Efficient method for synthesizing bitter theophylline
By using trimethyl phosphate and potassium carbonate in the presence of alkali, the problem of low extraction efficiency of picophylline is solved, and pyophylline synthesis is achieved with high yield and high purity, which is suitable for industrial applications.
Patent Information
- Application Number
- CN202380091575.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-01-17
- Filing Date
- 2023-07-05
- Publication Date
- 2025-08-12
AI Technical Summary
In the prior art, the extraction method of picophylline is cumbersome, low efficiency and difficult to commercialize, and the biological conversion cost of natural raw materials is high, resulting in poor atomic economy.
The reaction of one or more compounds of formula I and a methylating agent in the presence of a base is preferably carried out using trimethyl phosphate, potassium carbonate and dimethylformamide as solvents, and the methylation reaction is carried out at 150°C, and then high purity picoyl is obtained by purification.
The synthesis of picophylline with high yield and high purity is achieved, which simplifies the post-treatment process, is suitable for large-scale production, reduces costs, and avoids the use of toxic chemicals.
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Abstract
Description
Field of the Invention
[0001] The present invention relates to an industrial method for synthesizing theophylline with high purity and high quality. Background of the Invention
[0003] Theacrine, also known as tetramethyluric acid, is a caffeine metabolite present at low levels in various coffee plants. In chemistry, theacrine is 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione with the following structure:
[0004]
[0005] In recent years, studies have shown that caffeine and theophylline, due to their structural similarity to methylxanthines, have similar physiological properties, but without the undesirable stimulant effects. Available molecular toxicology information suggests that theophylline does not cause any genotoxicity or potential health risks, leading to continued interest in its use as an ingredient in functional foods and dietary supplements.
[0006] The content of this purine alkaloid in coffee plants is low and its extraction method is cumbersome. From the reports available in the literature, it is observed that the biotransformation of natural raw materials such as caffeine into theophylline compounds is expensive, inefficient and difficult to commercialize due to poor atom economy.
[0007] Therefore, the present inventors believe that the deficiencies in the production of theophylline (2) can be overcome by providing a synthetic industrial process by which theophylline can be obtained in quantities sufficient for industrial applications without restrictions on the starting materials. SUMMARY OF THE INVENTION
[0009] In view of the above objectives, the present invention provides a method for synthesizing theophylline in an efficient manner, comprising reacting one or more compounds of formula I with a methylating agent in the presence of a base to obtain theophylline (2). This synthesis method is shown in the following reaction formula 1.
[0010] Reaction 1:
[0011]
[0012] wherein R1 is hydrogen or methyl; R2 is hydrogen or R2 is absent; R3 is methyl,
[0013] Virtual bonds can be single or double bonds.
[0014] Provided that: when the virtual bond is a double bond to oxygen, R1 and R2 are hydrogen, and R3 is absent;
[0015] Provided that when the virtual bond is a single bond to oxygen, R1 and R3 are methyl groups and R2 is not present.
[0016] Therefore, in one embodiment, the compound of formula I is selected from the compounds of formula 1 and formula 3 as shown below:
[0017] . Detailed Description of the Invention
[0019] The present invention is explained in detail below through various preferred embodiments and optional embodiments, but they should not be considered as limiting the scope of the present invention.
[0020] In one embodiment, the object of the present invention is to provide a process for preparing theophylline (2) in an efficient and industrially scalable manner.
[0021] To achieve the above object, the present inventors have developed a method for synthesizing theophylline, wherein 1,3-dimethyl-1H-purine-2,6,8(3H,7H,9H)-trione, i.e., a compound of formula 1, is reacted with various methylating agents in the presence of various bases and solvents to provide theophylline (2).
[0022] Therefore, in one embodiment, the methylation reaction is carried out using a methylating agent selected from the group consisting of dimethyl sulfate, DMF-DMA, methyl iodide, trimethyl phosphate, and the like.
