DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

AN EFFICIENT PROCESS FOR THE SYNTHESIS OF PARAXANTHINE

FERTIS INDIA PVT. LTD., an Indian company of 6-3-668/10/56, Plot No 56, Ist Floor Durga Nagar Colony, Punjagutta, Hyderabad, Telangana, India-500082

The following specification particularly describes the invention & the manner in which it is to be performed.

FIELD OF THE INVENTION

The disclosure generally relates to an efficient process for the preparation of Paraxanthine.

BACKGROUND OF THE INVENTION

Paraxanthine (1,7-dimethylxanthine), a purine alkaloid derivative of caffeine (1,3,7-trimethyl xanthine), is a high-value methylxanthine with several applications in the nutraceutical, pharmaceutical and cosmetic industries. It can be represented by formula 1 as shown below.

Paraxanthine, the primary metabolite of caffeine in humans, has notable advantages over its parent compound. While both compounds share stimulant properties, paraxanthine offers enhanced wake-promoting potency due to its heightened affinity for adenosine A1 and A2 receptors. Importantly, this heightened potency is achieved with lower toxicity and diminished anxiogenic effects compared to caffeine. Given these characteristics, paraxanthine presents a promising alternative for applications requiring robust wakefulness promotion and addressing hypersomnia linked to neurodegenerative diseases without the potential drawbacks associated with high doses of caffeine.

In addition to the above, paraxanthine also protects against dopaminergic cell death, loss of synaptic function and reduces the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons.

It was recently demonstrated that paraxanthine significantly promoted wakefulness and proportionally reduced non-REM and REM sleep in both control and narcoleptic mice. The wake-promoting potency of paraxanthine is greater than that of the parent compound, caffeine, and comparable to that of modafinil.

It has several advantages over caffeine like longer half-life, beneficial for individuals with respiratory conditions like asthma, more stable plasma, has cognitive-enhancing properties, such as improved memory and learning. These advantages positioned paraxanthine as a promising alternative to caffeine and other methylxanthines for various medical and therapeutic applications.

This purine alkaloid is low in content in coffee plants and the extraction process is cumbersome. From the available reports in the literature, it is observed that biotransformation of natural raw materials such as caffeine into paraxanthine is expensive, the efficiency is low, and it is difficult to commercialize due to poor atom economy.

The method described by Meredith B. Mock, Shelby Brooks Mills, Ashley Cyrus, et al. in Biotechnology and Bioprocess Engineering; Volume 27, Pages 640-651 (2022) for producing paraxanthine from caffeine using Escherichia coli strains as whole-cell biocatalysts has notable shortcomings. Despite incorporating various Escherichia coli strains engineered with differing dosages of ndmA4, ndmD, and the frmAB formaldehyde dehydrogenase genes, the process yields very low quantities of paraxanthine. This low yield significantly diminishes the efficiency and practicality of the method for large-scale production.

WO1991017993A1 discloses the synthesis of paraxanthine wherein 1-methyl-2-methoxy hypoxanthine was methylated with dimethyl sulfate or with dimethyl epoxide. However, a notable drawback of this approach is the formation of undesired isomeric mixtures comprising methylated compounds positioned at both the 7 and 9 positions. This complicates the purification process, requiring labour-intensive and time-consuming techniques such as preparative high-performance liquid chromatography (HPLC), fractional crystallization, and flash chromatography. Moreover, these purification methods yield low quantities of paraxanthine, decrease the efficiency and practicality of the overall production process, particularly for large-scale manufacturing.

The method described by Christa E. Müller, Dirk Deters, Andreas Dominik, et al. in the article "Synthesis," pages 1428-1436, titled "Synthesis of Paraxanthine and Isoparaxanthine Analogs," presents certain limitations. The process, involves starting from 6-amino-2-methoxy pyrimidine-4-one. Alkylation with alkyl halides in acetone/potassium carbonate, in the presence of a phase-transfer catalyst (PTC), leads to the formation of an equimolar mixture of N3- and O4-alkylated products. Separation of these products by column chromatography proves challenging and results in poor yield. This limitation in yield poses a significant obstacle to the practical application of the method, particularly for large-scale production purposes.

