Synthesis method of isopentenyl substituted acylated phloroglucinol

Abstract

The invention discloses a synthesis method of isopentenyl substituted acylated phloroglucinol, and an intermediate, a preparation method and application thereof. The method is easy to operate and environmentally friendly, and the obtained isopentenyl substituted acylated phloroglucinol is high in purity, suitable for industrial production and capable of meeting medical application of the isopentenyl substituted acylated phloroglucinol.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a natural product intermediate, specifically a method for synthesizing the phloroglucinol skeleton of Hyphenrone K in Hypericum henryi Lévl., a traditional Chinese medicine. Background Art

[0002] Hyphenrone K is a polycyclic polyprenyl-substituted acylated phloroglucinol (PPAPs) natural product isolated from the traditional Chinese medicine Hypericum henryi Lévl., and has strong Cav3.1 calcium channel inhibitory activity. It is the most potent natural Cav3.1 calcium channel blocker discovered so far. The IC50 value is 0.19 μM.

[0003] Currently, Hyphenrone K used in experiments is all extracted from plants. Due to the limited resources of Hypericum henryi Lévl., the long production cycle, and the extremely low content of PPAPs natural products in plants, if it is to be used in large quantities for drug production, relying on the extraction method from plants obviously cannot meet the clinical needs, and the price will be quite expensive. Therefore, it is very meaningful to develop new drug sources, and the artificial synthesis of Hyphenrone K is an important way.

[0004] The prenyl-substituted acylated phloroglucinol is the basic skeleton of Hyphenrone K. There is no literature report on the synthesis of this skeleton yet. All Hyphenrone K reported in the literature is obtained by the plant extraction method (CN202010000560). This method uses phloroglucinol as a raw material, and hopes to provide a new and industrially producible synthesis method to realize the synthesis technology of prenyl-substituted acylated phloroglucinol in Hyphenrone K, and lay a foundation for the total synthesis of Hyphenrone K.

[0005]

[0006] The above structural formula is prenyl-substituted acylated phloroglucinol, including two side chains of prenyl and 2-methylbutyryl. The present invention mainly relates to the selective coupling of side chains while synthesizing the prenyl-substituted acylated phloroglucinol, an intermediate of Hyphenrone K. Summary of the Invention

[0007] The present invention provides a simple and efficient method for synthesizing prenyl-substituted acylated phloroglucinol, an intermediate of Hyphenrone K, containing two side chains of prenyl and 2-methylbutyryl. This method has high synthesis efficiency, and the total yield can reach about 50%, providing a practical synthesis route for future industrial production.

[0008] The reaction process of the synthesis method of the present invention is as follows: Using 1,3,5-benzenetriol as a raw material, through Friedel-Crafts acylation and alkylation, the key intermediate 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (Compound E) is obtained.

[0009]

[0010] The present invention specifically may include two reaction steps

[0011]

[0012] The first step: Friedel-Crafts acylation reaction: Compound A reacts with Compound B in a solvent in the presence of a Lewis acid to obtain Compound C;

[0013] Among them, the Lewis acid is one or more of aluminum trichloride, iron trichloride, tin tetrachloride, boron trifluoride, titanium tetrachloride, zinc dichloride; preferably, the Lewis acid is one of aluminum trichloride and iron trichloride.

[0014] The solvent used is one, two or a mixture of two or more of aprotic solvents such as dichloromethane, dichloroethane, nitromethane, nitrobenzene and carbon disulfide; preferably, the solvent is a mixture of carbon disulfide and nitrobenzene.

[0015] In the above process, the temperature and time of the reaction are to react for 1-3 h at 50-70 °C.

[0016] After the first-step reaction, the yield of Compound C can reach 60% - 80%.

[0017] The second step: Alkylation: Compound C reacts with Compound D in a solvent under basic conditions to obtain Compound E.

[0018] Among them, the basic condition is provided in the presence of one or more of lithium diisopropylamide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, potassium hydroxide, potassium bis(trimethylsilyl)amide (KHMDS) or lithium bis(trimethylsilyl)amide (LHMDS); preferably, the base is one of potassium hydroxide, potassium tert-butoxide and sodium methoxide.

[0019] The solvent used is one, two or a mixture of two or more of toluene, tetrahydrofuran, methanol, N,N-dimethylformamide, water, 1,4-dioxane; preferably, the solvent used is a mixture of one or several of water, tetrahydrofuran and sodium methoxide.

[0020] The temperature and time of the reaction are to react for 2-5 h at 0-5 °C.

