7-Nitro-3,4-dihydroisoquinolin-1(2H)-one → 7-Amino-1,2,3,4-tetrahydroisoquinolin-1-one

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Reaction Steps

Compounds within the scope of the invention may be prepared as depicted in Scheme 1. In general, an aldehyde, such as 4-cyanobenzaldehyde, and an amine, such as N1-boc-1,3-diamino-n-propane can be reacted in a suitable solvent (eg., THF or chloroform) to form an imine intermediate. The solvent may then be evaporated under reduced pressure, and the residue redissolved in DMF. The imine is then reacted with 7-nitro-homopthallic anhydride, (i.e., 7-Nitro-1H-2-benzopyran-1,3(4H)-dione) to produce a 7-nitro-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(3-(4-cyanophenyl)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 1). The nitro group of the 7-nitro-3,4-dihydroisoquinolin-1(2H)-one can then be treated with a reducing agent, such as hydrogen in the presence of 10% palladium on carbon, in a suitable solvent (MeOH) to give a 7-amino-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(7-amino-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 13). The 7-amino-3,4-dihydroisoquinolin-1(2H)-one may be dissolved in a suitable solvent (eg., benzene) and then be treated with an organic isocyanates, such as 4-acetylphenyl isocyanates, in the presence of a strong base (eg, DIPEA) to produce a urea, such as tert-butyl {3-[7-({[(4-acetylphenyl)amino]carbonyl}amino)-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]propyl}carbamate (Intermediate 23), a compound which falls under the scope of the invention. At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. For instance, a sulfide group may be oxidized to sulfoxide or sulfone groups by treatment with a suitable oxidizing agent (eg., m-chloroperbenzoic acid). Or, for example, the t-butylcarbamate group may be removed by treatment with a strong acid, such as trifluoroacetic acid, to give an amine product, such as 1-(4-acetyl phenyl)-3-[2-(2-aminoethyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]urea (Compound 2). Details of certain specific chemical transformations are provided in the examples.

Provenance & Evidence