Reacción #80914

Ecuación de reacción

2,4-diamino-6-cyano-5-methylquinazoline

3,4,5-trimethoxyaniline

hydrogen

→

2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylamino)methyl]quinazoline

Rendimiento 27.1%

Disolventes

water

acetic acid

Condiciones de reacción

Tratamiento posterior

1. 1
   FiltraciónAfter this time the reaction mixture was filtered
2. 2
   workup.ADDITIONThe filter cake was slurried with a boiling mixture of 15 mL of water and 35 mL of acetic acid
3. 3
   Filtraciónwas then filtered
4. 4
   FiltraciónAfter this time the reaction mixture was filtered
5. 5
   Concentraciónconcentrated under reduced pressure to a residual oil
6. 6
   LavadoElution
7. 7
   Concentraciónconcentrated under reduced pressure to a residual solid
8. 8
   OtroThe solid was recrystallized from water

Procedimiento

A mixture of 1.1 grams (0.005 mole) of 2,4-diamino-6-cyano-5-methylquinazoline, 4.6 grams (0.025 mole) 3,4,5-trimethoxyaniline and 2.0 grams (catalyst) of Raney nickel (50% slurry in water) in 30 mL of water and 70 mL of acetic acid was hydrogenated at 50 psi of hydrogen for 6 hours using a Parr hydrogenator. After this time the reaction mixture was filtered. The filter cake was slurried with a boiling mixture of 15 mL of water and 35 mL of acetic acid and was then filtered. The filtrates were combined and subjected to thin layer chromatography (TLC). The TLC analysis indicated that a small amount of the starting quinazoline remained unreacted. The filtrate was combined with 1.0 gram of Raney nickel and the mixture was again hydrogenated for an additional 1.5 hours using the Parr hydrogenator. After this time the reaction mixture was filtered and concentrated under reduced pressure to a residual oil. The residual oil was subjected to column chromatography on silica gel. Elution was accomplished initially using 25% N,N-dimethylformamide in ethyl acetate and, finally 40% N,N-dimethylformamide in ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure to a residual solid. The solid was recrystallized from water, yielding 0.5 gram of 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylamino)methyl]quinazoline, mp 95°-210° C. The NMR analysis was consistent with the proposed structure; however, it indicated that the compound was a complex with acetic acid and water. NOTE: The compound of Example 14 is known in the literature as Trimetrexate®, for use in treatments of certain kinds of cancers. [J. Med. Chem., 26, 1753-1760 (1983)]

Fuente