WO2006059700A1

WO2006059700A1 - Polysulfonamide derivative and use thereof

Info

Publication number: WO2006059700A1
Application number: PCT/JP2005/022147
Authority: WO
Inventors: Yasufumi Tamai
Original assignee: Nihon University
Priority date: 2004-12-02
Filing date: 2005-12-02
Publication date: 2006-06-08
Also published as: JPWO2006059700A1; JP5035960B2

Abstract

Disclosed is a separating agent for asymmetric substances which has high separation performance. Specifically disclosed is a polysulfonamide derivative represented by the following formula (1) or (2). (In the formulae, R represents an optionally substituted hydrocarbon group, or two Rs may combine together and represent an optionally substituted five-membered or six-membered cyclic group; Ar represents an optionally substituted aromatic ring; and n represents a number within the range of 2-1000.)

Description

Specification

Polysulfonamide derivatives and their use

Technical field

[0001] The present invention relates to a novel polysulfonamide derivative. More specifically, the present invention relates to a polysulfonamide derivative used for the separation of an asymmetric substance, a production method thereof, use as a separating agent, and the aforementioned separating agent. The present invention relates to a high performance liquid chromatography column and a method for separating asymmetric substances.

Background art

[0002] The separation of optical isomers is becoming increasingly important in pharmaceuticals, agricultural chemicals, and other related fields. Here, an optical isomer is an isomer having at least one chiral center such as a carbon atom substituted with four different groups in a molecule, and generally has two enantiomers. The biological activity of the body is different. For example, in the case of pharmaceutical pe- sylamine, the D isomer has a useful therapeutic effect, while the L isomer is known to be highly toxic, and in the pharmaceutical manufacturing process, pe-sylamine is used. It is necessary to analyze the purity of the optical isomers. The prerequisite for optical purity analysis is the effective separation of enantiomers, and such analysis is generally performed by high performance liquid chromatography.

[0003] The packing material for high-performance liquid chromatography includes a substance having separability in the form of particles (beads, crushed particles, etc.), a substance obtained by chemically bonding the substance to a carrier, or a carrier on which The thing etc. which coated the substance are known. In particular, for the separation of optical isomers, a force obtained by coating a carrier with an optically active substance having the ability to separate optical isomers is actually used in many cases (see, for example, Patent Documents 1 to 5).

Patent Document 1: Japanese Patent Laid-Open No. 57-150432

Patent Document 2: JP-A-60-40952

Patent Document 3: JP-A-60-82858

Patent Document 4: Japanese Patent Laid-Open No. 60-108751

Patent Document 5: Japanese Patent Laid-Open No. 62-210053 Disclosure of the invention

Problems to be solved by the invention

[0004] However, when separation is performed using a column packed with these fillers, there are problems such as short lifetime as a column and limited types of asymmetric substances that can be applied. The point has been pointed out, and the development of a separating agent with higher separation performance is desired.

Means for solving the problem

[0005] Therefore, the present inventor has intensively studied a separating agent having a further high separation ability, and has found a separating agent composed of an optically active polysulfonamide derivative, thereby completing the present invention.

That is, in the first aspect of the present invention, [1] the following formula (1)

[0007] [Chemical 1]

Or the following formula (2)

[0008]

(In the formula, R represents a hydrocarbon group which may have a substituent, or two R or a 5-membered or 6-membered cyclic group which may have a substituent, Represents an aromatic ring which may have a substituent, and n represents a number in the range of 2 to: LOOO).

[0009] In a preferred embodiment of the polysulfonamide derivative according to the present invention, [2] R may have a substituent, is an alkyl group or a phenyl group, or two Rs are combined. A cyclopentane which may have a substituent, a cyclohexane which may have a substituent, a pyrrolidine which may have a substituent, tetrahydrofuran, or [0010] [Chemical 3]

(Wherein R ¹ has the same definition as R in formula (1)), and is a polysulfonamide derivative according to the preceding item [1].

[0011] In a preferred embodiment of the polysulfonamide derivative according to the present invention, [3] the polysulfone according to [1] or [2] above, wherein R is a phenyl group which may have a substituent. It is an amide derivative.

[0012] In a preferred embodiment of the polysulfonamide derivative according to the present invention, [4] Ar may have a substituent, and is selected from the following group, [1] or [3] A polysulfonamide derivative according to any one of the above is provided.

[0013] [Chemical 4]

[0014] In a preferred embodiment of the polysulfonamide derivative according to the present invention, [5] Ar is the following: The polysulfone amide derivative according to any one of [1] and [4] above, selected from the group consisting of:

[0015] [Chemical 5]

[0016] Further, in the second aspect of the present invention, [6] a method for producing a polysulfonamide derivative represented by the following formula (1) or (2),

[0017] [Chemical 1]

[0018] [Chemical 2]

Jiamine represented by the following formula (3) or (4),

[0019] [Chemical 6]

[0020] [Chemical 7]

A disulfoyl saccharide represented by the following formula (5):

[0021] [Chemical 8]

C10 ₂ S- Ar -S0 ₂ C1 (5)

(In the above formula, R represents a hydrocarbon group which may have a substituent, or two R together may represent a 5-membered or 6-membered cyclic group which may have a substituent, Ar Represents an aromatic ring which may have a substituent, and n represents a number in the range of 2 to: LOOO.)

Provided is a production method comprising a step of reacting in water and a solvent immiscible with water in the presence of a surfactant and an alkaline substance.

[0022] In a preferred embodiment of the production method according to the present invention, [7] the immiscibility with water !, and the solvent is chloride methylene or 1,2-dichloroethane, Is the method.

[0023] In a preferred embodiment of the production method according to the present invention, [8] the production method according to [6] or [7], wherein the surfactant is an ionic surfactant.

[0024] In a preferred embodiment of the production method according to the present invention, [9] the production method according to any one of [6] to [8], wherein the alkaline substance is sodium carbonate. is there.

[0025] In a preferred embodiment of the production method according to the present invention, [10] R may have a substituent.

