WO2008059960A1

WO2008059960A1 - Method for producing quarter-pyridine derivative and intermediate of quarter-pyridine derivative

Info

Publication number: WO2008059960A1
Application number: PCT/JP2007/072287
Authority: WO
Inventors: Yong Wang
Original assignee: Jsr Corporation
Priority date: 2006-11-16
Filing date: 2007-11-16
Publication date: 2008-05-22
Also published as: JPWO2008059960A1; JP5407332B2

Abstract

Disclosed is a method for producing a quarter-pyridine derivative wherein a bipyridine derivative represented by the formula (1) below is reacted with an organic metal intermediate represented by the formula (2) below by using a transition metal catalyst, thereby producing a quarter-pyridine derivative represented by the formula (3) below. This method enables to produce a quarter-pyridine derivative easily.

Description

Specification

Method for producing quarterpyridine derivative and its intermediate

Technical field

TECHNICAL FIELD [0001] The present invention relates to a production method of a quarterpyridine derivative and an intermediate thereof, and more particularly to a production method of a quarterpyridine derivative and an intermediate thereof capable of easily producing a quarterpyridine derivative.

Background art

[0002] A dye-sensitized solar cell including a dye, a semiconductor electrode, an electrolyte, and a metal electrode is called a Gretzell cell, and is considered to be advantageous in terms of cost as compared with a conventional silicon solar cell. Not only that, it is also excellent in terms of flexibility and design, and is expected to be applied in a wide range of fields. However, the photoelectric conversion efficiency is still not sufficient, and the current situation is that development of high-performance dyes is required for practical use. Various metal complexes and organic dyes (metal-free) are being considered as dyes. Ruthenium complexes are promising in terms of power and performance, and many ruthenium complexes have already been studied and developed. Broadly speaking, bipyridine complexes (for example, see Non-Patent Documents 1, 2 and 3), terpyridine complexes (for example, see Non-Patent Document 4), quaterpyridine complexes (for example, Non-Patent Documents) 5, 6 and Patent Document 1). The bipyridine and terpyridin complexes are generally specific in that the two NCS ligands are in the cis form, and the quarterpyridine complex is in the trans form. The petals become broader and the absorption on the longer wavelength side becomes stronger.

[0003] As the quarterpyridine ruthenium complex, a ruthenium complex of a quarterpyridine derivative represented by the following formula (1B) is disclosed (for example, see Patent Document 1).

[0004] [Chemical 1]

[0005] The "COOEt" group of the quarterpyridine derivative is converted to a Ru complex (dye) and then converted to a "COOH" group by hydrolysis. The COOH group is a TiO battery for dye-sensitized solar cells.

2 Substituent necessary for adsorbing the dye to the electrode. The alkyl group of R is important for the weather resistance of dye-sensitized solar cells. The quarterpyridine derivative is obtained by synthesizing a biviridine derivative (organic metal) represented by the following formula (2A) from a biviridine derivative represented by the following formula (1A), and then a biviridine derivative represented by the following formula (3A): The compound was synthesized by reacting with a bipyridine derivative represented by the following formula (2A).

[0006] [Chemical 2]

(1 A) (2 A) (3 A)

[0007] However, the above-described method for producing quarterpyridine derivatives has not always produced the desired quarterpyridine derivative easily.

Non-Patent Document 1: J. Phys. Chem. B, 2003, 107, 8981-8987

Non-Patent Document 2: Langmuir, 2002, 18, 952-954

Non-Patent Document 3: Langmuir, 2001, 17, 5992- 5999

Non-Patent Document 4: J. Am. Chem. Soc., 2001, 123, 1613-1624

Non-Patent Document 5: Inorg. Chem., 2002, 41, 367-378

Non-Patent Document 6: Inorg. Chem., 2006, 45, 4642-4653

Patent Document 1: JP-A-2005-190875

Disclosure of the invention

[0008] In the production method of the quarterpyridine derivative, 1A and 3A to be produced as intermediates are extremely difficult to synthesize. Therefore, the quarterpyridine derivative cannot be easily produced by the above production method. Furthermore, when it was assumed that it would be used industrially, it was considered that it was more difficult to manufacture.

[0009] The present invention has been made in view of the above-mentioned problems, and can be easily derived from quarterpyridine. It is characterized by providing a production method of a quarterpyridine derivative and an intermediate thereof capable of producing a product.

[0010] The production method of the quarterpyridine derivative of the present invention and the intermediate thereof for solving the above-mentioned problems are as follows.

[0011] [1] A biviridine derivative represented by the following formula (1) and an organometallic intermediate represented by the following formula (2) are reacted with each other using a transition metal catalyst. A method for producing a quarterpyridine derivative, wherein the quarterpyridine derivative is represented.

[0012] [Chemical 3]

(In Formula (1), Z is a monovalent organic group, Y is a perfluoroalkylsulfonyl group, R ³ and R ⁴ are each independently a monovalent organic group, and are bonded to each other to form a cyclic structure. To form an ayo lei group.)

[0013] [Chemical 4]

(In Formula (2), M is a metal, R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group, L is a ligand, and n is; It is an integer of 3.)

[0014] [Chemical 5]

(In Formula (3), Z is a monovalent organic group, R ¹ and are each independently hydrogen, an alkyl group, an aryl group or a substituted alkyl group, and R ³ and R ⁴ are each independently A monovalent organic group that may be bonded to each other to form a cyclic structure.

[2] The acetal and ester of the quarterpyridine derivative represented by the following formula (3) are hydrolyzed to formyl group and carboxyl group, respectively, and the resulting formyl group is oxidized to form a carboxyl group by the following formula A method for producing a quarterpyridine derivative, wherein the quarterpyridine derivative represented by (4) is produced.

[0016] [Chemical 6]

(In Formula (3), Z is a monovalent organic group, R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group, and R ³ and R ⁴ are each Independently a monovalent organic group, which may be bonded to each other to form a cyclic structure.

[0017] [Chemical 7]

(In Formula (4), R ¹ and IT are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group.)

[0018] [3] A biviridine derivative represented by the following formula (1):

[0019] [Chemical 8]

(In Formula (1), Z is a monovalent organic group, Y is a perfluoroalkylsulfonyl group, R ³ and R ⁴ are each independently a monovalent organic group, and are bonded to each other to form a cyclic structure. To form Ayorayo.)

[0020] [4] An organometallic intermediate represented by the following formula (2):

[0021] [Chemical 9]

(In Formula (2), Μ is a metal, R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group or a substituted alkyl group, L is a ligand, and η is; It is an integer of 3.

)

[0022] [5] A kuoi derivative represented by the following formula (3):

[0023] [Chemical 10]

(In Formula (3), Ζ is a monovalent organic group, R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group, and R ³ and R ⁴ are each Independently a monovalent organic group, which may be bonded to each other to form a cyclic structure.

[0024] The method for producing a quarterpyridine derivative of the present invention easily produces a predetermined intermediate in the production process, and finally produces a quarterpyridine derivative using them. It becomes possible to produce derivatives. It is possible to produce it stably industrially.

[0025] In addition, since the intermediate of the quarterpyridine derivative of the present invention can be easily synthesized, the quarterpyridine derivative can be easily produced as a whole by using these for the production of the quarterpyridine derivative. Therefore, it is possible to produce industrially stably.

BEST MODE FOR CARRYING OUT THE INVENTION

[0026] Next, the best mode for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and is within the scope of the present invention. It should be understood that design changes and improvements can be made as appropriate based on normal knowledge.

[0027] (Method for producing quarterpyridine derivative A)

The production method of the quarterpyridine derivative (quarterpyridine derivative A) of the present invention includes the biviridine derivative (biviridine derivative A) of the present invention represented by the above formula (1) and the present invention represented by the above formula (2). An organometallic intermediate (organometallic intermediate 1) is reacted with a transition metal catalyst to produce the quarterpyridine derivative (quarterpyridine derivative A) of the present invention represented by the above formula (3). . The reaction is preferably carried out by adding organometallic intermediate 1, biviridine derivative A and a transition metal catalyst to an organic solvent in an inert gas atmosphere. The reaction temperature is preferably 20 to; 180 ° C is preferred for the reaction time;! To 72 hours is preferred. Examples of transition metal catalysts include organic palladium catalysts and organic nickel catalysts. Among these, phosphine, dibenzylideneacetone, an organopalladium catalyst having a acetyl group or a halogen group is preferable as a ligand. Specifically, Pd (PPh), Pd

3 4 2

(dba), Pd (〇Ac) ゝ Pd (PPh) CI, etc. (Ph is a phenyl group, dba is

3 2 3 2 2

Nylideneacetone, Ac represents a acetyl group). The amount of transition metal catalyst with respect Bibirijin derivative A represented by the above formula (1);! That it ~ 20 mole ^_0/0 is preferred instrument 2-5 mole ^_0/0 Further preferred. During the reaction, salts such as LiCl, CsF, Cul, AsPh are added.

Three

Addition is preferable because the yield of the reaction may increase. The addition amount of a salt such as LiCl is preferably from! To 5 mol, and more preferably from! To 3 mol, per 1 mol of bipyridine derivative A. The organic solvent is preferably a hydrocarbon solvent or an amide solvent. For example, mention can be made of toluene, xylene, DMF and the like. The addition amount of the organic solvent is preferably 0.1 to 5 L with respect to 1 mol of the biviridine derivative A; more preferably! To 3 L.

In the above formula (2), examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, an i-butyl group, an s-butyl group, and a t-butyl group. it can. Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the substituted alkyl group include a benzyl group and a methoxymethyl group. Among these, as R ¹ and R ² , hydrogen, methyl group, pentyl group, nonyl group, and heptadecyl group are preferable. As the metal (M), tin, zinc, boron and the like are preferable. Examples of the ligand L include an alkyl group, an aryl group, an alkoxyl group, chlorine, bromine and iodine.

[0029] (Quotapyridine derivative A)

One embodiment of the quarter pyridine derivative of the present invention obtained by the method for producing quarter pyridine derivative A of the present invention is a quarter pyridine derivative (quarter pyridine derivative A) represented by the above formula (3).

