AMD070, a CXCR4 Chemokine Receptor Antagonist: Practical Large-Scale Laboratory Synthesis

Abstract

An efficient and convergent four-step synthetic route to the CXCR4 chemokine receptor antagonist AMD070 (1) has been developed which employs only a single chromatographic step in the entire sequence. Novel reductive amination methods have been developed for the coupling of 2 and 3 in which a dehydrative imine formation is followed by reduction with an attenuated borohydride reagent (zinc chloride and sodium borohydride). Selective extraction methods were employed to purify synthetic intermediates and remove reagents and impurities. A procedure has also been developed to isolate 1 in a pure crystalline form.

Synthesis and Structure−Activity Relationships of Azamacrocyclic C-X-C Chemokine Receptor 4 Antagonists: Analogues Containing a Single Azamacrocyclic Ring are Potent Inhibitors of T-Cell Tropic (X4) HIV-1 Replication

“…[3][4][5] Recently, we reported the results of clinical trials with our prototype CXCR4 antagonist AMD3100 [6][7][8] (1) and an orally bioavailable CXCR4 antagonist, (S)-N 0 -(1H-benzimidazol-2-ylmethyl)-N 0 -(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070). [9][10][11] When administered to HIV positive patients whose virus was confirmed to use CXCR4 for viral entry, both agents were able to suppress the replication of CXCR4 and dual-tropic strains of HIV. Similarly, the CCR5 antagonist Maraviroc suppresses replication of HIV-1 that exclusively uses CCR5 for entry 12 and was recently approved by the FDA for combined antiretroviral therapy in treatmentexperienced patients.…”

Enantioselective Transfer Hydrogenation of Aryl Ketones: Synthesis and 2D-NMR Characterization of New 8-amino-5,6,7,8-tetrahydroquinoline Ru(II)-complexes

“…Unless otherwise stated, materials are obtained from commercial source and used without further purification; [RuCl 2 (PPh 3 ) 3 ] [9] and rac-5,6,7,8-tetrahydroquinolin-8-amine (rac-2) [6] were synthesized according to literature procedures.…”

“…(2), was evaluated. This compound is known and used as a subunit in medicinal compounds like chemokine receptor ligands [6] but its application as source of chirality in catalytic reductions was never highlighted. In this work, we report the preparation and characterization of the corresponding chiral ruthenium complexes as precatalysts for asymmetric transfer hydrogenation of aryl ketones.…”

“…C 52.35 H 6.08 N 9.39; found C 52.76 H 5.98 N 9.20.N-acetyl-derivates of CAPMYs, obtained by reaction of free base with acetic anhydride in diethyl aether, were used to evaluated enantiomeric excess by HPLC analysis and assign the absolute configuration by comparison with literature [ ] d rotation value[6]. (Eluent: Exane/isopropanol/DEA (90:10:0.1); Rf (R)(-)-Ac-CAMPY = 11.2 min., Rf (S)(+)-Ac-CAMPY =16.2 min.…”

An efficient, microwave-assisted, one-pot synthesis of novel 5,6,7,8-tetrahydroquinoline-3-carbonitriles

“…However, most of them describe the synthesis of the 1,2,3,4-tetrahydroquinoline nucleus, 10-12 and concise methods to access usefully functionalized 5,6,7,8-tetrahydroquinolines are scarce in the literature. 13 Recently, 5,6,7,8-tetrahydroquinolines have drawn considerable attention due to their interesting pharmacological applications as RET tyrosine kinase inhibitors, 14 anti-HIV, 15,16 anti-fungal, 17 anti-cancer 18 and C5a receptor antagonists agents. 19 The development of simple synthetic routes for widely used organic compounds from readily available reagents is one of the major tasks in organic synthesis.…”