Synthesis of enantiomerically pure amino-substituted fused bicyclic rings

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 either a substituted 5,6,7,8-tetrahydroquinoline of the formula III or a substituted 5,6,7,8-tetrahydroisoquinoline of the formula IV
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• with at least 2 equivalents of an alkyllithium base, or a lithium, sodium, or potassium amide base, and then with a nitrosating agent to form an oxime;
• and
• b) reducing the oxime to produce the racemic amino-substituted 5,6,7,8-tetrahydroquinoline or the racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline;
• wherein the amino is located at the 8-position on the quinoline or the 5-position on the isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline ring;
• m is 0-4;
• and wherein R2 is selected from the group consisting of halo, nitro, cyano, a protected carboxylic acid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protected thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.

A process for synthesizing a keto-substituted 5,6,7,8-tetrahydroquinoline or a keto-substituted 5,6,7,8-tetrahydroisoquinoline comprising:

• a) reacting either a substituted 5,6,7,8 tetrahydroquinoline of the formula III or a substituted 5,6,7,8-tetrahydroisoquinoline of the formula IV
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• with at least 2 equivalents of an alkyllithium base, or a lithium, sodium, or potassium amide base;
• and then with a nitrosating agent to form an oxime;
• and
• b) hydrolyzing the oxime to produce the corresponding ketone;
• wherein the keto is located at the 8-position on the quinoline or the 5-position on the isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline;
• m is 0-4;
• and R2 is selected from the group consisting of halo, nitro, cyano, a protected carboxylic acid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protected thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group, and a heterocyclic group.

A process for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline of the formula V or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VI to produce the two enantiomers,

• comprising:
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• a) enantioselectively acylating or carbamoylating the racemic amino-substituted 5,6,7,8-tetrahydroquinoline or the racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline using an enantioselective enzyme as a catalyst;
• and
• b) separating the unreacted amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline as the first enantiomer, from the enantiomeric amide-or carbamate-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
• and
• c) cleaving the amide or carbamate group to isolate the second enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
• wherein NH2 is located at any position on the saturated portion of the quinoline or isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline ring;
• m is 0-4;
• and R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.

A process for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline of the formula V or amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VI to produce one of the enantiomers,

• comprising:
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• a) enantioselectively acylating or carbamoylating the racemic amino-substituted 5,6,7,8-tetrahydroquinoline or the racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline using an enantioselective enzyme as a catalyst to produce a mixture of the corresponding unreacted amine in the first enantiomeric form and the reacted amide or carbamate in the second enantiomeric form;
• and
• b) isolating the first enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
• wherein NH2 is located at any position on the saturated portion of the quinoline or isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline ring;
• m is 0-4;
• and R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.

A process for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline to produce the two enantiomers, comprising:

• a) reacting racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII
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• with water, an alcohol, or a primary or secondary amine using an enantioselective enzyme as a catalyst to produce a mixture of the corresponding amine in the first enantiomeric form, and the unreacted amide or carbamate in the second enantiomeric form;
• b) separating the first enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or amino-substituted 5,6,7,8-tetrahydroisoquinoline, from the unreacted amide or carbamate;
• and
• c) cleaving the amide or carbamate group to produce the second enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or amino-substituted 5,6,7,8-isoquinoline;
• wherein the amide or carbamate group is located at any position on the saturated portion of the quinoline or isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline ring;
• m is 0-4;
• R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group;
• and R3 is an optionally substituted carbon atom or an optionally substituted oxygen atom.

A process for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline to produce one of the enantiomers, comprising:

• a) reacting racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII
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• with water, an alcohol, or a primary or secondary amine using an enantioselective enzyme as a catalyst to produce a mixture of the corresponding amine in the first enantiomeric form, and the unreacted amide or carbamate in the second enantiomeric form;
• and
• b) isolating the first enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
• wherein the amide or carbamate is located at any position on the saturated portion of the quinoline or isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline ring;
• m is 0-4;
• R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group;
• and R3 is an optionally substituted carbon atom or an optionally substituted oxygen atom.

