An efficient process for synthesizing theacrine

Abstract

The present invention provides an industrial process for synthesizing high-purity, high-quality theacrine.

Description

[Technical Field]

[0001] The present invention relates to an industrial process for synthesizing high-purity, high-quality theacrine. [Background technology]

[0002] Theacrine, a form of tetramethyluric acid, is a caffeine metabolite present in low concentrations in various coffee plants. Chemically, theacrine is 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione and has the following structure:

[0003] [ka]

[0004] Recently, studies have shown that caffeine and theacrine have similar physiological properties without any undesirable stimulating effects due to their structural similarity to methylxanthines. The available toxicological information on the molecule indicates that theacrine does not pose genotoxic or health hazards, and therefore theacrine is of continuing interest as an ingredient in functional foods and dietary supplements.

[0005] This purine alkaloid is present in low amounts in coffee plants and its extraction process is tedious. Available reports in the literature indicate that the biotransformation of natural sources such as caffeine into theacrine compound is expensive, inefficient, and atom-inefficient, making it difficult to commercialize. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, the inventors considered that it would be possible to fill the unmet gap in the production of theacrine (2) by providing an industrial synthesis method that is not limited by raw materials and that can obtain theacrine in sufficient quantities for industrial use. [Means for solving the problem]

[0007] In order to achieve the above object, the present invention provides a process for efficiently synthesizing theacrine, which comprises reacting a compound represented by formula I with a methylating agent in the presence of a base to obtain theacrine (2). The synthesis process is shown in Scheme 1 below.

[0008] Scheme 1 : [ka]

[0009] where: R1 is hydrogen or methyl; R2 is hydrogen or absent; and R3 is methyl; The dashed bond can be a single or double bond; however, If the dashed bond is a double bond to oxygen, R1 and R2 are hydrogen and R3 is absent; however, If the dashed bond is a single bond to oxygen, R1 and R3 are methyl and R2 is absent.

[0010] Thus, in one embodiment, the compound of formula I is selected from the compounds of formula 1 and formula 3 shown below.

[0011] [ka] DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention will be described in detail with reference to various preferred and optional embodiments thereof, which should not be construed as limiting the scope of the invention.

[0013] In one embodiment, the present invention aims to provide a process for preparing theacrine (2) in an efficient and industrially scalable manner.

[0014] In pursuit of the above objectives, the present inventors have explored a method for synthesizing theacrine by reacting 1,3-dimethyl-1H-purine-2,6,8(3H,7H,9H)-trione (the compound represented by formula 1) with various methylating agents in the presence of various bases and solvents to produce theacrine (2).

[0015] Thus, in one embodiment, the methylation reaction was explored using a methylating agent selected from the group consisting of dimethyl sulfate, DMF-DMA, methyl iodide, trimethyl phosphate, and the like.

[0016] In another embodiment, the methylation reaction was carried out in the presence of various organic and inorganic bases, more preferably, the methylation reaction was carried out using an inorganic base selected from the group consisting of sodium hydroxide, sodium hydride, potassium carbonate, etc.

[0017] In yet another embodiment, the methylation reaction was also explored in the presence of various solvents selected from the group consisting of alcoholic solvents (e.g., methanol), water, acetone, DMF, DMA, NMP, and the like.

[0018] In yet another embodiment, the methylation reaction was carried out under various temperature conditions ranging from 50°C to 170°C.

[0019] The results of various embodiments of the methylation reaction of compounds of Formula 1 are disclosed in Table 1. The methylation reaction is shown in Scheme 2.

[0020] Scheme 2 : [ka]

[0021] [Table 1]

[0022] As can be seen from Scheme 2 and Table 1 (serial numbers 1-5), the methylation of trione intermediate 1 using various methylating agents and reaction conditions to obtain theacrine 2 resulted in the formation of compound 3 as an impurity in various proportions ranging from 10 to 25%. The presence of compound 3 in the product makes purification difficult, reduces atom efficiency, and therefore incurs additional costs.

