WO2002070567A1

WO2002070567A1 - Novel compound, process for producing the same, and use thereof as support for solid-phase reaction

Info

Publication number: WO2002070567A1
Application number: PCT/JP2002/002108
Authority: WO
Inventors: Hiroshi Handa; Takashi Takahashi; Hiroshi Ohno; Kuniaki Kawamura; Atsushi Ohtake
Original assignee: Japan Represented By President Of Tokyo Institute Of Technology; Toray Industries, Inc.
Priority date: 2001-03-07
Filing date: 2002-03-07
Publication date: 2002-09-12
Also published as: JPWO2002070567A1

Abstract

A novel compound useful as a support capable of being used for solid-phase reactions under acidic conditions and under such conditions that sulfoxide groups are reduced. The compound is, for example, 4-hydroxymethyl-3-nitrophenoxyethylpolystyrene.

Description

Novel compound, its production method and its use as a carrier for solid phase reaction

Technical field

The present invention relates to a novel compound useful as a solid phase reaction carrier, a method for producing the same, and its use as a solid phase applied carrier.

Background art

Conventionally, synthesis of an organic compound on a solid support has been performed. For example, it is possible to chemically bind a desired amino acid sequence to a solid support such as a polystyrene resin one by one, and finally cut out the peptide from the solid support to chemically synthesize a peptide having a desired amino acid sequence. Is being done.

In such a chemical synthesis method using a solid phase reaction, an organic compound as a starting material is not directly bonded to a solid support such as a polystyrene resin, but is bonded to a solid support via a linker for solid phase reaction. Is widely practiced. As such a solid-phase reaction carrier having a linker, a so-called Wang resin has been widely used since ancient times. This Wang resin is obtained by bonding a 4-hydroxymethyl-1-phenoxymethyl group to a polystyrene resin as a linker, and a starting material to be subjected to the reaction is covalently bonded to a hydroxyl group of the linker. Further, Japanese Patent Publication No. 10-507160 discloses a solid phase reaction linker that is rapidly cleaved under mild conditions and does not generate highly reactive by-products. This linker has a benzene ring similarly to the Wang resin, and has a nitro group on the benzene ring at an ortho position as viewed from a site where the starting material to be subjected to the reaction is bonded.

However, Wang resin and the linker described in Japanese Patent Application Laid-Open No. 10-507160 cannot be reacted under acidic conditions because a part of the linker is cleaved by an acid. There is a disadvantage in that only the reaction product cannot be separated from the solid support by acid treatment later, and the reaction conditions that can be used are limited. On the other hand, a linker having a sulfoxide group on the benzene ring is known as a solid-state reaction linker usable under acidic conditions (Kiso, Y., Fukui, T., Tanaka, S., K i mura, Τ., Aka ji, Κ ·, Tetrahedron Lett., 1994, 35, 3571 -3574) 0 Mr. Kaka Shinano However, when such a linker is used, the reaction cannot be carried out under the condition that the sulfoxide group is reduced, and there is a disadvantage that the reaction conditions that can be used are limited. Further, as a solid-state reaction linker usable under acidic conditions, a linker having a nitro group on a benzene ring is known (Synlett 2000, 1241, J. Am. Chem. Soc. 2001, 123). , 3848). However, since the linker described in this report has -0-G (= 0) -CH2- as a structure corresponding to A in the formula (I) of the present application, the reduction reaction of the nitro group is carried out. If this is done, the excision reaction proceeds with the linker added to the target. Therefore, when such a linker is used, there is a drawback that the protecting group must be deprotected after performing a cleavage reaction from the solid phase carrier in order to obtain the desired product. In addition, a support for solid-phase synthesis in which bromine is introduced into wander resin has been disclosed (丄 Combi. Chem. 1999, 1, 177). However, this report only introduces bromine to check the conversion of the solid-state reaction by X-ray photoelectron spectroscopy, and does not describe use under acidic conditions.

Disclosure of the invention

Therefore, an object of the present invention is to perform a reaction under acidic conditions and under conditions of reducing a sulfoxide group, and to be useful as a solid-phase reaction carrier capable of obtaining a target product only by a cleavage reaction from the solid-phase carrier. To provide a novel compound.

As a result of intensive studies, the present inventors have found that, as a linker, a nitro group or halogen is not present at a site other than ortho when viewed from a functional group to which a starting material to be subjected to a reaction is bonded without having a sulfoxide group. It has been found that the above object can be achieved by adopting a structure containing a benzene ring, and the present invention has been completed.

That is, the present invention provides a compound of the formula (I):

(I)

In the formulas, R represents a solid support; A is _{_{- (CH 2) n -,}} - GH 2 -NH- GO- (GH 2) n -, -GH 2 - 0 - (GH 2) n - or _{_{- GO- NH- (CH 2) n}} - and it is; n is an integer from. 1 to 8; R ¹ and R ² Germany respectively Standing hydrogen, 0广¹ c υ _{8 8} a-alkyl, and is also good Ariru or substituted optionally be substituted, be a good I Ariru (GfCs) alkyl optionally; R ³ and R ⁴ are each independently Te, hydrogen, halogen, 0广0 ₈ alkyl or C _r G ₈ alkoxy,; R ⁵ is hydrogen, di- Bok port, halogen, C _r G ₈ alkyl or G _r G ₈ alkoxy,; R ⁶ Is nitro or halogen (however, when R ⁶ is bromine, R ⁵ is not hydrogen); X ¹ is halogen, — SH, — SP, —OH, — OP, one NH ₂ , one NH P ( Wherein P is a protecting or activating group, or NR ⁷ R ⁸ (where R ⁷ and R ⁸ are independently hydrogen, optionally substituted G _r C ₈ alkyl, optionally substituted Ariru, replacement which may have been good I § Li Ichiru 0广G ₈ alkyl, the optionally substituted Teroari - Le That is selected from the group) represents, or X ¹ represents a connexion force Lupo two Le such together with R ^1]

Is provided.

Further, the present invention provides R-A-Y (where Y is hydroxy or halogen, R and A are as defined in the above formula (I)) and formula (III):

RRR ⁵ , R ⁶ and X ¹ are reacted with a compound represented by the above formula (I), and if necessary, a chemical reaction is carried out on a solid phase to produce a compound represented by the above formula (I) I will provide a.