In the domain of prior art techniques and methods, the conventional chemical synthesis of paraxanthine typically involves harsh conditions and often yields mixtures of non-specific N-methylated compounds and their isomers, leading to inefficiencies in production. Consequently, the present inventors felt that there exists a pressing need for a more efficient method for preparing paraxanthine that circumvents these challenges. In addressing this need, the present inventors have discovered a novel process for the preparation of paraxanthine that is characterized by its simplicity, cost-effectiveness, and suitability for large-scale production. Importantly, this innovative method yields paraxanthine of high purity and quality, making it industrially advantageous for various applications.

SUMMARY OF THE INVENTION
The specification discloses a process for the preparation of Paraxanthine of formula 1

comprising steps of
i a. reacting compound of formula 2 with a regioselective mono N-methylating agent in a suitable solvent to obtain a desired compound of formula 3,

i b. reacting a compound of formula 3 with a formylating agent followed by cyclization to obtain a compound of formula 5,

and
i c. reacting compound of formula 5 with an acid to obtain Paraxanthine of formula 1.
or
ii. reacting a compound of formula 4 with a regioselective N-methylating agent in a suitable solvent to obtain compound of formula 5, followed by treatment with an acid to obtain Paraxanthine of formula 1.

or
iii. reacting compound of formula 2 with paraformaldehyde in a suitable solvent to obtain a compound of formula 5, followed by treatment with an acid to obtain Paraxanthine of formula 1.

The specification further discloses a compound of formula 3
,
and a compound of formula 5
.

Detailed Description of the Invention
The synthetic scheme according to the specification is depicted below.

In one embodiment, the specification discloses a process for the preparation of Paraxanthine of formula 1

comprising steps of
i a. reacting a compound of formula 2 with a methylating agent in a suitable solvent to obtain a compound of formula 3,

i b. reacting a compound of formula 3 with a formylating agent followed by cyclization to obtain a compound of formula 5,

i c. reacting compound of formula 5 with an acid to obtain Paraxanthine of formula 1.

Step i a) reacting a compound of formula 2 with a regioselective mono N-methylating agent, specifically methyl triflate, in a suitable solvent, such as dichloromethane or hexafluoro isopropanol. This process leads to the formation of the desired regioselective compound, as depicted by formula 3, with a high yield. The use of methyl triflate offers significant advantages due to its exceptional regioselectivity, with aminomethylation predominantly occurring at the 5th position of compound 2. This specificity ensures precise control over the regiochemistry of the reaction, preventing undesired N-methylation at the 6th position or multiple methylations at 5th/6th amino positions. The choice of dichloromethane/ hexafluoro isopropanol as the solvent provides an optimal reaction environment, is cost-effective and facilitates efficient mixing of reactants while maintaining stability. Alternatively other chlorinated solvents such as dichloroethane or chloroform or fluorinated solvents such as trifluoroethanol (TFE) and trifluoroacetic acid (TFA) were used for this conversion.

Overall, the combination of methyl triflate and dichloromethane/ hexafluoro isopropanol solvent enhances the required regio selective N-Methylation, efficiency, precision, and success of the synthetic process, leading to the production of novel, high-quality key intermediate of compound 3.

In another embodiment, the specification discloses a process the preparation of Paraxanthine of formula 1

comprising steps of
ii. reacting compound of formula 4 with methylating agent in a suitable solvent to obtain compound of formula 5, and

i c. reacting compound of formula 5 with acid to obtain Paraxanthine of formula 1.