In the above formula (3), Z is a monovalent organic group, R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group or a substituted alkyl group, and R ³ and R ⁴ are Are each independently a monovalent organic group and may be bonded to each other to form a cyclic structure. Examples of the alkyl group for R ¹ and R ² include a methyl group, an ethyl group, a propyl group, an i propyl group, a butyl group, an i butyl group, an s butyl group, and a t butyl group. Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the substituted alkyl group include a benzyl group and a methoxymethyl group. Among these, as R ¹ and R ² , hydrogen, a methyl group, a pentyl group, a Noel group, and a heptadecyl group are preferable. Examples of Z that is a monovalent organic group include an alkyl group and an aryl group. Examples of the alkyl group include an ethyl group, a propyl group, an i-propyl group, a butyl group, an i-butyl group, and a cyclohexyl group. Z is preferably an i propyl group. Examples of R ³ and R 4 include an alkyl group and an aryl group. The alkyl group is preferably an alkyl group having! Further, when R ³ and R ⁴ are bonded to each other to form a cyclic structure is "one CH C (CH) CH one" and the like are preferable. [0031] The quarterpyridine derivative A of the present invention further becomes an intermediate of the quarterpyridine derivative B represented by the above formula (4). The quarterpyridine derivative A can be synthesized from the organometallic intermediate 1 of the present invention synthesized from the following biviridine derivative B and the biviridine derivative A of the present invention, and therefore can be easily synthesized in high yield. . Therefore, it is possible to easily produce the quarterpyridine derivative B with a high yield, and thereby it is possible to produce it industrially and stably.

[0032] (Method for producing quarterpyridine derivative B)

In the production method of the quarterpyridine derivative (quarterpyridine derivative B) represented by the above formula (4), first, the acetal and ester of the quarterpyridine derivative A represented by the above formula (3) are hydrolyzed to formyl. The formyl group obtained in step 1 / is oxidized to form a carboxyl group, thereby producing quarterpyridine derivative B. Hydrolysis is acid hydrolysis and can be performed by stirring in an aqueous solution in the presence of an acid. The oxidation can be performed by using a general oxidizing agent. Examples of acids that can be used for acid hydrolysis include acetic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, TFA, and the like. The amount of the acid used is preferably 100 to 500 mL with respect to 1 mol of the quarterpyridine derivative A. The amount of water is preferably 100 to 500 mL with respect to 1 mol of quarterpyridine derivative A. Adding an aldehyde compound such as pyridinecarboxaldehyde during the reaction is preferable because the yield of the reaction increases. The amount of the aldehyde compound added is preferably 1 to 10 moles per mole of quarterpyridine derivative A. The reaction temperature is preferably 0 to 100 ° C. The reaction time is preferably 0.5 to 24 hours. Examples of the oxidizing agent that can be used for the oxidation of aldehydes include chromates, permanganates, silver oxide, and chlorites. The amount of oxidizing agent used is preferably 0.5 to 5 moles per mole of quarterpyridine derivative A. The reaction temperature is preferably 0 to 50 ° C. The reaction time is preferably! ~ 12 hours. By this reaction, the target compound can be obtained in a yield of 50 to 80 mol%.

[0033] In the above formula (4), the alkyl group may be linear or branched, preferably having 1 to 20 carbon atoms. Specifically, methyl group, ethyl group, propyl group, i-propyl group, butyl group Examples include i-butyl group, S-butyl group, and t-butyl group. As the aryl group, a phenyl group, a naphthyl group, and the like are specifically mentioned which preferably have 120 carbon atoms. The substituted alkyl group may be a straight chain or a branched chain which preferably has 120 carbon atoms. Specific examples include a benzyl group and a methoxymethyl group. Among these, as R ¹ and R ² , hydrogen, methyl group, pentyl group, nonyl group, and heptadecyl group are preferable.

[0034] As shown below, the biviridine derivative A represented by the above formula (1) and the organometallic intermediate 1 represented by the above formula (2) can be easily synthesized, as described above. The quarterpyridine derivative A represented by the above formula (3) can be easily synthesized from the bibilidine derivative A and the organometallic intermediate 1, and the quarterpyridine represented by the above formula (4) can be synthesized from the quarterpyridine derivative A. Derivative B can be easily synthesized. Therefore, according to the present invention, the quarterpyridine derivative A represented by the above formula (3) and the quarterpyridine derivative B represented by the above formula (4) can be easily produced in high yield. By using these production methods, it is possible to produce industrially and stably.

[0035] (Bibiridin derivative A)

The bipyrrolidine derivative of the present invention, which is an intermediate in the production method of the quarterpyridine derivative of the present invention, is a biviridine derivative (biviridine derivative A) represented by the above formula (1).

[0036] In the formula (1), examples of the monovalent organic group (Z) include an alkyl group and an aryl group. Examples of the alkyl group include an ethyl group and a propyl group, and examples of the perfluoroalkylsulfonyl group include “CF SO —” and “C F SO—”.

3 2 4 9 2

it can. Examples of R ³ and R ⁴ include an alkyl group. As the alkyl group, those having 14 carbon atoms are preferred. Further, when R ³ and R ⁴ are bonded to each other to form a cyclic structure, “one CH 2 C (CH 2) 2 CH—” or the like is preferable.

2 3 2 2

[0037] The biviridine derivative A of the present invention is a synthetic equivalent of the above-mentioned biviridine derivative 3A, and is an intermediate of the quarterpyridine derivative of the present invention. In the present invention, biviridine derivative A, which is an intermediate in the production of quarterpyridine derivatives, can be easily synthesized in a high yield by a simple operation using only a less toxic reactant. one Generally, when synthesizing a quarterpyridine derivative, there are many examples of using a pyridine compound having a chlorine group or a bromine group. However, when introducing a chlorine group or a bromine group, POC1 or POBr is used.

3 Three highly toxic reactants are required, and the reaction operation is complicated at the same time. On the other hand, when a perfluoroalkyl sulfonate group is introduced instead of a chlorine group or a bromine group, it can be synthesized in a high yield by a simple reaction operation using a general-purpose reagent. Therefore, it is possible to easily and efficiently produce quarterpyridine derivatives with high yield.

[0038] (Method for producing biviridine derivative A)

In the production method of the biviridine derivative A of the present invention, first, a pyridine derivative 2 represented by the following formula (6) in which a formyl group is protected by reacting a pyridine derivative represented by the following formula (5) with an alcohol is generated. Let The reaction is carried out in an organic solvent in the presence of an acid while stirring an alcohol and a pyridine derivative represented by the following formula (5). As the alcohol, diol is preferable, and 2,2-dimethyl-1,3-propanediol is particularly preferable. The reaction temperature is preferably 0 to 120 ° C, and the reaction time is preferably 1 to 72 hours. As the organic solvent, dichloromethane, toluene and the like are preferable. Examples of acids include p-toluenesulfonic acid, sulfuric acid, phosphoric acid, and the like. The addition amount of 2,2-dimethylpropanediol is preferably from! To 5 mol, and more preferably from 2 to 2 mol, based on 1 mol of the pyridine derivative represented by the following formula (5). The addition amount of the acid is preferably 0... To 3 moles, more preferably 2 to 2 moles, with respect to 1 mole of the pyridine derivative represented by the following formula (5). By this reaction, the target pyridine derivative 2 can be obtained in a yield of 80 to 95 mol%.

[0039] [Chemical 11]

(5) (6) (7)

In formulas (6) and (7), M is a metal, L is a ligand, n is an integer from !! to 3, R ³ and R ⁴ are each independently a monovalent organic group And may be bonded to each other to form a cyclic structure. Examples of R ³ and R ⁴ include alkyl groups and aryl groups. wear. The alkyl group is preferably an alkyl group having 1 to 4 carbon atoms. In addition, when — and R ⁴ are bonded to each other to form a cyclic structure, “—CH 2 C (CH 2) 2 CH 1” or the like is preferable.

2 3 2 2

Examples of the ligand L include an alkyl group, aryl group, alkoxyl group, chlorine, bromine and iodine. As the metal (M), tin, zinc, boron and the like are preferable.

Next, the pyridine derivative 2 and the metal compound are reacted to produce the organometallic intermediate 2 represented by the above formula (7). The reaction is carried out by adding and stirring the pyridine derivative 2, strong base and activator in an organic solvent under an inert gas atmosphere, and then adding and stirring the metal compound. Nitrogen or argon is preferable as the inert gas. As the organic solvent, those which are stable to a strong base are preferred, and hydrocarbon solvents or ether solvents are particularly preferred. Hexane and toluene are particularly preferred as the hydrocarbon solvent. Particularly preferred ether solvents are jetyl ether, THF, and t-butyl methyl ether. The amount of the organic solvent is preferably 2 to 4 L, more preferably! To 5 L with respect to 1 mol of the pyridine derivative represented by the above formula (6). As the strong base, n-butyl lithium, s-butynole lithium, t-butyl lithium, lithium tetramethylpiperidine and the like are preferable. The addition amount of the strong base is preferably 0 · !! to 5 mol; more preferably! To 3 mol with respect to 1 mol of the pyridine derivative represented by the above formula (6). As the activator, lithium dimethylamino ethoxide (Me N (CH 3) OLi, Me represents a methyl group) and boron trifluoride are preferable. activation

2 2 2

The addition amount of the agent is preferably 0. !!-5 mol, more preferably! -3 mol, per 1 mol of the pyridine derivative represented by the above formula (6). The stirring before the addition of the metal compound is preferably performed at a temperature of −100 to 30 ° C., more preferably 80 to −40 ° C. The stirring time is preferably 0.;! To 10 hours; more preferably! To 3 hours. As the metal compound, an organic tin compound, an organic boron compound, or a zinc compound is preferable. The organotin compound is preferably a trialkyltin halide, particularly tributyltin chloride. As the organoboron compound, trialkoxyborane is preferred, and triisopropoxyborane is particularly preferred. As the zinc compound, zinc halide is preferred, and zinc chloride is particularly preferred. The addition amount of the organometallic compound is preferably 0... To 10 mol, more preferably 1 to 4 mol, relative to 1 mol of the pyridine derivative represented by the above formula (6). Stirring after the addition of the metal compound is preferably performed at a temperature of 100 ° C to 100 ° C, more preferably 80 ° C to 30 ° C. Stirring time is 0.;! ~ 24 hours 2 to 4 hours is more preferable. If the temperature is too high, side reactions may occur, and if the temperature is too low, the reaction may be slow. By this reaction, the organometallic intermediate 2 can be obtained with a yield of 40 to 90 mol%.