[0023] In another embodiment, the methylation reaction is carried out in the presence of various organic and inorganic bases. More preferably, 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.
[0024] In yet another embodiment, the methylation reaction is also carried out in the presence of various solvents selected from alcohol solvents, such as methanol, water, acetone, DMF, DMA, NMP, and the like.
[0025] In yet another embodiment, the methylation reaction is carried out under various temperature conditions ranging from 50°C to 170°C.
[0026] Table 1 lists the results of various embodiments of the methylation reaction of the compound of Formula 1. The methylation reaction is shown in Reaction Scheme 2.
[0027] Reaction 2:
[0028]
[0029] Table 1
[0030]
[0031] As can be seen from Reaction Scheme 2 and Table 1 (Series Nos. 1-5), the methylation reaction of the triketone intermediate (1) using various methylating agents and reaction conditions to provide theophylline (2) results in the formation of compound (3) as an impurity in varying proportions ranging from 10 to 25%. The presence of compound 3 in the product makes purification difficult, resulting in a loss of atom economy and, in turn, in additional costs.
[0032] Therefore, in a preferred embodiment, the present invention provides a method for preparing theophylline, which comprises: methylating compound (1) with trimethyl phosphate in the presence of a base to obtain theophylline (2). In one embodiment, the base is selected from the group consisting of sodium hydroxide, sodium hydride and potassium carbonate.
[0033] 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.
[0034] In a preferred embodiment, the solvent is dimethylformamide.
[0035] 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. to obtain theophylline in good yield and high purity.
[0036] Therefore, in one embodiment, the present inventors have developed the following reaction conditions: using trimethyl phosphate as a methylating agent, in the presence of potassium carbonate as a base and DMF as a solvent, at a temperature of about 150°C, which results in the formation of only theophylline (2) in high yield and high quality, as shown in the following reaction formula 3.
[0037] Reaction 3:
[0038]
[0039] Furthermore, the present inventors surprisingly discovered that when the mixtures of theophylline (2) and compound (3) obtained in different ratios (as shown in series numbers 1 to 5 in Table 1) were subjected to a methylation reaction using trimethyl phosphate as a methylating agent, potassium carbonate as a base, and DMF as a solvent at a temperature of 150°C, only theophylline (2) was formed in high yield, which constitutes an additional embodiment of the present invention. The method of this embodiment is shown in the following reaction formula 4.
[0040] Reaction 4:
[0041]
[0042] In yet another embodiment, when a mixture of compound 2 and compound 3 is heated at about 150° C. in a solvent such as DMF, DMA, NMP or DMF-DMA or in a mixture of DMF / PO(OMe) 3, compound 3 is observed to completely rearrange to form theophylline 2 in high yield and high purity. In the presence of potassium carbonate, the reaction rate is further increased. Encouraged by the above results, compound 3 is N-methylated in the presence of trimethyl phosphate as a methylating agent under the conditions shown in series number 6 in Table 1 to form only theophylline (2) in higher yield and shorter reaction time, which becomes an additional embodiment of the present invention. This method is shown in the following reaction formula 5.
[0043] Reaction 5:
[0044]
[0045] Therefore, the present invention provides a method for preparing theophylline (2) in an efficient manner, which method comprises one or more of the following:
[0046] a) reacting one or more compounds of formula I with a methylating agent in the presence of a base to obtain theophylline (2); or
[0047] b) heating a mixture of the compound of formula 1 and the compound of formula 3 in a solvent such as DMF, DMA, NMP, etc. at about 150° C. in the presence of a base, preferably potassium carbonate, to obtain theophylline (2); or
[0048] c) heating the compound of formula 3 in a solvent such as DMF, DMA, NMP, etc. at about 150° C. to obtain theophylline (2); or
[0049] d) optionally purifying theophylline from methanol.
[0050] The synthesis method is shown in the following reaction formula 1.
