Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-15
2001-01-30
Aulakh, Charanjit S. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S153000, C546S165000, C546S062000, C546S077000, C546S078000
Reexamination Certificate
active
06180794
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to 1,2-dihydroquinoline compounds that are useful as steroid receptor modulators and as key intermediates in the preparation of steroid receptor modulators, and methods for their synthesis.
BACKGROUND OF THE INVENTION
Tetracyclic 1,2-dihydroquinolines of structure 7 are key intermediates in the preparation of a number of steroid receptor modulating compounds [see for example: “Preparation of Quinolines and Fused Quinolines as Steroid Receptor Modulators”, T. K. Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, L. G. Hamann, R. L. David, L. J. Farmer, PCT Int. Appl. Pub. No. WO 96/19458; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, C. M. Tegley, L. Zhi, J. P. Edwards, S. J. West, U.S. Pat. No. 5,693,646; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, L. Zhi, J. P. Edwards, C. M. Tegley, S. J. West, U.S. Pat. No. 5,696,127}, and are prepared by a multi-step route culminating in the treatment of an aniline of structure 5 with a ketone and iodine at elevated temperatures in a process known as the Skraup reaction {see: “The Skraup Synthesis of Quinolines”, R. H. F. Manske and M. Kulka,
Organic Reactions,
7(1953) 59-98; “2,4-Dimethylquinoline”, W. R. Vaughan,
Org. Synth. Coll. Vol III,
(1955) 329-332}:
Many 1,2-dihydroquinolines of structure 7 are themselves receptor modulating compounds. {See for example: “Preparation of Quinolines and Fused Quinolines as Steroid Receptor Modulators”, T. K. Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, L. G. Hamann, R. L. David, L. J. Farmer, PCT Int. Appl. Pub. No. WO 96/19458; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, L. Zhi, C. M. Tegley, D. T. Winn, L. G. Hamann, J. P. Edwards, S. J. West, U.S. Pat. No. 5,693,647.} Other 2,2-disubstituted 1,2-dihydroquinolines are also modulators of steroid receptors. {See for example: “Preparation of Quinolines and Fused Quinolines as Steroid Receptor Modulators”, T. K. Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, L. G. Hamann, R. L. Davis, L. J. Farmer, PCT Int. Appl. Pub. No. WO 96/19458; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, D. T. Winn, L. Zhi, L. G. Hamann, C. M. Tegley, C. L. F. Pooley, U.S. Pat. No. 5,688,808; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, U.S. Pat. No. 5,688,810; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, D. T. Winn, M. E. Goldman, L. G. Hamann, L. Zhi, L. J. Farmer, R. L. David, U.S. Pat. No. 5,696,130; “Steroid Receptor Modulator Compounds and Methods”, T. K. Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, L. G. Hamann, L. J. Farmer, R. L. David, U.S. Pat. No. 5,696,133.}
The conversion of 5 to 7 utilizing a Skraup reaction limits the variety of compounds that can be prepared by this route due to the need to use a ketone (6) as one of the reaction partners; the substituents on C(2)-C(4) cannot be varied independently. The present invention addresses this limiting aspect of the Skraup reaction.
SUMMARY OF THE INVENTION
The present invention provides a novel route for the conversion of anilines 5 to 1,2-dihydroquinolines 12 (the set of compounds represented by general structure 7 being recognized as a subset of the set of compounds represented by general structure 12) in which the substituents on C(2)-C(4) can be varied independently:
First the carbon atom flanked by the aniline nitrogen and lactone carbonyl is functionalized with a halogen atom, forming a compound of structure 8. Performing a cross-coupling reaction of 8 (or an N-protected analogue of 8) with an approximately substituted metalated olefin 9 affords an ortho-alkenyl aniline 10, by a process known as a Stille, Suzuki, or Negishi coupling. {See for example: “Coupling Reactions Between sp
2
Carbon Centers”, D. W. Knight, In
Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry Vol.