[0021] The molar ratio of compound C to the base in the reaction is 1:2 to 3; the preferred molar ratio is 1:2 to 2.5. The yield of product E reaches 40 to 60%.

[0022] Examples are provided below to assist in understanding the present invention. However, it should be understood that these examples are only for illustrating the present invention and do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention. Detailed implementation manners

[0023] To make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below in conjunction with examples. The specific examples described herein are only for explaining the present invention and do not constitute any limitation to the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessarily confusing the concepts of the present invention. Such structures and technologies have also been described in many publications.

[0024] Unless otherwise defined, all technical terms and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of explaining this specification, the following definitions will be applied, and where appropriate, terms used in the singular form will also include the plural form, and vice versa.

[0025] Unless the context clearly indicates otherwise, the expressions "a" and "an" used herein include plural referents. For example, referring to "a cell" includes a plurality of such cells and equivalents known to those skilled in the art and the like.

[0026] The term "about" used herein represents a range of ±20% of the value following it. In some embodiments, the term "about" represents a range of ±10% of the value following it. In some embodiments, the term "about" represents a range of ±5% of the value following it.

[0027] The solvents used herein are commercially available. The following abbreviations are used herein:

[0028] TLC: Thin layer chromatography

[0029] THF: Tetrahydrofuran

[0030] DCM: Dichloromethane

[0031] DMF: Dimethylformamide

[0032] CDI: N,N-Carbonyldiimidazole

[0033] eq: Equivalent

[0034] Concentration N: g / L

[0035] The compounds are named manually or by software. For commercially available compounds, the supplier's catalog name is used. Detailed Description of the Invention

[0037] The technical solutions of the present invention will be described in detail below in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.

[0038] The general synthesis formula is as follows:

[0039]

[0040] Example 1

[0041] The Lewis acid for the first-step reaction is aluminum trichloride, and the solvent is carbon disulfide. The base for the second-step reaction is potassium hydroxide, and the solvent is water.

[0042] First step: Friedel-Crafts acylation: 3 g (24 mmol) of compound A was dissolved in 30 ml of carbon disulfide, and the temperature was maintained at 20 °C. 13 g (96 mmol) of aluminum trichloride was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then the temperature was raised to 60 °C, and 2.86 g (24 mmol) of compound B was slowly added to the reaction system, and the reaction was carried out for 2 h. While maintaining 0 °C, 100 ml of water was slowly added to the reaction system, and the temperature was gradually raised to room temperature. 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with ethyl acetate, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3.8 g of 3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one (compound C), and the yield was 74%. The relevant data of the first-step product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.27 (s, 2H), 10.35 (s, 1H), 5.82 (s, 2H), 3.76 (p, J = 6.7 Hz, 1H), 1.79–1.67 (m, 1H), 1.33 (dt, J = 13.3, 7.1 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H) ppm.

[0043] Step 2: Alkylation: 2.5 g (12 mmol) of Compound C was dissolved in 30 ml of water, and the temperature was maintained at 0 °C. 1.3 g (24 mmol) of potassium hydroxide was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then, 3.6 g (24 mmol) of Compound D was slowly added to the reaction system, and the reaction was carried out for 1 hour. While maintaining 0 °C, 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with dichloromethane, dried and concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 2.3 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (Compound E), with a yield of 57%. The relevant data of the product in Step 2 are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 5.57 (s, 1H), 4.83–4.74 (m, 2H), 3.85 (q, J = 6.7 Hz, 1H), 2.59 (dt, J = 15.3, 7.6 Hz, 2H), 2.44 (dd, J = 13.6, 7.6 Hz, 2H), 1.75–1.57 (m, 2H), 1.54 (q, J = 3.1, 1.7 Hz, 13H), 1.31 (dddd, J = 26.1, 19.1, 12.2, 5.4 Hz, 2H), 1.02 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 4H) ppm.

[0044] Example 2

[0045] The Lewis acid in the first-step reaction was ferric chloride, and the solvent was nitrobenzene. The base in the second-step reaction was potassium hydroxide, and the solvent was water.

[0046] First step: Friedel-Crafts acylation: 3 g (24 mmol) of Compound A was dissolved in 30 ml of nitrobenzene, and the temperature was maintained at 20 °C. 16 g (96 mmol) of ferric chloride was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then, the temperature was raised to 60 °C, and 2.86 g (24 mmol) of Compound B was slowly added to the reaction system, and the reaction was carried out for 2 hours. While maintaining 0 °C, 100 ml of water was slowly added to the reaction system, and the temperature was gradually raised to room temperature. Then, 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with ethyl acetate, dried and concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 3.7 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (Compound C), with a yield of 72%.