V, an alkyl group or a phenyl group, or two R together may have a substituent, an optionally substituted cyclopentane, an optionally substituted cyclohexane, an optionally substituted group Pyrrolidine, tetrahydrofuran, or

[0026] [Chemical 3]

(Here, R ¹ has the same definition as R in formula (1).) The manufacturing method according to any one of [6] and [9] above, wherein

[0027] In a preferred embodiment of the production method according to the present invention, [11] R may have a substituent and may be V or a phenyl group, and any one of [6] and [10] above The manufacturing method according to any one of the above.

[0028] In a preferred embodiment of the production method according to the present invention, [12] Ar may have a substituent V, selected from the following group, [6] or [11] It is the manufacturing method as described in any one of them.

[0029] [Chemical 4]

[0030] In a preferred embodiment of the production method according to the present invention, [13] The production method according to any one of [6] to [12], wherein Ar is selected from the following group power: It is.

[0031] [Chemical 5]

[0032] Further, in a third aspect of the present invention, [14] a separating agent is provided, wherein the polysulfonamide derivative described in any one of [1] to [5] above is supported on a carrier.

[0033] In a preferred embodiment of the separation agent according to the present invention, [15] The separation agent according to item 14, wherein the carrier is selected from silica gel, alumina, and a group force that also forms a cross-linked polystyrene force.

[0034] Furthermore, in the fourth aspect of the present invention, there is provided [16] a high performance liquid chromatography column packed with the separating agent described in [14] or [15] above.

[0035] In addition, in the fifth aspect of the present invention, [17] provides a method for separating an asymmetric substance, comprising the step of passing the asymmetric substance through the high performance liquid chromatography column described in [16] above. To do.

[0036] The term "asymmetric substance" used in this specification includes an asymmetric molecule or an asymmetric ionic substance.

The invention's effect

[0037] The polysulfonamide derivative according to the present invention is useful as a separating agent for asymmetric substances, and can be applied as a column packing material for high-performance liquid chromatography for separation of optical isomers.

BEST MODE FOR CARRYING OUT THE INVENTION

The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

[0039] The structure of the polysulfonamide derivative according to the present invention is represented by the following chemical formula (1) or (2). It is.

[0040] [Chemical 1]

-

Or the following formula (2)

[0041] [Chemical 2]

-

— SO Kuichi Ar— SO, (2)

[0042] In the above formula (1), R is a hydrocarbon group which may have a substituent, or two R may be bonded together to have a substituent. And Ar represents an aromatic ring which may have a substituent, n represents a number (integer) in the range of 2 to: L000, preferably a number of 2 to 800, more preferably 2 Represents a number of ~ 700.

[0043] As used herein, the term "hydrocarbon group" in the term "may have a substituent !, hydrocarbon group" includes, for example, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group, and an aromatic group. Group hydrocarbon group and the like, and those having 1 to 10 carbon atoms are preferred. Specifically, an alkyl group

, Alkyl groups, alkyl groups, cycloalkyl groups, aryl groups and the like are used. The “alkyl group” includes, for example, methyl, ethyl, propyl, which are preferably lower alkyl groups.

, C alkyl groups such as isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. “Alkaryl group” includes, for example, lower alkyl

1-6

Preferred are alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl and isobutyl. The “alkyl group” includes

2-6

For example, C alkyl groups such as ethynyl, propargyl, 1-propynyl and the like are preferred, such as lower alkyl groups. “Cycloalkyl group” includes, for example, lower

2-6

Cycloalkyl, cyclobutyl, cyclopentyl, cyclo and the like are preferred C cycloalkyl groups such as hexyl. For example, “aryl” is

3-6

C-aryl groups such as phenyl, 1-naphthyl, 2-naphthyl and biphenyl are preferred.

6-10

Includes a phenyl group having a substituent. Here, the “substituent” in the “substituted phenyl group” includes a hydroxyl group, a nitrile group, a methyl group such as methyl, ethyl and propyl, an alkoxy group such as methoxy, ethoxy and propoxy, fluorine, chlorine and bromine. And halogens of iodine, dialkylamino groups such as N, N dimethylamino-containing N-methyl, N-ethylamino-containing N, N jetylamino groups, and the like.

[0044] Further, the two R forces in formula (1) may be joined together to form a 5-membered or 6-membered cyclic group. For example, cyclopentane or a substituent which may have a substituent may be substituted. Hexane which may have, pyrrolidine which may have a substituent, tetrahydrofuran or

[0045] [Chemical 3]

(Here, R ¹ has the same definition as R in formula (1).)

May be formed. Here, the “substituent” in “cyclopentane which may have a substituent, cyclohexane which may have a substituent, and pyrrolidine which may have a substituent” is the above-mentioned “substituent”. It has the same definition as the “substituent” in the “phenyl group”, and R has the same definition as the scale in the formula (1).

[0046] The "hydrocarbon group" of "may have a substituent !, hydrocarbon group" may have, for example, a halogen atom (fluorine, chlorine, bromine, iodine, etc.) , Nitro group, cyano group, hydroxyl group, lower alkyl group which may be halogenated (methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2 trifluoride) Oroethyl, pentafluoroethyl, propyl, 3, 3, 3 trifluoropropyl pill, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4, 4, 4 trifluorobutyl, pentyl, isopentyl, neopentyl, 5 , 5, 5-trifluoropentyl, hexyl, 6, 6, 6-trifluorohexyl, etc., may be halogenated C Alkyl group), lower alkoxy group (for example, C alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, cyclobutoxy, pentenoreoxy, cyclopentyloxy, hexyloxy, cyclohexyloxy, etc. Base

1-6

Etc.), amino group, mono-lower alkylamino group (eg, mono-C alkylamino group such as methylamino, ethylamino, etc.), di-lower alkylamino group (eg, dimethyl)

1-6

Di-c alkylamino groups such as amino-containing jetylamino), carboxyl groups, lower

1-6

Alkyl carbo groups (eg C alkyl carbo yls such as acetyl and propiool)

1-6

), Lower alkoxy carbo groups (for example, C alkoxy carboxy such as methoxy carbo yl, ethoxy carbonyl, propoxy carbonyl, butoxy carbonyl)

1-6

Such as dimethylcarbamoyl, jetylcarbamoyl, etc., carbamoyl group, mono-lower alkyl group, carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl group, etc.)