3, B. M. Trost (Ed.), Pergamon: New York, (1991) 481-520; “Palladium-Catalysed Reactions of Organotin Compounds”, T. N. Mitchell,
Synthesis,
(1992) 803-815; “Palladium-Catalyzed Coupling of 2-Bromoanilines with Vinylstannanes—A Regiocontrolled Synthesis of Substituted Indoles”, M. E. Krolski, A. F. Renaldo, D. E. Rudisill and J. K. Still,
J. Org. Chem.,
53 (1982) 1170-1176; “The Cross-Coupling Reactions of Organic Halides with Organic Derivatives of Tin, Mercury, and Copper Catalyzed by Palladium”, I. P. Beletskaya,
J. Organomet. Chem.,
250 (1983) 551-564; “The Palladium-Catlyzed Cross-Coupling Reaction of Phenylboronic Acid with Halorenes in the Presence of Bases”, N. Miyaura, T. Yanagi and A. Suzuki,
Synth. Commun.,
11(1981) 513-519; “Synthetic Studies via the Cross-coupling Reaction of Organoboron Derivatives with Organic Halides”, A. Suzuki.,
Pure Appl. Chem.,
63(1991) 419-422.} An ortho-alkenyl aniline 10 can be converted to the target compounds 12 by reaction with a ketone 11 and an appropriate catalyst. {Ser for example: “Eine Neue Einfache Synthese Spirocyclischer 1H-Chinolin-Derivatives”, H. Walter,
Helv. Chim. Acta,
75(1992) 1274-1280; “Acid Catalyzed Reactions of 2-Vinylaniline Derivatives with Cylic Ketones of the Tetralone-, Chroman-4-one- and 2,3-Dihydro-1H-Quinolin-4-ones Series. N(O)-Heterocycles via 6&pgr; Electronic Rearrangements or [1,5]Dipolar Electrocyclizations. Part 3”, H. Walter and J. Schneider,
Heterocycles,
41(1995) 1251-1269.}. Using this alternatives procedure, compounds with substitution patterns not available from the traditional Skraup reaction route are now readily accessible.
The present invention is directed to methods for the preparation of 1,2-dihydroquinolines, some of which are key intermediates in the preparation of steroid receptor modulating compounds and/or are themselves steroid receptor modulators. The invention provides a novel route to compounds of structure 12 and, more particularly, to 1,2-dihydroquinolines that are not accessible from a previously disclosed route. Intermediate compounds prepared enroute to 1,2-dihydroquinolines of structure 12 as well as compounds of structure 12 that cannot be synthesized via the traditional Skraup reaction (i.e. the reaction that yields 7 directly from 5) are also within the scope of this invention. In addition, the general process consisting of the preparation of 2,2-disubstituted 1,2-dihydroquinolines optionally substituted at C(3) and/or C(4) by treatment of an ortho-alkenyl aniline with a ketone in the presence of a Lewis acid is also within the scope of this invention.
DEFINITIONS
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The terms “alkyl” and “allyl” refer to straight-chain, branched-chain, and cyclic structures, and combinations thereof. These “alkyl” and “allyl” structures may be optionally substituted with one or more heteroatoms, including for example, without limitation, fluorine, oxygen, nitrogen, phosphorus and sulfur.
The term “aryl” refers to an optionally substituted, six-membered aromatic ring, including polyaromatic rings.
The term “heteroaryl” refers to an optionally substituted, five-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur, including polycyclic rings or six-membered heterocyclic rings containing one or more heteroatoms selected from the group consisting of carbon and nitrogen, including polycyclic rings.
A 1,2-dihydroquinoline is defined by the following structure:
A 1,2-dihydro-5-coumarino[3,4-f]quinoline is defined by the following structure:
DETAILED DESCRIPTION OF THE INVENTION
The novel process for the preparation
Carreira Erick M.
Edwards James P.
Jones Todd K.
Riggenberg Josef D.
Aulakh Charanjit S.
Elmer J. Scott
Ligand Pharmacueticals Incorparated
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