Solvent-Free or Low-Solvent Large-Scale Preparation of Chloropyrimidine and Analogues

Abstract

Chloropyrimidine or other N-containing aromatic heterocyclic analogues can be efficiently prepared from the corresponding hydroxylated precursors under solvent-free or low-solvent conditions with equimolar or less chlorinating reagents. This high-yielding protocol allows successful preparations of multigram and kilogram batches of these important synthetic intermediates.

Large-Scale Solvent-Free Chlorination of Hydroxy-Pyrimidines, -Pyridines, -Pyrazines and -Amides Using Equimolar POCl3

“…Yet, the isolated yield was very good at 88% for the dichloro product, indicating that each POCl 3 provided more than one chlorine atom to form the final product. This result is consistent with findings in our original report that in some cases even substoichiometric amount of POCl 3 was sufficient to produce respectable results using our solvent-free protocol [ 7 ].…”

“…We recently reported a protocol for large scale (milligram to kilogram batches) chlorination of hydroxypyrimidines using equimolar or less POCl 3 with heating in a sealed reactor under solvent-free or low solvent conditions [ 7 ]. Our procedure has simple work up steps involving filtration or distillation, and generally gives high yields and purity of final products.…”

Development of a Commercial Manufacturing Route to 2-Fluoroadenine, The Key Unnatural Nucleobase of Islatravir

“…This would circumvent the Balz–Schiemann chemistry, avoiding associated safety/handling challenges and the product loss due to 8 . 2,6-Dichloropurine 11 is readily available in two well-established steps from guanine, and precedent in the literature showed that the halogen exchange could likely be induced by benign fluoride salts. ,, …”

Csp2–O and C–C Bond Formation via Pd‐Catalyzed Coupling Reaction of 2,4‐Dichloroquinazoline

“…A variety of conditions and combinations of catalyst systems, bases, and solvents were screened for optimal reaction conditions for 2,4‐dichloroquinazoline (derived from anthranillic acids and urea followed by chlorination with POCl 3 ) with phenyl boronic acid (Table ). Interestingly, under most of the reaction conditions, C4 hydroxylated/C2 arylated was the major product, with varying amounts of C2 and C4 diarylation product resulting from different aryl/heteroaryl boronic acid.…”