JP2000143553A - Linker bonding supporter for organic synthesis, its production and the use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject supporter capable of readily carrying various compounds, especially a synthetic compound having an aromatic hydroxy group as a substrate and readily cutting out the objective synthetic compound by bonding a specific linker. SOLUTION: This linker bonding supporter for organic synthesis or its salt is expressed by formula I A is a supporter; X is an eliminable group; Y is a connector or a spacer; Z is a bifunctional group; when Z is an electron attractive bifunctional group, W is an aromatic ring, and when Z is a non-electron attractive bifunctional group, W is an aromatic ring substituted with an electron- attractive group; (m) is 1 or 2}. Preferably, it is a supporter expressed by formula II P is a polystyrene supporter; R is a lower alkyl; (n) is 0-4, (m+n)<=5} and is obtained by reacting a compound of formula III with a halogenating reagent or an activation reagent of a sulfonic acid. Various organic compounds having different substituting groups are efficiently obtained in a short time by using the supporter.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel support which is extremely useful in the synthesis of organic compounds (particularly in the field of combinatorial chemistry), its production method and use.

[0002]

2. Description of the Related Art In the field of combinatorial chemistry, when organic synthesis is carried out on a support, it is necessary to form a covalent bond between the synthetic compound and the support (eg, a resin). Various chemical structures are known for this binding mode. For example, G. Jung et al. (Angew. Chem. Int. Ed. Engl.,
35, 17 (1996)).
This covalent linking moiety that connects the synthetic compound and the support is commonly referred to in the art as a linker.
When the target synthetic compound is cleaved from the support in the conventional bonding mode, a functional group derived from the chemical structure of the linker usually remains on the product side. As such a functional group, for example, a group derived from a carboxyl group and a derivative thereof, a hydroxyl group, an amino group, and the like are known. Such a functional group is not always necessary for the expression of the function of the functional substance of the synthetic compound, or the presence of the functional group often hinders the expression of the function. It was also one factor that significantly limited the types of compounds that could be synthesized by the method. However, recently, a method in which such a functional group derived from a linker is not left on a compound, that is, a synthesis method using a traceless linker has been reported. For example, A. Ellman et al. (J. Org. C
hem., 60, 6006 (1995)); F. Veb
er et al. (J. Am. Chem. Soc., 11
Vol. 7, p. 11999 (1995)) reports a traceless linker utilizing the property of an aryl-silane bond. However, in this method, when forming an aryl-silane bond, the aryl group must be lithiated with a strong base, and at this stage, a base-labile functional group cannot be present on the aryl group side. Further, the aryl-silane bond may not be easily cleaved depending on the nature of the substituent on the aryl group. For these reasons, the types of compounds applicable to the aryl-silane type traceless linker have been limited. Meanwhile, DJ Wustrow et al. (Tetra
Hedron Lett., Vol. 39, p. 3651 (1998)) report a method of obtaining a corresponding benzene derivative by reacting a phenol derivative bonded to a sulfonic acid resin with a palladium catalyst and formate. However, this method using a linker-bonded support derived from a sulfonic acid-type ion exchange resin is applicable only to the synthesis of a benzene derivative substituted with an electron-withdrawing group such as a carboxyl group or a carbamoyl group. It cannot be said that this is a highly versatile synthesis method for obtaining an aromatic compound.

[0003]

DISCLOSURE OF THE INVENTION The present invention carries a novel versatile traceless linker which does not leave a linker-derived functional group on a target synthetic compound and is applicable to the synthesis of various synthetic compounds. An object of the present invention is to provide a linker-bound support for organic synthesis, a method for producing the same, and a use thereof.

[0004]

Means for Solving the Problems The present inventors have made various studies and found that a new formula is obtained.

Embedded image Wherein the symbols are as defined below. The first step is to synthesize a support to which a linker represented by the following formula (1) is synthesized, and this support unexpectedly prepares various compounds based on the specific chemical structure of the linker moiety, in particular, synthetic compounds having an aromatic hydroxyl group as a substrate. The support on the support is easy, the synthetic compound is stably supported on the support under various organic synthesis reaction conditions, and the target synthetic compound can be easily cut out. Have been found to have excellent characteristics such as leaving no functional group, and based on these, the present invention has been completed.

That is, the present invention provides the following equation (1)

Embedded image [Where,

Embedded image Represents a support, X represents a leaving group, Y represents a bond or a spacer, Z represents a divalent group, and when Z represents an electron-withdrawing divalent group, W may be substituted. When Z represents a non-electron-withdrawing divalent group, W represents a non-electron-withdrawing divalent group, and W represents an aromatic ring which may be further substituted with m.
Represents 1 or 2. (2) X is a sulfonyloxy group optionally substituted by (i) a halogen atom or (ii) alkyl or aryl; Or (3) X is (i) a halogen atom or (ii) a sulfonyloxy group optionally substituted with C _1-6 alkyl or C _6-14 aryl. (1) the linker-bonded support for organic synthesis or a salt thereof according to (1), (4) the linker-bonded support for organic synthesis or salt thereof according to (1), wherein X is a halogen atom, and (5) X is (1) The linker-bonded support for organic synthesis or a salt thereof according to the above (1), which is a chlorine atom, (6) The spacer represented by Y may be substituted, and may be a carbon atom, a nitrogen atom, a hydrogen atom, an oxygen atom. And sulfur fields (7) a linker-bonded support for organic synthesis or a salt thereof according to (1), which is a linear divalent group composed of 1 to 20 atoms selected from the group consisting of in spacer is shown, wherein _{(i) - (CH 2)} p -, (ii) -
(CH ₂ ) q-NR ^1- (CH ₂ ) r-, (iii)-(CH
_{2) q-O- (CH 2} ) r -, (iv) - (CH 2) q-S
_{- (CH 2) r -,} (v) - (CH 2) q-SO- (CH
_{2) r -, (vi)} - (CH 2) q-SO 2 - (CH 2) r
-, (Vii)

Embedded image , (Viii)

Embedded image Or (ix)

Embedded image (In the formula, p is an integer of 1 to 6, q is an integer of 1 to 3, r is an integer of 0 to 3, and R ¹ is a C _1-6 alkyl group.) the (1) for organic synthesis linker binding carrier or a salt thereof according to claim, spacer represented by (8) Y, wherein _{(i) - (CH 2)} q-NR 1 -
(CH ₂₎ r-, or (ii)

Embedded image Wherein q is an integer of 1 to 3, r is an integer of 0 to 3, and R ¹ is a C _1-6 alkyl group. (9) Y is a bond, —CH ₂ NH— or a compound of the formula

Embedded image (1) a linker-bonded support for organic synthesis or a salt thereof according to item (1), and (10) a divalent electron-withdrawing group represented by Z having a Hammett's substituent constant σ value of (1) the linker-bonded support for organic synthesis or a salt thereof according to (1), which is a group having a positive value; (11) the electron-withdrawing divalent group represented by Z is a carbonyl group, a thiocarbonyl group,
(1) a linker-bonded support for organic synthesis or a salt thereof, which is a sulfonyl group, a sulfinyl group, a carbamoyl group, a thiocarbamoyl group, a halogenomethene group or a halogenoethene group; (13) the linker-bound support for organic synthesis or a salt thereof according to (1), wherein the valence group is a carbonyl group, a thiocarbonyl group, a sulfonyl group or a sulfinyl group;
Wherein the electron-withdrawing divalent group represented by is a carbonyl group or a sulfonyl group, or a linker-bound support for organic synthesis according to (1) or a salt thereof; When the divalent group is hydroxy, amino, carboxyl, nitro, (mono- or di-C _1-6 alkyl)
(I) a C _1-6 alkylene group, (ii) a C _2-6 alkenylene group, or (iii) a C _1-6 alkylene group which may be substituted with amino, C _1-6 alkoxy, (C _1-6 alkyl) carbonyloxy or halogen. _The linker-bound support for organic synthesis or a salt thereof according to item (1), which is a _2-6 alkynylene group, (1)
5) The linker-supporting compound for organic synthesis described in (1) or a salt thereof, wherein the non-electron-withdrawing divalent group represented by Z is a methylene group or an ethylene group, and (16) Y is a bond , Z is a sulfonyl group or a carbonyl group, the linker-bonded support for organic synthesis according to (1) or a salt thereof, (17) Y is —CH ₂ NH—

Embedded image Wherein the Z is a sulfonyl group or a carbonyl group, the linker-bound support for organic synthesis according to (1) or a salt thereof, and (18) an optionally substituted aromatic ring represented by W (I) a halogen atom, (ii) a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms,
(Iii) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogens, (iv) a C _1-6 alkylthio group optionally substituted with 1 to 3 halogens, and (v)
A group consisting of (1) a C _6-14 aromatic cyclic hydrocarbon or (2) an oxygen atom, a sulfur atom and a nitrogen atom, which may be substituted with one or two substituents selected from the group consisting of a hydroxyl group. (19) a linker-bound support for organic synthesis or a salt thereof according to (1), which is an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of:
_6-14. The (18) wherein the aromatic cyclic hydrocarbon is a benzene ring
The linker-bonded support for organic synthesis according to the above or a salt thereof,
(20) An aromatic heterocycle or a fused ring thereof is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene , Indole, isoindole, 1H-
Indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, benzopyran, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, α-carboline, β-carboline, γ ―Carboline, acridine,
(18) a phenoxazine, phenothiazine, phenazine, phenoxatiin, thianthrene, phenanthridine or phenanthroline, a linker-bound support for organic synthesis described in (18) or a salt thereof, (21) substituted with an aromatic ring represented by W When the monovalent electron-withdrawing group is a halogen atom, a halogeno-C _1-6 alkyl group, a halogeno-C _6-14 aryl group, a C _1-6 alkylsulfonyl group, a C _6-14 arylsulfonyl group, a C _1-6 Alkylsulfamoyl group, C
_6-14 arylsulfamoyl group, C _1-6 alkylsulfinyl group, C _6-14 arylsulfinyl group, C _1-6 alkoxycarbonyl group, C _6-14 aryloxycarbonyl group, a carbamoyl group, a thiocarbamoyl group, a carboxyl The linker-bound support for organic synthesis or a salt thereof according to (1), which is a group, an acyl group, a formyl group, a nitro group or a cyano group, (22)