Further, the present invention provides a solid-phase reaction carrier comprising the compound represented by the above formula (I). Further, the present invention provides a compound represented by the above formula (I), wherein (i) an organic compound is bound by a covalent bond, and (ίi) a structural change of the organic compound is carried out by a chemical reaction on a solid phase. And (iii) cutting out the organic compound from a solid phase, if desired, to provide a method for producing an organic compound.

According to the present invention, a solid-phase reaction support that can be used under acidic and reducing conditions Novel compounds have been provided that can be used as bodies. When the compound of the present invention is used as a carrier for solid phase reaction, it is possible to carry out the reaction under acidic conditions or reducing conditions that could not be achieved by the conventional solid phase reaction, so that the choice of reaction conditions is widened. The effect is achieved.

BEST MODE FOR CARRYING OUT THE INVENTION

As described above, the compound of the present invention is represented by the above formula (I). In the formula (I), R represents a solid phase support. The solid support may be made of any material capable of providing a solid phase insoluble in the reaction solvent on which the reaction is performed, and capable of covalently bonding a linker described below. Various synthetic resins can be preferably used. Among them, polystyrene resin and polystyrene-polyethylene glycol (PEG) copolymer resin are preferred. In the latter case, the degree of polymerization of PEG is preferably about 50 to 200. The shape of the solid support is not limited at all, and may be any shape, preferably a bead shape, and the diameter is usually about 1 μm to 1 mm.

In formula (I), _{_{A, - (GH 2) n -}} , - GH 2 - NH-C0- (GH 2) n -, - GH 2 - 0- (GH 2) n - or - CO-NH- (GH ₂ ) _n- . n is an integer of 1 to 8. Particularly preferred _{_{A, - (GH 2) n}} -, -CH 2 -NH-C0- (CH 2) n -, - GH 2 - 0 - (CH 2) n - and is, n force 1-8, preferably Is an integer of 1 to 4, more preferably 1 or 2.

In the formula (I), R ¹ and R ² each independently represent hydrogen, C 2 -Gs alkyl, substituted or unsubstituted or substituted or unsubstituted (G1-G8) alkyl. Here, "aryl" refers to the remaining atomic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and preferable examples thereof include phenyl, biphenyl, naphthyl, and anthryl. It is not limited to these. Ariru and § Li Lumpur (G广G ₈₎ carbon atoms of Ariru moiety in the alkyl 6-1 2 is preferred. Further, Ariru or Ariru (G _r G ₈₎ alkyl may be substituted. Here, examples of the substituent include —C 1 -C ₈ alkyl, C i -C ₈ alkoxy, nitro, and halogen. In the case of an alkyl group or an alkoxy group, the number of carbon atoms is preferably 1 to 4. Halogen includes fluorine, chlorine, bromine and iodine. In addition, the number of substituents is not particularly limited, and any number is possible as long as the number is theoretically possible. For example, if aryl is phenyl, the number of substituents is 0-5, if biphenyl is 0-9, if naphthyl is 0-7, if anthranyl, it is 0-9. Further, the substituent may be on the aromatic ring, or may be on the alkyl group in the case of aryl (G-Gs) alkyl. Further, Ariru (0 0 ₈₎ carbon atoms in the alkyl moiety of the alkyl 1-4 is preferred. R ¹ and R ² are each independently preferably hydrogen, methyl or optionally substituted phenyl.

In the formula (I), R ³ and R ⁴ are each independently hydrogen, halogen, G _r G ₈ alkyl, or G factory G ₈ alkoxy. Halogen includes fluorine, chlorine, bromine and iodine. In the case of an alkyl group or an alkoxyl group, it preferably has 1 to 4 carbon atoms. It is particularly preferred when R ³ and R ⁴ are both hydrogen.

In the formula (I), R ⁵ is hydrogen, nitro, halogen, -G ₈ alkyl, or G "G ₈ alkoxy. Examples of the halogen include fluorine, chlorine, bromine and iodine. In the case of an alkoxyl group, the number of carbon atoms is preferably from 1 to 4. R ⁵ is preferably hydrogen, nitro or halogen, particularly preferably hydrogen or halogen.

In formula (I), R ⁶ is nitro or halogen. Halogen includes fluorine, chlorine, bromine and iodine. However, when R ⁶ is bromine, the above R ⁵ is not hydrogen. Especially, it is preferable that R ⁶ is nitro. A preferable example is a compound in which both R ⁵ and R ⁶ are halogen.

In the formula (I), X ¹ is halogen, one SH'-SP, one OH, -OP, -NH ₂ , one N

HP (where P is a protecting or activating group) or one NR ⁷ R ⁸ (where R ⁷ and R ⁸ are independently hydrogen, optionally substituted-^ alkyl, substituted which may be Ariru, optionally substituted § Li Ichiru 0广0 ₈ alkyl, it represents to) selected from the group consisting of heteroaryl optionally substituted, or X ¹ together with ^ Represents carbonyl. Here, the term "protecting group" refers to a group used to protect a specific functional group, and selectively reacts with the functional group to give a stable derivative in a reaction performed in a subsequent step. If desired, can be selectively displaced from the functional group without affecting other parts; This is a group that can be deprotected. Hydroxyl by a protecting group, an amino group, preferred examples of the thiol group is _{_{protected, - OTHP, -0CH 2 0CH 3}} , -0CH 2 CH = CH 2, -OCH Ph,

-OAc, -0C0 ₂ CH ₃ , -OSi (CH ₃ ) ₃ , -NHBoc, -NHF _moc , -NHCH ₂ CH = CH ₂ , -NHC0 ₂ GH ₃ ,

-NHCH ₂ CGI ₃ , -NHAc,-SGH ₂ Ph,

Examples include, but are not limited to, -STrt. In addition, an `` activating group '' is a group that enhances the reactivity of forming a covalent bond when a second functional group or a reactive group reacts with a specific functional group or a reactive site to form a covalent bond. . For example, preferred examples of the hydroxyl group by activating group is activated, - 0 (G 0) CI , -0CH 2 CI, -0 and (C0) Ar (where Ar is an optionally substituted Ariru Represent

The meanings of “caryl” and “optionally substituted” are as described above for R ¹ and R ² . Among them, a P-nitrophenyl group is preferred. ), -0 (G = NH) GGI _{3 and the} like, but are not limited thereto. The meanings of “aryl” and “optionally substituted” in the definitions of R ⁷ and R ⁸ are as described above for the description of R ¹ and R ² . The term "heteroaryl" means a carbon atom constituting the aryl ring replaced by another atom. In this case, the meaning of "aryl" is as described above for the description of R ¹ and R ^2. is there. Specific examples of heteroaryl include pyridyl, pyrrolyl, furyl, chenyl and the like. X ¹ is preferably halogen, 1 OH, 1 OP, 1 NH ₂ , 1 NHP, more preferably —OH or —OP, and particularly preferably —0H. Further, X ¹ may represent carbonyl together with R ^1, and these cases are also preferable examples. Among the compounds of the present invention represented by the above formula (I), the following formula (II):

(II)

(However, R, A, RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X ¹ have the same meaning as in the formula (I)). The description of each substituent in the formula (II) and preferred examples thereof are the same as those described above for the formula (I).

