Highly enantiomerically pure lactam-substituted propanoic...

Details Highly enantiomerically pure lactam-substituted propanoic... Highly enantiomerically pure lactam-substituted propanoic...

2001-09-20

2004-02-03

Kifle, Bruck (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S550000, C548S551000

Reexamination Certificate

active

06686477

ABSTRACT:

BACKGROUND OF THE INVENTION
Asymmetric catalysis is the most efficient method for the generation of products with high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in the generation of the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals. The asymmetric catalysts employed can be enzymatic or synthetic in nature. The latter types of catalyst have much greater promise than the former due to much greater latitude of applicable reaction types. Synthetic asymmetric catalysts are usually composed of a metal reaction center surrounded by an organic ligand. The ligand usually is generated in high enantiomeric purity, and is the agent inducing the asymmetry. A prototypical reaction using these types of catalyst is the asymmetric hydrogenation of enamides to afford amino-acid derivatives (Ohkuma, T.; Kitamura, M.; Noyori, R. In
Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp. 1-17).
Although the preparation of enamides through Homer-Emmons Wittig chemistry is known, the preparation and use of substrates such as lactam-substituted 2-propenoic acid derivatives which possess a fully substituted nitrogen on the enamide are not known and the viability of the standard preparative sequence for the enamide is unclear. In general, the majority of enamides that have undergone asymmetric hydrogenation possess a hydrogen substituent on the nitrogen of the enamide. Thus the efficacy of asymmetric catalysts for the hydrogenation of lactam-substituted 2-propenoic acid derivatives is also unclear.
U.S. Pat. No. 4,696,943 discloses the synthesis of single enantiomer lactam-substituted propanoic acid derivatives useful as pharmaceutical agents for various conditions. However, these compounds were prepared by a cyclization reaction and not by the asymmetric hydrogenation of an enamide.
In light of the above, it would be desirable to produce single enantiomer lactam-substituted propanoic acid derivatives useful as pharmaceutical compounds.
SUMMARY OF THE INVENTION
The present invention relates to highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using therefor. The invention involves a multi-step synthesis to produce the lactam compounds. In one step of the reaction sequence, asymmetric hydrogenation of a lactam-enamide was performed to produce an intermediate that can ultimately be converted to a series of pharmaceutical compounds. The invention also contemplates the in situ synthesis of an intermediate of the multi-step synthesis, which provides economic advantages to the overall synthesis of the lactam compounds.
Additional advantages of the invention will be set forth in part in the description that follows, and in part will be apparent from the description or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention may be understood more readily by reference to the following detailed description of aspects of the invention and the Examples included therein.
Before the present compositions of matter and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods or to particular formulations, and, as such, may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
The singular forms a, an, and the include plural referents unless the context clearly dictates otherwise.
Optional or optionally means that the subsequently described event or circumstances may or may not occur, and that the description included instances where said event or circumstance occurs and instances where it does not.
The term “alkyl group” may include straight- or branched-chain, aliphatic hydrocarbon radicals containing up to about 20 carbon atoms and may be substituted, for example, with one to three groups selected from C
1
-C
6
-alkoxy, cyano, C
2
-C
6
-alkoxycarbonyl, C
2
-C
6
alkanoyloxy, hydroxy, aryl and halogen. The terms “C
1
-C
6
-alkoxy,” “C
2
-C
6
-alkoxycarbonyl,” and “C
2
-C
6
-alkanoyloxy” are used to denote radicals corresponding to the structures —OR, —CO
2
R, and —OCOR, respectively, wherein R is C
1
-C
6
-alkyl or substituted C
1
-C
6
-alkyl.
The term “cycloalkyl” is used to denote a saturated, carbocyclic hydrocarbon. The term “substituted cycloalkyl” is a cycloalkyl group substituted with one or more of the groups described above.
The term “aryl group” may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, or anthracenyl substituted with one to three substituents selected from C
1
-C
6
-alkyl, substituted C
1
-C
6
-alkyl, C
6
-C
10
aryl, substituted C
6
-C
10
aryl, C
1
-C
6
-alkoxy, halogen, carboxy, cyano, C
1
-C
6
-alkanoyloxy, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfonyl, trifluoromethyl, hydroxy, C
2
-C
6
-alkoxycarbonyl, C
2
-C
6
-alkanoylamino and —OR, SR, —SO
2
R, —NHSO
2
R and —NHCO
2
R, wherein R is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C
1
-C
6
-alkyl, C
6
-C
10
aryl, C
1
-C
6
-alkoxy and halogen.
The term “heteroaryl group” includes a 5- or 6-membered aromatic ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen. Examples of such heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and the like. The heteroaryl group may be substituted, for example, with up to three groups such as C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, substituted C
1
-C
6
-alkyl, halogen, C
1
-C
6
-alkylthio, aryl, arylthio, aryloxy, C
2
-C
6
-alkoxycarbonyl and C
2
-C
6
-alkanoylamino. The heteroaryl group also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence.
Reference will now be made in detail to the present aspects of the invention. Wherever possible, the same reference numbers and letters are used throughout the various formulas in the invention to refer to the same or like parts.
The present invention relates to the synthesis of enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using therefor. A reaction scheme that depicts a general sequence of reaction steps to produce the compounds of the invention is shown in Scheme 1.
The first step depicted in Scheme 1 involves the reaction (i.e., condensation) between a compound having the formula I
with glyoxylic acid, wherein R
1
is hydrogen, substituted or unsubstituted, branched or straight chain C
1
to C
20
alkyl; substituted or unsubstituted C
3
to C
8
cycloalkyl; substituted or unsubstituted C
6
to C
20
aryl; or substituted or unsubstituted C
4
to C
20
heteroaryl, and
n is from 0 to 5,
to produce a compound having the formula II.
The condensation reaction between lactam I and glyoxylic acid is generally conducted in a solvent. Examples of useful solvents include, but are not limited to, aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes, and the like, cyclic or acyclic ethers such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, or polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like. The amount of glyoxylic acid relative to the amoun

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