Synthesis of enantiomerically pure amino-substituted fused...

Details Synthesis of enantiomerically pure amino-substituted fused... Synthesis of enantiomerically pure amino-substituted fused...

2002-09-12

2004-11-30

Davis, Zinna Northington (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S143000, C546S152000, C546S159000

Reexamination Certificate

active

06825351

ABSTRACT:

TECHNICAL FIELD
This invention describes various processes for synthesis and resolution of racemic amino-substituted fused bicyclic ring systems, in particular, amino-substituted tetrahydroquinolines or tetrahydroisoquinolines. One process utilizes selective hydrogenation of an amino-substituted fused bicyclic ring. An alternative process prepares a 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 ring systems, such as amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline. Another aspect of the invention describes a process to racemize the enantiomerically enriched (R)- and (S)-forms of amino-substituted fused bicyclic ring systems. Further provided by this invention is an asymmetric synthesis of an amino-substituted fused bicyclic ring to produce the desired enantiomer.
BACKGROUND OF THE INVENTION
It is desired by those of skill in the art to produce enantiomeric forms of pharmaceutical compounds, since such enantiomers often have increased activity for selected diseases when compared with the racemic form of the same compound. For example, 8-amino-5,6,7,8-tetrahydroquinolines are utilized as intermediates in the preparation of novel heterocyclic compounds that bind to chemokine receptors and demonstrate protective effects against infection of target cells by human immunodeficiency virus (HIV). See WO 00/56729.
Approximately 40 human chemokines have been described, that function, at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: P. Ponath,
Exp. Opin. Invest. Drugs
, 7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute a family of proteins, approximately 8-10 kDa in size. Chemokines appear to share a common structural motif, that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the “CC” or &bgr;-chemokines and the “CXC” or &agr;-chemokines. The receptors of these chemokines are classified based upon the chemokine that constitutes the receptor's natural ligand. Receptors of the &bgr;-chemokines are designated, “CCR”; while those of the &agr;-chemokines are designated “CXCR”.
Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation. More specifically, chemokines have been found to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and re-endothelialization after injury (Gupta et al.,
J. Biolog. Chem
., 7:4282-4287, 1998). Two specific chemokines have been implicated in the etiology of infection by human immunodeficiency virus (HIV).
For example, U.S. Pat. Nos. 5,583,131, 5,698,546 and 5,817,807 disclose cyclic compounds that are active against HIV-1 and HIV-2. These compounds exhibit anti-HIV activity by binding to the chemokine receptor CXCR4 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilizes the CXCR-4 receptor for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural CXC-chemokine for CXCR-4, stromal cell-derived factor 1 &agr; (SDF-1).
Additionally cyclic polyamine antiviral agents described in the above-mentioned patents have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. See U.S. Pat. No. 6,365,583. Thus, these agents are useful for controlling the side-effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
Therefore, a skilled artisan would be interested in more effective and efficient processes for producing racemates and enantiomers of various ring systems. This invention provides such processes.
SUMMARY OF THE INVENTION
The invention provides 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:
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.
The invention also provides 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
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; R
2
is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; and wherein R
2
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.
Further provided is 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
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; R
2
is located at any other hydrogen position on the quinoline or isoquinoline; m is 0-4; and R
2
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.
Also, this invention provides 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:
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 catalys

Affiliated with

Also associated with

Rating

Synthesis of enantiomerically pure amino-substituted fused... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Synthesis of enantiomerically pure amino-substituted fused..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of enantiomerically pure amino-substituted fused... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3289776