[0042] Next, the organometallic intermediate 2 and the pyridine derivative A represented by the following formula (8) are reacted with each other using a transition metal catalyst, and the biviridine derivative of the present invention represented by the above formula (1) is used. (Biviridine derivative A) is produced. Examples of the transition metal catalyst include an organic palladium catalyst and an organic nickel catalyst. Among these, an organic palladium catalyst having a phosphine, dibenzylideneacetone, acetyl group or halogen group as a ligand is preferable. Specific examples include Pd (PPh), Pd (dba), Pd (OAc), Pd (PPh) CI, etc. (Ph

3 4 2 3 2 3 2 2

Is a phenyl group, dba is dibenzylideneacetone, and Ac is a acetyl group. The transition metal catalyst is preferably used in an amount of 0.01 to 0.20 mono to 1 mole of the organometallic intermediate 2 represented by the above formula (7), and 0.02 to 0.05. More preferably, it is mono. The reaction is preferably performed between the organometallic intermediate 2 and the pyridine derivative A in the presence of the transition metal catalyst in an organic solvent under an inert gas atmosphere. As the organic solvent, a hydrocarbon solvent, an ether solvent, or an amide solvent is preferable. For example, toluene, xylene, THF, DMF, DMAc, or the like is preferably used. The amount of the organic solvent used is preferably 0.;! To 5 L with respect to 1 mol of the organometallic intermediate 2 represented by the above formula (7); Further preferred. The reaction temperature is preferably 15 to 200 ° C, and more preferably 50 to 180 ° C. If the temperature is too high, side reactions may occur, and if the temperature is too low, the reaction may be slow. The reaction time is preferably:! -72 hours. In addition, adding a salt such as LiCl, CsF, Cul, AsPh during the reaction may increase the reaction yield.

Three

More preferable. The addition amount of the salt such as LiCl is preferably 1 to 5 mol per mol of the organometallic intermediate 2 represented by the above formula (7); Is more preferable. By this reaction, the biviridine derivative A of the present invention can be obtained in a yield of 5 to 30 mol%.

[0043] (Pyridine derivative A)

The pyridine derivative, which is an intermediate in the production method of the biviridine derivative A and is an intermediate in the production method of the quarterpyridin derivative of the present invention, is represented by the following formula (8). This is a pyridine derivative (pyridine derivative A).

[0044] [Chemical 12]

In the above formula (8), Ζ is a monovalent organic group, and 、 is a perfluoroalkylsulfonyl group. The monovalent organic group (Ζ) is preferably an alkyl group having 1 to 10 carbon atoms or an aryl group. Specific examples include an ethyl group, a propyl group, an i propyl group, a butyl group, an i butyl group, a cyclohexyl group, and a phenyl group. As the perfluoroalkylsulfonyl group, “CF The ability to list “SO—”, “CF SO—”, etc.

3 2 4 9 2

[0046] (Production method of pyridine derivative A)

The method for producing the pyridine derivative A comprises esterifying the carboxyl group of the pyridine derivative represented by the following formula (9), substituting the hydrogen of each of the two hydroxyl groups with a perfluoroalkylsulfonyl group, and then formula (8) This produces a pyridine derivative represented by the formula (pyridine derivative A).

[0047] [Chemical 13]

(

9)

[0048] The esterification of the carboxyl group of the pyridine derivative represented by the above formula (9) can be performed by reacting the carboxyl group with an alcohol while refluxing at 70 to 150 ° C in the presence of an acid. preferable. Examples of acids used include sulfuric acid and p-toluenesulfonic acid. The amount of acid added is preferably 0 · ;! to 2 mol force S, more preferably 0.5 · 1 mol to 1 mol of the pyridine derivative represented by the above formula (9). Examples of alcohols include ethanol, 2-propanol, and cyclohexanol. The amount of alcohol added is preferably 0... To 2 mol, more preferably 0.5 to 1 mol, per 1 mol of the pyridine derivative represented by the above formula (9). In this reaction, alcohol is also a reaction solvent. This reaction can be obtained the desired ester in 40 to 90 mole ^_0/0 yield

^ o [0049] As a method of substituting the hydrogen of each of the two hydroxyl groups of the pyridine derivative represented by the above formula (9) with a perfluoroalkylsulfonyl group, (CF 2 SO 4) 0 may be used in an inert gas atmosphere. , (CF 2 SO 4) O and other perfluoroalkylsulfonic anhydrides and salts

3 2 2 4 9 2 2

A method of stirring in an organic solvent to which a group is added at 40 to 30 ° C. for 1 to 12 hours is preferable. Examples of the organic solvent include dichloromethane, black mouth form, pyridine and the like. The amount of the perfluoroalkylsulfonic anhydride added is preferably 1 to 4 moles, more preferably 2 to 3 moles per mole of the pyridine derivative represented by the above formula (9). Examples of the base include triethylamine, pyridine and the like. The addition amount of the base is preferably 2 to 3 moles, more preferably! To 4 moles per mole of the pyridine derivative represented by the above formula (9). The amount of the organic solvent used is preferably 0.;! To 10 L, more preferably 0.5 to 2 L, more preferably /, relative to 1 mol of the pyridine derivative represented by the above formula (9). This reaction can Rukoto force S to obtain a pyridine derivative substituted with the purpose of per full O b alkylsulfonyl group 80-95 Monore ^_0/0 yield. This reaction is preferably performed after the esterification of the carboxyl group.

[0050] (Organic metal intermediate 1)

In the organometallic intermediate 1 represented by the above formula (2) used in the production method of the quarterpyridine derivative A of the present invention, R ¹ and R ² are each independently hydrogen, alkyl group, aryl group or The alkyl group is a substituted alkyl group, and the alkyl group may be a straight chain or a branched chain, preferably having carbon atoms of !!-20. Specific examples include methyl, ethyl, propyl, open-ended pill, butyl, i-butyl, s-butyl, and t-butyl. Specific examples of the aryl group include phenyl and naphthyl which preferably have 1 to 20 carbon atoms. The substituted alkyl group may be a straight chain or branched chain, preferably having 1 to 20 carbon atoms. Specific examples include benzyl and methoxymethyl. Among these, as R ² , hydrogen, methyl group, pentyl group, Noel group, and heptadecyl group are particularly preferable. M is a metal, and examples of the metal include tin, zinc, and boron. L is a ligand, and examples of the ligand include an alkyl group, an alkoxyl group, chlorine and bromine.

[0051] (Method for producing organometallic intermediate 1) The organometallic intermediate 1 represented by the above formula (2) is produced by reacting the biviridine derivative B represented by the following formula (10) with a metal compound. The organometallic intermediate 1 can be obtained by reacting a biviridine derivative B represented by the following formula (10), metal magnesium, and a metal compound in an organic solvent under an inert gas atmosphere. At this time, the timing for adding the metal compound is not limited. That is, the power that can be obtained by synthesizing a Grignard reagent of biviridine derivative B first, and then adding a metal compound and conducting a metal exchange reaction. It can also be obtained by the so-called Barbier type method in which the bibilidine derivative B and magnesium are added to the reaction from the beginning and the reaction is carried out. A method for producing a Grignard reagent (not limited to this, known methods such as “J. Org. Chem., 2004, 69, 1401—1404”) can be used. The exchange reaction is not particularly limited, and it is possible to use the publicity method described in “J. Org. Chem., 2004, 69, 1401—1404”, etc. As the organic solvent used in the reaction, Ether solvents such as THF, jetyl ether, etc. The amount of the organic solvent used is 0.;! To 1 L with respect to 1 mol of the biviridine derivative B represented by the following formula (10). The strength S is preferable, and it is more preferably 0 · 3 to 0.5 · L monolayer.The magnesium metal used in the reaction is 0.5 to 5 mol per 1 mol of bibilidine derivative 表 represented by the following formula (10). It is preferably 5 mol ;! to 3 mol is more preferable, and the reaction temperature is preferably 0 to 40 ° C. 15 Further, the metal compound used for the metal exchange reaction is preferably an organotin compound, an organoboron compound, or a zinc compound, and the organotin compound is preferably a trialkyltin halide, particularly tributyltin chloride. The organoboron compound is preferably trialkoxyborane, particularly preferably triisopropoxyborane, and the zinc compound is preferably zinc halide, particularly preferably zinc chloride. It is preferable that the biviridine derivative B represented by (10) is 0.5 to 5 mol per mol, more preferably! To 3 mol, and the solvent used for the metal exchange reaction is , THF, diethyl ether, DMF, etc. The amount of solvent used is 0. 1 mol of bipyridine derivative B represented by the following formula (10). The power is preferably from 1 to 1 L, more preferably from 0.4 to 0.6 L. The reaction temperature is preferably from 0 to 140 ° C. [0052] (Bibiridin derivative B)

The biviridine derivative, which is an intermediate in the production method of the organometallic intermediate 1 and an intermediate in the production method of the quarterpyridin derivative of the present invention, is a biviridine derivative (biviridine derivative B) represented by the following formula (10). It is.

[0053] [Chemical 14]

In formula (10), R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group. The alkyl group may be a straight chain or branched chain, preferably having 1 to 20 carbon atoms. Specific examples include methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, and t-butyl. Specific examples of aryl groups include phenyl and naphthyl, which preferably have 1 to 20 carbon atoms. The substituted alkyl group may be a straight chain or branched chain, preferably having 1 to 20 carbon atoms. Specific examples include benzyl and methoxymethyl. Among these, as R ¹ or R ² , hydrogen, methyl group, pentyl group, nonyl group, and heptadecyl group are particularly preferable.

[0055] In the method for producing a quarterpyridine derivative of the present invention, the bipyridine derivative B, which is an intermediate in the production of the quarterpyridine derivative, can be easily synthesized, so that the quarterpyridine derivative can be easily produced. This makes it possible to produce industrially and stably.

