Method for synthesizing pterosin d using ammonia-based reducing agent

Abstract

The present invention relates to a method for synthesizing pterosin D using an ammonia-based reducing agent, and more specifically, to a method for synthesizing pterosin D by dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent and then adding an ammonia-based reducing agent thereto. In addition, the method for preparing pterosin D according to the present invention enables the production of pterosin D with high yield and excellent purity, and is suitable for mass production, thereby being useful for drug research and pharmaceutical production based on pterosin D.

Description

Synthesis method of pterosin D using ammonia-based reducing agents

[0001] The present invention relates to a method for synthesizing pterosin D using an ammonia-based reducing agent, and more specifically, to a method for synthesizing pterosin D by dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent and then adding an ammonia-based reducing agent.

[0002] Pterosin, possessing a 1-indanone skeleton, is a compound belonging to the sesquiterpenoid and norsesquiterpenoid classes that was first isolated from the fern *Pteridium aquilinum* in Japan. Since then, it has been confirmed that this compound is widely expressed in ferns and is known to be found in certain fungi belonging to the phylum Basidiomycetes, such as *Fomes annosus*, *Fomitopsis insularis*, and *Cyathus bulleri*. Approximately 31 types of pterosin, including pterosin A, B, C, D, E, F, K, and L, have been isolated from various ferns. These pterosin compounds are known to have various effects, such as preventing diabetes and obesity, hair loss, and degenerative brain diseases, and are therefore receiving attention as substances for the development of new drugs for various diseases.

[0003] Against this backdrop, the currently known methods for producing pterosin, particularly pterosin D, are limited to direct extraction from bracken followed by separation and purification using chromatography, or chemical methods. The method of extraction from bracken has the disadvantage of high production costs due to low yields and the need for a separate process to isolate and purify only pterosin D from the extract. Meanwhile, the chemical methods known to date suffer from low yields, as they are intended for small-scale production for research purposes.

[0004] Therefore, there is an increasing need for a method to mass-produce pterosin D with high yield and excellent purity suitable for clinical administration, for the research and production of pterosin D-based drugs.

[0005] The objective of the present invention is to provide a step of preparing a first solution by dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent; a step of preparing a second solution by dissolving an ammonia-based reducing agent in water; a step of reducing the first solution by adding the second solution and stirring; and (d) a step of concentrating an organic layer to form crystals.

[0006] Another objective of the present invention is to provide a method capable of producing pterosin D of excellent purity suitable for clinical administration in large quantities with high yield.

[0007] The technical problems that the invention aims to solve are not limited to those mentioned above, and other unmentioned technical problems can be clearly understood by those skilled in the art from the description of the invention.

[0008] The present invention provides a method for producing pterosin D, characterized by comprising: (a) a step of preparing a first solution by 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 preparing a second solution by dissolving an ammonia-based reducing agent in water; (c) a step of preparing a reduced product by adding the second solution to the first solution and stirring; and (d) a step of concentrating the reduced product to produce crystals.

[0009] In the present invention, the ether solvent of step (a) is characterized as being tetrahydrofuran (THF), dimethyl ether, diethyl ether, or ethylene glycol dimethyl ether.

[0010] In the present invention, the ammonia-based reducing agent of step (b) is characterized as being ammonia borane (AB).

[0011] In the present invention, step (a) is characterized by preparing a first solution by 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 at a concentration of 0.4 to 0.5% (w / v).

[0012] In the present invention, step (b) is characterized by preparing a second solution by dissolving ammonia borane (AB) in water at a concentration of 2.5 to 3.5% (w / v).

[0013] In the present invention, step (c) is characterized by adding the second dissolved substance to the first dissolved substance and stirring at 20 to 40°C for 3 to 5 hours.

[0014] In the present invention, the step (a) comprises: (a1) synthesizing the compound 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 3) from the compound 2-(2-methoxyethyl)-1,3-dimethylbenzene (Chemical Formula 1) and the compound dimethylmalonyl chloride (Chemical Formula 2) using a Friedel-Crafts acylation reaction; (a2) demethylating the compound of Chemical Formula 3 synthesized in step (a1) by treating it with BBr3; and (a3) ​​crystallizing it using methanol and diisopropyl ether (DIPE).

