A Novel and Practical Synthesis of Mavorixafor

Abstract

A novel and practical synthesis of mavorixafor (1) is reported. The novelty of this synthetic route is the use of 8chloro-5,6,7,8-tetrahydroquinoline (9) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline (4) and N,N-diprotected aminobutyraldehyde (6a or 6b). The preparation of (S)-8-(4-aminobutylamino)-5,6,7,8-tetrahydroquinoline (13) by resolution with N-acetyl-L-leucine was first achieved. Then the one-pot synthesis of 1 from 13 involving protection, condensation, and subsequent hydrolysis was successfully developed. In addition, the final product with a satisfactory purity (>99.5%, detected by both achiral and chiral HPLC) was obtained by a simple operation (salification) without column chromatographic purification.

Polar Heterobenzylic C(sp3)–H Chlorination Pathway Enabling Efficient Diversification of Aromatic Nitrogen Heterocycles

“…Direct use of NCS in acetonitrile (methods c ) led to significantly improved yields of 3 and 4 (30% and 45%, respectively) relative to that observed with TCCA, but the best results were obtained with catalytic quantities of TfCl when paired with basic additives, 10 mol % 4-(dimethylamino)­pyridine and 1.1 equiv of Li 2 CO 3 (method d , 85% and 84% yield of 3 and 4 , respectively). The data in Figure reflect results obtained with six different polar reaction conditions (methods a – f ), including the original conditions reported for the preparation of 1 (method e ) and the NCSI conditions of Britton et al (method f ) . The latter method led to a notable yield of 4 (35%), showing the best performance, aside from the NCS-based conditions.…”

“…Some precedents exist for the polar chlorination of alkyl-substituted heteroarenes. Chlorination at the 8-position of 5,6,7,8-tetrahydroquinoline ( 1a ) has been achieved with trichloroisocyanuric acid (TCCA) in refluxing dichloromethane (Figure A) . These conditions had limited utility with other substrates, however.…”