Embedded image The support represented by the formula

Embedded image [Where,

Embedded image Indicates a polystyrene support. (1) a linker-bound support for organic synthesis or a salt thereof according to the above (1), wherein the polystyrene support is a copolymer of styrene and 0 to 5 mol% of divinylbenzene with respect to the styrene. (22) a linker-bound support for organic synthesis according to (22) or a salt thereof,

Embedded image [Where,

Embedded image Represents a polystyrene support, R represents a lower alkyl group, n represents an integer of 0 to 4, and when n is 2 or more, Rs may be the same or different and m + n ≦ 5; Has the same meaning as described in item (1). (1) the linker-bonded support for organic synthesis or a salt thereof according to (1), (25) the linker-supported organic synthesis bond or salt thereof according to (24), wherein X is a chlorine atom, (2
6) Y is of the formula —CH ₂ NH— or

Embedded image Wherein Z is a sulfonyl group or a carbonyl group and n is 0, or a linker-bound support for organic synthesis according to (24) or a salt thereof, (27)

Embedded image The support represented by the formula

Embedded image [Where,

Embedded image Indicates a polystyrene support. ] The support represented by
X is a halogen atom, Y is a bond, —CH ₂ NH— or

Embedded image Wherein Z is a sulfonyl group or a carbonyl group, W is a benzene ring, and m is 1 or 2;
The linker-bonded support for organic synthesis according to the above or a salt thereof,
Equation (28)

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting a compound represented by the formula or a salt thereof with (1) a halogenating reagent or (2) a sulfonic acid activating reagent.

Embedded image [In the formula, X ¹ represents (1) a halogen atom or (2) a sulfonyloxy group substituted with a lower alkyl or an aromatic ring, and other symbols have the same meanings as described in the item (24). (29) The method according to (28), wherein the halogenating reagent is a sulfuryl halide, (3) the method for producing a linker-bonded support for organic synthesis represented by the formula
0) Formula

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting a compound represented by or a salt thereof with halogenosulfonic acid,

Embedded image [X ² is a halogen atom, and other symbols are (24)
The meaning is the same as described in the section. A method for producing a linker-bonded support for organic synthesis or a salt thereof represented by the formula:

Embedded image [Where,

Embedded image Has the same meaning as described in the item (24). ] And the support represented by the formula

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image [Wherein the symbols have the same meanings as described above. A method for producing a linker-bound support for organic synthesis represented by the formula or a salt thereof, formula (32)

Embedded image [Wherein the symbols have the same meanings as in Item (24)]. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image [Wherein the symbols have the same meanings as described above. A method for producing a linker-bonded support for organic synthesis or a salt thereof represented by the formula:

Embedded image [Wherein the symbols have the same meanings as in Item (24)]. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image [Wherein the symbols have the same meanings as described above. A method for producing a linker-bonded support for organic synthesis or a salt thereof represented by the formula:

Embedded image [Wherein the symbols have the same meanings as in Item (24)]. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image [Wherein the symbols have the same meanings as described above. A method for producing a linker-bonded support for organic synthesis or a salt thereof represented by the formula:

Embedded image [Wherein the symbols have the same meanings as in Item (24)]. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described in the item (24). ]
Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image [Wherein the symbols have the same meanings as described above. A method for producing a linker-bound support for organic synthesis represented by the formula or a salt thereof, formula (36)

Embedded image [Wherein the symbols have the same meanings as in Item (24)]. Wherein the compound represented by the formula (I) or a salt thereof is reacted with a sulfuryl halide.

Embedded image [In the formula, X ² represents a halogen atom, and other symbols have the same meanings as described above. [37] a method for producing a linker-bound support for organic synthesis or a salt thereof represented by the following formula (37):
Item 38. A method for synthesizing an organic compound, comprising using a linker-bonded support for organic synthesis or a salt thereof according to the above item, (38) a formula Ar—OH (XIX) wherein Ar has a substituent. Shows a good aromatic ring. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described in item (1). And a salt thereof, which is obtained by reacting with a linker-bonded support for organic synthesis represented by

Embedded image [Wherein the symbols have the same meanings as described above. A substituent is introduced on Ar of the compound represented by the formula or a salt thereof, if necessary, and / or the substituent on Ar is converted into another substituent;
The resulting expression

Embedded image [Wherein, Ar ′ represents an aromatic ring which may have a substituent,
Other symbols are as defined above. Subjecting the compound represented by the formula (I) or a salt thereof to a reduction reaction,
Formula Ar′-H (XXII) wherein Ar ′ has the same meaning as described above. (37) wherein the compound or salt thereof is subjected to a reduction reaction using a formate or a trialkylsilane in the presence of a palladium phosphine complex catalyst. (3
8) The method according to item 38, wherein the aromatic ring represented by Ar and Ar 'is a benzene ring,

Embedded image [Wherein, Ar ′ represents an aromatic ring which may have a substituent,
Other symbols have the same meanings as described in item (1). Or a salt thereof represented by the formula (42):

Embedded image [Wherein, Ar ′ represents an aromatic ring which may have a substituent,
Other symbols have the same meanings as described in item (1). Wherein the compound represented by the formula: Ar'-H wherein Ar 'has the same meaning as described above. A method for synthesizing a compound represented by the formula
And (43) a novel organic compound or a salt thereof synthesized using the linker-bound support for organic synthesis described in (1) or a salt thereof.

[0006]

Embedded image As the support represented by, various supports used as supports in the field of organic synthetic chemistry, especially combinatorial chemistry, for example, synthetic supports and silica gels generally used as supports for peptide synthesis can be used. And the like, but polystyrene available as a commercial preparation is preferred. Among them, in order to enhance the insolubility and stability in an organic solvent, a support made of polystyrene in the form of a copolymer of styrene and about 0 to about 5 mol% of divinylbenzene is preferred, and about 1 to about 2 mol%. Is more preferably in the form of a copolymer with divinylbenzene. As a preferred support, a granular support, for example, a support having a particle size of 30 to about 1500 μm is used.

[0007]

Embedded image As a support made of polystyrene of a preferred example,
For example, a compound represented by the formula (II) can be used, and the phenyl group in the formula (II) is derived from a styrene group in polystyrene, and is not limited to one and means a large number of phenyl groups. However, for convenience, only one representative example is described in this specification. Therefore, in equation (II)

Embedded image The polystyrene support represented by represents the remaining portion obtained by removing at least one phenyl group from a resin made of polystyrene. Further, the shape of the support is not particularly limited,
A resin, a gel, a sol, or the like other than a granular one is preferably used.

The leaving groups represented by X and X ¹ include:
For example, a leaving group generally used in the field of organic synthetic chemistry is used, and specifically, for example, Comprehensive Orga
nicSynthesis, Vol. 6, Chapter 5.1 (A. Krebs et al., Pergam
on Press, Oxford, 1991) and the like, and preferably (1) a halogen atom (for example,
(2) alkyl (for example, C, such as methyl, ethyl, propyl, isopropyl, etc.)
_1-6 alkyl, etc.) or aryl (eg, phenyl,
A sulfonyloxy group (for example, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc.) substituted with a C _6-14 aryl such as tolyl, preferably a C _6-10 aryl, and the like are used. Among them, X and X ¹ are preferably a halogen atom such as a chlorine atom. As the halogen atom represented by X ² , a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like are used, but a chlorine atom and a bromine atom are preferably used, and among them, a halogen atom such as a chlorine atom is preferable.

As the spacer represented by Y, carbon,
A linearly composed atom selected from nitrogen, hydrogen, oxygen, sulfur and the like, having 1 to 20 atoms, which is not cleaved under the reaction conditions in each step and which may be substituted;
Although a valent group is used, a group containing a carbon atom and a nitrogen atom is particularly preferable. As the spacer, particularly the formula _{(i) - (CH 2)} p -, (ii) - (CH 2)
_{^{q-NR 1 - (CH 2}} ) r -, (iii) - (CH 2) q-O
_{- (CH 2) r -,} (iv) - (CH 2) q-S- (C
_{H 2) r -, (v} ) - (CH 2) q-SO- (CH 2) r
-, (vi) - (CH 2) q-SO 2 - (CH 2) r- other such,

(Vii)

Embedded image , (Viii)

Embedded image , (Ix)

Embedded image Wherein p is an integer of 1 to 6, q is an integer of 1 to 3, r is an integer of 0 to 3, and R ¹ is a C _1-6 alkyl group.

Embedded image (Wherein ^one of Q ¹ and Q ² is a nitrogen atom, the other is a nitrogen atom or a carbon atom, the ring B forms a 5- to 7-membered ring with Q ¹ and Q ² , and q is an integer of 1 to 3 And r is 0
Or a group represented by an integer of 3), and among others, a group represented by the formula

(I)-(CH ₂ ) q-NR ^1- (CH ₂ )
r-, or (ii)

Embedded image (Wherein, q represents an integer of 1 to 3, r represents an integer of 0 to 3, and R ¹ represents a C _1-6 alkyl group). Y represents a bond, —CH ₂ NH— or a formula

Embedded image And the like are preferred.