[0015]

[0016] In the present invention, the method for producing pterosin D is characterized by further including the step of adding water to the crystal of step (d), cooling, and filtering.

[0017] In addition, the present invention provides pterosin D produced according to the method for producing pterosin D.

[0018] In the present invention, the pterosin D is characterized as a substance having a mass-to-charge ratio (m / z) measured by LC-MS analysis in the range of 200 to 300 m / z.

[0019] In the present invention, the pterosin D is hydrogen nuclear magnetic resonance spectroscopy ( 1 As a result of H NMR spectroscopy analysis, it is characterized by showing peaks at 1H 7.38±0.5 ppm, 1H 4.76±0.5 ppm, 2H 3.62±0.2 ppm, 2H 3.01±0.2 ppm, 3H 2.66±0.05 ppm, 3H 2.50±0.05 ppm, 3H 1.20±0.05 ppm, and 3H 1.06±0.05 ppm.

[0020] The present invention can provide a method for synthesizing pterosin D using ammonia borane (AB), an ammonia-based reducing agent.

[0021] In addition, the method for producing pterosin D according to the present invention can produce pterosin D of excellent purity with a high yield and is suitable for mass production, so it can be usefully utilized in drug research and the production of pharmaceuticals based on pterosin D.

[0022] The effects of the present invention are not limited to those mentioned above, and other unmentioned effects will be clearly understood by those skilled in the art from the description in the claims.

[0023] Figure 1 is a schematic diagram showing the process of synthesizing 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 3) using the Friedel-crafts acylation reaction.

[0024] Figure 2 is a schematic diagram showing the synthesis process of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 4) using a BBr3 demethylation reaction.

[0025] Figure 3 is a schematic diagram showing the process of synthesizing pterosin D using ammonia borane as a reducing agent.

[0026] Figure 4 shows pterosin D synthesized using ammonia borane as a reducing agent. 1 This is a figure showing the results of the H NMR analysis.

[0027] Figure 5 shows the LC-MS analysis results of pterosin D synthesized using ammonia borane as a reducing agent.

[0028] Figure 6 shows the HPLC analysis results of pterosin D synthesized using ammonia borane as a reducing agent.

[0029] The terms used in this specification have been selected based on currently widely used general terms whenever possible, taking into account their functions in the present invention; however, these terms may vary depending on the intent of those skilled in the art, case law, the emergence of new technologies, etc. Additionally, in specific cases, terms have been arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the relevant description of the invention. Therefore, the terms used in this invention should be defined not merely by their names, but based on their meanings and the overall content of the invention.

[0030] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0031] Numerical ranges include the values ​​defined in the above ranges. All maximum numerical limits given throughout this specification include all lower numerical limits as clearly written. All minimum numerical limits given throughout this specification include all higher numerical limits as clearly written. All numerical limits given throughout this specification will include all better numerical ranges within a wider numerical range, as clearly written.

[0032]

[0033] The present invention will be described in detail below.

[0034]

[0035] The present invention provides a method for producing pterosin D, characterized by comprising: (a) a step of preparing a first solution by dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent; (b) a step of preparing a second solution by dissolving an ammonia-based reducing agent in water; (c) a step of preparing a reduced product by adding the second solution to the first solution and stirring; and (d) a step of concentrating the reduced product to produce crystals.

[0036] While researching a method to increase purity and yield in a conventionally known method for manufacturing pterosin D, the inventors confirmed that pterosin D of superior purity can be produced in a high yield 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 an ammonia-based reducing agent dissolved in water.

[0037]

[0038] Hereinafter, each step of the method for manufacturing pterosin D of the present invention will be described in detail.

[0039]

[0040] (a) a step of preparing a first solution by dissolving a 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound in an ether solvent;

[0041]

[0042] In step (a) above, the compound 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 4) refers to a compound having the following chemical structure.

[0043]

[0044] The ether solvent in step (a) above may be tetrahydrofuran (THF), dimethyl ether, diethyl ether, or ethylene glycol dimethyl ether, and preferably tetrahydrofuran (THF).

[0045] Step (a) above may be characterized by preparing a first solution by 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 at a concentration of 0.4 to 0.5% (w / v), preferably at a concentration of 0.41 to 0.49% (w / v), 0.42 to 0.48% (w / v), 0.43 to 0.47% (w / v), or 0.44 to 0.46% (w / v), more preferably at a concentration of 0.45 to 0.46% (w / v).

