A process for the preparation of 2,4-dihydroxy cyclohepta-2,4,6-trien-1-one

Abstract

This application discloses a method for preparing 2,4-dihydroxycyclohepta-2,4,6-trien-1-one. Addressing the technical problems of low yield and high cost of natural extraction of this compound in existing technologies, this application uses 1,1,3,3-tetramethoxypropane as the starting material. A dielyl structural unit is introduced via a coupling reaction mediated by potassium iodide and stannous chloride. A seven-membered carbon ring skeleton is then constructed in one step through hydroxysilyl protection and intramolecular olefin metathesis cyclization. Subsequently, a carbonyl group is introduced through allylic oxidation, followed by the removal of the silyl protecting group. Finally, the target product is obtained through an oxidative aromatization reaction. The synthetic route of this application is simple, with mild reaction conditions. The core coupling step uses a non-precious metal reaction system, and the raw materials and reagents are inexpensive and readily available. The reaction steps exhibit excellent selectivity, and the overall yield of the six-step linear synthesis is at a high level compared to similar total synthetic routes. The operation is simple and easy to scale up for production, providing a reliable technical solution for the pharmaceutical research and mass production of tropenophenone compounds.

Description

Technical Field

[0001] This application relates to the fields of medicinal chemistry and organic synthesis technology, specifically to a method for preparing 2,4-dihydroxycyclohepta-2,4,6-trien-1-one. Background Technology

[0002] Tolphenones are a class of naturally occurring seven-membered ring aromatic compounds with significant biological activity, mainly derived from fungal secondary metabolites. Most possess antibacterial, antiviral, insecticidal, and antitumor activities. 2,4-Dihydroxycyclohepta-2,4,6-trien-1-one (dihydroxytolphenone), as a member of the tolphenone family, shows promising potential in antibacterial, antitumor, and metal ion chelation activities.

[0003] Currently, existing technologies mainly rely on extraction and separation from plants, but the yield is extremely low and cannot meet the needs of drug development. Although chemical synthesis methods have been developed, many problems remain: First, the core seven-membered aromatic ring skeleton (cycloheptatrienone) differs significantly from the synthetic routes of conventional benzene aromatic compounds. Traditional ring expansion methods (such as the Büchner reaction) and oxidation methods have low yields and are prone to generating isomer byproducts, with the low yield problem being particularly prominent when scaled up. Second, classic multi-step synthetic routes often use hazardous reagents such as bromine and require operation under strong acid-base reflux conditions, resulting in harsh reaction conditions, difficulty in process safety control, and high energy consumption. Third, in the synthesis of polyhydroxytoluene, the position and number of hydroxyl groups introduced are difficult to control precisely. As the number of target substituents increases, the actual degree of substitution of the product is lower than expected, accompanied by the generation of a large number of byproducts. The yield of different products on the same route can fluctuate between 24% and 94%, with significantly insufficient selectivity and controllability. In addition, the separation and purification of the product from the starting materials, reagents, and halogen-containing byproducts is very difficult. Traditional methods require multiple operations such as crystallization, vacuum distillation, extraction, and even the formation of copper complexes followed by decomposition and regeneration, which are cumbersome and result in significant product loss.

[0004] Therefore, existing methods for preparing tropenophenone compounds mainly face problems such as low synthesis yield, harsh reaction conditions involving hazardous reagents, interference from isomer byproducts, and the use of expensive transition metal catalysts. Summary of the Invention

[0005] In view of the above-mentioned shortcomings of the prior art, the purpose of this application is to provide a method for preparing 2,4-dihydroxycyclohepta-2,4,6-trien-1-one, so as to solve the problems of low synthesis yield, harsh reaction conditions and use of expensive transition metal catalysts in the preparation methods of tropenophenone compounds in the prior art.

[0006] To solve the above-mentioned technical problems, this application adopts the following technical solution:

[0007] A method for preparing 2,4-dihydroxycyclohepta-2,4,6-trien-1-one, the specific synthetic route is as follows:

[0008] ;

[0009] In the formula, R is selected from tert-butyldimethylsilyl or methoxymethyl; X is selected from Cl, Br, and I.

[0010] Step 1: The compound of formula I undergoes a coupling reaction to obtain the compound of formula II;

[0011] Step 2: The compound of formula II is protected by protecting its two hydroxyl groups to obtain the compound of formula III;

[0012] Step 3: The compound of formula III undergoes an olefin metathesis reaction and cyclization under the action of Grubbs catalyst to generate compound of formula IV;

[0013] Step 4: Compound IV is oxidized at the allylic site to obtain compound V;

[0014] Step 5: Compound V is obtained by removing the TBS protecting group to obtain compound VI;

[0015] Step 6: The compound of formula VI is used to construct an aromatic seven-membered ring structure by oxidizing the hydroxyl group to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one.

[0016] Preferably, R is tert-butyldimethylsilyl and X is Br.

[0017] Preferably, the synthetic route is as follows:

[0018] .

[0019] Preferably, in step 1, the compound of formula I is used as a raw material and coupled with allyl bromide via KI or SnCl2 catalysis to generate compound of formula II; wherein, the molar ratio of each reagent is based on the amount of substance of compound of formula I, with KI molar equivalent of 3~6; SnCl2 molar equivalent of 3~6; allyl bromide molar equivalent of 1.5~4; the reaction solvent is tetrahydrofuran and water; the reaction temperature is 0℃~25℃; and the reaction time is 4 h~48 h.