[0051] Reaction 1:
[0052]
[0053] wherein R1 is hydrogen or methyl; R2 is hydrogen or R2 is absent; R3 is methyl,
[0054] Virtual bonds can be single or double bonds.
[0055] Provided that, when the virtual bond is a double bond to oxygen, R1 and R2 are hydrogen, and R3 is not present;
[0056] Provided that, when the imaginary bond is a single bond to oxygen, R1 and R3 are methyl groups and R2 is not present.
[0057] Therefore, the compound of formula I is selected from the compounds of formula 1 and formula 3 as shown below:
[0058] .
[0059] In one embodiment, the methylating agent is selected from the group consisting of dimethyl sulfate, DMF-DMA, methyl iodide, trimethyl phosphate, and the like.
[0060] 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.
[0061] In yet another embodiment, the solvent suitable for the methylation reaction is selected from the group consisting of methanol, water, acetone, DMF, DMA, NMP, etc. The methylation reaction is carried out under various temperature conditions ranging from 50°C to 170°C.
[0062] In another embodiment, the present invention provides a method for preparing theophylline 2, which comprises reacting one or more compounds of formula 3 in a solvent and optionally in the presence of potassium carbonate as a base at 150°C to obtain theophylline (2), wherein the solvent is selected from the group consisting of DMF, DMA and NMP. The reaction is a thermal rearrangement reaction of compound 3 to compound 2, which is promoted by the presence of higher temperature and potassium carbonate. Although the reaction can be carried out in the absence of potassium carbonate, the time required to complete the reaction is longer.
[0063] In another embodiment, the present invention provides a method for preparing theophylline 2, which comprises reacting a mixture of a compound of formula 2 and a compound of formula 3 with trimethyl phosphate as a methylating agent in the presence of a solvent and optionally in the presence of potassium carbonate as a base to obtain theophylline (2), wherein the solvent is selected from the group consisting of DMF, DMA and NMP.
[0064] In another embodiment, the obtained theophylline is purified by dissolving it in methanol under reflux and cooling it to 40° C. The obtained solid is washed with hot methanol (40-45° C.) to obtain theophylline with excellent purity, which is greater than 99% as determined by HPLC.
[0065] Thus, various embodiments of the present invention avoid the use of toxic chemicals and solvents and form the final product 2 with excellent atom economy, typically greater than 95% yield, and high purity of 99% as determined by HPLC.
[0066] The following examples include various preferred embodiments to illustrate the practice of the present invention; however, it should be understood that the details described are exemplary only and are intended to illustrate the discussion of these preferred embodiments of the present invention. Example
[0067] Example 1: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2)
[0068] 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) was 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 hours, DMF was removed under vacuum, 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 Na2SO4, filtered and concentrated under vacuum. The crude product was dissolved in MeOH (5 vol) and heated under reflux for 2 hours, then cooled to 40° C. The resulting solid was filtered and washed with hot (40-45° C.) MeOH (1 vol) to provide pure theophylline (2) as a white solid. Yield: 27.5 g (96.7 %). 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) + . Purity (HPLC): 99.8%.
[0069] Example 2: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2).
[0070] To a mixture of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2) and O-methoxy compound 3 (5.0 g, 25.7 mmol; ratio 3: 1) 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 hours. After 5 hours, it was cooled to room temperature, treated with water and extracted with 10% MeOH / DCM (3 × 50 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was dissolved in MeOH (5 vol), heated under reflux for 2 hours, and then cooled to 40 ° C. The resulting solid was filtered and washed with hot (40-45 ° C) MeOH (1 vol) to provide pure theophylline (2) as a white solid. Yield: 4.8 g (96.0%). Purity (HPLC): 99.5%.
[0071] Example 3: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2).
