Method for purifying an amino acid-n-carboxy anhydride

Patent metadata

Field	Value
Publication number	US-10975042-B2
Application number	US-201916418154-A
Country	US
Kind code	B2
Filing date	May 21, 2019
Priority date	May 25, 2018
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present invention is a method for purifying an NCA, including the steps of: a) dissolving an NCA contaminated with impurities into a solvent which is a good solvent and is not a chlorinated solvent followed by stirring to precipitate an undissolved impurity to afford a suspension, b) adding an acidic filter aid having ability to trap a basic impurity to the obtained suspension followed by filtration and/or forming a fixed bed of the acidic filter aid having ability to trap a basic impurity followed by filtering the suspension to bring the suspension to be in contact with the acidic filter aid having ability to trap a basic impurity, and c) adding the obtained filtrate dropwise to a poor solvent for NCA to crystallize out the NCA in which the impurities are removed. This makes it possible to purify a low-purity NCA conveniently to afford a high-purity NCA.

First claim

The invention claimed is:

1. A method for purifying an amino acid-N-carboxyanhydride shown by the following general formula (1):

wherein R 1 represents a hydrogen atom, an alkyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, a hetero ring optionally having a substituent, or a commonly used protective group for an amino acid selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzoyl group, and an acetyl group, provided that R 1 does not contain a reactive group of unprotected hydroxy group nor a reactive group of unprotected amino group; X is shown by the following general formula (a) and represents a divalent hydrocarbon group optionally having a substituent, provided that X does not contain a reactive group of unprotected hydroxy group nor a reactive group of unprotected amino group; and R 1 and X are optionally bonded with each other to form a cyclic amino acid structure,

wherein R 2 and R 3 each independently represent a hydrogen atom, an alkyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, or a hetero ring optionally having a substituent; and “m” is an integer of 1 to 3,
the method comprising the steps of:
a) dissolving the amino acid-N-carboxyanhydride contaminated with impurities into a solvent which is a good solvent for the amino acid-N-carboxyanhydride and is not a chlorinated solvent followed by stirring to precipitate an undissolved impurity to afford a suspension,
b) adding an acidic filter aid having ability to trap a basic impurity to the suspension obtained in the step a) followed by filtration and/or forming a fixed bed of the acidic filter aid having ability to trap a basic impurity followed by filtering the suspension to bring the suspension to be in contact with the acidic filter aid having ability to trap a basic impurity, and
c) adding the filtrate obtained by the step b) dropwise to a poor solvent for the amino acid-N-carboxyanhydride to crystallize out the amino acid-N-carboxyanhydride in which the impurities are removed,

wherein the acidic filter aid having ability to trap a basic impurity used in the step b) is selected from magnesium sulfate, calcium sulfate, barium sulfate, copper sulfate, and silica gel having a surface modified with sulfonic acid or carboxylic acid.

2. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the amino acid-N-carboxyanhydride is α-amino acid-N-carboxyanhydride, with the “m” being 1.

3. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the amino acid-N-carboxyanhydride is a compound shown by any of the following structural formulae:

wherein Bn represents a benzyl group, tBu represents a tert-butyl group, Et represents an ethyl group, and Ph represents a phenyl group.

4. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein a mass of the good solvent for the amino acid-N-carboxyanhydride used in the step a) is 1 time or more relative to a mass of the used amino acid-N-carboxyanhydride.

5. The method for purifying an amino acid-N-carboxyanhydride according to claim 2 , wherein a mass of the good solvent for the amino acid-N-carboxyanhydride used in the step a) is 1 time or more relative to a mass of the used amino acid-N-carboxyanhydride.

6. The method for purifying an amino acid-N-carboxyanhydride according to claim 3 , wherein a mass of the good solvent for the amino acid-N-carboxyanhydride used in the step a) is 1 time or more relative to a mass of the used amino acid-N-carboxyanhydride.

7. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the good solvent for the amino acid-N-carboxyanhydride used in the step a) is a polar solvent selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate, n-butyl acetate, γ-butyrolactone, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile.

8. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein a mass of the poor solvent for the amino acid-N-carboxyanhydride used in the step c) is 2 times or more relative to a mass of the used amino acid-N-carboxyanhydride.

9. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the poor solvent for the amino acid-N-carboxyanhydride used in the step c) is a solvent selected from n-hexane, n-heptane, n-octane, n-nonane, n-decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, diethyl ether, diisopropyl ether, and t-butyl methyl ether.

10. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the amino acid-N-carboxyanhydride in which the impurities are removed has a residual chlorine concentration of 0.05 mass % or less.

11. The method for purifying an amino acid-N-carboxyanhydride according to claim 10 , wherein the amino acid-N-carboxyanhydride in which the impurities are removed has a residual chlorine concentration of 0.01 mass % or less.

12. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the amino acid-N-carboxyanhydride in which the impurities are removed has a purity of 98 mol % or more measured by differential scanning calorimetry.

13. The method for purifying an amino acid-N-carboxyanhydride according to claim 1 , wherein the steps a), b), and c) are performed in the air.

Assignees

• Shinetsu Chemical Co

Inventors

• Suka Yuki
• Harada Yuji
• Nonaka Shiori
• Sato Kazuomi
• Watanabe Takeru
• Ishii Takehiko

Classifications

• C07F7/0812

  comprising a heterocyclic ring · CPC title

• C07D267/06

  having the hetero atoms in positions 1 and 3 · CPC title

• C07D265/06

  not condensed with other rings · CPC title

• C07D263/44 Primary

  Two oxygen atoms · CPC title

• B01D9/004

  Fractional crystallisation; Fractionating or rectifying columns · CPC title