[0020] Preferably, in step 2, the two hydroxyl groups of the compound of formula II are protected with TBSCl or imidazole to obtain the compound of formula III; wherein, the molar ratio of each reagent is based on the amount of substance of the compound of formula II, the molar equivalent of TBSCl is 2~3, the molar equivalent of imidazole is 2~4, the reaction solvent is dichloromethane, the reaction temperature is 0℃~25℃, and the reaction time is 4h~48h.

[0021] Preferably, in step 3, the compound of formula III undergoes intramolecular olefin metathesis cyclization under the action of a Grubbs catalyst to generate compound of formula IV; wherein, the molar ratio of each reagent is based on the amount of substance of compound of formula III, the molar equivalent of the Grubbs catalyst is 0.01~0.2; the reaction solvent is dichloromethane, the reaction temperature is 0℃~25℃; the reaction process is carried out in the dark under anhydrous and oxygen-free conditions; the reaction time is 4 h~12 h.

[0022] Preferably, in step 4, the compound of formula IV is subjected to allylic oxidation by sequentially adding TBHP and PDC as oxidants in the reaction solvent, and Celite diatomaceous earth is added to prevent PDC solid agglomeration, thereby generating compound of formula V; wherein, the molar ratio of each reagent is based on the amount of substance of compound of formula IV, the molar equivalent of TBHP is 2~4; the molar equivalent of PDC is 2~10; the molar ratio of Celite diatomaceous earth to PDC is (1:2)~(1:1); the reaction solvent is toluene; the reaction temperature is 25℃~120℃; and the reaction time is 24~72 h.

[0023] Preferably, in step 5, the compound of formula V is reacted in a reaction solvent with TBAF as the deprotecting agent to remove the TBS protecting group, thereby obtaining the compound of formula VI; wherein the molar ratio of each reagent is based on the amount of substance of the compound of formula V, the molar equivalent of TBAF is 2~3; the reaction solvent is dichloromethane; the reaction temperature is 0℃~25℃; and the reaction time is 6 h~24 h.

[0024] Preferably, in step 6, the compound of formula VI is oxidized to construct an aromatic seven-membered ring structure to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one; wherein the oxidant is CrO3, the molar ratio of the reagents is based on the amount of substance of the compound of formula VI, the molar equivalent of CrO3 is 1.5~3, the reaction solvent is a mixed solution of diethyl ether and dichloromethane, and the volume ratio of diethyl ether to dichloromethane is (3:1)~(1:1); the reaction temperature is 0~35℃, and the reaction time is 2 h~12 h.

[0025] Compared with the prior art, this application has the following beneficial effects:

[0026] 1. This application uses 1,1,3,3-tetramethoxypropane as the starting material and employs a non-precious metal system composed of potassium iodide and stannous chloride to mediate a coupling reaction to construct a diene chain intermediate. This avoids the use of expensive transition metal catalysts, effectively reducing the preparation costs of raw materials and catalysis, and solving the technical problems of existing technologies relying on high-value catalysts and having high production costs. A seven-membered carbon ring skeleton is constructed through a cyclization strategy combining hydroxyl silyl ether protection and intramolecular olefin metathesis. The reaction conditions are mild and the cyclization selectivity is excellent, eliminating the cumbersome functional group transformation steps in traditional seven-membered ring synthesis and solving the technical problems of lengthy synthetic routes and harsh reaction conditions in existing technologies. In the allylic oxidation step, an oxidation system using tert-butyl hydroperoxide and pyridine dichromate is employed, along with diatomaceous earth to optimize the dispersion state of the reaction system. This ensures the conversion efficiency of the allylic oxidation and simplifies the post-processing of solid-liquid separation, reducing the difficulty of process control.

[0027] 2. The synthetic route designed in this application adopts a linear synthetic logic, with each step being a conventional organic synthesis operation under normal pressure, requiring no special reaction equipment and facilitating large-scale production. The low-cost non-precious metal catalytic system and mild reaction conditions work together to further reduce the safety control requirements and equipment investment threshold during process scale-up; the highly selective cyclization and oxidation reactions are interconnected, effectively suppressing the formation of byproducts in each step, improving the yield of each step, and jointly ensuring the overall yield of the entire synthetic route, thus solving the technical problems of low overall yield and difficulty in large-scale preparation in existing technologies. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0029] Figure 1 This is a high-resolution mass spectrum of compound 6 (2,4-dihydroxycycloheptane-2,4,6-trien-1-one) prepared in Example 6 of this application. Detailed Implementation

[0030] The technical solutions of this application will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on this application are within the scope of protection of this application. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments used are not specified, they can be obtained commercially.

[0031] Unless otherwise specified in the specific circumstances, the numerical ranges listed herein include upper and lower limits, as well as all integers and fractions within those ranges, and are not limited to the specific values ​​listed when defining the range. For numerical ranges, endpoint values ​​of various ranges, endpoint values ​​of various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. The term "and / or" used herein is inclusive; for example, "A and / or B" means only A, or only B, or both A and B. Terms such as "about," "substantially the same," and similar expressions herein indicate that reasonable deviations are permissible.

