Amino acid derivatives

Details Amino acid derivatives Amino acid derivatives

2002-07-24

2004-10-26

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S013000, C549S058000, C549S070000, C549S074000, C549S076000, C549S426000, C546S246000, C546S247000, C546S248000, C546S335000, C560S032000, C560S037000, C560S115000, C562S418000, C562S442000, C562S507000

Reexamination Certificate

active

06809207

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain alpha-amino acetic acids and derivatives thereof, such as, but not limited to, esters, amides and salts. This invention also relates to methods to synthesize these alpha-amino acids.
BACKGROUND OF THE INVENTION
Amino acid derivatives have applications in the manufacture of a wide range of pharmaceutical products and therapeutic agents used for the treatment of human disease. For example, amino acid derivatives have been used in the development of peptide and non-peptide based drugs, including HIV protease inhibitors for the treatment of AIDS, and the anti-cancer drug Abrelix, a decapeptide used for the treatment of cancer. Therapeutics for the treatment of hypertension and congestive heart failure (e.g. Captopril and Enalapril) are also synthesized from amino acid derivatives. Specific examples of the use of pyridine and piperidine based amino acids are include thrombin inhibitors and GPIIb/IIIa antagonists (Adang, A. E. P., Peters, C. A. M., Gerritsma, S., Zwart, E., and Veeneman, G., Bioorganic & Medicinal Chemistry Letters 9: 1227-1232 (1999)). In addition, such compounds may be used to develop reagents for cleavage of DNA, and thus may be used as anti-cancer agents.
As reported in the literature, a number of routes are known for the synthesis of alpha-amino acids. The best known route to alpha-amino acids is the Strecker synthesis route (see, Introduction to Organic Chemistry, Streitwieser and Heathcock, Macmillan Publishing Co., Inc. New York, 1981). In this method a suitable aldehyde is treated with ammonia and HCN, so that an alpha-amino nitrile is formed, which is subsequently subjected to a hydrolysis reaction to provide the corresponding alpha-amino acid.
Also, it has been shown (see, Ugi, I. Angew. Chem., Intl. Ed. Engl., 1982, Vol. 21, pp. 810-819) that the reaction of an isocyanide (X
1
—NC) with a carboxylic acid (X
2
—CO
2
H), an aldehyde (X
3
—CHO) and an amine (X
4
—NH
2
) under the appropriate conditions provides the corresponding dipeptide (N-alkyl-N-acylalpha amino amide) as follows:
X
1
—NC+X
2
—CO
2
H+X
3
—CHO+X
4
—NH
2
→X
2
—CO—NX
4
—CHX
3
—CO
2
H
In an attempt to convert the dipeptides to their corresponding alpha-amino acids, chiral ferrocenylamine was used in the above-mentioned reaction. The desired amino acids were obtained with low to modest diastereoselectivity. (See, Sigmüller, et al., Tetrahedron, 1986, Vol. 42, pp. 5931-5940).
The use of a convertible isocyanide in the Ugi reaction, namely cyclohexene-isocyanide, followed by hydrolysis to provide the corresponding peptide carboxylic acid, has been demonstrated (see, Keating, T. A., et al., J. Am. Chem. Soc., 1996, Vol. 118, p. 2574) as follows:
In addition, the use of phenyl-isocyanide and pyridyl-isocyanide was demonstrated in the conversion of dipeptides into pyrrole derivatives (see, Mjalli, et al., Tetrahedron. Lett., 1996, Vol. 37, pp. 2943-2946).
Moreover, the use of sugar derivatives (protected galactososylamine and arabinopyranosylamine) as chiral amines with t-butyl-isocyanide converted dipeptides into the corresponding sugar dipeptides, which were then converted in four chemical steps using very harsh conditions to produce the corresponding alpha-amino acids as shown below:
X
2
—CO—N(sugar)—CHX
3
—CO—NH—C(CH
3
)
3
→NH
2
CHX
3
—CO
2
H. HCl
where X
3
=—Ph, —
t
Bu, —(CH
2
)
3
—COOH, —Bn, or -para-Cl—Ph (Kunz, H. et al., Tetrahedron. Lett., 1989, Vol. 30, pp. 4109-4110).
Also, it has been reported (see, Demharter, A. et al., Angew. Chem. Intl. Ed. Engl., 1996, Vol. 35, p. 173) that the reaction of unprotected alpha-amino acids (namely valine, phenyl alanine and proline) with a series of isocyanides and aldehydes in MeOH provided the corresponding three amino peptides with excellent yield and good diastereoselectivity as shown below:
X
4
—NC+NH
2
—CXH—CO
2
H+X
3
—CHO→X
4
—NH—CO—CHX
3
—NH—CHX—CO
2
Me
N-alkyl-N-acyl-alpha amino amide.
SUMMARY OF INVENTION
The present invention provides certain alpha-amino acetic acids and derivatives thereof, such as, but not limited to, esters, amides and salts. The present invention also provides a novel method for the synthesis of alpha-amino acids and derivatives thereof.
The invention provides alpha-amino acids and derivatives thereof as shown in Formula (1):
wherein W comprises a C
1
-C
6
alkylene group or a direct bond. R
1
comprises hydrogen or a C
1
-C
6
alkylene group. R
2
comprises an alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused cycloalkylaryl, fused arylcycloalkyl, fused heterocyclylaryl, fused arylheterocyclyl, fused cycloalkylheteroaryl, fused heteroarylcycloalkyl, fused heterocyclylheteroaryl, and fused heteroarylheterocyclyl group, optionally substituted 1 to 7 times. R
3
comprises hydrogen or an amino protecting group.
The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula (1) along with methods for the preparation of compounds of Formula (1).
The method for preparing compounds of Formula (1) disclosed herein comprises reacting an aldehyde of the formula R
2
—W—CHO with ammonium formate and a C
1
-C
6
alkyl isocyanide, wherein R
2
and W are defined as in Formula (1). This reaction provides a compound of Formula (2):
which can be used to prepare compounds of Formula (1) using readily available starting materials and reagents, and conventional synthetic procedures.


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Demharter, A. et al. Synthesis of a Chiral 1,1′—Iminodicarboxylic Acid Derivatives from—&agr; Amino Acids Aldehydes, Isocyanides, and Alchohols by the Diastereoselective Five-Center-Four-Component Reactron. Angew. Chem. Int. Ed. Engl. 35: 173-175 (1996).
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