In yet another embodiment, the specification discloses a process for the preparation of Paraxanthine of formula 1

comprising steps of
iii. reacting compound of formula 2 with paraformaldehyde in a suitable solvent to obtain a compound of formula 5,

i c. reacting a compound of formula 5 with Conc. HCl to obtain Paraxanthine of formula 1,
Regioselective mono N-methylation of amine at 5th position of compound 2 in step (a) primarily utilizes methyl triflate, while incorporating a diverse range of methylating agents such as Dimethylaminoethanol, N, N-Dimethylformamide dimethyl acetal (DMF-DMA), N,N-Dimethyl aminomethyl trimethylsilane (DMATMS), Dimethylamine-borane complex (DMAB), dimethylamino ethyl methacrylate (DMAEMA), Methyl iodide, Dimethylsulphate-p-TSA, methyl trifluoroacetate, tetramethyl ammonium fluoride, methyl tosylate (MeOTs), methyl acetate (MeOAc), or methyl methane sulfonate-p-TSA (MMS), alcohols as alkylating agents under the catalytic influence of ruthenium, rhenium, manganese, palladium, iron, cobalt, nickel, or indium. This process enables the efficient and precise introduction of methyl groups into the 5th position of compound 2, resulting in the desired compound of formula 3 with high yields.

The solvent selected for regioselective mono aminomethylation, preferably, dichloromethane (DCM). Additionally, alternatives include hexafluoroisopropanol, a fluorinated alcohol known for its unique properties. Other potential solvents are chlorinated solvents such as chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene, perchloroethylene, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,2-trichloroethane, and tetrachloroethene. Moreover, fluorinated alcohols like trifluoroethanol (TFE) and trifluoroacetic acid (TFA), and well as other common solvents such as isopropanol, tert-Butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (MeCN).
Methylation step can be carried out at a temperature from 0 to 100 °C, preferably at room temperature.

The solvent used in the reaction of compound of formula 2 with paraformaldehyde can be selected from water, ethanol, propanol, isopropanol, tert-butanol or mixtures thereof. This reaction can be carried out at a temperature from 25 to 150 °C, preferably at 110 °C.

The reaction of a compound of formula 3 with various formylating agents, preferably with triethyl or methyl orthoformates, formic acid, N, N-dimethylformamide with phosphoryl chloride, hexamethylenetetramine, dichloromethyl methyl ether, to yield a compound of formula 5, can be conducted at a temperature ranging from 25 to 150 °C, with a preference for 110 °C.

Acid used in step (c) can be selected from Conc. HCl, Hydrogen bromide, Lewis acids such as Boron tribromide (BBr3), Aluminium chloride (AlCl3), or Pyridinium bromide or chloride. Step (c) can be carried out at a temperature from 25 to 150 °C, preferably at 110 °C.

In another embodiment, the specification discloses a process for crystallization of Paraxanthine from a solvent selected from water, lower alcohols such as ethanol, methanol, isopropanol, propanol, n-butanol, tert-butanol; acids like acetic acid, propionic acid, butanoic acid, halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl ethyl ketone; ethers such as diethyl ether, THF or mixtures thereof.

In another embodiment, the specification discloses a process for the preparation of polymorphs of paraxanthine which comprises crystallization of paraxanthine from a suitable solvent selected from water, lower alcohols such as ethanol, methanol, isopropanol, propanol, n-butanol, tert-butanol; acids like acetic acid, propionic acid, butanoic acid, halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl ethyl ketone; ethers such as diethyl ether, THF; and such like alone or mixtures thereof.

In another embodiment, the specification discloses a compound 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one having formula 3
.

In another embodiment, the specification discloses a compound 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one having formula 5
.
The process of the disclosure is advantageous in respect of high yield, high purity, and scalable process hence industrially useful.

In another embodiment, the specification discloses Paraxanthine having purity of at least 95 %w/w, at least 97 %w/w, at least 98 %w/w, at least 99 %w/w, at least 99.7 %w/w, at least 99.8 %w/w or at least 99.9 %w/w.

