Tetrapeptide compound and method for producing same
The present invention is to provide a method for the efficient production on an industrial scale of SS-31 (D-Arg-Dmt-Lys-Phe-NH 2 ), which is an SS peptide. According to the present invention, the desired SS-31 is produced by efficiently synthesizing a tetrapeptide compound as a precursor of SS-31 and improving the tetrapeptide purity by crystallization.
1. A tetrapeptide compound represented by the following formula (1)
where R is a hydrogen atom, benzyl group, or benzyloxycarbonyl group.
2. The tetrapeptide compound according to claim 1 , which is an intermediate for producing a peptide drug represented by the following formula (2)
3. The tetrapeptide compound according to claim 1 , where R is a hydrogen atom.
4. The tetrapeptide compound according to claim 1 , where compound (1) is an amorphous solid.
5. The tetrapeptide compound according to claim 1 , wherein the compound is in the form of a crystalline solid and exhibits one or more peaks at 2θ±0.1 selected from 5.4°, 10.5°, 15.6°, 17.6°, 18.0°, 18.6°, 20.1°, or 20.6° in a powder X-ray diffraction spectrum obtained using Cu-Kα radiation.
6. The tetrapeptide compound according to claim 1 , wherein compound (1) is in a form of an amorphous solid or a crystalline solid.
7. A method for producing a peptide pharmaceutical, characterized in that the tetrapeptide compound represented by the following formula (1)
is catalytically reduced in the presence of a palladium catalyst to produce a peptide pharmaceutical represented by the following formula (2)
wherein in formula (1), R is a hydrogen atom, benzyl group, or benzyloxycarbonyl group.
8. The production method according to claim 7 , characterized in that compound (1) is produced by condensation via a carbodiimide compound in the presence of a hydroxylamine compound or via a dehydrocondensation agent of Z-D-Arg(Z)2-OH represented by the following formula (3)
and the tripeptide compound represented by the following formula (4)
9. The production method according to claim 7 , wherein R is a hydrogen atom.
10. The production method according to claim 7 , wherein compound (1) is a solid precipitated from an aprotic polar solvent.
11. The production method according to claim 10 , wherein the aprotic solvent is at least one selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, dimethylsulfoxide, N-methylpyrrolidone, and 1,3-dimethylpropylene urea.