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A new procedure for regioselective synthesis of 8,9‐dichloro‐2,3,4,5‐tetrahydro‐1 H ‐2‐benzazepine (LY134046) and its 3‐methyl analogue as inhibitors of phenylethanolamine N ‐methyltransferase (PNMT)
Author(s) -
Grunewald Gary L.,
Paradkar Vidyadhar M.,
Stillions Duane M.,
Ching Feei
Publication year - 1991
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570280622
Subject(s) - chemistry , sodium cyanoborohydride , nitrile , regioselectivity , benzazepine , sodium hydride , sodium borohydride , borane , yield (engineering) , reagent , reductive amination , propionitrile , benzazepines , medicinal chemistry , organic chemistry , stereochemistry , acetonitrile , materials science , metallurgy , catalysis
A regioselective synthesis of 8,9‐dichloro‐2,3,4,5‐tetrahydro‐1 H ‐2‐benzazepine (LY134046, 10 ) and its 3‐methyl analogue 26 from 6,7‐dichloro‐3‐hydroxyphthalide ( 16 ) is described. The key step involved 1,4‐hydride addition to the α,β ‐unsaturated nitrile 17 to give the saturated nitrile 18 using sodium borohydride in 2‐propanol. In the preparation of LY134046 10 , the COOH group in 18 was first esterified and then the nitrile function was selectively reduced with borane to yield the aminoester 20 . The aminoester 20 was then cyclized to the azepinone 21 which on reduction with borane provided LY134046 10 in an overall yield of 22%. The route is adaptable to the preparation of hitherto unknown 3‐substituted‐2‐benzazepines as demonstrated by the preparation of the 3‐methyl analogue 26 . In this case the nitrile 18 was reacted with an excess methylmagnesium iodide to give the ketoacid 22 . Esterification of 22 followed by reductive amination with sodium cyanoborohydride and ammonium acetate provided the aminoester 24 , which was then converted to the target benzazepine 26 as described earlier for the title compound. The reaction conditions and the reagents used throughout the sequence are fairly mild and many functional groups may be tolerated. The only limitation to this procedure is the availability of the corresponding hydroxyphthalide. A variation in the choice of reagent in the Grignard reaction of 18 should provide an access to a variety of 3‐substituted‐2‐benzazepines.