In addition, among the compounds of the present invention represented by the above formula (I), R is a polystyrene resin, A7¾-GH ₂ -or -GH ₂ CH _2- , and R ¹ , R ² , R ³ , And R ⁴ are each hydrogen, R ⁵ is hydrogen or halogen, R ⁶ is nitro or halogen, and X ¹ is 1 OH, —OP.

The compound of the present invention represented by the formula (I) is represented by R-A-Y (where Y is hydroxy or halogen, R and A are as defined in the above formula (I)) and the formula (I II):

(However, R, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X ¹ have the same meanings as those of the formula (I)). It can be manufactured by performing a chemical reaction above. The description of each substituent in Formula (III) and preferred examples thereof are the same as those described above for Formula (I).

The reaction conditions of R-A-Y with the compound represented by the formula (III) are not particularly limited, and are appropriately selected depending on the kind of each substituent. Usually, when Y is hydroxy, the Mitsunobu reaction

(However, in the formula (III), except when X ¹ is hydroxy) or the Lewis acid-catalyzed nucleophilic substitution reaction after converting hydroxy to trichloroimidate, when Y is a halogen, Is a nucleophilic substitution reaction or the like.

When Y is hydroxy and bonded to the compound represented by the formula (111) by Mitsunobu reaction As the condensation reagent, a combination of a phosphorus compound such as triphenylphosphine or tributylphosphine and an azo compound such as getyl azodicarboxylate-diisopropylcarboxylate can be used. The concentration of the compound of the formula (III) is usually 0.05 to M, preferably 0.1 to 0.3 M, and the reaction ratio of the compound of the formula (I11) to RAY is 1: ·! ~ 20: 1, preferably 2: 1 to 10: 1. The concentration of the phosphorus compound and the azo compound is usually 0.05 to 1,0 M, preferably 0,1! The molar ratio of the phosphorus compound and the azo compound to RA-Y is 1: 1 to 20: 1, preferably 1: 1 to 10: 1. Usually, the reaction temperature is from 120 ° C. to 100 ° C., preferably from 0 ° C. to 40 ° C., and the reaction time is from 0.1 ”to 48 hours, preferably from 0.5 to 24 hours. The medium is also appropriately selected according to the compound to be used, but usually, tetrahydrofuran or the like can be preferably used.

In the case where Υ is hydroxy and this is converted to trichloride imidate, it can be carried out by using trichloroacetonitrile in the presence of a base. In this case, preferred examples of the base group include diazabicycloundecene. The reaction temperature is from 1 to 50 ° C., preferably from 110 to 40 ° C. The reaction time is from 0.1 to 48 hours, preferably from 0.5 to 24 hours. The reaction solvent is THF, methylene chloride. The concentration of the base is 0.01 to 2 M, preferably 0.03 to 1 M, and the reaction ratio of the base to R-A-Y is 1: 1 to 50: 1, preferably 1 to 1 in molar ratio. : 1 to 30: 1. The concentration of trichloroacetonitrile is 0.01 to 3 M, preferably 0.1%. The molar ratio of trichloroacetonitrile to R-A-Y is 1: "! To 50: 1, preferably 10: 1 to 30: 1.

The reaction of the triclomouth imidate with the compound of formula (III) can be achieved in the presence of a Lewis acid. Preferable examples of the Lewis acid include a trifluoroporangetyl ether complex. The reaction temperature is -50 to 100 ° C, preferably 0 to 40 ° C, and the reaction time is 0.1 to 48 hours, preferably 0.1 "! To 24 hours. The reaction solvent is methylene chloride or cyclohexane. Preferred is a mixed solvent of xane and methylene monochloride, etc. The concentration of the Lewis acid is 0.005 to 0.3 M, preferably 0.01 to 0.1 M, and the reaction ratio of the Lewis acid to trichloroimide is 0.05: 1 to 20: 1, preferably about 0.1: 1 to 10: 1. When Y is a halogen and is bonded to the compound represented by the formula (III) by a nucleophilic substitution reaction, it is preferable to use a base by a conventional method. Examples of a preferable base include cesium carbonate, sodium carbonate, potassium carbonate, and the like. Diazabicycloundecene, potassium t-butoxide, and the like. An additive may be added, and sodium iodide can be preferably used as the additive. The concentration of the base is about 0.01 to 1 M, preferably about 0.1 to 0.3 M, and the reaction ratio of the base to R-AY is 1: 1 to 20: 1 in molar ratio, preferably 2: 1 to 10: Is one. The reaction solvent is appropriately selected according to the reagent to be used, but usually DMF, acetonitrile, THF and the like can be preferably used. Usually, the reaction temperature is from 120 to 100 ° C, preferably from 20 to 80 ° C, and the reaction time is from 1 to 48 hours, preferably from 5 to 24 hours. The concentration of the compound of the formula (III) is 0.01 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the compound of the formula (II I) to R-A-Y is 1: "!" After reacting the compound of the formula (111) with 1-6- 丫, a substituent introduction reaction on the solid phase, A desired one of the compounds represented by the formula (I) can also be produced by converting the introduced substituent into another substituent, etc. A reaction for introducing a substituent into an aromatic ring or a substituent Reactions for converting to other substituents are well known in the art, and these can be performed on a solid phase by applying well-known methods.