A process for synthesizing an enantiomer of a primary amino-substituted fused bicyclic ring of formula IX comprising:

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• a) forming the Schiff base of a keto group located on ring B of the fused bicyclic ring by reacting it with an enantiomerically-pure primary amine chiral auxiliary R*NH2 of the formula X
• 123
• to produce the corresponding enantiomerically-pure imine of the fused bicyclic ring;
• b) diastereoselectively reducing the imine to produce the corresponding enantiomerically-pure secondary amine on the fused bicyclic ring;
• and
• c) removing the chiral auxiliary R* to form the enantiomer of the primary amino-substituted fused bicyclic ring;
• wherein ring A is a heteroaromatic 5- or 6-membered ring, P is a nitrogen atom, sulfur atom or oxygen atom;
• ring B is a 5- or 6-membered cycloalkyl or heterocycloalkyl;
• wherein NH2 is located at a position on ring B;
• and R2 is located at any other hydrogen position on the fused bicyclic ring;
• wherein m is 0-4;
• R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group;
• and
• R4, R5, and R6 are each different and selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, and a 5- or 6-membered aromatic ring;
• and at least one of R4, R5, or R6 is a 5- or 6-membered aromatic or heteroaromatic ring.

A process for racemizing an enantiomerically enriched amino-substituted 5,6,7,8-tetrahydroquinoline of the formula XIII or amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula XIV to produce the corresponding racemic mixture:

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• comprising:
• a) heating the enantiomerically enriched amino-substituted 5,6,7,8-tetrahydroquinoline or amino-substituted 5,6,7,8-tetrahydroisoquinoline neat or in an organic solvent in the presence or absence of an additive;
• and
• b) when either R7 or R8 is not hydrogen, cleaving the R7 or R8 group under conditions to form the corresponding amino group;
• wherein NR7R8 is located at any position on the saturated portion of the quinoline or isoquinoline;
• R2 is located at any other hydrogen position on the quinoline or isoquinoline ring;
• m is 0-4;
• R is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group, and a heterocyclic group;
• and
• R7 and R8 are each selected from the group consisting of hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, aralkyl, alkanoyl, alkylsulfonyl, a carbonyl- or sulfonyl-group substituted by an aromatic or heterocyclic ring, aryloxycarbonyl, alkoxycarbonyl, arylcarbamoyl, alkylcarbamoyl, arylthiocarbonyl, alkylthiocarbonyl, and carbamoyl.

N-(2-Methyl-5,6,7,8-tetrahydro-quinolin-4-yl)-acetamide or N-(1,2,3,4-Tetrahydro-quinolin-7-yl)-acetamide or N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide or (R,S)-N-(2-Methyl-5,6,7,8-tetrahydro-quinolin-8-yl)-acetamide or 1,2,3,4-Tetrahydro-quinoline-8-carboxylic acid methyl ester or (R,S)-N-(2-Methyl-1,2,3,4-tetrahydro-quinolin-8-yl)-acetamide or 3-Methoxy-5,6,7,8-tetrahydro-quinoline or (R,S)-8-Amino-2-methyl-5,6,7,8-tetrahydroquinoline or (R)-N-(2-Methyl-5,6,7,8-tetrahydro-quinolin-8-yl)-acetamide or (S)-8-Amino-2-methyl-5,6,7,8-tetrahydroquinoline or (S)-5-Amino-5,6,7,8-tetrahydroquinoline or (R)-N-(5,6,7,8-tetrahydro-quinolin-5-yl)-acetamide or (S)-6-Amino-5,6,7,8-tetrahydroquinoline or (R)-N-(5,6,7,8-tetrahydro-quinolin-6-yl)-acetamide or (R,S)-5-Amino-5,6,7,8-tetrahydroisoquinoline or (S)-5-Amino-5,6,7,8-tetrahydroisoquinoline or (R)-N-(5,6,7,8-tetrahydro-isoquinolin-5-yl)-acetamide or (S)-6,7-Dihydro-5H-[1]pyrindin-7-ylamine or (R)-N-(6,7-Dihydro-5H-[1]pyrindin-7-yl)-acetamide or (S)-6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine or (R)-N-(6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-acetamide or (S)-5,6,7,8-tetrahydroquinoxalin-5-ylamine or (R)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)acetamide or (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine or (R)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide or (S)-4,5,6,7-tetrahydrobenzofuran-7-ylamine or (R)-N-(4,5,6,7-tetrahydrobenzofuran-7-yl)acetamide or (1-(R)-1-Phenylpropyl)-(8-(R)-5,6,7,8-tetrahydroquinolin-8-yl)-amine.