[0023] Thus, in one preferred embodiment, the present invention provides a method for preparing theacrine, comprising methylating compound (1) with trimethyl phosphate in the presence of a base to obtain theacrine (2). In one embodiment, the base is selected from the group consisting of sodium hydroxide, sodium hydride, and potassium carbonate.

[0024] In another embodiment, the reaction is carried out in the presence of a solvent selected from the group consisting of methanol, acetone, dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine, acetonitrile, ethyl acetate, and the like.

[0025] In one of the preferred embodiments, the solvent is dimethylformamide.

[0026] In one embodiment, the methylation reaction of compound 1 can be carried out at a temperature ranging from 50 to 170° C. More preferably, the methylation reaction is carried out at a temperature of 150° C., which provides theacrine in good yield and high purity.

[0027] Thus, in one embodiment, the inventors developed reaction conditions using trimethyl phosphate as the methylating agent in the presence of potassium carbonate base and DMF as the solvent at a temperature of about 150° C., which results in the exclusive formation of theacrine (2) in high yield and high quality, as shown in Scheme 3 below.

[0028] Scheme 3 : [ka]

[0029] Furthermore, the present inventors have surprisingly found that theacrine (2) is exclusively formed in high yield by subjecting the resulting mixtures of theacrine (2) and compound (3) in various ratios (shown as serial numbers 1 to 5 in Table 1) to methylation using trimethyl phosphate as a methylating agent in the presence of potassium carbonate base and DMF as a solvent at a temperature of 150°C. This represents a further embodiment of the present invention. The process of this embodiment is shown in Scheme 4 below.

[0030] Scheme 4 : [ka]

[0031] In yet another embodiment, when a mixture of compound 2 and compound 3 in a solvent (e.g., DMF, DMA, NMP, or DMF-DMA) or in a mixture of DMF PO(OMe) was heated to about 150° C., compound 3 was observed to rearrange exclusively to theacrine 2 in high yield and purity. The reaction rate was further increased in the presence of potassium carbonate.

[0032] Encouraged by the above results, compound 3 was N-methylated in the presence of trimethyl phosphate as a methylating agent under the conditions set forth in Serial No. 6 of Table 1, resulting in the formation of theacrine (2) in higher yield and in a relatively short reaction time, which represents a further embodiment of the present invention. This process is shown in Scheme 5 below.

[0033] Scheme 5 : [ka]

[0034] Thus, the present invention provides a process for efficiently preparing theacrine (2), wherein the process comprises one or more of the following:

[0035] (a) reacting a compound of formula I with a methylating agent in the presence of a base to obtain theacrine (2); or

[0036] (b) heating a mixture of the compound of formula 1 and the compound of formula 3 in a solvent (e.g., DMF, DMA, NMP, etc.) to about 150°C in the presence of a base (preferably potassium carbonate) to obtain theacrine (2); or

[0037] (c) heating the compound of formula 3 in a solvent (e.g., DMF, DMA, NMP, etc.) to about 150°C to obtain theacrine (2); or

[0038] (d) optionally purifying theacrine from methanol;

[0039] The synthesis process is shown in Scheme 1 below.

[0040] Scheme 1 : [ka]

[0041] where: R1 is hydrogen or methyl; R2 is hydrogen or absent; and R3 is methyl; The dashed bond can be a single or double bond; however, If the dashed bond is a double bond to oxygen, R1 and R2 are hydrogen and R3 is absent; however, If the dashed bond is a single bond to oxygen, R1 and R3 are methyl and R2 is absent.

[0042] Thus, the compound of formula I is selected from the compounds of formula 1 and formula 3 shown below.

[0043] [ka]

[0044] In one embodiment, the methylating agent is selected from the group consisting of dimethyl sulfate, DMF-DMA, methyl iodide, trimethyl phosphate, and the like.