1-6

Rubamoyl group, etc.), aryl rubamoyl (for example, vinylcarbamoyl, naphthylcarbamoyl and other c carbyl group, carbamoyl), allyle group (for example, phenyl)

6-10

, Naphthyl and other C aryl groups), aryloxy groups (for example, phenyl,

6-10

C aryloxy group such as naphthyloxy), halogenated! /, May! /, Lower al

6-10

Kill carbo-amino groups (for example, halogenated acetylamino-containing trifluoroacetylamino groups, C alkyl carbo-amino groups, etc.) and the like can be mentioned.

1-6

The In the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)”, the above substituent is 1 to 5, preferably 1 to 3 at the substitutable position of the hydrocarbon group. If there are two or more substituents, each substituent may be the same or different.

[0047] As used herein, the term "aromatic ring" of the term "optionally substituted aromatic ring" includes, for example, a benzene ring, naphthalene ring, anthracene ring, tetracene ring, pentacene ring, pyrene ring. And aromatic hydrocarbon rings such as phenanthrene ring, and heteroaromatic rings such as pyridine ring, biviridine ring, phenantorin ring, quinoline ring, isoquinoline ring, thiophene ring, furan ring and pyrrole ring.

[0048] The term "substituent" in the term "may have a substituent !, aromatic ring" used in the present specification includes, for example, a hydroxyl group, a halogen atom (fluorine, chlorine, bromine, iodine, etc.), Nitro group, alkyl group , Alkoxy group, alkylthio group, aryl group, aryloxy group, aryl group, aryl group, aryl group, aryl group, aryl group, aryl group, aryl group, aryl group, substituted amino group, acyl group And a substituent selected from the group consisting of a group, an acyloxy group, an amide group, a carboxyl group, a substituted carboxyl group and a cyano group. Furthermore, when there are a plurality of substituents, they may be the same or different.

Here, the alkyl group is linear, branched or cyclic! /, And the number of carbon atoms that can be shifted is usually about 1-20, preferably 1-: LO. Specific examples thereof include a methyl group , Ethyl group, propyl group, i propyl group, butyl group, i butyl group, t butyl group, pentyl group, hexyl group, cyclohexyl group, heptyl group, octyl group, 2-ethyl hexyl group, Nonyl, decyl, 3,7-dimethyloctyl, lauryl, trifluoromethyl, pentafluoroethyl, perfluorobutyl, perfluorohexyl, perfluorooctyl, etc. . The alkoxy group may be linear, branched or cyclic, and usually has about 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms. Specific examples thereof include methoxy group, ethoxy group, and propyloxy group. Group, i-propyloxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group, hexyloxy group, cyclohexyloxy group, heptyloxy group, octyloxy group, 2-ethylhexyloxy group, noroxy group, decyloxy group 3,7-dimethyloctyloxy group, lauryloxy group, trifluoromethoxy group, pentafluoroethoxy group, perfluorobutoxy group, perfluorinated hexyl group, perfluorooctyl group, methoxymethyloxy Group, 2-methoxyethyloxy group and the like. The alkylthio group has a straight-chain, branched or cyclic carbon number of usually about 1 to 20, preferably 1 to 10, and specific examples thereof include a methylthio group, an ethylthio group, and a propylthio group. I propylthio group, butylthio group, i-butylthio group, t-butylthio group, pentylthio group, hexylthio group, cyclohexylthio group, heptylthio group, octylthio group, 2-ethylhexylthio group, northio group, decylthio group, 3, 7 Examples include dimethyloctylthio group, laurylthio group, and trifluoromethylthio group. The aryl group is an atomic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and has a condensed ring. In which two or more independent benzene rings or condensed rings are bonded directly or via a group such as beylene. The aryl group usually has about 6 to 60 carbon atoms, preferably 6 to 20 carbon atoms. Specific examples thereof include a phenol group, a C alkoxyphenol.

1-12

Group (C 1 represents a carbon number of 1 to 12. The same applies to the following. For example, methoxy

1-12

, Ethoxy, propyloxy, i propyloxy, butoxy, i butoxy, t butoxy, pentyloxy, hexyloxy, cyclohexyloxy, heptyloxy, octyloxy, 2-ethylhexyloxy, nonyloxy, decyloxy, 3,7 dimethyloxyloxy, lauryloxy, etc.) Alkylphenol groups (eg methylphenol)

1-12

Group, ethyl group, dimethyl group, propyl group, mesityl group, methyl group group, i propyl group, butyl group, i butyl group, t-butyl group, Pentyl furol group, isoamyl furol group, hexyl furol group, heptyl furol group, octyl furol group, norphenyl group, decyl phenyl group, dodecyl phenyl group), 1 naphthyl group, 2 —Examples include a naphthyl group, a 1 anthracyl group, a 2 anthracel group, a 9 anthracyl group, and a pentafluorophenyl group. The aryloxy group usually has about 6 to 60 carbon atoms, preferably 6 to 20 carbon atoms. Specific examples thereof include a phenoxy group and a C alkoxyphenoxy group (for example,

1-12

For example, methoxy, ethoxy, propyloxy, i-propyloxy, butoxy, i-butoxy, t-butoxy, pentyloxy, hexyloxy, cyclohexyloxy, heptyloxy, octyloxy, 2-ethylhexyloxy, nonyloxy, decyloxy, 3,7 dimethyloxy Ctyloxy, lauryloxy, etc.), C alkylphenoxy groups (for example,

