture was heated to 80 °C and reacted overnight. After cooling to room temperature, DMAP (90 mg, 0.74 mmol) and acetic anhydride (7 mL, 74 mmol) were added. After reacting at room temperature for two hours, the mixture was diluted with ethyl acetate, washed with water, 1N hydrochloric acid aqueous solution, saturated copper sulfate aqueous solution, saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by column chromatography purification with Hex:EA as the eluent (3:1-2:1) to give product 6b (2.4 g, 6.6 mmol), in 89% yield. 1 H NMR(400MHz,DMSO-d6)δ7.83(d,J=1.9Hz,1H),7.49–7.38(m,2H),5.07–4.84(m ,2H),3.20(dd,J=16.9,3.6Hz,1H),2.93(p,J=6.9Hz,1H),2.87–2.82(m,1H),2 .83–2.71(m,1H),2.59–2.47(m,2H),2.44–2.32(m,1H),2.26(s,3H),1.68(td, J=12.2,6.3Hz,1H),1.21(d,J=6.9Hz,3H),1.21(d,J=6.9Hz,3H),0.92(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.3,168.4,162.0,160.1,146.7,146.5,129.5,127.5,123.9,12 3.6,123.3,70.4,38.2,35.5,33.1,30.8,24.0,23.9,23.7,20.7,19.7,17.3.MS(ESI):m / z calcd for C 22 H 26 NO4 + [M+H] + :368.2,found:368.3.

[0127] Example 4: Preparation of compound 7a

[0128]

[0129] Compound 6a (6.7 g, 19.7 mmol) was dissolved in HOAc (67 mL) and Ac₂O (67 mL), then Pd(OAc)₂ (0.44 g, 1.97 mmol) and PhI(OAc)₂ (12.7 g, 39.4 mmol) were added, and the mixture was heated to 90 °C for four hours. After cooling to room temperature, the solvent was removed by rotary evaporation. The residue was diluted with ethyl acetate, neutralized with saturated sodium bicarbonate aqueous solution, separated, and washed once with saturated sodium chloride aqueous solution. The solution was dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by column chromatography purification with Hex:EA = 10:1-5:1-3:1 as the eluent, yielding compound 7a (7.2 g, 18.1 mmol), in 92% yield. 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.2Hz,1H),7.24(d,J=8.2Hz,1H),4.92–4. 66(m,2H),4.00(s,3H),3.22–3.07(m,0.5H),3.05–2.91(m,0.5H),2.91–2.7 8(m,1H),2.77–2.43(m,4H),2.42–2.35(m,1H),2.32(s,3H),1.83–1.70(m, 1H),1.25(d,J=6.9Hz,3H),1.16(d,J=6.9Hz,3H),1.00(s,3H).MS(ESI):m / z calcd for C 23 H 28 NO5 + [M+H] + :398.2,found:398.3.

[0130] Example 5: Preparation of compound 7b

[0131]

[0132] Compound 6a (242 mg, 0.7 mmol), Pd(OAc)₂ (8 mg, 0.036 mmol), PPh₃ (18.3 mg, 0.07 mmol), and Oxone (potassium peroxymonosulfonate) (516 mg, 0.84 mmol) were dissolved in 1,1,2,2-tetrachloroethane (2.0 mL), and the mixture was heated to 100 °C and reacted for 24 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by column chromatography purification with Hex:EA = 10:1-5:1-3:1 as the eluent, yielding product 7b (185 mg, 0.52 mmol), in 74% yield. 1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),7.22(d,J=8.0Hz,1H),6.94(d,J=8.0Hz,1H),4.94(d t,J=3.4,2.0Hz,2H),4.02(s,3H),3.32–3.24(m,1H),3.21(dd,J=18.3,4.9Hz,1H),2.83(d ,J=14.3Hz,1H),2.69–2.58(m,1H),2.48–2.43(m,1H),2.42–2.29(m,1H),2.30–2.14(m,1H ),1.66(td,J=12.2,6.3Hz,1H),1.19(d,J=6.9Hz,3H),1.17(d,J=6.9Hz,3H),0.91(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.3,162.4,157.8,155.1,146.1,133.6,127.6,123.6,114.0 ,111.7,70.4,62.5,37.7,35.5,31.1,26.1,23.2,22.4,22.3,21.0,17.3.MS(ESI):m / z calcd for C 21 H 26 NO4 + [M+H] + :356.2,found:356.3.