[0046] The above step (a) may include: (a1) synthesizing the compound 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 3) from the compound 2-(2-methoxyethyl)-1,3-dimethylbenzene (Chemical Formula 1) and the compound dimethylmalonyl chloride (Chemical Formula 2) using a Friedel-crafts acylation reaction; (a2) demethylating the compound of Chemical Formula 3 synthesized in step (a1) by treating it with BBr3; and (a3) ​​crystallizing it using methanol and diisopropyl ether (DIPE).

[0047]

[0048] In step (a1) above, the 2-(2-methoxyethyl)-1,3-dimethylbenzene compound may refer to a compound having the structure of Chemical Formula 1 below, the dimethylmalonyl chloride compound may refer to a compound having the structure of Chemical Formula 2 below, and the 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione compound may refer to a compound having the structure of Chemical Formula 3 below.

[0049]

[0050] The above step (a1) may include: (a1-1) a step of preparing a fourth mixture by dissolving the compound of Formula 1 in dichloromethane (DCM); (a1-2) a step of adding AlCl3 to the fourth mixture and stirring; (a1-3) a step of adding the compound of Formula 2 to the stirred fourth mixture; (a1-4) a step of preparing a fifth mixture by adding ice water to the fourth mixture to which the compound of Formula 2 has been added; and (a1-5) a step of treating the organic layer of the fifth mixture with MgSO4.

[0051] The above step (a1-1) may be characterized by dissolving the compound of Formula 1 in a DCM solvent at a concentration of 10 to 30 %v / w, preferably at a concentration of 11 to 29 %v / w, 12 to 28 %v / w, 13 to 27 %v / w, 14 to 26 %v / w, 15 to 25 %v / w, 16 to 24 %v / w, 17 to 23 %v / w, or 18 to 22 %v / w, and more preferably at a concentration of 19 to 21 %v / w.

[0052] The above step (a1-2) may be characterized by stirring for 0.5 to 2 hours after adding AlCl3 to the fourth mixture, preferably for 0.5 to 1.5 hours, 0.6 to 1.4 hours, 0.7 to 1.3 hours, or 0.8 to 1.2 hours, more preferably for 0.9 to 1.1 hours.

[0053] The above step (a1-2) may be characterized by adding 3 to 4 parts by weight of AlCl3, preferably 3.2 to 3.6 parts by weight, and more preferably 3.3 to 3.4 parts by weight to the fourth mixture for every 1 part by weight of the compound of Formula 1 of the above step (a1-1).

[0054]

[0055] The above step (a2) may be characterized by dissolving the compound of Formula 3 synthesized in step (a1) in DCM, then adding BBr3 drop by drop and stirring.

[0056] In step (a2) above, the compound of Formula 3 can be dissolved in DCM at a concentration of 4 to 6% (w / v), preferably the compound of Formula 3 can be dissolved in DCM at a concentration of 4.1 to 5.9% (w / v), 4.2 to 5.8% (w / v), 4.3 to 5.7% (w / v), 4.4 to 5.6% (w / v), 4.5 to 5.5% (w / v), 4.6 to 5.4% (w / v), 4.7 to 5.3% (w / v), or 4.8 to 5.2% (w / v), and more preferably at a concentration of 4.9 to 5.1% (w / v).

[0057]

[0058] The above step (a3) ​​may be characterized by crystallizing using methanol and diisopropyl ether (DIPE), but is not limited thereto. However, a method of crystallizing by treating with methanol and DIPE may be more preferable in that it is more suitable for a mass production process.

[0059]

[0060] The method for preparing the compound of Formula 4 described above is merely an example, and it is obvious to a person skilled in the art that in the method for preparing pterosin D according to the present invention, the method according to the present invention can be applied equally regardless of how the compound of Formula 4 is prepared.

[0061]

[0062] (b) a step of preparing a second solution by dissolving an ammonia-based reducing agent in water;

[0063] The above step (b) may be characterized by dissolving an ammonia-based reducing agent in water to produce a second solution.