The divalent group represented by Z is not particularly limited as long as the object of the present invention is achieved, and either a divalent electron-withdrawing group or a non-electron-withdrawing group may be used. it can. Here, the divalent electron-withdrawing group refers to an atom (group) having a stronger ability to attract electrons from the bonding atom side than a hydrogen atom, and specifically, a Hammett's substituent constant σ value (LP Hammett) , Physical Organic Chemistry
Organic Chemistry) Second Edition, McGrow-Hill, New York,
1970.) is a substituent having a positive value. Examples of such a divalent electron-withdrawing group include a carbonyl group, a thiocarbonyl group, a sulfonyl group, a sulfinyl group, a carbamoyl group, a thiocarbamoyl group, a halogenomethene group, and a halogenoethene group. , A thiocarbonyl group, a sulfonyl group, a sulfinyl group and the like are preferably used. The divalent non-electron withdrawing group, 1 in substitutable positions respectively to three is optionally substituted a C _1-6 alkylene group (e.g., methylene group, ethylene group or the like), C _2-6 Alkenylene group (for example, vinylene group and the like), C _2-6 alkynylene group (for example,
And the like, and a methylene group, an ethylene group and the like are preferably used. C _1-6 alkylene group, C _2-6
Examples of the “substituent” for the alkenylene group and the C _2-6 alkynylene group include hydroxy, amino, carboxyl, nitro, (mono- or di-C _1-6 alkyl) amino,
_1-6 alkoxy, (C _1-6 alkyl) carbonyloxy,
Halogen or the like is used.

When Z represents an electron-withdrawing group, W represents an "optionally substituted aromatic ring", and the "substituent" may be substituted at a substitutable position on the aromatic ring. , (1)
Halogen atoms (eg, chlorine, bromine, fluorine, etc.),
(2) 1 with halogen (eg, chlorine, bromine, fluorine, etc.)
To three optionally substituted C _1-6 alkyl group (e.g., methyl group, ethyl group, etc.), (3) halogen (e.g., chlorine, bromine, fluorine, etc.) also to 1 in are three substituents Good C _1-6 alkoxy groups (eg, methoxy groups,
Ethoxy group etc.), (4) C optionally substituted with 1 to 3 halogens (eg, chlorine, bromine, fluorine, etc.)
One or two selected from _1-6 alkylthio groups (for example, methylthio group, ethylthio group, etc.), (5) hydroxyl group and the like are used. When two "substituents" are used, they may be the same or different. Good.

As the "aromatic ring", for example, an aromatic cyclic hydrocarbon or an aromatic heterocyclic ring or a condensed ring thereof is used, and preferably an aromatic cyclic hydrocarbon is used.
As the aromatic cyclic hydrocarbon, monocyclic or condensed polycyclic aromatic hydrocarbons, for example, those having 6 to 14 carbon atoms such as benzene, naphthalene, anthracene, phenanthrene, and acenaphthalene are preferable, and benzene is particularly preferable. . As the aromatic heterocyclic ring, for example, at least one to three (preferably one or two) heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like are used as atoms (ring atoms) constituting a ring system. An aromatic heterocyclic ring containing one (preferably 1 to 4, more preferably 1 to 2) or the like is used. More specifically, as the "aromatic heterocycle", for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine,
5 such as pyridazine, pyrimidine, pyrazine, triazine, etc.
A 6-membered aromatic monocyclic heterocyclic ring is used. Examples of the aromatic heterocyclic fused ring include, for example, benzofuran, isobenzofuran, benzothiophene, indole, isoindole, 1H-indazole, benzindazole, benzoxazole, 1,2-benzoisoxazole, benzothiazole, benzopyran, Quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, α-carboline, β-carboline,
8-14 such as γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxatiin, thianthrene, phenanthridine, phenanthroline and the like
A fused aromatic heterocyclic ring of 5 or 6 members is preferably used, and a heterocyclic ring obtained by condensing a 5- or 6-membered aromatic monocyclic heterocyclic ring with a benzene ring or a 5- or 6-membered aromatic monocyclic heterocyclic ring described above is preferable. A heterocyclic ring in which two identical or different heterocyclic rings in the ring group are fused is used.

When Z represents a divalent non-electron-withdrawing group, W
Represents an aromatic ring substituted with a monovalent electron-withdrawing group and which may be further substituted. Examples of the monovalent “electron-withdrawing group” include a halogen atom, a halogenoalkyl group (preferably an alkyl group in which at least the carbon atom at the 1-position is substituted with a halogen, more preferably a perhalogenoalkyl group), Aryl group, alkylsulfonyl group, arylsulfonyl group, alkylsulfamoyl group, arylsulfamoyl group, alkylsulfinyl group, arylsulfinyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, thiocarbamoyl group, carboxyl group, An acyl group, a formyl group, a nitro group, a cyano group and the like are used. Among them, a halogenoalkyl group (preferably, an alkyl group in which at least the first carbon atom is substituted with a halogen, more preferably a perhalogenoalkyl group) , Alkyl or An arylsulfonyl group, a carbamoyl group, an acyl group, and the like are preferably used. Examples of the alkyl group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.),
Examples of the aryl group include a C _6-14 aryl group (eg, phenyl and the like), examples of the alkoxy group include a C _1-6 alkoxy group (eg, methoxy and ethoxy), and examples of the acyl group include (C _1-6 alkyl) Preferred are carbonyl (eg, acetyl, ethylcarbonyl, etc.). One to two or more (preferably 1 to 4) such electron-withdrawing groups may be present on W, and a group represented by the formula SO ₂ X wherein X is as defined above. ] Hammett's substituent constant σ value of all substituents other than the group represented by (LP Hammett)
et), Physical Organic Chemistry second edition, McGrow-Hill, New York, 1970.)
It is preferably 35 or more. "Substituent" and "aromatic ring" of "aromatic ring which may be further substituted" are the same as described in "optionally substituted aromatic ring" represented by W when Z is an electron-withdrawing group. The same substituents as those for "substituent" and "aromatic ring" can be used.

The substituent represented by R is not particularly limited as long as the object of the present invention is achieved. For example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group and an isopropyl group is used. Among them, a C _1-6 alkyl group is preferably used.

The "aromatic ring" of the "aromatic ring optionally having substituent (s)" represented by Ar and Ar 'is not particularly limited as long as the object of the present invention is achieved. In addition to those described above for the “aromatic ring” represented by W, benzazepine, benzodiazepine, benzoxazepine, benzothiepine, benzothiazepine, phenothiazine, chroman, isochroman and the like can be preferably used. Among them, benzene, thiophene, pyridine, thiazole and the like are preferable, and benzene is particularly preferable. In the production method of the present invention, Ar and Ar 'are characterized by being aromatic rings, so that the substituents on the aromatic ring are not limited at all, and the number of substituents is not limited as long as substitution is possible. As the substituent of the aromatic ring, for example, the aforementioned “substituent” which the “aromatic ring” represented by W may have
Besides, phenyl group, naphthyl group, anthryl group, phenanthryl group, _C6-14 aryl group such as acenaphthenyl group, cyclopropyl group, _C6-14 cyclic hydrocarbon group such as cyclohexyl group, furyl group, thienyl group, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups Or a monocyclic heterocyclic group comprising a structurally possible hydrogenated product thereof, benzofuranyl group, isobenzofuranyl group, benzothienyl group, indolyl group, isoindolyl group, 1H-indazolyl group, benzimidazolyl group, benzoxa Zolyl group, 1,2-benzisoxazolyl group, benzothiazolyl Group, benzopyranyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, carbazolyl group,
α-carbolinyl group, β-carbolinyl group, γ-carbolinyl group, acridinyl group, phenoxazinyl group, phenothiazinyl group, phenazinyl group, phenoxathiinyl group, thianthrenyl group, phenanthridinyl group, phenanthrolinyl group and the like An 8 to 14-membered fused aromatic heterocyclic group,
Or a condensed heterocyclic group, a carboxyl group, a sulfo group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylcarbamoyl group, an arylcarbamoyl group, an alkylamidino group, an arylamidino group, or an acylamidino comprising a structurally possible hydrogenated product. Group, alkylguanidino group, arylguanidino group, acylguanidino group, alkylsulfonyl group, arylsulfonyl group,
Alkylsulfamoyl, arylsulfamoyl, alkylsulfinyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, thiocarbamoyl, carboxyl, acyl, formyl, nitro, cyano, acyloxy , An amino group, an acylamino group, a mono- or dialkylamino group, a mercapto group and the like can be used, and a substitutable number, preferably 1 to 5 may be substituted at a substitutable position. C _1-6 alkyl groups as the above-described alkyl group (e.g., methyl, ethyl, propyl, etc.), etc., C _6-14 aryl group (e.g., phenyl, etc.) As the aryl group and the like, C ₁ is the alkoxy group _{A -6} alkoxy group (eg, methoxy, ethoxy, etc.) is preferred, and an acyl group is (C _1-6 alkyl) carbonyl (eg, acetyl, ethylcarbonyl, etc.).

Among the above substituents, for example, an amino group, a (C _1-6 alkoxy) carbonylamino group (eg, t
_{-Butoxycarbonylamino} , etc.), a C _7-15 aralkylamino group (eg, benzylamino), an amino group having a C _1-6 alkyl substituted with a 5- or 6-membered heterocyclic ring (eg, (2-thienylmethyl ) Amino, (2-imidazolylmethyl) amino, etc.)

Embedded image [In the formula, Ar ² is substituted by C _1-6 alkoxy (eg, methoxy) or C _6-14 aryloxy (eg, phenyloxy) which may have C _1-6 alkoxy (eg, methoxy), etc. A C _6-14 aryl group (eg, phenyl) or a 5- or 6-membered heterocyclic group (eg, pyridyl,
Thienyl, imidazolyl), R ² is a phenyl group optionally substituted with C _1-6 alkoxy (eg, methoxy),
A C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl) or a 5- or 6-membered heterocyclic group (eg, a pyridyl group), and R ² ′ is a C _1-6 alkyl group (eg, methyl, etc.) Is shown. And the like are used. Ar
Preferred as ² is, for example, phenyl, methoxyphenyl, methoxyphenoxyphenyl, pyridyl, thienyl, thiazolyl and the like. As R ² , for example, trimethoxyphenyl, isopropyl, methanesulfonyl, pyridyl and the like are preferable. As R ² ′, methyl and the like are preferable.