[0032] I. A method for preparing 2,4-dihydroxycyclohepta-2,4,6-trien-1-one

[0033] To address the numerous shortcomings of existing techniques for preparing 2,4-dihydroxycyclohepten-2,4,6-trien-1-one, this application proposes a synthetic route based on the construction of a chain precursor and a seven-membered ring framework. Starting with 1,1,3,3-tetramethoxypropane, two allyl structural units are first introduced into the molecule via a coupling reaction mediated by potassium iodide and stannous chloride, yielding a chain-like diene intermediate containing dihydroxyl groups. The two hydroxyl groups of the intermediate are then protected with a tert-butyldimethylsilyl group, followed by intramolecular olefin metathesis to complete the cyclization of the seven-membered carbon ring. Subsequently, the allyl position within the ring is oxidized to introduce a carbonyl structure, and the silyl protecting group is removed to obtain a hydroxyl-substituted cycloheptenone intermediate. Finally, an oxidative aromatization reaction is performed to construct a seven-membered aromatic ring system, yielding the target product. The specific synthetic route is as follows:

[0034] ;

[0035] In the formula, R is selected from tert-butyldimethylsilyl or methoxymethyl; X is selected from Cl, Br, I; the Grubbs catalyst can be a first-generation Grubbs catalyst, a second-generation Grubbs catalyst, or a Hoveyda-Grubbs catalyst.

[0036] Step 1: The compound of formula I undergoes a coupling reaction to obtain the compound of formula II;

[0037] Step 2: The compound of formula II is protected by protecting its two hydroxyl groups to obtain the compound of formula III;

[0038] Step 3: The compound of formula III undergoes an olefin metathesis reaction and cyclization under the action of Grubbs catalyst to generate compound of formula IV;

[0039] Step 4: Compound IV is oxidized at the allylic site to obtain compound V;

[0040] Step 5: Compound V is obtained by removing the TBS protecting group to obtain compound VI;

[0041] Step 6: The compound of formula VI is used to construct an aromatic seven-membered ring structure by oxidizing the hydroxyl group to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one.

[0042] The preparation method described in this application has achieved many unexpected technical effects after practical application: the synthetic route uses commercially available conventional raw materials and reagents, and the total yield of the six-step linear synthesis process can reach more than 25%. Each step of the reaction is carried out in the conventional temperature range of atmospheric pressure, 0°C to solvent reflux, without the need for special reaction equipment such as ultra-low temperature and high pressure. Among them, the carbon-carbon coupling step can achieve a single-step separation yield of 90% using a reaction system composed of non-precious metal salts. The intramolecular olefin metathesis cyclization step can obtain a cyclization product yield of 93% using only the first-generation Grubbs catalyst. In the oxidation step, the addition of diatomaceous earth can improve the reaction system state and maintain stable conversion efficiency without introducing additional complex auxiliaries. The entire route completes the efficient construction of the seven-membered tropenone aromatic skeleton while abandoning the high-cost precious metal catalytic system and maintaining the simplicity of operation. The obtained product can be directly used for subsequent bioactivity testing and drug development after column chromatography purification, and has a very good application prospect.

[0043] In some embodiments of this application, R is tert-butyldimethylsilyl and X is Br.

[0044] In some embodiments of this application, the synthesis route is as follows:

[0045] .

[0046] In some embodiments of this application, in step 1, compound I (1,1,3,3-tetramethoxypropane) is used as a starting material and coupled with allyl bromide via KI or SnCl2 catalysis to generate compound II (nonadiene-4,6-diol). In this step, two allyl structural units are symmetrically introduced into the substrate molecule in a one-step reaction, simultaneously completing the acetal conversion to construct a nonadiene chain intermediate containing dihydroxyl groups. The single-step separation yield can reach 90%. The entire reaction does not require precious metal catalysis and can proceed stably at room temperature and pressure, thus solving the technical problems of existing technologies where the construction of diene chain precursors relies on expensive transition metal catalysis, the synthesis steps are cumbersome, and the reaction cost is high. In this step, the molar ratio of each reagent is based on the amount of substance of compound I. The molar equivalent of KI is 4~6, which can be 4, 5, 6, etc., and all ranges and sub-ranges between these values; the molar equivalent of SnCl2 is 4~6, which can be 4, 5, 6, etc., and all ranges and sub-ranges between these values; the molar equivalent of allyl bromide is 1.5~3, which can be 1.5, 2.0, 2.5, 3.0, etc., and all ranges and sub-ranges between these values; the reaction solvent is tetrahydrofuran and water. KI, SnCl2, and allyl bromide are coupled and dissolved in water, and compound I is dissolved in tetrahydrofuran. Tetrahydrofuran can readily dissolve compound I, thus allowing compound I to be slowly added to the reaction system; the reaction temperature is 0℃~25℃; the reaction time is 4 h~48 h. It should be understood that in this embodiment, any of the above ranges can be combined with any other ranges, as long as the technical effect of this application is achieved.