The compound of the present invention can be used as a carrier for solid phase reaction. In the present specification, when the compound of the present invention is used as a solid phase in a solid phase reaction, the resin or the like represented by R above is called a “solid support”, and the structure other than R in the formula (I) The part is called a linker, and the entire compound represented by the formula (I) in which the linker is bound to a solid support is called a solid-phase applied carrier.

When the compound of the present invention is used as a carrier for a solid phase reaction, (i) an organic compound serving as a starting material to be subjected to the reaction is bonded to a portion other than R and A of the compound represented by the formula (I); (Ii) Structural conversion of the organic compound is performed by a chemical reaction on the solid phase, and then (iii) the organic compound having the desired structural change is cut out from the solid phase.

The carrier for solid phase reaction of the present invention exhibits particularly excellent effects when the step (M) includes a chemical reaction under acidic conditions. Here, the acidic condition means that the reaction is carried out on a solid phase. Not all steps of the reaction need to be performed under acidic conditions, meaning that at least one step is performed under acidic conditions.

In addition, as the carrier for solid phase reaction, a compound including a case where R ⁶ is bromine and R ⁵ is hydrogen in the above general formula (I), that is, a compound represented by the following general formula (IV) Things can also be used.

(IV)

In the formulas, R represents a solid support; A is _{_{- (CH 2) n -,}} - GH 2 - NH- GO- (GH 2) n -, - GH 2 -0- (GH 2) n - or _{_{- GO- NH- (CH 2) n}} - and it is; n is 1 foot J an integer of 8; R ¹ and R ² are independently, respectively therewith hydrogen, - G ₈ alkyl, optionally substituted good be Ariru or optionally substituted Ariru (0厂G ₈₎ alkyl; R ³ and R ⁴ are each independently hydrogen, halogen, G _r G ₈ alkyl or C-G ₈ alkoxy; R ⁵ is hydrogen, nitro, halogen, G factory G ₈ alkyl, or G _r G ₈ alkoxy; R ⁶ is nitro or halogen; X ¹ is halogen, one SH, -SP, -OH, one OP , -NH ₂ , -NH P (where P is a protecting group or an activating group), or -NR ⁷ R ⁸ (where R ⁷ and R ⁸ are independently hydrogen, optionally substituted Gi-G ₈ alkyl, optionally § substituted Reel, optionally substituted aryl G represents "alkyl, optionally substituted heteroaryl"), or X ¹ together with R ¹ represents carbonyl.

The description and preferred examples of each substituent in the formula (IV) are as described above for the general formula (I).

Organic compounds as a starting material, it is preferred to attach the X ^1. When X ¹ forms a ketone or aldehyde together with R ¹ or R ¹ and R ² , it is preferable to bond this ketone or aldehyde with a starting material. Binding of X ¹ and the functional group in the starting material, depending on the type of the functional group, leaving at be carried out by a conventional method. After binding the starting material to the carrier for solid phase reaction of the present invention, the starting material is subjected to a desired structural transformation. This structural change is not limited at all, and may be any such as addition of a structure by condensation or the like, addition or conversion of a substituent, or cleavage of a starting material. In the solid-phase reaction support of the present invention, a part of the linker is not cleaved under acidic conditions or under the conditions of reducing sulfoxide, so that a part of the linker of the conventional solid-state reaction support is cleaved. Under the conditions, a reaction for structural transformation can be performed.

After completing the desired structural transformation, the product is cut out from the solid-phase reaction support, if desired. When R ⁶ is a nitro group, this step is carried out by reducing the nitro group and then subjecting it to acidic conditions, or after reducing the nitro group, acylating or sulfonylating the amino group and then subjecting it to acidic conditions. It can be carried out. Here, the reduction of the nitro group can be preferably performed as follows.

The reducing agent is preferably a low-valent metal, more preferably tin dichloride dihydrate, and the reaction solvent is preferably DMF, DMAA, N-methylpyrrolidinone, or the like. The reaction temperature is usually from 120 to 80 ° C, preferably from 0 to 40 ° C, and the reaction time is usually from 0.5 to 24 hours, preferably from 1 to 8 hours. The molar ratio of the reducing agent to the dinitro group is usually 1 ::! To 50: 1, preferably 3 ::! ~ 20: 1. The concentration of the reducing agent is usually from 0.05 to 1 M, preferably from 0.1 to 0.5 M.

When the amino group is acylated, the acyl group is not particularly limited. Preferred examples thereof include an acetyl group, a propionyl group, a benzoyl group, a phenylaminocarbonyl group, a propylaminocarbonyl group, and a cyclohexylaminocarbocarbonyl group. A phenyl group, a phenylaminothiocarbonyl group, an ethylaminothio group, an ethoxycarbonyl group, and a phenyloxycarbonyl group.

The acylation can preferably be performed as follows. The acylation reaction for forming an amide is carried out by condensing various carboxylic acids with an amino group by a conventional method, and a condensing agent is used if necessary. As the condensing agent, a combination of diisopropylcarbodiimide and N-hydroxybenzotriazole, benzotriazole-1

-Yloxy-tripyrrolidino-phosphonium hexafluorophosph A combination of ether and disopropylethylamine is used, but is not limited thereto. The concentration of the carboxylic acid is 0.05 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the carboxylic acid to the amino group is 1 は to 50: 1, preferably 5: 1 to 30: in molar ratio. The concentration of the condensing agent is 0.05-33, preferably 0.1-11, and the reaction ratio of the condensing agent to the amino group is 1: 1-50: 1, preferably 5: 1-30 in molar ratio. The reaction temperature is from 150 to 100 ° C., preferably from 0 to 50 ° C., and the reaction time is from 0.1 to 48 hours, preferably from 1 to 24 hours. , DMF, DMAA, etc. The amide-forming acylation reaction can also be carried out by reacting with sulfonic acid halide in the presence of a base. Usually, diisopropylethylamine, triethylamine, etc. are used. Concentration 0.05~3 M, preferably, 0. "! The molar ratio of the carboxylic acid halide to the amino group is 1: 1 to 50: 1, preferably 5: 1 to 30: 1. The concentration of the base is 0.05 to 3 M, preferably 0.1 to 11, and the molar ratio of the base to the amino group is 1: ·! To 50: 1, preferably 5: 1 to 30: 1. The reaction temperature is -50 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. The reaction solvent is not particularly limited, but DMF, DMAA and the like are preferably used.