[0072] To a stirred solution of O-methoxy compound 3 (1.0g, 4.46mmol) in DMF (5 mL) was added potassium carbonate (1.85g, 13.38mmol), and the mixture was stirred at 150°C for 5 hours. After 5 hours, DMF was removed under vacuum, and the mixture was cooled to room temperature, treated with water and extracted with 10% MeOH / DCM (3 × 20mL). The organic phases were merged, and the combined phases of the gained were washed with salt water, passed through Na2SO4, dried, filtered and concentrated under vacuum. The residue was dissolved in MeOH (5vol), and heated under reflux for 2 hours, then cooled to 40°C. The solid gained was filtered, and washed with hot (40-45°C) MeOH (1vol), thus providing pure theophylline (2), which was a white solid. Yield: 0.95g (95.0%).
[0073] Example 4: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2).
[0074] 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 hours. After 8 hours, DMA was removed under vacuum, the mixture was cooled to room temperature, water was added and extracted with 10% MeOH / DCM (3 × 20 mL). The organic phases were merged, the combined phases of the obtained were washed with salt water, passed through Na SO dried, and concentrated under vacuum. The residue was dissolved in MeOH (5 vol) and heated under reflux for 2 hours, then cooled to 40 ° C. The solid obtained was filtered and washed with hot (40-45 ° C) MeOH (1 vol), thus providing pure theophylline (2), which was a white solid. Yield: 0.96 g (96.0%).
[0075] Example 5: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2).
[0076] To a stirred solution of compound 3 (1.0g, 4.46mmol) in NMP (5mL) was added potassium carbonate (1.85g, 13.38mmol), and the mixture was stirred at 150°C for 8 hours. After 8 hours, NMP was removed under vacuum, and the mixture was cooled to room temperature. It was treated with water, extracted with 10% MeOH / DCM (3 × 20mL), and the organic phases were merged, and the combined phases of gained were washed with salt water, passed through Na2SO4, dried, filtered, and concentrated under vacuum. The crude product was dissolved in MeOH (5vol), and heated under reflux for 2 hours, then cooled to 40°C. The solid gained was filtered, and washed with the MeOH (1vol) of heat (40-45°C), thus providing pure theophylline (2), which was a white solid. Yield: 0.93g (93.0%).
[0077] Example 6: Preparation of 1,3,7,9-tetramethyl-1H-purine-2,6,8(3H,7H,9H)-trione (theophylline, 2).
[0078] Compound 3 (1.0g, 4.46mmol) was stirred in DMF (5mL) at 150°C for 16 hours. After 16 hours, DMF was removed under vacuum, and the residue was cooled to room temperature. It was treated with water, extracted with 10% MeOH / DCM (3X 20mL), and the organic phases were merged, and the combined phases of the obtained were washed with salt water, passed through Na2SO4, dried, filtered and concentrated under vacuum. The residue was dissolved in MeOH (5vol) and heated under reflux for 2 hours, then cooled to 40°C. The solid obtained was filtered and washed with hot (40-45°C) MeOH (1 vol), thus providing pure theophylline (2), which was a white solid. Yield: 0.97g (97.0%).
[0079] The method of the present invention provides suitable reaction conditions for synthesizing theophylline with high conversion and high yield. This synthesis method is convenient, the post-processing / processing technology is relatively simple, and the method is suitable for large-scale production. Moreover, the method can be implemented using low-cost equipment and does not require high-pressure conditions; by adopting simple recrystallization, high-purity theophylline is obtained in an economically feasible manner. Therefore, the present invention provides pure theophylline with high yield and the method is relatively inexpensive.
[0080] Although the present invention has been described in detail above for purposes of illustration, it should be understood that such details are for illustrative purposes only and that variations may be made by those skilled in the art without departing from the spirit and scope of the invention, except as defined in the appended claims.