[0056] (Production method of biviridine derivative B)

In the production method of the biviridine derivative B, first, a pyridine derivative represented by the following formula (11) is reacted with a metal compound to produce an organometallic intermediate 3 represented by the following formula (12). The reaction is performed by adding a pyridine derivative represented by the following formula (11), a strong base, and an activator to an organic solvent under an inert gas atmosphere and stirring, and then adding a metal compound and stirring. Do. Nitrogen or argon is preferable as the inert gas. As the organic solvent, those which are stable to strong bases are preferred, and hydrocarbon solvents or ether solvents are particularly preferred. Hexane and toluene are particularly preferred as the hydrocarbon solvent. ether As the solvent, jetyl ether, THF, or t-butyl methyl ether is particularly preferable. The amount of the organic solvent is preferably 2 to 4 L (liter), more preferably 1 to 5 L (liter) with respect to 1 mol of the pyridine derivative represented by the following formula (11). Strong bases include n-butyllithium, s-butynolethium, tert-butylenolithium,

preferable. The addition amount of the strong base is preferably from 0.;! To 5 mol, more preferably from 3 to 3 mol, based on 1 mol of the pyridine derivative represented by the following formula (11). Activating agents include lithium dimethylamino ethoxide (Me N (CH 2) OLi, Me represents methyl group), boron trifluoride

2 2 2

Is preferred. The addition amount of the activator is preferably 0 .;! To 5 mol, more preferably! To 3 mol, per 1 mol of the pyridine derivative represented by the following formula (11). The stirring prior to the addition of the metal compound is preferably performed at a temperature of 100 to 30 ° C, more preferably 80 to 40 ° C. The stirring time is preferably 0.;! ~ 10 hours; more preferably! ~ 3 hours. As the metal compound, an organic tin compound, an organic boron compound, or a zinc compound is preferable. As the organic tin compound, trialkyltin halide is preferred, and tributyltin chloride is particularly preferred. As the organoboron compound, trialkoxyborane is preferred, and triisopropoxyborane is particularly preferred! /. As the zinc compound, zinc halide is preferred, and zinc chloride is particularly preferred. The addition amount of the organometallic compound is preferably 0.;! To 10 mol, more preferably! To 4 mol, per 1 mol of the pyridine derivative represented by the following formula (11). The stirring after the addition of the metal compound is preferably 100 to; preferably 100 to 100 ° C, more preferably 80 to 30 ° C. The agitation time is 0.;!-24 hours is preferred, and 2-4 hours is more preferred. If the temperature is too high, side reactions may occur, and if the temperature is too low, the reaction may be slow. By this reaction, organometallic intermediate 3 represented by the following formula (12) can be obtained in a yield of 60 to 90 mol%.

[Chemical 15]

(1 1) (1 2) (1 3) (1 4) [0058] In the production method of biviridine derivative B, the chlorine group of the product bipyridine derivative B represented by the above formula (10) is derived from the chlorine group of the pyridine derivative represented by the above formula (11). To do. Therefore, it is necessary that the chlorine group reaction of the pyridine derivative represented by the above formula (11) does not change, and the production method of biviridine derivative B has one feature that this chlorine group does not change. There is. Biviridine derivative B has a force S that is required to have a halogen group for the subsequent reaction, a halogen group force S, and if it is a bromine group or an iodine group, If a strong base is used for this, the halogen group such as bromine reacts, and the biviridine derivative B cannot be easily produced. On the other hand, if it is a chlorine group, it does not react even when a strong base is used, and the biviridine derivative B can be easily synthesized by the reaction step shown in the production method of the biviridine derivative B. In addition, pyridine derivatives having a chlorine group are cheaper and easier to obtain than pyridine derivatives having a bromine group or an iodine group.

[0059] Next, the organometallic intermediate 3 represented by the above formula (12) and the pyridine derivative 1 represented by the above formula (13) are reacted using a transition metal catalyst. To produce the biviridine derivative represented (biviridine derivative B). Examples of the transition metal catalyst include an organic palladium catalyst and an organic nickel catalyst. Among these, an organic palladium catalyst having phosphine, dibenzylideneacetone, a acetyl group or a halogen group as a ligand is preferable. Specifically, Pd (PPh), Pd (dba), Pd (OAc), Pd (PPh) CI, etc.

3 4 2 3 2 3 2 2 (Ph represents a phenyl group, dba represents a dibenzylideneacetone, and Ac represents a acetyl group). The amount of the catalyst used is preferably 0.;! To 20 mol%, more preferably 2 to 5 mol%, relative to the pyridine derivative 1 represented by the above formula (13). Further, the organometallic intermediate 3 is preferably 0.5 to 2 monoreca S, more preferably 0.8 to 1.2 moles per mole of the pyridin derivative 1. The reaction is preferably performed between the organometallic intermediate 3 and the pyridine derivative 1 in an organic solvent in an inert gas atmosphere, in the presence of the transition metal catalyst, and under reflux conditions. As the inert gas, nitrogen or argon is preferable. As the organic solvent, hydrocarbon solvents, ether solvents, or amide solvents are preferable. For example, toluene, xylene, THF, DMF, DMAc and the like are preferably used. The amount of the organic solvent is preferably 0.1 to 5 L (liter), more preferably 1 to 3 L (liter) with respect to 1 mole of pyridine derivative 1. . The reaction temperature is preferably 15 to 200 ° C., 50 to; more preferably 180 ° C. If the temperature is too high, side reactions may occur, and if the temperature is too low, the reaction may be slow. The reaction time is preferably;!-72 hours. During the reaction, LiCl CsF Cul AsPh etc.

Addition of the salt 3 is preferable because the reaction yield may be increased. The addition amount of a salt such as LiCl is preferably 15 mol per mol of pyridine derivative 1; more preferably 3 to 3 mol. By this reaction, the force S can be obtained to obtain a biviridine derivative (biviridine derivative B) in a yield of 50 80 mol%.

[0060] In addition to the above method, R ¹ and R ² are CH and biviridine derivatives and halogenated alkyls.

Three

Bibilidine derivative B represented by the above formula (10) can be produced by reacting with kill. This reaction is preferably carried out by the method described in “: Langmuir 2002 18 952-954”. The reaction is carried out by adding a biviridine derivative and lithium diisopropylamide (LDA) in an organic solvent under an inert gas atmosphere and stirring at a temperature of −80 to 40 ° C .; Is preferably added and stirred at −400 ° C. for 26 hours. By this reaction, the hydrogen atom of the methyl group of the biviridine derivative can be replaced with the alkyl group contained in the alkyl halide to obtain the biviridine derivative B of the above formula (10). The addition amount of LDA is preferably ˜3 mol, more preferably 2.0 2.5 mol, with 1 mol of the biviridine derivative. As the organic solvent, it is preferable to use tetrahydrofuran (THF), jetyl ether or the like. The amount of the organic solvent is preferably 15 L, more preferably 24 L, relative to 1 mol of the pyridine derivative. The halogenated alkyl preferably has 120 carbon atoms. Specific examples include butane bromide, octane bromide, and hexadecane bromide. The addition amount of the alkyl halide is more preferably 23 to 3 mol, preferably from! To 5 mol, when the bibilidine derivative is 1 mol.

[0061] In the above formulas (11) to (; 14), R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group or a substituted alkyl group, M is a metal, and L is a coordination group. N is an integer from! To 3; X ¹ is bromine, iodine or trifluoromethanesulfonate (“one OSO CF

twenty three

]). n varies depending on the metal M. For example, when M is Sn, n = 3, when M is B, n = 2, and when M is Zn, n = 1. The alkyl group may be a straight chain or a branched chain, preferably having 120 carbon atoms. Specifically, methyl group, ethyl group, propylene Group, i-propyl group, butyl group, i-butyl group, S-butyl group, t-butyl group, etc. Specific examples of the aryl group include a phenyl group and a naphthyl group, which preferably have 1 to 20 carbon atoms. The substituted alkyl group preferably has 1 to 20 carbon atoms and may be linear or branched. Specific examples include benzyl and methoxymethyl. Among these, as R ¹ or R ² , hydrogen, methyl group, pentyl group, nonyl group, and heptadecyl group are particularly preferable. The metal (M) is preferably tin, zinc, boron or the like. Examples of the ligand L include an alkyl group, an alkoxyl group, chlorine, bromine and the like.

[0062] (Method for producing quarterpyridine derivative C)

Another method for producing quarterpyridine derivative C represented by the following formula (16) is to react bibilidine derivative B represented by the above formula (10) with an organic metal to produce the above formula (2). ), An organometallic intermediate 1 represented by the following formula (15) is reacted with a biviridine derivative represented by the following formula (15) using a transition metal catalyst: This produces the quarterpyridine derivative C. Since the production method of the quarterpyridine derivative C is thus produced using the biviridine derivative represented by the above formula (10), it is necessary to use a difficult-to-produce biviridine derivative represented by the above formula (1A). Therefore, the quarterpyridine derivative C can be easily produced. The quarter pyridine derivative C is produced using a biviridine derivative B represented by the above formula (10) and a biviridine derivative represented by the following formula (15) which is a biviridine derivative having a more general structure. As a biviridine derivative represented by the following formula (15), when a quarterpyridine derivative is produced using the biviridine derivative A represented by the above formula (1), it is represented by the above formula (3). This is a method for producing quarterpyridine derivative A.

[0063] [Chemical 16]

[0064] The above formula (15), in (16), R ¹ and R ² are each independently hydrogen, alkyl group, a § aryl group or a substituted alkyl group, a monovalent organic group each R is independently J is an integer from 1 to 3, k is an integer from 1 to 4, and X ¹ is bromine, iodine, or “one OSO CF”.

There are 2 3. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an i propyl group, a butyl group, an i butyl group, an S butyl group, and a t butyl group. Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the substituted alkyl group include a benzyl group and a methoxymethyl group. Among these, as R ¹ and R ² , hydrogen, a methyl group, a pentyl group, a Noel group, and a heptadecyl group are preferable. The metal (M) is preferably tin, zinc, boron or the like. Examples of the ligand L include an alkyl group, aryl group, alkoxy group, chlorine, bromine and iodine. Monovalent organic group (R

) Includes alkyl groups, carboxyl groups and derivatives thereof, formyl groups and derivatives thereof.

[0065] In the method for producing quarterpyridine derivative C, biviridine derivative B represented by the above formula (10) is reacted with an organometallic to produce organometallic intermediate 1 represented by the above formula (2). The method is preferably the same as in the above-mentioned “Method for producing quarterpyridine derivative A”.

The biviridine derivative represented by the above formula (15) can be obtained by the method described in “J. Org. Chem., 2002, 67, 8269-8272”, for example. In particular, when the biviridine derivative A represented by the above formula (1) is used as the biviridine derivative represented by the above formula (15), it can be obtained by the method for producing the biviridine derivative A described above. Specific examples of the biviridine derivative represented by the formula (15) include 6 bromo-4,4 ′ dimethyl-2,2 ′ biviridine and the like.

[0067] As a method of reacting the organometallic intermediate 1 represented by the above formula (2) and the biviridine derivative represented by the above formula (15) using a transition metal catalyst, the above-described quarterpyridine is used. In the method for producing the derivative A, the organometallic intermediate 1 is reacted with the biviridine derivative A represented by the above formula (1) using a transition metal catalyst to produce the quarterpyridine having the above formula (3). It is preferred to use a method similar to the method of forming derivative A! /.