The linker-bound support (I) for organic synthesis of the present invention includes, for example,

Embedded image The support represented by the formula

Embedded image [Where,

Embedded image Indicates a polystyrene support. ] The support represented by
X is a halogen atom, Y is a bond, —CH ₂ NH— or

Embedded image Wherein Z is a sulfonyl group or a carbonyl group, W is a benzene ring, and m is 1 or 2, a linker-bonded support for organic synthesis is preferred.

Further, as the linker-bonded support (II) for organic synthesis of the present invention, for example, X is a chlorine atom and Y is a compound of the formula —CH ₂ NH— or

Embedded image Wherein Z is a sulfonyl group or a carbonyl group, and n is 0, and a linker-bonded support for organic synthesis is preferred.

The linker-bonded support for organic synthesis of the present invention, its synthesis raw material or intermediate can be used as a salt as long as it does not hinder the reaction. For example, a salt with an inorganic base or a salt with an organic base can be used. Salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be used. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt, potassium salt, lithium salt and cesium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt Is mentioned. Preferred examples of salts with organic bases include, for example, organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, diisopropylamine And the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Salts with phthalate, citrate, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, alkylsulfonic acid or arylsulfonic acid, etc. . Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

[0022]

DETAILED DESCRIPTION OF THE INVENTION The use of the linker-bonded support for organic synthesis of the present invention can be achieved by using various types of compounds having an aromatic ring group (for example, having a specific basic skeleton containing an aromatic ring group, It is advantageous to easily produce various kinds of different compounds at the same time or within a short time. Therefore, by using the support of the present invention, it is possible to efficiently produce many kinds of organic compounds having different substituents in a short time, and at the same time, in a field that requires a small amount and many kinds of similar structural compounds, For example, it is advantageous in the field of quantitative analysis, the field of reagent production, and the like, and is also useful in automation of organic synthesis. The support of the present invention is described in Chem. Rev., Vol. 97, No. 2, 34
It can be used as an advantageous support in "combinatorial chemistry" described in the literature such as pages 7-509 (1997), for example, drugs for infectious diseases, drugs for cardiovascular diseases, drugs for arteriosclerosis, bone・ It is extremely useful for highly efficient synthesis of compounds that can be targeted for biological activity evaluation, such as drugs for joint diseases, drugs for central nervous system diseases, drugs for diabetes, drugs for digestive system diseases, drugs for allergic diseases, etc. It is. With respect to the production of the combinatorial library and the method of selecting a compound having a biological activity therefrom, the method described in JP-A-9-504511 or the like or a method analogous thereto is used.

The linker-bonded support for organic synthesis according to the present invention has the formula W- (SO ₂ X) m wherein each symbol is as defined above. The most characteristic feature is that the group represented by the formula [1] is modified with an electron-withdrawing group. The formula of the present invention having such characteristics

Embedded image [Wherein the symbols have the same meanings as described above. )), A linker-bound support for organic synthesis represented by the formula Ar-OH [wherein
Ar has the same meaning as described above. By reacting a compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above. The aromatic compound in which the aromatic hydroxyl group (OH of Ar-OH) used when introducing the compound into the support is substituted with a hydrogen atom by reducing the compound represented by the formula

Embedded image [Wherein, Ar ′ has the same meaning as described above. ] Can be cut from the support.

The linker-bound support for organic synthesis of the present invention or a salt thereof can be produced by the production method described below or a method analogous thereto. A. The support of the present invention represented by the formula (I) or a salt thereof is, for example, a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. ] Of the compound represented by the formula

Embedded image Is represented by X (showing the same meaning as above)
Can be produced by converting to a leaving group represented by

Specifically, (1) the support (I) wherein X is a halogen atom or a salt thereof can be produced by halogenating the compound (XXIII) or a salt thereof. Compound used (XXII
As I) or a salt thereof, a commercially available product, a method obtained by condensing 3,5-disulfobenzoate on a support having an amino group at the end, or a method obtained by a method analogous thereto, and the like are used. Examples of the halogenating reagent include sulfuryl halide such as chlorosulfuryl, thionyl halide such as thionyl chloride, halogenosulfonic acid such as chlorosulfonic acid, phosphorus halide such as phosphorus pentachloride, and oxyhalogenation such as phosphorus oxychloride. Phosphorus or the like is used. The reaction can be carried out by reacting about 1 mol of compound (XXIII) or a salt thereof with about 1 to about 10 mol of a halogenating reagent. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane is used as such a solvent. The reaction is usually completed at about -50 ° C to about 100 ° C for about 0.5 to about 72 hours. The method of halogenating compound (IV) or a salt thereof, or the reaction of compound (XVII) or a salt thereof with a sulfuryl halide can be carried out in the same manner as the present reaction.

(2) Compound (XXIII) or a salt thereof is reacted with a sulfonic acid activating reagent to form a support (I) wherein X is a sulfone group substituted with (i) alkyl or (ii) aryl. ) Or a salt thereof. As the sulfonic acid activating reagent, for example, tosyl chloride, mesyl chloride and the like can be used.
The reaction can be carried out by reacting about 1 mol of compound (XXIII) or a salt thereof with about 1 to about 10 mol of a sulfonic acid activating reagent. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane is used as such a solvent. The reaction is usually completed at about -50 ° C to about 100 ° C for about 0.5 to about 72 hours. The reaction of compound (IV) or a salt thereof with a sulfonic acid activating reagent can be carried out in the same manner as in the present reaction.

B. Equation (1)

Embedded image [Wherein the symbols have the same meanings as described above. Reaction of the compound represented by the formula (I) or a salt thereof with halogenosulfonic acid to form a support contained in the support (I)

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

Compound (XXIV) or a salt thereof can be produced by applying a reaction condition usually used for producing a similar compound by a liquid phase reaction to a commercially available support.
For example, when the support is polystyrene, it can be obtained by a method of reacting a commercially available polystyrene resin with benzenesulfonyl chloride and aluminum chloride or a method analogous thereto. As the halogenosulfonic acid, for example, chlorosulfonic acid or the like can be used. The reaction can be carried out by reacting about 1 mol of compound (XXIII) or a salt thereof with about 1 to about 10 mol of a halogenating reagent. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane is used as such a solvent. The reaction is usually completed at about -50 ° C to about 100 ° C for about 0.5 to about 72 hours. Further, the reaction of compound (VI) or a salt thereof with halogenosulfonic acid is carried out in the same manner as the present reaction,
Support (VII) or a salt thereof can be prepared.

C. (1) Support (II) and formula

Embedded image [Wherein the symbols have the same meanings as described above. By reacting the compound represented by the formula (I) or a salt thereof to obtain a compound represented by the formula (I)

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

The support (II) used in this reaction
Can be used a commercially available product, and the compound (XXVI) or a salt thereof can be obtained by reacting a commercially available product or a corresponding sulfonic acid compound with a halogenating reagent such as phosphorus halide (VV Kozlov et al., J. Gen. Chem. USSR (Engl Trans
l), Vol. 19, p. 740 (1949)). The reaction is carried out using about 1 support (II) or a salt thereof.
The reaction can be carried out by reacting about 1 to about 10 mol of compound (XXVI) with about 1 to about 10 mol of a Lewis acid such as aluminum chloride per mol. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane is used as such a solvent. The reaction is usually completed at about -50 ° C to about 100 ° C for about 0.5 to about 72 hours. Further, the support (I) is reacted with the compound (VIII) or a salt thereof to form the support (I).
Can be obtained in the same manner as in the present reaction.

(2) Support (II) and Formula

Embedded image [Wherein the symbols have the same meanings as described above. By reacting the compound represented by the formula (I) or a salt thereof to obtain a compound represented by the formula (I)

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

Support (II) used in this reaction
Can be used a commercially available product, and the compound (XXVIII) or a salt thereof can be obtained by reacting a commercially available product or a corresponding carboxylic acid compound with a halogenating reagent such as phosphorus oxyhalide (D. Binder et al., J. Am. Med. Chem. 30 vol.6
78 (1987)).
The reaction can be carried out by reacting about 1 to about 10 mol of compound (XXVIII) with about 1 to about 10 mol of Lewis acid such as aluminum chloride per about 1 mol of support (II) or a salt thereof. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane is used as such a solvent. The reaction is usually performed at about -50 ° C to about 100 ° C for about 0.5 hour to about 72 hours.
Complete in time.

D. (1) Reaction of compound (X) or a salt thereof with compound (XXVI) or a salt thereof yields a compound represented by the formula (I)

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

The support (X) used in this reaction
Can be obtained by reacting a commercially available product or a commercially available Merrifield resin with phthalimide and then reacting with hydrazine, and the compound (XXVI) or a salt thereof can be obtained by a commercially available product or the aforementioned method . The reaction can be carried out by reacting about 1 to about 10 mol of compound (XXVI) with about 1 to about 10 mol of a base such as diisopropylethylamine or triethylamine per about 1 mol of the support (X) or a salt thereof. . This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane and tetrahydrofuran is used as such a solvent. The reaction is usually about-
It is completed at 50 ° C. to about 100 ° C. in about 0.5 to about 72 hours. Further, a method of reacting compound (X) or a salt thereof with compound (VIII) or a salt thereof to obtain a support (XI) or a salt thereof contained in a support (I) is also carried out in the same manner as the present reaction. be able to.

(2) The reaction of the compound (X) or a salt thereof with the compound (XXVIII) or a salt thereof gives a support (I)
Expression included in

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

The support (X) used in this reaction
Can be obtained by reacting a commercially available product or a commercially available Merrifield resin with phthalimide and then reacting with hydrazine, and the compound (XXVIII) or a salt thereof can be obtained by a commercially available product or the above-described method. . In the reaction, about 1 to about 10 mol of the compound (XXVIII) is added to about 1 mol of the support (X) or a salt thereof, and about 1 mol of a base such as diisopropylethylamine or triethylamine.
To about 10 moles. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane and tetrahydrofuran is used as such a solvent. The reaction is usually performed at about -50 ° C to about 100 ° C for about 0.5 hour to about 7 hours.
Complete in 2 hours. The compound (X) or a salt thereof is reacted with the compound (XII) or a salt thereof to form a support (I)
The method for obtaining the support (XIII) or a salt thereof contained in
The reaction can be carried out in the same manner as in this reaction.