[0047] In some embodiments of this application, in step 2, two hydroxyl groups of the compound of formula II (non-1,8-diene-4,6-diol) are protected with TBSCl or imidazole to obtain compound III (a bis-OTBS protected intermediate). In this step, the hydroxyl groups are stably capped in the form of silyl ether bonds, avoiding side reactions of the hydroxyl groups in subsequent highly reactive systems such as cyclization and oxidation. This significantly improves the functional group stability of the intermediate in multi-step reactions, and the single-step separation yield can reach 85%. Ultimately, this solves the technical problems of poor hydroxyl functional group compatibility and easy occurrence of side reactions during multi-step reactions in existing synthetic routes, which lead to a decrease in product purity and yield. In this process, the molar ratio of each reagent is based on the amount of substance of compound II. The molar equivalent of TBSCl is 2-3, which can be 2, 2.5, 3, etc., and all ranges and sub-ranges between these values; the molar equivalent of imidazole is 2-4, which can be 2, 2.5, 3, 3.5, 4, etc., and all ranges and sub-ranges between these values; the reaction solvent is dichloromethane; the reaction temperature is 0℃-25℃, which can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, etc., and all ranges and sub-ranges between these values; the reaction time is 4 h-48 h, which can be 4h, 8h, 12h, 16h, 20h, 24h, 28h, 32h, 36h, 40h, 44h, 48h, etc., and all ranges and sub-ranges between these values. It should be understood that in this embodiment, any of the above ranges can be combined with any other range, as long as the technical effect of this application can be achieved.

[0048] In some embodiments of this application, in step 3, the compound of formula III (the bis-OTBS protected intermediate) undergoes intramolecular olefin metathesis cyclization under the action of a first-generation Grubbs catalyst to generate compound of formula IV (4,6-bis-OTBSoxycyclohepta-1-ene). The construction of the seven-membered carbon ring skeleton is completed in one step through intramolecular double bond recombination. The cyclization reaction exhibits excellent selectivity, with no obvious ring-opening or polymerization side reactions, and a single-step separation yield of up to 93%. This process is carried out at room temperature and pressure, without the need for harsh conditions such as high temperature and high pressure, thus solving the technical problems of lengthy seven-membered carbon ring construction routes, poor cyclization selectivity, and stringent reaction conditions in the prior art. In this process, the molar ratio of each reagent is based on the amount of substance of compound III. The molar equivalent of the Grubbs catalyst (first-generation, second-generation, and Hoveyda-Grubbs catalysts can be used) is 0.01~0.2, which can be 0.01, 0.05, 0.1, 0.15, 0.2, etc., and all ranges and sub-ranges between the above values; the reaction solvent is dichloromethane; the reaction temperature is 0℃~25℃, which can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, etc., and all ranges and sub-ranges between the above values; the reaction process is carried out under anhydrous and oxygen-free conditions in the dark; the reaction time is 4 h~12 h, which can be 4 h, 8 h, 12 h, etc., and all ranges and sub-ranges between the above values. It should be understood that in this embodiment, any of the above ranges can be combined with any other ranges, as long as the technical effect of this application can be achieved.

[0049] In some embodiments of this application, in step 4, the compound of formula IV (4,6-bisOTBSoxycycloheptan-1-ene) is subjected to allylic oxidation by sequentially adding TBHP (tert-butyl hydroperoxide) and PDC (pyridinium dichromate) as oxidants in the reaction solvent, and adding Celite diatomaceous earth to prevent PDC solid agglomeration, which is beneficial to the reaction and post-processing, to generate compound V (5,7-bisOTBSoxycycloheptan-2-ene-1-one). This step can selectively introduce a carbonyl structure at the α-position of the double bond in the ring to construct the cycloheptenone intermediate; wherein diatomaceous earth can effectively avoid solid agglomeration of pyridinium dichromate, improve the mass transfer efficiency and conversion uniformity of the oxidation reaction, and at the same time, the solid residue can be directly removed by filtration, simplifying the post-processing operation. The single-step separation yield can reach 60%, which solves the technical problems of poor oxidant dispersibility, low conversion efficiency and cumbersome post-processing separation operation in the existing allylic oxidation process. In this process, the molar ratio of each reagent is based on the amount of substance of compound IV. The molar equivalent of TBHP is 2~4, which can be 2, 3, 4, etc., as well as all ranges and subranges between these values; the molar equivalent of PDC is 2~5, which can be 2, 3, 4, 5, etc., as well as all ranges and subranges between these values; the molar ratio of Celite diatomaceous earth to PDC is (1:2)~(1:1), which can be 1:2, 1:1.5, 1:1, etc., as well as all ranges and subranges between these values; the reaction solvent is toluene; the reaction temperature is 25℃~120℃, which can be 25℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, etc., as well as all ranges and subranges between these values; the reaction time is 24~72 seconds. h can be 24h, 28h, 32h, 36h, 40h, 44h, 48h, 72h, etc., as well as all ranges and sub-ranges between the above values. It should be understood that in this embodiment, any of the above ranges can be combined with any other range, as long as the technical effect of this application can be achieved.

[0050] In some embodiments of this application, in step 5, the compound of formula V (5,7-bis(OTBS)oxycyclohepta-2-en-1-one) is deprotected in a reaction solvent using TBAF (tetrabutylammonium fluoride) as the deprotecting agent to obtain the compound of formula VI (5,7-dihydroxycyclohepta-2-en-1-one). This step is based on the strong coordination of fluorine and silicon to selectively break the silicon-oxygen bond. Without destroying the intracyclic double bond and carbonyl structure, two tert-butyldimethylsilyl protecting groups are quantitatively removed, reducing to obtain free hydroxyl groups. The single-step separation yield can reach 82%, solving the technical problems of harsh deprotection process conditions, easy damage to sensitive intramolecular functional groups, and numerous byproducts in existing deprotection processes. In this step, the molar ratio of each reagent is based on the amount of substance of compound V. The molar equivalent of TBAF is 2 to 3, which can be 2, 2.5, 3, etc., or any range and sub-range between these values. The reaction solvent is dichloromethane. The reaction temperature is 0°C to 25°C, which can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, etc., or any range and sub-range between these values. The reaction time is 6 h to 24 h, which can be 6 h, 12 h, 16 h, 20 h, 24 h, etc., or any range and sub-range between these values. It should be understood that in this embodiment, any of the above ranges can be combined with any other ranges, as long as the technical effect of this application can be achieved.