[0068] (Method for producing quarterpyridine derivative D) In the method for producing quarterpyridine derivative D of the present invention, a bibilidine derivative represented by the following formula (17) is reacted with an organometallic to produce an organometallic intermediate 4 represented by the following formula (18). The quarterpyridine derivative D represented by the following formula (19) is produced by reacting the biviridine derivative represented by the above formula (1) with the organometallic intermediate 4 using a transition metal catalyst. is there.

[0069] [Chemical 17]

[0070] In the above formulas (17) to (; 19), each R is independently a monovalent organic group, j is an integer of 1 to 3, k is an integer of 1 to 4, X ² Is a halogen atom, M is a metal, L is a ligand, n is an integer from;! To 3, Z is a monovalent organic group, R ³ and R ⁴ are Each is independently a monovalent organic group and may be bonded to each other to form a cyclic structure. As the metal (M), tin, zinc, boron and the like are preferable. Examples of the ligand L include an alkyl group, an aryl group, an alkoxy group, chlorine, bromine and iodine. Examples of the monovalent organic group (R) include an alkyl group, a carboxyl group and a derivative thereof, a formyl group and a derivative thereof. Examples of the monovalent organic group (Z) include an alkyl group and an aryl group. As R ³ and R ^4, it is possible to enumerate alkyl groups, aryl groups, and the like. The alkyl group is preferably an alkyl group having 1 to 4 carbon atoms. When R ³ and R ⁴ are bonded to each other to form a cyclic structure, “one CH C (CH 2) CH one” or the like

2 3 2 2 is preferred.

The biviridine derivative represented by the above formula (17) can be obtained by the method described in “J. Org. Chem., 2002, 67, 8269-8272”, for example. In particular, represented by the above formula (17) When the biviridine derivative B represented by the above formula (10) is used as the biviridine derivative, it can be obtained by the “production method of the biviridine derivative B” described above. In addition, specific examples of the biviridine derivative represented by the formula (17) include 6-bromo-4,4′dimethyl-2,2′-biviridine.

[0072] In the method for producing quarterpyridine derivative D of the present invention, a biviridine derivative represented by the above formula (17) is reacted with an organic metal to obtain an organometallic intermediate 4 represented by the above formula (18). The method of formation is preferably the same as in the case of the above-mentioned “Method for producing quarterpyridine derivative A”.

[0073] As a method of reacting the organometallic intermediate 4 represented by the above formula (18) and the biviridine derivative A represented by the above formula (1) using a transition metal catalyst, the above-mentioned quarter In the method for producing pyridine derivative A, a quarterpyridine derivative represented by the above formula (3) is prepared by reacting the organometallic intermediate 1 with the biviridine derivative A represented by the above formula (1) using a transition metal catalyst. It is preferable to use a method similar to the method of generating A! /.

[0074] (Method for producing terpyridine derivative A)

A production method (1) of a terpyridine derivative represented by the following formula (21) is obtained by reacting a bipyridine derivative B represented by the above formula (10) with an organic metal to produce an organometallic represented by the above formula (2). Intermediate 1 is produced, and terpyridine derivative A represented by the following formula (21) is produced by reacting organometallic intermediate 1 with a pyridine derivative represented by the following formula (20) using a transition metal catalyst. It is something to be made.

[0075] [Chemical 18]

In the formulas (20) and (21), R is each independently a monovalent organic group, j is an integer of 1 to 4, X ¹ is bromine, iodine or “one OSO CF”, R ¹ And R ² are German In particular, it is hydrogen, an alkyl group, an aryl group or a substituted alkyl group. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an i propyl group, a butyl group, an i butyl group, an s-butyl group, and a t butyl group. Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the substituted alkyl group include a benzyl group and a methoxymethyl group. Among these, as R ¹ and R ^2, hydrogen, a methyl group, pentyl group, nonyl group, heptadecyl group. Examples of the monovalent organic group (R) include an alkyl group, a carboxyl group and derivatives thereof, a formyl group and derivatives thereof, and the like.

[0077] In the method for producing terpyridine derivative A of the present invention, an organometallic intermediate 1 represented by the above formula (2) is obtained by reacting the bibilidine derivative B represented by the above formula (10) with an organometallic. The method for producing is preferably the same as in the above-mentioned “method for producing quarterpyridine derivative A”.

The pyridine derivative represented by the above formula (20) can be obtained, for example, by the method described in “Eur. J. Org. Chem., 2003, 19, 3855-3860”. Specific examples of the pyridine derivative represented by the formula (20) include 2 bromo-4-methylpyridine.

[0079] As a method of reacting the organometallic intermediate 1 represented by the above formula (2) with the pyridine derivative represented by the above formula (20) using a transition metal catalyst, the above-mentioned quarter pyridine derivative is used. In the production method of Form A, a quarterpyridine derivative represented by the above formula (3) is prepared by reacting the organometallic intermediate 1 with the biviridine derivative A represented by the above formula (1) using a transition metal catalyst. It is preferable to use a method similar to the method of generating A! /.

[0080] (Method for producing terpyridine derivative B)

The terpyridine derivative B represented by the following formula (24) is produced by reacting a pyridine derivative represented by the following formula (22) with an organic metal to produce an organometallic intermediate 5 represented by the following formula (23). The terpyridine derivative B represented by the following formula (24) is produced by reacting the biviridine derivative represented by the above formula (1) with the organometallic intermediate 5 using a transition metal catalyst. is there.

[0081] [Chemical 19]

[0082] In the formulas (22) to (24), R is each independently a monovalent organic group, j is an integer of 1 to 4, X ² is a halogen atom, and L is a ligand. , N is an integer from;! To 3, Z is a monovalent organic group, R ³ and R ⁴ are each independently a monovalent organic group, and are bonded to each other to form a cyclic structure. It may be a group. As the metal (M), tin, zinc, boron and the like are preferable. Examples of the ligand L include an alkyl group, aryl group, alkoxyl group, chlorine, bromine and iodine. Examples of the monovalent organic group (R) include an alkyl group, a carboxyl group and a derivative thereof, a formyl group and a derivative thereof. Examples of the monovalent organic group (Z) include an alkyl group and an aryl group. Examples of R ³ and include an alkyl group and an aryl group. The alkyl group is preferably an alkyl group having 1 to 4 carbon atoms. When R ³ and R ⁴ are bonded to each other to form a cyclic structure, “one CH 2 C (CH 2) 2 CH—” or the like is preferable.

2 3 2 2

[0083] The pyridine derivative represented by the above formula (20) can be obtained by the method described in "Eur. J. Org. Chem., 2003, 19, 3855-3860", for example. Specific examples of the pyridine derivative represented by the formula (20) include 2 bromo-4-methylpyridine.

[0084] In the method for producing terpyridine derivative B of the present invention, an organometallic intermediate 5 represented by the above formula (23) is obtained by reacting a pyridine derivative represented by the above formula (22) with an organometallic. The method for producing the organic metal intermediate 3 represented by the formula (12) is obtained by reacting the pyridine derivative represented by the formula (11) with an organic metal in the above-mentioned “production method of the biviridine derivative B”. It is preferable to use a method similar to the method of generating.

[0085] As a method for reacting the organometallic intermediate 5 represented by the above formula (23) with the biviridine derivative A represented by the above formula (1) using a transition metal catalyst, In the method for producing pyridine derivative A, a quarterpyridine derivative represented by the above formula (3) is prepared by reacting the organometallic intermediate 1 with the biviridine derivative A represented by the above formula (1) using a transition metal catalyst. It is preferable to use a method similar to the method of generating A! /.

Example

[0086] (Synthesis Example 1)

In a 1 L flask equipped with a magnetic stirrer and a three-way cock, 2-bromo-4-methylpyridine (10 · Og, 58 mmol) and anhydrous THF (400 mL) were taken and stirred in a nitrogen stream using a dry ice bath. — Cooled to 78 ° C. To the solution, 2 mol / L lithium diisopropylamide in THF / heptane / ethylbenzene (44 mL, 88 mmol) was added dropwise over about 5 minutes using a syringe and stirred at −78 ° C. for 1.5 hours. To this solution, 1 bromohexadecane (19.5 g, 64 mol) in THF (lOOmU) was added at once using a syringe. After the addition, the temperature was raised to -20 ° C over about 15 minutes. The mixture was stirred for 2 hours at 20 ° C. The mixture was further warmed to room temperature over about 15 minutes and stirred for 2 hours.After adding water (about 50 mL), the mixture was extracted three times with ethyl acetate. The combined organic phase was dried over magnesium sulfate and concentrated using a rotary evaporator, and the resulting crude product was purified using a silica gel column to obtain the following formula (25). A yellow oil of bromo-4heptadecyl pyridine was obtained (16.7 g, 42 mmol, yield 73%).

[0087] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 8. 23 ppm (d, J = 5. OHz, 1H), 7. 31 (s, 1

Three

H), 7.05 (d, 5.2Hz, 1H), 2.57 (t, 7.7Hz, 2H), 1.61 (m, 2H), 1.29 (m, 28H), 0.88 (t, 6.6Hz, 3H)

LC / MS (API-ES) m / z: 396.2 (100%, [M + H] ⁺ ), 398.2 (100%), 397.2 (25%), 399.2 (25% )

[0088] [Chemical 20]

[0089] (Synthesis Example 2)

In a 300 mL flask equipped with a magnetic stirrer and a three-way cock, take 2- (N, N-Dimethylolamino) ethanolanol (10 mL, 100 mmol) and hexane (50 mU) and stir under a nitrogen stream using an ice bath. To this solution, 1.6 mol / L n-butyllithium hexane solution (125 mL, 200 mmol) was added dropwise over about 10 minutes using a syringe and stirred at 0 ° C. for 15 minutes. Then, using a dry ice bath, the solution was cooled to 78 ° C. To this solution, a 2-hexane pyridine (5 · 67 g, 50 mmol) in hexane (50 mL) was added using a syringe for about 5 minutes. After stirring at 78 ° C. for 2 hours, tributyltin chloride (29 mL, 100 mmol) was added to the solution at once using a syringe. And then stirred at room temperature for 2 hours To this solution was added water (about lOOmL), followed by extraction three times with ethyl acetate, and the organic phase combined with the three extracts was dried over magnesium sulfate and then used with a rotary evaporator. The resulting crude product was purified using a silica gel column to obtain a yellow oil of 2-tributylstannyl-6-chloropyridine.

[0090] The analysis values are as follows.

