Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides with at least one nonpeptide bond other than a...
Reexamination Certificate
2002-03-04
2003-12-30
Rotman, Alan L. (Department: 1626)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides with at least one nonpeptide bond other than a...
C530S334000, C530S335000, C548S226000
Reexamination Certificate
active
06670447
ABSTRACT:
TECHNICAL FIELD
This invention relates to activated amino acid derivatives which are important intermediates useful in many fields led by the fields of pharmaceuticals and agrochemicals. The present invention is also concerned with novel amino acid N-carboxyanhydrides each of which has a substituent of the N-acyl type on a nitrogen atom thereof, and also with a process for the production of diamides, which makes use of the amino acid N-carboxyanhydrides, requires fewer steps and is economical.
BACKGROUND ART
Amino acids are available rather readily at low prices and have diverse structures and asymmetric carbon atoms, so that they have been widely used for many years as raw materials or the like for a variety of optically active compounds led by peptides. In particular, production technology of peptides, which uses amino acids as raw materials, has been one of important basic technologies for many years in many fields led by the fields of pharmaceuticals and agrochemicals. Keeping in step with the advance of molecular biology in recent years, the importance of peptides tends to increase progressively. There is, accordingly, an outstanding demand for an economical production process of peptides, which is suited for industrial practice on large scale.
The principle of peptide production resides a reaction in which a carboxyl group of an amino acid and an amino group of an amine derivative, which may be an amino acid, are subjected to dehydrating condensation to form an amide bond. In practice, however, a free amino acid becomes an ampholytic ion, forms an internal salt and is stabilized, so that the above-mentioned reaction does not occur spontaneously. Even if the reaction should proceed, high-yield production of a specific target product cannot be expected because the amino groups contained in the respective reactants are free and many dipeptides, diketopiperazine derivatives and the like are hence byproduced.
To obtain the target peptide with good yield, functional groups other than those needed have to be masked beforehand to prevent occurrence of undesired reactions. In the case of a methyl ester or the like, its reaction velocity is low and impractical so that a carboxyl component must be activated suitably. A protecting group used as a mask not only plays a role to prevent a side reaction but also has an effect to reduce the polarity of the amino acid and to render it more readily soluble in an organic solvent.
Examples of the protecting group can include urethane-type protecting groups such as tert-butoxycarbonyl (Boc) group and benzyloxycarbonyl (Z) group, alkyl-type protecting groups such as trityl group, and acyl-type protecting groups such as formyl group, tosyl group, acetyl group and benzoyl group. In these protecting groups, urethane-type protecting groups can hardly induce racemization [Jiro Yajima, Yuki Gosei Kyokai Shi (Journal of Synthetic Organic Chemistry, Japan), 29, 27 (1971); Noboru Yanaihara, Pharmacia, 7, 721 (1972)], but acyl-type and alkyl-type protecting groups are accompanied by a drawback that they tend to induce racemization. Further, alkyl-type protecting groups do not fully mask the basicity of an amino group so that the amino group may still be subjected to further acylation. With a trityl group, no second acylation can take place owing to its steric hindrance. Conversely, this steric hindrance makes it difficult to achieve introduction itself of a trityl group, and further, it is not easy to conduct a condensation reaction between a trityl-protected amino acid with and a trityl-protected amine.
A synthesis process which includes introduction of protecting groups requires protecting and deprotecting steps, each of which requires a costly reagent, and also purification steps after the protecting and deprotecting groups, respectively. This synthesis process, therefore, results in multi-step production, leading to an increase in cost.
If it is difficult to allow a condensation reaction to proceed easily between an amino acid and an amine, there are processes in each of which a carboxyl group of an amino acid derivative with a protected amino group is activated by an electron-attracting substituent to facilitate its nucleophilic attack on the carbon atom of a carbonyl group of the amine. Illustrative of these processes are the acid chloride process in which an activated amino acid is derived using PCl
5
, PCl
3
or thionyl chloride, the azidation process in which an activated amino acid is derived from an amino acid ester or the like via a hydrazide, the mixed acid anhydride process in which an activated amino acid is derived from a protected amino acid and another acid, and the crosslinking process making use of a conventional condensing agent such as N,N′-dicyclohexylcarbodiimide (DCC) or 1,1-carbonyl-diimidazole (hereinafter abbreviated as “CDI”). However, the acid chloride process involves a problem that many side reactions occur, the azidation process is accompanied by a problem that the derivation into an azide is very cumbersome, and the mixed acid anhydride process has a problem that disproportionation tends to occur when the temperature rises (“Peptide Synthesis” written by Nobuo Izumiya et al.). The process making use of a condensing agent is also accompanied by some drawbacks. In the case of DCC, for example, an acylisourea which is an intermediate formed by a reaction between a carboxyl group and DCC may undergo an intermolecular rearrangement in the presence of a base to form an acylurea, thereby lowering the yield of the target product or making it difficult to separate the acylurea from the target product. Further, DCC dehydrates the &ohgr;-amide of asparagine or glutamine to form a nitrile. On the other hand, CDI is an expensive reagent, and the crosslinking process making use of CDI is not considered to be an economical production process of peptides.
As described above, many peptide production processes have been studied. To be industrially stable production technology or low-cost production technology, however, these processes have to be considered to be still insufficient.
On the other hand, amino acid N-carboxyanhydrides (referred to as “NCAs” when abbreviated) which have been studied as active amino acids readily react with most free amines. Primary merits of NCAs include that they themselves are effective acylating agents (“Peptides”, 9, 83) and that they permit more economical production through fewer steps than the commonly-employed crosslinking process making use of a condensing agent such as N,N-dicyclohexylcarbodiimide or 1,1-carbonyldiimidazole or the N-hydroxysuccinimide ester crosslinking process. In addition, these amino acid NCAs do not develop the problem of racemization or the like of amino acids under reaction conditions commonly employed for the production of peptides. NCAs have, therefore, been expected for many years to serve as important intermediates for the synthesis of peptides [Pheiol Chem., 147, 91 (1926)].
The peptide synthesis which uses an N-unsubstituted NCA as a production intermediate and has been known well for many years, however, involves many problems in that side reactions such as a polymerization reaction are always hardly controllable and the reactivity and stability differ depending on the kinds of the reactants. This peptide synthesis, therefore, has not been considered as a common peptide production process although its potential utility has been recognized. With a view to solving these problems, numerous improvements have been made. For example, Bailey et al. reported an illustrative condensation reaction between L-alanine-NCA and glycine under low temperature (−40° C.) conditions in an organic solvent [J. Chem. Soc., 8461 (1950)]. Further, Robert G. D. et al. reported illustrative production of a dipeptide under 0 to 5° C. conditions in an aqueous solution (around pH 10) by using L-phenylalaline-NCA [J. Am. Chem. Soc., 88, 3163 (1966)]. In addition, Thomas J. B. et al. reported potential industrial utility of a condensation reaction m
Iizuka Hajime
Sakai Kazuya
Sekiguchi Michiru
Tsunoda Hidetoshi
Mitsui Chemicals Inc.
Rotman Alan L.
Shiao Robert
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