In another embodiment, the specification discloses a pure Paraxanthine having less than 5 %w/w, less than 3 %w/w, less than 2 %w/w, less than 1 %w/w, less than 0.5 %w/w, less than 0.2 %w/w or less than 0.1 %w/w of a compound of formula 6
.
The following examples illustrate specific embodiments; however, the full scope of the disclosure is not limited to the examples described below.

Examples
Example 1
Preparation of 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one (3)
To a stirred solution of 5,6-diamino-2-methoxy-3-methylpyrimidin-4(3H)-one (2) (25 g, 147.05 mmol) in dichloromethane (3 vol), was added slowly methyl triflate (24.1 g, 147.05 mmol). The reaction mixture was stirred for 4 h at 25 °C. The reaction mixture was evaporated under vacuum and washed with diethyl ether to afford 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one (3), as a light yellow solid. Yield: Yield: 21.5 g (80%). 1HNMR (400 MHz, DMSO-d6): d 2.38 (3H, s), 3.16 (3H, s), 3.89 (3H, s), 5.97 (2H, bs). 13C NMR (DMSO-d6, 400 MHz) d 27.7, 34.5, 56.2, 93.6, 154.3, 155.5, 158.5. MS: m/z: 185.13 (M+H)+. IR: vKBr 3335.1, 3217.6, 2966.4, 1581.63, 1533.9, 1291.3, 1175.8, 1150.2, and 781.4 cm-1.

Example 2
Preparation of 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one (3)
To a stirred solution of 5,6-diamino-2-methoxy-3-methylpyrimidin-4(3H)-one (2) (25 g, 147.05 mmol) in IPA (2 vol), were added p-TSA (0.279 g, 1.47 mmol), dimethyl sulphate (55.64 g, 441.15 mmol). The reaction mixture was stirred for 12 h at 25 °C. The reaction mixture was evaporated under vacuum and washed with diethyl ether to afford 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one (3), as a off white solid. Yield: 17.8 g (66%).

Example 3
Preparation of 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one (3)
To a stirred solution of 5,6-diamino-2-methoxy-3-methylpyrimidin-4(3H)-one (2) (25 g, 147.05 mmol) in tert-BuOH (10 vol), were added p-TSA (2.79 g, 14.7 mmol), methyl methane sulfonate (16.19 g, 147.05 mmol). The reaction mixture was stirred for 12 h at 25 °C. The reaction mixture was evaporated under vacuum and washed with diethyl ether to afford 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidin-4(3H)-one (3), as a off white solid. Yield: 17.0 g (63%).

Example 4
Preparation of 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one (5)
To a stirred solution of 6-amino-2-methoxy-3-methyl-5-(methylamino) pyrimidine-4 (3H)-one (3), (20.0 g, 103.05 mmol) in formic acid (5 vol), the reaction mixture was stirred at 110 °C for 12 h. Then formic acid was distilled out under vacuum and the residue was cooled to room temperature, cold water was added to the residue and stirred for 15 min and neutralized with 50% aqueous NaOH solution, filtered and washed with cold water, to obtain 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one (5) as an off white solid. Yield: 20.0 g (93%). 1HNMR (400 MHz, DMSO-d6): d 3.35 (3H, s), 3.90 (3H, s), 3.97 (3H, s), 8.04 (1H, s). 13C NMR (DMSO-d6, 400 MHz) d 27.8, 34.3, 56.5, 110.0, 141.3, 148.5, 153.6, 155.8. Mass spectrum m/z: 195.11 (M+H)+. IR: vKBr 3094.3, 1686.0, 1571.2, 1520.7, 1436.8, 1408.6, 1386.1, 1151.0, 1029.2, 774.3 and 637.3 cm-1.