[0133] Example 6: Preparation of compound 7c

[0134]

[0135] Compound 6a (580 mg, 1.7 mmol), Pd(OAc)₂ (38.2 mg, 0.17 mmol), and Oxone (potassium peroxymonosulfonate) (2.1 g, 3.4 mmol) were dissolved in methanol (9.0 mL), and the mixture was heated to 80 °C for six hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by column chromatography purification with Hex:EA = 10:1-5:1-3:1 as the eluent, yielding product 7c (475 mg, 0.52 mmol), in 76% yield. 1H NMR(400MHz, DMSO-d6)δ7.30(d,J=8.1Hz,1H),7.16(d,J=8.2Hz,1H),5.00–4.78(m,2H),3. 95(s,3H),3.68(s,3H),3.32–3.26(m,1H),2.89(dd,J=18.0,6.2Hz,1H),2.78–2.68(m,1H) ,2.62(d,J=13.6Hz,1H),2.45(dd,J=13.0,5.7Hz,1H),2.40–2.29(m,1H),2.28–2.13(m,1H ),1.63(td,J=12.2,6.2Hz,1H),1.21(d,J=7.0Hz,3H),1.15(d,J=6.9Hz,3H),0.88(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.4,162.5,155.3,151.2,147.5,140.4,127.1,123.3,122.2 ,118.6,70.4,61.7,38.0,36.1,31.4,25.9,24.1,24.0,23.3,19.4,17.2.MS(ESI):m / z calcd for C 22 H 28 NO4 + [M+H] + :370.2,found:370.2.

[0136] Example 7: Preparation of Compound 1

[0137]

[0138] Compound 7a (6.7 g, 16.9 mmol) was dissolved in 1,4-dioxane (80 mL), and concentrated hydrochloric acid (80 mL) was added. The mixture was heated to 100 °C and reacted overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed once with water, once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by purification by column chromatography with Hex:EA = 10:1-5:1-3:1 as the eluent, yielding product 1 (5.4 g, 16.6 mmol), in 98% yield. 1H NMR (400MHz, CDCl3) δ13.04(s,1H),7.42(d,J=7.9Hz,1H),6.88(d,J=7.9Hz,1H),4.8 5–4.69(m,2H),3.35(hept,J=7.0Hz,1H),3.25–3.10(m,1H),2.80(d,J=5.2Hz,1H),2. 78(s,1H),2.55(td,J=15.1,13.5,9.4Hz,2H),2.41(tdd,J=14.8,6.5,3.1Hz,1H),1. 81(td,J=12.5,6.6Hz,1H),1.24(d,J=7.1Hz,3H),1.23(d,J=7.1Hz,3H),1.14(s,3H); 13 C NMR (100MHz, CDCl3) δ202.2,173.3,161.7,159.6,149.1,136.1,133.7,126.1,114 .7,113.6,69.9,40.4,36.5,36.4,31.6,26.2,22.2,22.1,21.7,17.8; MS(ESI):m / z calcd for C 20 H 23 O4 + [M+H] + :327.2,found:327.2.

[0139] Example 8: Preparation of Compound 1

[0140]

[0141] Compound 7b (152 mg, 0.43 mmol) was dissolved in 1,4-dioxane (2 mL), and concentrated hydrochloric acid (2 mL) was added. The mixture was heated to 100 °C and reacted overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed once with water, once with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, followed by purification by column chromatography with Hex:EA = 10:1-5:1-3:1 as the eluent, yielding product 1 (98 mg, 0.3 mmol), in 70% yield.

[0142] The overall yield from compound 4 to compound 1 reached 43.68%.

