Novel method for synthesizing pterosin d

Abstract

The present invention relates to a novel method for synthesizing pterosin D and, more specifically, to a method for preparing pterosin D by the steps of: dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent; adding thereto a boron-based reducing agent dissolved in water, thereby performing reduction; and performing extraction and crystallization therefrom.

Description

A novel synthetic method for pterosin D

[0001] This application claims priority to Republic of Korea Patent Application No. 10-2024-0102466, filed on August 1, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a novel method for synthesizing pterosin D, and more particularly, to a method for producing pterosin D, comprising the steps of: dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent; reducing the compound by adding a boron-based reducing agent dissolved in water; and extracting and crystallizing the compound therefrom.

[0003]

[0004] Pterosin, which has a 1-indanone skeleton, is a compound belonging to the sesquiterpenes and norsesquiterpenes groups, first isolated from the bracken (Pteridium aquilinum) in Japan. Pterosin compounds are known to have various effects, including those related to diabetes, obesity, hair loss prevention, and degenerative brain diseases, and are thus attracting attention as potential new drug candidates for various diseases.

[0005] Against this backdrop, the only known methods for producing pterosin, especially pterosin D, are direct extraction from bracken and separation / purification using chromatography, or chemical methods. However, the method for extracting from bracken has a low yield and requires a separate process for isolating and purifying only pterosin D from the extract, which has the disadvantage of high production costs. In addition, the chemical methods known to date have a low yield as they are methods for small-scale production for research. Therefore, there is a growing need for a method that can produce pterosin D in large quantities with a high yield and high purity that can be administered clinically for research on pterosin D-based drugs and for the production of pharmaceuticals.

[0006]

[0007] Accordingly, the inventors of the present invention have made great efforts to develop a novel method for producing pterosin D, and as a result, in particular, in the final stage of pterosin D synthesis, the 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound is reduced using tetrahydrofuran (THF), water (H20), and sodium cyanoborohydride (NaBH3CN), and as a result of extraction and crystallization, it has been confirmed that pterosin D can be produced with excellent purity and high yield, and the present invention has been completed.

[0008]

[0009] Accordingly, an object of the present invention is to provide a method for producing pterosin D, which comprises the steps of dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent; adding a boron-based reducing agent dissolved in water and stirring to reduce the compound; adding ethyl acetate and water to extract the compound; and concentrating and crystallizing the compound.

[0010]

[0011] In order to achieve the above purpose, the present invention provides a method for producing pterosin D, which comprises the steps of dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent; adding a boron-based reducing agent dissolved in water and stirring to reduce the compound; adding ethyl acetate and water to extract the compound; and concentrating to crystallize the compound.

[0012]

[0013] The present invention is described in detail below.

[0014]

[0015] The present inventor, while studying a method for increasing the purity and yield in a conventionally known method for producing pterosin D, confirmed that by dissolving 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione, a precursor compound of pterosin D, in an ether solvent and then reducing it using a boron-based reducing agent dissolved in water, pterosin D with superior purity can be produced at a yield approximately twice as high as that of a conventionally known method.

[0016]

[0017] Therefore, the present invention,

[0018] (a) a step of dissolving a compound of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) in an ether solvent;

[0019] (b) a step of dissolving a boron series reducing agent in water, adding it, and stirring to reduce it;

[0020] (c) a step of extracting by adding ethyl acetate (EA) and water; and

[0021] (d) a step of concentrating and crystallizing the organic layer;

[0022] It relates to a method for producing pterosin D including .

[0023]

[0024] Below, each of the above steps is explained in detail.

[0025]

[0026] (a) a step of dissolving a compound of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) in an ether solvent;

[0027]

[0028] In the above step (a), the 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) compound refers to a compound having the following chemical structure.

[0029]

[0030] At this time, the compound of chemical formula 4 can be synthesized using a known method. For example, first, a 2-(2-methoxyethyl)-1,3-dimethylbenzene (chemical formula 1) compound and a Dimethylmalonyl chloride (chemical formula 2) compound are synthesized into a 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 3) compound using a Friedel-crafts acylation reaction, and then the synthesized compound of chemical formula 3 is subjected to a demethylation (BBr3demethylation) process of treating it with BBr3. Here, the chemical formulas 1, 2, and 3 refer to compounds having the following chemical structures.

[0031] , ,

[0032] More specifically, the compound of chemical formula 1 is dissolved in dichloromethane (DCM), aluminum chloride (AlCl3) is added at 0°C, stirred, and then the compound of chemical formula 2 is added and stirred. Afterwards, ice water and DCM are added to perform extraction, and the organic layer is treated with MgSO4 to dehydrate and concentrated under reduced pressure, thereby synthesizing the compound of chemical formula 3.

[0033] Afterwards, the compound of chemical formula 3 is dissolved again in DCM, and BBr3 is added dropwise and stirred. Afterwards, ice water and DCM are added to extract, the organic layer is dehydrated by treating with MgSO4, concentrated under reduced pressure, and then ethanol is added. The solid produced at this time is filtered off and discarded, the filtrate is collected, concentrated under reduced pressure, and then crystallized to obtain the compound of chemical formula 4.

[0034] At this time, the crystallization method is not limited thereto, but silica gel column chromatography can be used, and crystallization can be performed by treating methanol and diisopropyl ether (DIPE), but a method of crystallization by treating methanol and DIPE is more preferable in that it is more suitable for a mass production process.

[0035] However, the method for producing the above-described chemical formula 4 compound is merely an example, and it is obvious to those skilled in the art that the method according to the present invention can be applied equally to the method for producing pterosin D according to the present invention regardless of the method by which the chemical formula 4 compound is produced.

[0036]

[0037] In the above step (a), the ether solvent may mean any one of tetrahydrofuran (THF), dimethyl ether, diethyl ether, or ethylene glycol dimethyl ether, but most preferably, the ether solvent may mean tetrahydrofuran.

[0038]

[0039] (b) a step of dissolving a boron series reducing agent in water, adding it, and then stirring to reduce it;

[0040]

[0041] In the above step (b), in the case of the boron-based reducing agent, the method according to the present invention is characterized in that the yield and purity are improved by minimizing the generation of flexible substances by lowering the reduction reactivity, and therefore, the boron-based reducing agent is not limited thereto, but may refer to sodium cyanoborohydride (NaBH3CN), pyridine-borane (Py-BH3), dimethylamine-borane, trimethylamine-borane, or isopropoxyborohydride (iPrOBH3), which are reducing agents having relatively weak reactivity. However, considering its stability and selectivity, sodium cyanoborohydride (NaBH3CN) is most preferable.

[0042] In this step, it is preferable to dissolve the boron series reducing agent in water and then add it to the solution prepared in step (a), and when stirring thereafter, the stirring may be performed at 40°C to 80°C, preferably 50°C to 70°C, and most preferably 55°C to 65°C, for 12 hours or more, preferably 18 hours or more, and most preferably 24 hours or more to ensure a good reaction, but the present invention is not limited thereto.

[0043]

[0044] (c) Extraction step by adding ethyl acetate (EA) and water;

[0045]

[0046] The above step (c) refers to a step of extracting pterosin D synthesized through steps (a) and (b) using a polar organic solvent.

[0047] In this step, the ethyl acetate is a polar organic solvent, and may be, but is not limited to, hexane or dichloromethane.

[0048] Meanwhile, in the above step (c), the process of extracting pterosin D may be performed 1, 2, 3, 4 or 5 times or more, but is not limited thereto, and a person skilled in the art may appropriately repeat the extraction process as needed.

[0049]

[0050] (d) a step of concentrating and crystallizing the organic layer;

[0051]

[0052] The above step (d) refers to the final step of removing the solvent from the organic layer and obtaining pterosin D crystals. The method of concentration is not particularly limited, and a person skilled in the art can appropriately perform the method based on common technical knowledge in the art.