Example 5
Preparation of Paraxanthine (1)
To a stirred solution of 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one (5) (5.0 g, 25.76 mmol) in water (2.5 vol), Conc. HCl (5 vol) was added dropwise, The reaction mixture was stirred at 110 °C for 12 h and the reaction mixture was cooled to room temperature and the reaction mixture was neutralized with 25% aqueous NaOH solution, solid was formed, solid filtered and washed with cold water, to afford Paraxanthine (1) as white solid. Yield: 4.0 g (86 %). HPLC purity: 99.5%; 1HNMR (400 MHz, DMSO-d6): d 3.17 (3H, s), 3.85 (3H, s), 7.92 (1H, s), 11.82 (1H, bs). 13C NMR (DMSO-d6, 400 MHz) d 26.7, 32.9, 106.4, 142.9, 147.3, 151.1, 155.3 Mass spectrum m/z: 181.08 (M+H)+. IR: vKBr 3109.2, 2940.2, 1698.1, 1650.4, 1440.8, 1404.5, 1322.3, 1212.0, 1011.0, 761.3, 750.2, 717.1, and 611.7 cm-1.

Example 6
Preparation of 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one (5) from compound (4)
To a stirred solution of 2-methoxy-1-methyl-1H-purin-6(7H)-one (4) (25 g, 147.05 mmol) in dichloromethane (3 vol), was added slowly methyl triflate (24.1 g, 147.05 mmol). The reaction mixture was stirred for 4 h at 25 °C. The reaction mixture was evaporated under vacuum and washed with diethyl ether to afford 2-methoxy-1,7-dimethyl-6H-purin-6-one (5), as a light yellow solid. Yield: 24.5 g (91%).

Example 7
Preparation of 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one (5) from compound (2)
To a stirred solution of 5,6-diamino-2-methoxy-3-methylpyrimidin-4(3H)-one (2) (25 g, 147.05 mmol) in water (2 vol), was added paraformaldehyde (6.62 g, 220.57 mmol), the reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was cooled rt and extracted with 10% MeOH in DCM (3x250 mL), the combined organic layer was washed with brine solution, and dried with Na2SO4. The organic layer was concentred under vacuum, the crude was washed with MTBE (2 x 1.0 vol), to obtain 2-methoxy-1,7-dimethyl-1,7-dihydro-6H-purin-6-one (5) as an off-white solid. Yield: 17.5 g (70%).

Example 8
Process for the crystallization of Paraxanthine
The crude (Paraxanthine 20.0 g) was dissolved in a mixture of Acetone (40 mL) and water (40 mL), heated at reflux for 2 h, then cooled to 40 oC, solid formed was filtered and washed with hot (30 °C) Acetone (20 mL), to afford Paraxanthine (1) as a white solid. Yield: 15.0 g (75%).