1-12

For example, methylphenoxy group, ethylphenoxy group, dimethylphenoxy group, propylphenoxy group, 1,3,5 trimethylphenoxy group, methylethylphenoxy group, i-propylphenoxy group, butylphenoxy group, i-butylphenoxy group Group, t-butylphenoxy group, pentylphenoxy group, isoamylphenoxy group, hexylphenoxy group, heptylphenoxy group, octylphenoxy group, norphenoxy group, decylphenoxy group, dodecylphenoxy group), 1 naphthyloxy group , 2-naphthyloxy group, pentafluorophenyl-oxy group and the like. The arylthio group usually has about 6 to 60 carbon atoms, preferably 6 to 20 carbon atoms. Specific examples thereof include phenolthio groups, C alkoxyphenols. Diruthio group, C alkylphenylthio group, 1 naphthylthio group, 2-naphthylthio group

1-12

Group, pentafluorophenylthio group and the like are exemplified. The arylalkyl group usually has about 7 to 60 carbon atoms, preferably 7 to 20 carbon atoms. Examples of the arylalkyl group include: a phenyl — C alkyl group, a C alkoxyphenol C alkyl group, a C alkylphenol.

1-12 1-12 1-12 1-12

Lu C alkyl group, 1 naphthyl C alkyl group, 2-naphthyl C alkyl

1-12 1-12 1-12 group and the like are exemplified. The arylalkoxy group usually has about 7 to 60 carbon atoms, preferably 7 to 20 carbon atoms. Examples of the arylalkoxy group include a phenylmethoxy group, a phenyloxy group, a vinylbutoxy group, and a phenylpentyloxy. Group, phenyl hexyloxy group, phenyl hexyloxy group, phenoxyl group, phenyl Coxy group, C alkoxy group,

1-12 1-12 Lucoxyphenyl C alkoxy group, C alkylphenol C alkoxy group,

1- 12 1-12 1-12

1 naphthyl C alkoxy group, 2-naphthyl C alkoxy group, etc.

1-12 1-12

The The arylalkylthio group usually has about 7 to 60 carbon atoms, preferably 7 to 20 carbon atoms. Specific examples thereof include a phenyl C alkylthio group and a C alkoxyphenol.

1-12 1-12

C alkylthio group, C alkylthio group C alkylthio group, 1 naphthi

1-12 1-12 1-12

Examples thereof include a C-alkylthio group and a 2-naphthyl-C alkylthio group.

1-12 1-12

The arylalkyl group usually has about 8 to 60 carbon atoms, preferably 8 to 20 carbon atoms. Examples of the arylalkyl group include a ferrule C alkell group, a C alkoxyphenol C

2-12 1-12 2-12 alkenyl group, c alkyl ferrule C alkell group, 1 naphthyl C al

Examples include 1-12 2-12 2-12 kenyl group, 2-naphthyl-C alkenyl group and the like. Ariel Archi

2-12

The carbon group usually has about 8 to 60 carbon atoms, preferably 8 to 20 carbon atoms. Specific examples thereof include a ferrule C alkyl group, a C alkoxyphenol C alkyl group, and a C group.

2-12 1-12 2-12 1-12 Alkylphenol C alkyl group, 1 naphthyl C alkyl group, 2-naphthyl

2- 12 2-12

An example is a tilu C alkynyl group. As the substituted amino group, an alkyl group

2-12

, Aryl groups, aryl alkyl groups, or monovalent heterocyclic groups, and amino groups substituted with one or two selected groups. The alkyl group, aryl group, aryl alkyl group or monovalent heterocyclic group may have a substituent. The substituted amino group usually has about 1 to 60 carbon atoms, preferably 1 to 20 carbon atoms not including the carbon number of the substituent, and specific examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, a jetylamino group, The Oral pyramino group, dipropylamino group, i-propylamino group, diisopropylamino group, butylamino group, i-butylamino group, t-butylamino group, pentylamino group, hexylamino group, cyclohexylamino group, heptylamino group, octylamino group, 2-ethylhexylamino group, nonylamino group, decylamino group, 3,7-dimethyloctylamino group, laurylamino group, cyclopentylamino group, dicyclopentylamino group, cyclohexylamino group, dicyclohexylamino group, Pyrrolidyl group, piperidyl group, ditrifluoromethylamino group phenolamino group, diphenylamino group, C alkoxyphenolamino group, di (C

1-12 1-12 Lucoxyphenyl) amino, di (C alkylphenol) amino, 1-naphthylamino

1-12

Group, 2-naphthylamino group, pentafluorophenylamino group, pyridylamino group, pyridazidilumino group, pyrimidylamino group, bilazylamino group, triazylamino group phenol C

1- alkylamino group, C alkoxyphenyl C alkylamino group, C alkyl

12 1-12 1-12 1-12 phenyl C alkylamino group, di (C alkoxy phenyl C alkyl) amino

1-12 1-12 1-12

Group, di (C alkylphenol C alkyl) amino group, 1 naphthyl C alkyl

1-12 1-12 1-12 Ruamino group, 2-naphthyl-C alkylamino group and the like are exemplified. The acyl group is

1-12

The number of carbon atoms is usually about 2-20, preferably 2-10. Specific examples thereof include acetyl, propiol, butyryl, isobutyryl, bivaloyl, benzoyl, trifluoroacetyl. Group, pentafluorobenzoyl group and the like. The acyloxy group usually has about 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms. Specific examples thereof include an acetoxy group, a propio-loxy group, a butyryloxy group, an isobutyryloxy group, a pivaloyloxy group, a benzoyloxy group. Group, trifluoroacetyloxy group, pentafluorobenzoyloxy group and the like. The amide group usually has about 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms. Specific examples thereof include a formamide group, acetamide group, a propioamide group, a ptylamide group, a benzamide group, a trifluoroacetamide group, a pentafluoro group. Examples include oral benzamide group, diformamide group, diacetamide group, dipropioamide group, dibutyroamide group, dibenzamide group, ditrifluoroacetamide group, dipentafluoro oral benzamide group, and the like. Examples of the substituted carboxyl group include an alkyl group, an aryl group, an aryl alkyl group, or a carboxyl group substituted with a monovalent heterocyclic group. The substituted carboxyl group usually has about 2 to 60 carbon atoms, preferably 2 to Specific examples thereof include methoxy carbo yl group, ethoxy carbo ol group, propoxy carbo yl group, i propoxy carbo ol group, butoxy carbo ol group, i butoxy carbo ol group, t butoxy Carbon, pentyloxycarbonyl, hexyloxycarbonyl, cyclohexyloxycarbonyl, heptyloxycarbol, octyloxycarbol, 2-ethylhexyl Siloxycarbol group, Noroxycarbon group, Decyloxycarbol group, 3,7-Dimethyloctyloxycarboro group, Dodecyloxycarboro group, Trifluoromethoxycarboro group Group, pentafluoroethoxycarbonyl group, perfluorobutoxycarbol group, perfluorohexoxycarboxyl group, perfluorooctylcarboxyl group, phenoxycarboro group -L group, naphthoxycarbol group, pyridyloxycarbol group, and the like.