[0064] In step (b) above, the second solution may be prepared by dissolving an ammonia-based reducing agent in water at a concentration of 2.5 to 3.5% (w / v), preferably by dissolving an ammonia-based reducing agent in water at a concentration of 2.6 to 3.4% (w / v), 2.7 to 3.3% (w / v), 2.8 to 3.2% (w / v), or 2.9 to 3.1% (w / v), and more preferably by dissolving an ammonia-based reducing agent in water at a concentration of 3.0 to 3.1% (w / v).

[0065]

[0066] (c) a step of preparing a reduced product by adding the second dissolved product to the first dissolved product and stirring;

[0067] The above step (c) may be characterized by preparing a reduced product by adding the second dissolved product to the first dissolved product and stirring at 20 to 40°C for 3 to 5 hours, preferably by preparing the reduced product by stirring at 21 to 39°C, 22 to 38°C, 23 to 37°C, 24 to 36°C, 25 to 35°C, 26 to 34°C, 27 to 33°C, or 28 to 32°C for 3.1 to 4.9 hours, 3.2 to 4.8 hours, 3.3 to 4.7 hours, 3.4 to 4.6 hours, 3.5 to 4.5 hours, 3.6 to 4.4 hours, 3.7 to 4.3 hours, or 3.8 to 4.2 hours, and more preferably by stirring at 29 to 31°C for 3.9 to 4.1 hours. It can be characterized by manufacturing.

[0068]

[0069] (d) a step of concentrating the above-mentioned reduction product to form crystals;

[0070] Step (d) above 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 can be appropriately performed by a person skilled in the art based on common technical knowledge in the art, but preferably, the crystals may be produced by concentrating the reduction product under reduced pressure.

[0071] Additionally, the above step (d) may further include the steps of adding water to the crystal, cooling, and filtering.

[0072]

[0073] According to one embodiment of the present invention, the present invention can provide pterosin D produced according to the pterosin D production method described above.

[0074] According to one embodiment of the present invention, pterosin D having a purity of 97.8% can be produced with a final yield of 87% using the manufacturing method of the present invention.

[0075] According to one embodiment of the present invention, the pterosin D may be characterized as a material having a mass-to-charge ratio (m / z) measured by LC-MS analysis in the range of 200 to 300 m / z, preferably in the range of 210 to 290 m / z, in the range of 220 to 280 m / z, in the range of 230 to 270 m / z, or in the range of 230 to 260 m / z, more preferably in the range of 240 to 250 m / z.

[0076] According to one embodiment of the present invention, the pterosin D is hydrogen nuclear magnetic resonance spectroscopy ( 1 Based on the results of H NMR spectroscopy analysis, it may be characterized by exhibiting peaks at 1H 7.38±0.5 ppm, 1H 4.76±0.5 ppm, 2H 3.62±0.2 ppm, 2H 3.01±0.2 ppm, 3H 2.66±0.05 ppm, 3H 2.50±0.05 ppm, 3H 1.20±0.05 ppm, and 3H 1.06±0.05 ppm, and more preferably at 1H 7.38±0.2 ppm, 1H 4.76±0.2 ppm, 2H 3.62±0.1 ppm, 2H 3.01±0.1 ppm, 3H 2.66±0.02 ppm, 3H 2.50±0.02 ppm, and 3H It can be characterized by showing a peak at 1.20±0.02 ppm and 3H at 1.06±0.02 ppm.

[0077]

[0078] The embodiments of the present invention are described in detail below, but it is obvious that the present invention is not limited by the following embodiments.

[0079]

[0080] The reagents and solutions used in the following examples are as shown in Table 1.

[0081]

[0082] 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 / A

[0083]

[0084] 실시예 1. H3NBH3를 이용한 프테로신 D (pterosin D)의 합성

[0085]

[0086] 1-1. 2-(2-methoxyethyl)-1,3-dimethylbenzene(화학식 1)의 합성

[0087]

[0088] A first mixture was prepared by adding 2,6-dimethylbenzaldehyde (1.2 kg, 8.94 mol, 1.0 eq) 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 bath and stirring for 1 hour. 9 L of water was added to the first mixture, followed by the addition of 24 ml of HCl, and extraction was performed using 20 L of EA. The organic phases were combined and concentrated, and the crude product containing impurities was purified by Prep-HPLC to obtain 1.1 kg of 2-(2-methoxyvinyl)-1,3-dimethylbenzene.