Example 9
Process for the preparation of Paraxanthine polymorphs
Paraxanthine Form I:
Paraxanthine (5.0 g) was dissolved in 500 mL of methanol at 60 °C, filtered and the filtrate was kept in rt for 10 days, crystals was formed and filtered the crystals, the crystals was dried under vacuum, to afford Paraxanthine. Yield: 3.5 gm (70%). PXRD : 2O (% relative intensity): 12.89 (90.5%); 13.19 (100%); 13.63 (41.4%); 17.51 (14.1%); 17.73 (17.5%); 22.80 (5.8%); 23.02 (8.5%); 25.07 (4.8%); 26.00 (23.8%); 26.27 (24.4%); 26.9 (4.2%); 27.45 (15.1%); 28.6 (2.9%); 29.69 (2.6%); 30.77 (6.7%); 31.01 (7.3%); 41.17 (2.7%); 42.64 (1.7%); 44.98 (1.3%); 46.74 (1.4%); 48.12 (2.0%); 50.86 (1.5%); 53.59 (1.9%); 55.41 (1.2%); 56.65 (1.0%); 59.60 (1.1%).
Paraxanthine Form II:
Paraxanthine (5.0 g) was dissolved in 500 mL of ethanol at 60 °C, filtered and the filtrate was kept in rt for 10 days, crystals was formed and filtered the crystals, the crystals was dried under vacuum, to afford Paraxanthine. Yield: 3.0 gm (60%). PXRD : 2O (% relative intensity): 12.92 (97.7%); 13.42 (100%); 17.49 (14.2%); 18.91 (1.0%); 22.75 (3.6%); 24.93 (1.9%); 25.98 (15.0%); 26.99 (4.5%); 27.39 (4.4%); 28.49 (1.1%); 30.7 (6.9%); 34.82 (1.3%); 35.53 (1.3%); 36.94 (1.5%); 38.14 (3.8%); 39.42 (3.5%); 40.98 (1.4%); 48.26 (1.0%); 49.20 (1.1%).
Paraxanthine Form III:
Paraxanthine (5.0 g) was dissolved in 5 mL of acetic acid at 60 °C, filtered and the filtrate was kept in rt for 10 days, crystals was formed and filtered the crystals, the crystals was dried under vacuum, to afford Paraxanthine. Yield: 2.0 gm (40%). PXRD : 2O (% relative intensity): 12.94 (100%); 13.49 (46.4%); 14.26 (1.3%); 17.47 (8.4%); 17.79 (3.6%); 19.06 (1.5%); 22.83 (4.9%); 25.04 (4.0%); 25.90 (17.0%); 26.14 (13.1%); 27.00 (2.3%); 27.40 (9.7%); 27.63 (11.9%); 28.65 (1.5%); 29.51 (1.6%); 30.91 (2.2%); 33.29 (1.1%); 34.87 (1.8%); 35.72 (2.0%); 37.10 (1.2%); 38.26 (2.0%); 39.40 (4.8%); 41.12 (1.8%); 48.55 (1.0%); 53.49 (1.2%).
Paraxanthine Form IV:
Paraxanthine (5.0 g) was dissolved in 5 mL of water at 60 °C, filtered and the filtrate was kept in rt for 10 days, crystals was formed and filtered the crystals, the crystals was dried under vacuum, to afford Paraxanthine. Yield: 2.5 gm (50%). PXRD : 2O (% relative intensity): 11.74 (17.3%); 12.47 (35.6%); 12.95 (19.5%); 19.40 (20.9%); 23.45 (20.8%); 24.9 (24.0%); 25.9 (76.2%); 26.04 (74.0%); 28.64 (46.9%); 35.02 (100%); 37.77 (81.9%); 39.37 (94.4%); 39.51 (92.3%); 49.0 (90.8%); 53.40 (65.5%); 53.55 (47.0%); 55.39 (48.3%); 59.21 (49.2%); 62.68 (73.2%); 68.44 (28.9%).
Paraxanthine Form V:
Paraxanthine (5.0 g) was dissolved in 5 mL of IPA at 60 °C, filtered and the filtrate was kept in rt for 10 days, crystals was formed and filtered the crystals, the crystals was dried under vacuum, to afford Paraxanthine. Yield: 3.0 gm (60%). PXRD : 2O (% relative intensity): 12.83 (66.7%); 13.34 (100%); 14.37 (2.6%); 17.41 (17.3%); 18.84 (2.4%); 22.67 (4.3%); 24.86 (8.2%); 25.88 (9.0%); 26.70 (2.2%); 26.92 (4.6%); 27.32 (13.1%); 28.41 (2.0%); 29.04 (1.0%); 29.50 (1.1%); 30.67 (7.3%); 33.12 (1.1%); 34.74 (1.1%); 35.50 (1.4%); 36.87 (1.7%); 38.08 (3.2%); 39.32 (1.3%); 40.90 (1.4%); 42.35 (1.0%).
,CLAIMS:We claim:

1. A process for the preparation of Paraxanthine of formula 1

comprising steps of
i a. reacting compound of formula 2 with a regioselective mono N-methylating agent in a suitable solvent to obtain compound of formula 3,

i b. reacting compound of formula 3 with formylating agent followed by cyclization to obtain compound of formula 5,

and
i c. reacting compound of formula 5 with an acid to obtain Paraxanthine of formula 1.
or
ii. reacting a compound of formula 4 with a regioselective N-methylating agent in a suitable solvent to obtain compound of formula 5, followed by treatment with an acid to obtain Paraxanthine of formula 1

or
iii. reacting compound of formula 2 with paraformaldehyde in a suitable solvent to obtain a compound of formula 5, followed by treatment with an acid to obtain Paraxanthine of formula 1.