[0051] In some embodiments of this application, in step 6, the compound of formula VI (5,7-dihydroxycyclohepta-2-en-1-one) is oxidized to construct an aromatic seven-membered ring structure, yielding the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one. Aromatization of the seven-membered ring is achieved through oxidative dehydrogenation, successfully constructing a 2,4-dihydroxy-substituted aromatic skeleton of tyrosine, thus obtaining the target product. Low-temperature batch feeding effectively controls the oxidation depth, reduces excessive oxidation byproducts, and achieves a single-step separation yield of up to 72%, ultimately solving the technical problems of poor selectivity, numerous excessive oxidation byproducts, and low overall yield in existing tyrosine aromatic ring construction reactions. In this step, the oxidant is CrO3, and the molar ratio of the reagents is based on the amount of substance of the compound of formula VI. The molar equivalent of CrO3 is 2 to 4, which can be 2, 2.5, 3, 3.5, 4, etc., as well as all ranges and sub-ranges between the above values. The reaction solvent is a mixed solution of diethyl ether and dichloromethane, and the volume ratio of diethyl ether to dichloromethane is (3:1) to (1:1), which can be 3:1, 2:1, 1:1, etc., as well as all ranges and sub-ranges between the above values. The reaction temperature is 0 to 35°C, which can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, etc., as well as all ranges and sub-ranges between the above values. The reaction time is 2 h to 12 h, which can be 2 h, 4 h, 8 h, 12 h, etc., as well as all ranges and sub-ranges between the above values. It should be understood that in this embodiment, any of the above ranges can be combined with any other ranges, as long as the technical effect of this application can be achieved.

[0052] II. Examples and Comparative Examples

[0053] Example 1: Preparation of Compound 2

[0054] In a round-bottom flask, stannous chloride dihydrate (6.68 g, 30 mmol), potassium iodide (9.96 g, 60 mmol), and allyl bromide (3.63 g, 30 mmol) were dissolved in 100 mL of deionized water and stirred for 30 min. Then, compound 1 (1.65 g, 10 mmol) dissolved in tetrahydrofuran (10 mL) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was stirred at room temperature for 48 h, and the reaction endpoint was monitored by TLC. After the reaction was complete, the resulting mixture was neutralized with Na₂CO₃ solution and extracted with dichloromethane (3 times × 150 mL). The organic phases were combined, washed with Na₂S₂O₃ solution (5% aqueous solution, 3 times × 150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 2 (white oily liquid, 1.40 g, yield 90%).

[0055] 1H NMR (600 MHz, CDCl3) δ 5.76-5.83 (m, 2H), 5.09-5.12 (m, 4H), 3.94-4.00 (m, 2H), 2.23-2.26 (m, 4H), 1.59-1.62 (m, 2H), 13 C NMR (151MHz, CDCl3) δ 134.8, 118.1, 68.1, 42.0.

[0056] Example 2: Preparation of Compound 2

[0057] In a round-bottom flask, stannous chloride dihydrate (8.91 g, 40 mmol), potassium iodide (13.28 g, 80 mmol), and allyl bromide (4.84 g, 40 mmol) were dissolved in 200 mL of deionized water and stirred for 30 min. Then, compound 1 (1.65 g, 10 mmol) was added directly to the reaction system. After the addition was complete, the reaction system was stirred at room temperature for 24 h, and the reaction endpoint was monitored by TLC. The mixture was then extracted with dichloromethane (3 times × 150 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 2 (white oily liquid, 1.23 g, yield 79%).

[0058] Example 3: Preparation of Compound 3

[0059] Compound 2 (3.12 g, 20 mmol) prepared in Example 1 was dissolved in dichloromethane (50 mL). o Imidazole (2.72 g, 40 mmol) and tert-butyldimethylchlorosilane (9.01 g, 60 mmol) were added at C and stirred for 24 h. The mixture was extracted with dichloromethane (3 times × 75 mL), the organic phases were combined, washed with saturated brine, and dried over anhydrous Na₂SO₄. After concentration under reduced pressure, the mixture was purified by column chromatography to give compound 3 (6.53 g, 85% yield, pale yellow oil).

[0060] 1 H NMR (600 MHz, CDCl3) δ 5.78-5.85(m, 2H), 5.04-5.07(m, 4H), 3.81-3.85(m, 2H), 2.20-2.27(m, 4H), 0.85-0.91(m, 18H), 0.06-0.08(12 H); 13 C NMR (75 MHz, CDCl3) δ135.1, 117.0, 69.9, 69.3, 42.6, 42.0, 26.0, 18.2, -4.1.