[0143] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing 7-oxorepinel lactone, characterized in that, The method includes the following steps: (a) Compound 4 was mixed with a first oxidizing agent in a first solvent and benzylic oxidized to give compound 5. ； The first oxidant is selected from the group consisting of: selenium dioxide, chromium trioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, potassium dichromate, cerium ammonium nitrate, cerium trifluoromethanesulfonate, 2-iodobenzoic acid, Dys-Martin reagent, copper bromide, copper sulfate, pyridine chlorochromate, 3,5-dimethylpyrazole, pyridine dichlorochromate, diphenyldiselenes, iodobenzoyl dichromate, sodium dichromate, chromium hexacarbonyl, peroxytert-butanol, palladium on carbon, palladium hydroxide on carbon, manganese acetate, palladium acetate, cuprous bromide, cuprous iodide, cobalt acetylacetonate, oxygen, ruthenium trichloride, iodobenzoic acid acetate, and trifluoroacetyliodobenzoic acid. The first solvent is selected from the group consisting of acetic acid, water, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, benzene, ethyl acetate, or combinations thereof. (b) In the second solvent, compound 5 undergoes a condensation reaction with a hydroxylamine compound to give compound 6. ； Among them, R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl; The second solvent is selected from the group consisting of: pyridine, 2,6-dimethylpyridine, methanol, ethanol, isopropanol, tert-butanol, acetic acid, trifluoroacetic acid, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, benzene, ethyl acetate, or combinations thereof; (c) In a third solvent, under the action of a second catalyst, compound 6 is mixed with a second oxidant and optionally a ligand to undergo an oxidation reaction to give compound 7. ； Where R 2 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl; The second oxidant is selected from the group consisting of hydrogen peroxide, potassium persulfate, potassium peroxymonosulfate, potassium peroxymonosulfate, potassium peroxymonosulfonate, (diacetoxyiodine)benzene, trifluoroacetyliodobenzene, benzoquinone, copper acetate, oxygen, or combinations thereof; The ligand is selected from the group consisting of triphenylphosphine, dimethyl azodicarbonate, diethyl azodicarbonate, or diisopropyl azodicarbonate, or combinations thereof. The second catalyst is selected from the group consisting of palladium acetate, palladium trifluoroacetate, palladium chloride, or palladium neopentanoate; The third solvent is selected from the group consisting of: acetic acid, acetic anhydride, trifluoroacetic acid, methanol, ethanol, isopropanol, tert-butanol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, acetonitrile, water, DMSO, DMF, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetone, pyridine, benzene, ethyl acetate, or combinations thereof; (d) In a fourth solvent, compound 7 was mixed with a hydrolysis reagent to give compound 1. The fourth solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, toluene, acetonitrile, water, DMSO, tetrahydrofuran, 1,4-dioxane, ethyl acetate, or combinations thereof.

2. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, When the hydroxylamine compound is hydroxylamine, step (b) further includes: (b.1) The obtained oxime compound 6-1 was mixed with an esterifying agent and subjected to an esterification reaction to obtain compound 6. ； Among them, R 1 Selected from the following group: C1-C6 alkyl acyl or C6-C10 aryl acyl.

3. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, R 1 Selected from the following group: hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl; R 2 Selected from the following group: hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl.

4. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, R 1 It is a C1-C3 alkyl group; R 2 It is a C1-C3 alkyl or C1-C3 alkyl acyl group.

5. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, Step (a) has one or more features selected from the group consisting of: (i) The first oxidant is selected from the group consisting of oxygen, selenium dioxide, chromium trioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, potassium dichromate, cerium ammonium nitrate, or combinations thereof; (ii) The equivalence ratio of the first oxidant to compound 4 is 0.1-5.0; (iii) Step (a) is performed at 15-40°C; (iv) The reaction time for step (a) is 8-16 h.

6. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, In step (a), the equivalence ratio of the first oxidant to compound 4 is 0.1-5.

0.

7. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, The first solvent is a mixed solvent.

8. The method for preparing 7-oxorepinel lactone according to claim 7, characterized in that, The first solvent is a mixture of water and organic solvent.

9. The method for preparing 7-oxorepinel lactone according to claim 7, characterized in that, The first solvent is a mixture of water and acetic acid.

10. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, Step (b) has one or more features selected from the group consisting of: (i) The hydroxylamine compound is selected from the group consisting of: methoxyamine or a salt thereof, ethoxyamine or a salt thereof, propoxyamine or a salt thereof, hydroxylamine or a salt thereof, hydroxylamine formate or a salt thereof, hydroxylamine acetate or a salt thereof, or combinations thereof; (ii) The equivalent ratio of the hydroxylamine compound to compound 5 is 1.0-5.0; (iii) Step (b) is performed at 15-80°C; (iv) The reaction time for step (b) is 6-18 hours.

11. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, In step (b), the equivalence ratio of the hydroxylamine compound to compound 5 is 1.5-3.

0.

12. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, Step (b.1) has one or more features selected from the group consisting of: (i) The esterification reagent is an acid anhydride; (ii) The equivalence ratio of the esterifying agent to oxime compound 6-1 is 5-20; (iii) Step (b.1) also requires the addition of a first catalyst, namely DMAP; Wherein, the equivalence ratio of the first catalyst to compound 6-1 is 0.05-0.5; (iv) Step (b.1) is performed at 15-40°C; (v) The reaction time for step (b.1) is 1-3 hours.

13. The method for preparing 7-oxorepinel lactone according to claim 11, characterized in that, Step (b.1) has one or more features selected from the group consisting of: (i) The esterification reagent is acetic anhydride; (ii) The equivalence ratio of the esterifying agent to oxime compound 6-1 is 8-12; (iii) The equivalent ratio of the first catalyst to compound 6-1 is 0.05-0.

1.

14. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, Step (c) has one or more features selected from the group consisting of: (i) The second oxidant is selected from the group consisting of: trifluoroacetyliodobenzene, potassium peroxymonosulfonate, or (diacetoxyiodo)benzene; (ii) The second catalyst is palladium acetate; (iii) The ligand is triphenylphosphine.

15. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, Step (c) has one or more features selected from the group consisting of: (i) The equivalence ratio of compound 6 to the ligand is 5-100; (ii) The third solvent is selected from the group consisting of acetic acid, acetic anhydride, 1,1,2,2-tetrachloroethane, trifluoroacetic acid, methanol, or combinations thereof; (iii) Step (c) is performed at 60-100°C; (iv) The reaction time for step (c) is 4-24 hours.

16. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, In step (c), the equivalence ratio of compound 6 to the ligand is 10-30.

17. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, Step (d) has one or more features selected from the group consisting of: (i) The hydrolysis reagent is an acid selected from the group consisting of: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, trifluoroacetic acid, zinc chloride, boron trifluoride ether, lithium chloride, ferric chloride, cerium trichloride or cobalt dichloride, or combinations thereof; (ii) The mass-to-volume ratio of the hydrolysis reagent to compound 7 is 0.05-0.2 g / mL; (iii) Step (d) is performed at 60-120°C; (iv) The reaction time for step (d) is 8-16 hours.

18. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, In step (d), the hydrolysis reagent is selected from the group consisting of hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid, or combinations thereof.

19. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, In step (d), the mass-to-volume ratio of the hydrolysis reagent to compound 7 is 0.05-0.1 g / mL.

20. The method for preparing 7-oxorepinel lactone according to claim 1, characterized in that, The fourth solvent is selected from the group consisting of methanol, tetrahydrofuran, 1,4-dioxane, or combinations thereof.

21. A compound, characterized in that, The compound has the following structure: or Among them, R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl; R 2 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl acyl, or C6-C10 aryl acyl.

22. The compound according to claim 21, characterized in that, R 1 Selected from the following group: hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl; R 2 Selected from the following group: hydrogen, C1-C4 alkyl, C1-C4 alkyl acyl.

23. The compound according to claim 21, characterized in that, R 1 It is a C1-C3 alkyl group; R 2 It is a C1-C3 alkyl or C1-C3 alkyl acyl group.

24. The compound according to claim 21, characterized in that, The compounds are selected from the group consisting of: ； ； ； 。 25. The use of the compound as claimed in claim 21, characterized in that, The compounds are used to prepare 7-oxo-repôtide, triptolide, and / or triptolide ketone.

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