E. (1) Reaction of compound (XIV) or a salt thereof with compound (XXVI) or a salt thereof yields a compound represented by the formula (I)

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

The support used in this reaction (XI
V) can be obtained by a method of reacting a commercially available product or a commercially available Merrifield resin with piperazine, and the compound (XXVI) or a salt thereof can be obtained by a commercially available product or a method described above. The reaction is carried out on a support (XI
The reaction can be carried out by reacting about 1 to about 10 mol of compound (XXVI) with about 1 to about 10 mol of a base such as diisopropylethylamine or triethylamine per about 1 mol of V) or a salt thereof. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane and tetrahydrofuran is used as such a solvent. The reaction is usually carried out at about -50 ° C to about 100 ° C.
And is completed in about 0.5 to about 72 hours. Further, the support (XV) contained in the support (I) by reacting the compound (XIV) or a salt thereof with the compound (VIII) or a salt thereof
Alternatively, a method for obtaining a salt thereof can be carried out in the same manner as in the present reaction.

(2) The compound (XXIV) or a salt thereof is reacted with the compound (XXVIII) or a salt thereof to form a compound represented by the formula (I)

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

The support used in this reaction (XI
V) can be obtained by a method of reacting a commercially available product or a commercially available Merrifield resin with piperazine, and the compound (XXVIII) or a salt thereof can be obtained by a commercially available product or a method described above. The reaction is carried out on a support (XI
About 1 mol of compound (XXVIII) per 1 mol of V) or a salt thereof
To about 10 moles and about 1 to about 10 moles of a base such as diisopropylethylamine and triethylamine. This reaction is advantageously performed in a solvent, and an aprotic solvent such as dichloromethane and tetrahydrofuran is used as such a solvent. The reaction is usually carried out at about -50 ° C to about 100 ° C.
C. in about 0.5 to about 72 hours. Also,
Support (XVI) contained in support (I) by reacting compound (XIV) or a salt thereof with compound (XII) or a salt thereof
Alternatively, a method for obtaining a salt thereof can be carried out in the same manner as in the present reaction. The compound (XXI) or a salt thereof is a novel synthetic intermediate for producing the compound (XXII) or a salt thereof.

The target linker-bound support (I) or a salt thereof for organic synthesis obtained as described above can be isolated and purified by known means, for example, filtration, washing, centrifugation and the like. When the product (I) is obtained as a free form, it is converted into a salt according to a conventional method, or when the support (I) is obtained as a salt, it is converted into a free form or after being converted into another salt, and then isolated and purified. You can also. It is also possible to use the reaction mixture as a raw material in the next step.
Specific examples of the method for producing the support (I) or a salt thereof of the present invention are described below. Here, an example in which a polystyrene resin is used as a support is described for the sake of simplicity, but this does not limit the present invention, and the same production can be performed from another support in the same manner.

A) Method for converting sulfonic acid resin to halogenosulfonyl resin A compound having a sulfonic acid group, which is commercially available or produced by a known method,

Embedded image [Wherein the symbols have the same meanings as described above. With a sulfuryl halide and a trisubstituted phosphine (for example, triphenylphosphine) to obtain a resin having a halogenosulfonyl group at a terminal. This reaction is usually carried out in an aprotic solvent such as dichloromethane at about -50 ° C to about 50 ° C, preferably at about 0 ° C.
C. to about 25.degree. C. in about 0.5 to about 24 hours.

B) Method of producing a resin having a halogenosulfonylphenyl group by reacting an optionally substituted phenyl group on the resin with a halogenosulfonic acid Resin having an optionally substituted phenyl group such as a polystyrene resin Can be reacted with a halogenosulfonic acid to produce a resin having a halogenosulfonylphenyl group. This reaction is usually completed without solvent or in an inert solvent such as dichloromethane at about 0 ° C to about 150 ° C, preferably at about 70 ° C to about 110 ° C, for about 1 hour to about 24 hours. c) A method of producing a resin having a halogenosulfonyl group by reacting an amino group on the resin with a 1,3-benzenedisulfonyldihalide derivative. For example, primary to secondary resins such as aminomethylpolystyrene and piperazinomethylpolystyrene. A resin having a halogeno sulfonyl group is produced by reacting a 1,3-benzenedisulfonyl dihalide derivative with a resin having a primary amino group. This reaction is usually carried out in an inert solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as diisopropylethylamine at about -50 ° C to about 50 ° C, preferably at about 0 ° C to about 25 ° C for about 0.5 hour to about Complete in 24 hours. d) A method of producing a resin having a halogenosulfonyl group by reacting a polystyrene resin with a 1,3-benzenedisulfonyldichloride derivative. This reaction is usually carried out in an inert solvent such as dichloromethane, 1,2-dichloroethane or nitromethane. About -50 ° C to about 100 ° C in the presence of a Lewis acid catalyst such as aluminum
And preferably at about 0 ° C. to about 25 ° C. for about 1 hour to about 24 hours.

E) A method of producing a resin having a halogenosulfonyl group by reacting a 3,5-bis (halogenosulfonyl) benzoyl halide derivative with an amino group on the resin to obtain a primary or secondary resin such as aminomethylpolystyrene or piperazinomethylpolystyrene. 3,5 for resin with secondary amino group
-Reacting a bis (halogenosulfonyl) benzoyl halide derivative to produce a resin having a halogenosulfonyl group. This reaction is usually carried out in an inert solvent such as dichloromethane or tetrahydrofuran at about -50 ° C to about 50 ° C in the presence of a base such as diisopropylethylamine.
It is preferably completed at about 0 ° C. to about 25 ° C. for about 0.5 hours to about 24 hours. The thus-obtained linker-bound support (I) for organic synthesis or a salt thereof of the present invention, which has various kinds of organic compounds having a similar chemical structure, particularly, may have a base-labile functional group. It is extremely useful for producing good compounds in a short time. The typical production method is exemplified below.

Step 1. Supporting a compound having an aromatic hydroxyl group on a linker-bound support for organic synthesis (I) The linker-bound support for organic synthesis obtained by the above-mentioned method (I)
Or a salt thereof has the formula Ar-OH [wherein Ar has the same meaning as described above. By reacting a compound having an aromatic hydroxyl group represented by the following formula:

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof.

The salt of the compound represented by the above formula may be any salt as long as it does not hinder the reaction. For example, a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid may be used. And salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include, for example, sodium salt, potassium salt,
Alkali metal salts such as lithium salts and cesium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts, ammonium salts and the like are used. Preferred examples of salts with organic bases include, for example, organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, diisopropylamine And the like. Preferred examples of the salt with an inorganic acid include a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, phthalate, citrate, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, alkylsulfonic acid or arylsulfonic acid are used. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is used.

This reaction is usually carried out in the presence of a base. As a base, organic amines such as triethylamine, diisopropylethylamine and pyridine; metal hydrides such as sodium hydride; metal alkoxides such as t-butoxypotassium; Carbonates and the like are preferably used. As a reaction solvent, an organic solvent that can swell the resin and is inert under the reaction conditions can be used, but tetrahydrofuran, dichloromethane and the like are preferably used. The reaction is usually completed at about -50 ° C to about 50 ° C, preferably about 0 ° C to about 25 ° C, for about 1 hour to about 24 hours. After completion of the reaction, an excess amount of the substrate (the compound having an aromatic hydroxyl group), the base, and the salts generated during the reaction can be usually removed by washing away with a suitable solvent.

Step 2. Introduction of a substituent on Ar of the above compound or its salt or / and conversion of a substituent on Ar into another substituent Ar of the compound or its salt obtained in the above step 1
If desired above, substituents can be introduced or / and the substituents on Ar can be converted to other substituents by applying various organic synthesis reactions. The linker-bonded support (I) for organic synthesis of the present invention is generally chemically stable and can withstand many synthesis reaction conditions such as acidity, basicity, oxidation, reduction, and heating. As the synthesis reaction, a wide range of reactions can be adopted as long as the reaction conditions are such that the support does not undergo cleavage. For example, TW Green and PGM Wuts, Protective Groups in Organic Synthesis
(Protective Groups in Organic Synthesis), 2nd edition, John Wely & Sons Inc. New York (1991), etc., which can easily be inferred from the stability of arylmethanesulfonate and aryltoluenesulfonate. . After the desired reaction, excess reagents, by-products derived from the reagents and the like can be usually removed by washing away with a suitable solvent or distilling off under reduced pressure.

Step 3. Cutting out the obtained compound or a salt thereof The formula obtained in Step 2

Embedded image [Wherein the symbols have the same meanings as described above. The compound represented by the formula or a salt thereof is reacted with a reducing agent to reductively cleave the O-Ar 'bond of the aromatic sulfonic acid ester, and the formula H-Ar' wherein the symbols are as defined above. Show. ] Can be obtained.

Examples of such a reducing agent include M. Hudlicky, Reductions in Organic
Chemistry (Reductions in organic chemistry),
90, John Wely & Sons Inc. New York (1984) and the like can be used a reagent capable of reductively cleaving a sulfonyl aryl ester, etc., but a combination of a homogeneous transition metal complex catalyst and a hydride source can be used. Is preferably used. As such a homogeneous transition metal complex catalyst, a palladium complex, a nickel complex and the like are preferably used. As the hydride source, various formate, various tin (IV) hydrides, various silyl hydrides, various alkali boron hydrides and the like are used, and more preferably, a salt of formic acid and an organic amine which can be easily removed by distillation. Alternatively, triethylsilane or the like is used. Formula H-Ar 'cut out by these treatments, wherein Ar' has the same meaning as described above. Or a salt thereof may be purified by ordinary purification means such as silica gel column chromatography, distillation, sublimation, and recrystallization.
When H-Ar 'is obtained in a free form, it is converted into a salt according to a conventional method, or when H-Ar' is obtained as a salt, it is converted into a free form or converted into another salt and then isolated and purified. You can also.