The acylation reaction for forming perylene or thioperia can be carried out by reacting an amino group with various isocyanates or isothiocynates by a conventional method. The concentration of the isocyanate or isothiocyanate is 0.05 to 3 M, preferably 0.1 to 1 Μ, and the reaction ratio of the isocyanate or isothiocyanate to the amino group is 1: ·! 5050: 1, preferably 5: 1 to 30: 1. The reaction temperature is between 150 and 100 ° C, preferably between 0 and 50 ° C, and the reaction time is between 0.1 and 48 hours, preferably between 1 and 24 hours. The reaction solvent is not particularly limited, but methylene chloride and the like are preferably used.

When the amino group is sulfonylated, the sulfonyl group is not particularly limited, but preferred examples thereof include methanesulfonyl, ethanesulfonyl, phenylsulfonyl, and p-toluenesulfonyl. Sulfonates forming sulfonamides The reaction can be carried out by reacting a lamino group with various sulfonyl chlorides in the presence of a base by a conventional method. As the base, diisopropylethylamine and the like are preferable. The concentration of the sulfonyl chloride is 0.05 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the sulfonyl chloride to the amino group is 1: 1 to 50: 1, preferably 5: 1 to 5: 1. The base concentration is 0.05 to 2 M, preferably 0.1 to 1 M, and the reaction ratio of the base to the amino group is 1: 1 to 50: 1, preferably 5: 1 to 30: The reaction temperature is 1 to 100 ° C., preferably 0 to 50 ° C., and the reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. And methylene chloride are preferably used.

After the reduction of the nitro group, or after the amino group generated by the reduction is acylated or sulfonylated, the product is cleaved from the solid-phase reaction carrier under acidic conditions. Acids used under acidic conditions include TFA, acetic acid, hydrochloric acid and the like. Examples of the solvent include methylene chloride, THF, water, methanol and the like. Further, an additive may be used, and as the additive, triethylsilane, triisobutyl silane, dimethylsulfide and the like are preferably used. As the acidic condition, usually 1% to 100% TFA, 1% to "! 00% acetic acid, 1% to saturated hydrochloric acid are preferably used. The reaction temperature is usually 0 to 100 ° C, and preferably <0. The reaction time is usually 0.1 to 24 hours, preferably 0. "! ~ 2 hours.

When R ⁶ is a halogen, the product can be cleaved from the solid-phase reaction support by reducing or substituting the halogen with an aryl group and then subjecting the product to acidic conditions. Here, reduction of the halogen or substitution with the aryl group can be preferably carried out as follows.

The reduction of halogen can be carried out by a conventional method under conditions using a palladium catalyst. The palladium catalyst is preferably a zero-valent palladium bonded with a suitable ligand, and more preferably tetrakis (triphenylphosphine) palladium. An aqueous sodium carbonate solution is preferably used as the base, and dimethylformamide dimethoxetane is preferably used as the solvent. The concentration of the palladium catalyst is 0.001-1 M, preferably 0.005-0.1 M, The reaction ratio with respect to halogen is 0.001: "! To 5: 1, preferably 0.01: 1 to 2: 1. The concentration of the base is 0.01 to 3 M, preferably 0.1 to 1 M, and the halogen of the base is The reaction ratio with respect to the molar ratio is 1: ·! To 30: 1, preferably 2: to 10: 1. The reaction temperature is usually 20 to 120 ° C, preferably 70 to 100 ° C. The reaction time is generally 0.5 to 48 hours, preferably 2 to 24 hours.

In addition, the reaction of substituting a halogen with an aryl group can be carried out by a coupling reaction using a palladium catalyst by a conventional method. The palladium catalyst is preferably a zero-valent palladium bonded with a suitable ligand, more preferably tetrakis (triphenylphosphine) palladium. As the arylating reagent, aryl (trialkyl) tin diaryl boric acid or the like is used, and among them, phenyl boric acid is preferable. As the base, an aqueous solution of sodium carbonate or triethylamine is preferably used, and as the solvent, dimethylformamide or the like is preferably used. The concentration of the palladium catalyst is 0.001-1 M, preferably 0.005-0.1 M, and the reaction ratio of the palladium catalyst to halogen is 0.001: 1-5: 1, preferably 0.01: 1-2: 1 in molar ratio. is there. The concentration of the base is 0.01 to 3 M, preferably 0.1 to 1 M, and the reaction ratio of the base to the halogen is 1: 1 to 30: 1, preferably 2: 1 to 10: 1 in molar ratio. The concentration of aryl boric acid is 0.01 to 3 M, preferably 0.2 to 1 M, and the reaction ratio of aryl boric acid to halogen is 1: 1 to 30: 1, preferably 2: "! To 10: 1 in molar ratio. The reaction temperature is usually 20 to 120 ° C., preferably 70 to 100 ° C., and the reaction time is generally 0.5 to 48 hours, preferably 2 to 24 hours. Can be performed in the same manner as described above.

After the excision, the product can be recovered by separating the solid phase and the liquid phase as in the case of the known solid-phase reaction carrier. The recovered product can be further purified by a conventional method, if necessary, to remove the remaining reagents. However, one advantage of the solid phase reaction is that the product can be obtained only by separating the liquid phase from the solid phase, and as shown in the examples below, the reagents for cutting out by vacuum drying etc. The cut-out can be removed by vacuum drying, for example with trifluoroacetic acid, so that a product with the desired purity can be obtained by simply removing the solvent. It is preferably carried out using an acid.

Example

Hereinafter, the present invention will be described more specifically based on examples. The pole-shaped part in the chemical formulas described in the following examples indicates polystyrene.

Example 1

Synthesis of 4-formyl-1--2-trophenoxymethyl polystyrene

Hydroxymethyl polystyrene (0.68 mmol / g, 1.01 g, 0.68 mmol) was combined with 4-hydroxy xy-3-nitrobenzaldehyde (337 mg, 2.04 ol) and triphenylphosphine (282 mg, 1.02 ol). It was suspended in THF (10 ml). Getyl azodicarponic acid (40% toluene solution, 445 A <I, 1.02 mmol) was added and the mixture was shaken at room temperature for 2 hours. The mixture was filtered, and the resin was washed with THF (5 mU twice), DMF (5 ml, 5 times), THF-H20 (1: 1) (8 m and 3 times), methanol (5 ml, 5 times), THF (5 ml, 5 times), washed with methylene chloride (5 m, 5 times), and dried in vacuo to obtain the target compound (1.25 g).

