Method for analyzing enantiomer

Patent metadata

Field	Value
Publication number	US-11327060-B2
Application number	US-201815938450-A
Country	US
Kind code	B2
Filing date	Mar 28, 2018
Priority date	Oct 2, 2015
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Enantiomers may be analyzed by:(1) reacting a mixture of a first compound and a second compound that are a pair of enantiomers with an axially chiral compound that is one of a pair of axially chiral isomers, to generate a derivative mixture containing a first derivative obtained by a reaction of the first compound with the axially chiral compound and a second derivative obtained by a reaction of the second compound with the axially chiral compound;(2) separating the first derivative and the second derivative in the derivative mixture; and(3) detecting the separated first derivative and second derivative by mass spectrometry.

First claim

The invention claimed is:

1. A compound represented by formula (I′) or a salt thereof, or a mixture thereof:

wherein
ring A and ring B each independently represent a benzene ring or a heteroaromatic ring,
a bond between the ring A and the ring B represents an axis of chirality,
R 1 represents a group bonded to one ring-constituting atom adjacent to a ring A-constituting atom bonded to the ring B,
R 2 represents a group bonded to the other ring-constituting atom adjacent to the ring A-constituting atom bonded to ring B,
R 3 represents a hydrogen atom or a group,
or R 2 and R 3 optionally form a ring together,
R 4 represents a group bonded to one ring-constituting atom adjacent to a ring B-constituting atom bonded to the ring A,
R 5 represents a group bonded to the other ring-constituting atom adjacent to the ring B-constituting atom bonded to the ring A,
R 6 represents a hydrogen atom or a group,
or R 5 and R 6 optionally form a ring together,
rings A and B optionally further have one or two R A s and one or two R B S that are bonded to an atom constituting each ring, wherein the one or two R A s and the one or two R B s each represent a group,
the groups of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R A , and R B are (a′) a group represented by the general formula (i), or a group containing the group represented by the general formula (i), (b) a group having a charged atom or a chargeable atom, or (c) a substituent,
(a′) the group represented by the general formula (i), or the group containing the group represented by general formula (i) exists only in any one of R 1 to R 6 , R A , and R B ,
at least one of R 1 to R 6 , R A , and R B is the group having a charged atom or a chargeable atom,
the group having a charged atom or a chargeable atom is a di(C 1 to C 6 alkyl)amino group, a tri(C 1 to C 6 alkyl)ammonio group, a piperidino group, a morpholino group, or a group represented by the general formula (d1) or the general formula (d2),
formula (i) is as below:

wherein
R 7 represents a hydroxy group or a leaving group, wherein the leaving group is selected from the group consisting of C 1 to C 6 alkylcarbonyloxy, a halogen atom, succinimidooxy, phenyloxy having an electron-withdrawing group, imidazolyl, and triazolyl,
n represents 0 or 1,
R 8 does not exist when n is 0, and
R 8 represents a hydrogen atom or a C 1 to C 6 alkyl group when n is 1,
formula (d1) is as below:

wherein
X represents a nitrogen atom or an oxygen atom,
r represents an integer of 0 to 10,
R 11 represents a substituent having a positively charged nitrogen atom or a substituent having an uncharged nitrogen atom, and
formula (d2) is as below:

wherein
Y represents a nitrogen atom or an oxygen atom,
s represents an integer of 0 to 10,
R 12 represents a substituent having a positively charged nitrogen atom or a substituent having an uncharged nitrogen atom,

wherein said (c) a substituent is not an amino group.

2. The compound, salt thereof, or mixture thereof according to claim 1 , represented by formula (II′):

wherein
a bond between benzene rings represents an axis of chirality,
R 1 and R 4 each represent a group,
R 2 represents a group,
R 3 represents a hydrogen atom or a group,
or R 2 and R 3 optionally form a ring together,
R 5 represents a group,
R 6 represents a hydrogen atom or a group,
or R 5 and R 6 optionally form a ring together,
the two benzene rings optionally further have one or two R A s and one or two R B S that are bonded to an atom constituting each ring, wherein the one or two R A s and the one or two R B s each represent a group,
the groups of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R A , and R B are (a′) a group represented by the general formula (i) as defined in claim 1 , or a group containing the group represented by the general formula (i), (b) a group having a charged atom or a chargeable atom, or (c) a substituent,
(a′) the group represented by the general formula (i), or the group containing the group represented by the general formula (i) exists only in any one of R 1 to R 6 , R A , and R B , and
at least one of R 1 to R 6 , R A , and R B is the group having a charged atom or a chargeable atom,
wherein said (c) a substituent is not an amino group.

3. The compound, salt thereof, or mixture thereof according to claim 1 , represented by formula (II-1):

wherein
a bond between two benzene rings represents an axis of chirality,
R 1 represents a group represented by the general formula (i) as defined in claim 1 , or a group containing the group represented by the general formula (i),
R 4 represents a group having a charged atom or a chargeable atom,
R 2 and R 5 each represent (c) a substituent, and
the two benzene rings optionally further have one or two R A s and one or two R B S that are bonded to an atom constituting each ring, wherein the one or two R A s and the one or two R B s each represent (c) a substituent
wherein said (c) a substituent is not an amino group.

4. A method for analyzing an enantiomer, comprising (1) to (3) below:
(1) reacting a mixture of a first compound and a second compound that are a pair of enantiomers with an axially chiral compound that is one of a pair of axially chiral isomers, to generate a derivative mixture containing a first derivative obtained by a reaction of the first compound with the axially chiral compound and a second derivative obtained by a reaction of the second compound with the axially chiral compound;
(2) separating said first derivative and said second derivative in the derivative mixture; and
(3) detecting the separated first derivative and second derivative by mass spectrometry,
wherein said axially chiral isomer is a compound according to claim 1 .

5. The method according to claim 4 , wherein said axially chiral compound is an R form.

6. The method according to claim 4 , wherein said separating is performed by chromatography, electrophoresis, or ion mobility spectrometry.

7. The method according to claim 4 , wherein said separating is performed by liquid chromatography using a hydrophobic column.

8. The method according to claim 4 , wherein in separation, retention times of the first derivative and the second derivative are within 120 minutes.

9. The method according to claim 4 , wherein said first compound and said second compound are a pair of enantiomers of a chiral compound selected from the group consisting of a chiral amino acid, a chiral amine, a chiral alcohol, a chiral carboxylic acid, and a chiral thiol.

10. The method according to claim 9 , wherein said chiral amino acid is one or more amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, serine, threonine, cysteine, lysine, arginine, aspartic acid, glutamic acid, asparagine, glutamine, methionine, phenylalanine, tyrosine, tryptophan, histidine, and proline.

11. The method according to claim 10 , wherein said separating is performed so that resolution R represented by the math

Assignees

• Ajinomoto Kk

Inventors

• Harada Masashi
• Karakawa Sachise
• Shimbo Kazutaka
• Yamada Naoyuki

Classifications

• B01D15/327 Primary

  with hydrophobic interaction · CPC title

• B01D15/38

  involving specific interaction not covered by one or more of groups {B01D15/265 and} B01D15/30 - B01D15/36, e.g. affinity, ligand exchange or chiral chromatography · CPC title

• C07C233/62

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups · CPC title

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07D207/46

  with hetero atoms directly attached to the ring nitrogen atom · CPC title