Manufacturing Process
Synthesis of 1,8-dimethyl-3-(2-methyl-1-butyl)xanthine included 7 steps:
1). 1-Methyl-3-(2-methyI-1-butyl)urea:
1.03 kg (11.8 mole) of 2-methyl-1-butylamine was added to 4.5 L of
chloroform and the solution cooled to 0-5°C. Then 674.0 g (11.8 moIe) of
methyl isocyanate was added slowly while maintaining the temperature at
0.5°C. After the addition was complete the reaction was allowed to reach
room temperature. Stirring was continued for 18 hours. The chloroform was
removed under vacuum to yield 1.7 kg of 1-methyl-3-(2-methyl-1-butyl)urea
as an oil. Yield 100%.
2). 1-Methyl-1-cyanoacetyl-3-(2-methyl-1-butyl)urea:
To 1.7 kg (11.8 mole) of 1-methyl-3-(2-methyl-1-butyl)urea were added 4.3 L
of methyl isocyanate and 1.18 kg (13.9 mole) of cyanoacetic acid. This was
heated for 2 hours at 60-70°C. The acetic anhydride was removed under
vacuum to yield 2.9 kg of oil. This material is a mixture of cyanoacetic acid
and 1-methyl-1-cyanoacetyl-3-(2-methyl-1-butyl)urea. No attempt was made
at purification; the crude oil was used immediately in the next step.
3). 1-Amino-1-methyl-3-(2-methyl-1-butyl)uracil:
10.3 L of 10% NaOH solution was slowly added to 2.9 kg (11.8 mole) of crude
1-methyl-1-cyanoacetyl-3-(2-methyl-1-butyl)urea with stirring. The oil
dissolved and shortly another oil precipitated. The temperature rose to about
60°C and then dropped. After stirring for a while at room temperature the oil
crystallized. After cooling the product was filtered. The crude product was
slurred in water and dried at 50°C in vacuum to yield 2.1 kg of 4-amino-1-
methyl-3-(2-methyl-1-butyl)uracil. MP: 121-124°C. Yield 85%.
4). 4-Amino-5-nitroso-1-methyl-3-(2-methyl-1-butyl)uracil:
21 kg (9.9 mole) of 4-amino-1-methyl-3-(2-methyl-1-butyl)uracil was
suspended in 22.0 L of water. A solution of 745.5 g (10.8 mole) of sodium
nitrite in 5.7 L of water was added to the suspension. Then 1.2 L of glacial
acetic acid was added dropwise and the suspension was stirred for 18 hours at
room temperature. After cooling the precipitate was filtered. The crude
product was slurred in water and dried at 80°C in vacuum to yield 1.9 kg of
4-amino-5-nitroso-1-methyl-3-(2-methyl-1-butyl)uraciI. MP: 202-204°C. Yield
80%.
5). 4,5-Diamino-1-methyl-3-(2-methyl-1-butyl)uracil:
8.65 L of conc. ammonium hydroxide (58%) was added to 1.9 kg (7.9 mole)
of 4-amino-5-nitroso-1-methyl-3-(2-methyl-1-butyl)uracil. An orange salt
formed. The suspension was placed in an oil bath at 80-90°C and a solution
resulted. 5.6 kg (32.3 mole) of sodium dithionite was added in portions over
about 30 min. When the addition was complete stirring was continued for 30
min. The reaction was allowed to cool to room temperature and stirred
overnight. After cooling the precipitate was filtered, slurred with water and
dried at 80°C in vacuum to yield 1.25 kg of 4,5-diamino-1-methyl-3-(2-
methyl-1-butyl)uracil. MP: 161-163°C. Yield 70%.
6). 4-Amino-5-acetylamino-1-methyl-3-(2-methyl-1-butyl)uracil:
1.25 kg (5.5 mole) of 4,5-diamino-1-methyl-3-(2-methyl-1-butyl)uracil was
added to 4.5 L of glacial acetic acid and heated to reflux for 2 hours. The
acetic acid was evaporated and the residue triturated with ether. The solid was
filtered and dried at 60°C in vacuum to yield 1.26 kg of 4-amino-5-
acetylamino-1-methyl-3-(2-methyl-1-butyl)uracil. MP: 178-182°C. Yield 85%.
7). 1,8-Dimethyl-3-(2-methyl-1-butyl)xanthine:
1.26 kg (4.7 mole) of 4-amino-5-acetylamino-1-methyl-3-(2-methyl-1-
butyl)uracil was added to 3.9 L of 10% sodium hydroxide solution and heated
at reflux for 30 min. The solution was filtered and the filtrate cooled to room
temperature. The pH of the filtrate was adjusted to 5.0 with glacial acetic
acid. After cooling the precipitate was filtered. The crude product was slurred
twice with water and dried at 80°C in vacuum to yield about 1.0 kg of 1,8-
dimethyl-3-(2-methyl-1-butyl)xanthine. MP: 189-191°C. Yield 85%.