IR (cm ^-1 ): 1680 (aldehyde), 1521 (nitro)

Example 2

Synthesis of 4-hydroxymethyl 1-2-2-trophenoxymethyl polystyrene

Example 4 one formyl one 2-nitro-phenoxyethanol polystyrene (514 mg, ca 0.28瞧ol) obtained in 1 was suspended in TH F (5 ml), sodium borohydride (145 mg, 3.84 stroke ₀ | ) And methanol (0.5 ml) were added and shaken at room temperature for 1 hour. The mixture is filtered and the resin is methanol (5 ml, 2 times), DMF (5 m, 5 times), methanol (5 ml, 5 times), THF (5 m, 5 times), methylene chloride ( (5 times 5 m) and dried under vacuum to obtain the target compound (572 mg). IR (cm ^-1 ): disappearance of aldehyde (1680ctif ¹ )

Example 3

Synthesis of 4-formyl-1-nitrophenoxyshethyl polystyrene

Hydroxyethyl polystyrene (0.99 mmol / g, 1.995 g, 1.98 mmol) was added to 4-hydroxy-3--3-nitrobenzaldehyde (1.07 g, 6.4 mol), and triphenylphenyl phosphine (891 mg, 3.4 mmol) and suspended in THF (20 ml). Jetylazodicarboxylic acid (40% toluene solution, 1.56 ml, 3.4 mmol) was added and the mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was washed with DMF (10 ml, 5 times), methanol (10 m, 5 times), THF (10 ml, 5 times), methylene chloride (10 m, 5 times), and vacuum. Drying was performed to obtain the target compound.

IR (cm ^-1 ): 1679 (aldehyde)

Example 4

Synthesis of 4-Hydroxymethyl-2-nitrophenoxethyl Polystyrene

The 4-formyl-1-2-nitrophenoxethyl polystyrene obtained in Example 3 was suspended in HF (20 ml), and sodium borohydride (750 mg, 19.8 mmol) and methanol (2 ml) were added. Shaking was performed at room temperature for 1 hour. The mixture was filtered, and the resin was treated with methanol (10 ml, 2 times), DMF (10 m, 5 times), methanol (10 ml, 5 times), THF (10 ml, 5 times), methylene chloride (10 ml, 5 times) ) And dried under vacuum to obtain the target compound (2.30 g).

IR (cm- ^1): aldehyde (Ιδ θοηΓ ¹⁾ disappearance

Example 5

Synthesis of 2-promo 4-formylphenoxetyl polystyrene

Hydroxyethyl polystyrene (0.99 mmol / g, 244 mg, 0.24 mmol) with 3-pro 1

Mo-4-Hydroxybenzaldehyde (144 mg, 0.72 mol) and triphenylphosphine (98 mg, 0.36 mol) were added, and suspended in THF (2 ml). Getyl azodicarboxylic acid (40% toluene solution, 165 I, 0.36 country ol) was added and the mixture was shaken at room temperature for 2.5 hours. The mixture was filtered and the resin was washed with DMF (2 ml, 5 times), methanol (2 ml, 5 times), THF (2 m, 5 times), methylene chloride (2 m, 5 times), Vacuum drying was performed to obtain the target compound (275 mg).

IR (cm ^-1 ): 1676 (aldehyde)

Example 6

Synthesis of 2-bromo-1-hydroxymethylphenoxethyl polystyrene

The 2-promo 4-formylphenoxicetyl polystyrene (275 mg, ca 0.24 country ol) obtained in Example 5 was suspended in THF (2 ml), and sodium borohydride (47.6 mg, 1.21 mmol), methanol ( 0.2 ml) and shaken at room temperature for 1 hour. The mixture is filtered and the resin is methanol (2 ml, 2 times), DMF (2 m, 5 times), methanol (2 ml, 5 times), THF (2 m, 5 times), methylene chloride (2 m) 5 times) and dried under vacuum to obtain the target compound (281 mg).

IR (cm ^-1 ): disappearance of aldehyde (1676 τΓ ¹ )

Example 7

Synthesis of 2,6-Jib Mouth 4-I-formylphenoxshetyl polystyrene

Hydroxyethyl polystyrene (0.99 mmol / g, 239 mg, 0.24 mol) was added with 3,5-dibromo-4-hydroxybenzaldehyde (183 mg, 0.64 mol) and triphenylphosphine (89 mg, 0.34 mmol). In THF (2 ml). Jethylazodicarponic acid (40% solution in toluene, 154 to 0.34 mmol) was added and the mixture was shaken at room temperature for 62 hours. The mixture is filtered and the resin is treated with DMF (2 m then 5 times), methanol (2 ml, 5 times), HF (2 m then 5 times), methylene chloride (2 m then 5 times). After washing and vacuum drying, the target compound (319 mg) was obtained.

IR (cm ^-1 ): 1682 (aldehyde)

Example 8

Synthesis of 2, 6-dibromo-1-hydroxymethylphenoxethyl polystyrene

The 2,6-dibromo-4-formylphenoxicetyl polystyrene (304 mg, ca 0.23 mol) obtained in Example 1 was suspended in THF (2 ml), and sodium borohydride (46 mg, 1.22 mol. ) And methanol (0.2 ml) were added, and the mixture was shaken at room temperature for 45 minutes. The mixture was filtered, and the resin was washed with methanol (2 m twice), DMF (2 ml, 5 times), methanol, THF, methylene chloride, and dried in vacuo to give the target compound (306 mg) .

IR (cm- ¹ ): Aldehyde (1682 cm- ¹ ) disappears

Example 9

Loading of Naltrexone on 4-Hydroxymethyl-12-nitrophenoxetyl Polystyrene

4-Hydroxymethyl-2-nitrophenoxetyl polystyrene (807 mg), naltrexone (882 mg, 2.56 country ol), and triphenylphosphine (357 mg, 1.36 mmol) are added to THF (8 ml). Suspended. Getylazodicarboxylic acid (40% toluene solution, 620 I, 1.36 concen- tration) was added, and the mixture was shaken at room temperature for 21 hours. The mixture was filtered, and the resin was washed with DMF (10 ml, 5 times), methanol (10 m, 5 times), THF (10 ml, 5 times), methylene chloride (10 ml, 5 times), and dried in vacuo. After drying, a resin (1.04 g) was obtained.