[0089] The obtained 2-(2-methoxyvinyl)-1,3-dimethylbenzene (300g, 1.85mol) was dissolved in 1L of EA, and 60g of Pd(OH)2 / C was added at room temperature to prepare a second mixture. After adding hydrogen to the second mixture, the mixture was stirred at 55°C and 60 Psi for 12 hours, and then the second mixture was filtered and concentrated to obtain 300g of 2-(2-methoxyethyl)-1,3-dimethylbenzene (Chemical Formula 1).

[0090]

[0091] 1-2. Synthesis of dimethylmalonyl chloride (2,2-dimethylpropanedioyl dichloride) (Chemical Formula 2)

[0092]

[0093] A third mixture was prepared by adding 608 ml of oxalyl dichloride to 2,2-dimethylmalonic acid (335 g, 2.53 mol) dissolved in DMF (24 ml) and DCM (2.4 L) in an ice bath, and stirring at room temperature for 16 hours. The third mixture was concentrated to obtain 425 g of dimethylmalonyl chloride (Formula 2).

[0094]

[0095] 1-3. Synthesis of 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Formula 3) using Friedel-Crafts acylation reaction

[0096]

[0097] First, 1 g of the previously obtained 2-(2-methoxyethyl)-1,3-dimethylbenzene (Chemical Formula 1) was dissolved in 20 ml of DCM (20% v / w) to prepare the fourth mixture, and then the temperature of the fourth mixture was lowered to 0°C. 3.37 g of AlCl3 was added to the fourth mixture all at once and stirred for 1 hour (at this point, the solution turns yellow).

[0098] 0.98 ml of dimethylmalonyl chloride (Formula 2) obtained in Examples 1-2 was added all at once to the stirred fourth mixture and stirred again for 1 hour. Subsequently, 50 ml of ice water was slowly added while taking care to avoid heat and fume generation to prepare the fifth mixture. Then, the fifth mixture was transferred to a separatory funnel, and 50 ml of ice water and 50 ml of DCM were added for primary extraction. Through this process, the fifth mixture, which was yellow, turned transparent. Afterward, 100 ml of DCM was added to the aqueous layer of the fifth mixture for further extraction, and water was removed from the organic layer by treating it with MgSO4. Subsequently, by concentrating under reduced pressure, 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Formula 3) in a crude state mixed with impurities was obtained. The synthesis process of Examples 1-3 is shown in Fig. 1.

[0099]

[0100] 1-4. Synthesis of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Formula 4) using BBr3 demethylation reaction

[0101]

[0102] 1.5 g of the crude 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione obtained in Examples 1-3 above was dissolved in 30 ml of DCM, and the temperature was lowered to 0°C. At this temperature, 0.83 ml of BBr3 was added dropwise. Since BBr3 is highly reactive, it should not be added all at once but added drop by drop. Once the addition was complete, the mixture was stirred at 0°C for 3 hours. Subsequently, 30 ml of ice water was added slowly while taking care to prevent fume generation, then transferred to a separatory funnel, and 100 ml of DCM and 70 ml of ice water were added for the first extraction. Afterward, the organic layer was treated with MgSO4 to remove moisture, and the crude brown oil was obtained by concentrating under reduced pressure. 30 ml of EtOH was added to the obtained crude, and the resulting solid was filtered and discarded. The filtrate was collected and concentrated under reduced pressure, and the collected filtrate was crystallized using MeOH and DIPE to obtain 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 4). The synthesis process of Examples 1-4 is shown in Figure 2.

[0103]

[0104] 1-5. Synthesis of Pterosin D

[0105]

[0106] 3.37 g (150.22 mmol) of 5-(2-hydroxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 4) obtained in Examples 1-4 above was dissolved in 740 mL (20T) of tetrahydrofuran (THF) in a reactor to prepare a first solution. At this time, the compound of Chemical Formula 4 was dissolved in THF solvent at a concentration of 0.455% (w / v). 5.56 g (1.2 eq) of ammonia borane (Ammonia borane, AB) was dissolved in 180 mL of water to prepare a second solution. At this time, the ammonia borane was dissolved in water at a concentration of 3.08% (w / v). The second solution was slowly added to the reactor and stirred at 30°C for 4 hours to prepare a reduced product. The above reduction product was concentrated under reduced pressure to produce crystals, 740 mL of water was added to the crystals, and the mixture was cooled to 0°C. Subsequently, 32.5 g of pterosin D was obtained by stirring and filtration. At this time, the yield was 87% and the purity was 97.8%. The synthesis process of Examples 1-5 is shown in Fig. 3.