2. The process according to claim 1 wherein the regioselective mono N- methylating agent is selected from methyl triflate, Dimethylaminoethanol, N, N-Dimethylformamide dimethyl acetal (DMF-DMA), N,N-Dimethylaminomethyltrimethylsilane (DMATMS), Dimethylamine-borane complex (DMAB), dimethylamino ethyl methacrylate (DMAEMA), Methyl iodide, Dimethyl sulphate-p_TSA, methyl trifluoroacetate, tetramethyl ammonium fluoride, methyl tosylate (MeOTs), methyl acetate (MeOAc), or methyl methane sulfonate-p-TSA (MMS), alcohols as alkylating agents under the catalytic influence of ruthenium, rhenium, manganese, palladium, iron, cobalt, nickel, or indium.

3. The process according to claim 1 wherein the solvent used with the methylating agent is selected from the list of dichloromethane (DCM) and 1,1,1,3,3,3-hexafluoro-2-propanol, but not limited to chlorinated solvents such as chloroform (Trichloromethane), carbon tetrachloride (Tetrachloromethane), 1,1,1-trichloroethane (Methyl chloroform), trichloroethylene (TCE), perchloroethylene (Tetrachloroethylene), 1,2-dichloroethane (Ethylene dichloride), 1,1-dichloroethene (Vinylidene chloride), 1,1,2-trichloroethane, and tetrachloroethene (Perchloroethene), fluorinated alcohols like trifluoroethanol (TFE) and trifluoroacetic acid (TFA), and other solvents such as isopropanol, tert-Butanol dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (MeCN).

4. The process according to claim 1 wherein the solvent used in step iii can be selected from water, ethanol, propanol, isopropanol, butanol or mixtures thereof.

5. The process according to claim 1 wherein the acid in step (i c) is selected from Conc. HCl, Hydrogen bromide (HI), Lewis acid’sBoron tribromide (BBr3) or Aluminium chloride (AlCl3), Pyridinium Bromide or Chloride.

6. The process according to claim 1 wherein the process further comprises crystallization of Paraxanthine from a solvent selected from water, lower alcohols such as ethanol, methanol, isopropanol, propanol, n-butanol, tert-butanol; acids like acetic acid, propionic acid, butanoic acid, halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; ketones such as acetone, methyl ethyl ketone; ethers such as diethyl ether, THF or mixtures thereof.

7. The process according to claim 6, wherein the process comprises dissolving paraxanthine in a mixture of acetone and water, heating at reflux, cooling and isolating Paraxanthine (1).

8. A compound selected from a compound of formula 3
,
and a compound of formula 5
.

9. The process according to claim 6, wherein the process comprises dissolving Paraxanthine in methanol at 60 °C, filtered, and the filtrate was kept at room temperature for 10 days and isolating Paraxanthine Form I having PXRD peaks at 2O (% of relative intensity) : 12.89 (90.5%); 13.19 (100%); 13.63 (41.4%); 17.51 (14.1%); 17.73 (17.5%); 22.80 (5.8%); 23.02 (8.5%); 25.07 (4.8%); 26.00 (23.8%); 26.27 (24.4%); 26.9 (4.2%); 27.45 (15.1%); 28.6 (2.9%); 29.69 (2.6%); 30.77 (6.7%); 31.01 (7.3%); 41.17 (2.7%); 42.64 (1.7%); 44.98 (1.3%); 46.74 (1.4%); 48.12 (2.0%); 50.86 (1.5%); 53.59 (1.9%); 55.41 (1.2%); 56.65 (1.0%); 59.60 (1.1%).

