Enantioselective synthesis of 3-aminopyrrolidines

Details Enantioselective synthesis of 3-aminopyrrolidines Enantioselective synthesis of 3-aminopyrrolidines

2000-06-13

2001-04-03

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Sulfonate esters

Reexamination Certificate

active

06211395

ABSTRACT:

TECHNICAL FIELD OF INVENTION
The present invention relates to a process for the preparation of chiral 3-aminopyrrolidine derivatives which have use as intermediates in the preparation of certain pyrido [1,2-a]pyrimidine and quinolone antibacterial agents.
BACKGROUND
The therapeutic use of certain pyrido[1,2-a]pyrimidine derivatives as antibacterial agents has been described in PCT patent applications WO 9116894, published Nov. 14, 1991, and WO 9510519, published Apr. 20, 1995. Quinolone antibacterial agents are well known and are described, for example, in U.S. Pat. Nos. 4,990,517; 5,140,033; 5,059,597; and PCT application WO 9415938. The U.S. Pat. No. 5,286,723 describes amine substituted spiro compounds which are attached to quinoline derivatives for providing compounds having antibacterial use.
Chiral preparation of 3-aminopyrrolidine derivatives via an optically active tartrate ester intermediate is described in U.S. Pat. No. 5,703,244. Enantioselective synthesis of 3-aminopyrrolidine derivatives by chirally reducing a &bgr;-hydroxy ester intermediate is not disclosed.
More efficient processes for the preparation of key chiral intermediates for use in the synthesis of antibiotic agents are needed to ensure the ready availability of the compounds. A process of the invention has not previously been described in the prior art.
SUMMARY OF THE INVENTION
A process of the present invention involves efficient enantioselective preparation of chiral 3-aminopyrrolidine and derivatives thereof. The prepared compounds have use as intermediates in the preparation of certain pyrido[1,2-a]pyrimidine and quinolone antibacterial agents.
In one aspect, the invention relates to an enantioselective process for preparing a compound of the formula:
wherein R
2
and R
2′
are the same, and R
2
and R
2′
are selected from a group consisting of hydrogen and primary alkyl, or R
2
and R
2
′ taken together form a C
3
to C
6
cycloalkyl, comprising the steps of:
(a) chirally reducing a &bgr;-keto ester of the formula:
wherein R
p
is an amino-protecting group, R
2
and R
2
′ are as defined above, and R
3
is selected from the group consisting of lower alkyl and aryl, in the presence of an enantiomerically pure ruthenium catalyst to afford a stereoisomerically pure &bgr;-hydroxy ester of formula:
wherein * represents a carbon stereocenter of (R) or (S) configuration;
(b) activating the stereoisomerically pure &bgr;-hydroxy ester with sulfonic acid or a derivative thereof to provide an activated &bgr;-hydroxy ester of formula:
wherein the group represented by the formula —O—L is a sulfonate leaving group;
(c) treating the activated &bgr;-hydroxy ester with an azide salt to afford an aminoester azide of the formula:
(d) deprotecting and cyclizing the aminoester azide under hydrogenation conditions to afford a pyrrolidinone of the formula:
(e) reducing the pyrrolidinone.
In another aspect, the invention relates to a process of preparing a sterioisomerically pure compound of formula:
wherein R
2
and R
2
′ are the same, and R
2
and R
2
′ are selected from a group consisting of hydrogen and primary alkyl, or R
2
and R
2
′ taken together form a C
3
to C
6
cycloalkyl, comprising the steps of:
(a) protecting the amino moiety of a pyrrolidinone as prepared in step (d) above having a formula:
wherein R
2
and R
2
′ are as described above, with a compound of formula R
4
COR
5
, wherein R
4
is selected from the group consisting of hydrogen, tert-butoxy, fluorenylmethoxy, and benzyloxy, and R
5
is hydroxy or a halide selected from the group consisting of bromine, chlorine, fluorine, and iodine, to afford a compound of formula:
(b) reducing the pyrrolidinone.
In yet another aspect, An enantioselective process of preparing a compound of formula:
wherein R
1
is selected from the group consisting of hydrogen and lower alkyl, and R
2
and R
2′
are the same, and R
2
and R
2′
are selected from a group consisting of hydrogen and primary alkyl, or R
2
and R
2
′ taken together form a C
3
to C
6
cycloalkyl, comprising the steps of:
(a) chirally reducing a &bgr;-keto ester of the formula:
wherein R
p
is an amino-protecting group, R
2
and R
2
′ are as defined above, and R
3
is selected from the group consisting of lower alkyl and aryl, in the presence of an enantiomerically pure ruthenium catalyst to afford a stereoisomerically pure &bgr;-hydroxy ester of formula:
wherein * represents a carbon stereocenter of (R) or (S) configuration;
(b) activating the stereoisomerically pure &bgr;-hydroxy ester with sulfonic acid or a derivative thereof to provide an activated &bgr;-hydroxy ester of formula:
wherein the group represented by the formula —O—L is a sulfonate leaving group;
(c) treating the activated &bgr;-hydroxy ester with an amine of the formula R
1
—NH
2
, wherein R
1
is primary alkyl, to afford a diaminoester of formula:
(d) hydrogenating the diaminoester to afford a pyrrolidinone of the formula:
(e) reducing the pyrrolidinone.
DETAILED DESCRIPTION OF THE INVENTION
The term “amino-protecting group” as used herein refers to an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of amino-protecting groups is well known in the art for protecting groups against undesireable reactions during a synthetic procedure and many such protecting groups are known, cf., for example, T. H. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis,
2nd edition, John Wiley & Sons, New York (1991). Examples of amino-protecting groups include, but are not limited to, acyl groups, including acetyl, trifluoroacetyl, benzoyl, and the like; acyloxy groups, including t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluoroethenylmethoxycarbonyl (Fmoc), and the like.
The term “aprotic solvent” as used herein refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks of specialized monographs, for example:
Organic Solvents Physical Properties and Methods of Purification,
4th ed., edited by John A. Riddick, et al., Vol. 11, in the Techniques of Chemistry Series, John Wiley & Sons, NY 1986.
The term “C
3
-C
6
-cycloalkyl” as used herein refers to saturated cyclic hydrocarbon radicals containing from three to six carbon atoms. Illustrative of C
3
-C
6
-cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “lower alkyl” as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms, sometimes represented as Cx—Cy-alkyl where x and y respectively represent the minimum and maximum number of carbon atoms in the alkyl radical. Examples of lower alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like. The term “primary alkyl” as used herein particularly refers to straight chain alkyl radicals of 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.
The term “aryl” as used herein refers to an aromatic ring which can be

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