[0061] Example 4: Preparation of Compound 3

[0062] Compound 2 (3.12 g, 20 mmol) prepared in Example 1 was dissolved in dichloromethane (50 mL). o Imidazole (2.72 g, 40 mmol) and tert-butyldimethylchlorosilane (5.95 g, 40 mmol) were added at C and stirred for 48 h. The mixture was extracted with dichloromethane (3 times × 75 mL), the organic phases were combined, washed with saturated brine, and dried over anhydrous Na₂SO₄. After concentration under reduced pressure, the mixture was purified by column chromatography to give compound 3 (4.91 g, 64% yield, pale yellow oil).

[0063] Example 5: Preparation of Compound 4

[0064] Compound 3 (768 mg, 2.0 mmol) prepared in Example 2 was dissolved in 5 mL of dichloromethane, followed by the addition of a Grubbs first-generation (bis(tricyclohexylphosphine)benzylruthenium dichloride) catalyst (48 mg, 0.06 mmol). The reaction flask was then wrapped with aluminum foil and reacted in the dark for 4 h. The dichloromethane solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain compound 4 (662 mg, 93% yield, pale yellow oily liquid).

[0065] 1 H NMR (600 MHz, CDCl3) δ 5.67-5.70 (m, 2H), 3.48-3.55 (m, 2H), 2.18-2.32 (m, 5H), 1.77-1.85 (m, 1H), 0.89 (s, 18H), 0.06 (s, 12H); 13 C NMR (151 MHz, CDCl3) δ128.0, 68.1, 52.5, 37.8, 25.7, 18.0, -4.9.

[0066] Example 6: Preparation of Compound 4

[0067] Under an argon atmosphere, compound 3 (768 mg, 2.0 mmol) prepared in Example 2 was dissolved in 5 mL of anhydrous dichloromethane, followed by the addition of Grubbs Catalyst 2nd Generation (purchased from Innochem, catalog number G1310) catalyst (48 mg, 0.06 mmol). The reaction flask was then wrapped with aluminum foil and reacted in the dark for 8 h. The dichloromethane solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain compound 4 (676 mg, 95% yield, pale yellow oily liquid).

[0068] Example 7: Preparation of Compound 5

[0069] Compound 4 (1.78 g, 5.0 mmol) prepared in Example 3 was dissolved in toluene (20 mL), and Celite diatomaceous earth (2.28 g), tert-butyl hydroperoxide (1.93 g, 15.0 mmol), and pyridine dichromate (4.45 g, 15.0 mmol) were added sequentially. After the addition was complete, the reaction was carried out at room temperature for 48 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, concentrated under reduced pressure to remove the solvent, and purified by SiO2 column chromatography to obtain compound 5 (1.12 g, 60% yield, pale yellow oil).

[0070] 1 H NMR (600 MHz, CDCl3) δ 6.60-6.62 (m, 2H), 5.89-5.92 (m, 2H), 4.50-4.52 (m, 1H), 4.13-4.15 (m, 1H), 2.72-2.82 (m, 2H), 2.01-2.05 (m, 2H), 0.88 (s, 18H), 0.06 (s, 12H); 13 C NMR (151 MHz, CDCl3) δ 199.1, 140.1, 126.5, 77.0, 70.3, 41.1, 34.6, 25.7, 18.0, 17.9, -4.5.

[0071] Example 8: Preparation of Compound 5

[0072] Compound 4 (1.78 g, 5.0 mmol) prepared in Example 3 was dissolved in toluene (20 mL), and Celite diatomaceous earth (2.28 g), tert-butyl hydroperoxide (1.93 g, 15.0 mmol), pyridine dichromate (4.45 g, 15.0 mmol), and chromium trioxide (1.50 g, 15.0 mmol) were added sequentially. After the addition was complete, the mixture was refluxed at 100 °C for 48 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, concentrated under reduced pressure to remove the solvent, and purified by SiO2 column chromatography to obtain compound 5 (1.21 g, yield 65%, pale yellow oil).

[0073] Comparative Example 1: Preparation of Compound 5

[0074] Compound 4 (1.78 g, 5.0 mmol) prepared in Example 3 was dissolved in 1,4-dioxane (20 mL), and tert-butyl hydroperoxide (1.93 g, 15.0 mmol) and selenium dioxide (1.66 g, 15.0 mmol) were added sequentially. After the addition was complete, the reaction was carried out at room temperature for 48 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered with diatomaceous earth, washed with dichloromethane, concentrated under reduced pressure to remove the solvent, and purified by SiO2 column chromatography. The desired product compound 5 was not obtained.

[0075] Comparative Example 1 used a system combining selenium dioxide and tert-butyl hydroperoxide for allylic oxidation. This system had insufficient oxidizing power and poor reaction selectivity, failing to directly oxidize the allylic carbon to the carbonyl group, and only yielding a complex mixture of allylic hydroxylated products. Furthermore, this reaction system produced numerous byproducts, with a low proportion of the target hydroxyl intermediate, making separation and purification difficult and resulting in high product yield loss. Adding an additional oxidation step to attempt to convert the hydroxyl group to the carbonyl group would not only lengthen the synthetic route, increase operating costs and material losses, but also easily trigger side reactions such as intracyclic double bond shifting and oxidative degradation of the seven-membered carbon skeleton during deep oxidation, making it impossible to stably and efficiently obtain the target allylic carbonyl product with high purity.

