N&agr;-2-(4-nitrophenylsulfonyl)ethoxycarbonyl-amino acids

Details N&agr;-2-(4-nitrophenylsulfonyl)ethoxycarbonyl-amino acids N&agr;-2-(4-nitrophenylsulfonyl)ethoxycarbonyl-amino acids

1999-07-12

2001-07-24

Padmanabhan, Sreeni (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S013000, C560S016000, C560S027000, C560S029000, C560S159000, C560S160000

Reexamination Certificate

active

06265590

ABSTRACT:

BACKGROUND OF THE INVENTION
The field of the invention concerns new protected amino acid derivatives useful for peptide synthesis, namely, N
&agr;
-2-(4-nitrophenylsulfonyl)ethoxycarbonyl-amino acids having the general formula I:
wherein R
1
represents a hydrogen atom, and R
2
may represent hydroxymethyl, 1-hydroxyethyl, 4-hydroxybenzyl, imidazolyl-2-methyl, benzyloxymethyl, 1-benzyloxyethyl, 4-benzyloxybenzyl, benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl, S-benzylthiomethyl, S-(diphenylmethyl)thiomethyl, 4-(benzyloxycarbamido)butyl, 3-guanidinopropyl, 3-N
G
-toluenesulfonyl) guanidinopropyl, 3-(N
G
-nitro) guanidinopropyl, 3-[N
G
-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)]-guanidinopropyl, N-(4,4′-dimethoxybenzhydryl)carboxamidomethyl, 2-[N-(4,4′-dimethoxybenzhydryl) carboxamido]ethyl, S-tert-butyldithiomethyl, 4-[2-(4-nitrophenylsulfonyl)ethoxycarbamicdo]-butyl, propyl, butyl, ethyl, 3-(benzyloxycarbamido)propyl, or 3-(tert-butoxycarbamido)propyl, and methods for the preparation thereof.
N
60
-2-(4-Nitrophenylsulfonyl) ethoxycarbonyl-amino acids (Nsc-amino acids) I represent a class of protected amino acid derivatives which are used in the chemical synthesis of peptides. In these derivatives, N
&agr;
-2-(4-nitrophenylsulfonyl) -ethoxycarbonyl (Nsc) group serves as a temporary N
&agr;
-protection which can be selectively removed after each step of the peptide chain elongation. Nsc-Group is fairly resistant to acidic reagents and is cleaved according to the &bgr;-elimination mechanism by organic bases in aprotic solvents. Mild conditions of the cleavage allow for use of the temporary N
&agr;
-Nsc-protection in the peptide synthesis together with the acid-sensitive side chain protection of widely used t-butyl or benzyl type, thus providing the so-called “orthogonality” of the synthetic strategy.
Recently N
&agr;
-Nsc-amino acids, methods for their preparation, and their employment for the solid phase peptids synthesis have been disclosed in International Publication No. WO96/25394. However, only a minimal set of N
&agr;
-Nsc-derivatives of proteogenic amino acids has been described, which is intended for the solid phase peptide synthesis with full side-chain protection of acid-labile tert-butyl or compatible type.
SUMMARY OF THE INVENTION
It is, therefore, desirable to develop new N
&agr;
-Nsc-amino acids to extend the list of derivatives available for solid phase synthesis. On the other hand, it is useful to provide N
&agr;
-Nsc-amino acid derivatives with another type of side protection (e.g., benzyl of compatible) or without side protection which may give new opportunities for liquid phase peptide synthesis.
An object of the present invention is to provide new N
&agr;
-Nsc-amino acids derivatives, more particularly, N
&agr;
-2-(nitrophenylsulfonyl)ethoxycarbonyl-amino acids having the general formula I:
wherein R
1
represents hydrogen atom, and R
2
may represent a hydroxymethyl, 1-hydroxyethyl, 4-hydroxybenzyl, imidazolyl-2-methyl, benzyloxymethyl, 1-benzyloxyethyl, 4-benzyloxybenzyl, benzyloxycarbonylmethyl, 2- (benzyloxycarbonyl) ethyl, S-benzylthiomethyl, S-(diphenylmethyl)thiomethyl, 4-(benzyloxycarbamido)butyl, 3-guanidinopropyl, 3- (N
G
-toluenesulfonyl) guanidinopropyl, 3-(N
G
-nitro) guanidinopropyl, 3-[N
G
-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)]-guanidinopropyl, N-(4,4′dimethoxybenzhydryl) carboxamidomethyl, 2-[N-(4,4′-dimethoxybenzhydryl)carboxamido]ethyl, S-tert-butyldithiomethyl, 4-[(2-(4-nitrophenylsulfonyl)ethoxycarbamido]-butyl, propyl, butyl, ethyl, 3-(benzyloxycarbamido)propyl, or 3-(tert-butoxycarbamido)propyl, which can be employed as N
&agr;
-protected amino acid derivatives in peptide synthesis.
Another object of the present invention is to provide methods for the preparation of said N
&agr;