IR (cm— ¹ ): 1517 (nitro), 1708 (ketone).

Example 10 Excision of Naltrexone Supported on 4-Hydroxymethyl-1-nitrophenoxethyl Polystyrene

DMF solution (2 ml) of tin dichloride dihydrate (100 mg) was added to naltrexone (32 mg) supported on 4-hydroxymethyl-2-ditrophenoxetylpolystyrene obtained in Example 9, and the mixture was added to room temperature. For 1 hour, and washed with DMF (2 ml, 5 times), methanol (2 m, 5 times), THF (2 m, 5 times), and methylene chloride (2 m, 5 times). To the obtained resin, a methylene chloride solution (1 ml) of tosyl chloride (80 mg) and a methylene chloride solution (1 ml) of diisopropylethylamine (140 μI) were added, and the mixture was shaken at room temperature for 1 hour. did. Washed with DMF (2 mU 5 times), methanol (2 ml, 5 times), THF (2 ml, 5 times), methylene chloride (2 ml, 5 times). A 50% trifluoroacetic acid solution in methylene chloride (2 ml) was added to the obtained resin, and the mixture was shaken for 30 minutes. After filtration, the resin was washed with methylene chloride (2 ml), combined with the filtrate, and dried under vacuum to obtain naltrexone trifluoroacetate (3.0 mg).

LC-MS data:

Column: HYPERS IL ODS 5 ^ m, 4 * 125 mm (GL Sciences Inc.)

Developing solvent 20 mM ammonium acetate aqueous solution: methanol = 70:30 (0 min) → 10:90 (6 min-12 min)

Retention time 4.3 min

MS = 342 (M + H)

Example 1 1

Indole synthesis on solid phase

To a solution of 4-hydroxymethyl-1-nitrophenoxetyl polystyrene-supported nartrexone (202 mg), 5% trifluoroacetic acid in methylene chloride (4 ml) and phenylhydrazine (53I) were added and shaken at room temperature for 18 hours. I shouted. Methylene chloride (2 mU 2 times), DMF (2 ml, 5 times), methanol (2 m 5 times), THF (2 mU 5 times), methylene chloride (2 ml, 5 times) Wash, vacuum Drying was performed to obtain resin A (310 mg).

IR (cm ^-1 ): ketone (1708 cm- ¹ ) disappearance,

To the resin A (51 mg) obtained above, a DMF solution (1 ml) of tin dichloride dihydrate (52.8 mg) was added, and the mixture was shaken at room temperature for 21 hours. Wash), methanol (2 m then 5 times), THF (2 m then 5 times), methylene chloride (2 m then 5 times). Methylene chloride (1 ml), tosyl chloride (39 mg), and diisopropylethylamine (70I) were added to the obtained resin, and the mixture was shaken at room temperature for 4 hours. The resultant was washed with DMF (2 m to 5 times), methanol (2 m to 5 times), THF (2 m to 5 times), and methylene chloride (2 m to 5 times), and dried under vacuum. A 50% trifluoroacetic acid solution in methylene chloride (2 ml) was added to the obtained resin, and the mixture was shaken for 30 minutes. After filtration, the resin was washed with methylene chloride (2 ml), combined with the filtrate, and dried under vacuum to obtain naltrudol tritrifluoroacetate (4.4 mg). LG-MS data:

Column: HYPERS I L ODS 5 Aim, 4 * 125 mm (GL Sciences Inc.)

Developing solvent: 20 mM ammonium acetate aqueous solution: methanol = 70: 30 (0 min) → 10:90 (6 min-12 min)

Retention time: 5.8 min

MS = 415 (M + H)

Example 1 2

N-benzylation of indole on solid phase

To the resin A (52 mg) obtained in Example 11, sodium hydride (55% in oil, 22 mg, 438 umo \) and DF (1 ml) were added, and the mixture was shaken at room temperature for 1 hour. Benzyl bromide (11 I, 88 umol) was added and shaken for 20 hours. The reaction mixture was filtered, and the resin was washed with DMF (2 ml, 5 times), methanol (2 ml, 5 times), THF (2 ml, 5 times), methylene chloride (2 ml, 5 times), and dried in vacuo. Was done. DMF (1 ml) and tin dichloride.dihydrate (58.2 mg) were added to the obtained resin, and the mixture was shaken at room temperature for 8 hours. The reaction mixture was filtered, and the resin was washed with DMF (2 ml, 5 times), methanol (2 ml, 5 times), THF (2 ml, 5 times), methylene chloride (2 ml, 5 times), and dried in vacuo. Went. To the resulting resin was added trisyl chloride (42.2 mg), methylene chloride (1 ml), and diisopropylethylamine (00 μl), and the mixture was shaken at room temperature for 15 hours. The reaction mixture was filtered, and the resin was washed with DMF (5 x 2 mU), methanol (5 x 2 mU), THF (5 x 2 mU), methylene chloride (5 x 2 mU), and dried in vacuo. went. A 50% trifluoroacetic acid methylene chloride solution (2 ml) was added to the obtained resin, and the mixture was added for 30 minutes. Shake. The reaction mixture was filtered, the resin was washed with methylene chloride (2 ml), combined with the filtrate, and dried under vacuum to obtain N-benzylnaltruindole trifluoroacetate (7.4 mg).

LG-MS data:

Column: HYPERS IL ODS 5 ^ m, 4 * 125 mm (GL Sciences Inc.)

Developing solvent: 20 mM ammonium acetate aqueous solution: methanol = 70:30 (0 min) → 10:90 (6 mm-12 mm)

Retention time: 7.3 min

MS = 505 (M + H)

Comparative Example 1

Naltrexone was carried on the Wang resin by performing the same operation as in Example 9 except that the solid-phase reaction carrier was replaced with a conventionally widely used Wang resin. Next, indole synthesis was attempted on the solid phase by the same operation as in Example 11, but the excision of naltrexone proceeded and indole synthesis could not be performed on the solid phase.

Comparative Example 2

Loading and cutting of naltrexone on photolinker

Naltrexone was supported on the photolinker by performing the same operation as in Example 9 except that the photolinker having the above structure was used as the solid phase reaction carrier. Further, when the same operation as in Example 10 was performed to cut out the naltrexone, the naltrexone was cut out from the carrier at the stage when the reduction operation with tin dichloride was performed. This indicates that the photolinker cannot be used for the reaction under such reducing conditions.