LC / MS (API-ES) m / z: 404.1 (100%, [M + H] ⁺ ), 402.1 (75%), 403.1 (40%), 406.1 (40%) , 400.1 (35%), 401.1 (30%), 405.1 (25%), 408.1 (20%), 407.1 (10%)

[0091] 2-tributylstannyl 6-chloropyridine synthesized above was added 2-bromo-l-methylmethylidine (7.74 g, 45 mmol) and p-xylene (25 mU, then 3 times using a vacuum apparatus). Tetrakis (triphenylphosphine) palladium (1.45 g, 1.3 mmol) was placed in a 500 mL flask equipped with a magnetic stirrer, oil bath, three-way cock, and Jim mouth condenser, and purged with nitrogen as described above. The degassed mixed solution was added using a syringe, and the mixed solution was refluxed for about 10 hours under a nitrogen stream at 150 ° C. After cooling to room temperature, the solution was acidified with 1N hydrochloric acid, Extract this solution three times with 1N hydrochloric acid. I put it out. The aqueous phase combined with the three extracts was basified with sodium carbonate, and the aqueous phase was extracted 5 times with ethyl acetate. The ethyl acetate phase combined with the extract of 5 times was dried with magnesium sulfate and then concentrated using a rotary evaporator. The obtained crude product was purified using a silica gel column to obtain a white ligation day of 6-chloro-4, -methinole 2, 2, monobiviridine represented by the following formula (26) (7. 32g, 35mm monore, yield 71%).

[0092] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 8.52 ppm (d, J = 4.9 Hz, 1H), 8.34 (d, 8

Three

lHz, 1H), 8.24 (s, 1H), 7.76 (dd, 7.8Hz, 7.6Hz, 1H), 7.33 (d, 7.8Hz, 1H), 7.15 ( d, 5. lHz, 1H), 2.44 (s, 3H)

LC / MS (API-ES) m / z: 205.1 (100%, [M + H] ⁺ ), 207.1 (30%), 206.1 (15%)

[0093] [Chemical 21]

[0094] (Synthesis Example 3)

In a 50 mL flask equipped with a magnetic stirrer and a three-way cock, take 6 chloro-4, -methinole-1,2,2, bibilysine (2.05 g, 10 millimonole) and anhydrous THF (20 mL) and stir under a nitrogen stream while stirring. Cooled to 78 ° C using a dry ice bath. This solution solution (6 mL, 12 mmol) was added dropwise over about 5 minutes using a syringe and stirred at 78 ° C. for 2 hours. To this solution, 1-bromohexadecane (3.05 g, 10 mmol) in THF (20 mU) was added at once using a syringe. After the addition, the temperature was raised to 20 ° C over about 1 hour. The mixture was stirred for 4 hours at 20 ° C. After adding water, the mixture was warmed to room temperature and extracted three times with ethyl acetate, and the combined organic phase was dried over magnesium sulfate. The resulting crude product was purified using a silica gel column, and 6 Chloro-4, 1-heptadecinole represented by the following formula (27) was then obtained. -A pale yellow powder of 2,2, -biviridine was obtained (2.96 g, 6.9 mmol, 69% yield).

[0095] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 8.54 ppm (d, J = 5.1 Ηζ, 1H), 8.34 (d, 7

Three

6Hz, 1H), 8.23 (s, 1H), 7.76 (dd, 7.8Hz, 7.6Hz, 1H), 7.33 (d, 7.6Hz, 1H), 7.15 ( d, 5. lHz, 1H), 2.69 (t, 7.8 Hz, 2H), 1.68 (m, 2H), 1.40 to 1.25 (m, 28H), 0.88 (t , 7.0Hz, 3H)

LC / MS (API-ES) m / z: 439.3 (100%, [M + H] ⁺ ), 431.3 (45%), 430.3 (40%), 432.3 (10%)

[0096] [Chemical 22]

[0097] (Synthesis Example 4)

Take l- (N, N dimethylamino) ethanol (4 mL, 40 mmol) and hexane (lOmL) in a lOOmL flask equipped with a magnetic stirrer and three-way cock and cool with an ice bath while stirring under a nitrogen stream. did. A 1.6 mol / L n-butyllithium hexane solution (50 mL, 80 mmol) was added dropwise to the solution using a syringe for about 10 minutes. After stirring at 0 ° C for 15 minutes, the mixture was cooled to 78 ° C using a dry ice bath. To this solution, a hexane solution (10 mL) of 2-chloropyridine (2-27 g, 20 mmol) was added dropwise over about 5 minutes using a syringe. After stirring at 78 ° C for 2 hours, tributyltin chloride (5.5 mL, 20 mmol) was added to the solution all at once using a syringe. After raising the temperature to room temperature over about 1 hour, the mixture was stirred at room temperature for 2 hours. Water was added to this solution, followed by extraction three times with ethyl acetate. The organic phase combined with the three extracts was dried over magnesium sulfate and then concentrated using a rotary evaporator. The obtained crude product was purified using a silica gel column to obtain a yellow oil of 2-triptylustanil 6-clopyridine.

[0098] After adding 2 bromo-4-heptadecyl pyridine (6 · 90 g, 17 mmol) and p-xylene (40 mU) to 2 tributinorestaninole 6 Degassed three times using an empty device. A 50 mL flask equipped with a magnetic stirrer, oil bath, three-way cock, and Dimroth condenser was charged with tetrakis (triphenylphosphine) paradium (0.69 g, 0.6 mmol), purged with nitrogen, and then the above-mentioned degassed mixed solution Was added using a syringe. This mixed solution was refluxed at 140 ° C. for about 8 hours under a nitrogen stream. After allowing to cool to room temperature, water (about 40 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phase of the three extracts was dried over magnesium sulfate and then concentrated using a rotary evaporator. The obtained crude product was purified using a silica gel column to obtain white crystals of 6 chloro-4,1-heptadecyl-2,2′-biviridine represented by the above formula (27) (2.83 g, 6. 6 mm monore, yield 33%).

[0099] (Synthesis Example 5)

In a 50 mL flask equipped with a magnetic stirrer and a three-way cock, take 6 chloro-4, -methinole-1,2,2, bibilysine (2.05 g, 10 millimonole) and anhydrous THF (20 mL) and stir under a nitrogen stream while stirring. Cooled to -78 ° C using a dry ice bath. The solution Zen solution (6 mL, 12 mmol) was added dropwise using a syringe over a period of about 5 minutes at 78 ° C.

Stir for 2 hours. To this solution, 1-bromooctane (2.06 g, 10 mmol) in THF (20 mL) was added dropwise using a syringe. After dropping, the temperature was raised to −20 ° C. over about 1 hour, and the mixture was stirred at 20 ° C. for 4 hours. After adding water, the mixture was warmed to room temperature and extracted three times with ethyl acetate. The combined organic phase of the three extracts was dried over magnesium sulfate and then concentrated using a rotary evaporator. The resulting crude product was purified using a silica gel column to obtain 6-chloro-4, nonyl-2,2′-bibilidine yellowish violet, represented by the following formula (28) (2.05 g, 6. 5 Mirimonore, yield 65 ^_0/0).

[0100] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 8.54 ppm (d, J = 4.9 Hz, 1H), 8.34 (dd,

Three

7. 8Hz, 1. lHz, 1H), 8.23 (d, J = l. LHz, 1H), 7.76 (dd, 7.8Hz, 7.6Hz, 1H), 7.33 (dd, 7 6Hz, 1.lHz, 1H), 7.15 (dd, 4.9Hz, 1.9Hz, 1H), 2.69 (t, 8.0Hz, 2H), 1.68 (m, 2H), 1.33 ~ 1.23 (m, 12H), 0.88 (t, 6.8 Hz, 3H) LC / MS (API-ES) m / z: 317.2 (100%, [M + H] ⁺ ), 319.2 (40%), 318.2 (25%), 320.2 (10%)

[0101] [Chemical 23]

Cg

[0102] (Synthesis Example 6)

Take a 2- (N, N dimethylamino) ethanol (20 mL, 200 mmol) and hexane (lOOmL) in a 1 L flask equipped with a magnetic stirrer and a three-way cock, and cool in an ice bath while stirring under a nitrogen stream. did. To this solution, 1.6 mol / L n-butyllithium hexane solution (250 mL, 400 mmol) was added dropwise over about 5 minutes using a syringe. After stirring at 0 ° C for 15 minutes, the mixture was cooled to 78 ° C using a dry ice bath. To this solution, a mixture of 2 chloro-4-methinorepyridine (12.8 g, 100 millimonole) and hexane (lOOmL) was added dropwise over about 5 minutes using a syringe. After stirring at 78 ° C. for 2 hours, tributyltin chloride (57 mL, 210 mmol) was added to the solution all at once using a syringe. After raising the temperature to room temperature over about 1 hour, the mixture was stirred at room temperature for 2 hours. To this solution was added water (about 200 mU, followed by extraction three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and then concentrated using a rotary evaporator. By purifying using a column, 2-tributylbutanyl 6-chloro-4-methylpyridine was obtained.

[0103] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 7.llppm (s, 1H), 6.97 (s, 1H), 2.28 (s

Three

3H), 1.54 (m, 6H), 1.31 (m, 6H), 1.12 (t, J = 8.1 = ζ, 6H), 0.88 (t, 7.3Hz, 9H)

LC / MS (API-ES) m / z: 418.1 (100%, [M + H] ⁺ ), 416.1 (80%), 417.1 (40%), 420.1 (40%), 414.1 (35%) , 415.1 (25%), 419.1 (25%), 42 2.1 (20%), 421.1 (10%)

[0104] 2-tributylstannyl synthesized above 4 Mo 4 Methylpyridine (14.2 g, 80 mmol) and p-xylene (150 mU were added and then degassed three times using vacuum. 1 L flask equipped with magnetic stirrer, oil bath, three-way cock and Dimroth condenser After taking tetrakis (triphenylphosphine) paradium (2.14 g, 1.9 mmol) and replacing with nitrogen, the above-mentioned degassed mixed solution was added. After cooling to room temperature, the solution was acidified with 1N hydrochloric acid, and the solution was extracted three times with 1N hydrochloric acid.The combined aqueous phase was basified with sodium carbonate, and The aqueous phase was extracted five times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and concentrated using a rotary evaporator, and the resulting crude product was purified using a silica gel column. Thus, white crystals of 6chloro-4,4′dimethyl-2,2′-biviridine represented by the following formula (29) were obtained (13.3 g, 60 mmol, yield 60%).

[0105] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 8. 49 ppm (d, J = 4.9 Hz, 1 H), 8. 20 (s, 1

Three

H), 8.14 (s, 1H), 7.13 (s, 1H), 7.11 (d, 4.9Hz, 1H), 2.41 (s, 3H), 2.