[0050] In the present invention, Ar in formula (1) is preferably a group selected from the following group powers, particularly from the viewpoint of ease of synthesis and resolution of optical isomers.

[0051] [Chemical 4]

[0052] [Chemical 5]

More preferably, the group power of the group is also selected.

[0053] The polysulfonamide derivative according to the present invention is a diamine, particularly, a group belonging to Group C.

2

Obtained by polycondensation reaction of diamines, which are the other enantiomers, with disulfonyl chlorides (see the following reaction formula)

[0054] [Chemical 9]

Or + C10 ₂ S- Ar -S0 ₂ C1

Or

[0055] In the reaction of the present invention, diamine and disulfonyl chloride are not limited to the following methods, but the interfacial polycondensation method is applied to induce polysulfonamide as a polymer. Conductors can be easily synthesized. Therefore, water and an organic solvent immiscible with water are combined to synthesize the polysulfonamide derivative according to the present invention. The solvent that is not miscible with water used in the above reaction is not particularly limited as long as it is an inert solvent for the reaction. Usually, however, a halogen-based solvent or aromatic that sufficiently dissolves the raw materials used in the reaction. A group solvent or the like can be used. Specific examples of the solvent include methylene chloride, black form, 1,2-dichloroethane, tonolene, xylene, nitrobenzene, and tetramethylene sulfone. In the interfacial polycondensation reaction in the present invention, it is preferable to add a surfactant. Specific surfactants include ionic surfactants such as sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, and sodium lauryl sulfate.

[0056] The polysulfonamide derivative according to the present invention can also be synthesized by a solution polycondensation method other than the interfacial polycondensation method described above. Solvents used in this case include N, N-dimethylformamide, N, N-dimethylacetamide, black-mouth formtetramethylenesulfolane mixed solvent, pyridine, 1,3-dimethyl-2-imidazolidinone, N— Methylpyrrolidine can be used.

[0057] In the above reaction, hydrochloric acid is by-produced as an acid. However, polycondensation reaction is performed in the presence of an excess of diamine with respect to disulfonyl chloride or in the presence of an alkaline substance as an acid acceptor. It can be carried out. Specific examples of the alkaline substance include sodium carbonate.

[0058] The temperature of the synthesis reaction of the polysulfonamide derivative according to the present invention varies depending on the synthesis starting material diamine and disulfonyl chloride, and is not particularly limited, but is 10 to 50 ° C, more preferably 15 °. C to 45 ° C, more preferably 20 ° C to 40 ° C. In addition, the reaction time of the polysulfonamide derivative according to the present invention varies depending on the synthesis starting materials diamines and disulfonyl chlorides, and is not particularly limited, but is 10 to 60 hours, more preferably 15 to 50 hours. More preferably, it is 20 hours to 45 hours.

[0059] After completion of the reaction, the reaction solution is low in solubility of the product, and is crystallized dropwise in a solvent such as hexane, heptane, methanol, etc., and is represented by the above (1) or (2) A polysulfonamide derivative is obtained. In order to increase the purity of the polysulfonamide derivative according to the present invention, N, It can be re-dissolved in a solvent such as N-dimethylformamide or tetrahydrofuran and then charged again in a solvent such as methanol for recrystallization.

[0060] Specific examples of diamines that can be used in the synthesis of the polysulfonamide derivative according to the present invention include, but are not limited to, the following compounds.

[0061] [Chemical 10]

R ² = OH, CN, OMe, OMe, OH, Me,

,

In addition to the above diamines, trans-cyclohexane-1,2-diamine and the like can also be mentioned. In the present invention, the other enantiomer of the above compound can also be used. [0063] Specific examples of disulfonyl chlorides that can be used for the synthesis of the polysulfonamide derivative according to the present invention include, but are not limited to, the following compounds.

[0064] [Chemical 11]

[0065] The alkyl, aryl, and acyl groups described in the above compound are as defined above.

[0066] Next, as is clear from the formula (1) or (2), the polysulfonamide derivative according to the present invention itself has optical activity and can be used as an optical resolution agent for an asymmetric substance. it can . Although the polysulfonamide derivative itself according to the present invention can be used as a separating agent, it is supported on a carrier in order to improve the pressure resistance as a separating agent, prevent swelling and shrinkage by solvent substitution, increase the number of theoretical plates, etc. You can also. In the present invention, specific carriers include porous carriers such as silica gel, alumina, and crosslinked polystyrene. The bridged polystyrene refers to a polystyrene dibutene benzene copolymer and the like. The particle size of the carrier varies depending on the size of the column used, but is not particularly limited. Omm, preferably 3 to 300 μm. The average pore diameter of the carrier is 1θΑ to 100 μm, preferably 60 to LOOOOA. When used as a stationary phase of a column packing material for high performance liquid chromatography, a porous carrier having a particle size of 1 to 200 μm and an average pore size of 10 to 3000 A is preferred.