[0045] In another embodiment, the methylation reaction is carried out using an inorganic base selected from the group consisting of sodium hydroxide, sodium hydride, potassium carbonate, and the like.

[0046] In a further embodiment, the solvent suitable for the methylation reaction is selected from the group consisting of methanol, water, acetone, DMF, DMA, NMP, and the like.

[0047] The methylation reaction is carried out under various temperature conditions ranging from 50°C to 170°C.

[0048] In a further embodiment, the present invention provides a process for preparing theacrine 2, comprising reacting a compound of formula 3 in a solvent, optionally in the presence of potassium carbonate base, at 150°C to obtain theacrine (2), wherein the solvent is selected from the group consisting of DMF, DMA, and NMP. The reaction is a thermal transformation of compound 3 to compound 2, which is promoted at higher temperatures and in the presence of potassium carbonate. However, the reaction can also be carried out in the absence of potassium carbonate; however, the reaction takes longer to complete.

[0049] In a further embodiment, the present invention provides a process for preparing theacrine 2, comprising reacting a mixture of a compound represented by formula 2 and a compound represented by formula 3 with trimethyl phosphate as a methylating agent at 150° C. in the presence of a solvent, and optionally in the presence of potassium carbonate in the solvent, to obtain theacrine (2), wherein the solvent is selected from the group consisting of DMF, DMA, and NMP.

[0050] In another embodiment, the so obtained theacrine is purified by dissolving it in methanol under reflux conditions and cooling to 40° C. The so obtained solid is washed with hot methanol (40-45° C.) to obtain theacrine with a purity of better than 99% by HPLC.

[0051] Thus, various embodiments of the present invention avoid the use of toxic chemicals and solvents and, further, form the final product 2 with good atom efficiency, generally in yields greater than 95% and high purity of 99% by HPLC.

[0052] The following examples, which include preferred embodiments, serve to illustrate the practice of the present invention, it being understood that the individual items shown are offered by way of example and are intended as illustrative illustrations of preferred embodiments of the invention. [Example]

[0053] Working Example: Example 1: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) To a stirred solution of 1,3-dimethyl-1H-purine-2,6,8(3H,7H,9H)-trione 1 (25.0 g, 12.8 mmol) in DMF (150 mL) were added potassium carbonate (53.3 g, 38.6 mmol) and trimethyl phosphate (72.2 g, 51.2 mmol). The mixture was stirred at 150 °C. After 5 h, DMF was removed under reduced pressure, and the residue was cooled to room temperature, treated with water, and extracted with a mixture of 10% MeOH and DCM (3 × 200 mL). The organic phases were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was dissolved in MeOH (5 vol) and heated at reflux for 2 h, then cooled to 40 °C. The solid formed was filtered and washed with hot (40-45°C) MeOH (1 volume) to give pure theacrine (2) as a white solid. Yield: 27.5g (96.7%). Purity (HPLC): 99.8%. 1 HNMR spectrum (400 MHz, DMSO-d6, δ, ppm, J / Hz): 3.19 (3H, s), 3.39 (3H, s), 3.52 (3H, s), 3.63 (3H, s), 3.76 (6H, s). MS (m / z): 225.22 (M+H). + .

[0054] Example 2: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) To a mixture of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) and the O-methoxy compound 3 (5.0 g, 25.7 mmol; 3:1 ratio) in DMF was added trimethyl phosphate (25 mL) and potassium carbonate (10.7 g, 77.3 mmol). The mixture was stirred at 150 °C for 5 h. After 5 h, it was cooled to room temperature, treated with water, and extracted with 10% MeOH / DCM (3 × 50 mL). The combined organic phases were washed with brine, dried over NaSO, filtered, and extracted under reduced pressure. The residue was dissolved in MeOH (5 vol), heated at reflux for 2 h, and then cooled to 40 °C. The solid formed was filtered and washed with hot (40–45 °C) methanol (1 vol) to give pure theacrine (2) as a white solid. Yield: 4.8 g (96.0%). Purity (HPLC): 99.5%.