[0053]

[0054] In one embodiment of the present invention, pterosin D having a purity of 98.1% and a final yield of 70% was produced using the method according to the present invention.

[0055]

[0056] The method for producing pterosin D according to the present invention can produce pterosin D of excellent purity in a high yield and is suitable for mass production, and therefore can be usefully used in drug research and production of pharmaceuticals based on pterosin D.

[0057]

[0058] Figure 1 briefly illustrates the entire process of a method for producing pterosin D according to the present invention.

[0059] Figure 2 shows the results of confirming the compound manufactured according to the method of the example through proton nuclear magnetic resonance (H-NMR).

[0060] Figures 3a and 3b show the HPLC results of compounds manufactured according to the method of the example.

[0061] Figures 4a and 4b show the HPLC results of compounds manufactured according to the comparative example method.

[0062]

[0063] The present invention is described in detail below.

[0064] However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0065]

[0066] The reagents and solutions used in the examples below are as follows.

[0067] ReagentSupplierLot No.물 (H2O)N / AN / A메탄올 (MeOH)CONCORD TECHNOLOGY2022MH007Dichloromethane (DCM)SHENGDIDA220515214Hydrochloric acid (HCl)KERMEL20003568Tetrahydrofuran (THF)SHENGDIDA220529719ethyl acetate (EA)SHENGDIDA220605307Dimethyl Formamide (DMF)FUCHEN202201032,6-dimethylbenzaldehydeAnhui Senrise Technologies20015939(methoxymethyl)triphenylphosphonium chlorideBidepharmCQW597potassium tert-butylateEnergy chemicalMGESREX7Pd(OH)2 / C (Palladium hydroxide on carbon)N / AN / A수소 (hydrogen)N / AN / Adiisopropyl ether (DIPE)N / AN / A2,2-dimethylmalonic acidBidepharmCNC571oxalyl dichlorideEnergy chemicalODDD5RYQaluminium trichloride (AlCl3)N / AN / ABoron tribromide (BBr3)N / AN / Asodium borohydride (NaBH4)N / AN / Asodium cyanoborohydride (NaBH3CN)N / AN / A

[0068]

[0069] 실시예 1. 중간체 화합물의 제조

[0070] 실시예 1-1. 2-(2-methoxyethyl)-1,3-dimethylbenzene (화학식 1)의 합성

[0071]

[0072] 2,6-dimethylbenzaldehyde (1.2 kg, 8.94 mol, 1.0 eq) was added to (methoxymethyl)triphenylphosphonium chloride (5.4 kg, 15.75 mol, 1.5 eq) and potassium tert-butylate (1.8 kg, 16.04 mol, 1.5 eq) dissolved in THF (14.4 L) in an ice-water bath, and the mixture was stirred for 1 hour. 9 L of water was added to the mixture, followed by 24 ml of HCl, and extraction was performed using 20 L of EA. The organic phases were combined and concentrated, and the crude product mixed with impurities was purified by Prep-HPLC to obtain 1.1 kg of 2-(2-methoxyvinyl)-1,3-dimethylbenzene.

[0073] The obtained 2-(2-methoxyvinyl)-1,3-dimethylbenzene (300 g, 1.85 mol) was dissolved in 1 L of EA, and 60 g of Pd(OH)2 / C was added at room temperature. After adding hydrogen to the mixture, the mixture was stirred at 55°C for 12 hours, and then the mixture was filtered and concentrated to obtain 300 g of 2-(2-methoxyethyl)-1,3-dimethylbenzene (chemical formula 1).

[0074]

[0075] Example 1-2. Synthesis of dimethylmalonyl chloride (2,2-dimethylpropanedioyl dichloride) (chemical formula 2)

[0076]

[0077] 608 ml of oxalyl dichloride was added to 2,2-dimethylmalonic acid (335 g, 2.53 mol) dissolved in DMF (24 ml) and DCM (2.4 L) in an ice-water bath, and the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated to obtain 425 g of dimethylmalonyl chloride (formula 2).