[0067] The method for supporting the polysulfonamide derivative according to the present invention on a carrier is not particularly limited, and may be a physical method or a chemical method. For example, the physical method includes a method of bringing the polysulfonamide derivative according to the present invention into contact with a porous carrier. On the other hand, as a chemical method, a raw material having a functional group is used during the production of the polysulfonamide derivative according to the present invention, and the silanol group of the porous carrier is mediated by an alkyl group equal to or higher than the ethyl group. Examples thereof include a method of chemically bonding to a functional group such as an amino group or a hydroxy group.

[0068] The amount of the polysulfonamide derivative according to the present invention varies depending on the type and physical properties of the carrier to be supported, and is not particularly limited, but is 1 to 50% by weight based on the weight of the carrier. Preferred to be in range.

[0069] In the present invention, the force splitting method for splitting an asymmetric substance using the derivative represented by the formula (1) as a separating agent is not limited to the following methods, but thin layer chromatography, high performance liquid Chromatographic methods such as chromatography can be mentioned, and asymmetric substances can be easily separated. In particular, the separation agent containing the polysulfonamide derivative according to the present invention is suitable as a stationary phase for the packing material of a column for high-speed liquid chromatography, and the polysulfonamide derivative according to the present invention is dissolved or used as an asymmetric substance eluent. The present invention is not limited except for the liquid that reacts with this, and it can be applied to a normal phase system using hexane or the like, or a reverse phase system using alcohol, water, etc.

[0070] When the separating agent containing the polysulfonamide derivative according to the present invention is used as a column packing material for high performance liquid chromatography, for example, a j8-hydroxy (or amino) carbonyl compound, an _a -hydroxycarbonyl compound, etc. The following compounds can be separated:

[0071] [Chemical 12]

R Vz— ゝ R, Ar ¾, " _{ゝ To} RRV ₀ ' _{R To} RZ _nr1r2

Fi 丫 NH ₂ R 丫 NH ₂

Example

[0072] Examples are shown below to show the advantageous effects of the polysulfonamide derivative according to the present invention. However, these examples are illustrative, and the present invention is in any case limited to the following specific examples. It ’s not something that ’s done.

[0073] [Example 1] Polymer synthesis example

In a two-necked large test tube, sodium carbonate 0.6662 g (6.25 mmol) and distilled water (21.5 mL) were added to dissolve the sodium carbonate. From the side tube, 10% aqueous sodium lauryl sulfate solution (2.5 mL), (IS, 2S)-(-) l, 2-diphenylethane, 0.665 g (3. 13. mmol) and 2,6 naphthalenedisulfuroyl chloride 0.680 g (2.09 mmol) in salt and methylene (30 mL) were sequentially added, and the mixture was stirred using a homogenizer (6500 rpm).

After stirring for 17 hours, the reaction solution is poured into methanol lOOmL while stirring, and the inside of the test tube is further washed with methylene chloride (80 mL). After the cleaning solution is filled in the methanol, it is passed through a membrane filter (pore size 0.5 m). Suction filtered. Cake is methylene chloride (20 mL), methanol (15 mL), distilled water (40 mL), washed sequentially with acetone (15 mL), and dried in vacuo (1.7xlO ^_1 mmHg, 3 hours).

Further, N, N dimethylformamide (hereinafter simply referred to as “DMF”: 8.5 mL) was added to the dried filter cake, and after irradiating with ultrasonic waves for 1 hour, the insoluble matter was filtered, and the filtrate was reconstituted from methanol (350 mL). The precipitate was purified. The white precipitate formed was filtered by suction, and the filter cake was washed successively with methanol (25 mL), distilled water (40 mL), and acetone (25 mL), and then dried by heating under vacuum (24 hours, 80. C, 2.4 × 10—nHg yield) : 0.491 g, yield: 50.6%.

IR (KBr, cm—, instrument: Perkin Elmer Model 1600: 3278 cm 1328 cm—1155 cm—secondary sulfonamide).

^J H-NMR (400MHz,

δ in ppm), device: Bruker AVANCE 400F type 8.39 (2H, br.s): NH; 8.01 (2H, br.d): ArH; 7.77 (2H, br.d): ArH; 7.56 (2H, br .d): ArH; 6.99 (4H, br.d): Ph; 6.71 (4H, br.t): Ph; 6.62 (2H, br.t): Ph; 4.80 (2 H'br.s): — CHPh.

¹³ C—NMR (100 MHz DMF—d ⁷ , δ in ppm), device: AVANCE 400F type 60.3 CN manufactured by Bruker; 128.9, 132.3, 132.4, 133.0, 133.3, 135.6, 138.4, 143.5, 146.4:

Ar.

FIG. 1 is a graph showing the results of various physical properties of polysulfonamide derivatives obtained by the present invention using (IS, 2S) (−) 1,2 diphenylethanediamine. As can be seen from FIG. 1, the polysulfonamide derivative according to the present invention was synthesized in terms of efficiency, although there was a difference in molecular weight obtained by the skeleton of the aromatic ring of disulfolucide.

[0075] [Example 2] (IS, 2S) —polymer synthesis of 1,2 diphenylethanediamine and 1,3 benzenedisulfonyl chloride

In a 200 mL three-necked eggplant flask immersed in an ultrasonic cleaner and equipped with a stirrer, add distilled water (21 5 mL), sodium carbonate 0.6625 g (6.251 mmol), and 10% aqueous sodium lauryl sulfate solution (2.5 mL) were added. Next, 0.692 g (3.251 mmol) of (IS, 2S)-(-)-l, 2-diphenylethanediamine was dissolved in methylene chloride (3 mL) and prepared. In addition, 0.8602 g (3.127 mmol) of 1,3-benzenedisulfuryl chloride was dissolved in methylene chloride (15 mL) and added. After all the cleaning was completed, the ultrasonic irradiation was stopped, and the mixture was immersed in a 30 ° C oil bath and allowed to stir for 48 hours. Methanol (12.5 mL) was slowly added thereto to stop the reaction. The suspension was filtered with suction and washed three times with water and alcohol, and then the filter cake was dried by heating under vacuum (80 ° C., 0.64 mmHg, 31 hours).