39 (s, 3H)

LC / MS (API-ES) m / z: 219.1 (100%, [M + H] ⁺ ), 221.1 (40%), 220.1 (20%)

[0106] [Chemical 24]

(Synthesis Example 7)

Into a 50 mL flask equipped with a magnetic stirrer and a three-way cock, take 6 chloro-4,4, monodimethyl-2,2, -biviridine (0.66 g, 3.0 mmol) and anhydrous THF (9 mL) and stir in a nitrogen stream While being cooled to 78 ° C. using a dry ice bath. To the solution, a 2 mol / L lithium diisopropylamide in THF / heptane / ethyl benzene solution (6 mL, 12 mmol) was added dropwise over about 5 minutes using a syringe and stirred at −78 ° C. for 2 hours. . To this solution, 1-bromobutane (0 · 90 g, 6.6 mmol) of T HF solution (3 mL) was added dropwise using a syringe. After the dropwise addition, the mixture was brought to 0 ° C using an ice bath and stirred for 3 hours. After adding water at 0 ° C, the mixture was warmed to room temperature and extracted three times with ethyl acetate. The combined organic phase of the three extracts was dried over magnesium sulfate and concentrated using a rotary evaporator. The obtained crude product was purified using a silica gel column to obtain a yellow oil of 6 chloro-4,4′-dipentyl-2,2 ′ biviridine represented by the following formula (30) (0 · 38 g, 1.1). Mmol, 38% yield).

[0108] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 8.53 ppm (d, 4.9 Hz, 1H), 8.22 (s, 1H)

Three

8.17 (s, 1H), 7.16 (s, 1H), 7.14 (dd, 5.lHz, 1.6Hz, 1H), 2.69 (t, 7.8Hz, 2H), 2 67 (t, 7.8Hz, 2H), 1.69 (m, 4H), 1.35 (m, 8H), 0.90 (t, 6.5Hz, 6H)

LC / MS (API-ES) m / z: 331.2 (100%, [M + H] ⁺ ), 333.2 (40%), 333.2 (30%), 333.2 (10%)

[0109] [Chemical 25]

[0110] (Synthesis Example 8)

Citrazic acid (71 g, 460 mmol) and 2 propanol (about 1 L) were taken in a 2 L flask equipped with a magnetic stirrer, oil bath and Dimroth condenser. Concentrated sulfuric acid (about 50 mU was added to this suspension and then refluxed for about 60 hours. Water (about 1 L) was placed in a 2 L beaker equipped with a magnetic stirrer, and the above solution (refluxed for 60 hours). The latter solution was added dropwise to obtain a solid, which was collected by filtration using a Kiriyama funnel, and the obtained solid was washed with ethanol, and the solid was dried under heat (<10 torr, about 50 torr). This gave a white solid of isopropyl citrate shown in the following formula (31) (74 g, 380 mmol, yield 82%).

[0111] The analysis values are as follows.

¹ H-NMR (270MHz, DMSO-d6) δ: 6.29ppm (s, 2Η), 5.09 (qq, J = 6. 3Hz, 1H), 1.30 (d, 6.3Hz, 6H)

LC / MS (API-ES) m / z: 198.1 (100%, [M + H] ⁺ ), 156.1 (40%), 199

Kio%)

[0112] [Chemical 26]

[0113] (Synthesis Example 9)

Into a 2 L flask equipped with a magnetic stirrer and a three-way cock, isopropyl citrate (50 g, 250 mmol) and dichloromethane (about 1.2 L) were taken and stirred under a nitrogen stream. To this, triethylamine (104 mL, 750 mmol) was added, and then cooled to 78 ° C. using a dry ice bath. Trifluoromethanesulfonic anhydride (126 mL, 750 mmol) was added dropwise to the solution using a syringe over about 5 minutes, and the mixture was stirred at 78 ° C. for about 0.5 hours. After raising the temperature to room temperature over about 0.5 hour, the mixture was further stirred at room temperature for 2 hours. The reaction solution was washed twice with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated using a rotary evaporator. By purifying the obtained crude product using a silica gel column, yellow crystals of 2, 6 bis (trifluoromethanesulfonoxy) -4 isopropoxycarbonylpyridine represented by the following formula (32) were obtained (97 3 g, 211 mmol, 84% yield).

[0114] The analysis values are as follows.

— NMR (90MHz, CDC1) δ: 7.81ppm (s, 2H), 5.33 (qq, J = 6.2Hz, 1

Three

H), 1.43 (d, 6.5Hz, 6H)

[0115] [Chemical 27]

[0116] (Synthesis Example 10)

In a 2L flask equipped with 0.7 g, 375 millimonoles), 2,2 dimethinole 1,3 pronone monole (77.7 g, 750 mmol), P-toluenesulfonic acid monohydrate (40.7 g, 750 mmol) and dichloromethane (About 1L) was taken. Stir in air at room temperature for approximately 24 hours. The reaction solution was washed four times with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated using a rotary evaporator. White crystals of 2,6 dioxanyl) pyridine were obtained (63.5 g, 329 mmol, 88% yield).

[0117] The analysis values are as follows.

— NMR (90MHz, CDC1) δ: 8.63ppm (d, J = 6.2Hz, 2H), 7.42 (d, 6

Three

2Hz, 2H), 5.38 (s, 1H), 3.75 (d, 10.7Hz, 2H), 3.70 (d, 10.7Hz, 2H), 1.27 (s, 3H), 0.81 (s, 3H)

LC / MS (API-ES) m / z: 194.1 (100%, [M + H] ⁺ ), 195.1 (15%)

[0118] [Chemical 28]

[Example 1]

In a 300 mL flask equipped with a magnetic stirrer and a three-way cock, take 2- (N, N-dimethylinoamino) ethanolol (5 mL, 50 mmol) and t-butyl methyl ether (30 mL), and stir it in a nitrogen stream while stirring in an ice bath. Used to cool. To this solution, 1.6 mmol / L of n-butyllithium hexane solution (63 mL, 100 millimonoles) was added dropwise over about 5 minutes using a syringe. After stirring at 0 ° C for 15 minutes, the mixture was cooled to 78 ° C using a dry ice bath. To this solution, a solution of 4- (4,4 dimethyl-2,6 dioxanyl) pyridine (4 · 83 g, 25 mmol) in t-butyl methyl ether (30 mL) was added dropwise over about 5 minutes using a syringe. . After stirring at 78 ° C. for 2 hours, tributyltin chloride (14 mL, 50 mmol) was added to the solution all at once using a syringe. The mixture was allowed to warm to room temperature over about 1 hour and then stirred at room temperature for 2 hours. Add water (about lOOmL) to this solution. And extracted three times with ethyl acetate. The organic phase combined with the three extracts was dried over magnesium sulfate and then concentrated using a rotary evaporator. The 2 tributylstannyl-4 (4,4 dimethyl-2,6 dioxanyl) pyridine thus obtained was used in the next coupling reaction without further purification.

[0120] The analysis values are as follows.

LC / MS (API-ES) m / z: 484.2 (100%, [M + H] ⁺ ), 482.2 (80%), 480.2 (40%), 483.2 (40%), 481.2 (35%) 485.2 (25%), 486.2 (20%), 48 8.2 (20%)

[0121] 2 Tributylstannyl-4 1 (4,4 1-dimethyl-2,6 dioxanyl) pyridine synthesized above and 2, 6 bis (trifluoromethanesulfodioxy) 4 isopropoxycarbonylpyridine (11.7 g, 25 mmol) and toluene (75 mU were added and then degassed three times using a vacuum apparatus. Tetrakis (triphenylphosphine) para-dioxide was added to a 300 mL flask equipped with a magnetic stirrer, oil bath, three-way cock, and Jim mouth condenser. (0.87 g, 0.75 mmol) and lithium chloride (3.18 g, 75 millimonore) were replaced with nitrogen, and then the above-mentioned degassed mixed solution was added and refluxed at 110 ° C for 8 hours under a nitrogen stream. After cooling to room temperature, the mixture was concentrated using a rotary evaporator, and the resulting crude product was purified using a silica gel column. As shown in (34), a yellow solid of 4 isopropoxycarbonyl 4′-one (4,4 dimethyl-2,6 dioxanyl) -6 (trifluoromethanesulfonyloxy) 2,2,1 bibiridine was obtained (3 · 40 g, yield 26 %).

[0122] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 9.02 ppm (s, 1H), 8.74 (d, J = 4.9 Hz, 1

Three

H), 8.45 (s, 1H), 7.72 (s, 1H), 7.55 (dd, 4.9Hz, 1.6 Hz, 1H), 5.48 (s, 1H), 5.33 (qq, 6.2Hz, 1H), 3.83 (d 11.3Hz, 2H), 3.70 (d, 10.8Hz, 2H), 1.43 (d, 6.3Hz, 6H), 1.30 (s, 3H), 0.84 (s, 3H)

LC / MS (API-ES) m / z: 505.1 (100%, [M + H] ⁺ ), 506.1 (30%), 507

Kio%)

[0123] [Chemical 29]

[0124] (Example 2)

Into an lOOmL flask equipped with a magnetic stirrer, condenser and three-way cock, take magnesium metal (30 mg, 1.2 mmol), dry by heating under reduced pressure, and then anhydrous THF (0.5 mL) under a nitrogen stream Add and I (small pieces) and stir at room temperature for about 10 minutes

2

did. Thereto was added dropwise an anhydrous THF solution (5 mL) of 6 bromo-2,2, monobipyridine (200 mg, 0.8 mmol) over about 10 minutes using a syringe. After dropping, the mixture was stirred at room temperature for about 4 hours. To this solution, anhydrous THF (10 mU and 0.5 mol / L of zinc chloride in THF (1.6 mL, 0.8 mmol)) was added at once using a syringe and stirred at room temperature for about 3 hours. Then, 4 isopropoxycarbonyl 4'one (4,4 dimethyl-2,6 dioxanyl) -6 (trifluoromethanesulfonyloxy) 2,2'-biviridine (390 mg, 0.8 mmol) in THF ( 10mU was added and degassed 3 times using a vacuum device.Tetrakis (triphenylphosphine) palladium (92mg, 0.08mmol) was taken into a lOOmL flask equipped with a magnetic stirrer, oil bath, three-way cock and Dimroth condenser. After purging with nitrogen, the above-mentioned degassed mixed solution was added, and the mixture was refluxed for about 6 hours under a nitrogen stream at 70 ° C. After standing to cool to room temperature, water was added, and the mixture was filtered through celite. Acid ethyl The combined organic phase was dried over magnesium sulfate and concentrated using a rotary evaporator, and the resulting crude product was purified using a silica gel column. 4 'isopropoxy carbolulu 4 (4, 4 dimethyl-2, 6 dioxanyl) 2, 2': 6 \ 2 ": 6 '\ 2,,,, quater pyridine yellow solid shown in the following formula (35) (12 mg, 3% yield) was obtained.

