Valuable Synthetic Building Blocks: Useful 2-Substituted 5-Amino­pyrimidines from a Stable Precursor

Abstract

-S u b s t i t u t e d 5 -A m i n o p y r i m i d i n e s f r o m a S t a b l e P r e c u r s o rAbstract: An efficient large-scale synthesis of 5-aminopyrimidine derivatives is described. The dihexafluorophosphate salt of a vinamidinium cation important in 5-aminopyrimidine synthesis has been prepared as a stable, easily purified intermediate. It has been used to prepare several 2-functionalized aminopyrimidines, valuable as synthetic building blocks.2,5-Disubstituted pyrimidines with have been widely synthesized. However, very few methods are available for the preparation of otherwise unsubstituted 2-functionalized 5-aminopyrimidines 1 or related 2 compounds. Nevertheless, such compounds are valuable synthetic building blocks. Present syntheses are unsuitable for large-scale chemistry, as they use hazardous precursors such as potentially explosive nitromalonaldehyde 3 or vinamidinium salts. Key compounds derived from the latter include 2, accessed by Arnold et al. 4 via the vinamidinium diperchlorate 3a 5 ( Figure 1). Figure 1Recently, we required access to a wide variety of 2-functionalized 5-aminopyrimidines. Some of these were used in the preparation of potential anti-cancer compounds or their precursors, by reaction with 4-chloroquinazolines as described in our recent patent application 6 and as exemplified in the conversion of 4 to 5 (Scheme 1).The likely thermal-and proven shock-sensitivity of vinamidinium perchlorate salts 7 made the salt 3a unsuitable for use by us as a large scale intermediate. It has also to be isolated by crystallization from a viscous solution in aqueous DMF at -10 to -35°C. Other salts of related vinamidinium cations previously described and used by Arnold and others include tetrafluoroborates, 7-9 and hexafluorophosphates. 9 Scheme 1We were unable to isolate the ditetrafluoroborate salt 3b usefully owing to its high solubility, and therefore turned our attention to the dihexafluorophosphate. 10 Hexafluorophosphate salts of amines and similar compounds are more easily isolated and less water-soluble than most other salts, for instance as diazonium salts in the Balz-Schiemann reaction; 11 also, widely used reagents such as HATU are commonly supplied as stable non-hygroscopic hexafluorophosphate salts.We have prepared the vinamidinium species as its dihexafluorophosphate salt 3c and have shown it to be an easily isolated, stable salt. The vinamidinium species was prepared, using a modification of Arnold's conditions, 5 from glycine hydrochloride in DMF and phosphorus oxychloride (see safety note 12 ). Research into improved preparations of similar salts from other less volatile formamides is ongoing.In our hands Arnold's original reaction conditions of 125°C for two hours gave, in addition to the product 3c, significant amounts of a by-product (Scheme 2) that formed a hexafluorophosphate salt inseparable from 3c; data from NMR and mass spectroscopy suggested this impurity was the previously undescribed salt 6. This presumably forms by attack on the product by dimethylamine generated ...