10. The process according to claim 6, wherein the process comprises dissolving Paraxanthine in ethanol at 60 °C, filtering the solution, allowing the filtrate to stand at room temperature for 10 days and isolating Paraxanthine Form II having PXRD peaks at 2O (% of relative intensity) : 12.92 (97.7%); 13.42 (100%); 17.49 (14.2%); 18.91 (1.0%); 22.75 (3.6%); 24.93 (1.9%); 25.98 (15.0%); 26.99 (4.5%); 27.39 (4.4%); 28.49 (1.1%); 30.7 (6.9%); 34.82 (1.3%); 35.53 (1.3%); 36.94 (1.5%); 38.14 (3.8%); 39.42 (3.5%); 40.98 (1.4%); 48.26 (1.0%); 49.20 (1.1%).

11. The process according to claim 6, wherein the process comprises dissolving Paraxanthine in acetic acid at 60 °C, filtering the solution, allowing the filtrate to stand at room temperature for 10 days and isolating Paraxanthine Form III having PXRD peaks at 2O (respective % relative intensities): 12.94 (100%); 13.49 (46.4%); 14.26 (1.3%); 17.47 (8.4%); 17.79 (3.6%); 19.06 (1.5%); 22.83 (4.9%); 25.04 (4.0%); 25.90 (17.0%); 26.14 (13.1%); 27.00 (2.3%); 27.40 (9.7%); 27.63 (11.9%); 28.65 (1.5%); 29.51 (1.6%); 30.91 (2.2%); 33.29 (1.1%); 34.87 (1.8%); 35.72 (2.0%); 37.10 (1.2%); 38.26 (2.0%); 39.40 (4.8%); 41.12 (1.8%); 48.55 (1.0%); 53.49 (1.2%).

12. The process according to claim 6, wherein the process comprises dissolving Paraxanthine in water at 60 °C, filtering the solution, allowing the filtrate to stand at room temperature for 10 days and isolating Paraxanthine Form IV having PXRD peaks at 2O (% relative intensities): 11.74 (17.3%); 12.47 (35.6%); 12.95 (19.5%); 19.40 (20.9%); 23.45 (20.8%); 24.9 (24.0%); 25.9 (76.2%); 26.04 (74.0%); 28.64 (46.9%); 35.02 (100%); 37.77 (81.9%); 39.37 (94.4%); 39.51 (92.3%); 49.0 (90.8%); 53.40 (65.5%); 53.55 (47.0%); 55.39 (48.3%); 59.21 (49.2%); 62.68 (73.2%); 68.44 (28.9%).

13. The process according to claim 6, wherein the process comprises dissolving Paraxanthine in IPA at 60 °C, filtering the solution, allowing the filtrate to stand at room temperature for 10 days Paraxanthine Form V having PXRD peaks at 2O (% relative intensities): 12.83 (66.7%); 13.34 (100%); 14.37 (2.6%); 17.41 (17.3%); 18.84 (2.4%); 22.67 (4.3%); 24.86 (8.2%); 25.88 (9.0%); 26.70 (2.2%); 26.92 (4.6%); 27.32 (13.1%); 28.41 (2.0%); 29.04 (1.0%); 29.50 (1.1%); 30.67 (7.3%); 33.12 (1.1%); 34.74 (1.1%); 35.50 (1.4%); 36.87 (1.7%); 38.08 (3.2%); 39.32 (1.3%); 40.90 (1.4%); 42.35 (1.0%).

14. A Paraxanthine polymorph selected from
Paraxanthine Form I,
Paraxanthine Form II,
Paraxanthine Form III,
Paraxanthine Form IV or
Paraxanthine Form V.