[0107]

[0108] Comparative Example 1. Synthesis of pterosin D using NaBH4

[0109]

[0110] Unlike Example 1 above, pterosin D was synthesized using sodium borohydride (NaBH4) as a reducing agent. More specifically, the compound of Formula 4 was prepared in the same manner as in Examples 1-1 to 1-4 above.

[0111] Next, 0.5 g of the compound of Chemical Formula 4 was dissolved in 10 mL of MeOH and the temperature was lowered to 0°C. Then, 0.12 g (0.3 eq) of NaBH4 was added while taking care to prevent bubble formation, and the mixture was stirred for 1 hour and 30 minutes. Afterward, 10 mL of saturated NH4Cl was added to the reaction solution, transferred to a separatory funnel, and washed once by adding 100 mL of EA, 20 mL of saturated NH4Cl, and 50 mL of H2O. After washing the resulting organic layer once more by adding 100 mL of H2O, pterosin D was obtained through a crystallization process. As a result of Comparative Example 1, pterosin D was synthesized with a purity of 92.6% and a yield of 36%.

[0112]

[0113] Comparative Example 2. Synthesis of Pterosin D using NaBH3CN

[0114]

[0115] Unlike Example 1 above, pterosin D was synthesized using sodium cyanoborohydride (NaBH3CN) as a reducing agent. More specifically, a compound of Formula 4 was prepared in the same manner as in Examples 1-1 to 1-4 above.

[0116] Next, 1 g of the compound of Chemical Formula 4 above was dissolved in THF. To this, 3.8 g (15 eq) of the reducing agent NaBH3CN dissolved in water was added, and the mixture was stirred at 60°C for 24 hours. Afterward, the mixture was extracted three times with EA and H2O, and the resulting organic layer was concentrated to obtain crystallized pterosin D. As a result of Comparative Example 2, pterosin D was synthesized with a purity of 98.1% and a yield of 70%.

[0117]

[0118] Experimental Example 1. Pterosin D 1 H NMR Spectroscopic Analysis

[0119] The pterosin D prepared in Example 1 above 1It was analyzed using ¹H NMR spectroscopy. The NMR measurement results of the above pterosin D are shown in Figure 4.

[0120] 1 H NMR (400 MHz, CDCl3): δ 7.38 (s, 1H), 4.76 (s, 1H), 3.62 (d, J = 8Hz, 2H), 3.01 (d, J = 8Hz, 2H), 2.66 (s, 3H), 2.50 (s, 3H), 1.20 (s, 3H), 1.06 (s, 3H)

[0121]

[0122] Experimental Example 2. Pterosin D LC-MS Analysis

[0123] The pterosin D prepared in Example 1 above was analyzed by liquid chromatography-mass spectrometry (LC-MS), and the results are shown in Fig. 5. As a result of Experimental Example 2 above, the mass-to-charge ratio (m / z) of pterosin D of Example 1 was confirmed to be 249.29.

[0124]

[0125] Experimental Example 3. Comparison of Purity and Yield of Pterosin D According to Type of Reducing Agent

[0126] The purity and yield of pterosin D prepared in Example 1 and Comparative Examples 1 and 2 were compared and are shown in Table 2 below. More specifically, in Example 1, pterosin D was synthesized using H3NBH3 as a reducing agent, in Comparative Example 1, pterosin D was synthesized using NaBH4 as a reducing agent, and in Comparative Example 2, pterosin D was synthesized using NaBH3CN as a reducing agent.

[0127]

[0128] Classification Reagent Solvent Purity Yield Remarks Example 1 H3NBH3THF / H2O 97.8% 87% Excellent quality and yield due to the use of a low-cost reducing agent, reduction of reducing agent usage to 1 / 12, and not conducting the reaction at high temperatures. Smooth supply of new reducing agents and easy preparation and use of reducing agents. Comparative Example 1 NaBH4MeOH 92.6% 36% High reactivity results in significant generation of impurities and low yield. Comparative Example 2 NaBH3CNTHF / H2O 98.1% 70% Yield and quality were improved by minimizing the generation of impurities, but there are issues such as high reducing agent usage and difficulty in supplying the reducing agent.

