Synthesis of enantiomerically pure amino-substituted fused bicyclic rings
View Patent ↗This invention describes various processes for synthesis and resolution of racemic amino-substituted fused bicyclic ring systems. One process utilizes selective hydrogenation of an amino-substituted fused bicyclic aromatic ring system. An alternative process prepares the racemic amino-substituted fused bicyclic ring system via nitrosation. In addition, the present invention describes the enzymatic resolution of a racemic mixture to produce the (R)- and (S)-forms of amino-substituted fused bicyclic rings as well as a racemization process to recycle the unpreferred enantioner. Further provided by this invention is an asymmetric synthesis of the (R)- or (S)-enantiomer of primary amino-substituted fused bicyclic ring systems.
1. A process for synthesizing a racemic amino-substituted 5,6,7,8-tetrahydroquinoline or a racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline comprising:
a) reacting an amino-substituted quinoline of the formula I or an amino-substituted isoquinoline of the formula II with an amine-protecting group compound in an organic solvent to produce an amine-protected, substituted quinoline or isoquinoline:
wherein the amine-protecting group is an acyl, carbamate, or sulfonamide;
b) hydrogenating the amine-protected, substituted quinoline or isoquinoline in a strongly acidic solvent at an elevated temperature to form the 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline; and
c) hydrolyzing the amine-protecting group to produce the desired racemic amino-substituted 5,6,7,8-tetrahydroquinoline or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline;
wherein NH 2 is located at any position on the benzene portion of the quinoline or isoquinoline, R 1 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; and wherein R 1 is selected from the group consisting of nitro, cyano, carboxylic acid, alkyl, alkoxy, cycloalkyl, a protected hydroxyl, a protected thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.
2. The process of claim 1 wherein the amine-protecting group is acetyl.
3. The process of claim 1 wherein the strongly acidic solvent is selected from the group consisting of trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trichloroacetic acid, acetic acid, and any combination thereof.
4. The process of claim 3 wherein the strongly acidic solvent is trifluoroacetic acid (TFA).
5. The process of claim 1 wherein the elevated temperature is from about 50 to about 70° C.
6. The process of claim 5 wherein the elevated temperature is about 60° C.
7. The process of claim 1 wherein a catalyst is used for the hydrogenation and is selected from the group consisting of platinum black, platinum on carbon (0.5-20%), platinum on alumina (0.5-20%), platinum (IV) oxide (PtO 2 ), and platinum (IV) oxide hydrate.
8. The process of claim 1 wherein the hydrogenation is performed with 0.3M of substrate in TFA using 5 mol % of PtO 2 at 60° C. under 1 atmosphere of hydrogen.
9. The process of claim 1 wherein the amine-protecting group is hydrolyzed by heating with aqueous acid, heating with aqueous base, or heating in a solvent in the presence of hydrazine.
10. The process of claim 1 wherein the amino group is located at the 8-position of the quinoline; m is 0 or 1; and R 1 is methyl or methoxy.
11. The process of claim 1 wherein the amino group is located at the 8-position of the quinoline of Formula I and m is 0.