Claims
1. A method for preparing theophylline (2) in an efficient manner, the method comprising: a) reacting one or more compounds of formula I with a methylating agent in the presence of a base and a solvent to obtain theophylline (2); and optionally purifying theophylline from methanol, wherein R1 is hydrogen or methyl; R2 is hydrogen or R2 is absent; R3 is methyl, Virtual bonds can be single or double bonds. Provided that, when the virtual bond is a double bond to oxygen, R1 and R2 are hydrogen, and R3 is not present; Provided that, when the imaginary bond is a single bond to oxygen, R1 and R3 are methyl groups and R2 is not present.
2. The method according to claim 1, wherein the compound of formula I is selected from the compounds of formula 1 and formula 3 as shown below: 。 3. The method according to claim 1, wherein the methylating agent is selected from the group consisting of dimethyl sulfate, DMF-DMA, DMA, NMP, methyl iodide, trimethyl phosphate, etc.
4. The method of claim 1, wherein the base is selected from the group consisting of sodium hydroxide, sodium hydride, potassium carbonate, etc. The method according to claim 1 , wherein the solvent is selected from the group consisting of methanol, water, acetone, DMF, DMA, NMP, etc. The method according to claim 1 , wherein the methylation reaction is carried out at a temperature ranging from 50° C. to 170° C.
7. The process according to any one of the preceding claims, wherein the process comprises reacting one or more compounds of formula 1 with trimethyl phosphate as a methylating agent in the presence of potassium carbonate as a base and in DMF solvent at 150°C to obtain theophylline (2).
8. The process according to any one of the preceding claims, wherein the process comprises reacting a mixture of the compound of formula 1 and the compound of formula 3 with trimethyl phosphate as a methylating agent in the presence of potassium carbonate as a base and in DMF solvent at 150°C to obtain theophylline (2).
9. The process according to any one of the preceding claims, wherein the process comprises reacting one or more compounds of formula 3 in a solvent, optionally in the presence of potassium carbonate as a base, at 150°C to obtain theophylline (2).
10. The method of claim 9, wherein the solvent is selected from the group consisting of DMF, DMA and NMP.
11. The method for preparing theophylline 2 according to claims 9 and 10, wherein the method comprises heating the compound of formula 3 in DMF solvent optionally with potassium carbonate at 150°C to obtain theophylline (2).
12. The method for preparing theophylline 2 according to claims 9 and 10, wherein the method comprises heating the compound of formula 3 in DMA solvent optionally with potassium carbonate at 150°C to obtain theophylline (2).
13. The method for preparing theophylline 2 according to claims 9 and 10, wherein the method comprises heating the compound of formula 3 in NMP solvent optionally with potassium carbonate at 150°C to obtain theophylline (2).
14. A method for preparing theophylline 2, which comprises reacting a mixture of a compound of formula 2 and a compound of formula 3 with trimethyl phosphate in the presence of a solvent and optionally in the presence of potassium carbonate as a base at 150°C to obtain theophylline (2).
15. The method for preparing theophylline 2 according to claim 14, wherein the solvent is selected from the group consisting of DMF, DMA and NMP.
16. The method for preparing theophylline 2 according to claim 14, wherein the method comprises heating a mixture of the compound of formula 2 and the compound of formula 3 in DMF solvent at 150°C optionally in the presence of potassium carbonate to obtain theophylline (2).
17. The method for preparing theophylline 2 according to claim 14, wherein the method comprises heating a mixture of the compound of formula 2 and the compound of formula 3 in DMA solvent at 150°C, optionally in the presence of potassium carbonate, to obtain theophylline (2).
18. The method for preparing theophylline 2 according to claim 14, wherein the method comprises heating a mixture of the compound of formula 2 and the compound of formula 3 in NMP solvent at 150°C, optionally in the presence of potassium carbonate, to obtain theophylline (2).
19. The method according to any one of the preceding claims, wherein the purification of crude theophylline 2 comprises: a) dissolving crude theophylline 2 in methanol under reflux; b) Cool to 40°C and then wash the solid with hot methanol (40-45°C) to provide pure theophylline (2).