-Nsc-amino acids. These and other objects of the present invention will be apparent from the following description
DETAILED DESCRIPTION OF THE INVENTION
N
&agr;
-Nsc-amino acids (I) of the present invention can be prepared by the treatment of amino acids of the general formula II, wherein R
1
and R
2
represent the definitions meanings given for formula I, with 2-(4-nitrophenylsulfonyl)ethylchloroformate III in mixed aqueous/organic solvent in the presence of a base and at a temperature of from 0 to 40° C., preferably from 0 to 20° C. (Scheme 1).
Chloroformate III is introduced into the reaction in amounts of from 0.5 to 1.5 molar equivalents, preferably from 0.7 to 0.9, as related to the amino acid. As an organic component of the solvent any aprotic organic solvent may be used which is capable of dissolving the acylating reagent and is mixible with water, for example, acetonitrile, DMF, tetrahydrofuran or dioxane. A base may be an organic or inorganic base, for example, sodium or potassium carbonate, magnesium or calcium oxide, triethylamine, or N-methylmorpholine.
According to another method of the present invention, amino acids of the general formula II are firstly converted into N,O-trimethylsilyl dervatives using methods known in the art and then treated with equivalent amount of chloroformate III in anhydrous organic solvent, for example, dichloromethane in the presence of base, for example, tertiary amine. After aqueous hydrolysis of the intermediate acylated trimethylsilyl derivatives desirable N
&agr;
-Nsc-amino acids I are obtained in a free form.
Derivatives of the formula I, wherein R
1
is hydrogen, and R
2
represents N-(4,4′-dimethoxybenzhydryl) carboxamidomethyl or 2-[N-(4,4′-dimethoxybenzhydryl)carboxamido]ethyl, may be prepared by the reaction of the known derivatives I, wherein R
1
is hydrogen, and R
2
represents carboxamidomethyl or 2-(carboxamido)ethyl, with 4,4′-dimethoxybenzhydrol in an organic solvent in the presence of a strong acid. As a solvent, acetic acid may be used, and as a strong acid sulfuric or methanesulfonic acid may be used.
A derivative of the formula I, wherein R
1
is hydrogen, and R
2
represents 3-guanidinopropyl(N
&agr;
-Nsc-Arg-OH), may be prepared by the reaction of arginine with 2-(4-nitrophenylthio) -ethylchloroformate in water in the presence of sodium bicarbonate, resulting N
&agr;
-2- (4-nitrophenylthio)ethoxycarbonyl -arginine which is then oxidized into the desired N
&agr;
-Nsc-arginine with hydrogen peroxide in an organic solvent, for example, ethanol or acetic acid.
A derivative of the formula I, wherein R
1
is hydrogen, and R
2
represents imidazolyl-2-methyl(N
&agr;
-Nsc-His-OH), may be prepared from N
&agr;
-Nsc-N
im
-protected histidine derivative by selective deprotection of imidazole ring, for example, by selective acidic detritylation of known N
&agr;
-Nsc-N
im
-triphenylmethyl-histidine.
It is seen from the molecular formula that the compounds of formula I have an asymmetric &agr;-carbon atom. Because the &agr;-carbon atom does not participate in reactions employed for the preparation of compounds of formula I, the configuration of this chiral center existing in starting amino acids II is retained in the resulting N
&agr;
-Nsc-derivatives I. Therefore, it is clear that the methods of the present invention can be used for the preparation of N
&agr;
-Nsc-amino acids I in any chiral form (L or D), as well as racemic compounds, depending on the configuration of the compound II.
The meaning of R
1
and R
2
substituents in derivatives of the formula I according to the present invention correspond to structures of side chains of known &agr;-amino acids containing or not containing protective groups known in the art (Table 1).
TABLE 1
Meanings of R
1
and R
2
substituents in compounds I
No
R1
R2
Amino acid
Abbreviation
I-1
H
Hydroxymethyl
Serine
Nsc-Ser-OH
I-2
H
1-Hydroxyethyl
Threonine
Nsc-Thr-OH
I-3
H
4-Hydroxybenzyl
Tyrosine
Nsc-Tyr-OH
I-4
H
Imidazolyl-2-methyl
Histidine
Nsc-His-OH
I-5
H
Benzyloxymethyl
O-Benzyl-serine
Nsc-Ser(Bzl)-OH
I-6
H
1-Benzyloxyethyl
O-Benzyl-threonine
Nsc-Thr(Bzl)-OH
I-7
H
4-Benzyloxybenzyl
O-Benzyl-tyrosine
Nsc-Tyr(Bzl)-OH
I-8
H
Benzyloxy-
Asparti

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