2,6-Dichloro-7-methyl-7H-purine

2, 6-dichloropurine (5.0 gram), methyl iodide (1. 1 eq. , 1.81 mL) and K.) C03 (1.2 eq. , 4.39 gram) were dissolved in 200 mL of MECN. After stirring for 70 hours at 20°C, the MECN was evaporated. Both isomers were separated by column chromatography using CH2C12/MEOH (90/10). Yield: 3.55 g (66percent) of intermediate 33 and 1.61 g (30percent) of intermediate 40.Step 1: Preparation of 2, 6-dichloro-9-methyl-9H-purine and 2, 6-dichloro-7-methyl-7H-purine (a-2) To a solution of 2, 6-dichloropurine (1.10 g, 5.82 mmol) in anhydrous THF (5.0 mL) was added tetra-n-butylammonium fluoride (0.58 mL, 10.58 mmol, 1.8 eq; 1M in THF). Methyl iodide (0.40 mL, 6.42 mmol, 1.1 eq) was added, and the reaction mixture was stirred at RT under NIntermediate 12.2, 6-Dichloro-7-methyl-7H-purine To a solution of 2, 6-dichloro-7H-purine (1.05 g, 5.56 mmol) in THF (8 mL) at 0 °C under nitrogen was added NaH (60percent in mineral oil, 525 mg, 13.1 mmol) in one portion and, after stirring for 30 min at 0 °C, iodomethane (0.38 mL, 6.12 mmol) was added. The mixture was stirred at 0 °C for 1 h and then at room temperature for 16 h. After this time, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was concentrated under reduced pressure and the residue obtained was purified by column chromatography (silica, 0–30percent EtOAc in CHSodium hydride (60percent in mineral oil, 2.53 g, 63.5 mmol) was added to an ice-cooled solution of 2, 6-dichloropurine (10.0 g, 52, 9 mmol) in tetrahydrofuran (75 ml_) and the mixture was stirred for 30 min. Methyl iodide (3.29 ml_, 52.9 mmol) was added drop-wise and the reaction mixture was stirred over night. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. Dichloromethane was added and undissolved material was collected by filtration. The crystalline compound turned out to be 2, 6-dichloro-7-methyl-7/-/-puhne (1.19 g, 11 percent) The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hepatane) to give 2, 6-dichloro-9-methyl- 9H-puhne (3.0 g, 28percent)Sodium hydride (60percent in mineral oil, 2.53 g, 63.5 mmol) was added to an ice-cooled solution of 2, 6-dichloropurine (10.0 g, 52, 9 mmol) in tetrahydrofuran (75 mL) and the mixture was stirred for 30 min. Methyl iodide (3.29 mL, 52.9 mmol) was added drop-wise and the reaction mixture was stirred over night. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. Dichloromethane was added and undissolved material was collected by filtration. The crystalline compound turned out to be 2, 6-dichloro-7-methyl-7H-purine (1.19 g, 11percent) The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hepatane) to give 2, 6-dichloro-9-methyl-9H-purine (3.0 g, 28percent).A mixture of 2, 6-dichloro-7H-purine (5.0 g, 26.7 mmol), KTo a solution of dichloropurine 27 (1.36 g, 7.20 mmol) was dissolved in acetone (22.7 mL) and potassium carbonate (1.49 mg, 10.8 mmol) was added at room temperature. Methyl iodide (537 i.il, 8.67 mmol) was added and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was concentrated, water was added to the residue and stirred stirred for 5 mm, and then extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried on Mg504, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography. Compound 29 was the major product formed (952 mg, 65percent) and was obtained as off-white solid and compound 28 was the minor product (389 mg, 27percent) aslo isolated pure as an off-white solid; these results are consistant with the literature (for example WO 2010/034706)Synthesis of 2, 6-dichloro-7-methyl-7H-purine from 3, 7 dimethyl-1H-purine 2, 6(3H, 7H) dione (theobromine) (a-2) 2, 6 dichloro-7-methyl-7H-purine was prepared from theobromine (a-1) in 10percent yield following the procedure of Uretskaya, G. Ya., Rybinka, E. I., and Men'shikov, G. P. Zh. Obshch. Ki., 1960, 30, 327 with the modification of N, N, diethylaniline disclosed by Stanovik, B. et at in the Australian Journal of Chemistry, 1981, 34, 1729. 1H NMR was identical in all respects to the material prepared by alkylation of commercially available 2, 6 dichloropurine with base and iodomethane. For example, the procedure reported by Feng et al. (WO2004/087053) utilizes 60percent NaH as base, dimethylformamide (DMF) as the solvent and iodomethane yielded a 1:1 mixture of the N-7/N-9 methylated products which were separated via silica chromatography. The procedure reported by Lewi et et al (WO2005/028479 A2) utilizes potassium carbonate as the base, acetonitrile as solvent (rt 70 h) and iodomethane and yielded a 2:1 isolated yield of methylated purines after silica chromatography (60percent yield N9Me/30percent yield N-7 Methylated). Similarly acetone can replace acetonitrile as the solvent and after refluxing with potassium carbonate and iodomethane for 24 h a 3:1 mixture of N9/N7 is obtained. The N-7 methylated product was isolated in 16.3percent purified yield after silica chromatography. A report by Chi-Huey Wong et al. (see, Bioorg Example 12, 6-Dichloro-9-methyl-9/-/-purine and 2, 6-Dichloro-7-methyl-7/-/-purineSodium hydride (60percent in mineral oil, 2.53 g, 63.5 mmol) was added to an ice- cooled solution of 2, 6-dichloropuhne (10.0 g, 52.9 mmol) in tetrahydrofuran (75 ml_) and the mixture was stirred for 30 min. Methyl iodide (3.29 ml_, 52.9 mmol) was added drop-wise and the reaction mixture was stirred over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. Dichloromethane was added and undissolved material was collected by filtration. The crystalline compound turned out to be 2, 6-dichloro-7-methyl-7/-/-purine (1.19 g, 11 percent) The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hepatane) to give 2, 6-dichloro-9-methyl-9/-/-purine (3.0 g, 28percent).

Molecular Weight:203.03
XLogP3:2
Hydrogen Bond Acceptor Count:3
Exact Mass:201.9813015
Monoisotopic Mass:201.9813015
Topological Polar Surface Area:43.6
Heavy Atom Count:12
Complexity:179
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes