JP2001335556A - Method for producing 5-(3-cyanophenyl)-3-formylbenzoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producingy a 5-(3-cyanophenyl)-3- formylbenzoic acid derivative useful as an intermediate for producing a medicine. SOLUTION: This method for producing a compound represented by formula (I) comprises reacting a compound represented by formula (V) with a Grignard reagent obtained from a compound represented by formula (IV) by using a divalent palladium catalyst with an optional phosphine ligand, and a halide of a divalent zinc as a cocatalyst to provide 5-(3-formylphenyl)isophthalic acid derivative, reacting the obtained derivative with hydroxylamine hydrochloride and a metal salt of a 1-3C carboxylic acid in an organic solvent to provide 5-(3-cyanophenyl)isophthalic acid derivative, reacting the resultant 5-(3- cyanophenyl)isophthalic acid derivative with a boron hydride or sodium trimethoxyboron hydride to provide 5-(3-cyanophenyl)-3-(hyroxymethyl)benzoic acid derivative, and further reacting the 5-(3-cyanophenyl)-3-(hyroxymethyl) benzoic acid derivative with manganese dioxide in an organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 5- (3-cyanophenyl) -3-formylbenzoic acid derivative (hereinafter abbreviated as "cyanobiphenyl derivative"). More specifically, the present invention relates to a method for producing a cyanobiphenyl derivative which is useful as an intermediate for producing a biphenylamidine derivative which can be a selective inhibitor of activated blood coagulation factor X (hereinafter abbreviated as “FXa”).

[0002]

2. Description of the Related Art Hitherto, antithrombin agents have been developed as antithrombotic agents. However, it is known that this antithrombin agent has a risk of causing a bleeding tendency because it also inhibits the thrombin aggregation of platelets together with the anticoagulant effect. Did not. Therefore, an anticoagulant based on a mechanism other than the thrombin inhibitory action was developed, and a biphenylamidine derivative described in International Publication WO99 / 26918 was found as an anticoagulant having an excellent FXa inhibitory action. ing.

[0003] A method of oxidizing a hydroxymethyl group to a formyl group using inexpensive manganese dioxide is known (see Japanese Patent Application Laid-Open No. 10-503770).

[0004] On the other hand, a method of reducing only one ester group of aromatic diesters (see JP-A-7-17937) is also known. However, using this method,
5- (3-cyanophenyl) -isophthalic acid derivative
When synthesizing a (3-cyanophenyl) -3-hydroxymethylbenzoic acid derivative, 5- (3-cyanophenyl) -3-hydroxymethylbenzyl in which both ester groups of isophthalic acid have been reduced as by-products Alcohol is by-produced at about 10%, and column purification which is industrially difficult in subsequent steps is required to remove the alcohol.

As a coupling reaction between a Grignard reagent and a halogenated aromatic compound, a cross-coupling reaction is known (US Pat. No. 5,922,89).
No. 8). However, there is no description about the compound used in the present invention.

[0006]

An object of the present invention is to provide a clinically applicable F described in WO 99/26918.
An object of the present invention is to provide a novel method for producing a 5- (3-cyanophenyl) -3-formylbenzoic acid derivative which is an intermediate for producing a Xa inhibitor.

As a method for synthesizing 5- (3-cyanophenyl) -3-formylbenzoic acid derivative, 5-cyanophenyl boric acid synthesized from 3-bromobenzonitrile and 5-bromoisophthalic acid derivative synthesized from 5-bromoisophthalic acid derivative are used. After the coupling reaction of the bromo-3- (hydroxymethyl) benzoic acid derivative, the hydroxymethyl group of the obtained biphenyl compound is oxidized to give 5- (3-cyanophenyl)-
A method for obtaining a 3-formylbenzoic acid derivative has been known (see International Publication WO99 / 26918).

However, when synthesizing 3-cyanophenylboric acid, an extremely low temperature reaction of -78 ° C., which is industrially difficult, is used, or expensive tetrabutylammonium bromide is used in the coupling reaction. In the purification, column purification which is industrially difficult was used. In the oxidation reaction, methylene chloride, which is environmentally problematic, was used. Thus, each reaction had a number of problems.

[0009]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above object, and as a result, the following formula (I)

[0010]

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Wherein R represents a hydrogen atom or an unsubstituted or substituted C ₁ -C ₁₀ alkyl group. A 5- (3-cyanophenyl) -3-formylbenzoic acid derivative represented by the following formula has been found that can be industrially easily produced without using a low-temperature reaction and without using methylene chloride as a solvent. Specifically, it is a production method represented by the following reaction formula.

[0012]

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That is, the present invention provides the following formula (V)

[0014]

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[Wherein, the definition of R is the same as that in formula (I). A 5-bromo-isophthalic acid derivative represented by the following formula (VI):

[0016]

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Wherein R ₁ represents an unsubstituted or substituted C ₁ -C ₁₀ alkyl group. A Grignard reagent obtained by treating a 3- (dialkoxymethyl) bromobenzene derivative represented by the formula (I) with a metal magnesium in a solvent of ethers to form a divalent palladium catalyst and, if necessary, a phosphine ligand And a reaction using a divalent zinc halide as a co-catalyst;

[0018]

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[Wherein, the definition of R is the same as that in formula (I). ]-(3-formylphenyl) -3-isophthalic acid derivative represented by the formula:

The present invention also relates to a compound represented by the formula (IV):
-(3-formylphenyl) isophthalic acid derivative is reacted with hydroxylamine hydrochloride and a metal carboxylate having 1 to 3 carbon atoms in an organic solvent to obtain the following formula (III):

[0021]

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[Wherein, the definition of R is the same as that in the formula (I). 5- (3-cyanophenyl) represented by the formula:
This is a method for producing an isophthalic acid derivative.

The present invention also relates to the following formula (III) obtained by reacting a 5- (3-cyanophenyl) isophthalic acid derivative represented by the above formula (III) with a metal borohydride or sodium trimethoxyborohydride. II)

[0024]

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Wherein R has the same definition as in formula (I) above. 5- (3-cyanophenyl) represented by the formula:
-3- (Hydroxymethyl) benzoic acid derivative.

Further, the present invention provides a method for producing 5- (3-cyanophenyl) -3 represented by the above formula (I) by reacting a compound represented by the above formula (II) with manganese dioxide in an organic solvent. -A process for producing formyl benzoic acid derivatives.

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, general reaction conditions will be described with respect to Production Methods 1 to 6 in the above reaction formula. It is generally known that in Production Method 1, the target compound can be obtained by reacting alkyl orthoformate as a dehydrating agent with an alcoholic solvent such as methanol or ethanol in the presence of an acid catalyst such as p-toluenesulfonic acid or camphorsulfonic acid. ing. A case where the reaction is carried out using methyl orthoformate in a suitable amount of an acid catalyst using methanol as a solvent has good operability, and is a particularly preferred example.

In the production method 2, it is generally known that an ether solvent such as diethyl ether or tetrahydrofuran is preferable. In this case, tetrahydrofuran is particularly preferable because it is used as it is in the next production method.

In the production method 3, it is preferable to use tetrahydrofuran as a solvent. Examples of the divalent palladium catalyst include palladium chloride (in this case, triphenylphosphine is used as a ligand in an amount of 2 equivalents to the catalyst), dichlorobis (triphenylphosphine) palladium, dibromobis (triphenylphosphine) palladium, and the like. It is preferable to use a divalent palladium salt of the above as a catalyst. The amount of the divalent palladium catalyst to be used is preferably 0.02 mol to 0.1 mol per 1 mol of the compound represented by the formula (IV). In addition, it is preferable to use a divalent zinc halide as a cocatalyst in an amount of 1 to 5 times the equivalent of the palladium catalyst in that the target compound can be obtained with high yield and high selectivity.

It is known that when zero-valent palladium is used, the raw material remains even when the reaction time is increased. When nickel is used as a catalyst,
Formula (VIII), which is difficult to remove by recrystallization alone

[0031]

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[Wherein, the definition of R is the same as that in the formula (I). It is known that about 10% to 50% of the impurities represented by the formula [1] are obtained, and industrialization is difficult.

As a particularly preferred example, zinc (II) chloride is used as a cocatalyst as a catalyst system, and its use amount is up to 5%, preferably 2.5%, based on a palladium catalyst.
The lower limit is 0.01%, preferably 0.5%. Also,
Palladium chloride is used as a catalyst with an upper limit of 2%, preferably 1%.
%, The lower limit is 0.005%, preferably 0.25%,
Further, it is preferable to use triphenylphosphine twice as much as palladium chloride. Alternatively, bistriphenylphosphine palladium dichloride having an upper limit of 2%, preferably 1% and a lower limit of 0.005%, preferably 0.25% may be used as a catalyst. The reaction is carried out in a tetrahydrofuran solvent at an upper limit of 100 ° C., preferably 80 ° C.
C., the lower limit being 25.degree. C., preferably 40.degree. C., in an oil bath for 1 hour to 4 hours.

In connection with the production method 4, the reaction of hydroxylamine hydrochloride with hydroxylamine hydrochloride in the presence of an acid catalyst under reflux of an alcohol solvent, or the reaction of a metal carboxylate with hydroxylamine hydrochloride in an acetic acid or formic acid solvent. It is generally known that the cyanation reaction progresses. A preferable example of the production method 4 includes a case where a metal carboxylate, for example, sodium formate or sodium acetate is reacted with hydroxylamine hydrochloride in an acetic acid or formic acid solvent at a reaction temperature of 80 ° C. to 120 ° C.
A particularly preferred example is a case where sodium formate and hydroxylamine hydrochloride are reacted at a reaction temperature of 100 ° C. to 120 ° C. in a formic acid solvent.

In the production method 5, generally, in an organic solvent,
A metal borohydride salt other than sodium tetrahydroboride or a sodium salt is reacted in the presence of a lower alcohol. Preferred solvents include tetrahydrofuran and 1,1
Ethers such as 4-dioxane and isopropyl ether and tertiary alcohols such as tertiary butanol are preferred. A particularly preferred example is tetrahydrofuran. Further, as a preferable reducing agent, sodium borohydride is exemplified. Examples of the lower alcohol include methanol, ethanol, propanol, and butanol, and preferable examples include methanol and ethanol. These may also serve as reaction solvents. Alternatively, the reaction may be performed by reacting with sodium trimethoxyborohydride in tetrahydrofuran.

The reaction temperature is determined as follows: 5- (3) in which both ester groups as by-products have been reduced to alcohol.
In order to suppress the by-product of (-cyanophenyl) -3-hydroxymethylbenzyl alcohol, the upper limit is 30 ° C, preferably 25 ° C or lower, and the lower limit is 0 ° C, preferably 10 ° C or higher. Further, it is preferable to use water or an aqueous solution of ammonium chloride as the quenching agent used in the reaction stopping step.
The formation of (3-cyanophenyl) -3-hydroxymethylbenzyl alcohol can be suppressed.

The lower limit of the equivalent of the metal borohydride or sodium trimethoxyborohydride is 2 equivalents, preferably 3 equivalents.
The equivalent, the upper limit, is 5 equivalents, preferably 4 equivalents. This is because the catalyst used in Production Method 3 is not completely removed only by purification in Production Methods 3 and 4, and as a result, the reaction does not proceed unless excessive reducing agent is used.

In the production method 6, manganese dioxide is added in an organic solvent, and the mixture is reacted at a reaction temperature from room temperature to the boiling point of the organic solvent. As the organic solvent to be used, acetone or ethyl acetate is preferable. It is particularly preferable to use ethyl acetate from the viewpoint of. The reaction is preferably performed at a temperature lower by about 20 ° C. than the boiling point of the reaction solvent from the viewpoint of safety.

[0039]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 3- (dimethoxymethyl)
Synthesis of bromobenzene 125 g of 3-formylbromobenzene, 53 mL of trimethyl orthoformate and 1 g of Amberlyst-151 were weighed and stirred at room temperature for 24 hours. After confirming the completion of the reaction by GC / MS, Amberlyst-15 was filtered, triethylamine was added, and the mixture was concentrated under reduced pressure. The solution is distilled under reduced pressure to give 3- (dimethoxymethyl) bromobenzene 144
g was obtained. ¹ H-NMR (270 MHz, chloroform-d): δ
3.32 (s, 6H) 5.36 (s, 1H) 7.2
4 (dd, J = 7.8 Hz, 1H) 7.37 (d, J
= 7.8 Hz, 1H) 7.45 (d, J = 7.8H)
z, 1H) 7.62 (s, 1H)

Reference Example 2 3- (Dimethoxymethyl)
11.42 g of synthetic magnesium of phenylmagnesium bromide was weighed and placed in a dropping funnel.
90 mL TH of (dimethoxymethyl) bromobenzene
The F solution was charged. About 20 mL of a THF solution of 3- (dimethoxymethyl) bromobenzene was dropped from the dropping funnel to start the reaction. After warming to reflux, 200 mL of THF was placed in the flask. The dripping is controlled so that the reflux and the dripping are synchronized.
The dripping was completed in time. After stirring at room temperature for 1 hour, the reaction solution was transferred to a 500-mL stock bottle by filtration with a cotton plug, and washed with 100 mL of THF. The titration was performed by transferring 1 mL of the Grignard solution to a beaker containing 20 mL of 0.1 M hydrochloric acid and using a 0.1 M aqueous sodium hydroxide solution using phenolphthalein as an indicator. The normality was 1.10.

Example 1 5- (3-formylphenyi)
B) Synthesis of dimethyl isophthalate Ester 266 mg of palladium chloride and triphenylphosphine 7
86 mg is weighed, 200 mL of THF is added, and 6
Stirred at 0 ° C. for 30 minutes. 6. 0.5 M solution of zinc chloride
5 mL, 5-bromoisophthalic acid dimethyl ester 8
1.9 g and 100 mL of THF were added to the flask. 300 mL of a 1.1 M THF solution of 3- (dimethoxymethyl) phenylmagnesium bromide was added dropwise over 30 minutes. The reaction solution turned reddish brown. 60 ° C
After stirring for 90 minutes at, the reaction solution was poured into 300 mL of 1M hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. After extraction (ethyl acetate-aqueous sodium bicarbonate solution), the organic layer was dried (magnesium sulfate), and the solvent was distilled off under reduced pressure. Ethanol 75 in the residue
0 mL was added, and the mixture was heated under reflux for 30 minutes to obtain a homogeneous solution. This was returned to room temperature and recrystallized to give 5-
68.9 g of (3-formylphenyl) isophthalic acid dimethyl ester were obtained. ¹ H-NMR (400 MHz, chloroform-d): δ
4.00 (s, 6H) 7.68 (dd, J = 7.
6.94 (d, J = 7.6 Hz, 2)
H) 8.18 (s, 1H) 8.50 (d, J = 1.
6.71 (dd, J = 1.6 Hz, 1)
H) 10.12 (s, 1H)

Example 2 5- (3-cyanopheny)
B) Synthesis of dimethyl isophthalate Ester 24.0 g of hydroxylamine hydrochloride, sodium formate 2
3.8 g and 68.8 g of 5- (3-formylphenyl) isophthalic acid dimethyl ester were weighed, and formic acid 15
0 mL was added, and the mixture was stirred in an oil bath at 110 ° C. for 3 hours. G
After confirming the disappearance of the raw materials by C / MS, the mixture was allowed to cool, and 450 mL of water was
And stirred at room temperature for 1 hour. The mixture was filtered as it was, and the residue was dissolved in 1.5 L of ethyl acetate and extracted (ethyl acetate-aqueous sodium bicarbonate solution). The organic layer was dried (magnesium sulfate), and the solvent was distilled off under reduced pressure. 1050 mL of ethanol was added to the residue, and the mixture was heated under reflux for 30 minutes to obtain a homogeneous solution. This was returned to room temperature and recrystallized to obtain 55.3 g of dimethyl 5- (3-cyanophenyl) isophthalate. ¹ H-NMR (400 MHz, chloroform-d): δ
4.00 (s, 6H) 7.62 (dd, J = 7.8H)
z, 1H) 7.71 (d, J = 7.8 Hz, 1H)
7.89 (d, J = 7.8 Hz, 1H) 7.94
(S, 1H) 8.18 (s, 1H) 8.42 (d,
J = 1.5 Hz, 2H) 8.71 (dd, J = 1.5
Hz, 1H)