Synthesis of a linker-bound support for organic synthesis represented by the formula (I) or a salt thereof, wherein Ar'-H [wherein Ar '
Is as defined above. In each step of the synthesis of the compound represented by the formula (1), a protecting group is used when present as a functional group such as NH ₂ , OH or COOH, and it can be removed after the reaction, if necessary. When a protected functional group such as a protected amino group, a protected hydroxy group, or a protected carboxyl group is present on Ar-OH, these protecting groups may be removed on the support. If necessary, these protective groups may be removed after the release from the support. Various organic compounds having an aromatic ring can be synthesized by performing the above steps using this support. In particular, the method is suitable for a technique for simultaneously synthesizing various kinds of compounds called a combinatorial chemistry, and in that case, it can be applied to any of a so-called split-mix method and a parallel method.

Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Comparative Examples, but these are not intended to limit the present invention. Abbreviations used in the text are listed below. Boc: t-butoxycarbonyl THF: tetrahydrofuran HOBt: 1-hydroxybenzotriazole DMF: dimethylformamide DPPP: 1,3-bis (diphenylphosphino) propane TFA: trifluoroacetic acid

[0053]

EXAMPLES Reference Example 1 Production of N-Boc-aminophenol

Embedded image p-Aminophenol (10.9 g, 0.1 mol) in dry THF (10
0 ml) and di-t-butyl dicarbonate (23 ml, 0.12 mo
l) was added and the mixture was stirred at room temperature overnight. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (200
g, ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystals.
0.47 g was obtained. IR (KBr) 1693 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) d 1.51 (3H, s),
4.86 (1H, s), 6.33 (1H, brs), 6.7-6.8 (2H, m), 7.
2-7.3 (2H, m).

Reference Example 2 Production of phenylsulfonyl resin

Embedded image Swell a polystyrene resin (1% DVB, 100-200 mesh, 5 g) in dry dichloromethane and add benzenesulfonyl chloride
(6.4 ml, 0.50 mmol) and aluminum chloride (6.7 g, 50
mmol) and stirred at room temperature for 16 hours. THF (50 ml)
Was added and the resin was collected by filtration, THF, 1N-hydrochloric acid-THF (1: 1), THF
The residue was washed sequentially with F and diethyl ether, and dried under vacuum to obtain 9.64 g of the title resin. Anal. S 10.70.

Reference Example 3 Production of piperazin-1-ylmethyl resin

Embedded image Chloromethyl polystyrene resin (Merrifield resin) (20
g) was swelled in dry dioxane (200 ml), piperazine (10.3 g, 0.12 mol) was added, and the mixture was stirred at 70 ° C for 16 hours. After filtering the resin, THF, 1N NaOH-THF, water, THF,
After washing with diethyl ether and drying under vacuum, 20.1 g of the title resin was obtained. Anal. N 2.65.

Reference Example 4 Production of diphenyl 1,3-benzenedisulfonate

Embedded image To a solution of phenol (19 g, 0.2 mol) in dry THF (200 ml) was added triethylamine (28 ml, 0.2 mol), and the mixture was cooled on ice.
1,3-benzenedisulfonyl dichloride (25 g, 91 mmol)
Was added and stirred at room temperature for 3 hours. 0.5N hydrochloric acid (200 ml)
And extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was recrystallized from ethyl acetate-hexane to give 35.5 g of the title compound as colorless crystals. IR (KBr) 1589, 1484, 1380 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) d
6.9-7.0 (4H, m), 7.2-7.4 (6H, m), 7.71 (1H, t, J =
8.0 Hz), 8.10 (2H, dd, J = 1.8 and 8.0 Hz), 8.3-8.
4 (1H, m).

Reference Example 5 Production of 3- (phenoxysulfonyl) phenylsulfonyl resin

Embedded image Polystyrene resin (1% DVB, 100-200 mesh, 6 g) was swollen in dry cyclohexane (30 ml), and TMEDA (10 ml,
66 mmol) and 1.6 M n-butyllithium hexane solution (50
ml, 80 mmol) and stirred at 65 ° C. for 4.5 hours. The supernatant is removed by decantation, dry cyclohexane,
Washed sequentially with dry toluene. The obtained resin was swollen in dry toluene (80 ml), diphenyl 1,3-benzenedisulfonate (9.37 g, 24 mmol) was added, and the mixture was stirred at 50 ° C. overnight. 1N Hydrochloric acid (50 ml) was added and the resin was collected by filtration.
The residue was washed sequentially with F, 1N-hydrochloric acid-THF (1: 1), THF, and diethyl ether, and dried under vacuum to obtain 8.67 g of the title resin. Anal. S 5.50.

Reference Example 6 Production of 3-sulfophenylsulfonyl resin

Embedded image 3- (phenoxysulfonyl) phenylsulfonyl resin
(8.45 g) was swelled in THF (30 ml), a 3N aqueous sodium hydroxide solution (15 ml) was added, and the mixture was stirred at 50 ° C. overnight. The resin was collected by filtration, washed successively with water, 1N-hydrochloric acid-THF (1: 1), THF, and diethyl ether, and dried in vacuo to give 7.60 g of the title resin. Anal. S 5.74.

Reference Example 7 Preparation of 3,5-disulfobenzoylaminomethyl resin diisopropylethylamine salt

Embedded image 3.5-Disulfobenzoic acid disodium salt (51.4 g, 157.5
mmol) aqueous solution (300 ml) with sulfonic acid type ion exchange resin
(HCR-W2, 20-50 mesh, 1 l)
Eluted with water. After concentrating the obtained eluate under reduced pressure, N-methylpyrrolidone (160 ml) and diisopropylethylamine (5
4.9 ml, 315 mmol) and toluene (300 ml).
The mixture was heated at reflux for 12 hours while removing water using an an-Stark apparatus. Toluene was distilled off under reduced pressure, and the residue obtained was dried N-
Methylpyrrolidone (160 ml), HOBt (23.4 g, 173 mmo
l), aminomethyl resin (1.7 mmol / g, 30 g, 51 mmol),
DIPCI (27.1 ml, 173 mmol) was added, and the mixture was stirred at room temperature for 4 days. The resin was collected by filtration, washed with DMF, THF-H ₂ O (1: 1), DMF, methanol, THF, and ether in that order, and dried in vacuo to give 59.22 g of the title resin. Anal. N3.72, S 5.64.

Example 1 Production of 3- (chlorosulfonyl) phenylsulfonyl resin

Embedded image Phenylsulfonyl resin obtained by the method of Reference Example 2 (8.
Chlorosulfonic acid (80 ml) was added to
Stirred for hours. The obtained resin was collected by filtration, washed sequentially with dry dichloromethane, dry THF, and dry diethyl ether, and dried in vacuo to give 11.6 g of the title resin. Anal.S 15.65, Cl 8.22.

Example 2 N-Boc-aminophenol 3-
Loading on (chlorosulfonyl) phenylsulfonyl resin

Embedded image A solution of N-Boc-aminophenol (6.3 g, 30 mmol) and triethylamine (4.2 ml, 30 mmol) in dry THF (30 ml) was prepared by using a 3- (chlorosulfonyl) phenylsulfonyl resin (3 g) and stirred at room temperature for 21 hours. After filtering the obtained resin, DMF, 1N-hydrochloric acid-THF (1:
1), washed sequentially with DMF, methanol, THF, and diethyl ether, and dried under vacuum to obtain 3.59 g of N-Boc-aminophenoxysulfonylphenylsulfonyl resin. Anal. N 1.65, S 13.00.

Example 3 Removal of Boc from N-Boc-aminophenoxysulfonylphenylsulfonyl resin

Embedded image TFA-dichloromethane (1: 1, 20 ml) was added to N-Boc-aminophenoxysulfonylphenylsulfonyl resin (3.4 g), and the mixture was stirred at room temperature for 2 hours. After filtering the obtained resin, TH
The residue was sequentially washed with F, DMF, methanol, THF, and diethyl ether, and dried under vacuum to obtain 3.06 g of an aminophenoxysulfonylphenylsulfonyl resin. Anal. N 1.75, S 13.78.

Example 4 Production of N-benzylaminophenoxulfonylphenylsulfonyl resin

Embedded image (1) Aminophenoxysulfonylphenylsulfonyl resin (600 mg) was swollen in dichloromethane (2 ml),
Benzaldehyde (0.16 ml) was added and the mixture was stirred at room temperature for 3 hours. Dichloromethane (4 ml) was added to the obtained suspension, and acetic acid (0.22 ml, 3.8 mmol) and sodium triacetoxyborohydride (0.8 g, 3.8 mmol) were added.
Stir for 18 hours. The obtained resin was collected by filtration, washed sequentially with methanol, DMF, methanol, THF, and diethyl ether, and dried in vacuo to give 647 mg of the title resin.

(2) In the same manner as in (1), nicotinaldehyde (b), 2-thiophenecarboxaldehyde (c), 2-formylthiazole (d), p-methoxybenzaldehyde (e) is used instead of benzaldehyde (a). ), M-
By reacting with methoxybenzaldehyde (f), 4-phenoxybenzaldehyde (g) and 3- (4-methoxyphenoxy) benzaldehyde (h), the corresponding resin as shown below was obtained.

[0065]

Embedded image

Example 5 Preparation of N-benzyl-N- (3,4,5-trimethoxybenzoyl) -aminophenoxysulfonylphenylsulfonyl resin

Embedded image N-benzylaminophenoxulfonylphenylsulfonyl resin (40 mg) was swollen in dry THF (0.4 ml), pyridine (0.06 ml, 0.6 mmol) was added, and 3,4,5-trimethoxybenzoyl chloride (115 mg) was added. , 0.5 mmol) in dry THF
(0.4 ml) solution was added and stirred at room temperature for 14 hours. The obtained resin was collected by filtration, washed sequentially with DMF, water-THF (1: 1), DMF, methanol, THF, and diethyl ether, and dried in vacuo to obtain 46 mg of the title resin.