[0047] Step 2: Alkylation: 2.5 g (12 mmol) of compound C was dissolved in 30 ml of tetrahydrofuran, and while maintaining at 0 °C, 2.7 g (24 mmol) of potassium tert-butoxide was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then, 3.6 g (24 mmol) of compound D was slowly added to the reaction system, and the reaction was carried out for 1 h. While maintaining at 0 °C, 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with dichloromethane, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 2 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (compound E), with a yield of 50%.

[0048] Example 3

[0049] The Lewis acid for the first-step reaction is ferric chloride, and the solvent is a mixed solvent of nitrobenzene and carbon disulfide. The base for the second-step reaction is sodium methoxide, and the solvent is methanol.

[0050] Step 1: Friedel-Crafts acylation: 3 g (24 mmol) of compound A was dissolved in a mixed solution of 15 ml of nitrobenzene and 15 ml of carbon disulfide, and while maintaining at 20 °C, 16 g (96 mmol) of ferric chloride was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then, the temperature was raised to 60 °C, and 2.86 g (24 mmol) of compound B was slowly added to the reaction system, and the reaction was carried out for 2 h. While maintaining at 0 °C, 100 ml of water was slowly added to the reaction system, and the temperature was gradually raised to room temperature. Then, 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with ethyl acetate, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 4.0 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (compound C), with a yield of 80%.

[0051] Step 2: Alkylation: 2.5 g (12 mmol) of compound C was dissolved in 30 ml of methanol, and while maintaining at 0 °C, 1.3 g (24 mmol) of sodium methoxide was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then, 3.6 g (24 mmol) of compound D was slowly added to the reaction system, and the reaction was carried out for 1 h. While maintaining at 0 °C, 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with dichloromethane, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 1.8 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (compound E), with a yield of 45%.

[0052] Example 4

[0053] The Lewis acid for the first-step reaction is aluminum trichloride, and the solvent is a mixed solution of nitrobenzene and carbon disulfide. The base for the second-step reaction is sodium methoxide, and the solvent is methanol.

[0054] First step: Friedel-Crafts acylation: 3 g (24 mmol) of compound A was dissolved in a mixed solution of 15 ml of nitrobenzene and 15 ml of carbon disulfide. While maintaining 20°C, 13 g (96 mmol) of ferric chloride was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then the temperature was raised to 60°C, and 2.86 g (24 mmol) of compound B was slowly added to the reaction system, and the reaction was carried out for 2 hours. While maintaining 0°C, 100 ml of water was slowly added to the reaction system, and the temperature was gradually raised to room temperature. Then 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with ethyl acetate, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3.4 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (compound C), and the yield was 67%.

[0055] Second step: Alkylation: 2.5 g (12 mmol) of compound C was dissolved in 30 ml of methanol. While maintaining 0°C, 1.3 g (24 mmol) of sodium methoxide was slowly added to the reaction system, and the mixture was stirred for 0.5 h. Then 3.6 g (24 mmol) of compound D was slowly added to the reaction system, and the reaction was carried out for 1 hour. While maintaining 0°C, 20 ml of 1N hydrochloric acid was added to the reaction system. The mixture was extracted with dichloromethane, dried and concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 1.8 g of 3,5-dihydroxy-6,6-bis(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (compound E), and the yield was 45%.

[0056] As described above, it is only the specific implementation manner of the present invention and cannot be used to limit the protection scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing isopentenyl substituted acylated phloroglucinol, comprising the following steps: (1) Compound A reacts with compound B in a solvent in the presence of a Lewis acid to obtain compound C; (2) Compound C reacts with compound D in an alkaline solvent to obtain compound E.

2. The synthesis method according to claim 1: the reaction temperature in step (1) is 55-70° C.; the solvent is one, two or more of dichloromethane, dichloroethane, nitromethane, nitrobenzene and carbon disulfide.

3. The synthesis method according to claim 1, wherein the Lewis acid described in step (1) is one, two or more of aluminum chloride, iron trichloride, tin tetrachloride, boron trifluoride, titanium tetrachloride and zinc dichloride.

4. The synthesis method according to claim 1, wherein the reaction temperature in step (2) is 0-5°C; and the solvent is one, two or more of toluene, tetrahydrofuran, methanol, N,N-dimethylformamide, water, and 1-4-dioxane.

5. The synthesis method according to claim 1, wherein the alkaline conditions described in step (2) are provided in the presence of one or more of lithium diisopropylamide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, potassium hydroxide, potassium bis(trimethylsilyl)amide (KHMDS) or lithium bis(trimethylsilyl)amide (LHMDS).

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