Toluene → Di-tert-butyl ether

The exemplary synthesis depicted in Scheme 1 involves condensation of 2-chloromalonic acid dimethyl ester 11 with an appropriately deuterated guaiacol 10 to afford the 2-(2-methoxyphenoxy)malonic acid dimethyl ester 12, followed by cyclization of 12 with 13 to afford the corresponding bipyrimidinedione 14. This compound 14 is treated with refluxing POCl3 to afford the dichlorobipyrimidine 15, which is subsequently treated with an appropriately deuterated 4-tert-butylphenylsulfonamide 16, K2CO3 and tetrabutylammonium bromide (TBAB) in toluene to provide the monosubstituted sulfonamide 17. Compound 17 is thereafter treated with an appropriately deuterated or fluorinated ethyleneglycol mono-tert-butyl ether 18 and NaOH in hot toluene to afford the tert-butyl ether protected intermediate, which is thereafter deprotected by reaction with formic acid to afford the formate ester. This ester is then hydrolyzed with NaOH in a mixture of water and ethanol, to afford the target compounds of Formula I. Such compounds of Formula I are readily purified by crystallization, comprising heating the crude product into a mixture of ethanol and water to afford a solution and thereafter allowing the solution to cool. Other approaches to synthesizing compounds of the formulae herein (e.g., Formula I) can readily be adapted from references cited herein. Variations of these procedures and their optimization are within the skill of the ordinary practitioner.

ORD record

ord-31de9705776a43c7b680b49fc31ee715

Source dataset

uspto-grants-2011_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08071596B2