The filtrate containing polymer particles passing through the filter paper was separated by a centrifuge (15 OOOrpm, 30 minutes). After centrifugation, the supernatant was removed, distilled water was added to the centrifuge tube, and further washed with a centrifuge (15000 rpm, 30 minutes, 3 times in total). Then, it dried under reduced pressure and obtained the residue.

The first dried filter cake was dissolved in DMF (50 mL) and purified by reprecipitation with distilled methanol (800 mL). The produced white precipitate was filtered by suction, and the filter cake was washed and dried under vacuum heating (80 ° C., 0.40 mmHg, 21 hours). This dried filter cake was dissolved again in DMF (50 mL) and purified by reprecipitation with distilled methanol (850 mL). The produced white precipitate was filtered by suction, and the filter cake was washed and dried under vacuum heating (80 ° C., 0.40 mmHg, 21 hours). Yield: 1.049 g, Yield: 81%.

IR (KBr, cm—, device: Model 1600 manufactured by Perkin Elmer

3287 cm— 1333 cm— 1153 cm— ¹ (secondary sulfonamide).

^{1H- NMR (400MHz, DMF- d 7} , δ in ppm), apparatus: Bruker Ltd. AVANCE 400F type

8.29 (2H, br.s): NH; 7.64 (1H, br.s): ArH; 7.27 (2H, br.s): ArH; 6.96 (1H, brs): ArH; 6.85 (10H, br.s ): Ph; 4.64 (2H, br.s):-CHPh _G

1 ³ C—NMR (100 MHz DMF-d ⁷ , δ in ppm), apparatus: AVANCE 400F type 68.4 CN manufactured by Bruker; 130.1, 132.6, 133.2, 133.3, 134.7, 134.8, 143.0, 147.6: Ar _G [Example 3 ] Polymer synthesis of trans-cyclohexane-1,2-diamine with 4,4-biphenyldisulfol chloride

In a 200 mL three-necked eggplant flask immersed in an ultrasonic cleaner and equipped with a stirrer, add distilled water (35 mL), 1.061 g (10. OOmmol) of sodium carbonate, and 10% aqueous sodium lauryl sulfate solution (4. OmL). Next, (IS, 2S) -cyclohexane-1,2-diamin 0.572 g (5.00 mmol) was dissolved in methylene chloride (6.5 mL) and prepared. Further, 1.693 g (4.820 mmol) of 1,3-benzenedisulfonino chloride was dissolved in salt methylene (35.5 mL) to obtain calorie. After all the cleaning was completed, the ultrasonic irradiation was stopped, immersed in an oil bath at 30 ° C, and stirred for 48 hours. Methanol (20 mL) was slowly added thereto to stop the reaction. The suspension was filtered with suction and washed 3 times with water and alcohol. The filter cake was dissolved in DMF, reprecipitated with methanol, and filtered with suction, and the filter cake was dried by heating under vacuum (80 ° C, 0.15 mmHg, 21 hours). Yield: 1.245 g, yield: 66%.

IR (KBr, cm—, device: Model 1600 manufactured by Perkin Elmer

3276 cm— 1326 cm— 1159 cm— ¹ (secondary sulfonamide)

^J H-NMR (400MHz,

δ in ppm), device: AVANCE 400F, manufactured by Bruker

1.18, 1.35, 1.54, 1.79 (each 2H, br.s):-CH- CH- CH- CH- CH- CH-; 3.15 (

~ 2 ~ 2 ~ 2 ~ 2

2H, br): — CH— CHNH— CHNH— CH—; 7.39 (2H, br): N— H; 8.05 (8H, br.s):

2 1 2 ―

Ar-H

¹³ C— NMR (100 MHz DMF-d ⁷ , δ in ppm), apparatus: AVANCE 400F type 28.6 manufactured by Bruker 28.6: — CH—One CH—One CH— CH— CH— CH—; 61.2: — CH — CHNH- CHNH -CH

2 2 1 2 1 2 1 2 1 1 2 1; 133.4, 133.5, 147.2, 148.2: Ar

[0077] [Example 4] Preparation and column packing of silica gel for high-performance liquid chromatography in which the polysulfonamide polymer obtained in Example 1 was physically adsorbed

Prepared using the following samples:

ODS silica gel for high performance liquid chromatography:

2. 658 g (Nagel, pore size: 10 nm, particle size: 5 μm)

Optically active polysulfonamide (synthesized in Example 1): 0.3945g

[0078] A DMF (20 mL) solution of the optically active polysulfonamide synthesized in Example 1 was prepared, half the amount was added to ODS silica gel, and ultrasonic irradiation was performed for 6 minutes using an ultrasonic washer. After the dispersion, the solvent was removed by heating under reduced pressure using a rotary evaporator (40 ° C., 1. OmmHg). Next, add the remaining polymer solution and DMF (20 mL) to the residue sequentially. Furthermore, after 6 minutes of ultrasonic irradiation, the solvent was distilled off in the same manner under reduced pressure. Thereafter, the residue was dried in vacuo (2. 3x10- immHg 3 hours, then, 2. 2χ10 ^_1 πιπιΗ _8, 24 hours) to give the chiral recognition material as a residue.

Next, connect the slurry filler to the dried high-performance liquid chromatography stainless steel column with an inner diameter of 4.6 mm and a length of 250 mm, add 16 mL of ethylene glycol / methanol = 2: 1 mixed solvent to the column, Ultrasonic irradiation was carried out for 60 minutes using an ultrasonic cleaner, and 16 mL of a mixed solvent of ethylene dalcol / methanol = 2: 1 was added little by little. Thereafter, ultrasonic irradiation was continued for 10 minutes to disperse the silica gel.

This slurry was poured into a filling device, and ethylene glycol / methanol = 2: 1 mixed solvent was fed at a constant pressure of 350 kg / cm ² . After 17 hours, since the flow rate was almost stable at a flow rate of 0.13 mL / min, the flow was stopped, and ethanol was fed until the absorbance was stabilized at a flow rate of 0.25 mL / min (21 hours, pressure 314 kgf / cm ² ). After checking the packing state, the column end was attached. Thereafter, heat treatment was performed at 60 ° C. for 42 hours, and the mixture was allowed to cool to room temperature and used for measurement.