[0078]

[0079] Example 2. Preparation of pterosin D

[0080] Example 2-1. Synthesis of 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Formula 3) (Friedel-crafts acylation)

[0081]

[0082] First, dissolve 1 g of the previously obtained 2-(2-methoxyethyl)-1,3-dimethylbenzene (chemical formula 1) in 20 ml of DCM (20 v / w), and then lower the temperature to 0°C. Add 3.37 g of AlCl3 all at once to the solution at 0°C (the solution turns yellow) and stir for 1 hour. Add 0.98 ml of the previously obtained dimethylmalonyl chloride (chemical formula 2) all at once and stir for another hour. Then, slowly add 50 ml of ice water to the reaction solution while being careful of the generation of heat and fumes, then transfer the solution to a separatory funnel, and perform primary extraction by adding 50 ml of ice water and 50 ml of DCM. Through this work-up, the yellow reaction solution turns transparent. After this, 100 ml of DCM is added to the aqueous layer to extract once more, and the organic layer is treated with MgSO4 to remove moisture and then concentrated under reduced pressure to obtain crude 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 3) mixed with impurities.

[0083]

[0084] Example 2-2. Synthesis of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) (BBr3demethylation)

[0085]

[0086] Dissolve 1.5 g of the crude 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione obtained previously in 30 ml of DCM, and then lower the temperature to 0℃. Slowly add 30.83 ml of BBr dropwise. Since BBr3 is highly reactive, do not add it all at once, but add it dropwise one by one. Once the addition is complete, stir at 0℃ for 3 hours. After that, slowly add 30 ml of ice water while being careful not to generate fumes, and then transfer to a separatory funnel and add 100 ml of DCM and 70 ml of ice water to perform the first extraction. After that, treat the organic layer with MgSO4 to remove moisture and concentrate under reduced pressure to obtain a crude brown oil. 30 ml of EtOH is added to the obtained crude, the resulting solid is filtered and discarded, the filtrate is collected and concentrated under reduced pressure, and the collected filtrate is crystallized using MeOH and DIPE to obtain 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4).

[0087]

[0088] Example 2-3. Synthesis of pterosin D

[0089]

[0090] 1 g of the previously obtained 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) was dissolved in THF. 15 eq of a boron-based reducing agent, NaBH3CN, dissolved in water was added thereto, and the mixture was stirred at 60°C for 24 hours. The mixture was then extracted three times with EA and H2O, and the organic layer was concentrated to obtain crystallized pterosin D.

[0091] The pterosin D obtained in this way was confirmed using proton nuclear magnetic resonance (H-NMR), and the results are shown in Fig. 2.

[0092]

[0093] Comparative Example 1. Synthesis of pterosin D

[0094]

[0095] For comparison with the above Example 2-3, pterosin D was prepared from the previously obtained 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) according to a conventionally known method.

[0096] First, dissolve 0.5 g of the compound of the above chemical formula 4 in 10 ml of MeOH, then lower the temperature to 0°C. Add 0.12 g of NaBH4 while being careful not to generate bubbles, and stir for 1 hour and 30 minutes. Then, add 10 ml of saturated NH4Cl to the reaction solution, transfer to a separatory funnel, and wash once by adding 100 ml of EA, 20 ml of saturated NH4Cl, and 50 ml of H2O. Add 100 ml of H2O to the organic layer, wash once more, and then obtain pterosin D through a crystallization process.

[0097]

[0098] Example 3. Comparison of manufacturing methods according to examples and comparative examples.

[0099] The method for producing pterosin D according to the above Example 2-3 was compared with the method for producing pterosin D according to Comparative Example 1.

[0100] First, in the case of the method according to Comparative Example 1, a large amount of flexible substances were generated due to high reactivity, and thus pterosin D could be obtained only after going through a lot of silica column chromatography. As a result of confirming this using HPLC, the purity of the produced pterosin D was 92.6% (see Figures 3a and 3b), and the yield was only 36%.