In addition, the same operation as in Example 11 was performed on naltrexone supported on the photolinker to synthesize indole on the solid phase. An indole compound was cut out in the liquid. This indicates that the photolinker cannot be subjected to the reaction under such acidic conditions.

Claims

The scope of the claims

1. Formula (I)

(I)

In the formulas, R represents a solid support; A is _{_{- (GH 2) n -,}} - GH 2 - NH- GO- (GH 2) n -, - GH 2 - 0- (CH 2) n - Or -CO-NH- (GH ₂ ) _n- ; n is an integer of 1 to 8; R ¹ and R ² are each independently hydrogen, GG ₈ alkyl, optionally substituted R ³ and R ⁴ are each independently hydrogen, halogen, G _r G ₈ alkyl, or G _r G ₈ alkoxy; R ⁵ is aryl, optionally substituted or aryl (-Gs) alkyl; Is hydrogen, nitro, halogen, G _r C ₈ alkyl, or C ^ -Gs alkoxy; R ⁶ is nitro or halogen (provided that when R ⁶ is bromine, R ⁵ is not hydrogen); X ¹ is halogen, 1 SH, -SP, -OH, — OP, NH-NHP (where P is a protecting or activating group), or 1 NR ⁷ R ⁸ (where R ⁷ and R ⁸ are independent And hydrogen, optionally substituted -Gs alkyl, optionally substituted aryl, optionally substituted aryl, GfCs alkyl, optionally substituted heteroaryl), or X ¹ together with R ¹ To represent carbonyl]

A compound represented by the formula:

2. The compound according to claim 1, wherein the formula (I) is represented by the following formula (II).

(Π)

^{(Wherein, R, A, RR 2,} R 3, R 4, R 5, R6 and X ¹ formula (I) synonymous) 3. R ¹ and R ² are each independently hydrogen, methyl or substituted, R ³ and R ⁴ are each hydrogen; and R ⁵ is hydrogen, nitro, Or R ⁶ is nitro or halogen, and X ¹ is halogen, one OH, one OP, one NH ₂ , one NH P (where P is a protecting or activating group), or Or the compound according to claim ¹ , wherein X ¹ and R ¹ are taken together to be carbonyl.

4. The compound according to claim 1, wherein the compound is R ⁶ nitro.

5. The compound according to claim 1, wherein R ⁵ is halogen and R ⁶ is halogen.

6. A is _{_{- (GH 2) n -,}} -CH 2 -NH-C0- (CH 2) n -, or _{_{- GH 2 - 0- (CH 2}} ) n - and is, n is 1-4 integer The compound according to any one of claims 1 to 5, which is:

7. The compound according to any one of claims 1 to 6, wherein R is a polystyrene resin or a polystyrene-polyethylene glycol copolymer resin.

8. R is a polystyrene resin, A is -GH ₂ -or -GH ₂ GH _2- , R ¹ , R ² , R ³ , and R ⁴ are each hydrogen, and R ⁵ is hydrogen or halogen. 7. The compound according to claim 6, wherein R ⁶ is nitro or halogen, and X ¹ is 1 OH, —OP, wherein P is a protecting or activating group.

9. R-A-Y (where Y is hydroxy or halogen, R and A are as defined in formula (I) of claim 1) and formula (III):

(However, R, A, R ¹ , R ² , RRR ⁵ , R. and X ¹ have the same meanings as in formula (I) according to claim 1)

The method for producing a compound according to claim 1, wherein the compound is reacted with a compound represented by the following formula, and a chemical reaction is carried out on a solid phase, if necessary.

10. A solid-phase reaction carrier comprising the compound according to any one of claims 1 to 8.

1 1. Part other than R and A of the compound according to any one of claims 1 to 8 To (i) an organic compound by a covalent bond, (ii) a structural transformation of the organic compound by a chemical reaction on a solid phase, and then (M i) an organic compound having a structural transformation as desired. For producing an organic compound, comprising cleaving a compound from a solid phase.

1 2. R ⁶ is a nitro group, and the step (ίίί) is carried out by reducing the nitro group, then acylating or sulfonylating as required, and then subjecting to acidic conditions. 11. The method described in 1.

1 3. R ⁶ is halogen, wherein step a (ii i), was reduced or § Li Lumpur replace the halogen, then the method of claim 1 1, wherein the performing by the acidic conditions.

14. The method according to any one of claims 11 to 13, wherein the step (ί) is performed by bonding the organic compound to X ¹ of the formula (I).

1 5. The following formula [IV]:

(IV)

Wherein R is a solid support; Α is-(GH ₂ ) _n- , -CH ₂ -NH-C0- (CH ₂ ) _n --CH ₂ -0- (CH ₂ ) _n -or _{_{- GO- NH- (CH 2) n}} - and it is; n is an integer from. 1 to 8; R ¹ and R ^2, respectively it independently hydrogen, C _r G ₈ alkyl, optionally substituted be Ariru or optionally substituted Ariru (C -GG) alkyl; R ³ and R ⁴ are each independently hydrogen, halogen, G-Gs alkyl or C _r G ₈ alkoxy,; R ⁵ is hydrogen, nitro, halogen, GFG ₈ alkyl or C _r G ₈ alkoxy,; R ⁶ is nitro or halogen; X ¹ is a halogen, one SH, one SP, -OH, -OP, - NH 2, One NH P (where P is a protecting or activating group), or one NR ⁷ R ⁸ (where R ⁷ and R ⁸ are independently hydrogen, optionally substituted -C ₈ alkyl, Ary that may be replaced , Optionally substituted Ariru _G -ΰ ΰ alkyl, represents to) selected from the group consisting of Teroariru to optionally substituted, or X ¹ represents a connexion carbonyl such together with R ^1]

(Ii) a covalent bond of an organic compound to a portion other than R and A of the compound represented by (ii), and performing a structural transformation of the organic compound by a chemical reaction under acidic conditions on a solid phase; Next, (i ί) a method for producing an organic compound, which comprises slicing the organic compound which has been subjected to structural transformation as desired from a solid phase.

16. Use of the compound according to any one of claims 1 to 8 for producing a carrier for solid phase reaction.