Asymmetric synthesis of piperazic acid and derivatives thereof

Details Asymmetric synthesis of piperazic acid and derivatives thereof Asymmetric synthesis of piperazic acid and derivatives thereof

2002-06-14

2003-10-14

Kifle, Bruck (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C544S224000

Reexamination Certificate

active

06632942

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to a method for the asymmetric synthesis of piperazic acid and derivatives thereof. The method is useful for preparing compounds, especially biologically active compounds, that contain predominantly either a (3R)- or (3S)-piperazic acid moiety. Most particularly, the method may be used to prepare certain caspase inhibitors, such as inhibitors of interleukin-1&bgr; converting enzyme (“ICE”).
BACKGROUND OF THE INVENTION
Piperazic acid is the common name for hexahydropyridazine-3-carboxylic acid. Since the 3-position bearing the carboxylic acid group is a chiral center, piperazic acid may exist in either the (3S) or (3R) enantiomeric form. The enantiopurity or optical purity of piperazic acid may be conventionally defined in terms of percent enantiomeric excess (%ee) which is the percent of the major enantiomer minus the percent of the minor enantiomer. A racemic mixture has an enantiomeric excess of zero.
The enantiomeric forms of piperazic acid derivatives are important intermediates in natural product synthesis and in the synthesis of biologically useful compounds having non-natural amino acids or peptidomimetic moieties. The angiotensin converting enzyme (“ACE”)inhibitor, Cilazapril®, contains the S-isomer of piperazic acid (Adams et al., Synthetic Comm, 1988, 18, 2225). Recently a class of caspase inhibitors, particularly interleukin-1&bgr; converting enzyme (“ICE”) inhibitors, have been described that also contain piperazic acid, preferably the S-enantiomer (U.S. Pat. Nos. 5,874,424; 5,756,466; 5,716,929; 5,656,627; and 6,204,261). Examples of other pharmacologically active molecules having a piperazic acid moiety include the monamycin family of antibiotics (Bevan et al.,
J. Chem. Soc
. (C), 1971, 522), the azinothricin antitumor antibiotics (see Hale et al.,
Tetrahedron
, 1996, 52, 1047 and references cited therein), verucopeptin (Suguwara et al.,
J. Antibiotics
, 1993, 46, 928), the aurantimycins (Grafe et al.,
J. Antibiotics
, 1995, 48, 119), the C5a antagonist L-156,602 (Hensens et al.,
J. Antibiotics
, 1991, 44, 249), the immunosuppressant IC101 (Ueno et al.,
J. Antibiotics
, 1993, 46, 1658), the oxytocin antagonist L-156,373 (Pettibone et al.,
Endocrinology
, 1989, 125, 217), and the matylastin type-IV collagenase inhibitors (Ogita et al.,
J. Antibiotics
, 1992, 45, 1723; Tamaki et al.,
Tetrahedron Lett
., 1993, 34, 683; Tamaki et al.,
Tetrahedron Lett
., 1993, 34, 8477). Several asymmetric syntheses of piperazic acid and derivatives thereof have been described [Aspinall et al.,
J. Chem. Soc. Chem. Commun
., 1993, 1179; Decicco et al.,
Syn. Lett
., p. 615 (1995); Schmidt et al.,
Synthesis
, p. 223 (1996); Hale et al.,
Tetrahedron
, 1996, 52, 1047; U.S. Pat. No. 5,716,929; and Attwood et al.,
J. Chem. Soc
. Perkin 1, 1986, 1011).
Resolution of enantiomers of piperazic acid from a racemic mixture has been described by Hassell et al.,
J. Chem. Soc. Perk. Trans. I
, pp. 1451 (1979). That method involves using a chiral amine to form a crystalline salt with piperazic acid that has been amino protected. The resulting chiral salt, which is a mixture of diastereomers, is then crystallized from an appropriate solvent to separate the desired isomer from the mixture.
The resulting isomer of piperazic acid may then be esterified by known techniques. Unfortunately, if certain esters are desired, such as the commonly used t-butyl ester, the esterification reaction is slow, low-yielding and may require special laboratory equipment (Hassall et al., supra; PCT publications WO 97/22619 and WO 95/35308).
These syntheses are not desirable on a large scale for one or more of the following reasons: too many steps, less than desirable yields, inconveniently low temperatures, or expensive reagents.
