Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-16
2001-12-11
Solola, Taofiq A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S307000
Reexamination Certificate
active
06329536
ABSTRACT:
BACKGROUND OF THE INVENTION
The addition reactions of a beta-dicarbonyl compounds such as IV to nitroolefins such as III can proceed to give either of two enantiomers, Va or Vb of the insipient nitromethyl group. No methods currently exist to select for the formation of Va or Vb via the action of a catalyst.
SUMMARY OF THE PRESENT INVENTION
The present invention provides a process for enantioselectively producing a nitromethyl compound having formula Va or Vb from a nitroolefin having formula III and a beta dicarbonyl compound having formula IV wherein, R1=aryl, alkyl or arylalkyl, and R2 and R3 are independently selected from alkoxy, alkyl, arylalkyl, and or aryl, in the presence of a catalyst complex and a base, said catalyst complex comprising a ligand and a metal complex, wherein the ligand has the formula I
wherein
R9 and R10 are independently selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl, or R9 and R10 taken together can form a 3, 4, 5, or 6-membered cycloalkyl ring or a bicyclic ring;
X and X′ are independently selected from the group consisting of oxygen, sulfur, and nitrogen;
R11 or R12 may be independently selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl, or R11 and R12 taken together with the ring to which they are attached may form a bicyclic or tricyclic fused ring; and R13 or R14 may be independently selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl, or R13 and R14 taken together with the ring to which they are attached may form a bicyclic or tricyclic fused ring; or the ligand can have the formula II,
wherein n is 1-3, and R15 and R16 are independently selected from the group consisting of alkyl, aryl, and arylalkyl.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention provides a process for enantioselectively producing a nitromethyl compound from a nitroolefin having formula III and a beta dicarbonyl compound having formula IV wherein, R1=aryl, alkyl or arylalkyl, R2 and R3 are independently selected from alkoxy, alkyl, arylalkyl, or aryl, in the presence of a catalyst complex and a base, said catalyst complex comprising a ligand and a metal complex, wherein the ligand has the formula I
wherein
R9 and R10 are independently selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl, or R9 and R10 taken together can form a 3, 4, 5, or 6-membered cycloalkyl ring or a bicyclic ring;
X and X′ are independently selected from the group consisting of oxygen, sulfur, and nitrogen;
R11 or R12 may be independently selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl, or R11 and R12 taken together with the ring to which they are attached may form a bicyclic or tricyclic fused ring; and R13 or R14 may be independently selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl, or R13 and R14 taken together with the ring to which they are attached may form a bicyclic or tricyclic fused ring; or the ligand can have the formula II,
wherein n is 1-3, and R15 and R16 are independently selected from the group consisting of alkyl, aryl, and arylalkyl.
A more preferred embodiment of the present invention provides for a Michael addition of a nitrostyrene compound and a ketoester substrate in the presence of a base and a catalyst complex to provide a stereoselective nitro compound.
Another preferred embodiment of the present invention provides for a Michael addition of a nitrostyrene compound and a ketoester substrate in the presence of a base and a catalyst complex to provide a nitro compound.
Another preferred embodiment of the present invention relates to a process of producing 2-arylnitroethane derivatives by reacting an arylnitrostyrene compound with a 1,3 dicarbonyl substrate in the presence of a base and a catalyst complex.
Another preferred embodiment of the present invention relates to a process of reacting a a nitroolefin having formula III and a beta dicarbonyl compound having formula IV wherein R1 is aryl, R2 is aryl or all, and R3 is alkoxy.
Another preferred embodiment of the present invention relates to a process of reacting a a nitroolefin having formula III and a beta dicarbonyl compound having formula IV wherein R1 is substituted 3,4-dioxanylphenyl, R2 is aryl or alkyl, and R3 is alkoxy. The processes and intermediates contained herein are useful in the production of pharmaceuticals, particularly endothelin antagonists. In particular, the processes and intermediates contained herein are useful in synthesizing endothelin antagonists having a pyrrolidine core and obtaining high optical purity.
For purposes of the disclosure, the following terms are defined herein.
The terms “loweralkyl” or “alkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term “alkoxy” as used herein refers to R
41
O— wherein R
41
is a loweralkyl group, as defined above. Examples of alkoxy include, but are not limited to, ethoxy, tertbutoxy, and the like.
The term “aryl” as used herein refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term “arylalkyl” as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term “cycloalkyl” as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The catalyst complex is formed by reacting a ligand and a metal complex together. The ligand and the metal complex may be reacted together in the presence of a solvent. The time necessary for the catalyst complex to form can vary for the particular ligand and metal complex used. For example, a particular ligand and metal complex may need only 30 minutes or as much as several hours depending on the reactants used. Alternatively, one skilled in the art may add the base, nitroolefin and dicarbonyl compounds simultaneously to the ligand, metal complex and solvent. Solvents suitable for the formation of the catalyst complex include but are not intended to be limited to, tetrahydrofuran (THF), toluene, methylene chloride, and chloroform. The preferred solvent is chloroform.
Ligands suitable for the present invention have the formula I
wherein
R9 and R10 are independently selected from the group consisting of hydrogen, aryl, and arylalkyl, or R9 and R10 taken together can form a 3, 4, 5, or 6-membered cycloalkyl ring or a bicyclic ring;
X and X′ are independently selected from the group consisting of oxygen, sulfur, and nitrogen;
R11 or R12 may be independently selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl, or R11 and R12 taken together with the ring to which they are attached may form a bicyclic or tricyclic fused ring;
R13 or R14 may be independently selected from the group consisting of hydrogen, alkyl, arylalkyl, and aryl, or R13 and R14 taken together with the ring to which they are attached may form a bicyclic or tricyclic fuse
Barnes David M.
Ji Jianguo
King Steve
Plagge Frederick A.
Wittenberger Steven J.
Abbott Laboratories
Donner B. Gregory
Solola Taofiq A.
Ward Michael J.
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