Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-06-21
2002-12-03
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S313000, C564S314000, C546S249000, C546S277400, C546S329000
Reexamination Certificate
active
06489512
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods for making aryl hydrazines and substituted indoles, which are useful intermediates and end products in pharmaceutical and agricultural applications.
BACKGROUND OF THE INVENTION
Certain 3,5-disubstituted indole compounds have been found to be selective agonists which act on 5-hydroxytryptamine receptors and to be useful in the treatment of migrane and other medical conditions, see U.S. Pat. No. 5,607,960.
Syntheses of such indole compounds have typically been based on the approach of functionalizing an existing indole nucleus, necessitating a large number of processing steps and reduced theoretical efficiency for the sequence of steps, see for example, U.S. Pat. No. 5,998,438, which discloses synthesis of 5-(1-Aza-1-methylcyclohex-3-en-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-H-indole. The route desclosed in the '438 patent also requires use of a toxic reagent, that is, 4-tributylstannyl-1-aza-1-tertbutoxycarbonylcyclohex-3-ene, and the use of a hazardous reagent, LAH.
There is an interest in development of a simplified synthetic route to such indole compounds.
SUMMARY OF THE INVENTION
In a first aspect, the present invention is directed to a method for making an aryl hydrazine, comprising:
(a) reacting a substrate aromatic compound, said substrate aromatic compound bearing an activated carbon atom, and a hydrazone in the presence of a transition metal catalyst under conditions suitable to form an aryl hydrazone having a new carbon-nitrogen bond between the activated carbon of the substrate aromatic compound and a nitrogen atom of the hydrazone, and
(b) hydrolyzing the aryl hydrazone to form the aryl hydrazine.
The method of the present invention for making an aryl hydrazine provides a simple, two step linear synthesis of substituted aryl hydrazine compounds and does not require the use of toxic or hazardous reagents.
In a second aspect, the present invention is directed to a method for making an indole compound, comprising:
(a) reacting a substrate aromatic compound, said substrate aromatic compound bearing an activated carbon atom, and a hydrazone in the presence of a transition metal catalyst under conditions suitable to form an aryl hydrazone having a new carbon-nitrogen bond between the activated carbon of the substrate aromatic compound and a nitrogen atom of the hydrazone,
(b) hydrolyzing the aryl hydrazone to form an aryl hydrazine, and
(c) cyclizing the aryl hydrazine in the presence of an aldehyde or ketone and acid catalyst to form the substituted indole compound.
The method of the present invention for making an indole compound provides a simple, three step linear synthesis of substituted indole compounds and does not require the use of toxic or hazardous reagents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In a preferred embodiment, a substrate aromatic compound and a hydrazone are coupled to form a hydrazone according to reaction scheme 1:
wherein:
Ar is aryl and may, optionally, be further substituted beyond X,
X is a leaving group that is capable of being replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction, and
R
1
is H, substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted alkynyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl, and
each R
2
is independently H, substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted alkynyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl, or, alternatively, the R
2
groups are fused to form, together within the carbon atom to which they are each attached, a substituted or unsubstituted monocyclic cycloalkyl, cycloalkenyl, aryl or heterocyclyl ring.
As used herein, the term “substituted” denotes the conceptual replacement of a hydrogen atom of a given organic moiety with a substituent group other than a hydrogen atom and includes all permissible substituent groups, including acyclic hydrocarbon groups, alicyclic hydrocarbon groups, monocyclic aromatic hydrocarbon groups, polycyclic aromatic hydrocarbon groups, heteroacyclic groups, heterocyclic groups, fused ring systems and bridged ring systems, of which the substituents specifically described below are illustrative examples.
As used herein the term “heteroatom” means an element other than carbon, such as for example, oxygen, nitrogen and sulfur.
“Alkyl” refers to a linear, branched or cyclic saturated hydrocarbon group, preferably a (C
1
-C
30
) linear, branched or cyclic saturated hydrocarbon group that may, optionally, contain one or more heteroatoms, such as, for example, methyl, ethyl, propyl, n-butyl, isobutyl, t-butyl, neopentyl, cyclopentyl, hexyl, cyclohexyl, decyl, stearyl, eicosyl, methoxy, triacontyl, 2,5,7-trioxanonanyl, 2,5,8-triazadecenyl, and that may, optionally, be substituted at one or more positions with other moieties, such as, for example, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, halo, hydroxy, sulfhydryl, hydroperoxy, carbonyl-containing groups (including, for example, carboxy, ketone, ester and aldehyde groups), alkyloxy, alkyldioxy, amino, amido, imino, hydrazino, nitro, cyanato, thiocyanato, mercapto, thiocarbonyl-containing groups (including, for example, thioketone groups, thioester groups and thioaldehyde groups), sulfonyl-containing groups (including, for example, sulfate, sulfonate and sulfamoyl groups), silyl, siloxy and phosphoruscontaining substituent groups (including, for example, phosphoranyl, phosphinyl, phosphinothioyl, phosphinimyl). Such substituent groups may themselves be further substituted with, for example, any of the groups described above as suitable substituents for alkyl groups, to form compound substituent groups, such as, for example, aralkyl, aminoalkyl, haloalkyl, heterocyclylalkyl.
“Alkenyl” refers to a linear, branched or cyclic hydrocarbon group, preferably a (C
2
-C
20
) linear, branched or cyclic hydrocarbon group, that contains one or more carbon-carbon double bonds per group and that may, optionally, contain one or more heteroatoms, such as, for example, ethenyl, propenyl, allyl, isopropenyl, ethenylidenyl, cyclopentyl, cyclohexadienyl, azanonenyl, and that may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
“Alkynyl” refers to a linear, branched or cyclic unsaturated hydrocarbon group, preferably a (C
2
-C
20
) unsaturated hydrocarbon group, that contains one or more carbon-carbon triple bonds per group and that may, optionally, contain one or more heteroatoms, such as, for example, ethynyl, propynyl, thianonynyl, and that may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
“Aryl” refers to an unsaturated hydrocarbon group that contains one or more six membered rings in each of which the unsaturation may be represented by three conjugated carbon-carbon double bonds, including monocyclic and polycyclic ring systems, such as, for example, phenyl, naphthyl, anthryl, phenanthryl, indenyl, fluorenyl, which may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
“Heterocyclyl” refers to a saturated or unsaturated organic group that contains one or more rings in which one or more ring members is a heteroatom, preferably a nitrogen, sulfur or oxygen heteroatom, such as, for example, thiacyclopentadienyl, thiaindenyl, thianthrenyl, oxacyclopentadienyl, oxaindenyl, isobenzylfuranyl, pyranyl, azacyclopentadienyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, quinolinyl, isoquinolinyl, phthalazinyl, cinnolinyl, azafluorenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenarsazinyl, isothiazolyl, isoxazolyl, phenoxazinyl, pyrrolidinyl, pyrimadinyl, imidazolidinyl, pi
Benetti Richard E.
Gou Da-Ming
Hicks Frederick
Marchese Salvatore Anthony
Martel Lawrence J.
Barts Samuel
Rhodia Chirex Inc.
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