Example 6 N-benzyl-N by reductive cleavage
Of 3-phenyl-3,4,5-trimethoxybenzamide

Embedded image N-benzyl-N- (3,4,5-trimethoxybenzoyl) -aminophenoxysulfonylphenylsulfonyl resin (46 mg)
Then, palladium acetate (33 mg, 0.15 mmol) and DPPP (69
mg, 0.17 mmol) in dry THF.
(1.7 ml, 12 mmol) and 0.3 ml of the solution obtained by adding formic acid (0.45 ml, 12 mmol).
Stir for 2 hours. The obtained resin was removed by filtration, washed with THF, and the filtrate and washings were collected and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (0.25 g, ethyl acetate).
And 2.7 mg of the title compound was obtained. IR (KBr) 1644 cm ^-1 ; ¹ H-NM
R (CDCl ₃ ) d 3.61 (6H, s),
3.78 (3H, s), 5.13 (2H,
s), 6.59 (2H, s), 6.9-7.3.
(10H, m).

Example 7 N-benzyl by reductive cleavage
Of -N-phenyl-3,4,5-trimethoxybenzamide

Embedded image (1) The title compound was obtained by performing the same operation as in Example 6 except that triethylsilane was used instead of triethylamine and formic acid.

(2) The following compounds were obtained in the same manner as in (1).

Embedded image (In the formula, Ar ″ represents the following group.

Embedded image

1a: 1644 cm ^-1 , 1b: 1644 cm ^-1 , 1c: 1642
cm ^-1 , 1d: 1645 cm ^-1 , 1e: 1642 cm ^-1 , 1f: 1642 c
m ^-1 , 1g: 1642 cm ^-1 , 1h: 1644 cm ^-1 2a: 1655 cm ^-1 , 2b: 1655 cm ^-1 , 2c: 1655 cm ^-1 , 2d: 1
659 cm ^-1 , 2e: 1655 cm ^-1 , 2f: 1655 cm ^-1 , 2g: 1655 c
m ^-1 , 2h: 1655 cm ^-1 3a: 1335 cm ^-1 , 3b: 1339 cm ^-1 , 3c: 1335 cm ^-1 , 3d: 1
343 cm ^-1 , 3e: 1335 cm ^{- 1} , 3f: 1339 cm ^-1 , 3g: 1341 c
m ^-1 , 3h: 1341 cm ^-1 4a: 1644 cm ^-1 , 4b: 1644 cm ^-1 , 4c: 1644 cm ^-1 , 4d: 1
652 cm ^-1 , 4e: 1644 cm ^-1 , 4f: 1644 cm ^-1 , 4g: 1644 c
m ^-1 , 4h: 1646 cm ^-1

Example 8 Production of 3- (chlorosulfonyl) phenylsulfonyl resin

Embedded image Dissolve triphenylphosphine (10 g, 38 mmol) in dry dichloromethane (50 ml) and add sulfuryl chloride under ice-cooling.
(3.1 ml, 38 mmol) and the 3-sulfophenylsulfonyl resin (7.46 g) obtained by the method of Reference Example 6 were sequentially added, and left at room temperature for 20 hours with occasional shaking. The obtained resin was collected by filtration, washed with dry dichloromethane, and dried under vacuum to obtain 8.28 g of the title resin. Anal. S 4.97.

Example 9 Production of 3- (chlorosulfonyl) phenylsulfonylaminomethyl resin

Embedded image The aminomethyl resin (1 g) was washed successively with dry THF and dry dichloromethane, then dried dichloromethane (10 ml), diisopropylethylamine (0.63 ml, 3.6 mmol), 1,1 chloride
3-benzenedisulfonyl (0.99 g, 3.6 mmol) was sequentially added, and the mixture was stirred at room temperature for one day. After filtering the resin, 1N hydrochloric acid-TH
The residue was washed with F, THF, and diethyl ether, and dried under vacuum to obtain 1.40 g of the title resin. Anal. S 6.47.

Example 10 4- [3- (chlorosulfonyl)
Preparation of [phenylsulfonyl] piperazin-1-ylmethyl resin

Embedded image The piperazin-1-ylmethyl resin (1 g) obtained by the method of Reference Example 3 was washed successively with dry THF and dry dichloromethane, and then dried with dichloromethane (10 ml), diisopropylethylamine (0.63 ml, 3.6 mmol), and 1,1 chloride. 3-benzenedisulfonyl (0.99 g, 3.6 mmol) was sequentially added, and the mixture was stirred at room temperature for one day. After filtering the obtained resin, 1N hydrochloric acid-THF,
The residue was washed with THF and diethyl ether and dried under vacuum to obtain 1.26 g of the title resin. Anal. S 3.10.

Example 11 Production of 3,5-bis (chlorosulfonyl) benzoylaminomethyl resin

Embedded image A solution of triphenylphosphine (23.6 g, 90 mmol) in dichloromethane (150 ml) was cooled to -78 ° C, sulfuryl chloride (8.0 ml, 100 mmol) and 3,5-disulfo obtained by the method of Reference Example 7. Benzoylaminomethyl resin didiisopropylethylamine salt (10 g) was added, and the mixture was stirred at room temperature for 22 hours. After filtering the obtained resin, THF, THF-1N hydrochloric acid
(1: 1), washed successively with THF and dry ether and dried under vacuum to obtain 8.27 g of the title resin.

Example 12 3- (chlorosulfonyl) -2,
Production of 4,6-trimethyl-phenylsulfonyl resin

Embedded image Dry polystyrene resin (1 g) in dry dichloromethane (10 m
l), swell in 2,4,5,6-tetramethyl-1,3-benzenedisulfonyl dichloride (4 g) and aluminum chloride
(1.6 g) was added and the mixture was stirred at room temperature overnight. The obtained resin was collected by filtration, washed with dichloromethane, 1N hydrochloric acid-THF, THF, and diethyl ether, and dried in vacuo to give the title resin.
2.06 g were obtained. Anal.S 10.34 Cl 5.47.

Comparative Example 1 (1) Production of chlorosulfonyl resin

Embedded image Triphenylphosphine (47.2 g) in dichloromethane
(100 ml) Sulfuryl chloride (16 ml) was slowly added dropwise at −78 ^° C. to the solution, and then a sulfonic acid type ion exchange resin (Bi
o-Rad AG50WX2, dried over diphosphorus pentoxide, 10
g) was added and stirred at room temperature for 22 hours. The resin was collected by filtration, washed with dry dichloromethane, and dried under vacuum to obtain 11.7 g of a chlorosulfonyl resin.

(2) Loading of 4-acetamidophenol on chlorosulfonyl resin

Embedded image Dry THF (10 m) was added to the resin (937 mg) obtained in (1) above.
l), 4-acetamidophenol (2.27 g) and triethylamine (2.1 ml) were added, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added 1N hydrochloric acid (20 ml), and the resin was collected by filtration.DMF, 1N
The mixture was washed with hydrochloric acid-THF (1: 1), DMF, THF, methanol, THF, and diethyl ether in that order, and dried under vacuum to obtain 1.31 g of 4-acetamidophenoxysulfonyl resin. Anal. N 3.78, S 9.80.

(3) Examination of reductive cleavage

Embedded image The resin obtained in the above (2) was reacted under the same conditions as in Example 6, but the desired acetanilide was not obtained.

[0079]

By using the linker support (I) for organic synthesis of the present invention or a salt thereof, various kinds of organic compounds having different substituents can be efficiently produced in a short time.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 295/22 C07D 295/22 A 333/20 333/20 C08F 10/00 C08F 10/00

Claims (43)

