Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-09-20
2003-10-21
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S506000
Reexamination Certificate
active
06635784
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to a process for the preparation of enantiomerically-enriched cyclopropylalanine derivatives. More specifically, this invention pertains to the synthesis of enantiomerically-enriched cyclopropylalanine derivatives by the hydrogenation of certain enamides in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. The present invention also pertains to a novel 3-step process for the preparation of enantiomerically-enriched cyclopropylalanine derivatives comprising the steps of forming an azlactone from an N-acylglycine and cyclopropanecarboxaldehyde, converting the azlactone to the aforesaid enamide which then is hydrogenated in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. In addition, the present invention pertains to a novel two-step process for the preparation of enantiomerically-enriched cyclopropylalanine derivatives comprising the steps of reacting cyclopropylcarboxaldehyde with a substituted phosphorylglycine to afford the aformentioned enamide which then is hydrogenated in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. The present invention further pertains to certain novel intermediate enamide ester compounds which are intermediates in the process.
BACKGROUND OF THE INVENTION
Cyclopropylalanine and its derivatives are important intermediates in the synthesis of many valuable pharmaceuticals. For example, S. Thompson and coworkers (PCT Published Patent Application 99/53039) have identified a L-cyclopropylalanine-containing peptide as an effective cysteine protease inhibitor used for the treatment of parasitic diseases. Thus, an efficient and flexible synthesis of cyclopropylalanine derivatives in high yield and high enantiomeric purity is needed.
The synthesis of racemic cyclopropylalanine has been reported previously. Amino, Y., et al.,
Bull. Chem. Soc. Jpn.
1991, 64,1040-1042 describe the reaction of carbon monoxide and hydrogen with cyclopropane-methanol and acetamide in the presence of a cobalt catalyst to produce racemic N-acetyl cyclopropylalanine. Meek, J. S., et al.,
J. Org. Chem.
1955, 6675-6678; and Black, D., et al.
J. Chem. Soc.
(C), 1968, 288-289 disclose the hydrolysis of diethyl cyclopropylcarbinyl(formylamido)malonate to produce cyclopropylalanine after extensive work-up. However, no method for the preparation and/or isolation of enantiomerically enriched cyclopropylalanine is mentioned.
Chemoenzymatic syntheses of enantiomerically enriched cyclopropylalanine derivatives start from racemic cyclopropylalanine. For example, Chenault, H. K., et al.
J. Am. Chem. Soc.
1989, 111, 6354-6464 disclose the isolation of L-cyclopropylalanine 1 after treatment of racemic N-acetyl-cyclopropylalanine with Acylase I. Alternatively, Harmon, C.; Rawlings, C.
Syn. Commun.
1996, 26, 1109-1115 disclose the treatment of racemic N-acetyl-cyclopropylalanine with porcine pancreatic acylase I to produce L-cyclopropylalanine in the completely deprotected form. These enzymatic methods generally require several steps, e.g., greater than 6 synthetic steps, and the final step is limited to 50% yield.
Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W.
J. Am. Chem. Soc.
1997, 119, 656-673, describe the asymmetric synthesis of both D- and L-cyclopropylalanine derivatives using an asymmetric alkylation of the lithium enolate of pseudoephedrine glycinamide 2 with cyclopropylmethyl bromide to provide the amino acid derivative 3. However, this method requires the use of a stoichiometric amount of an expensive chiral auxiliary and further synthetic manipulation is required to remove the auxiliary after alkylation. Additionally, two distinct starting materials must be used to isolate either R- or S-cyclopropylalanine. The (S,S)-pseudoephedrine derivative provides only the D-amino acid derivative, whereas the (R,R)-pseudoephedrine derivative must be used to isolate the amino acid in the L-configuration.
Transition-metal catalyzed asymmetric hydrogenation has been used extensively in the production of &agr;-amino acids from the corresponding enamide esters. See, for example, Burk, M. J.; et al. in
Transition Metals for Organic Synthesis
, Beller, M., Bolm, C. Eds.; and Wiley-VCH: Basel, 1998; vol. 2, pg 13-25. Catalytic asymmetric hydrogenation of enamide esters has the advantage of the use of catalytic amounts (substrate to catalyst ratios of >100) of expensive chiral reagents as well as access to both R- and S-enantiomers of the &agr;-amino acid from a common starting material. Additionally, in some cases, a variety of different functionalities are tolerated at both the amine and carboxyl termini of the amino acid precursor, which eliminates the need for further protecting group manipulations. However, catalytic asymmetric hydrogenation of cyclopropylalanine derivatives has not been reported in the literature. This deficiency is not surprising since hydrogenation of substrates containing cyclopropyl moieties is not trivial, as it is well known that transition metal-catalyzed hydrogenolysis of cyclopropyl groups occurs readily (Newham,
J. Chem. Rev.
1963, 63,123-135).
BRIEF SUMMARY OF THE INVENTION
One embodiment of the present invention is a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having the formula
which comprises contacting an enamide having the formula
with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature; wherein R
1
is hydrogen, substituted or unsubstituted C
1
to C
20
alkyl, substituted or unsubstituted C
1
to C
20
alkoxy, substituted or unsubstituted C
3
to C
8
cycloalkyl, substituted or unsubstituted C
3
to C
8
cycloalkoxy, substituted or unsubstituted carbocyclic C
6
to C
20
aryl, substituted or unsubstituted carbocyclic C
6
to C
20
aryloxy, substituted or unsubstituted C
4
to C
20
heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen or substituted or unsubstituted C
4
to C
20
heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; and R
2
is hydrogen, substituted or unsubstituted C
1
to C
20
alkyl, substituted or unsubstituted C
3
to C
8
cycloalkyl, substituted or unsubstituted carbocyclic C
6
to C
20
aryl, or substituted or unsubstituted C
4
to C
20
heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen. This embodiment of our invention is unique since it produces an enantiomerically-enriched cyclopropylalanine compound without significant hydrogenolysis of the cyclopropyl ring.
Another embodiment of the present invention is a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of a novel combination of steps comprising (1) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula
in the presence of a carboxylic acid anhydride and a base at elevated temperature to produce an azlactone having the formula
(2) contacting azlactone 8 with an alcohol optionally in the presence of an alkali or alkaline earth metal alkoxide or hydroxide to produce an enamide having the formula
and (3) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature; wherein R
1
and R
2
are defined above.
A third embodiment of the present invention involves a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of another novel combination of steps comprising
(i) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula
in the presence of a carboxylic acid anhydride at elevated tempera
Boaz Neil Warren
Debenham Sheryl Davis
Blake Michael J.
Eastman Chemical Company
Graves, Jr. Bernard J.
Kumar Shailendra
Zucker Paul A.
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