Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Shawn D. Walker,* Christopher J. Borths, Evan DiVirgilio, Liang Huang, Pingli Liu, Henry Morrison, Kiyoshi Sugi, Masahide Tanaka, Jacqueline C. S. Woo, and Margaret M. Faul

Org. Process Res. Dev., 2011, 15, 570–580

DOI: 10.1021/op1003055

Summary: AMG 837 is a novel GPR40 receptor agonist developed at Amgen.  The end game of the synthesis involved an alkylative coupling between (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4′-(trifluoromethyl)biphenyl (2). The chiral non-racemic acid (1) (bottom left) was prepared in 35% overall yield via a classical resolution utilizing the amino alcohol, (1S,2R)-1-amino-2-indanol . The racemic acid (1) was prepared by a telescoped sequence which included the conjugate 1,4-addition of the Grignard reagent (resulting in the installation of the alkyne moiety) to the  Meldrum’s acid derived substrate. Additionally, the formation of (3) was monitored by react-IR.  The biaryl bromide (2) was prepared in short order utilizing a 2-step sequence involving (i) Suzuki−Miyaura coupling and (ii) a benzylic bromination. Key to the success of the process was application of a chemoselective alkylation (of a phenol derivative) mediated by tetrabutylphosphonium hydroxide that provided AMG 837 via direct coupling of (1) and (2). Ultimately, the more stable crystalline hemicalcium salt dihydrate form was used as the final salt form. In summary, the synthesis of AMG 837 was developed into an efficient 9-step route furnishing the desired target molecule in 25% overall yield.

Reaction Development and Mechanistic Study of a Ruthenium Catalyzed Intramolecular Asymmetric Reductive Amination en Route to the Dual Orexin Inhibitor Suvorexant (MK-4305)

Neil A. Strotman*, Carl A. Baxter, Karel M. J. Brands, Ed Cleator, Shane W. Krska, Robert A. Reamer, Debra J. Wallace, and Timothy J. Wright   
J. Am. Chem. Soc. 2011133, 8362–8371

Suvorexant (MK-4305) is a potent dual Orexin antagonist under development for the treatment of sleep disorders at Merck. The key transformation is an asymmetric Ru-catalyzed transfer hydrogenation (using a modified Noyori RuCl(p-cymene)(DPEN) complex) of an in-situ generated cyclic imine resulting in the formation of the desired chiral diazepane in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO2 (derived from the formic acid) has pronounced effect on reaction outcome.  Studies have determined that the efficiency of the Ru-catalyst, the composition of the resulting amine (via carbamate formation), and the reaction kinetics are mediated by the amount of CO2 generated during the reaction. The efficiency of the reductive-amination can be enhanced by either purging the CO2 or by trapping the newly formed nucleophilic secondary amine.

DOI:  10.1021ja202358f

References:

1) Org. Process Res. Dev., 2011, 15, 367–375  (DOI: 10.1021/op1002853)

2) http://www.kanto.co.jp/english/siyaku/pdf/fuseishokubai_02.pdf