Hydrochloric Acid → 8-Cyclohexyl-6-methylthio-3-(n-propyl)-7H-purin-2(3H)-one

Phosphorus pentasulfide (27.1 g, 122 mmol, 1.5 equivalents) was suspended in pyridine (150 mL) and the mixture was heated to 100° C. To the suspension was gradually added 5,6-diamino-1-propyluracil (15.0 g, 81.3 mmol), which was obtained by the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 32 (6), p. 1231, 1989, with heating and stirring, and then the mixture was stirred for 7 hours. After the reaction solution was cooled on ice, the deposited solid was separated by filtration using a filtration aid and washed with pyridine. The filtrate was concentrated, to the residue was added water (90 mL), and the mixture was stirred under reflux with heating for about 40 minutes until intense foaming ceased. The reaction mixture was cooled on ice and then further stirred overnight at room temperature. The deposited yellowish green ocher solid was collected by filtration, sufficiently washed with water and dried under reduced pressure to obtain 5,6-diamino-1,2-dihydro-4-mercapto-2-oxo-1-propylpyrimidine (Compound B4, 11.3 g, 69%). Compound B4 (10.0 g, 50.0 mmol) was suspended in 1,4-dioxane (200 mL) and water (100 mL), to the suspension were added cyclohexanecarboxylic acid (8.06 mL, 65.0 mmol, 1.3 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.3 g, 85.0 mmol, 1.7 equivalents) at room temperature, and then the mixture was stirred overnight. To the reaction mixture was added 2 mol/L aqueous sodium hydroxide (100 mL), and the mixture was stirred with heating for 2.5 hours. The reaction mixture was cooled on an ice bath, adjusted to pH 6 with 4 mol/L hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 0.5 mol/L aqueous sodium hydroxide (150 mL), and to the solution was added methyl iodide (4.70 mL, 75.0 mmol, 1.5 equivalents) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled on an ice bath, adjusted to pH 6.5 with 4 mol/L aqueous hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 96:4) to obtain the title compound (11.8 g, 78%).

1. stirringthe mixture was stirred
2. temperaturewith heating for 2.5 hours
3. temperatureThe reaction mixture was cooled on an ice bath
4. extractionextracted with chloroform
5. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
6. customthe solvent was evaporated
7. dissolutionThe residue was dissolved in 0.5 mol/L aqueous sodium hydroxide (150 mL)
8. stirringthe mixture was stirred overnight at room temperature
9. temperatureThe reaction mixture was cooled on an ice bath
10. extractionextracted with chloroform
11. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
12. customthe solvent was evaporated
13. customThen, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 96:4)

ORD record

ord-7cf5e7b5e24b414b933ab7a30f0ad027

Source dataset

uspto-grants-2006_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07005430B2