Example 3 3- (3-cyanopheny)
L) 5-methoxycarbonylbenzyl alcohol
Formation of 5- (3-cyanophenyl) weighed isophthalate ester 21.5g to 1000mL three-necked flask,
Attach dropping funnel and thermometer, THF 300mL
Was added and dissolved, and the resultant was immersed in an ice bath containing salt and stirred for about 15 minutes until the reaction solution temperature became 0 ° C. or lower. While stirring, NaBH ₄ was added little by little so that the reaction solution temperature did not exceed 5 ° C. After the addition, the liquid temperature was returned to 0 ° C. again, and 42 mL of methanol was added dropwise using a dropping funnel over about 40 minutes (the reaction liquid temperature increased with the addition, but the methanol addition speed was adjusted). Care was taken that the liquid temperature did not exceed 10 ° C). After stirring for 90 minutes under ice cooling as it was, the ice bath was replaced with a water bath (about 20 ° C.), and stirring was further continued for 6 hours while occasionally checking the progress of the reaction by liquid chromatography (254 nm). Liquid chromatography was used to confirm that the raw materials had disappeared to 5% or less, and the reaction solution was cooled to 0 ° C or less and stirred, and 200 mL of water and then 200 mL of a saturated ammonium chloride aqueous solution were added. The liquid temperature did not exceed 20 ° C. Carefully added slowly. After confirming the stop of the foaming, 300 mL of ethyl acetate was added and the mixture was separated, and the aqueous layer was extracted twice with 150 mL of ethyl acetate. Combine organic layers and water 200m
L, washed with 200 mL of saturated saline, dried over night with anhydrous sodium sulfate, and concentrated to obtain 18.0 g of a crude product (light yellow oil). 27 g of methanol was added to the obtained crude product, and dissolved by heating at 60 ° C.
The mixture was allowed to stand in a freezer overnight, whereupon a colorless solid precipitated. The solid was filtered off and washed with about 100 mL of methanol at 0 ° C. to obtain the desired product as a colorless solid (first crystal: purity 9)
0.7%, 8.99 g, 48% yield). The filtrate and the washings were combined and concentrated, and 7.44 g of a yellow oily substance obtained was recrystallized with 7.5 g of methanol in the same manner to obtain a second crystal (second crystal: purity 89.7%). , 1.68 g, yield 9.0%). The first crystal and the second crystal were combined to obtain 10.6 g of the desired product (total yield: 57%, purity: 90%). ¹ H-NMR (270 MHz, chloroform-d): δ
3.96 (s, 3H) 4.85 (s, 2H) 7.5
8 (dd, J = 7.8 Hz, 1H) 7.67 (d, J
= 7.8 Hz, 1H) 7.79 (s, 1H) 7.8
6 (d, J = 7.8 Hz, 1H) 7.90 (s, 1
H) 8.07 (s, 1H) 8.16 (s, 1H)

Example 4 5- (3-cyanopheny)
B) Synthesis of methyl 3-formylbenzoate 4.0 g of 5- (3-cyanophenyl) -3-hydroxymethylbenzoic acid methyl ester and 9.1 g of manganese dioxide were weighed, and 100 mL of ethyl acetate was added thereto. The mixture was stirred at 60 ° C for 2 hours. Further, 9.1 g of manganese dioxide was weighed and charged into the reaction solution. After another 2 hours, 9.1 g of manganese dioxide was weighed and charged into the reaction solution. After confirming the disappearance of the raw materials by LC / MS, the reaction solution was filtered while hot using celite. Further, the mixture was washed with 200 mL of ethyl acetate warmed at 60 ° C., and 100 mL of a 1M aqueous sodium hydroxide solution was added. Extraction was performed (ethyl acetate-1 M aqueous sodium hydroxide solution), and the organic layer was neutralized with 200 mL of a saturated aqueous ammonium chloride solution. The organic layer was dried (magnesium sulfate) and the solvent was distilled off under reduced pressure. 120 mL of ethanol was added to the residue, and the mixture was heated and refluxed for 30 minutes to form a uniform solution. The solution was returned to room temperature and recrystallized to obtain 3.8 g of methyl 5- (3-cyanophenyl) -3-formylbenzoate. . ¹ H-NMR (400 MHz, chloroform-d): δ
4.02 (s, 3H) 7.64 (dd, J = 7.8H)
z, 1H) 7.74 (d, J = 7.8 Hz, 1H)
7.91 (d, J = 7.8 Hz, 1H) 7.96
(S, 1H) 8.29 (s, 1H) 8.51 (s, 1H)
1H) 8.57 (s, 1H) 10.16 (s, 1
H)

