A Scalable Route to 5-Substituted 3-Isoxazolol Fibrinolysis Inhibitor AZD6564

Abstract

A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester.

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

“…In 2014, Sçrensen and co-workers at AstraZeneca were interested in the synthesis of an alkylated piperidine as akey fragment of AZD6564, ap otential antifibrinolytic agent (Scheme 3). [42] Thei ron-catalyzed cross-coupling of methyl 2-chloroisonicotinate with as terically hindered neopentyl Grignard reagent afforded the desired product in 73 %y ield on a2.3 kg scale using Fe(acac) 3 (5 mol %) as the catalyst and NMP (2.75 equiv) as the ligand. Thes alient features of this method include the implementation of ac itric acid/EDTA work-up to remove iron hydroxides.T he reaction proceeded efficiently upon slow addition of the Grignard reagent at 0 8 8C over 4h.D espite the success of this iron-catalyzed coupling, the Negishi cross-coupling using PEPPSI-IPr [43] (0.50 mol %) and neopentylzinc bromide (THF, < 40 8 8C, 66 %yield, 9.8 kg scale), which was investigated in parallel, was selected for the GMP campaign owing to as lightly cleaner reaction profile.…”

Iron-promoted C–C bond formation in the total synthesis of natural products and drugs

“…47 It is worth noting that Sörensen has used a coupling with alkyl Grignard reagent 61 with the 2-chloropyridine 62 under iron catalysis for a large scale preparation (2 kg) of the 3-isoxazolol brinolysis inhibitor AZD6564 (Scheme 24). 48 Iron-catalysed alkyl Grignard couplings can be applied to other heteroaryl halides. In particular, Cabri showed that a 2-chloropurine 64 can be coupled with n-butyl Grignard reagent in the presence of Fe(acac) 3 in the THF/NMP solvent mixture at 0 C, to afford a key intermediate 65 in 91% yield in the total synthesis of the adenosine A 2A receptor antagonist ST1535 (Scheme 25).…”

D‐Glucosamine in iron‐catalysed cross‐coupling reactions of Grignards with allylic and vinylic bromides: application to the synthesis of a key sitagliptin precursor

“…In the past few years, iron catalysis has often been used for large‐scale applications and/or in the synthesis of industrially relevant compounds . Examples are 5‐substituted 3‐isoxazolol fibrinolysis inhibitor AZD6564,[36a] a calcimimetic agent and calcium‐sensing receptor antagonist cinacalcet hydrochloride,[36b] highly selective adenosine A 2A receptor ligand antagonist ST1535,[36c] immunosuppressive agent FTY720[36d] and a new heterocyclic dual NK1/serotonin receptor antagonist [36e].…”

“…In the past few years, iron catalysis has often been used for large‐scale applications and/or in the synthesis of industrially relevant compounds . Examples are 5‐substituted 3‐isoxazolol fibrinolysis inhibitor AZD6564,[36a] a calcimimetic agent and calcium‐sensing receptor antagonist cinacalcet hydrochloride,[36b] highly selective adenosine A 2A receptor ligand antagonist ST1535,[36c] immunosuppressive agent FTY720[36d] and a new heterocyclic dual NK1/serotonin receptor antagonist [36e]. Encouraged by our results, we wanted to determine whether the presented catalytic methodology based on Fe(II)/ D ‐GlcN⋅HCl/Et 3 N could be used for the preparation of a target intermediate, namely 4‐(2,4,5‐trifluorophenyl)but‐2‐enoate ( 14 ), in an alternative process for the synthesis of the oral antihyperglycemic drug sitagliptin phosphate ( 15 ) .…”