[0055] Example 3: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) To a stirred solution of O-methoxy compound 3 (1.0 g, 4.46 mmol) in DMF (5 mL) was added potassium carbonate (1.85 g, 13.38 mmol), and the mixture was stirred at 150 °C for 5 h. After 5 h, DMF was removed under reduced pressure, and the mixture was cooled to room temperature, treated with water, and extracted with 10% MeOH / DCM (3 × 20 mL). The organic phases were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (5 vol), heated at reflux for 2 h, and cooled to 40 °C. The solid thus formed was filtered and washed with hot (40-45 °C) MeOH (1 vol) to give pure theacrine (2) as a white solid. Yield: 0.95 g (95.0%).

[0056] Example 4: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) To a stirred solution of compound 3 (1.0 g, 4.46 mmol) in DMA (5 mL) was added potassium carbonate (1.85 g, 13.38 mmol). The reaction mixture was stirred at 150 °C for 8 h. After 8 h, DMA was removed under reduced pressure, the mixture was cooled to room temperature, water was added, and extracted with 10% MeOH / DCM (3 × 20 mL). The organic phases were combined, and the combined phases were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was dissolved in MeOH (5 vol), refluxed for 2 h, and cooled to 40 °C. The solid formed was filtered and washed with hot (40-45 °C) MeOH (1 vol) to give pure theacrine (2) as a white solid. Yield: 0.96 g (96.0%).

[0057] Example 5: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) To a stirred solution of compound 3 (1.0 g, 4.46 mmol) in NMP (5 mL) was added potassium carbonate (1.85 g, 13.38 mmol), and the mixture was stirred at 150° C. for 8 hours. After 8 hours, NMP was removed under reduced pressure, and the mixture was cooled to room temperature. It was treated with water and extracted with 10% MeOH / DCM (3×20 mL). The organic phases were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was dissolved in MeOH (5 volumes), heated at reflux for 2 hours, and then cooled to 40° C. The solid formed was filtered and washed with hot (40-45° C.) MeOH (1 volume) to give pure theacrine (2) as a white solid. Yield: 0.93 g (93.0%).

[0058] Example 6: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theacrine, 2) A stirred solution of compound 3 (1.0 g, 4.46 mmol) in DMF (5 mL) was heated at 150° C. for 16 hours. After 16 hours, DMF was removed under reduced pressure, and the residue was cooled to room temperature. It was treated with water and extracted with 10% MeOH / DCM (3×20 mL). The organic phases were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (5 volumes), heated to reflux for 2 hours, and then cooled to 40° C. The solid formed was filtered and washed with hot (40-45° C.) MeOH (1 volume) to give pure theacrine (2) as a white solid. Yield: 0.97 g (97.0%).

[0059] The process of the present invention provides suitable reaction conditions for synthesizing theacrine with high conversion and high yield.The synthesis is simple, the post-treatment is simple, and the method is suitable for large-scale production.Furthermore, the method employs simple recrystallization to prepare high-purity theacrine in an economically feasible manner, does not require high-pressure conditions, and can be carried out using low-cost equipment.Therefore, the present invention provides a relatively high yield of pure theacrine, and the process is relatively low-cost.

[0060] While the present invention has been described in detail above for purposes of illustration, it is to be understood that such detailed description is for purposes of illustration only and that modifications may be made therein by those skilled in the art without departing from the spirit and scope of the invention except as may be limited by the claims.

Claims

1. A process for efficiently preparing theacrine (2), comprising: (a) reacting a compound of formula I with a methylating agent in the presence of a base and a solvent to obtain theacrine (2); and optionally purifying the theacrine from methanol; 【Chemistry 1】 where: R1 is hydrogen or methyl; R2 is hydrogen or absent; and R3 is methyl; The dashed bond can be a single or double bond; however, If the dashed bond is a double bond to oxygen, R1 and R2 are hydrogen and R3 is absent; however, If the dashed bond is a single bond to oxygen, R1 and R3 are methyl and R2 is absent.