[0076] Comparative Example 2: Preparation of Compound 5

[0077] Compound 4 (1.78 g, 5.0 mmol) prepared in Example 3 was dissolved in 1,4-dioxane (20 mL), and selenium dioxide (1.66 g, 10.0 mmol) was added. After the addition was complete, the mixture was refluxed at 100 °C for 48 h, and the reaction progress was monitored by TLC. After the reaction was completed, TLC monitoring showed that the TLC system was disordered, and the desired product compound 5 was not obtained.

[0078] Comparative Example 2 used selenium dioxide as a single oxidant to carry out an allylic oxidation reaction under high-temperature reflux conditions. This system had poor oxidation selectivity and was prone to various side reactions during the reaction, such as intracyclic double bond isomerization, oxidative degradation of the seven-membered carbon skeleton, and excessive oxidation at multiple sites. This resulted in an extremely complex composition of the reaction system, and the proportion of the target allylic carbonyl product was very low. It was impossible to obtain compound 5 with acceptable purity for subsequent reactions through conventional separation and purification methods.

[0079] Example 9: Preparation of Compound 6

[0080] Compound 5 (741 mg, 2.0 mmol) prepared in Example 4 was dissolved in dry tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.57 g, 5.0 mmol) was added. The reaction mixture was stirred for 4 h, and then quenched with deionized water (15 mL). The aqueous phase was extracted three times with dichloromethane (3 times × 50 mL), and the combined organic phases were dried over anhydrous Na₂SO₄. The solution was concentrated under reduced pressure to give compound 6 (233 mg, 82% yield).

[0081] HRMS(ESI,m / z): calculated for C7H 10 O3[M + H] + 143.0708, found143.0699.

[0082] Example 10: Preparation of Compound 6

[0083] Compound 5 (741 mg, 2.0 mmol) prepared in Example 4 was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1.26 g, 4.0 mmol) was added. The reaction mixture was stirred for 24 h, and then quenched with deionized water (15 mL). The aqueous phase was extracted three times with dichloromethane (3 times × 50 mL), and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was concentrated under reduced pressure to give compound 6 (224 mg, 79% yield).

[0084] Example 11: Preparation of 2,4-dihydroxycyclohepta-2,4,6-trien-1-one

[0085] Compound 6 (284 mg, 2.0 mmol) prepared in Example 5 was dissolved in a mixed solution of diethyl ether (15 mL) and dichloromethane (5 mL). Diatomaceous earth filter aid (300 mg) was added to the solution, and the mixture was cooled to 0 °C. Chromium trioxide was added in three portions (3 times × 200 mg, 6.0 mmol), and the reaction was continued with stirring for 6 h. The mixture was then filtered with diatomaceous earth, washed with dichloromethane, and the organic phases were combined. After concentration under reduced pressure, the mixture was purified by SiO2 column chromatography to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one (201 mg, 72%).

[0086] 1H NMR (600 MHz, CD3OD) δ 7.11 (dd, J = 10.0, 2.5 Hz, 1H), 6.99 (dd, J =10.0, 2.5 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 6.72 (ddd, J = 10.0, 2.5, 1.0 Hz, 1H).

[0087] Example 12: Preparation of 2,4-dihydroxycyclohepta-2,4,6-trien-1-one

[0088] Compound 6 (284 mg, 2.0 mmol) prepared in Example 5 was dissolved in anhydrous dichloromethane (20 mL). Under ice bath conditions, silica gel powder (650 mg) of half the weight of PCC (pyridinium chlorochromate) was added. After stirring until homogeneous, PCC was added in portions (3 times × 430 mg, 6.0 mmol), and the reaction was continued with stirring for 6 h. The mixture was then filtered through diatomaceous earth, washed with dichloromethane, and the organic phases were combined. After concentration under reduced pressure, the mixture was purified by SiO2 column chromatography to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one (170 mg, 61%).

[0089] Analysis of the experimental results from the above embodiments and comparative examples shows that:

[0090] (1) This application employs a six-step linear synthetic route to achieve the total synthesis of 2,4-dihydroxycyclohepta-2,4,6-trien-1-one. High-conversion carbon-carbon coupling is achieved through a non-precious metal system, and the seven-membered carbon ring framework is constructed in one step by combining olefin metathesis. Each step of the reaction has good conversion efficiency and selectivity, and the single-step separation yield is generally at a high level. The overall yield of the entire route is excellent among similar seven-membered aromatic ring total synthesis processes, effectively improving the shortcomings of the existing technology, which has lengthy synthesis steps and low overall yield. At the same time, each step of the reaction uses conventional raw materials and reagents and is carried out under mild atmospheric pressure conditions, without the need for special reaction equipment. The post-reaction processing is simple, which improves the synthesis efficiency while reducing the preparation cost, and is more suitable for the needs of large-scale production.