[0079] [Example 5] Optical resolution of methyl p-tolyl sulfoxide by high performance liquid chromatography

The high-performance liquid chromatography column for separation of optical isomers produced in Example 4 was connected to high-speed liquid chromatography (Hitachi L-6000 type liquid feed pump and L-4000 type UV detector) as an eluent. Use ethanol / hexane = 5:95 mixed solution at a flow rate of 0.5 ml / min, and inject 5 μL of a sample solution containing 15 mg of methyl p-tolylsulfoxide dissolved in 2 ml of isopropyl alcohol for analysis. went.

FIG. 2 is a diagram showing an analysis result according to Example 5 of the present invention. According to the result, the values of retention coefficient k, = 3.34, separation coefficient α = 1.27, and degree of separation Rs = l. 6 were obtained.

1

Separation became possible (see Figure 2).

[0081] [Example 6]

In Example 6, as disulfourel chloride, 2,6-naphthalenedisulfuroyl chloride used in Example 1 was replaced with 2,7-naphthalenedisulfuroyl chloride, and Example 1 and In the same manner as in Example 4, polysulfonamide-adsorbed ODS silica was prepared and a column was prepared. The yield of polysulfonamide obtained in Example 6 was 32%, and the number average fraction was It was 6000 (GPC, DMF, PSt conversion).

FIG. 3 shows the analysis result according to Example 6 of the present invention. From the results shown in Fig. 3, the retention factor k, = 7.84, separation factor H = 1 for the eluent of hexane / ethanol = 99/1 for the racemate that is the separation target shown in Fig. 3 34, separation Rs = l.

1

For eluents of xanthane / ethanol = 90/10, retention factor k, = 4.52, separation factor h =

1

1. The value of 64 and the degree of separation Rs = l. 2 were obtained, and separation became possible.

Industrial applicability

[0082] The polysulfonamide derivative according to the present invention is useful as a separation agent for asymmetric substances, and can be applied as a column filler for high-performance liquid chromatography for separation of optical isomers.

Brief Description of Drawings

[0083] [FIG. 1] FIG. 1 is a graph showing the results of various physical properties of polysulfonamide derivatives obtained by the present invention using (IS, 2S)-(−) 1, 2-diphenylethanediamine. It is.

FIG. 2 is a diagram showing the analysis results obtained in Example 5 of the present invention. The detection wavelength was 254 nm.

FIG. 3 shows the analysis results obtained by Example 6 of the present invention. The flow rate was 0.5 mL / min. Using the same apparatus as in Example 5, the analysis target racemic lOmg was dissolved in 1.0 mL of ethanol and injected. In Fig. 3, H means hexane and E means ethanol.

Claims

The scope of the claims

[1] The following formula (1)

[Chemical 1]

Or the following formula (2)

[Chemical 2]

-

(In the formula, R represents a hydrocarbon group which may have a substituent, or two R together may have a substituent and represent a 5-membered or 6-membered cyclic group,

Ar represents an aromatic ring which may have a substituent,

n represents a number ranging from 2 to: L000. )

A polysulfonamide derivative represented by:

[2] The R is an alkyl group or a phenyl group which may have a substituent, or two Rs taken together to form a cyclopentane which may have a substituent. Cyclohexane which may have, pyrrolidine which may have a substituent, tetrahydrofuran, or

[Chemical 3]

(Here, R ¹ has the same definition as R in formula (1).) The polysulfonamide derivative according to claim 1, which forms

[3] The polysulfonamide derivative according to claim 1 or 2, wherein R is a phenyl group which may have a substituent.

[4] The polysulfonamide derivative according to any one of [1] to [3], wherein Ar is selected from the following group power which may have a substituent.

[Chemical 4]

The polysulfonamide derivative according to any one of claims 1 to 4, wherein Ar is selected from the following group.

[Chemical 5]

A method for producing a polysulfonamide derivative represented by the following formula (1) or (2):

[Chemical 2]

Jiamine represented by the following formula (3) or (4),

[Chemical 6]

(3)

[Chemical 7]

A disulfoyl saccharide represented by the following formula (5):

[Chemical 8]

C10 ₂ S- Ar -S0 ₂ C1 (5)

A production method comprising reacting water in a solvent immiscible with water in the presence of a surfactant and an alkaline substance.

7. The production method according to claim 6, wherein the solvent immiscible with water is methylene chloride or 1,2-dichloroethane.

[8] The production method according to claim 6 or 7, wherein the surfactant is an ionic surfactant.

[9] The production method according to any one of [6] to [8], wherein the alkaline substance is sodium carbonate.

[10] R may have a substituent, an alkyl group or a phenyl group, or two groups together having a substituent, cyclopentane, or a substituent. Or cyclohexane, optionally substituted pyrrolidine, tetrahydrofuran, or

[Chemical 3]

(Here, R ¹ has the same definition as R in formula (1).)

The manufacturing method according to any one of claims 6 to 9, wherein:

[11] The production method according to any one of [6] to [10], wherein R is a full group which may have a substituent.

[12] The method according to any one of [6] to [11], wherein said Ar is selected from the following group which may have a substituent: The manufacturing method as described in any one of these.

[Chemical 4]

The manufacturing method according to any one of claims 6 to 12, wherein Ar is selected from the following group.

[Chemical 5]

6. A separating agent comprising the carrier supported on the polysulfonamide derivative according to claim 1.

The carrier is selected from the group force of silica gel, alumina, and cross-linked polystyrene force 13. The separating agent according to claim 12, wherein

[16] A high performance liquid chromatography column packed with the separation agent according to claim 14 or 15.

[17] A method for separating an asymmetric substance, comprising the step of passing the asymmetric substance through the high performance liquid chromatography column according to [16].