2,6-Dimethylaniline → Z-Dehydro-Ala-OMe

Beteiligte Stoffe

Reaktionsschritte

The synthesis of indazole amino acid B begins with the iodination of 2,6-dimethylaniline by the action of iodine monochloride (Scheme 3). This intermediate was temporarily set aside. N-CBZ-L-serine methyl ester undergoes a one-pot methanesulfonylation/elimination reaction to afford N-CBZ-dehydroalanine methyl ester. With the iodide and dehydroalanine in hand, they are efficiently coupled using palladium (II) acetate in a Heck coupling to afford the product in 65% yield. At this point, the chiral center is installed using a catalytic asymmetric hydrogenation utilizing (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) tetrafluoroborate and hydrogen (60 psi) to give the chiral amino acid in ˜96% ee. The indazole ring is then formed by the action of iso-amyl nitrite. The resulting indazole is highly crystalline. One recrystallization from acetone/hexanes affords the indazole amino acid in excellent purity and with an improved 99.8% ee. Removal of the CBZ protecting group under hydrogenation conditions completes the preparation of fragment B. Indazole amino acid B can also be prepared using enzymatic resolution of the racemic amino acid or keto acid (Hanson, Ronald L.; Davis, Brian L.; Goldberg, Steven L.; Johnston, Robert M.; Parker, William L.; Tully, Thomas P.; Montana, Michael A.; Patel, Ramesh N. Process Research and Development, Bristol-Myers Squibb, New Brunswick, N.J., USA. Organic Process Research & Development (2008), 12(6), 1119-1129.).

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