[0101] In contrast, in the case of the method according to Examples 2-3 of the present invention, the generation of related substances could be minimized by lowering the reactivity, and accordingly, pterosin D could be obtained through simple crystallization without silica column chromatography. As a result of confirming this using HPLC, the purity of the manufactured pterosin D was 98.1% (see FIGS. 4a to 4b), and the yield was 70%. This means that pterosin D with a superior purity could be manufactured at a significantly higher yield, about twice, compared to the manufacturing method according to the conventional Comparative Example 1. The above results are summarized in Table 2 below.

[0102]

[0103] Classification Reagent Solvent Purity Yield Remarks Comparison Example NaBH4MeOH 92.6% 36% High reactivity, generates a lot of flexible substances Example NaBH3CNTHF / H2O 98.1% 70% Reduces reactivity to minimize the generation of flexible substances, improving yield and quality

[0104]

[0105] As described above, the method for producing pterosin D according to the present invention can produce pterosin D of excellent purity in a high yield and is suitable for mass production, and therefore can be usefully used in drug research and production of pharmaceuticals based on pterosin D, and thus has high industrial applicability.

Claims

In a method for producing pterosin D, the method comprises: (a) a step of dissolving a compound of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 4) in an ether solvent; (b) a step of dissolving a boron series reducing agent in water, adding it, and stirring to reduce it; (c) a step of extracting by adding ethyl acetate (EA) and water; and (d) a step of concentrating and crystallizing the organic layer; A method for producing pterosin D, characterized in that it comprises: A method for producing pterosin D, characterized in that in the first paragraph, the ether solvent of step (a) is any one of tetrahydrofuran (THF), dimethyl ether, diethyl ether, or ethylene glycol dimethyl ether. A method for producing pterosin D, characterized in that in the first paragraph, the ether solvent of step (a) is tetrahydrofuran. A method for producing pterosin D, characterized in that in claim 1, the boron-based reducing agent of step (b) is any one of sodium cyanoborohydride (NaBH3CN), pyridine-borane (Py-BH3), dimethylamine-borane, trimethylamine-borane, or isopropoxyborohydride (iPrOBH3). A method for producing pterosin D, characterized in that in the first paragraph, the boron series reducing agent of step (b) is sodium cyanoborohydride (NaBH3CN). A method for producing pterosin D, characterized in that in the first paragraph, the stirring in step (b) is performed at 40°C to 80°C. A method for producing pterosin D, characterized in that in the first paragraph, the stirring in step (b) is performed at 50°C to 70°C. A method for producing pterosin D, characterized in that in the first paragraph, the stirring in step (b) is performed at 55°C to 65°C. A method for producing pterosin D, characterized in that in the first paragraph, step (c) is performed once, twice, three times, four times or five times. In the first paragraph, the compound of chemical formula 4 of step (a) is (1) A step of synthesizing a 2-(2-methoxyethyl)-1,3-dimethylbenzene (chemical formula 1) compound and a Dimethylmalonyl chloride (chemical formula 2) compound into a 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 3) compound using a Friedel-crafts acylation reaction; , , (2) a step of demethylating the compound of formula 3 synthesized in (1) above by treating it with BBr3; and (3) Crystallization step using methanol and diisopropyl ether (DIPE); A method for producing pterosin D, characterized in that it is synthesized using a method including: In the first paragraph, the compound of chemical formula 4 of step (a) is (1) A step of synthesizing a 2-(2-methoxyethyl)-1,3-dimethylbenzene (chemical formula 1) compound and a Dimethylmalonyl chloride (chemical formula 2) compound into a 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (chemical formula 3) compound using a Friedel-crafts acylation reaction; , , (2) a step of demethylating the compound of formula 3 synthesized in (1) above by treating it with BBr3; and (3) Step of crystallization through column chromatography using silica gel; A method for producing pterosin D, characterized in that it is synthesized using a method including:

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