[0125] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 9.18 ppm (d, J = l. 4 Hz, 1H), 8. 96 (d, 1

Three

6Hz, 1H), 8.78 (d, 5.1Hz, 1H), 8.72 (m, 3H), 8.70 (s, 1H), 8.52 (d d, 8.1Ηζ, 0.9Hz, 1H), 8.03 (dd, 8.1, 8.1Hz, 1H), 7.90 (dd, 7.6Hz, 7.6Hz, 1H), 7.56 (d, 4.9Hz, 1H), 7.35 (dd, 7.3Hz, 4.9Hz, 1H), 5.5 4 (s, 1H), 5.38 (qq, 6.2Hz, 1H), 3.86 (d, 11.3Hz, 2H), 3.73 (d, 10.5 Hz, 2H), 1.47 (d, 6.1Hz, 6H), 1.33 (s, 3H), 0.85 (s, 3H)

[Chemical 30]

[0127] (Example 3)

Into an lOOmL flask equipped with a magnetic stirrer, condenser and three-way cock, magnesium metal (96 mg, 4 mmol) was taken, dried by heating under reduced pressure, and then anhydrous THF (0.5 mL) and I ( A small piece) and stir at room temperature for about 10 minutes.

2

It was. There, 6 mouthpiece 4, 1-heptadesinore 2, 2,-, pyridine (5 · 86 g, 2 millimonole) and tributyltin chloride (1 mL, 4 mmol) in anhydrous THF solution (4 mU, syringe) After the addition, the mixture was stirred at room temperature for 3 hours, and water was added to the solution, followed by filtration through celite and extraction three times with ethyl acetate. The combined organic phase was dried over magnesium sulfate and concentrated using a rotary evaporator, and the 2 tributylstannyl 4'-heptadecyl-1,2 'bibilidine thus obtained was further purified. This was used for the next coupling reaction without.

[0128] The analysis values are as follows.

LC / MS (API-ES) m / z: 685.4 (100%, [M + H] ⁺ ), 683.4 (80%), 684.4 (55%), 681.4 (40%), 682.4 (40%) 686.4 (40%), 687.4 (20%), 68 9.4 (15%), 688.4 (5%), 690.4 (5%)

[0129] 2-tributylstannyl-4'-heptadecyl-2,2'biviridine synthesized above and 4 1-isopropoxycarbonyl 4 '1 (4,4 1-dimethyl-2,6 dioxanyl) -6- (trifnore After adding 1,2,2, bibilysine (0 · 50 g, 1 millimonole) and p-xylene (3 mL), the mixture was deaerated three times using a vacuum apparatus. Magnetic star Into an lOOmL flask equipped with an oil bath, oil bath, three-way cock, and Dimroth condenser, tetrakis (triphenylphosphine) palladium (58 mg, 0.05 mmol) and lithium chloride (0.13 g, 3 mmol) were taken. The above degassed mixed solution was added. The mixture was refluxed at 140 ° C for about 5 hours under a nitrogen stream. After allowing to cool to room temperature, water was added, the mixture was filtered using celite, and extracted three times using ethyl acetate. The organic phase combined with the three extracts was dried over magnesium sulfate and then concentrated using a rotary evaporator. By purifying the obtained crude product using a silica gel column, 4′-isopropoxycarbonyl 4-l (4,4-dimethyl-2,6-dioxanyl) −4, “” represented by the following formula (36) Heptadecyl-2,2 ': 6 2'':6'',2''' — Quotapyridine yellow solid was obtained (368 mg, 24% yield).

[0130] The analysis values are as follows.

¹ H-NMR (270 MHz, CDC1) δ: 9.19 ppm (d, J = l.6 Hz, 1H), 8.98 (d, 1

Three

.4Hz, 1H), 8.78 (d, 5.4Hz, 1H), 8.71 (s, 1H), 8.68 (d, 7.6Hz, 1H), 8.63 (d, 5.1Hz, 1H), 8.52 (d, 7.8Hz, 1H), 8.51 (s, 1H), 8.02 (dd, 7. 8, 7.8Hz, 1H), 7.55 (d, 4.9Hz, 1H), 7.18 (d, 4.9Hz, 1H), 5.54 (s, 1 H ), 5.36 (qq, 6.3Hz, 1H), 3.86 (d, 11.9Hz, 2H), 3.77 (d, 12.7Hz, 2H), 2.77 (t, 7.8Hz, 2H), 1.75 (m, 2H), 1.47 (d, 6.2Hz, 6H), 1.33 (s, 3H), 1.3—1.2 (m), 0.87 (t, 6.5Hz, 3H), 0.85 (s, 3H)

LC / MS (API-ES) m / z: 749.4 (60%, [M + H] ⁺ ), 375.3 (100%, [M + 2H] ²⁺ ), 750.4 (30%), 751.4 (10%)

[0131] [Chemical 31]

[0132] (Synthesis Example 11)

In a 50 mL flask equipped with a magnetic stirrer 4 'Isopropoxy Carbonyl 4 One (4,4 dimethyl-2,6 dioxanyl) -4 '', one heptadecyl-2,2 ': 6 \ 2'': 6 ,, 2 ,, one quarterpyridine (0.76 g, 1 mmol), 4 Pyridinecarboxyaldehyde (1.4 mL, 15 mmol) and concentrated hydrochloric acid (1.5 mU were taken and stirred for about 6 hours at 60 ° C. After cooling to room temperature, saturated brine was added, and the mixture was extracted 5 times with THF. The combined organic phase of the five extracts was concentrated using a rotary evaporator, and the resulting crude product 4 honoreminolay 4, 1 carboxy 1, 4, 1, heptadecyl-2, 2, 6, 6, 2 ,,: 6, 2,,, 1 quaterpyridine was used in the next reaction without further purification.

[0133] The analysis values are as follows.

LC / MS (API - ES) m / z: 621.3 (100%, [M + H] +), 622.3 (45%), 623 .3 (10%), 311.3 (5%, [M + 2H] 2 ⁺ )

[0134] 4-formyl 4 'carboxy-4', obtained from the above, 1-heptadecyl-2,2 ': 6', 2, ': 6 ", 2' ', 1-quarterpyridine and ethanol (20mU magnetic stirrer) Take in a 50 mL flask equipped and stir in air Aqueous solution of silver nitrate (0 · 34 g, 2 mmol) (2 mU in aqueous solution of sodium hydroxide (0 · 40 g, 10 mmol) (10 mU to add silver oxide) This suspension was added to the previous quarterpyridine suspension, and the resulting mixture was stirred in air at room temperature for about 2 hours, acidified with hydrochloric acid and then THF. The mixture was extracted three times with an 8: 2 mixture of concentrated hydrochloric acid and the organic phase combined with the three extracts, filtered through a membrane filter (0.1 lO ^ m, PTFE), and concentrated using a rotary evaporator. Wash the resulting solid with water and ethyl acetate and vacuum dry. Thus, 4, 4′-dicarboxy 4 ′, and one heptadecyl 2, 2 ′: 6 ′, 2 ″: 6 ”, 2, and one quarter pyridine represented by the following formula (37) were obtained (0 · 46 g Yield 70%).

[0135] The analysis values are as follows.

¹ H-NMR (270 MHz, DMSO-d6) δ: 9.14 ppm (s, 1H), 9.02 (s, 1H), 8.97 (d, J = 5.4 Hz, 1H), 8.96 (s, 1H), 8.73 (m, 1H), 8.70 (d, 8.6Hz, 1H), 8.55 (d, 7.OHz, 1H), 8.54 (s, 1H), 8.32 (dd, 8.2, 7.0Hz, 1H), 7. 97 (d, 4.6Hz, 1H), 7.59 (m, 1H), 2.85 (t, 7. OHz, 2H), 1.74 (m, 2H), 1.23-1.05 (m, 28H), 0.82 (t, 6.6Hz , 3H)

LC / MS (API-ES) m / z: 637.3 (100%, [M + H] ⁺ ), 638.3 (45%), 319 3 (25%, [M + 2H] ²⁺ ), 639. 3 (10%)

[0136] [Chemical 32]

Industrial applicability

[0137] The method for producing a quarterpyridine derivative of the present invention and its intermediate can be used for the production of a quarterpyridine derivative which is a dye raw material used in a dye-sensitized solar cell. The quarter pyridine derivative can be easily produced by the method for producing the derivative and its intermediate.

Claims

Claims A biviridine derivative represented by the following formula (1) and an organometallic intermediate represented by the following formula (2) are reacted using a transition metal catalyst and represented by the following formula (3) A method for producing a quarterpyridine derivative that produces a quarterpyridine derivative. [Chemical 1]

[Chemical 2]

[Chemical 3]

(In Formula (3), Z is a monovalent organic group, R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group, and R ³ and R ⁴ are each Independently a monovalent organic group, which may be bonded to each other to form a cyclic structure. The acetal and ester of the quarterpyridine derivative represented by the following formula (3) are hydrolyzed to formyl group and carboxyl group, respectively, and the resulting formyl group is oxidized to represent a carboxyl group represented by the following formula (4). A process for producing a quarterpyridine derivative.

[Chemical 4]

[Chemical 5]

(In Formula (4), R ¹ and R ² are each independently hydrogen, an alkyl group, an aryl group, or a substituted alkyl group.)

A biviridine derivative represented by the following formula (1).

[Chemical 6]

(In Formula (1), Z is a monovalent organic group, Y is a perfluoroalkylsulfonyl group, R ³ and R ⁴ are each independently a monovalent organic group, and are bonded to each other to form a cyclic structure. Forming It ’s Ayore. )

An organometallic intermediate represented by the following formula (2).

[Chemical 7]

A quarterpyridine derivative represented by the following formula (3).

[Chemical 8]

In (Equation (3), Z is a monovalent organic group, R ¹ and R ² each independently hydrogen, § alkyl group, an Ariru group or a substituted alkyl group, R ³ and R ⁴ are each Independently a monovalent organic group, which may be bonded to each other to form a cyclic structure.