A Practical Synthesis of 2-((1H-Pyrrolo[2,3-b]pyridine-4-yl)methylamino)-5- fluoronicotinic Acid

Abstract

A practical synthesis of a key pharmaceutical intermediate, 2-[(1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid (1), is described. To introduce the aminomethyl moiety of 2 via a palladium-catalyzed cyanation/reduction sequence, a regioselective chlorination of 7-azaindole via the N-oxide was developed. A highly selective monodechlorination of 2,6-dichloro-5-fluoronicotinic acid was discovered to afford the nicotinic acid 3. The two building blocks 2 and 3 were then coupled to complete the preparation of 1.

Cell‐Based Biological Evaluation of a New Bisamide FMS Kinase Inhibitor Possessing Pyrrolo[3,2‐c]pyridine Scaffold

“…Synthesis of the target compound 1 was successfully achieved as illustrated in Scheme . 7‐Hydroxy‐1 H ‐pyrrolo[2,3‐ b ]pyridinium 3‐chlorobenzoate ( 3 ) was prepared by reacting 7‐azaindole ( 2 ) with 3‐chloroperbenzoic acid . Compound 3 was then heated with phosphorus oxychloride to produce 4‐chloro‐7‐azaindole ( 4 ) .…”

“…7‐Hydroxy‐1 H ‐pyrrolo[2,3‐ b ]pyridinium 3‐chlorobenzoate ( 3 ) was prepared by reacting 7‐azaindole ( 2 ) with 3‐chloroperbenzoic acid . Compound 3 was then heated with phosphorus oxychloride to produce 4‐chloro‐7‐azaindole ( 4 ) . Compound 4 was prepared according to the literature procedure .…”

A General, Practical Palladium‐Catalyzed Cyanation of (Hetero)Aryl Chlorides and Bromides

“…For the preparation of 2-[(1 H -pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid, 4-cyano-7-azaindole ( 5 ) was used as an intermediate. [29] The reported synthesis utilized Zn(CN) 2 with 3.2 mol % (dppf)Pd (Eq 4). Using our procedure, 5 was obtained in similar yield using half the catalyst, in half the time, at lower temperature, and using K 4 [Fe(CN) 6 ]•3H 2 O in lieu of Zn(CN) 2 .…”

Design and Synthesis of an Anticancer Diarylurea Derivative with Multiple-Kinase Inhibitory Effect

“…7-Hydroxy-1H-pyrrolo[2,3-b]pyridinium 3-chlorobenzoate (3) was prepared by reacting 7-azaindole (2) with 3-chloroperbenzoic acid. 10,11 Compound 3 was heated with phosphorus oxychloride to produce 4-chloro-7-azaindole (4).…”