[Claims] (1) Formula (1) [Wherein, Represents a support, X represents a leaving group, Y represents a bond or a spacer, Z represents a divalent group, and when Z represents an electron-withdrawing divalent group, W may be substituted. When Z represents a non-electron-withdrawing divalent group, W represents a non-electron-withdrawing divalent group, and W represents an aromatic ring which may be further substituted with m.
Represents 1 or 2. ] Or a salt thereof for organic synthesis represented by the formula: 2. The linker-bound support for organic synthesis or a salt thereof according to claim 1, wherein X is (i) a halogen atom or (ii) a sulfonyloxy group optionally substituted with alkyl or aryl. (3) X is (i) a halogen atom or (ii) C
_The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is a sulfonyloxy group optionally substituted with _1-6 alkyl or C _6-14 aryl. 4. The linker-bound support for organic synthesis or a salt thereof according to claim 1, wherein X is a halogen atom. 5. The linker-bound support for organic synthesis or a salt thereof according to claim 1, wherein X is a chlorine atom. 6. The spacer represented by Y may be substituted and is composed of 1 to 20 atoms selected from the group consisting of a carbon atom, a nitrogen atom, a hydrogen atom, an oxygen atom and a sulfur atom. 2. The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is a linear divalent group. 7. The spacer represented by Y is a compound represented by the formula (i)-
_{(CH 2) p -, (} ii) - (CH 2) q-NR 1 - (C
_{H 2) r -, (iii} ) - (CH 2) q-O- (CH 2) r
-, (iv) - (CH 2) q-S- (CH 2) r -, (v)
_{- (CH 2) q-SO-} (CH 2) r -, (vi) - (CH
_{2) q-SO 2 - (} CH 2) r -, (vii) ## STR3 ## (Viii) Or (ix) Wherein p is an integer of 1 to 6, q is an integer of 1 to 3, r is an integer of 0 to 3, and R ¹ is a C _1-6 alkyl group. Item 4. A linker-bound support for organic synthesis according to Item 1, or a salt thereof. 8. The method according to claim 1, wherein the spacer represented by Y is a group represented by the formula (i)-
(CH ₂ ) q-NR ^1- (CH ₂ ) r-, or (ii) The linker bond for organic synthesis according to claim 1, wherein q is an integer of 1 to 3, r is an integer of 0 to 3, and R ¹ is a C _1-6 alkyl group. Support or salt thereof. 9. Y is a bond, —CH ₂ NH— or a compound of the formula The linker-bonded support for organic synthesis or a salt thereof according to claim 1, which is a group represented by the formula: 10. An electron-withdrawing divalent group represented by Z is
2. The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is a group having a positive Hammett's substituent constant σ value. 11. An electron-withdrawing divalent group represented by Z is
A carbonyl group, a thiocarbonyl group, a sulfonyl group, a sulfinyl group, a carbamoyl group, a thiocarbamoyl group, a halogenomethene group or a halogenoethene group.
The linker-bound support for organic synthesis according to the above or a salt thereof. 12. An electron-withdrawing divalent group represented by Z is
The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is a carbonyl group, a thiocarbonyl group, a sulfonyl group or a sulfinyl group. 13. An electron-withdrawing divalent group represented by Z is
The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is a carbonyl group or a sulfonyl group. 14. The non-electron-withdrawing divalent group represented by Z is hydroxy, amino, carboxyl, nitro, (mono- or di-C _1-6 alkyl) amino, C _1-6 alkoxy, (C _(1-6 alkyl) carbonyloxy or halogen which may be substituted with (i) a C _1-6 alkylene group, (ii) a C _2-6 alkenylene group or (iii) a C _2-6 alkynylene group. The linker-bound support for organic synthesis according to the above or a salt thereof. 15. The linker-bound support for organic synthesis or a salt thereof according to claim 1, wherein the non-electron-withdrawing divalent group represented by Z is a methylene group or an ethylene group. 16. The linker-bound support for organic synthesis or a salt thereof according to claim 1, wherein Y is a bond and Z is a sulfonyl group or a carbonyl group. 17. Y is --CH ₂ NH-- or a compound of the formula 2. The linker-bound support for organic synthesis or a salt thereof according to claim 1, wherein Z is a sulfonyl group or a carbonyl group. 18. An optionally substituted aromatic ring represented by W is (i) a halogen atom, (ii) a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms, (iii) Selected from the group consisting of a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, (iv) a C _1-6 alkylthio group optionally substituted with 1 to 3 halogen atoms, and (v) a hydroxyl group. (1) a C _6-14 aromatic cyclic hydrocarbon or (2) one or more selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, which may be substituted with one or two substituents. 2. The linker-bonded support for organic synthesis or a salt thereof according to claim 1, which is an aromatic heterocycle containing four heteroatoms or a fused ring thereof. 19. The linker-bound support for organic synthesis or a salt thereof according to claim 18, wherein the C _6-14 aromatic cyclic hydrocarbon is a benzene ring. 20. An aromatic heterocycle or a fused ring thereof is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole,
Pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran,
Benzothiophene, indole, isoindole, 1H
-Indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, benzopyran, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, α-carboline, β-carboline, 19. The linker-bound support for organic synthesis or a salt thereof according to claim 18, which is γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxatiin, thianthrene, phenanthridine or phenanthroline. 21. The monovalent electron-withdrawing group substituted on the aromatic ring represented by W is a halogen atom, a halogeno-C _1-6 alkyl group, a halogeno-C _6-14 aryl group, or a C _1-6 alkylsulfonyl. group, C _6-14 arylsulfonyl group, C _1-6 alkylsulfamoyl group, C _6-14 aryl sulfamoyl group, C _1-6 alkylsulfinyl group, C _6-14 arylsulfinyl group, C _1-6 Alkoxycarbonyl group, C _6-14
The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is an aryloxycarbonyl group, a carbamoyl group, a thiocarbamoyl group, a carboxyl group, an acyl group, a formyl group, a nitro group or a cyano group. 22. embedded image The support represented by the formula is represented by the following formula: [Wherein, Indicates a polystyrene support. The linker-bound support for organic synthesis or a salt thereof according to claim 1, which is a support represented by the formula: 23. The linker-bound support for organic synthesis or a salt thereof according to claim 22, wherein the polystyrene support is a copolymer of styrene and 0 to 5 mol% of divinylbenzene relative thereto. 24. The formula: [Wherein, Represents a polystyrene support, R represents a lower alkyl group, n represents an integer of 0 to 4, and when n is 2 or more, Rs may be the same or different and m + n ≦ 5; Has the same significance as described in claim 1. The linker-bound support for organic synthesis according to claim 1 or a salt thereof. 25. The linker-bound support for organic synthesis or a salt thereof according to claim 24, wherein X is a chlorine atom. 26. Y is a compound of the formula —CH ₂ NH— or 25. The linker-bound support for organic synthesis or a salt thereof according to claim 24, wherein Z is a sulfonyl group or a carbonyl group, and n is 0. 27. embedded image The support represented by the formula is represented by the formula: [Wherein, Indicates a polystyrene support. ] The support represented by
X is a halogen atom, Y is a bond, —CH ₂ NH— or Wherein Z is a sulfonyl group or a carbonyl group, W is a benzene ring, and m is 1 or 2.
The linker-bound support for organic synthesis according to the above or a salt thereof. 28. A compound of the formula [Wherein each symbol has the same meaning as described in claim 24. Or a salt thereof with (1) a halogenating reagent or (2) a sulfonic acid activating reagent. [Wherein, X ¹ represents (1) a halogen atom or (2) a sulfonyloxy group substituted with a lower alkyl or an aromatic ring, and each other symbol has the same meaning as in claim 24. ] The method for producing a linker-bonded support for organic synthesis or a salt thereof represented by the formula: 29. The method according to claim 28, wherein the halogenating reagent is a sulfuryl halide. 30. The formula [Wherein each symbol has the same meaning as described in claim 24. Characterized by reacting a compound represented by the formula (I) or a salt thereof with a halogenosulfonic acid. [X ² is a halogen atom, and the other symbols are as defined in claim 24.
The meaning is as described. ] The method for producing a linker-bonded support for organic synthesis or a salt thereof represented by the formula: 31. The formula [Wherein, Has the same significance as described in claim 24. And a support represented by the formula: [Wherein each symbol has the same meaning as described in claim 24. A compound represented by the formula: or a salt thereof. [Wherein each symbol has the same meaning as described above], a method for producing a linker-bound support for organic synthesis or a salt thereof. 32. The formula Wherein the symbols are as defined in claim 24. And a salt thereof, and a compound represented by the formula: [Wherein each symbol has the same meaning as described in claim 24. Wherein the compound or a salt thereof is reacted with a compound represented by the formula: [Wherein the symbols have the same meanings as described above. ] The method for producing a linker-bound support for organic synthesis or a salt thereof represented by the formula: 33. The formula: Wherein the symbols are as defined in claim 24. And a salt thereof and a compound represented by the formula: [Wherein each symbol has the same meaning as described in claim 24. Wherein the compound or a salt thereof is reacted with a compound represented by the formula: [Wherein the symbols have the same meanings as described above. ] The method for producing a linker-bound support for organic synthesis or a salt thereof represented by the formula: 34. The formula: Wherein the symbols are as defined in claim 24. And a salt thereof, and a compound represented by the formula: [Wherein each symbol has the same meaning as described in claim 24. Wherein a compound represented by the formula: or a salt thereof is reacted. [Wherein the symbols have the same meanings as described above. ] The method for producing a linker-bound support for organic synthesis or a salt thereof represented by the formula: 35. The formula: Wherein the symbols are as defined in claim 24. And a salt thereof, and a compound represented by the formula: [Wherein each symbol has the same meaning as described in claim 24. Wherein a compound represented by the formula: or a salt thereof is reacted. [Wherein the symbols have the same meanings as described above. ] The method for producing a linker-bound support for organic synthesis or a salt thereof represented by the formula: 36. The formula: Wherein the symbols are as defined in claim 24. Wherein the compound represented by the formula (I) or a salt thereof is reacted with a sulfuryl halide. [In the formula, X ² represents a halogen atom, and other symbols have the same meanings as described above. ] The method for producing a linker-bound support for organic synthesis or a salt thereof represented by the formula: 37. A method for synthesizing an organic compound, comprising using the linker-bound support for organic synthesis according to claim 1 or a salt thereof. 38. A compound of the formula Ar-OH wherein Ar represents an aromatic ring which may have a substituent. And a salt thereof, and a compound represented by the formula: [Wherein the symbols have the same meanings as in claim 1.] And the salt thereof is reacted under basic conditions with a linker-bonded support for organic synthesis represented by the following formula: [Wherein the symbols have the same meanings as described above. A substituent is introduced on Ar of the compound represented by the formula or a salt thereof, if necessary, and / or the substituent on Ar is converted into another substituent;
The resulting formula [Wherein, Ar ′ represents an aromatic ring which may have a substituent,
Other symbols are as defined above. Subjecting the compound represented by the formula (I) or a salt thereof to a reduction reaction,
Formula Ar'-H wherein Ar 'has the same meaning as described above. ]
38. The method according to claim 37, which is a method for synthesizing a compound represented by the formula or a salt thereof. (39) a palladium phosphine complex catalyst,
39. The method according to claim 38, wherein the reaction is carried out using a formate or a trialkylsilane. 40. The method according to claim 38, wherein the aromatic rings represented by Ar and Ar ′ are benzene rings. 41. The formula: [Wherein, Ar ′ represents an aromatic ring which may have a substituent,
Other symbols have the same meaning as in claim 1. Or a salt thereof. 42. The formula [Wherein, Ar ′ represents an aromatic ring which may have a substituent,
Other symbols have the same meaning as in claim 1. Wherein the compound represented by the formula: Ar'-H wherein Ar 'has the same meaning as described above. ] Or a salt thereof. 43. A novel organic compound or a salt thereof synthesized using the linker-bound support for organic synthesis according to claim 1 or a salt thereof.