[0129]

[0130] Referring to Table 2, the yields of pterosin D prepared in Comparative Examples 1 and 2 were only 36% and 70%, respectively, but the yield of pterosin D prepared in Example 1 was 87%, indicating a very excellent yield of the obtained compound. In addition, the purity of pterosin D prepared in Example 1 was 97.8%, which was very excellent.

[0131] More specifically, when comparing NaBH4 and H3NBH3, using H3NBH3 as a reducing agent resulted in a milder compound synthesis reaction, leading to significantly improved yield and quality.

[0132] In addition, when H3NBH3 was used as a reducing agent, the amount of reducing agent used was reduced to about 1 / 12 compared to when NaBH3CN was used as a reducing agent, and the reaction proceeded gently by lowering the temperature. Furthermore, when H3NBH3 was used as a reducing agent compared to when NaBH3CN was used as a reducing agent, the quality of the synthesized pterosin D was superior and the yield increased by 13%.

[0133] Finally, while NaBH3CN is difficult to source, H3NBH3 has the advantage of being readily available, making it easier to synthesize pterosin D.

[0134]

[0135] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. (a) A step of preparing a first solution by 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 preparing a second solution by dissolving an ammonia-based reducing agent in water; (c) a step of preparing a reduced product by adding the second dissolved product to the first dissolved product and stirring; and (d) a step of concentrating the above-mentioned reduction product to form crystals; A method for producing pterosin D characterized by including 2. In Paragraph 1, The ether solvent of step (a) above is A method for producing pterosin D characterized by being tetrahydrofuran (THF), dimethyl ether, diethyl ether, or ethylene glycol dimethyl ether.

3. In Paragraph 1, The ammonia-based reducing agent of step (b) above A method for producing pterosin D characterized by being ammonia borane (AB).

4. In Paragraph 1, The above (a) step A method for preparing pterosin D characterized by preparing a first solution by 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 at a concentration of 0.4 to 0.5% (w / v).

5. In Paragraph 1, The above step (b) A method for producing pterosin D characterized by dissolving ammonia borane (AB) in water at a concentration of 2.5 to 3.5% (w / v) to produce a second solution.

6. In Paragraph 1, The above (c) step A method for producing pterosin D characterized by adding the second dissolved product to the first dissolved product and stirring at 20 to 40°C for 3 to 5 hours.

7. In Paragraph 1, The above (a) step (a1) A step of synthesizing the compound 5-(2-methoxyethyl)-2,2,4,6-tetramethyl-1H-indene-1,3(2H)-dione (Chemical Formula 3) from the compound 2-(2-methoxyethyl)-1,3-dimethylbenzene (Chemical Formula 1) and the compound dimethylmalonyl chloride (Chemical Formula 2) using a Friedel-crafts acylation reaction; (a2) a step of demethylating the compound of Formula 3 synthesized in step (a1) by treating it with BBr3; and (a3) A method for producing pterosin D characterized by including the step of crystallizing using methanol and diisopropyl ether (DIPE).

8. In Paragraph 1, The above method for manufacturing pterosin D is A method for producing pterosin D characterized by further including the steps of adding water to the crystal of step (d) above, and cooling and filtering.

9. Pterosin D produced according to the manufacturing method according to any one of paragraphs 1 through 8.

10. In Paragraph 9, The above pterosin D is Pterosin D, characterized by being a substance having a mass-to-charge ratio (m / z) in the range of 200 to 300 m / z as measured by LC-MS analysis.

11. In Paragraph 9, The above pterosin D is Hydrogen nuclear magnetic resonance spectroscopy ( 1 Pterosin D, characterized by exhibiting peaks at 7.38±0.5 ppm, 4.76±0.5 ppm, 3.62±0.2 ppm, 3.01±0.2 ppm, 2.66±0.05 ppm, 2.50±0.05 ppm, 1.20±0.05 ppm, and 1.06±0.05 ppm, as a result of 1H NMR spectroscopy analysis.

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