Accordingly, it would be desirable to have an asymmetric synthesis of piperazic acid that is amenable to large-scale synthesis and overcomes the aforementioned shortcomings or otherwise improves upon the current methods. It would also be desirable to have a method of resolving a racemic or enantiomerically enriched piperazic ester in its deprotected form which is stable and may be easily utilized in further reactions.
SUMMARY OF THE INVENTION
This invention provides a short, asymmetric synthesis of piperazic acid and derivatives thereof, whereby either the (3S)- or (3R)-enantiomeric form may be obtained with high optical purity. dihydroxyvalerate ester. After the hydroxy groups are converted to suitable leaving groups, such as mesylates, the ester is treated with a bis-protected hydrazine to provide the desired (3S)-piperazic acid derivative. The general scheme is shown below.
The (3R) enantiomer of piperazic acid may be similarly obtained starting with L-glutamic acid.
The invention also provides a novel method for preparing an enantiomerically enriched piperazic ester from racemic piperazic ester. The method involves the treatment of the piperazic ester with a commercially available enantiomerically enriched acid to produce a crystalline salt. This method is also useful for enhancing the %ee of a piperazic ester prepared by the synthesis of this invention or by other methods known in the art.
By this method, piperazic acid derivatives may be obtained that are useful as intermediates for pharmacologically active compounds. For example, certain intermediates of this invention are useful for preparing caspase inhibitors, particularly inhibitors of ICE, through additional steps known in the art.
DETAILED DESCRIPTION OF THE INVENTION
Some of the abbreviations used throughout the specifications (including in chemical formulae) are:
Bu=butyl
t-Bu=tert-butyl
Et=ethyl
Cbz=benzoyloxycarbonyl
BOC=tert-butyloxycarbonyl
Alloc=allyloxycarbonyl
Fmoc=fluorenylmethoxycarbonyl
DMF=N,N-dimethylformamide
THF=tetrahydrofuran
MTBE=methyl tert-butyl ether
DCM=dichloromethane
%ee=percent enantiomeric excess.
According to one embodiment, this invention provides a method for preparing a compound having the formula:
wherein:
R is hydrogen or a carboxyl protecting group;
each R
1
and R
2
are independently selected from hydrogen or an amino protecting group, wherein R
1
and R
2
may be taken together to form a fused bicyclic or tricyclic amino protecting group; provided that R
1
and R
2
are not simultaneously hydrogen;
said process comprising the steps of:
(a) providing a compound of formula II:
 wherein —OR
4
is a suitable leaving group, and
(b) treating II with a compound of formula III:
in the presence of a suitable organic solvent, a suitable base, and optionally a water scavenger and/or a phase transfer catalyst, to produce I.
As used herein, the following definitions shall apply unless otherwise indicated. It is understood that combinations of substituents or variables are permissible only if such combinations result in stable compounds.
The term “stable compound”, as used herein, refers to a compound sufficiently stable to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
Unless otherwise specified herein, a bond on a chiral carbon atom not depicted with stereochemistry as used herein means that the compound containing the chiral carbon atom may have a %ee between 0 to 100.
The term “carboxyl protecting group” refers to a moiety that prevents chemical reactions from occuring on the carboxyl group to which that protecting group is attached. A carboxyl protecting group must also be removable by a chemical reaction. Examples of carboxyl protecting groups include esters, such as methyl, ethyl, t-butyl, (un)substituted benzyl, and silyl esters, among others. Other carboxyl protecting groups are well known in the art and are described in detail in
Protecting Groups in Organic Synthesis
, Theodora W. Greene and Peter G. M. Wuts, 1991, published by John Wiley and S

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