Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Synthesis of peptides
Reexamination Certificate
2002-10-31
2004-07-06
Russel, Jeffrey Edwin (Department: 1654)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Synthesis of peptides
C548S334100, C548S334500, C558S272000, C558S282000, C558S283000, C560S029000, C560S032000, C560S160000, C560S163000
Reexamination Certificate
active
06759511
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a new compound which can be used as an amino-protecting group, a process for preparing the same, and a process for synthesizing peptides using the same. More specifically, the present invention relates to a carbonic acid ester compound of the following formula (1):
in which
X represents para-nitrophenyloxy, imidazolyl, Cl, or Br,
Y represents S or SO
2
, and
Ar represents aryl group containing fluorine(s), which can be easily combined with the amino group of amino acids (capping or protection; ‘capping’ below) or removed therefrom (decapping or deprotection; ‘decapping’ below) under mild conditions, whereby the amino group can be effectively protected during peptide synthesis, a process for preparing the same, and a use of the same. Since the amino acid derivatives thus protected have high thermal and chemical stabilities and good solubility for organic solvents, peptides can be synthesized at a low cost with a high yield.
BACKGROUND ART
Typically known functional groups used for protecting the amino group of amino acids when preparing peptide compounds include tert-butoxycarbonyl (tBoc), 9-fluoroenylmethoxycarbonyl (Fmoc), 2-(4-nitrophenylsulfonyl)ethoxycarbonyl (Nsc), etc.
Among them, tBoc has a fatal demerit that it cannot be used for the amino acids having functional groups sensitive to acid because it should be removed by an acid.
Fmoc can be easily decapped from the amino group under weak basic conditions, which makes the peptide synthesis possible under much milder conditions than tBoc. However, Fmoc also has some fatal demerits. First, the amino acid derivatives protected by Fmoc have low thermal and chemical stabilities, which are particularly lowered in the case of amino acids containing aromatic groups. Therefore, in order to increase the yield of peptide synthesis from the aromatic amino acid derivatives protected by Fmoc group, short reaction time and excess amount of amino acid should be applied. Second, when it is used as a protecting group of amino acids containing a heterocycle, the low solubility of the amino acids in organic solvents may not be improved to a satisfactory level. Third, differently from tBoc, methyl or ethyl ester of amino acid cannot be used as a starting material, and t-butyl ester or carboxylic acid should be used as a starting material. Particularly, since decarboxylation may easily occur in the case of heterocycle compounds, carboxylic acid cannot be used, and t-butyl ester should be used. Since this t-butyl group should be removed under strong acidic conditions, however, it is practically impossible to use the protecting group of Fmoc for the heterocycle-containing amino acids. Fourth, the base piperidine used in the decapping step of Fmoc has weak reactivity with the resulting dibenzofulvene (DBF), and so has a limit in reducing side reactions by DBF by removing side products through a reaction.
On the other hand, since Nsc is more stable than Fmoc, it is useful for peptide synthesis. However, Nsc also has the disadvantage that it is inappropriate for the synthesis on a solid phase due to the low solubility in organic solvents depending on the kind of protected compounds.
DISCLOSURE OF THE INVENTION
Thus, the present inventors have extensively studied to provide a process for effectively synthesizing peptides, and so have identified that the new compound of formula (1) as defined above meets the inventor's requirements as an amino-protecting group. This new compound has the features that it has the advantage of Fmoc or Nsc, synthesis of peptides under weak basic conditions, and at the same time it cures the disadvantages thereof as illustrated above. That is, the amino acid derivatives protected by the amino-protecting group provided by the present invention have high thermal and chemical stabilities and good solubility for organic solvents; the cheap methyl or ethyl ester of amino acid can be used as a starting material in the peptide synthesis; and any side reaction by the products formed in the reaction for removing the protecting group does not occur.
Therefore, the object of the present invention is to provide the compound of formula (1) used as an amino-protecting group.
It is another object of the present invention to provide a process for preparing the compound of formula (1).
It is also another object of the present invention to provide a process for synthesizing peptides using the compound of formula (1) as a protecting group.
It is also another object of the present invention to provide an amino acid derivative protected by the compound of formula (1).
BEST MODE FOR CARRYING OUT THE INVENTION
First, the present invention relates to a new carbonic acid ester compound of the following formula (1):
in which
X represents para-nitrophenyloxy, imidazolyl, Cl, or Br,
Y represents S or SO
2
, and
Ar represents aryl group containing fluorine(s).
In the compound of formula (1), the substituent Ar defined as aryl group containing fluorine(s) preferably represents a radical selected from the following group:
The carbonic acid ester compound of formula (1) according to the present invention, {circle around (1)} enables peptide synthesis under strong basic conditions, {circle around (2)} produces amino acid derivatives protected thereby, which have high thermal and chemical stabilities and good solubility for organic solvents, {circle around (3)} enables use of the cheap methyl or ethyl ester of amino acid as a starting material in the peptide synthesis, {circle around (4)} makes it easy to convert the peptides to unstable derivatives under basic conditions for easy decapping of the protecting group, and {circle around (5)} does not cause any side reaction by the products formed in the decapping reaction.
The carbonic acid ester compound of formula (1) according to the present invention can be prepared by a process characterized in that a fluorinated derivative of aryl halide of the following formula (2):
Ar—L (2)
in which Ar is defined as above and L represents a leaving group, preferably halogen, is reacted with mercaptoethanol to give a fluorinated derivative of 2-(arylsulfanyl)-ethanol of the following formula (3):
in which Ar is defined as above; and the resulting fluorinated derivative of 2-(arylsulfanyl)-ethanol of formula (3) is reacted with a compound of the following formula (4):
in which X is defined as above and L′ represents a leaving group, preferably halogen, in order to introduce the para-nitrophenyloxy, imidazolyl, Cl, or Br group. Therefore, the present invention also relates to the above process for preparing the compound of formula (1).
Specifically, the fluorinated derivative of aryl chloride of formula (2) is dissolved in an organic solvent, mercaptoethanol is added thereto, and the mixture is reacted for 10~30 hours at 20~160° C. to give the fluorinated derivative 2-(arylsulfanyl)-ethanol of formula (3) (Step 1). Then, the compound of formula (3) thus obtained is dissolved in an organic solvent, the compound of formula (4) is added thereto, and the mixture is reacted for 1~5 hours at 0~100° C. to give the novel compound of formula (1) of the present invention (Step 2). For example, the reaction wherein 4-nitrophenyl chloroformate is used as the compound of formula (4) may be depicted as the following Reaction Scheme 1:
The present invention also provides a compound of the following formula (5),
in which Ar and Y are defined as above, and R represents an amino acid except for the amino group combined with the &agr;-carbon atom, which is an amino acid derivative of which amino group is protected by the carbonic acid ester compound of formula (1).
As stated in the following explanation on the capping step, the above compound of formula (5) is formed in the step of preparing a carbamate derivative of amino acid by reacting the compound of formula (1) according to the present invention with the amino group of an amino acid. When Y is S, the compound of formula (5) wherein Y is SO
2
may be obtained by additional oxidation reaction using a suita
Han Hogyu
Jeong Nakcheol
Lee Sang-Jo
Oh Jin Gab
Yu Hosung
Hanchem Co., Ltd.
Russel Jeffrey Edwin
LandOfFree
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