[0091] (2) Regarding the expected application of the target compound, based on the existing research on hydroxytropinone compounds, the 2,4-dihydroxycyclohepta-2,4,6-trien-1-one (2,4-dihydroxytropinone) prepared in this application has expected biological activity and research value. The prior art has confirmed that 3,7-dihydroxytropinone (antitumor antibiotic BMY-28438), which belongs to the dihydroxysubstituted tropinone family, has strong cytotoxicity against B16 melanoma cells and can significantly prolong the survival of mice bearing B16 melanoma. At the same time, it shows strong antibacterial activity against the plant pathogen Streptomyces thuringiensis. The parent compound of tropinone has also been reported to have multiple biological activities such as tyrosinase inhibition, antiviral, and antifungal activity. Moreover, the antibacterial effect of hydroxytropinone compounds has been confirmed to be related to the iron chelation mechanism. Based on the structure-activity relationship and common mechanism of action of this type of compound, those skilled in the art can reasonably expect that the 2,4-dihydroxytorhenone prepared in this application retains the core structure of totorhenone core and hydroxyl substitution, and has research and application potential in related fields such as antitumor, antibacterial, antiviral, and tyrosinase inhibition. The establishment of the preparation method described in this application provides a stable and reproducible synthetic basis for the subsequent activity evaluation and application development of this compound.

[0092] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application and not to limit the technical solutions. Those skilled in the art should understand that any modifications or equivalent substitutions to the technical solutions of this application without departing from the spirit and scope of this technical solution should be covered within the scope of the claims of this application.

Claims

1. A method for preparing 2,4-dihydroxycyclohepta-2,4,6-trien-1-one, characterized in that, The specific synthesis route is as follows: ； In the formula, R is selected from tert-butyldimethylsilyl or methoxymethyl; X is selected from Cl, Br, and I. Step 1: The compound of formula I undergoes a coupling reaction to obtain the compound of formula II; Step 2: The compound of formula II is protected by protecting its two hydroxyl groups to obtain the compound of formula III; Step 3: The compound of formula III undergoes an olefin metathesis reaction and cyclization under the action of Grubbs catalyst to generate compound of formula IV; Step 4: Compound IV is oxidized at the allylic position to obtain compound V; Step 5: Compound V is obtained by removing the TBS protecting group to obtain compound VI; Step 6: The compound of formula VI is used to construct an aromatic seven-membered ring structure by oxidizing the hydroxyl group to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one.

2. The preparation method according to claim 1, characterized in that, R is tert-butyldimethylsilyl, and X is Br.

3. The preparation method according to claim 1, characterized in that, The synthesis route is as follows: 。 4. The preparation method according to claim 1, characterized in that, In step 1, the compound of formula I is used as a raw material and coupled with allyl bromide via KI or SnCl2 catalysis to generate compound of formula II. The molar ratio of each reagent is based on the amount of substance of compound of formula I, with KI molar equivalent of 4-6, SnCl2 molar equivalent of 4-6, and allyl bromide molar equivalent of 2-3. The reaction solvents are tetrahydrofuran and deionized water. The reaction temperature is 0℃-35℃, and the reaction time is 4 h-48 h.

5. The preparation method according to claim 1, characterized in that, In step 2, under the alkaline conditions provided by imidazole, the two hydroxyl groups of the compound of formula II are protected with TBSCl or MOMCl to obtain the compound of formula III; wherein, the molar ratio of each reagent is based on the amount of substance of the compound of formula II, the molar equivalent of TBSCl is 2~3, the molar equivalent of imidazole is 2~4, the reaction solvent is dichloromethane, the reaction temperature is 0℃~35℃, and the reaction time is 4 h~48 h.

6. The preparation method according to claim 1, characterized in that, In step 3, the compound of formula III undergoes intramolecular olefin metathesis cyclization under the action of a Grubbs catalyst to generate compound of formula IV; wherein, the molar ratio of each reagent is based on the amount of substance of compound of formula III, the molar equivalent of the Grubbs catalyst is 0.01~0.2; the reaction solvent is dichloromethane, the reaction temperature is 0℃~35℃; the reaction process is carried out in the dark under anhydrous and oxygen-free conditions; the reaction time is 4 h~12 h.

7. The preparation method according to claim 1, characterized in that, In step 4, the compound of formula IV is subjected to allylic oxidation by adding TBHP and PDC as oxidants in the reaction solvent, and Celite diatomaceous earth is added to prevent PDC solid agglomeration, thereby generating compound of formula V. The molar ratio of each reagent is based on the amount of substance of compound of formula IV, with the molar equivalent of TBHP being 2~5; the molar equivalent of PDC being 2~8; the molar ratio of Celite diatomaceous earth to PDC being (1:2)~(1:1); the reaction solvent is toluene; the reaction temperature is 25℃~120℃; and the reaction time is 24~72 h.

8. The preparation method according to claim 1, characterized in that, In step 5, the compound of formula V is reacted in a reaction solvent with TBAF as the deprotecting agent to remove the TBS protecting group, thereby obtaining the compound of formula VI. The molar ratio of each reagent is based on the amount of substance of the compound of formula V, and the molar equivalent of TBAF is 2 to 3. The reaction solvent is dichloromethane. The reaction temperature is 0°C to 35°C. The reaction time is 6 h to 24 h.

9. The preparation method according to claim 1, characterized in that, In step 6, the compound of formula VI is oxidized to construct an aromatic seven-membered ring structure to obtain the target product 2,4-dihydroxycyclohepta-2,4,6-trien-1-one; wherein, the oxidant is CrO3, the molar ratio of the reagents is based on the amount of substance of the compound of formula VI, the molar equivalent of CrO3 is 2~4, the reaction solvent is a mixed solution of diethyl ether and dichloromethane, the volume ratio of diethyl ether to dichloromethane is (3:1)~(1:1); the reaction temperature is 0~35℃, and the reaction time is 2 h~12 h.

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