[0046]

According to the present invention, a 5- (3-cyanophenyl) -3-formylbenzoic acid derivative useful as a pharmaceutical intermediate can be produced simply and inexpensively. In addition, as an industrial production method, it is satisfactory in terms of facilities, operation, and environmental problems.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 255/57 C07C 255/57 // C07B 61/00 300 C07B 61/00 300 F-term (Reference) 4H006 AA02 AC12 AC22 AC24 AC41 AC45 AC54 BA07 BA25 BA37 BA48 BB17 BB25 BC10 BC31 BC34 BE23 BE33 4H039 CA41 CG20

Claims (13)

[Claims] 1. A compound represented by the following formula (II): [In the formula, R represents a hydrogen atom or an unsubstituted or substituted C ₁ -C ₁₀ alkyl group. Wherein the compound represented by the following formula (I) is reacted with manganese dioxide in an organic solvent. [Wherein, the definition of R is the same as that in the formula (II). ] The manufacturing method of the compound represented by this. 2. The method according to claim 1, wherein the organic solvent is ethyl acetate. 3. The following formula (III): [Wherein, the definition of R is the same as that in the formula (II). Wherein the compound represented by the formula (II) is reacted with a metal borohydride or sodium trimethoxyborohydride. 4. The method according to claim 3, wherein the metal borohydride is sodium borohydride. 5. The method according to claim 3, wherein the equivalent of the metal borohydride or sodium trimethoxyborohydride is 2 to 5 equivalents, and the reaction temperature is 0 to 30 ° C. 6. A compound represented by the following formula (IV): [Wherein, the definition of R is the same as that in the formula (II). Wherein the compound represented by the formula (III) is reacted with hydroxylamine hydrochloride and a metal carboxylate having 1 to 3 carbon atoms in an organic solvent. 7. The method according to claim 6, wherein the organic solvent is formic acid or acetic acid, and the metal carboxylate having 1 to 3 carbon atoms is sodium formate or sodium acetate. 8. The following formula (V): [Wherein, the definition of R is the same as that in the formula (II). And a compound represented by the following formula (VI): [Wherein, R ₁ represents an unsubstituted or substituted C ₁ -C ₁₀ alkyl group. A Grignard reagent obtained by treating a compound represented by the formula (I) with a metal magnesium in a solvent of ethers to form a divalent palladium catalyst, if necessary, a phosphine ligand, and a divalent zinc as a cocatalyst. Wherein the reaction is carried out using a halide.
Production method of the compound represented by V). 9. The method according to claim 8, wherein the ether solvent is tetrahydrofuran. 10. The process according to claim 8, wherein the divalent palladium catalyst is palladium chloride and a phosphine ligand in an amount of 1 to 4 equivalents to palladium chloride. 11. The method according to claim 8, wherein the divalent palladium catalyst is dichlorobis (triphenylphosphine) palladium or dibromobis (triphenylphosphine) palladium. 12. The use according to any one of claims 8 to 11, wherein the amount of the divalent palladium catalyst used is 0.02 mol to 0.1 mol per 1 mol of the compound represented by the formula (IV). The method described in. 13. The method according to claim 1, wherein the following reaction steps 1 to 4 are sequentially carried out, wherein the compound represented by the formula (V) and the compound represented by the formula (VI) are represented by the formula (I). For producing a compound to be prepared. Reaction step 1: The method according to any one of claims 8 to 12. The method according to claim 6 or 7, wherein reaction step 2 is performed. Reaction step 3: The method according to any one of claims 3 to 5. Reaction step 4: The method according to claim 1 or 2.