2. 2. The process of claim 1, wherein the compound of formula I is selected from compounds of formula 1 and formula 3 shown below: 【Chemistry 2】

3. 2. The process of claim 1, wherein the methylating agent is selected from the group consisting of dimethyl sulfate, DMF-DMA, DMA, NMP, methyl iodide, trimethyl phosphate, and the like.

4. 10. The process of claim 1, wherein the base is selected from the group consisting of sodium hydroxide, sodium hydride, potassium carbonate, and the like.

5. 10. The process of claim 1, wherein the solvent is selected from the group consisting of methanol, water, acetone, DMF, DMA, NMP, and the like.

6. 2. The process of claim 1, wherein the methylation reaction is carried out at a temperature in the range of 50°C to 170°C.

7. 10. The process of any one of the preceding claims, comprising reacting a compound of formula 1 with trimethyl phosphate as a methylating agent in the presence of potassium carbonate base in DMF solvent at 150°C to obtain theacrine (2).

8. 10. The process of any one of the preceding claims, comprising reacting a mixture of the compound represented by formula 1 and the compound represented by formula 3 with trimethyl phosphate as a methylating agent in the presence of potassium carbonate base in DMF solvent at 150°C to obtain theacrine (2).

9. 10. The process of any one of the preceding claims, comprising reacting a compound of formula 3 in a solvent, optionally in the presence of potassium carbonate base, at 150°C to obtain theacrine (2).

10. 10. The process of claim 9, wherein the solvent is selected from the group consisting of DMF, DMA, and NMP.

11. 11. A process for preparing theacrine 2 according to claims 9 and 10, comprising heating a compound represented by formula 3 in DMF solvent, optionally together with potassium carbonate, at 150°C to obtain theacrine (2).

12. 11. A process for preparing theacrine 2 according to claims 9 and 10, comprising heating a compound represented by formula 3 in DMA solvent, optionally together with potassium carbonate, at 150°C to obtain theacrine (2).

13. 11. A process for preparing theacrine 2 according to claims 9 and 10, comprising heating a compound represented by formula 3 in NMP solvent, optionally together with potassium carbonate, at 150°C to obtain theacrine (2).

14. A process for preparing theacrine 2, comprising reacting a mixture of a compound represented by formula 2 and a compound represented by formula 3 with trimethyl phosphate at 150°C in the presence of a solvent, optionally in the presence of potassium carbonate base, to obtain theacrine (2).

15. 15. The process for preparing theacrine 2 according to claim 14, wherein the solvent is selected from the group consisting of DMF, DMA and NMP.

16. 15. A process for preparing theacrine 2 according to claim 14, comprising heating a mixture of a compound represented by formula 2 and a compound represented by formula 3 in a DMF solvent, optionally in the presence of potassium carbonate, at 150°C to obtain theacrine (2).

17. 15. A process for preparing theacrine 2 according to claim 14, comprising heating a mixture of a compound represented by formula 2 and a compound represented by formula 3 in a DMA solvent, optionally in the presence of potassium carbonate, at 150°C to obtain theacrine (2).

18. 15. A process for preparing theacrine 2 according to claim 14, comprising heating a mixture of a compound represented by formula 2 and a compound represented by formula 3 in NMP solvent, optionally in the presence of potassium carbonate, at 150°C to obtain theacrine (2).

19. 10. The process of any one of the preceding claims, wherein the purification of crude theacrine 2 comprises: (a) dissolving crude theacrine 2 in methanol under reflux; (b) cooling to 40°C, followed by washing the solid with hot methanol (40-45°C) to obtain pure theacrine (2).

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