Process for the preparation of C(5)-substituted...

Details Process for the preparation of C(5)-substituted... Process for the preparation of C(5)-substituted...

2000-04-12

2001-07-31

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06268497

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for the preparation of C(5)-substituted 1,2-dihydro-5H-chromeno[3,4-ƒ]quinoline compounds that are useful as steroid receptor modulators.
BACKGROUND OF THE INVENTION
The 1,2-dihydro-5H-chromeno[3,4-ƒ]quinolines of structure 3 are modulators of steroid receptor function. In particular, progesterone receptor (PR) and glucocorticoid receptor (GR) agonist and antagonist activity and androgen receptor (AR) antagonist activity have been noted for compounds in this class. {See: “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, L. Zhi, J. P. Edwards, C. M. Tegley, S. J. West, U.S. Pat. No. 5,696,127; “5-Aryl-1,2-dihydro-5H-chromeno[3,4-ƒ]quinolines as Potent, Orally Active, Nonsteroidal Progesterone Receptor Agonists: The Effect of D-Ring Substituents”, J. P. Edwards, S. J. West, K. B. Marschke, D. E. Mais, M. M. Gottardis, T. K. Jones,
J. Med. Chem
. 41 (1998) 303-310.} Chromenoquinolines of structure 3 are prepared by a multi-step route culminating in the addition of an organometallic reagent to a lactone of structure 1 followed by reduction of the hemiketal intermediate 2 (R groups are defined under Detailed Description of the Invention):
Alternatively, certain chromenoquinolines of structure 3 can be prepared in three steps from lactones 1 via acetals 5 by a Lewis-acid mediated nucleophilic substitution reaction using electron-rich olefins or electron-rich aromatic compounds as nucleophiles:
However, these two routes have drawbacks. In the first, the acidic medium required for reduction of hemiketals 2 (R
10
=methyl or ethyl) often promotes the formation of undesired by-products of structure 7:
Additionally, only organolithium reagents add to lactone 1 with generality; for example, many alkyl magnesium halides afford complex mixtures when added to 1. And although certain aryilithium reagents add to the lactone functionality, the resulting hemiketal intermediate 2 cannot be reduced. The versatility of the second route is limited because the third step requires certain electron-rich nucleophiles.
SUMMARY OF THE INVENTION
The present invention provides a novel alternative for the conversion of lactols (hemiacetals) 4 to chromenoquinolines 3 by converting a lactol to one of a select number of mixed acetal derivatives of structure 8 or 9. The acetals 8 or 9 are then treated with an organomagnesium halide (Grignard reagent), thereby displacing the alcohol (or phenol) moiety introduced in the previous step:
Related reactions of acetals or ketals with Grignard reagents have been previously reported. {See, for example: “Synthesis of &agr;- and &bgr;-Branched Ethers from Alcohols by Reaction of Acetals with Grignard Reagents: Synthesis of Isopropyl and Isobutyl Ethers of (1S*,2R*S*, 4R*)-6-Methylenebicyclo[2.2.2]octan-2-ol”, T. M. Willson, J. Amburgey, S. E. Denmark,
J. Chem. Soc., Perkin Trans
. 1 (1991) 2899; “Asymmetric Induction via an Intramolecular Haloetherification Reaction of Chiral Ene Acetals: A Novel Approach to Optically Active 1,4- and 1,5-Diols”, H. Fujioka, H. Kitagawa, Y. Nagatomi, Y. Kita,
J. Org. Chem
. 61 (1996) 7309-7315; “Highly Diastereoselective Ring-Opening Reactions of Chiral Acetals with Secondary or Sterically Hindered Grignard Reagents”, T.-M. Yuan, S.-M Yeh, Y.-T. Hsieh, T.-Y. Luh,
J. Org. Chem
. 59 (1994) 8192-8196; “Novel Methodology for the Synthesis of Estrogenic and Antiestrogenic 3-Isoflavenes”, T. A. Grese, L. D. Pennington,
Tetrahedron Lett
. 36 (1995) 8913-16.} However reaction at a benzylic carbon in a ring has not been reported previously. Using this novel alternative procedure, chromenoquinolines of structure 3 are obtained in higher yields and require less purification. In addition, certain chromenoquinolines 3 that were difficult to access via the previous routes are now simple to obtain.
DETAILED DESCRIPTION OF THE INVENTION
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.
In accordance with the present invention and as used herein, the following structure is provided for nomenclature purposes. In an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. Furthermore, the structure below is provided as a guide for the numbering system for location of substituents and may be optionally substituted, including with aryl and heteroaryl rings.
A 1,2-dihydro-5H-chromeno[3,4ƒ]quinoline is defined by the following structure:
The novel process of the present invention begins with lactols (hemiacetals) 4 derived from the previously disclosed reduction of lactones 1 by a hydride delivery reagent {see: “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, L. Zhi, J. P. Edwards, C. M. Tegley, S. J. West, U.S. Pat. No. 5,696,127}:
In the first step of the present invention, lactol 4 is converted to a mixed acetal derivative derived from either an optionally substituted 1,2-diol or 1,2-diol monoether 10 or an optionally substituted phenol (ArOH) by admixture of the ethanol or phenol with 4 in the presence of a catalyst, especially a Lewis acid or a protic acid such as para-toluenesulfonic acid or oxalic acid, in an inert solvent such as methylene chloride, benzotrifluoride, 1,2-dichloroethane or toluene, to form either 8 or 9:
wherein R
1-6
independently represent H, C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, F, Cl, Br, I, CN, CF
3
, CF
2
CF
3
, CO
2
R
7
(where R
7
represents H, C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, ally substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), CONR
7
R
8
(where R
8
represents H, C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or where, alternatively, R
7
and R
8
combine to form a four- to seven-membered, optionally substituted ring), OR
9
(where R
9
represents C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), NR
7
R
9
, SR
9
, SOR
9
, SO
2
R
9
;
R
10-11
independently represent H, C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR
9
or Cl; R
12-13
independently represent C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or, alternatively, any two of R
10-13
can combine to form a three- to eigh

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